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High-dose chemotherapyNieboer, Peter

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High-dose chemotherap,y

studies on supportiv_e care, g�l1ity of life

and late effects of treatmelil,f. . -,

Peter N ieboer

High-dose chemotherapy studies on supportive care, quality of life

and late effects of treatment

Peter Nieboer

Stellingen behorende bij het proefschrift

High-dose chemotherapy; studies on supportive care, quality of life and late effects of treatment

1. Anemie is zelden de oorzaak van moeheid na de behandeling van borstkanker. (dit proefschrift)

2. Niet elke patient, die hoge dosis chemotherapie met stamceltransplantatie ondergaat, heeft een centrale lijn nodig. (dit proefschrift)

3. Vele jaren na hoge dosis chemotherapie dient men nog rekening te houden met verm i nderde beenmergreserve. ( dit proefschrift)

4. De noodzaak tot focusonderzoek, voorafgaand aan hoge dos is chemotherapie bij solide tumoren, wordt vooral bepaald door de anamnese. ( dit proefschrift)

5. Er is geen reden om hoge dosis chemotherapie bij solide tumoren anno 2008 als obsoleet te beschouwen. ( dit proefschrift)

6. Als het lukt de kankerstamcel selectief te behandelen, kan dit genezing brengen van veel soorten kanker.

7. Bij het voorschrijven van antidepressiva tijdens hormonale therapie voor borstkanker dient overwogen te warden tamoxifen te vervangen door een aromatase-remmer.

8. Het kiezen van telkens kleinere ziekenhuizen tot beste van Nederland (Assen 2006, Dokkum 2007) is een argument tegen "centralisatie van zorg".

9. Hoe beter de selectie van patienten is, des te kleiner de studie kan zijn.

10. Het gegeven dat in het eerste half uur na wakker warden op een vraag geen verstandig antwoord wordt gegeven, pleit sterk voor invoering van een wakkere voorwacht in elk ziekenhuis. (Wertz AT, et al. Effects of sleep inertia on cognition. JAMA 2006; 295: 163-164)

11 . Medisch specialisten zorgen voor inkomsten, niet voor uitgaven.

CcnlialP- Het �ve h van ijzer bij bloedarmoede, zonder dat er diagnostiek naar de oorzaak Mcd1sche is uit:8tv1 ,erd, dient te worden beschouwd als een kunstfout. Bibliotheek C Gron in gen G

9 januari 2008 I Peter Nieboer

Nieboer, P.

High-dose chemotherapy; studies on supportive care, quality of life and late effects of

treatment

Thesis Groningen. - With summary in Dutch.

ISBN: 978-90-367-3194-2

© Copyright 2008 P. Nieboer

All rights are reserved. No part of this publication may be reproduced, stored in a

retrieval system, or transmitted in any form or by any means, mechanically, by

photocopying, recording, or otherwise, without the written permission of the author.

Layout : Astrid Appelhof

Printed by : Optima Grafische Communicatie, Rotterdam

Financial support for the publication of this thesis was kindly provided by my parents

(drs. J.G. Nieboer and M. Nieboer-van der Velde).

RIJKSUNIVERSITEIT GRONINGEN

High-dose chemotherapy studies on supportive care, quality of life

and late effects of treatment

Proefschrift

ter verkrijging van het doctoraat in de

Medische Wetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de

Rector Magnificus, dr. F. Zwarts,

in het openbaar te verdedigen op

woensdag 9 januari 2008

om 16.15 uur

door

Peter Nieboer

geboren op 8 december 1965

te Purmerend Ct�11lr:1!e

Medi::;che Biblimheek Gronin6en

l_l !\1 C C -·

Promotores:

Prof.cir. E.G.E. de Vries

Prof.cir. W.T.A. van der Graaf

Prof.cir. N.H. Mulder

Beoordelingscommissie:

Prof.cir. S. Rodenhuis

Prof.cir. D.J. Richel

Prof.cir. T.S. van der Werf

ISBN: 978-90-367-3194-2

Aan mijn ouders

Paranimfen:

Bas Nieboer

Harald Faber

Contents

Chapter 1 Introduction and scope of this thesis 9

Chapter 2 Relevance of high-dose chemotherapy in solid tumours 13

Cancer Treat Rev 2005;31 :210-225

Chapter 3 Long-term heamatological recovery following high-dose chemotherapy 43

with autologous bone marrow transplantation or peripheral stem cell

transplantation in patients with solid tumours

Bone Marrow Transplant 2001;27:959-966

Chapter 4 Factors infuencing haematological recovery following high-dose

chemotherapy and peripheral stem-eel I transplantation for

haematological malignancies: 1-year analysis

Eur J Cancer 2004;40: 1199-1207

Chapter 5 Fatigue and relating factors in high-risk breast cancer patients

treated with adjuvant standard or high-dose chemotherapy:

a longitudinal study

J Clin Oncol 2005;23:8296-9302

Chapter 6 Sreening for infectious foci in breast cancer patients prior

to high-dose chemotherapy and stem cell transplantation

Anticancer Res 2003;23: 1719-1184

Chapter 7 Factors influencing catheter-related infections in the Dutch

multicenter study on high-dose chemotherapy followed by

peripheral stem-cell transplantation in high-risk breast

cancer patients

Submitted

Chapter 8 Summary and future perspectives

Chapter 9 Samenvatting en toekomstige ontwikkelingen

List of publications

Dankwoord

65

83

103

115

131

143

155

159

1 Introduction and scope of this thesis

Chapter 1

Drug resistance is a major problem in the treatment of solid tumors and hematological malignancies. Based on a steep dose-response relationship for especially alkylating agents on tumor cell survival, high-dose chemotherapy followed by peripheral stem-cell transplantation was considered of interest for the treatment of cancer. High-dose chemotherapy has proven to be beneficial in selected patients with Hodgkin's disease and non-Hodgkin's lymphoma. High-dose chemotherapy for solid tumors however is more controversial. Results of phase 1 and 2 studies with high-dose chemotherapy in a variety of solid tumor types showed good response rates, but the high expectations did not come true in the phase 3 studies.

Considerable morbidity results from the high-dose procedure. Therefore it is essential that short­term and long-term complications are well known. The aim of this thesis is to describe (long-term) hematological consequences of high-dose chemotherapy, fatigue and infectious complications after high-dose chemotherapy.

In chapter 2 the available randomized high-dose chemotherapy studies in solid tumors are reviewed and the discrepancy between findings in patients versus those in tissue culture is discussed.

Abnormalities in hematopoiesis have been shown up to five years following high-dose chemotherapy and stem-cell transplantation. Patients relapsing after high-dose chemotherapy show decreased hematological tolerance to reinduction chemotherapy. Radiotherapy and infections during follow-up can lead to hematopoietic stress and temporary cytopenias have been described in such circumstances. Clinical problems could therefore rise from the abnormalities in hematopoiesis following high-dose chemotherapy. In chapter 3 long-term peripheral blood counts and factors influencing long-term hematological recovery of 131 relapse-free patients treated with high-dose chemotherapy and autologous bone-marrow transplantation or peripheral stem-cell transplantation for various solid tumors were examined.

In chapter 4 we analyzed peripheral blood counts in the year following high-dose chemotherapy and peripheral stem-cell transplantation in another group of patients, namely 98 disease-free patients with hematological malignancies and we defined factors that determined the long-term hematological reconstitution.

A growing body of evidence indicates that breast cancer survivors can experience a variety of problems, such as fatigue (long) after the completion of cancer treatment. This symptom is reported to be highly distressing and a limiting factor in the quality of life. Studies in which fatigue has been investigated in treated, disease-free breast cancer patients are rare. A better understanding of long-term fatigue in cancer survivors is fundamental to the development of

Introduction and scope of this thesis

appropriate intervention strategies. In chapter 5 we evaluated whether standard- or high-dose chemotherapy would lead to changes in fatigue, hemoglobin, mental health, muscle and joint pain, and menopausal status from pre- to post-treatment and we analyzed whether fatigue was associated with these factors. 430 disease-free breast cancer patients (202 standard-dose and 228 high-dose) with at least three years follow-up were included in the study. We studied possible associations before, as well as one, two and three years after chemotherapy.

Following high-dose chemotherapy, patients have a period of profound neutropenia and mucositis during which there is a high incidence of fever and infections. Infections usually originate from the gastrointestinal tract (including the oral cavity), the respiratory tract (including sinus), skin and venous access devices. The approach for preventing infections from the gastrointestinal and respiratory tract remains controversial. In many oncological stem-cell transplantation centers, it is still standard policy to perform radiological examinations (chest roentgenogram, sinus roentgenogram and odontogram) in the work up before high-dose chemotherapy. The goal is to search for potential infectious foci and therefore patients are referred, prior to high-dose chemotherapy, to the ear-nose-throat surgeon and maxillofacial surgeon for screening and -if necessary- eradication of potential infectious foci. There are no data available of the incidence of infectious foci in solid tumor patients prior to high-dose chemotherapy. Therefore the yield and efficacy of screening procedures is unknown. In chapter 6 we evaluated the incidence of potential infectious foci in the upper respiratory and gastrointestinal tract, as diagnosed by radiological examinations, history taking and physical examinations performed by the ear-nose-throat surgeon and maxillofacial surgeon in 73 breast cancer patients, prior to high-dose chemotherapy. All patients were treated with identical courses of standard-dose chemotherapy followed by an identical high-dose regimen in an adjuvant setting.

It is common practice to insert a large-bore central venous catheter at some time prior to the regimen of high-dose chemotherapy. This catheter facilitates the administration of the chemotherapy, the drawing of blood samples, the infusion of drugs and various blood products, and the infusion of total parenteral nutrition. Complications of these central venous catheters however result in considerable morbidity and may even be fatal. Catheter-related infections predominate and sometimes prohibit the high-dose chemotherapy phase. In chapter 7 we analyzed in a group of 392 breast cancer patients, randomized to receive an identical regimen of high-dose chemotherapy, the complication rate of central venous catheters and factors associated with these complications.

111

Chapter 1

Thereafter the findings in this thesis are summarized and future perspectives described in chapter 8 and chapter 9 (Dutch version).

2 Relevance of high-dose chemotherapy in solid tumours

P. Nieboer, E.G.E. de Vries, N.H. Mulder, W.T.A. van der Graaf

Department of Medical Oncology, University Medical Center Groningen

Cancer Treat Rev 2005; 31: 210-225

Chapter 2

Summary

Drug resistance is a major problem in the treatment of solid tumours. Based on a steep dose­response relationship for especially alkylating agents on tumour cell survival, high-dose chemotherapy was considered of interest for the treatment of solid tumours. Results of phase 1 and 2 studies with high-dose chemotherapy in a variety of tumour types showed good response rates. Nowadays, several phase 3 studies are available especially in metastatic and high-risk breast cancer patients. The high expectations of high-dose chemotherapy did not come true.

This review analyses results of randomised studies and comments on the discrepancy between findings in patients versus those in tissue culture. Potential factors involved are the presence of tumour stem-cells with different characteristics from more mature tumour cells, limitations in drug escalation in the clinic, transplant mortality, trial design and tumour cell contamination of the haematopoietic stem-cell transplant. Maturation of the results from recent studies indicating a more modest benefit in, e.g., adjuvant breast cancer balanced versus long-term side effects will ultimately determine the role of high-dose chemotherapy in certain solid tumours. In case of well-defined indications for high-dose chemotherapy, further selection of patients based on patient and tumour characteristics as well as the introduction of new agents will most likely play a role.

14 I

Relevance of high-dose chemotherapy in solid tumours

Introduction

Communication in clinical research follows a predestined sequence of hesitating recognition of a new modality, of excitement and enthusiasm, of doubts and afterthoughts with ultimate acceptance or rejection after prolonged exposure of the novelty, to clinical reality. In the case of high-dose chemotherapy (HOC) for solid tumours, this sequence culminated prematurely in refusal due to a grand scale fraud.

In the 1 980s and 1 990s, many oncology centres began phase 1 and phase 2 trials, to explore the feasibility and different indications for HOC. After promising results for many indications, some phase 3 trials were executed, mostly in breast cancer. Early reports showed no clear benefit, with the exception of two small trials from South Africa. However, when the fraudulous nature of these two South African trials became clear, 1,2 a period of negativism in HOC in solid tumours began. The number of new studies diminished and studies already started had problems with accrual.

It is questionable if both the optimistic and pessimistic view to HOC in solid tumours is valid. Most studies have problems with design and power, are not able to detect small differences between treatment arms and do not allow firm conclusions. Recently, results from a large Dutch adjuvant study by Rodenhuis et al.3 showed a disease-free survival benefit in younger patients, patients with ten or more positive lymph nodes as well as in patients with a HER2/neu negative tumor. Also the data from other adjuvant studies in high risk breast cancer presented by Roche et al.4 at the 2001 ASCO meeting and by Nitz et al.5 at the 2003 ASCO meeting showed a prolongation of disease-free survival in the high-dose arm. Definitive data with longer follow-up from other large comparative studies in breast cancer will soon be available, giving the opportunity to perform meta-analyses (planned for 2005 by the Breast Cancer Trialists' Cooperative Group). It is time to critically review the current data and to speculate about mechanisms responsible for the success or failure of HOC.

Rationale for high-dose chemotherapy

The scientific basis for the concept of HOC is that dose-intensification may overcome a relative resistance of tumour cells to a cytotoxic drug. The demonstration in vitro that increased drug exposure increases tumour cell kill is termed "dose-response" and HOC is the translation of this concept to the clinical setting. Only drugs with a steep dose-response relationship in vitro and non-important extra-haematological dose-limiting toxicity are thus suitable for this situation. Although nearly all chemotherapeutic agents exhibit a dose-response curve in laboratory models, a very steep curve is only found for the alkylating agents, which include cyclophosphamide and

j 15

16

Chapter 2

thiotepa and non-classical alkylating agents, among which are some platinum agents. Also anthracyclines, such as mitoxantrone, exhibit this steep dose-response in vitro but have dose­limiting cardiac toxicity. When doses are escalated 5-1 0-fold, in vitro drug resistance can be overcome.6 Alkylating agents are not totally cross-resistant and show synergism with platinum agents. Therefore the role of these agents was studied in dose-intensification in vitro and vivo in various combinations. 7-9 In tumour-bearing animals, this concept of dose-response could be reproduced in vivo.10 However, these promising results from the laboratory were not directly applicable in clinical trials. Most randomised studies comparing the higher dose with the lower dose showed no advantage in survival. On the other hand, a very important conclusion that can be drawn from these studies is that lowering the dose below the standard-dose results in loss of anti-tumour effect. Therefore, the conclusion of most of these trials is rather a caution against dose-reduction.11-13

Feasibility and toxicity

All HDC regimens have significant acute and late toxicities. The acute and chronic side effects related to high-dose regimens are directly related to the type of drug and schedule. Mortality originally reported as high as 20%14 is reported now as low as 2-3% in most transplantation regimens. This is mostly due to advances in supportive care, the introduction of peripheral stem­cell reinfusion instead of bone-marrow reinfusion, the choice of cytostatic agents used for the HDC regimen, the use of haematopoietic growth factors and the growing experience with the procedure. Apart from haematological toxicity and non-haematological toxicity, catheter-related complications predominate.

Haematological toxicity

Severe granulocytopenia, thrombocytopenia and anaemia are major causes of treatment-related complications following HDC and autologous transplantation. Complications are directly related to the time to reach short-term haematological recovery.15 The introduction of haematopoietic growth factors resulted in slightly faster haematological reconstitution. Peripheral blood progenitor cells, mobilised by chemotherapy and/or haematopoietic growth factors even further reduced the time to engraftment and therefore represent the preferred source of stem-cells for autologous transplantation because of more favourable engraftment kinetics.16 The use of prophylactic antibiotics diminishes the number of infectious complications. All these factors have resulted in lower morbidity and mortality from the transplantation procedure.

Relevance of high-dose chemotherapy in solid tumours

Non-haematological toxicity

In addition to myelotoxicity, acute toxicities frequently include nausea, vomiting, diarrhoea,

fatigue and mucositis. Since most transplantation regimens include high-dose carboplatin, they

may be associated with long-lasting peripheral neuropathy, ototoxicity and renal function

impairment. The administration of high-dose cyclophosphamide or ifosfamide can be associated

with hemorrhagic cystitis, despite hyperhydration and the concomitant administration of mesna

and also with acute cardiotoxicity. Other chronic toxicities include infertility, premature

menopause, cancer-related fatigue syndrome and neuropsychological sequelae. The risk of

secondary haematological malignancies (myelodysplasia and leukaemia) and secondary solid

tumours related to preceding chemotherapy or radiotherapy is well known. The risk is considered

to be related to the pretreatment rather than to the high-dose chemotherapy and stem-cell

transplantation itself. The fact that anthracylines are frequently used in breast cancer patients and

are known inducers of leukemia is a clear factor. In the Bergh study17 even more patients in the

tailored arm, who also received more anthracylines, than in the high-dose arm developed

leukemia. The number of studies reporting secondary tumours after HOC for solid tumours are

limited.18'19 Tallman et al. reported 24 secondary tumours in 511 adjuvant treated breast cancer

patients (nine in the standard-dose patients and 15 in the high-dose patients). This high incidence

is probably partly explained by the relatively long follow-up compared to most other studies and

the treatment schedule used.20

(Randomised) trials of high-dose chemotherapy

Breast cancer

Metastatic breast cancer

Many phase 2 trials explored the value of HDC and autologous transplantation in metastatic

breast cancer. Five randomised studies comparing standard-dose to HDC are currently available,

of which four are only available in abstract form. The most important results of the five studies

are shown in Table 1. Data from the South African study are not included because of scientific

misconduct.21

Patients in the Philadelphia study reported by Stadtmauer et al.22 received four to six cycles CAF

(oral cyclophosphamide 100 mg/m2/day for 14 days, doxorubicin 30 mg/m2 and 500 mg 5-FU

day one and eight) or CMF (oral cyclophosphamide 100 mg/m2/day for 14 days, methotrexate 40

mg/m2 day one and eight and 5-FU 600 mg/m2 day one and eight) depending on their previous

received anthracycline dose. Patients responding to this treatment were randomised between

1 11

Chapter 2

Table 1. Randomised studies in metastatic breast cancer

First author, reference

Stadtmauer 22

Stadtmauer 23

Peters 24 a

Lotz 25 •

Biron 26

Crown 27

Number of patients randomised

184 184

98

61

180

110

Median EFS HDC Years follow-up (%)/EFS (months) control(%)

37 6/12 3 67.5 4/3 5

NM 25/10 3

NM 49/21 3

48 46/19

42 29/22 3

Abbrevations and notes: EFS, event-free survival and NS, non-significant.

P value

NS NS

<0.01

0.05

0.0001

0.047

a Abstract modified with data presented at ASCO meeting; NM, not mentioned.

Survival Years P value HOC(%)/ survival control(%)

32/38 3 NS 14/13 5 NS

33/38 3 NS

55/28 3 NS ------38/30 3 NS

NM/NM NM NM

HOC and autologous stem-cell transplantation or maintenance treatment with CMF during two years. The HOC consisted of carboplatin 800 mg/m2, cyclophosphamide 6000 mg/m2 and thiotepa 500 mg/m2 • Out of 553 patients, 310 responded (58 complete responses and 252 partial responses). Of those responding, only 184 patients were randomised into the study (101 in the high-dose arm and 83 in the CMF maintenance arm). Most of the other patients declined to undergo randomisation, withdrew from the study, had breast cancer cells in the bone-marrow or did not undergo randomisation for other reasons. There were no differences in time to progression (median 9.6 months in the high-dose arm versus 9.0 months in the CMF arm) and in overall survival (three-year survival 32% versus 38%). At the ASCO meeting 2002, the update showed that with a median follow-up of 67.5 months and 27 patients being alive, the median overall survival remains the same in both arms (25.8 months for HOC and 26.1 months for CMF).23 The five-year survival is 14% for HOC and 13% for CMF.

Patients in the study by Peters et al.24 received four courses of AFM (doxorubicin 25 mg/m2/d days three through five, 5-FU 750 mg/m2/d by continuous infusion for five days and methotrexate 250 mg/m2 day 15) repeated every three weeks until complete response. The 98 patients who achieved complete remission were randomised between HOC with CPB (carmustine 600 mg/m2,

cisplatin 165 mg/m2 and cyclophosphamide 5625 mg/m2) with autologous stem-cell transplantation immediately after AFM or intermediate-dose CPB and the HOC at time of reprogression. Progression-free survival was improved for the patients undergoing immediate HOC, but overall survival showed no significant difference. This study compared early and late transplantation and highlights the importance of timing in the administration of HOC. It is important to note that the intermediate group received more chemotherapy than standard doses.

Relevance of high-dose chemotherapy in solid tumours

The small French Pegase 04 study reported by Lotz et al.25 is until now only available in abstract form. Patients responding to four to six courses induction chemotherapy of whatever type were randomised to HOC or continuation of conventional treatment for another two to four cycles. HOC consisted of cyclophosphamide 1 20 mg/kg body weight, melphalan 1 40 mg/m2 and mitoxantrone 45 mg/m2 • There was a nearly significant difference in time to progression between the two treatment arms (p=0.05 at three years). Also a nearly doubling in overall survival at three years was reported, but since only 6 1 patients were included in this trial, this did not reach significance.

Preliminary results of the French Pegase 03 study were presented at the 2002 ASCO meeting by Biron et al.26 Patients responding to four courses FEC (5-FU 500 mg/m2, epirubicin 1 00 mg/m2 and cyclophosphamide 500 mg/m2) were randomised between no further treatment or HOC (thiotepa 800 mg/m2 and cyclophosphamide 6000 mg/m2) . Hundred-eighty patients were randomised and 80 of the 89 planned patients were actually transplanted. The one-year progression-free survival was 19% in the standard arm versus 46% in the high-dose arm (p=0.0001 ). However, in this small study the three-year overall survival was the same in both arms (30% in the standard arm versus 38% in the high-dose arm, p=0.7).

At the ASCO meeting of 2003, Crown et al. presented results in 11 0 patients with metastatic breast cancer.27 Patients received three cycles of AT (doxorubicin 50 mg/m2 and docetaxel 75 mg/m2) . Patients not progressive on this therapy were randomised between tandem HOC (first course: ifosfamide 1 2,000 mg/m2, cyclophosphamide 6000 mg/m2 and etoposide 1 200 mg/m2,

second course: cyclophosphamide 6000 mglm2 and thiotepa 800 mg/m2) or standard-dose chemotherapy (fourth course of AT followed by four courses of CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 and 5-FU 600 mg/m2, days one and eight). At a median follow­up of 42 months, median event-free survival was 437 days in the high-dose group, versus 291 days in the standard-dose group (p=0.043). Event-free survival at three years was 29% versus 22% (p=0.047). Definitive results concerning overall survival are not yet available.

A different approach was performed by Berry et al.28 They compared databases and studied the results of standard-dose chemotherapy in four Cancer and Leukemia Group B trials and high­dose therapy with haematopoietic support in patients of the Autologous Marrow Transplant Registry. Cox proportional hazard regression incorporated potentially confounding effects. They observed that HOC versus standard-dose had a similar short-term survival and might have a modestly higher long-term survival.

I 1 s

Chapter 2

Phase 2 stud ies frequently i ndicate a subgroup of long-term survivors . N ieto et a l .29 studied

prognostic factors i n stage IV o l igometastatic breast cancer patients who received h igh-dose

chemotherapy. F ive-year d isease-free survival was 52% and overa l l survival 62%. They observed

that H ER2/neu express ion, h igh primary axi l l ary nodal ratio and number of i nvolved s i tes

pred icted independently a worse outcome. These resu lts i ndicate that more prec i se patient

selection may sti l l be of interest. Patients with supraclavicu lar lymph nodes are s ince 2002 no

longer staged as metastatic disease,30 but may especia l ly benefit from intensified treatment based

on a relatively sma l l study i ndicating a subgroup of long-term survivors.3 1 However, currently

the randomised stud ies show no evidence for a benefit in terms of overal l survival of HOC in

metastatic breast cancer.

High risk primary breast cancer

Breast cancer patients treated with CMF or CMF-based chemotherapy have a median disease-free

survival of 1 1 . 1 years for patients with one to three positive axi l l ary nodes, 3.4 years for those with

four to n i ne nodes and 2 . 1 years for those with ten or more nodes.32 This is the clear justification

for h igh-dose chemotherapy studies in h igh-risk patients. Fourteen random ised studies are

currently avai lable for patients with h igh-risk breast cancer. Because of scientific m isconduct,

the study by Bezwoda, presented during the 1 999 ASCO meeti ng w i l l not be reviewed here.33

Seven of the 1 4 eva luated studies have a l ready been publ ished,3• 1 7•20,34-3 7 the seven remai n ing

are only avai lable i n abstract form.4•5•24•3 8-41 The most i mportant results of these 1 4 tria l s are shown

in Table 2 .

The sma l l study o f Hortobagyi et a l .34 (MD Anderson Cancer Center Tria l ) inc luded patients with

operable breast cancer with ten or more axi l l ary lymph nodes and patients with stage I l l loca l ly

advanced breast cancer treated with neo-adjuvant chemotherapy. The patients were randomised

between eight cycles FAC or eight cycles FAC fol lowed by two cycles CEP (cyclophosphamide

5250 mg/m2, etoposide 1 200 mg/m2 and cisplatin 1 65 mg/m2) and autologous transplantation.

The statistical analys is hypothesis was a 30% i mprovement i n survival without relapse i n the CEP

arm. At three years, there were no d ifferences i n relapse-free survival or overal l survival between

the two treatment arms.

A sma l l study by Rodenhuis et a l .35 i nc luded patients with a positive lymph node b iopsy infra­

c lavicu lar or level 3 of the axi l lary fold . They were fi rst treated with three courses FEC

chemotherapy (5-FU 500 mg/m2, epi rubic in 1 20 mg/m2 and cyclophosphamide 500 mg/m2) .

After surgery, patients stable o r respondi ng to chemotherapy were randomised between a fourth

course FEC or a fourth course FEC fol lowed by H OC (cyclophosphamide 6000 mg/m2, th iotepa

480 mg/m2 and carbop lat in 1 600 mg/m2) and autologous transplantation. The stati stica l

Relevance of high-dose chemotherapy in solrd tumours

Table 2. Randomised studies in high-risk primary breast cancer

First author, reference

Number of patients randomized

Median follow-up (months)

Hortobagyi 34 78 78

Rodenhuis 35 81 49 Schrama 42 81 82.8

Bergh 17 525 34.3 Bergh 43 525 NM

Rodenhuis 3 885 57 <!: 10 nodes 4 - 9 nodes low HER2/neu

Tallman 20 5 1 1 73.2

Zander 36 307 45.6

Leonard 37 605 72

Peters 44 a 783 37 Nikcevich 45 783 1 32

Gianni 38 382 52

Roche 4 3 14 39

Tokuda 39 95 NM

Basser 41 344 47

Bliss 40 280 NM

Nitz 5 403 34.6

OFS HOC (%) / Years P value Survival HOC (%) / survival control (%)

OFS control (%)

48/62

70/65 49/48

63/72 NM/NM

65/59 6 1 /51 67/64 NM/NM

49/47

52/42

57/54

7 1 /64 60/NM

65/62

7 1 /55

60/48

57/46

54/57

6 1 /41

3

4 5

3 NM

5 5 5 5

6

4

5

3 1 0

5

3

4

4

5

4

NS 58/77

NS 82/75 NS 61 /63

NS 77/85 NM NM/NM

NS NM/NM 0.05 NS 0.002

NS 58/62

NS 70/62

NS 62/64

NS 79/79 NM 63/NM

NS 76/77

<0.003 86/84

NS 67/66

NS 73/64

NS 66/67

0.00 1 9 NM/NM

Abbrevations and notes: DFS, disease-free survival and NS, non-significant. a Abstract modified with data presented at ASCO meeting; NM, not mentioned.

Years P value

3

4

5

3 NM

5

6

4

5

3 1 0

5

3

4

4

5

NM

NS

NS NS

NS NM

NS

NS

NS

NS

NS NM

NS

NS

NS

NS

NS

NM

hypothesis was a 30% improvement in four-year progression-free survival. After a median follow­up of 49 months, no differences were found in progression-free survival or overall survival between the two treatment arms. A recent update after a median follow-up of 6.9 years still showed no difference in overall survival or disease-free survival rates between the two treatment groups.42

Patients in the larger study by Bergh et al. 1 7 (the "Scandinavian" study) were randomised between four cycles FEC and high-dose CTC (cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2 and carboplatin 800 mg/m2) followed by reinfusion of haematopoietic stem-cells or nine cycles of FEC at increasing doses (tailored FEC; S FU 300-600 mg/m2, epirubicin 38-120 mg/m2,

I 2 1

Chapter 2

cyclophosphamide 450-1 800 mglm2) . In fact, the total dose of chemotherapy was h igher i n the

ta i lored arm than in the h igh-dose arm. After a median fol low-up of 20 months no s ign ificant

d ifferences were found between the two treatment groups in progress ion-free surviva l or overal l

surviva l . At the 2003 ASCO-meet ing these resu lts were updated.43 With a fo l low-up of 60.8

months, the number of relapses was h igher in the h igh-dose arm ( 1 3 8 versus 1 04, p=0.047),

while event-free surviva l and overal l survival were not d ifferent between the two arms. I n th i s

study seven acute leukaemias or myelodysplasias were reported i n the tai lored arm most l i kely

related to the cumulative anthracycl i ne and cyclophosphamide doses that were h igher in the

tai lored arm than i n the h igh-dose arm.

I n the Dutch study by Rodenh u i s et a l .,3 885 patients were randomised between standard

treatment with five cycles FEC (5-FU 500 mglm2, epirubicin 90 mglm2 and cyclophosphamide

500 mg/m2) or four cycles FEC fol lowed by CTC (cyclophosphamide 6000 mg/m2, thiotepa 480

mg/m2 and carboplati n 1 600 mg/m2) and autologous peripheral haematopoietic stem-cel l

transplantation. Patients i ncluded were 55 years or younger and had four or more positive axi l lary

lymph nodes. The patients received treatment i n ten centres, and H OC was never given outs ide

protocol . Of the 885 patients, 442 patients were ass igned to the h igh-dose group and 443 to the

conventional group. At a median fol low-up of 57 months, the actuaria l five-year relapse-free

survivals were 59. 1 % and 64.6% for the conventional and high-dose group, respectively (hazard

ratio for the h igh-dose group, 0.83; 95% confidence i nterval , 0 .66- 1 .03; p=0.09) . For the � 1 0

nodes group, the relapse-free survivals were 5 1 .3% and 60.6% for the conventional-dose and the

h igh-dose group, respectively (p=0.05). Further subgroup analyses were performed for a range

of predictive factors. Younger age (p=0.05), negativity for H ER2/neu expression (p=0.02), and

lower grade (p=0.002) were associated with a sign ificant pos itive effect of h igh-dose therapy on

relapse-free surviva l . Although these were not pre-defi ned subgroup analyses, they cou ld be

useful for future selection of patients, benefiting the most from H DC.

I n the study by Tal l man e t a l .,20 540 patients with a t least ten involved ips i lateral axi l lary lymph

nodes were randomised between s ix cycles CAF (cyclophosphamide 1 00 mg/m2 ora l ly day 1 -1 4,

doxorubic in 30 mg/m2 day one and eight and 5-FU 500 mg/m2 day one and eight every 28 days)

or the same regimen fol lowed by H OC (cyclophosphamide 6000 mglm2 and th iotepa 800 mglm2

over a four-day period) and autologous transplantation. With a med ian fol low-up of 6 . 1 years,

there was no difference in d isease-free survival and overa l l surv ival . However, among the 4 1 7

patients fu lfi l l ing strict e l igib i l ity criteria, the time to recurrence was longer for patients i n the

h igh-dose arm (p=0.045) .

22 I

Relevance of high-dose chemotherapy in solid tumours

In the study by Zander et al . , 36 307 patients with ten or more positive lymph nodes were randomised between standard-dose and HOC. After four cycles of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) patients were randomised between high-dose CTM (cyclophosphamide 6000 mg/m2, thiotepa 600 mg/m2 and mitoxantrone 40 mg/m2) or three cycles of CMF (cyclophosphamide 500 mg/m2 , methotrexate 40 mg/m2 and 5-FU 600 mg/m2

intravenously on day one and eight). There was a trend in favour of the HOC at four years for the primary end point event-free survival, but without statistical significance (52% versus 42%). Overall survival at four years after a median follow-up of 3.8 years was not different (70% versus 62%).

In a study by Leonard et al.,37 665 patients were entered with three or more positive axillary lymph nodes. The patients first received four cycles of doxorubicin (75 mg/m2) and were then randomised between CMF and HOC. Patients randomised to HOC subsequently received a mobilisation cycle of cyclophosphamide (4000 mg/m2) followed by HOC (cyclophosphamide 6000 mg/m2 and thiotepa 800 mg/m2) . The five-year disease-free and overall survival was the same in both arms after a median follow-up of six years.

In the study by Peters et al.44 (CALGB Intergroup study), patients with ten or more positive axillary lymph nodes received either four courses of standard-dose CAF followed by an intermediate­dose CPB (cyclophosphamide 900 mg/m2, cisplatin 90 mg/m2 and BCNU 90 mg/m2) or four courses CAF followed by a high-dose CPB (cyclophosphamide 5625 mg/m2, cisplatin 1 65 mg/m2

and BCNU 600 mg/m2) followed by reinfusion of stem-cells. Relapsing patients in the intermediate-dose arm were allowed to cross over to the high-dose arm. The study was designed to detect a difference of 20% in progression-free survival at three years with 340 patients included. In 1 995 however, the size of the study was doubled with as aim to demonstrate a five-year disease-free survival rate difference of 1 5%. Fewer relapses have occurred in the high-dose arm, but due to the high mortality in the high-dose arm there was no difference in overall survival between the two treatment arms after three years. This study had a high toxic death rate (7.4%) and HOC was compared with intermediate-dose instead of standard-dose. In the 2002 update, it was shown that the ten-year overall survival of the patients in the high-dose arm was 63%.45

This is much higher than the 42% ten-year survival for four or more positive lymph nodes patients reported by Bonadonna following CMF in node positive patients.46

A study by Gianni et al.,38 presented at the 2001 ASCO meeting included patients with four or more positive axillary lymph nodes. Patients were randomised between standard-dose chemotherapy consisting of three cycles epirubicin 1 20 mg/m2 followed by either six courses standard-dose CMF or HOC (one course of cyclophosphamide 7000 mg/m2, followed by one

I 23

24

Chapter 2

course methotrexate 8000 mg/m2, fol lowed by two courses epi rub ic in 1 20 mg/m2, fol lowed by

one course th iotepa 600 mg/m2, melphalan 1 60-1 80 mg/m2 with stem-cel l autografti ng). The

study was designed with a power of 80% to detect a 1 5% increase in progression-free survival

at five years in the HOC arm. With 382 patients el igible, the five-year progression-free survival

rates were 62% and 65% for the standard-dose and h igh-dose respectively after a median fol low­

up of 52 months. The overal l survival rates were, respectively, 77% and 76%. Among the 1 1 2

patients younger than 3 6 years and the 1 47 patients with four to n i ne positive lymph nodes, a

trend for progression-free survival advantage i n the H OC arm was noted. There is however sti l l

a short fol low-up.

Also at the 2001 ASCO meeting, Roche et a l .4 presented their resu lts of a h igh-dose study in 3 1 4

patients w ith more than seven positive axi l la ry lymph nodes. After surgery, patients were

random ised to receive fou r cyc les of FEC (5-FU 500 mg/m2, ep i ri bucin 1 00 mg/m2 and

cyclophosphamide 500 mg/m2), then either no further chemotherapy or one cycle of high-dose

CMA (cyclophosphamide 1 20 mg/kg body weight, mitoxantrone 45 mg/m2 and melphalan 1 40

mg/m2) . D isease-free surviva l at three years was h igher in the h igh-dose group compared to the

standard-dose group (71 % versus 55%, p<0.003) . Overal l survival was not different at three years

(86% versus 84%).

At the 2001 ASCO meeting Tokuda et a l .39 presented a sma l l study with 97 patients with ten or

more pos itive axi l lary lymph nodes. The standard-dose arm consi sted of six cyc les CAF

(cyclophosphamide 500 mg/m2, doxorub ic in 40 mg/m2 and 5-FU 500 mg/m2) . The high-dose

arm consi sted of six cyc les of CAF fo l lowed by H OC (cyclophospham ide 6000 mg/m2 and

th iotepa 600 mg/m2) . However, 1 5 of the 49 patients randomised for the high-dose arm did not

receive the H OC. In an i ntention-to-treat analysis, relapse-free surviva l and overal l survival was

not different.

At the 2003 ASCO meeti ng, another three randomised tria l s i n h igh-r isk breast cancer were

presented. Basser et a l .41 showed resu lts i n a tria l of 344 women with ten or more positive axi l lary

nodes or more than five nodes and an estrogen-negative tumor/T3 tumor. Patients were

randomised to a h igh-dose treatment with three cycles EC (ep i rub ic in 200 mg/m2 and

cyclophosphamide 4000 mg/m2) or to a standard-dose treatment with four cyc les AC/EC

(doxorubic in 60 mg/m2 or epi rubic in 90 mg/m2 and cyclophospham ide 600 mg/m2) fol lowed by

three cycles CMF (cyclophosphamide 1 00 mg/m2 po day 1 - 1 4, 5-FU 600 mg/m2 day one and

eight and methotrexate 40 mg/m2 day one and eight) . With a med ian fol low-up of 47 months,

there were no differences between the h igh-dose group and the standard-dose group in d isease­

free survival (5 7% versus 46%, p=0. 1 2) and overa l I survival (73% versus 64%, p=0.20).

Relevance of high-dose chemotherapy in solid tumours

The second study was presented by B l iss et al .40 Two hundred eighty patients with four or more positive axi l lary lymph nodes were randomised to receive either six cycles FEC (5-FU 600 mg/m2

day one and eight, epirubicin 50 mg/m2 day one and cyclophosphamide 600 mg/m2) or three cycles FEC fol lowed by high-dose CTC (cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2

and carboplatin 800 mg/m2) . No differences were found between the high-dose group and the standard-dose group in event-free survival (54% versus 57%) and overal l survival (66% versus 67%).

The last high-dose study at the 2003 ASCO meeting was presented by Nitz et al .5 Four hundred three patients with ten or more positive axil lary lymph nodes were randomised between standard­dose chemotherapy (four cycles of EC every 14 days (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) fol l owed by three cycles CMF every 14 days (cyclophosphamide 600 mg/m2,

methotrexate 40 mg/m2 and 5-FU 600 mg/m2) or two cycles HOC (epirubicin 90 mg/m2,

cyclophosphamide 3000 mg/m2 and thiotepa 400 mg/m2) . With a median fol low-up of 34.6 months, four-year event-free survival was higher in the high-dose arm (61 % versus 41 %, p=0.0019). Data concerning overal l survival were not given yet, however survival curves begin to separate after 52 months according to the presenters.

Several studies in breast cancer have found a better EFS/DFS without an improved OS. There are a number of potential explanations. Death due to toxicity of the high-dose regimen wil l affect the OS without an effect on EFS/DFS. There wil l be different treatment options after failure of primary treatment (high-dose versus standard-dose) and this may dilute the effect observed for DFS. For al l adjuvant studies the fol low-up is too short to know whether there is also an effect on overal l survival . In adjuvant breast studies, there is always a delay between effect on DFS and OS. More mature data are expected soon.

Germ-cell tumours

Salvage high-dose chemotherapy A smal l number of patients with relapse of metastatic germ-cel l tumours can stil l be cured with standard-dose second-l ine chemotherapy.47-49 Since germ-cel l tumours are extremely chemo­sensitive, many phase 2 trials with HOC have been completed in relapsed disease with the intention to increase the number of cured patients. The initial studies from the Indiana University reported some long-term remissions with salvage treatment, even in patients progressive after multiple preceding lines of chemotherapy or chemoresistant disease.50 More recently, long-term data showed that this type of treatment results in disease-free survival in over 52% and 57% after a median fol low-up of, respectively, 26 and 39 months.5 1 •52

I 2s

Chapter 2

However, resu l ts of tria l s with standard-dose salvage chemotherapy show that conventional

chemotherapy (usual ly ifosfamide-based) results in response rates between 33 and 50% and long­

term remissions rangi ng from 1 6 to 24% as wel l .47-49,53-55

An interesting retrospective analysis was performed in 1 93 patients with germ-cel l tumours from

a database from Germany and one from the United Kingdom, 56 compari ng standard second- l ine

chemotherapy with H DC. For 38 pai rs of patients fu l ly matched for five wel l-known prognostic

factors and a further 1 7 pai rs of patients with four matched factors, an estimated absol ute

improvement of H DC in event-free surviva l of 6-1 2% and i n overal l survival of 9-1 1 % at two

years was shown. Although th is i s not a randomised study and thus subject to multip le biases, it

suggests that the benefit from HDC in this situation is much lower than expected from the phase

1 and 2 trials . At the 2003 ASCO meeting, Vaena et a l .57 presented long-term fol low-up in 80

patients showing a low median survival of 1 5 months with only 30 patients a l ive at the last time

of fol low-up (range 1 1 -1 66 months).

It is estimated that in a few years time the defi n itive resu lts of a large prospective, randomised

European phase 3 tria l (European Group for Bone Marrow Transplantation IT-94) in relapsed

germ-cel l tumours w i l l be reported. The pre l im i nary results were reported at the 2002 ASCO

meeti ng with a median fol low-up of 41 months.58 The study has closed accrua l in September

2001 with 560 patients included. This trial compares four courses V IP (etoposide, ifosfamide and

cisplati n) or VelP (vinblastine, ifosfamide and cisplatin) as the standard arm, with three courses

of VIP or VelP fol lowed by h igh-dose CarboPEC (1 000-1 800 mg/m2 carboplatin depending on

renal function, etoposide 1 200 mglm2 and cyclophosphamide 6400 mg/m2) as the experimenta l

arm. Overa l l complete and partia l response marker negative rate were 41 % and 1 7% i n the

standard-dose arm and 44% and 1 8% in the h igh-dose arm . The one-year event-free survival

rates were not different with 48% in the standard-dose arm and 52% in the h igh-dose arm. Thus,

th is tria l shows that a s ing le course HDC does not affect outcomes. Severa l studies have

investigated the use of salvage therapy consisti ng of two or more cycles H DC for i nduction

fai l ures.51 ,59-64 The resu lts with these mu ltiple transplants with a d isease-free surviva l between 28

and 5 7% at (60-39 months) seem to be of i nterest. The Dutch study by Rodenhuis et a l .59 using

tandem HDC (two times CTC) fol lowed by two times autologous transplantation showed a 65%

salvage rate at two years. S i nce there are no mature publ ished randomised phase 3 tria ls in germ­

cel l tumours, it remains unknown whether HDC is superior to standard-dose chemotherapy in

refractory or recurrent germ-cel l tumours. However, it appears c lear that one cycle of HDC i s

ineffective. Outside a trial , the best ava i l able evidence i n 2003 shows that a regime with multiple

cycles of HDC is possib ly superior to standard-dose chemotherapy and is therefore considered

26 I

Relevance of high-dose chemotherapy in solid tumours

to be appropriate therapy in the setting of a refractory or relapsed germ-cell tumour. However, at the 2003 ASCO meeting this conclusion was tempted by Donadio et al. They showed that with four cycles TIP (paclitaxel 250 mg/m, ifosfamide 6000 mg/m2 and cisplatin 1 00 mg/m2) with granulocyte colony-stimulating factor support but without stem-cell support, the two-year relapse­free survival was 91 %.65 In this study 36 of 46 patients (78%) were alive at a median follow-up of 52 months. However, only patients with good prognostic features (gonadal primary, marker negativity after first line therapy, relapse-free interval > six months) were included. Therefore, the results only apply to these highly selected patients.

First-line high-dose chemotherapy It is currently also controversial if patients with high-risk germ-cell tumours will benefit from HOC as a first-line treatment. In phase 2 trials, two-year survival rates of 70-77% were obtained, which compare favourable to the 50% obtained with standard therapy.66

•67 A matched-pair

analysis with 292 poor prognosis patients compared sequential high-dose VIP with cisplatin­based standard-dose chemotherapy.68 The results showed significant 1 6% and 1 1 % improvements for the two-year disease-free survival and overall survival for the patients treated with HDC. This matched-pair analysis showed that HOC might result in prolongation of progression-free and overall survival as compared to standard chemotherapy. However, preliminary results from the only published (as an extended abstract) randomised phase 3 study failed to show an advantage from the high-dose arm.69 The patients (n=1 1 5) in this study were treated with four courses of cisplatin, etoposide, vinblastine and bleomycin (standard arm) or three identical courses, followed by HOC with cisplatin, etoposide and cyclophosphamide. However, this study has several limitations and is impossible to interpret. Only 1 1 4 patients were randomised. The treatment in the standard arm is currently not considered standard treatment for germ-cell tumours. The dose-intensity in the high-dose arm was relatively low and even lower than in the standard-dose arm. 30% of the patients randomised to the high-dose arm did not complete HDC due to early death or toxicity during the standard-dose induction phase.

Patients with poor-risk disease are currently being accrued in large phase 3 trials studying the role of HDC in the USA (SWOG, ECOG, CALGB), Europe (EORTC GUG, German TCSG, Spanish GCCSG) and Italy (NCI Milan), the results of which are eagerly awaited.

Ovarian cancer

Sixty to 70% of patients with invasive ovarian cancer have chemotherapy-sensitive tumours. Nevertheless, despite good responses many tumours eventually recur and the patients die of disease. The question whether a threshold for platinum dose-intensity exists has been a matter of

I 21

28

Chapter 2

debate. Fol lowing the demonstration of a correlation between increased dose intensity of cisplatin

and both the response rates and overal l survival in women with ovarian cancer, 1 3 numerous

c l i n ical trials were conducted that evaluated H DC. During the 1 980s and early 1 990s, several

teams explored H DC in relapsed p latinum-resistant patients. A review of a l l avai lable data did not

suggest that h igh-dose is superior to standard-dose in these patients. 70 It is apparent that patients

with drug-resistant or bulky disease are not candidates for HOC. The patients most l i kely to benefit

are those with low-volume chemo-sensitive d i sease. 71'

72 Applying H OC earl ier in the di sease

course when tumours are less resistant may perhaps yield more durable effects.

During the last few years, a large number of patients have been treated in the consol idation setting

a l lowi ng mu ltivariate analysis that i ndicates who is most l i kely to benefit from H OC. Young age,

Karnofsky performance score of at least 90%, non-clear cel l disease, remission at transplantation

and p latinum sensitivity were associated with better outcomes in the US experience reported to

the Autologous B lood and Marrow Transplant Registry of 42 1 women who received H OC in 5 7

centres between 1 989 and 1 996. 73 The 1 08 patients who received H OC either i n first remission

or very good partial remission (microscopic d isease) had the best outcome. In a retrospective

analysis of 254 patients in remiss ion, with a median fol low-up of 76 months from diagnos is, the

median d isease-free and overal l survival in stage I l l d isease was 42 and 59 months and for stage

IV d isease 26 and 40 months . 74

To further evaluate the effectiveness of H OC, G I N ECO has in itiated a phase I l l study for stage I l l/IV

ovarian cancer with smal l residual d isease fol lowing platinum-based induction regimen.75 Patients

are randomised after second-look surgery to receive either HOC (carboplati n 1 600 mglm2 and

cyclophosphamide 6000 mglm2) and haematopoietic stem-cel l support or three cyc les of

conventional-dose maintenance (q4w) with carboplati n (300 mg/m2) and cyclophosphamide (500

mg/m2) . Prel iminary data of th is sma l l study with 1 02 patients included (52 h igh-dose and 50

standard-dose) and a median fo l low-up of 36 months were presented at the 2001 ASCO

meeting.76 Median disease-free survival from inc lusion was eleven months in the standard-dose

arm and 22 months in the high-dose arm (p=0.03). In a selected popu lation of young women with

chemo-sensitive advanced ovarian cancer and sma l l residual d isease at second-look surgery,

h igh-dose consol idation chemotherapy ach ieved i n a retrospective analysis a better median

disease-free survival than conventional-dose treatment. No information i s ava i l able unti l now

about the overal l surviva l .

In conclusion, the opti mum indication for H OC in advanced ovarian cancer has not yet been

establ ished. It is clear, however, that there is no role for this modal ity of treatment in patients with

drug-resistant d isease and/or bu lky d isease. There i s an urgent need to conduct prospective

Relevance of high-dose chemotherapy in solid tumours

randomised studies in the first-line treatment of selected ovarian cancer patients. Until the results of such trials become available, HOC cannot be routinely recommended and should be limited to the clinical trial setting.

Soft tissue sarcomas

Soft tissue sarcomas represent a rare and heterogeneous entity. Only a few drugs have shown to be active in disseminated disease, with doxorubicin and ifosfamide being the only agents with reported response rates above 20%. However, the active drugs in soft-tissue sarcomas limit dose­escalation to a maximum of two to three fold because of dose-limiting non-haematological toxicity. Other drugs that can be dose-escalated, with the possible exception of thiotepa and cyclophosphamide, have not shown to be active in soft-tissue sarcoma.77 In adults, no randomised trials have been performed comparing standard-dose chemotherapy to HOC. Only small phase 2 trials with very heterogeneous patient populations and very different treatment protocols are available.78-82 Although high response rates in these trials are reported, no long-term survivors in metastatic disease are reported. In conclusion, there are no data showing superiority for HOC in soft-tissue sarcomas. This type of treatment should not be used for this indication outside a clinical trial. Future studies should search for other drugs or combinations of drugs that are active in sarcoma, permitting further dose-escalation.

Ewing sarcoma and PN ET

Most Ewing tumours are characterised by a unique gene rearrangement between the EWS gene and an ets transcription factor gene. The degree of neuroectodermal differentiation has been utilised for histological sub-classification of the Ewing family of tumours in classical Ewing sarcoma, atypical Ewing sarcoma and malignant peripheral neuroectodermal tumour (PNET). Despite initial good response to chemotherapy the overall survival is approximately 60% and especially in cases with bulky disease the prognosis is poor. Multiple phase 2 trials have been performed in high-risk, relapsed or metastatic Ewing sarcoma. Promising results are reported from these studies with an estimated rate of cure between 22 and 72%.83-87 However, since no phase 3 trial is available comparing between standard second-line chemotherapy and high-dose, the superiority of HOC in this setting is not established.

Currently a phase 3 study is being performed as a European Intergroup study (EURO EWING 99). Patients in this trial with intermediate risk will be randomised after six courses of VIDE (vincristine 1 .5 mg/m2, ifosfamide 9000 mg/m2, doxorubicin 60 mg/m2 and etoposide 450 mg/m2) to eight courses of standard VAi (actinomycin-D, etoposide, ifosfamide) or HOC with busulfan 600 mg/m2

I 29

Chapter 2

and melphalan 140 mg/m2 • Patients with high-risk disease wi l l immediately receive high-dose chemotherapy after upfront standard chemotherapy with VIDE. At present, this trial is recruiting.

NSCLC

The prognosis of patients with advanced non smal l-cel l lung cancer (N SCLC) has improved only minimal ly in the last decade, despite the development of many new combinations of surgery, chemotherapy and radiotherapy.BB A number of smal l-scale studies on HDC have been performed patients with NSCLC, of which a German study by Fetscher is the largest.B9 In this phase 1 / 1 1 trial, 1 07 patients with stage I-IV NSCLC received at least two cycles of standard-dose chemotherapy (etoposide 500 mg/m2, i fosfamide 4000 mg/m2, cisplatin 50 mglm2 and epi rubicin 50 mg/m2) .

Twenty-fi ve patients with responses proceeded to HDC (etoposide 1 500 mg/m2, i fosfamide 12,000 mg/m2, carboplatin 750 mg/m2 and epirubicin 1 50 mg/m2) with autologous peripheral blood stem-cel l transplantation. Treatment mortal i ty was 3-8% dependent of stage, even in the fi ttest patients responding to the induction treatment. Median duration of survival was 1 7 months in l imited disease and ten months in extensive disease. Two-year survival was 30% in l imited and 8% i n extensive, comparable to other publ i shed tria ls of standard-dose combination chemotherapy in N SCLC. Although better response-rates were achieved in the high-dose arm, this did not translate into improved survival.

Small-cell lung carcinoma

Contrary to NSCLC, smal l-cel l lung cancer (SCLC) is a very chemo-sensitive tumour with however a nearly 100% chance of relapse. There have been many "promising" high-dose phase 2 studies, however only one phase 3 trial has been publ ished.90 In this study, 101 patients received as induction therapy during a period of f ive months, a total dosage of 1 20 mg/m2 methotrexate, 4.5 mg/m2 vincristine, 1800 mglm2 cyclophosphamide, 1 80 mg/m2 doxorubicin, 160 mg/m2 cisplatin, 750 mg/m2 etoposide and 30 Gy prophylactic cranial i rradiation. The 45 patients responding were randomised to a l ast cycle of chemotherapy (cyclophosphamide 750 mg/m2, BCNU 60 mglm2 and etoposide 600 mg/m2) or HOC (cyclophosphami de 6000 mg/m2, BCNU 300 mg/m2

and etoposide 500 mglm2 ) . Median relapse-free survival for the intensif ied and control chemotherapy groups was, respectively, 28 and ten weeks (p=0.002). Median overal l survival was 68 weeks for the high-dose group compared with 55 weeks for the conventional therapy group (p=0. 1 3). Four patients died during intensif ication. Based on this study, it can be concluded that HDC for sensit ive SCLC could have a modest effect on relapse-free survival , but not on overal l survival and at the cost of a high morbidity and morta l i ty. A new phase 3 study (Random­ICE) has started in 1997. Patients with l imited disease or extensive disease < two metastatic sites

Relevance of high-dose chemotherapy in solid tumours

and good performance scores (ECOG 0-1) are randomised between six standard courses ICE

(ifosfamide, carboplatin and etoposide) or two courses epirubicin 150 mg/m2 and paclitaxel 175

mg/m2, followed by three courses of HOC with ICE (ifosfamide 10,000 mg/m2, carboplatin 1200

mg/m2 and etoposide 1200 mg/m2) and peripheral stem-cel l transplantation. Recently, Lorigan

presented a randomised study of patients with extensive SCLC receiving either four weekly ICE

(ifosfamide 5000 mg/m2, carboplatin 300 mg/m2 and etoposide 360 mg/m2) or dose-dense

treatment with the same regimen every two weeks with filgrastim and support of autologous

blood, collected on day 15 of the course and returned 24 hours after completion of therapy.91

With 318 patients randomised, no survival advantage was found. Obvious problems with SCLC

patients are the old age of the average patient, co-morbidity, low performance score and high

incidence of bone-marrow contamination.

Other

No randomised phase 3 trials are available in osteosarcoma. Standard-dose salvage

chemotherapy has no proven value in metastatic osteosarcoma,92 especially in heavily pre-treated

patients. However, a recently reported study in relapsed osteosarcoma showed the feasibility and

activity of two courses HOC (carboplatin 1500 mg/m2 and etoposide 1800 mg/m2) .93 In this small

study of 32 patients with median age of 15 years (range eight to 38 years), it was found that 25

patients were in complete response at the end of treatment. With a median follow-up of 23

months, 14 patients are still alive, eight in complete remission. Eighteen patients have died,

17 of disease and one of toxicity. Although it can be concluded that this type of treatment can

induce long-standing remissions in a large proportion of patients with metastatic osteosarcoma,

most patients have relapsed. Since no phase 3 data on HOC are available, no conclusion on the

efficacy of this treatment in osteosarcoma can be drawn. At the 2003 ASCO meeting, Linassier

et al.94 reported results of a randomised study in 69 patients with supra-tentorial glioblastoma.

After gross resection, patients were randomised between HOC (BCNU 800 mg/m2) fol lowed by

radiotherapy or radiotherapy fol lowed by BCNU 80 mg/m2 every six weeks for one year. The

study had to be stopped prematurely because of a greater than 10% mortality rate in the high­

dose arm. With a median fol low-up of 23 months, no differences were found in survival.

Paediatrics

HOC with autologous transplantation in children is widely used but mostly without proven value.

Many promising results from phase 2 trials have been reported, especial ly in rhabdomyosarcoma

and Ewing sarcomas, high-grade astrocytoma, neuroblastoma and medul loblastoma, but only

one randomised phase 3 study has been published.

I 31

Chapter 2

In a large (379 children randomised) phase 3 trial, patients with high-risk neuroblastoma were treated with five cycles of the same initial standard-dose induction chemotherapy.95 Patients without disease progression were randomised between HOC and total body irradiation or to receive three more cycles of standard chemotherapy. All patients who completed treatment were randomised between no further therapy or treatment with 1 3-cis-retinoid acid for six months. With a median follow-up of 43 months, the mean three-year event-free survival was significantly better among the 1 89 patients who were assigned to undergo HOC than among the 1 90 patients assigned to receive continuation standard-dose chemotherapy (34% versus 22%, p=0.034). The three-year overall survival was not different (43% versus 44%). The authors conclude therefore that treatment with myeloablative therapy and autologous bone-marrow transplantation improved event-free survival among children with high-risk neuroblastoma.

Why is the steep dose-response relationship in vitro absent in the clinic for solid tumours?

Based on the steep dose-response relationship in vitro for especially alkylating agents, there were high expectations for high-dose chemotherapy in the clinic in the treatment of solid tumours. These fundamental data seemed to allow for expectations of doubling cancer treatment results as they were known at the time. Certainly the high mortality rate in the early studies made it clear that anything less would not be worthwhile. Initially phase 1 and 2 studies were promising with good response rates but a major effect of high-dose chemotherapy could not be shown in subsequent randomised studies.

We indicated in the various paragraphs drawbacks of the various clinical study designs of the randomised studies. These drawbacks can explain part of the missed effect but do not explain that the expected major effect is not observed.

There could be a number of other reasons for the absence of the major effect of high-dose chemotherapy. Pharmacokinetics in humans is clearly different form tissue culture conditions. High intratumoral levels will be of relatively short duration. Although with haematopoietic stem­cells the bone-marrow toxicity can be bypassed, the final drug dose is still restricted by potential toxicity to other organs. We currently know that in tumours apart from active cycling cells, as also present in tissue culture, there are mature differentiated cells and dormant tumour stem-cells. These tumour stem-cells may well possess completely different characteristics from more mature cells.96 Dormancy is a state that renders a cell resistant to chemotherapy. This may explain the fact that high-dose chemotherapy can induce a high tumour response rate but does not completely eradicate tumour stem-cells and thus does not protect from relapse. Tumours are

Relevance of high-dose chemotherapy in solid tumours

heterogeneous in nature compared to cell lines. Therefore the high-dose treatment may be adequate for only part of the tumour.

Usually, high-dose chemotherapy is administered following standard induction chemotherapy. The haematopoietic stem-cells are harvested in a phase when the chance that tumour cells contaminate the harvest is lowest. There is always concern about the possibility that malignant cells in the autograft are reinfused and give rise to the relapse. However, it is much more likely that the origin of relapse consists of resistant tumour cells surviving the initial therapy. Probably relevant information concerning that dilemma could be found by analysing the site of relapse after high-dose. Resistance might lead to local relapse at the primary metastatic site, while contamination might lead to diffuse haematogenic relapse. Purging (physical, chemical or immunological) has until now not shown to result in survival advantage. There is also no direct evidence that tumour cells in the graft cause relapse, with the possible exception of non­Hodgkin's disease. Therefore graft contamination with tumour cells does not seem to explain the limited activity of high-dose chemotherapy.

High-dose chemotherapy is nowadays, in contrast to the initial studies with a death rate of 7-1 0% feasible and associated with acceptable 1 -2% post transplant (first 1 00 days) mortality. This reduction in death rate might result in better results of high-dose chemotherapy regimens in the future.

What remains for the future

What remains are a number of studies indicating not yet a major effect of high-dose chemotherapy but a significant better predominantly disease-free survival. The follow-up of the currently available studies in, e.g., adjuvant breast cancer setting is relatively short and compares unfavourable to the more than 20 years of follow-up in other adjuvant chemotherapy regimens.46

Only the MD Anderson study, the Dutch studies, the Chicago study and the Anglo-Celtic 1 study have presented results with reasonable, although for breast cancer still too short follow-up (6.5, 4. 1 , 4.8, 6. 1 and 6 years respectively).3 •20•34•35•37 Whether high-dose chemotherapy will obtain a significant role in anticancer treatment of solid tumours will depend on long-term effects on survival balanced versus long-term side effects that may occur.3

The large Dutch adjuvant breast cancer trial shows a benefit in patients with ten or more positive lymph nodes and a negative HER2/neu expression in the tumor.3 This supports the selection of patients not only based on patient characteristics but also on tumour characteristics. The development of micro-array analysis for prediction of treatment outcome may potentially facilitate the selection.97

I 33

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Most trials contained one course HOC most often at the end of the treatment. However, it might be more appropriate to incorporate two or more sequential cycles HOC with haematopoietic stem-cell support. Data on double transplants are derived from phase 1 to 2 studies and regretfully no randomised study comparing one transplant and a double transplant is available. The best available data are from the paper of Elias et al.98 They reported the long-term outcomes of women undergoing high-dose therapy for metastatic breast cancer over the past twelve years while participating in a sequence of research studies transitioning between a single to a double intensification approach. Univariate and multivariate analyses provide a framework to understand the prognostic factors important for event-free and overall survival. The results from this analyses showed a benefit of double transplants. Although selection biases may have contributed to this effect, a randomised comparison of single versus double transplantations might be warranted.

Results may also change if newer drugs are tested in HDC regimens. It is important to note that the choices for chemotherapy in the high-dose regimen are guided by the tolerance of the normal tissues. Drugs such as trastuzumab, taxanes and even the addition of immunotherapy could play a role in future HDC trials.

There is evidence that also in solid tumours an immunological therapeutic effect is induced by allogeneic haematopoietic stem-cell transplantation.99-1 01 The graft-versus-tumour effect usually appears when the graft-versus-host disease develops. It is suggested that this effect is mediated by T-lymphocytes against tumour-associated antigens. Only results from small phase 2 trials are available in breast cancer and renal cell carcinoma. This treatment also coincides with major toxicity. It is therefore as yet unclear whether allogeneic transplantation has a role in other solid tumours.

Maturation of the results from recent studies indicating a more modest benefit in, e.g., adjuvant breast cancer balanced versus long-term side effects will in the long run determine the role of high-dose chemotherapy in certain solid tumours. In case of further use of high-dose chemotherapy, selection of patients based on patient and tumour characteristics as well as the introduction of new agents will most likely play a role.

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l ung cancer. Ann Oncol 1 997;8:57-64.

90. Humblet Y, Symann M, Bosly A, et al: Late intensification chemotherapy with autologous bone marrow

transplantation i n selected smal l-ce l l carc inoma of the lung: a randomized study. J C l in Oncol

1 987;5 : 1 864-73.

91 . Lorigan P, Wol l P, O 'Brien M, et a l : Randomised phase 3 trial of dose dense ICE chemotherapy versus

standard ICE in good prognosis sma l l cel l l ung cancer (SCLC). Proc Am Soc Cl in Oncol 2003;abstract

2490.

92. Pratt CB, Epelman S, Jaffe N: B leomycin, cyclophosphamide, and dactinomycin in metastatic

osteosarcoma: lack of tumor regression in previously treated patients. Cancer Treat Rep 1 987;71 :42 1 -3 .

93. Fagiol i F, Agl ietta M, Tienghi A, et a l : H igh-dose chemotherapy in the treatment of relapsed

osteosarcoma: an Ita l ian sarcoma group study. J Cl in Oncol 2002;20:21 50-6.

94. Linassier C, Ben Hassel M, Figarel la-Branger D, et al: Phase I l l study comparing h igh-dose BCN U with

autologous blood stem cel l support versus standard dose BCNU, in combination with radiotherapy

after gross tota l resection in patients with supratentorial gl ioblastoma. Proc Am Soc Cl in Oncol

2003;abstract 399.

95. Matthay KK, Vi l lablanca JG, Seeger RC, et al: Treatment of h igh-risk neuroblastoma with intensive

chemotherapy, radiotherapy, autologous bone marrow transplantation, and 1 3-c i s-retinoic acid.

Chi ldren 's Cancer Group. N Engl J Med 1 999;341 : 1 1 65-73.

96. Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, C larke MF: Prospective i dentification of

tumorigenic breast cancer cel ls . Proc Natl Acad Sci U S A 2003; 1 00:3983-8.

97. Van de Vijver MJ, He YD, van 't Veer LJ, et al: A gene-expression signature as a predictor of survival in

breast cancer. N Engl J Med 2002;347: 1 999-2009.

I 41

42 I

Chapter 2

98. El ias AD, Ibrahim J, Richardson P, et a l : The impact of induction duration and the number of high-dose

cycles on the long-term survival of women with metastatic breast cancer treated with h igh-dose

chemotherapy with stem cell rescue: an analysis of sequentia l phase 1/1 1 trials from the Dana-Farber/Beth

Israel STAMP program. B iol B lood Marrow Transplant 2002;8: 1 98-205.

99. Bregni M, Dodero A, Peccatori J , et a l : Nonmyeloablative condition i ng fol lowed by hematopoietic cel l

a l lografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. B lood

2002;99:4234-6.

1 00. Pedrazzol i P, Da Prada GA, Giorgiani G, et al: Al logeneic b lood stem cell transplantation after a

reduced-intensity, preparative regimen: a pi lot study in patients with refractory mal ignancies. Cancer

2002;94:2409-1 5 .

1 01 . Ueno NT, Rondon G, Mirza NQ, et a l : Al logeneic peripheral-blood progenitor-cel l transplantation for

poor- risk patients with metastatic breast cancer. J Cl in Oneal 1 998; 1 6:986-93 .

3 Long-term haematological recovery following high-dose

chemotherapy with autologous bone marrow transplantation or

peripheral stem cell transplantation in patients with solid tumours

P. Nieboer1 , E.G.E. de Vries 1 , N.H. Mulder1 , D.Th. Sleijfer1 , P.H.B. Willemse1 , G.A.P. Hospers1 , J.A. Gietema1 , W.J. Sluiter2, W.T.A. van der Graafl

1 Department of Medical Oncology, University Medical Center Groningen 2Department of Internal Medicine, University Medical Center Groningen

Bone Marrow Transplant 2001 ; 2 7: 959-966

Chapter 3

Summary

Long-term peripheral blood counts and factors influencing long-term tril ineage haematological

recovery of consecutive patients in a single institution treated with high-dose chemotherapy

(HDC) and autologous bone-marrow transplantation (ABMT) or peripheral stem-cel l

transplantation (PSCT) for solid tumours were examined.

Patients with a relapse-free survival of > 1 year were included in the analysis (n=l 31 ). Peripheral

blood counts were examined 6 months and yearly fol lowing transplantation.

Median fol low-up was 4. 1 years (range 1-1 0+ years). Three years after transplantation 91 % of

patients had normal white blood counts (WBC), 94% normal haemoglobin (Hb) and 75% normal

platelets. Tri lineage recovery was complete in 70% (n=83) at three years and 85% (n=S0) at five

years. Recovery of Hb occurred before WBC and platelet recovery. Approximately 25% of

patients displayed an elevated MCV throughout the fol low-up period. These long-term results

were independent of age, high-dose regimen, number of reinfused stem-cel ls and stem-cel l

source. Double (n=l 2) versus single (n=l 19) transplantations showed significant slower trilineage

recovery and higher MCV. No secondary graft failure, myelodysplasia or leukaemia was

encountered.

In conclusion, complete trilineage recovery after HOC fol lowed by ABMT or PSCT occurs slowly.

PSCT and ABMT are capable of maintaining long-term haematopoiesis. S lower recovery is seen

after double transplantations. The results suggest lasting implications for the bone-marrow after

autologous transplantation.

Long-term haematological recovery following high-dose chemotherapy

Introduction

High-dose chemotherapy (HOC) followed by reinfusion of autologous stem-cells harvested from bone-marrow or peripheral blood has been increasingly applied for a variety of disorders. Autologous bone-marrow transplantation (ABMT) or peripheral stem-eel I transplantation (PSCT) permits the delivery of a higher, marrow-ablative dose of chemotherapy. In addition to patients with haematological diseases, an increasing number of patients with solid tumours have undergone HOC with ABMT or PSCT during the last decade. 1 HOC with ABMT or PSCT is not considered standard treatment for solid tumours, therefore benefits have to be studied in randomised studies and balanced against the risks of the treatment, both in the short- and the long-term.2

Solid tumours treated with HOC followed by ABMT or PSCT include breast cancer,3'4 ovarian carcinoma,5-7 relapsed germ-cell tumours8-1 0 and childhood sarcomas. 1 1 • 1 2 In the last decade, a shift from bone-marrow to peripheral blood as the source of haematopoietic stem-cells has occurred. It has been shown that PSCT compared to ABMT offers faster short-term recovery of peripheral blood counts resulting in lower morbidity, mostly due to fewer infections and haemorrhagic periods and a reduced usage of blood products. 1 3

Abnormalities in haematopoiesis have been shown following transplantation. 1 4-1 7 Decreased bone-marrow cellularity has been shown to persist up to three years following allogenic transplantation. 1 8 The amount of colony-forming units (CFU-GM, BFU-E, CFU-Meg and TL-CFU) was shown to be diminished following autologous transplantation persisting for as long as four to five years. 1 9-22 Patients relapsing after transplantation showed decreased haematological tolerance to reinduction-chemotherapy.23 Radiotherapy after transplantation and infections during follow-up can lead to haematopoietic stress and temporary cytopenias have been described in such circumstances.24 Clinical problems could therefore arise from the abnormalities in haematopoiesis following autologous transplantation .

Data about attaining and maintaining sustained long-term (i.e. > 1 year) haematopoiesis following ABMT or PSCT are scarce. Some data are available from patients with haematological malignancies and/or after allogenic transplantation, with, in general, a follow-up of one year at the most. 1 8,25,26 Studies usually report that peripheral blood counts will normalise within one year after transplantation. 2 1 •23•24,27-32

Factors influencing short-term recovery have been studied extensively.20,30,33-37 Most studies found a correlation with stem-cell source, number of infused stem-cells and use of haematopoietic

I 4s

Chapter 3

growth factors. Factors infl uenci ng long-term (> 1 year) recovery i n sol id tumours after ABMT or

PSCT have not been studied to date.

The present study analyses whether patients attain normal peripheral blood counts after H DC

fol lowed by ABMT or PSCT and whether ABMT or PSCT is capable of mainta in ing sustai ned

long-term haematopoiesis. Peripheral blood counts and factors i nfl uencing long-term tri l i neage

recovery of a l l sol id tumour patients (surviving relapse-free > 1 year) in a single institution treated

with HDC fol lowed by ABMT or PSCT were studied.

Patients and methods

Patient characteristics Data of a l l patients treated with H DC fol lowed by ABMT, PSCT or both for sol id tumours at the

Department of Medical Oncology, U n iversity Hospita l G ron ingen, The Netherlands, were

analysed. Only patients survivi ng relapse-free for more than one year were inc luded in th is study.

They were fol lowed for this analysis unti l relapse, loss to fol low-up, maxi mum fol low-up of ten

years or end of study (1 January 2 000).

Marrow transplant conditioning regimen and supportive measures High-dose regimens and abbreviations for different drugs are shown in Table 1 . Relapsed germ­

cel l tumour was treated with CyVP1 6 (year 1 987) or CTCy/CTCy (year 1 995). Ovarian carcinoma

was treated with CyVP1 6 ( 1 982-1 985), CyMi (year 1 985) or MiM ( 1 987-1 988). Loca l ly advanced

breast cancer (T1 -3 N 1 -2M0) was treated with MiT ( 1 990-1 994) or CTCy (1 993-2000), metastatic

breast cancer (Ml ) with MiM ( 1 987-1 993) or T/MMi ( 1 993-2000) and T4 breast cancer (T4N0M0)

with CyVP1 6 ( 1 984-1 990). Two patients original ly supposed to receive T/MMi received only T

and one patient supposed to receive CTCy/CTCy received on ly one course of CTCy. Three

separate k inds of chemotherapy cou ld be disti ngu ished: cyc lophosphamide-based regimens,

mitoxantrone-based regimens and ablative regimens used for double transplantations.

All patients were treated with selective gut decontamination. G ranu locyte-colony sti mulating

growth factor (G-CSF) was admin i stered subcutaneously s ince 1 992 at a dose of five µg/kg/day

starting the day of stem-cel l rei nfusion and was continued unti l white blood count (WBC) was

> 3 x 1 09/L on two consecutive days. Platelets were transfused if serum platelets fel l below 20 x

1 09/L or if bleeding occurred. Leukocyte-depleted blood was transfused when haemoglobin (Hb)

was below 8 g/dL or if the patient had symptomatic anaemia. A l l b lood products were i rradiated.

46

Long-term haematological recovery following high-dose chemotherapy

Table 1. High-dose regimens

Regimen Number Total dose mg/m2 Treatment days prior to reinfusion

Single CTCy 54 1 600, 480, 6000 -6, -5, -4, .3

CyVP16 22 7000 , 1000-3500 -7, -6, -5

MiM 12 60-75, 180 -7, -6, -5

MiT 28 50, 800 -7, -6, -5

T 2 800 -1

CyMi 7000 , 30 -7, -6, -5

Double T/MMi 11 800/180, 60 -1/-7, -6, .5

CTCy/CTCy 3200, 960 , 1 2000 -6, -5, -4, -3/-6, -5, -4, -3

Abbreviations: C, carboplatin; Cy, cyclophosphamide; T, thiotepa; VP16, etoposide; Mi, mitoxantrone; M, melphalan.

Bone-marrow harvest Between 1 982 and 1 994, bone-marrow was collected by multiple punctures from the posterior iliac crests under local anaesthesia with lidocaine. The marrow was aspirated in 1 0 ml disposable syringes and collected in Hanks' solution with hepes buffer and heparin. The marrow was centrifuged in a Haemonetics 30S apheresis machine (Haemonetics Corporation, Braintree, MA, USA). After sedimentation of red blood cells in a 1 0% hydroxy-ethyl starch solution and concentration of nucleated cells to 200 x 1 06 cells/ml, cryopreservation followed. A minimum number of 2 x 1 08 nucleated cells/ kg body weight were collected.

Mobilisation procedure and peripheral stem-cell harvest Peripheral stem-cells were collected following a disease-oriented course of chemotherapy and haematopoietic growth factors. Harvesting was performed via a dual lumen catheter using a Haemonetics MCS+ pheresis machine. CD34+ cells were stained using a monoclonal anti-CD34 (anti HPCA-2) and a quantitiation was performed by flow cytometry (FACSCalibur; Becton Dickinson, Woerden, The Netherlands). A target quantity of CD34+ cells of � 5 x 1 06/kg body weight was envisaged.

Marrow and stem-cell cryopreservation The bone-marrow suspension or leukapheresis product was mixed with minimal essential medium (MEM) containing 20% dimethyl sulfoxide. The final cell suspension was transferred into freezing bags and frozen to -40°C with a computer-controlled cryopreservation device. The frozen cells were then transferred into the liquid phase of nitrogen and stored at -1 96°C.

I 47

48

Chapter 3

Stem-cell reinfusion Immediately prior to infusion, the cryopreserved bone-marrow or peripheral stem-cells were rapidly thawed in a 40°C waterbath, aspirated in 50 ml syringes in a laminar flow cabinet and transfused through a double lumen Hickman catheter. Premedication consisted of steroids and antihistamines.

Radiotherapy Radiotherapy was given to 115 of 122 (94%) of breast cancer patients post transplantation. Reasons for not administering radiotherapy included slow recovery of platelets in two patients. After mastectomy the target volume included the regional lymph nodes (46-50 Gy) and the chest wall (40-50 Gy). After breast conserving therapy, the dose applied to the whole breast was 50 Gy with an extra dose to the area of the primary tumour of 16-20 Gy.

Haematological determinations Hb, WBC, platelets and mean corpuscular volume (MCV) were determinated by standard techniques using an automated Coulter particle count (Coulter Electronics Nederland, Mijdrecht, The Netherlands). Long-term haematological recovery was defined as WBC of � 4 x109/L, platelets of � 150 x 109/L and Hb of � 12 g/dL.2 1 ,25,30 Normal MCV was defined as 80-98 fl.38

Following recovery from transplantation, patients were seen in our hospital on an outpatient basis at three-month intervals. Peripheral blood counts and MCV were evaluated six months and one year after transplantation and yearly thereafter for a maximum of ten years.

Statistical analysis Most variables showed an asymmetric distribution, therefore, medians are presented. Long-term recovery was assessed using Kaplan-Meier probability curves and statistical comparison of curves was performed by the log-rank test. The prognostic value of different variables for long-term probability of reconstitution was assessed by multivariate analysis using the Cox multiple regression model. A p<0.05 was considered statistically significant.

Results

Patient characteristics (Table 2)

From January 1982 to January 2000, 247 patients were treated with HDC followed by ABMT or PSCT for solid tumours. A total of 131 out of these 247 survived relapse-free for at least one year after ABMT or PSCT and were included in this study. Of these 131 patients, end of study was

Long-term haematological recovery following high-dose chemotherapy

relapse in 39 patients, loss to follow-up in two patients, maximum follow-up of ten years in eleven patients, death without relapse in one patient and endpoint of study (1 January 2000) in 78 patients. Of these patients haematological recovery from 0.5 to 1 0 years after HOC was studied. Median fol low-up was 4. 1 years (range 1 to 1 O+ years). Median age at transplantation was 44. 1 years (range 2 1 to 54 years). Three males and 1 28 females were treated. Patients had been diagnosed as follows: germ-cell tumour in three, ovarian carcinoma in six and breast cancer in 1 22. At the time of HOC, al l patients were in partial or complete remission.

Table 2. Patient Characteristics (n=1 3 1 )

Characteristic Number of patients

Follow-up (years) Median 4.1 Range 1 - 1 0+

Age (years) Median 44. 1 Range 2 1 -54

Sex (male/female) 3 / 128

Diagnosis Breast cancer 1 22 Relapsed germ-cell tumour 3 Ovarian carcinoma 6

Transplantation Single 1 1 9 Double 1 2

Source of stem-cells Bone-marrow 43

Peripheral stem-cells 63

Both 25

Eleven patients were transplanted twice according to a local protocol for metastatic breast cancer, with a mean interval of 23.9 days (range 1 7 to 34 days) between courses, one patient was transplanted twice for refractory germ-cell tumour with an interval of 34 days between courses.

A total of 43 patients received bone-marrow stem-cells only (1 982-1 992), 25 patients received a combination of bone-marrow and peripheral stem-cel ls ( 1 992-1 994) and 63 patients received peripheral stem-cells only (1 993-2000).

I 49

so I

Chapter 3

Long-term haematological recovery and time to normalisation of haematological parameters

Haemoglobin: One year after transplantation median Hb was 12.6 gldl. Three years after transplantation a plateau was reached at 13.3-13.7 g/dl (Figure 1 A). The proportion of patients with a subnormal Hb (< 12 g/dl) declined quickly in the first three years after transplantation (Figure 1 B). Five years after transplantation all patients had a normal Hb.

White blood count: Normalisation of WBC was slower than that of Hb. Six months after transplantation median WBC had reached 4.0 x 109/l (Figure 2A) . During ten years median WBC increased steadily and reached a value of 7.0 x 1 09/l at 10 years. The proportion of patients with subnormal WBC (< 4 x 109/l) decreased slowly (Figure 2 B) . After one year, 33% and after three years, 9% of patients still had subnormal values.

Platelets: The number of platelets rose even more slowly after transplantation. Six months after transplantation median platelets was 130 x 109/l, one year after transplantation 147 x 109/l until it reached 257 x 109/l at ten years (Figure 3A). One year after transplantation only 51 % of the patients had normal platelet counts. Five years after transplantation 84% of patients had normal platelet counts (Figure 3B).

Mean corpuscular volume: Median MCV just prior to HOC was 90.0 fl. Median MCV post transplantation was increased to 96 fl after six months and decreased to a steady-state level of about 92 fl after five years (Figure 4). Approximately one quarter of patients persisted with elevated MCV (> 98 fl) during the complete follow-up period.

Long-term haematological recovery following high-dose chemotherapy

A 1 8

0

1 6 0 0

��������

14 ..9 C:

0

1 2 Q) ro

0 0

10

0

0 8

N= 1 3 1 1 30 1 07 83 66 50 37 29 23 14 1 1 1/2 2 3 4 5 6 7 8 9 1 0

time (years)

B 1 ,0

..c I

,8

0 C:

C:

,6 ro

C: Q)

,4 c.. 0 C: 0

0 ,2 c..

1,0

0 2 3 4 5 6 7 8 9 1 0

time (years)

Figure 1 A Hb during ten years fol lowing HOC and ABMT/PSCT. Boxplot shows the median , interquarti le range

and outl iers (circles). B Cumulative proportion of patients reach ing normal Hb during ten years fol lowing HOC and

ABMT/PSCT.

I s1

Chapter 3

A 18

16 -l+-

14 :it 0 0 -l+-* 12 0 0 * -l+-

::J'

tt���� ���

;;;- 10 0

(.) 8 al � 6

4

2

0 N= 130 128 1 06 81 65 48 36 28 22 12 10

1 12 1 2 3 4 5 6 7 8 9 1 0

time (years)

B 1 ,0

(.) al � ,8

0 C:

,6

C:

,4 a. 0 C: 0

,2 0 a.

0,0 0 2 3 4 5 6 7 8 9 1 0

time (years)

Figure 2 A WBC during ten years following HOC and ABMT/PSCT. Boxplot shows the median, interquartile

range, outliers (circles) and extreme values (asterisks) . B Cumulative proportion of patients reaching normal WBC during ten years fol lowing HOC and

ABMT/PSCT.

Long-term haematological recovery following high-dose chemotherapy

A 500

400

0 0 0

�Q i! 300

�

� c 200

1 00

0

N= 1 31 1 28 106 82 65 48 36 28 22 1 2 1 0 1 /2 1 2 3 4 5 6 7 8 9 1 0

time (years)

1 ,0

B .!!? Q)

ro ,8

0

C) ,6 C

ro

.!!? C ,4 Q)

a. 0 C 0 ,2 '2 0

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Figure 3 A Platelets during ten years following HOC and ABMT/PSCT. Boxplot shows the median , interquartile

range and outliers (circles). B Cumulative proportion of patients reaching normal platelets during ten years following HOC and

ABMT/PSCT.

' 53

Chapter 3

1 20 0

1 1 0

1 00

90

80

70 N= 60 108 1 05 94 73

pre 1 /2 1 2 3

�� 0

62 45 4 5

time (years)

31 6

26 7

@2� 0

20 1 1 1 0 8 9 1 0

Figure 4 . MCV during ten years following HDC and ABMT/PSCT. Boxplot shows the median, interquartile range and outliers (circles). 'Pre' denotes value just prior to HDC.

Time to trilineage recovery

Figure 5 shows the cumulative proportion of patients reach i ng complete tri l i neage recovery in

time after transplantation. One year after transplantation only 3 1 % of patients had reached fu l l

tri l i neage recovery. Three a n d five years after transplantation these figures were 70% a n d 85%,

respectively.

No secondary graft fai lure was observed. No dependency of b lood or platelet transfusion was

seen beyond six months of fol low-up. No myelodysplasia nor leukaemia were encountered.

Analysis of factors influencing trilineage recovery and MCV

The tri l i neage recovery with a cyclophosphamide-based regimen as compared to a mitoxantrone­

based regimen was not different ( log-rank p=0.38) . The probabi l ity of reach ing fu l l tri l i neage

recovery was lower for patients treated with two high-dose regi mens ( log-rank p=0.0076)

compared to patients treated with one regimen (F igure 6). No differences cou ld be found in long­

term tri l i neage recovery between patients receiving bone-marrow, peripheral stem-cel ls or both

as source of haematopoietic stem-cel ls . The number of patients with relapsed germ-cel l tumours

and ovarian carcinoma was too sma l l compared to the number of patients with breast cancer to

detect d i fferences between d iagnoses. Us ing a Cox mu lti p le regression model no s ign ificant

relations could be found between age (p=0.40) or amount of rei nfused stem-cel ls (p=0. 1 9) and

Long-term haematological recovery following high-dose chemotherapy

1 ,0

i'::' Q) > 8 � ,8 Q) Cl ca Q) £ E

,6 Cl C:

£ ca � .!!3 ,4 C:

� ca c.. 0 C: 0 ,2 'E 8-e c..

0,0

0 2 3 4 5 6 7 8 9 1 0

time (years)

Figure 5. Cumulative proportion of patients reaching trilineage recovery in ten years following HOC and ABMT/PSCT.

- · 1 ,0

i'::' r - -+ Q) r - - - -r- -> 8 . -� ,8 Q) 1"'" _ .J single Cl ca

I Q) .5

I '.5 Cl ,6 I C:

I £ double ca

, - J � Cl)

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.- - J :.::, ca c.. 0 I C: I 0 ,2 'E .,.. J 8-e I log-rank p=0.0076 c.. I

0,0

0 2 3 4 5 6 7 8 9 1 0

time (years)

Figure 6. Cumulative proportion of patients treated with a single (n= 1 1 9) or double (n= 1 2) transplantation reaching trilineage recovery in ten years following HOC and ABMT/PSCT.

I ss

Chapter 3

time to full trilineage recovery. Median dose of reinfused cells in our population was 12 (range 3.3-28.8) x 106 CD34+ cells/kg body weight. All patients treated with one course of HDC and PSCT (n=55) received more than 3.3 x 1 06 CD34+ cells/kg body weight. There was no relation between use of haematopoietic growth factors and probability of reaching long-term full trilineage recovery or normalisation of WBC.

During the whole follow-up period median MCV was supranormal. In the first four years after transplantation median MCV was higher in patients treated with double transplantations versus single transplantations (MCV 101 . 7 versus 94.5 after one year (p<0.001 ), MCV 99.4 versus 93.2 after two years (p=0.002), MCV 1 00 versus 92 .7 after three years (p=0.004) and MCV 1 00.2 versus 93.2 after four years (p=0.046)). Beyond four years the number of patients having received double transplantations was too small for comparison. MCV was significantly higher one year after transplantation in the group of patients treated with a mitoxantrone-based regimen versus a cyclophosphamide-based regimen (MCV 96.0 versus 93.5 (p=0.01 2)). Beyond one year no significant differences were found, although MCV remained higher in the mitoxantrone treated patients. No differences in MCV were seen when age, number of reinfused stem-cells or source of stem-cells was considered.

Discussion

HDC followed by ABMT or PSCT has increasingly been applied in the last decade for patients with high-risk or relapsed solid tumours in whom conventional therapy offers limited chance of cure. The value of this treatment has been shown for some haematological diseases, but with the exception of promising results from a phase 2 study with relapsed germ-cell tumours 1 °, this has not yet been shown for solid tumours. Since short-term mortality and morbidity is decreasing, it is important to have insight in the long-term effects of ABMT and PSCT, including long-term haematological recovery.

In the present study of 1 31 patients from a single institution surviving relapse-free for more than one year after HDC followed by ABMT or PSCT, it was observed that for the whole group it takes several years for haematological parameters (WBC, Hb and platelets) to normalise completely. We used the same criteria for normal haematological parameters as in most other studies that studied long-term haematological recovery.21 •28-30 After five years, 1 5% of patients in our study had still low values in one or more haematopoietic cell lineages. During the ten years of follow­up however, blood counts rose steadily. Hb was the first parameter to normalise, followed by WBC and platelets. This slow long-term recovery is not in accordance with other data suggesting full trilineage recovery within one year.2 1 ,23,24,27-32 Those data, however, are derived from

Long-term haematological recovery following high-dose chemotherapy

haematological malignancies mostly, with a maximum follow-up of one year and therefore not necessarily fully comparable with our long-term data from solid tumours.

Our study population showed an increased median MCV throughout the follow-up period. Median MCV was normal just before HOC and was increased six months after transplantation to the end of the follow-up period. In patients with a high MCV we never found vitamin B12 or folate deficiency nor thyroid or l iver dysfunction, to explain the raised MCV. The high MCV suggests increased haematopoiesis by increased destruction of erythrocytes. It could be part of some form of myelodysplasia, a smouldering disease sometimes leading to leukaemia. Whether changes in the haematopoietic microenvironment, which have been observed after transplantation are responsible for this phenomenon is subject for further research.39 During the fol low-up period, MCV was supranormal in roughly 25% of patients. The MCV was higher in patient receiving double transplantations and non-significantly higher in patients receiving single transplantations with a mitoxantrone-based regimen compared to a cyclophosphamide-based regimen. The elevated MCV is perhaps a sign of a more toxic regimen.

In a total follow-up of 558 patient-years, with 107 patients followed for more than two years, we did not encounter a single case of myelodysplasia (MD) or acute myeloid leukaemia (AML), the risk of which is reported to be increased following HOC with ABMT or PSCT.40-46 It is suggested that prolonged dysfunction of the haematopoietic system leads to the emergence of these secondary diseases,43'47 typically occurring between two and ten years after chemotherapy with the peak incidence after five years. Incidences up to 1 9.8% at ten years have been reported following transplantation for non-Hodgkin's lymphoma.41 The appearance of AML and MD seems to be more common after treatment of lymphomas with high-dose chemotherapy followed by ABMT or PSCT than of solid tumours and our results are in concordance with these data.42'44 The amount of CD34+ cells reinfused has been reported as a risk factor for AML and MD.41

Several factors have been found to influence short-term haematopoietic recovery of patients undergoing ABMT or PSCT. Factors most often reported are prior exposure to fewer cycles of conventional-dose chemotherapy, 2&,33,34,37,45 haematopoietic stem-eel I dose, 20,21 ,27-29,33,35-37,49 total body irradiation as part of the high-dose regime,20,23,49 the high-dose regimen,20•34 the use of haematopoietic growth factors, 20,33,50,51 underlying disease, 20,30,33,52 and age.28•30,49,52 Data about factors influencing the long-term haematopoietic reconstitution are largely unknown. Some data are available from patients with haematological malignancies or patients undergoing a l logenic transplantation, with in general a maximum follow-up of one year. Data extending beyond this period are even more scarce.

I s1

Chapter 3

We have stud ied factors i nfluenci ng long-term recovery fol lowi ng transp lantation. The factor

most often reported to i nfluence short-term recovery is the number of CD34+ cel l s reinfused. We

found no relationsh ip between the amount of rei nfused stem-cel ls and the t ime to long-term fu l l

tri l i neage recovery. Poss ib ly the explanation i s the use of a relatively h igh dose of CD34+ cel ls

as compared with the dose usua l ly rei nfused i n haematologica l patients. The med ian dose in our

population was 1 2 x 1 06 CD34+ cel l s/kg body weight. All patients received more than 3 .3 x 1 06

CD34+ cel ls/kg body weight. Data from other studies suggest a l i near correlation between short­

term haematological recovery and dose of CD34+ cel ls, but with a threshold of 2 .5-5 x 1 06

C D34+ cel l s/kg body weight.2 1 ,25,53 Rei nfusion of more CD34+ cel l s d id not result in faster

recovery in these studies . S i nce 98% of our popu lat ion received more than 5 x 1 06 CD34+

eel ls/kg, a correlation with long-term recovery was not to be expected.

S i nce the underlyi ng d iagnosis in 93% of our patient popu lation was breast cancer, it was not

poss ib le to study differences in recovery accord ing to underlying d isease. It has been shown that

u nderly i ng d isease i nfluences the short-t ime recovery of peripheral blood counts. Patients with

acute myelo id leukaemia recover s lower fol lowi ng H OC than pat ients w ith l ymphoma and

patients with sol id tumours have a faster short-term recovery compared with haematological

ma l ignancies, poss ibly reflecti ng an underly ing defect of the stem-cel l of the latter.20,30,49,52

S i nce 1 992, haematopoietic growth factors have been ava i lable and s ince then PSCT has been

i ncreasi ngly used i nstead of ABMT, l i m it ing ABMT to patients in whom it was imposs ib le to

col lect periphera l stem-cel l s . It has been shown that PSCT offers a quicker recovery with ear l ier

short-term recovery of peripheral b lood counts. 1 3 Our resu lts showed no d ifferences i n long-term

haematological recovery between patients receivi ng ABMT versus PSCT a lthough fol low-up with

ABMT was longer. There has been some concern that PSCT m ight be i nferior to ABMT i n terms

of long-term haematological recovery.54,55 Our data however suggest that peripheral stem-cel l s

are a safe and complete substitute for bone-marrow i n the long-term as source for stem-cel ls .

Our study a lso shows that secondary graft fa i lure did not occur after ABMT or PSCT.

We found no s ign ificant d ifferences between the s i ngle H OC reg i mens a lthough the

mi toxantrone-based regimen resu lted in an i n itia l ly i ncreased MCV. In autologous bone-marrow

transplantation, regimens us ing total body i rrad iation, busulphan, melphalan or BCNU have been

associated with slower short-term recovery.20,23,34

We found s ign ificant d ifferences in haematological recovery fol lowi ng one compared with two

transplantations. This suggests (part ia l ) recovery from original bone-marrow after a single course

of H OC, with a h igher contr ibution from the transplant after double transplantation. Another

5s I

Long-term haematological recovery following high-dose chemotherapy

explanation could be that damage to the marrow microenvironment (stroma) caused by the HOC results in slower haematological recovery. This stroma has an important role in the production of sufficient bone-marrow cells. 1 9,39,48

Growth factors may also influence long-term recovery, as indicated by delayed recovery when GM-CSF is not administrated.20 We found no differences in long-term recovery comparing patients treated with growth factors after transplantation and those who were not.

Prolonged dysfunction of the haematopoietic system can lead to poor tolerance to subsequent myelotoxic treatments. Few data are available concerning this subject. Brice et al.23 showed that chemotherapy for relapsing lymphoma after transplantation could be instituted without an increase in haematological toxicity. However, in this study it was more difficult to give additional chemotherapy after transplantation to the subgroup of patients with late platelet recovery after transplantation. The impairment of haematological recovery that we found might have clinical implications in planning chemotherapy or radiotherapy in case of relapse after transplantation.

In conclusion, we found that complete trilineage recovery after ABMT or PSCT for solid tumours occurs, but slowly. A significant proportion of patients has subnormal values in one or more cell lineages up to ten years after transplantation. PSCT and ABMT are capable of maintaining long­term haematopoiesis after high-dose chemotherapy since no secondary failure was encountered. Slower recovery was seen with double transplantations. The results suggest lasting implications for bone-marrow function after autologous transplantation.

Acknowledgements

We thank BE Oosterhuis, JS Dijkstra, oncology nurses for their help in patient care and follow-up.

References

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l 59

Chapter 3

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peripheral blood stem cel l transplantation. Bone Marrow Transplant 1 999;23 :901 -5.

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20. Domenech J, L inassier C, Gihana E, et a l : Prolonged impairment of hematopoiesis after h igh-dose

therapy followed by autologous bone marrow transplantation. Blood 1 995;85:3320-7.

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23. Brice P, Marol leau JP, Pautier P, et al: Hematologic recovery and survival of lymphoma patients after

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cel ls. Leuk Lymphoma 1 996;22:449-56.

24. Siena S, Bregni M, Di NM, et al: Durabi l ity of hematopoiesis fol lowing autografting with peripheral

blood hematopoietic progenitors. Ann Oneal 1 994;5:935-41 .

25. Begui n Y, Baudoux E, Sautois B, et a l : Hematopoietic recovery in cancer patients after transplantation

of autologous peripheral blood CD34+ cel ls or unmanipulated peripheral blood stem and progenitor

cel ls. Transfusion 1 998;38 : 1 99-208.

26. Bentley SA, Brecher ME, Powel l E, et al: Long-term engraftment fa i l ure after marrow ablation and

autologous hematopoietic reconstitution: differences between peripheral blood stem cel l and bone

marrow recipients. Bone Marrow Transplant 1 997; 1 9:557-63 .

27. Amigo ML, del Can izo MC, Cabal lero MD, et a l : Factors that i nfl uence long-term hematopoietic

function fol lowing autologous stem cel l transplantation. Bone Marrow Transplant 1 999;24:289-93.

28. Barbui T, Cortelazzo S, Rossi A, et al : Factors for rapid and sustained hematopoietic reconstitution by

circu lating progenitor-cel l transplantation in non-Hodgkin's lymphoma. Cancer Chemother Pharmacol

1 996;38 Suppl :S1 1 0-Sl 1 4.

29. Kiss JE, Rybka WB, Winkelstein A, et al : Relationship of CD34+ cel l dose to early and late hematopoiesis

following autologous peripheral blood stem cel l transplantation. Bone Marrow Transplant 1 997; 1 9:303-

1 0.

30. Rossi A, Cortelazzo S, Bel lavita P, et a l : Long-term haematological reconstitution following B EAM and

autologous transplantation of circu lating progenitor cel ls in non-Hodgkin 's lymphoma. Br J Haematol

1 997;96:620-6.

31 . Schwartzberg L, B i rch R, Blanco R, et al : Rapid and sustained hematopoietic reconstitution by peripheral

blood stem cel l i nfusion alone fol lowing h igh-dose chemotherapy. Bone Marrow Tra nsplant

1 993; 1 1 :369-74.

32. Stewart FM, Temeles D, Lowry P, et al: Post-5-fl uorouracil human marrow: stem cell characteristics

and renewal properties after autologous marrow transplantation. B lood 1 993;81 :2283-9.

33. Bensinger W, Appelbaum F, Rowley S, et al: Factors that infl uence col lection and engraftment of

autologous peripheral-blood stem cel ls. J Clin Oneal 1 995;1 3:2547-55.

I s1

Chapter 3

34. Dreger P, Kloss M, Petersen B, et a l : Autologous progenitor cel l transplantation: prior exposure to stem

cel l-toxic drugs determines yield and engraftment of peripheral blood progenitor cel l but not of bone

marrow grafts. B lood 1 995;86:3970-8.

35. Olivieri A, Offidani M, Montanari M, et al: Factors affecting hemopoietic recovery after high-dose

therapy and autologous peripheral blood progenitor cel l transplantation: a single center experience.

Haematologica 1 998;83 :329-37.

36. Perez SJ, Cabal lero MD, Corral M, et al: Min imal number of c i rcu lating CD34+ cel ls to ensure

successful leukapheresis and engraftment in autologous peripheral blood progenitor cel l transplantation.

Transfusion 1 998;38:385-91 .

37. Tricot G, Jagannath S, Vesole D, et a l : Peripheral blood stem cel l transplants for multiple myeloma:

identification of favorable variables for rapid engraftment in 225 patients. B lood 1 995;85:588-96.

38. Bessman J D, Gi lmer PR, Gardner FH: Improved classification of anemias by MCV and ROW. Am J Cl in

Pathol 1 983;80:322-6.

39. Novitzky N, Mohamed R: Alterations in both the hematopoietic microenvironment and the progenitor

cel l population follow the recovery from myeloablative therapy and bone marrow transplantation. Exp

Hematol 1 995;23 : 1 661 -6.

40. Darrington DL, Vose JM, Anderson J R, et al: I ncidence and characterization of secondary

myelodysplastic syndrome and acute myelogenous leukemia fol lowing high-dose chemoradiotherapy

and autologous stem-cel l transplantation for lymphoid mal ignancies. J C l in Oneal 1 994; 1 2 :2527-34.

41 . Friedberg JW, Neuberg D, Stone RM, et al: Outcome in patients with myelodysplastic syndrome after

autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Cl in Oncol 1 999;1 7:3 1 28-35.

42. Kol lmannsberger C, Hartmann JT, Kanz L, Bokemeyer C: Risk of secondary myeloid leu kemia and

myelodysplastic syndrome fol lowing standard-dose chemotherapy or high-dose chemotherapy with

stem cel l support i n patients with potentia l ly curable mal ignancies. J Cancer Res C l in Oneal

1 998;1 24:207-1 4.

43. Mil ler JS, Arthur DC, Litz CE, et al: Myelodysplastic syndrome after autologous bone marrow

transplantation: an additional late complication of curative cancer therapy. B lood 1 994;83 :3 780-6.

44. Sobecks RM, Le Beau MM, Anastasi J, Wi l l iams SF: Myelodysplasia and acute leukemia fol lowing high­

dose chemotherapy and autologous bone marrow or peripheral blood stem cel l transplantation. Bone

Marrow Transplant 1 999;23: 1 1 61 -5 .

45. Traweek ST, Slovak ML, Nademanee AP, e t a l : Myelodysplasia and acute myeloid leukemia occurring

after autologous bone marrow transplantation for lymphoma. Leuk Lymphoma 1 996;20:365-72 .

46. Van Leeuwen FE: Risk of acute myelogenous leukaemia and myelodysplasia following cancer treatment.

Bai l l ieres Cl in Haematol 1 996;9:57-85.

47. Deeg HJ, Witherspoon RP: Risk factors for the development of secondary malignancies after marrow

transplantation. Hematol Oneal Cl in North Am 1 993;7:41 7-29 .

Long-term haematological recovery following high-dose chemotherapy

48. Del Canizo C, Lopez N, Vazquez L, et a l : Hematopoietic damage prior to PBSCT and its i nfluence on

hematopoietic recovery. Haematologica 1 999;84:5 1 1 -6.

49. Bensinger WI, Longin K, Appelbaum F, et al: Periphera l blood stem cel ls (PBSCs) col lected after

recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with

the tempo of engraftment after transplantation. Br J Haematol 1 994;87:825-3 1 .

50. lppol iti C, Przepiorka D, G i ra lt S, et a l : Low-dose non-glycosylated rhGM-CSF is effective for the

treatment of delayed hematopoietic recovery after autologous marrow or peripheral blood stem cel l

transplantation. Bone Marrow Transplant 1 993; 1 1 :55-9.

5 1 . Klumpp TR, Mangan KF, Goldberg SL, Pearlman ES, Macdonald JS: Granulocyte colony-st imulating

factor accelerates neutroph i l engraftment fol lowing periphera l-blood stem-cel l transplantation: a

prospective, randomized tria l . J Cl in Oncol 1 995; 1 3 : 1 323-7.

52. Rowley SD, Piantadosi S, Marcel lus DC, et al: Analysis of factors predicting speed of hematologic

recovery after transplantation with 4-hydroperoxycyclophosphamide-purged autologous bone marrow

grafts. Bone Marrow Transplant 1 99 1 ;7 : 1 83-91 .

53. Van der Wal l E . , Richel DJ, Holtkamp MJ, et a l : Bone marrow reconstitution after h igh-dose

chemotherapy and autologous peripheral blood progenitor cel l transplantation: effect of graft size. Ann

Oncol 1 994;5 :795-802 .

54. Spitzer G, Dunphy FR, Petruska PJ, Velasquez WS, Adkins DR: Tandem transplants in sol id tumors:

marrow versus peripheral stem cel l transplant: peripheral blood cel l s as now practiced are not the

whole answer. J Hematother 1 993;2 :363-5 .

55. Mauch P, Ferrara J, Hel lman S: Stem cel l self-renewal considerations in bone marrow transplantation. Bone Marrow Transplant 1 989;4:601 -7.

I 63

4

Factors influencing haematological recovery following high-dose

chemotherapy and peripheral stem-cell transplantation for

haematological malignancies: 1 -year analysis

P. Nieboer1 , E.G.E. de Vries 1 , E. Vellenga2, W.T.A. van der Graaf ,

N.H. Mulder1 , W.J. Sluiter3, J .Th.M. de Wolf2

1 Department of Medical Oncology, University Medical Center Groningen 2Department of Haematology, University Medical Center Groningen

3Department of Internal Medicine, University Medical Center Groningen

Eur J ancer 2004; 40: 1 1 99-1 207

Chapter 4

Summary

Peripheral blood counts and factors influencing haematological recovery in 98 patients with a relapse-free survival of 2::: 1 year treated with high-dose chemotherapy (HOC) and peripheral stem­cell transplantation (PSCT) for haematological malignancies were analysed.

One year after PSCT full haematological recovery was demonstrated for haemoglobin (Hb) in 47% of patients, for the white blood count (WBC) in 94% and for platelets in 64%; 39% had a trilineage recovery. In the multivariate analysis, recovery was influenced by age (p=0.002), number of reinfused C034+ cells (p=0.016), Hb at start of HOC (p=0.001 ), and platelets at start of HOC (p=0.008).

One year following PSCT, 61 % of patients still have subnormal values in one or more haematopoietic cell lineage, suggesting a limited bone-marrow reserve. Long-term recovery is highly dependent on age, blood counts at start of HOC and number of reinfused C034+ cells without a threshold, all reflecting the residual function of bone-marrow before HOC. Reinfusing more C034+ cells can accelerate long-term haematological recovery.

66 I

Factors influencing haematological recovery

Introduction

High-dose chemotherapy (HOC) followed by peripheral stem-cell transplantation (PSCT) has

proven to be beneficial in selected patients with Hodgkin's disease and non-Hodgkin's

lymphoma.1 The consequence might be a defect in long-term haematopoiesis, which is reflected

by a reduced number of bone-marrow progenitors for as long as four to five years after

transplantation.2-5 Most investigators state that peripheral blood counts are normal in most patients

at one year after autologous transplantation.4•6

-1 0 Recently, however we showed that

haematological recovery in patients with solid tumours was incomplete in most at one year after

autologous transplantation and in a significant proportion years thereafter. 1 1

Factors influencing short-term haematological recovery (granulocytes ;? 0.5 xl 09/L and

untransfused platelets 2::: 20 xl 09/L) after autologous transplantation have been studied extensively,

but factors influencing long-term recovery (white blood count (WBC) 2::: 4 xl 09/L, platelets

2::: 1 50 x 109/L and haemoglobin (Hb) 2::: 7.45 mmol/L for females and 2::: 8. 7 mmol/L for males) are

largely unknown. The available data suggest that long-term recovery is dependent on the number

of CD34+ cells reinfused and the age of the patient.4•

6•

7•

1 0,

1 2 Whether delayed or incomplete

haematological reconstitution has functional consequences has not been systematically studied.

Although rarely described explicitly, it is well known that many patients who relapse after

autologous stem-cell transplantation display decreased haematological tolerance to reinduction

chemotherapy.1 3 In addition, radiotherapy after transplantation and infections during follow-up

might result in haematopoietic stress and temporary cytopenia.9 The observed abnormalities in

haematopoiesis could therefore lead to significant clinical problems in a selected group of

patients.

The present study analysed peripheral blood counts and mean corpuscular volume (MCV) at one

year after HOC and PSCT, and sought to define factors that determine long-term haematological

reconstitution after these two procedures.

Patients and methods

Patient characteristics All patients treated with HOC followed by PSCT at the Department of Haematology, University

Hospital Groningen, The Netherlands between June 1993 and June 2001 were analysed. Eighty­

nine out of a total of 162 patients survived relapse-free for at least one year after HOC and PSCT

and were evaluated for the present study.

I s1

Chapter 4

Mobilisation procedure and peripheral stem-cell harvest

Per ipheral stem-ce l l s were col lected fol lowi ng a d isease-oriented course of chemotherapy and

granu locyte-co lony stimu lati ng growth factor (G-CSF). Harvesti ng was performed via a dual­

l umen catheter us i ng a Hemonethi cs MCS+ pheres is machine. C034+ cel l s were stained us ing

a monoclonal anti-CD34 (anti HPCA-2) and quantified by flow cytometry (FACS Cal ibur; Becton

D ickinson Woerden, The Netherlands) . A target quantity of CD34+ cel ls of :2'.'. 2 x 1 06/kg body

weight was envisaged.

Supportive measures

None of the patients received blood or platelet transfusions i n the four weeks precedi ng PSCT.

Al l patients were treated with selective gut decontami nation during neutropen ia . Neither G-CSF

nor erytropoiet in was admin istered after PSCT. Platelets were transfused if the platelet count fel l

below 1 0 x 1 09/L o r if bleeding occurred. Erythrocytes were transfused if the Hb dropped below

five mmol/L or if the patient had symptomatic anaemia. Al l b lood products were i rradiated.

Stem-cell cryopreservation

The leukapheresis product was mixed with m in imal essentia l medium (MEM) conta in ing 20%

d i methyl su lfoxide. The final cel l suspens ion was transferred i nto freezi ng bags and frozen to

-40°C with a computer-contro l led cryopreservation device. The frozen cel l s were then transferred

i nto the l iquid phase of n itrogen and stored at -1 96°C.

Conventional chemotherapy and high-dose regimes

Conventional chemotherapy was defined as a chemotherapy regimen not fol lowed by rei nfusion

of stem-cel ls . H OC was defined as a regimen that was fol lowed by reinfusion of stem-cel ls . The

high-dose regimes were dependent on d iagnosis . Patients (n=1 2) with Hodgkin's d isease received

BEAM (carmusti ne 300 mg/m2 day one, etoposide 200 mg/m2 day two to five, cytarabi ne 1 00

mg/m2 day two to five and melphalan 1 40 mg/m2 day s i x) . 1 4 Patients with non-Hodgki n's

lymphoma ( N H L) received BEAM (n=36) or cyclophosphamide + TBI (total body i rrad iation)

(n=2, cyc lophosphamide 60 mg/kg for two days and TB I 9 Gy). 14 Patients with mu lt iple myeloma

(MM) received h igh-dose melphalan (n=3 7, melphalan 1 00 mg/m2) or cyclophosphamide + TBI

(n=8). 1 5 Patients with acute leukaemia received BEAM (n=1 ) or busu lphan + cyclophosphamide

(n=2, busulphan 4 mg/kg day one to four, cyclophosphamide 60 mg/kg day one to two). 1 6

Radiotherapy

Twenty-four patients received local radiotherapy because of bu lky disease or painfu l bone lesions

before H OC or in the year fol lowi ng H OC for pre-existent lesions.

68 I

Factors influencing haematological recovery

Stem-cell reinfusion Immediately before infusion, the cryopreserved peripheral stem-cells were rapidly thawed in a 40°C waterbath, aspirated in a laminar-flow cabinet and reinfused through a double lumen Hickman catheter. Premedication consisted of steroids and antihistamines.

Haematological determinations Hb, WBC, platelets and MCV were determinated by standard techniques using an automated Coulter particle count (Coulter Electronics Nederland, Mijdrecht, The Netherlands). Patients were considered to have reached short-term recovery when granulocytes were � 0.5 x109/L and untransfused platelets � 20 x109/ 1 . Long-term haematological recovery was defined as WBC � 4 x109/ 1 , platelets � 150 x 109/L and Hb � 7.45 mmol/L for females and � 8.7 mmol/L for males.4•6•7• 1 1 In the statistical analyses Hb was recalculated to a z-score because of the different normal Hb for males and females (z-score=Hbmeasured - Hbmean for normal/SD for normal Hb). Normal MCV was defined as 80-98 fl. 11• 1 7 Following recovery from transplantation, patients were seen in our hospital as outpatients at weekly to monthly intervals. Haematological recovery was examined in every blood count examined during the first year after PSCT.

Statistical analysis Many variables showed an asymmetrical distribution; therefore medians are presented. Haematological recovery was assessed using Kaplan-Meier probability curves and statistical comparison of curves was performed by the log-rank test. The prognostic value of different variables for probability of haematological recovery was assessed by univariate and multivariate analysis using the Cox multiple-regression model. A p<0.05 was considered statistically significant.

Results

Patient characteristics Median age at transplantation was 46.5 years (range 17-64 years) . Sixty-eight males and 30 females had been treated with HDC and PSCT. Patients had been diagnosed as follows: twelve Hodgkin's lymphoma, 38 N HL, 45 MM and three acute leukaemia. Patients had received a median of eight cycles (range 2-31) of conventional dose chemotherapy before HOC. Patients received a median 8.4 (range 1.57-51) x 106 CD34+ cells/kg body wt. Stem-cells were harvested in 1-5 days (median 1 ). Median 11.5 x 106 CD34+ cells/kg body wt were harvested during a pheresis day. Radiotherapy was given to 24 patients just before or in the year following PSCT.

I sg

Chapter 4

Peripheral blood counts and MCV

It appears that H b and platelet recovery conti nued to i mprove over time. Six months after PSCT

the median Hb was 7 .7 mmol/l (range 3 . 7 - 9.3), median WBC was 5 .3 x 1 09/l (range 1 .8 -

1 4. 1 ), median platelets were 1 3 6 x 1 09/l (range 7 - 338) and median MCV was 98.5 fl (range

79 - 1 1 3) ( Figures 1 -4). One year after PSCT these values were 8 . 1 mmol/l (range 5 .5 - 9 . 7) for Hb,

5.8 x 1 09/l (range 1 . 7 - 1 2 . 7) for WBC, 1 63 x 1 09/l (range 1 5 - 420) for platelets and 96 fl (range

79 - 1 1 6) for MCV. Approximately 25% of patients showed an elevated MCV from three months

fol lowi ng transplantation.

1 1 ...-----------------,

1 0

� 8

� 7

� 6 Cll ..c.

5

4 0

0

*ij! 0

0 § 0

0

0

3 ---�-------�------'

N= 68 68 66 67 68 30 30 30 30 30

male female

OHb 1 month

0Hb 3 months

.Hl 6 months

.Hb 9 months

.HJ 12 months

Figure 1. Haemog lobin (Hb) . Box and whisker plots of Hb for males and females during the twelve months following high-dose chemotherapy (HOC) and peripheral stem-cell transplantation (PSCT). The boxes on either side of the median (horizontal lines) indicate lower and upper quartiles. The whiskers indicate the closer of the 1 .5 x interquartile range of the minimum/maximum data points. Outlying points are plotted individually.

Factors influencing haematological recovery

16 0

0

0

0 0 8 12 § 0 0

0

::i" 0

E 8

4

0 N= 98 98 98 97 98

1 3 6 9 12

time (months}

Figure 2. White blood cell counts (WBC). Box and whisker plots of WBC during the twelve months fol lowing h igh-dose chemotherapy (HOC) and peripheral stem-cel l transplantation (PSCT) . The boxes on either side of the median (horizonta l l ines) ind icate lower and upper quarti les. The whiskers i ndicate the closer of the 1 .5 x interquartile range of the min imum/maximum data points. Outlying points are plotted i ndividually.

450

400

350

::i" 300

0

E 250

200

150

100

so

0 N=

0

98 98 98

time (months}

8 0

97 9

0

0

97 12

Figure 3. Platelets . Box and whisker plots of platelets during the twelve months following h igh-dose chemotherapy (HOC) and peripheral stem-cel l transplantation (PSCT) . The boxes on either side of the median (horizontal l ines) indicate lower and upper quartiles. The whiskers ind icate the closer of the 1 .5 x interquartile range of the min imum/maximum data points . Outlying points are plotted ind ividual ly.

I 11

Chapter 4

120

0 0

1 1 0

100 8 � 0

�

90

80 0 0 0 0 0

70 N= 98 97 97 97 96

6 1 2

time (months)

Figure 4. Mean corpuscular volume (MCV). Box and whisker plots of MCV during the twelve months following h igh-dose chemotherapy (HOC) and peripheral stem-cel l transplantation (PSCT). The boxes on either side of the median (horizontal lines) indicate lower and upper quartiles. The whiskers indicate the closer of the 1 .5 x interquartile range of the minimum/maximum data points. Outlying points are plotted individual ly.

Haematological recovery

Short-term recovery of granulocytes was observed after a median of 1 5 days (range 1 1 - 90) and of platelets after a median of 18 days (range 8 - 365). One year following PSCT 47% of patients had a normal Hb, 94% of patients had normal WBC, 64% had normal platelets and 39% had trilineage recovery. Recovery of WBC occurred first, followed by platelets and Hb (Figure 5). No dependency on blood or platelet transfusion was seen beyond six months of follow-up. No secondary myelodysplasia or leukaemia was encountered during the one-year follow-up.

Univariate analysis of variables influencing engraftment (Table 1 )

The results of a univariate analysis of variables affecting long-term recovery of Hb, WBC recovery, platelet recovery and trilineage recovery are shown in Table 1. Younger age, female sex, higher number of reinfused CD34+ cells and higher Hb at start of HDC were favourable factors that predict quicker long-term recovery of Hb. Diagnosis, higher number of CD34+ cells harvested per day, platelets and WBC at start of HDC influence long-term recovery of WBC. Furthermore it was demonstrated that female sex, higher number of reinfused CD34+ cel ls, higher number of CD34+ cells harvested per day, higher Hb and platelets at start of HDC are favourable factors predicting quicker long-term recovery of platelets. Trilineage recovery was faster in case of

Factors influencing haematological recovery

1,0

WBC Q)

ro ,8 ro 0 C

C ,6 Platelets

Hb C Q)

.4 Trilineage

C 0

,2

0,0 0 1 00 200 300 400 500

time (days)

Figure 5. Haematological recovery. Cumulative proportion of patients reaching normal haemoglob in (Hb) , white b lood cel l count (WBC), platelets and tri l ineage recovery in the twelve months fol lowing h igh-dose chemotherapy (HDC) and peripheral stem-cell transplantation (PSCT).

younger age, female sex, higher number of reinfused CD34+ cel ls and higher Hb and platelets at start of H DC.

Multivariate analysis of variables influencing long-term engraftment (Table 2)

To investigate independent factors with respect to haematological recovery, a multiple linear­regression analysis was performed. Al l variables with a p<0. 1 0 in the univariate analysis were included in the model . Stepwise backward el imination of variables from the regression model resulted in selection of variables significantly influencing long-term engraftment. Younger age, melphalan as HOC, higher number of reinfused CD34+ cel ls, and higher Hb at start of HOC were favourable factors predicting more rapid long-term recovery of Hb. Recovery of WBC was influenced by diagnosis (patients with MM had quicker recovery than patients with NHL and Hodgkin's disease) and WBC at start of HOC. Higher number of reinfused CD34+ cel ls, higher number of CD34+ cel ls harvested per day, higher Hb and platelets at start of HOC are favourable factors predicting long-term recovery of platelets. Tri l ineage recovery was more rapid in younger patients, patients with the higher number of reinfused CO34+ cel ls, and higher Hb and platelets at the start of HOC. In the multivariate analysis, long-term recovery was not influenced by sex (male versus female) or radiotherapy (yes/no).

I 13

Chapter 4

Table 1. Univariate analysis of factors influencing haematological recovery (P values)

Hb normal WBC normal Platelets normal Trilineage normal

Age (years) < 0.001 0.051 0 .333 0.0 13

Gender (male/female) < 0.001 0 . 1 59 0.002 < 0.001

Cycles of chemotherapy (number) 0 .553 0 .934 0.893 0.6 1 1 ----- -

High-dose chemotherapy (type) 0.088 0 .067 0.068 0.3 1 2

Radiotherapy (yes/no) 0.604 0 .645 0 .942 0.8 1 6 --- ---

Diagnosis (type) 0 .278 0.012 0. 1 65 0.401 - --

C034+ cel l s reinfused (number) 0.009 0 .346 0.001 0.003 -- -- --- ---

Pheresis (C034+ cells/day) 0.247 0.024 0.002 0. 1 33

Hb at start of HOC (z-score) < 0.001 0.051 0.001 < 0.001

Platelets at start of HDC (number) 0.064 0.008 < 0.001 0.020

WBC at start of HOC (number) 0 .378 0.001 0.70 1 0.697

Abbrevations and note: Numbers in bold type are statistically significant at the chosen P value. Hb, haemoglobin; WBC, white blood count; HOC, high-dose chemotherapy.

Table 2. Multivariate analysis of factors influencing haematological recovery (P values)

Hb normal WBC normal Platelets normal Trilineage normal

Age (years) < 0.001 0.895 0.002 ----

Gender (male/female) 0 . 1 08 0 .8 1 1 0 .064

H igh-dose chemotherapy (type) 0.003 0 .442 0.6 1 9

Diagnosis (type) 0.026 ---- - ---

C034+ cel ls reinfused (number) 0 .006 0.040 0.016 -- ---Pheresis (C034+ cells/day) 0 . 1 76 0.040

Hb at start of HDC (z-score) < 0.001 0.308 0.006 0.001

Platelets at start of HDC (number) 0 .087 0.092 < 0.001 0.008

WBC at start of HOC (number) 0.01 1

Abbrevations and note: Numbers in bold type are statistically significant at the chosen P value. Hb , haemoglobin; WBC, white blood count; HDC, high-dose chemotherapy.

14 I

Factors influencing haematolog1cal recovery

,7

,6 ro

Number of reinfused > ro p=0.22 CD34+ cells (x 1 06/kg) E ,5 0 C:

p=0.01

.4

p=0.08 - > ID C: ,3 .!!:!

C.

,2 C: - 5-10 0

0 C.

C. ,1

- o-5

100 200 300 400 500 600 700 800

time (days)

Figure 6. CD34+. Influence of number of reinfused CD34+ cel ls on long-term (one year) trilineage recovery.

Figure 6 shows the differences in the proportions of patients reaching complete trilineage recovery in the first year after transplantation, according to the number of reinfused CD34+ cells (< 5 x 106/kg body wt versus 5-10 x 106/kg body wt, log-rank p=0.08; 5-10 x 106/kg body wt versus > 10 x 106/kg body wt, log-rank p=0.22; < 5 x 106/kg body wt versus > 10 x 106/kg body wt, log-rank p=0.01 ).

Discussion

HOC followed by the infusion of autologous stem-cells has increasingly been applied in the last decade for patients with high-risk or relapsed haematological malignancies. 1 Long-term (haematological) side effects of this treatment are largely unknown, and indeed as a significant proportion of treated patients will require second-line chemotherapy, these long-term sequelae are worth studying.

In the present study of 98 patients with haematological malignancies, we investigated the factors that influence long-term haematological reconstitution after PSCT. The same criteria were used for normal haematological recovery as in a number of other studies that analysed long-term haematological recovery. 4•6•7• 1 1 • 1 8

I 1s

Chapter 4

In the present study, short-term haematological recovery following HOC and PSCT was reached in approximately two weeks, which is in accord with other studies. In contrast to short-term recovery, long-term haematological recovery was slow. Nearly all patients had a normal WBC one year after PSCT, but at that time 36% still had low platelets, 53% had low Hb and only 39% of patients had full trilineage recovery. Few data exist concerning long-term haematological recovery. Most investigators suggest there can be complete haematological recovery at one year after transplantation.4•6-1 0 However, more detailed study of the available data shows that in many patients haematological recovery is slower. In a study by Haas et al. in 93 patients with haematological malignancies, it is estimated from the given data that no more than 70% of patients had reached normal platelet count after a follow-up of ten months.4 In a study by Barbui et al. in 5 7 patients with NHL, trilineage long-term recovery was reached in 33 patients (58%) after a median follow-up of 11 7 days. The WBC was the first measure to recover, Hb being the last.6 In a study of Rossi et al. in 63 patients with NHL, approximately 80% of patients treated in first line reached trilineage recovery at one year compared to 60% of patients treated in relapse/resistance.7 In a study by Schwartzberg et al. in 52 patients with haematological and solid malignancies, it was shown that for the 26 patients alive one year after reinfusion the mean peripheral blood counts were normal, 8 but the range demonstrates that some patients had abnormally low counts after one year. Siena et al. describe that all patients reached "normal haematopoiesis" after approximately one year.9 In accordance with the results of the current study and an earlier study in patients with solid tumours, 1 1 however, Amigo et al. found, that among 79 patients 42.4% had one or more abnormal peripheral cell lineages after one year. 1 0

Considerable problems arise from the assessment of these data. Most studies contain small numbers of patients from whom long-term data are available, not all studies use the same criteria for long-term engraftment and sometimes data from patients with active disease and data from those receiving active treatment are included. In contrast, all of the 98 patients presented in the current study were in complete remission after PSCT. Radiotherapy was given to 32 patients just before or in the year following PSCT.

In our study, roughly 25% of patients displayed an elevated MCV throughout the follow-up period, in accordance with our earlier results. 1 1 Although not routinely determined in all patients with elevated MCV, we never found deficiencies of folate or vitamin 812, nor did we encounter patients with thyroid dysfunction that could explain the elevated MCV. The elevated MCV could be part of some smouldering form of myelodysplasia. None of the patients, however, developed manifest myelodysplasia or secondary acute myeloid leukaemia in the year following PSCT, the risk of which is described to be increased following HOC with PSCT.1 9-24 It is suggested that

Factors influencing haematological recovery

prolonged dysfunction of the haematopoietic system is a risk factor for the emergence of these secondary diseases.2 1 •22

We have studied several factors that could influence long-term haematological recovery fol lowing HDC and PSCT. In the multivariate analysis we found a clear correlation between long-term recovery and age, number of reinfused CD34+ cel ls and the blood count at start of HDC. Recovery of Hb was also relatively accelerated by melphalan used as HOC and recovery of WBC by a diagnosis of MM. Other factors such as radiotherapy, number of preceding conventional­dose chemotherapy cycles and sex did not influence haematological recovery in the multivariate analysis. It is difficult to compare these results with published data. Most studies on haematological recovery contain data on short-term recovery only.3•7•25-29 Most of these studies found a correlation with stem-cel l source (with bone-marrow delayed recovery versus peripheral stem-cel ls), number of reinfused stem-cel ls and use of haematopoietic growth factors, but factors such as age, use of radiotherapy, type of high-dose regimen and number of preceding conventional-dose chemotherapy cycles also influenced short-term recovery. A relation between long-term haematological recovery and the number of reinfused stem-cel ls has been suggested for doses up to 8 x 1 06 C034+ cel ls/kg body wt.4•6•1 0•1 2 Also, a relation has been observed with age and number of days to reach short-term recovery.6•7 Our finding of a relation between long­term haematological recovery and haematological status at the start of HDC has not been described before. This probably reflects the residual function of bone-marrow progenitors preceding therapy.

The number of stem-cel ls required for optimal short-term recovery is considered to be 2 .5-5 x 1 06

C034+ cel ls/kg body wt.4•29-3 1 Reinfusion of more stem-cel ls does not result in more rapid recovery. We showed, however, that for long-term recovery this threshold of 2.5-5 x 1 06 C034+ cel ls/kg body wt does not apply. When more than 1 0 x 1 06 CD34+ cel ls/kg body wt were reinfused, long-term recovery was sti l l accelerated. It is l ikely that the explanation is related to the type and function of the progenitor measured with the assay. The number of CD34+ cel ls reflects the committed stem-cel l that is critical for short-term engraftment.32 While more mature stem-cel ls are necessary for the short-term recovery with a clear threshold, long-term recovery is more dependent on more immature stem-cel ls. Apparently 2.5-5 x 1 06 CD34+ cel ls/kg body wt contain enough stem-cel ls for optimal short-term, but not enough immature stem-cel ls for optimal and fast long-term haematological recovery.

These results could have important implications for clinical practice in HOC and PSCT. Most factors shown to influence long-term haematological recovery, such as diagnosis, age and blood counts at start of HDC are not under the control of the transplant physician. However, it is

I n

Chapter 4

possible to harvest and subsequently reinfuse more stem-cells in those patients with the most negative risk factors for delayed long-term haematological recovery. Accelerating recovery could facilitate optimal dosing for new chemotherapy and radiotherapy in recurrent disease. Prolonged dysfunction of the haematopoietic system could lead to poor tolerance to subsequent myelotoxic treatments. Few clinical data are available on this subject. Brice et al. showed in 150 patients with Hodgkin's disease or NHL, that chemotherapy for relapsing lymphoma following autologous transplantation could be instituted without an increase in haematological toxicity. 1 3 However, they also demonstrated that it was more difficult to give additional chemotherapy after transplantation to the subgroup of patients with delayed platelet recovery. The impairment of haematological reconstitution that we observed might thus have clinical implications in planning full-dose chemotherapy or radiotherapy in relapse after transplantation.

On the other hand, the risk of tumour relapse might be increased when more stem-cells are reinfused. Data on this subject are conflicting. Peripheral blood can contain tumour cells. The clinical value of the presence of these tumour cells in the stem-cell harvest is not yet clear. It is shown in gene-marking studies that recurrent disease can originate from cells reinfused during autologous transplantation.33,34 However, there are no data showing a direct relation between the number of reinfused stem-cells and the chance of recurrent disease. Reinfusing more stem­cells might also have positive effects on immune reconstitution that might have a positive effect in deleting malignant cells after transplantation.35

In conclusion, in the present study long-term haematological recovery following HOC and PSCT was slow. One year after PSCT, 61% of patients have still subnormal values in one or more cell lineages, suggesting a limited residual bone-marrow reserve. Long-term recovery is highly dependent on age, number of reinfused CD34+ cells without a threshold and blood counts at start of HOC, all reflecting residual bone-marrow function before HOC. These data give further support to the concept of dual haematological recovery associated with progenitors at different stages of maturation following PSCT. Furthermore, they show that reinfusing more CD34+ cells can accelerate long-term haematological recovery.

Acknowledgements

Supported in part by a grant from the Dutch College for Health Care Assurances, The Netherlands (CVZ).

Factors influencing haematological recovery

References

1 . Mink SA, Armitage JO: High-dose therapy in lymphomas: a review of the current status of a l logeneic

and autologous stem cel l transplantation in Hodgk in ' s disease and non-Hodgkin 's lymphoma.

Oncologist 2001 ;6:247-56.

2. del Canizo C, Lopez N, Cabal lero D, et al: Haematopoietic damage persists 1 year after autologous

peripheral blood stem cel l transplantation. Bone Marrow Transplant 1 999;23 :901 -5.

3. Domenech J, L inassier C, G ihana E, et al: Prolonged impairment of hematopoies is after h igh-dose

therapy fol lowed by autologous bone marrow transplantation. B lood 1 995;85:3320-7.

4. Haas R, Witt B, Mohle R, et al: Susta ined long-term hematopoiesis after myeloablative therapy with

peripheral blood progenitor cel l support. B lood 1 995;85:3 754-61 .

5. Vel lenga E, Sizoo W, Hagenbeek A, Lowenberg B: D ifferent repopu lation kinetics of erythroid (BFU­

E), myeloid (CFU-GM) and T lymphocyte (TL-CFU) progenitor cel l s after autologous and a l logeneic

bone marrow transplantation. Br J Haematol 1 987;65 : 1 3 7-42 .

6 . Barbui T , Cortelazzo S , Rossi A, et a l : Factors for rapid a n d susta ined hematopoietic reconstitution by

circu lating progenitor-cel l transplantation in non-Hodgkin 's lymphoma. Cancer Chemother Pharmacol

1 996;38 Suppl :S1 1 0-S1 1 4.

7. Rossi A, Cortelazzo S, Bel lavita P, et a l : Long-term haematological reconstitution fol lowing B EAM and

autologous transplantation of circulating progenitor cel l s in non-Hodgkin ' s lymphoma. Br J Haematol

1 997;96:620-6.

8. Schwartzberg L, B i rch R, B lanco R, et al: Rapid and sustained hematopoietic reconstitution by peripheral

b lood stem cell infusion alone fol lowing h igh-dose chemotherapy. Bone Marrow Transplant

1 993; 1 1 :369-74.

9. Siena S, Bregni M, Di NM, et al: Durabi l ity of hematopoiesis fol lowing autografting with peripheral

blood hematopoietic progenitors. Ann Oncol 1 994;5 :935-41 .

1 0. Amigo ML, del Can izo MC, Cabal lero MD, et a l : Factors that i nfl uence long-term hematopoietic

function fol lowing autologous stem cel l transplantation. Bone Marrow Transplant 1 999;24:289-93 .

1 1 . N ieboer P, de Vries EG, Mulder NH, et a l : Long-term haematological recovery fol lowing h igh-dose

chemotherapy with autologous bone marrow transplantation or peripheral stem cel l transplantation in

patients with sol id tumours. Bone Marrow Transplant 2001 ;27:959-66.

1 2. To LB, Roberts MM, Haylock DN, et al: Comparison of haematological recovery times and supportive

care requ irements of autologous recovery phase peripheral b lood stem cel l transplants, autologous

bone marrow transplants and al logeneic bone marrow transplants. Bone Marrow Transplant

1 992;9:2 77-84.

1 3. Brice P, Marol leau J P, Pautier P, et al: Hematologic recovery and surviva l of lymphoma patients after

autologous stem-cel l transplantation: comparison of bone marrow and periphera l blood progenitor

cel ls. Leuk Lymphoma 1 996;22:449-56.

I 19

Chapter 4

1 4. Vellenga E, van Agthoven M, Croockewit AJ, et a l : Autologous peripheral blood stem cell transplantation

in patients with relapsed lymphoma results in accelerated haematopoietic reconstitution, improved

qual ity of l ife and cost reduction compared with bone marrow transplantation: the Hovon 22 study. Br

J Haematol 200 1 ; 1 1 4 :3 1 9-26.

1 5. Hovenga S, de Wolf JT, Guikema J E, et al: Autologous stem cel l transplantation in multiple myeloma

after VAD and EDAP courses: a h igh i ncidence of ol igoclonal serum lgs post transplantation. Bone

Marrow Transplant 2000;25 :723-8.

1 6. Vel lenga E, van Putten WL, Boogaerts MA, et al: Peripheral b lood stem cel l transplantation as an

alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia? Bone

Marrow Transplant 1 999;23 : 1 279-82.

1 7. Bessman J D, G i lmer PR, Gardner FH: Improved classification of anemias by MCV and RDW. Am J Cl in

Pathol 1 983;80:322-6.

1 8. Kiss J E, Rybka WB, Winkelstein A, et al: Relationship of CD34+ eel I dose to early and late hematopoiesis

fol lowing autologous peripheral b lood stem cel l transplantation. Bone Marrow Transplant 1 99 7; 1 9:

303-1 0.

1 9. Friedberg JW, Neuberg D, Stone RM, et al: Outcome in patients with myelodysplastic syndrome after

autologous bone marrow transplantation for non-Hodgkin 's lymphoma. J Cl in Oncol 1 999; 1 7:3 1 28-35.

20. Kol l mannsberger C, Hartmann JT, Kanz L, Bokemeyer C: Risk of secondary myeloid leukemia and

myelodysplastic syndrome fol lowing standard-dose chemotherapy or high-dose chemotherapy with

stem cel l support in patients with potentia l l y curable mal ignancies. J Cancer Res C l in Oncol

1 998; 1 24:207-1 4.

21 . Mi l ler JS, Arthur DC, Litz CE, et a l : Myelodysplastic syndrome after autologous bone marrow

transplantation: an additional late compl ication of curative cancer therapy. B lood 1 994;83 :3 780-6.

22. Sobecks RM, Le Beau MM, Anastasi J, Wi l l iams SF: Myelodysplasia and acute leukemia fol lowi ng high­

dose chemotherapy and autologous bone marrow or periphera l blood stem cel l transplantation. Bone

Marrow Transplant 1 999;23 : 1 1 61 -5.

23. Traweek ST, Slovak ML, Nademanee AP, et al : Myelodysplasia and acute myeloid leukemia occurring

after autologous bone marrow transplantation for lymphoma. Leuk Lymphoma 1 996;20:365-72 .

24. Van Leeuwen FE: Risk of acute myelogenous leukaemia and myelodysplasia fol lowing cancer treatment.

Ba i l l ieres C l in Haematol 1 996;9:5 7-85.

25. Bensinger W, Appelbaum F, Rowley S, et a l : Factors that i nfluence col lection and engraftment of

autologous periphera l-blood stem cel ls . J C l in Oncol 1 995; 1 3 :2547-55 .

26. Dreger P, Kloss M , Petersen B , et a l : Autologous progenitor cel l transplantation: prior exposure t o stem

cel l-toxic drugs determines yield and engraftment of periphera l blood progenitor cel l but not of bone

marrow grafts. B lood 1 995;86:3970-8.

Factors influencing haematolog1cal recovery

27. Ol ivieri A, Offidani M, Montanari M, et a l : Factors affecting hemopoietic recovery after h igh-dose

therapy and autologous peripheral blood progenitor cel l transplantation: a s ingle center experience.

Haematologica 1 998;83 :329-3 7.

28. Tricot G, Jagannath S, Vesole D, et al: Peripheral blood stem cel l transplants for multiple myeloma:

identification of favorable variables for rapid engraftment in 225 patients. Blood 1 995;85:588-96.

29. Bensinger WI, Longin K, Appelbaum F, et al: Peripheral blood stem cel ls (PBSCs) col l ected after

recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with

the tempo of engraftment after transplantation. Br J Haematol 1 994;87:825-3 1 .

30. Van der Wal l E. , Richel DJ, Holtkamp MJ, et a l : Bone marrow reconstitution after h igh-dose

chemotherapy and autologous peripheral blood progenitor cel l transplantation: effect of graft size. Ann

Oncol 1 994;5:795-802 .

31 . Weaver CH, Hazelton B, B i rch R, et a l : An analysis of engraftment kinetics as a function of the CD34

content of peripheral blood progenitor cel l col lections in 692 patients after the admin istration of

myeloablative chemotherapy. B lood 1 995;86:3961 -9 .

32 . Domenech J, Roingeard F , B inet C : The mechanisms i nvolved in the impairment of hematopoiesis after autologous bone marrow transplantation. Leuk Lymphoma 1 997;24:239-56.

33. Brenner MK, R i l l DR, Moen RC, et al: Gene-marking to trace origin of relapse after autologous bone­

marrow transplantation. Lancet 1 993;341 :85-6.

34. Heslop HE, Rooney CM, R i l l DR, Krance RA, Brenner MK: Use of gene marking in bone marrow

transplantation. Cancer Detect Prev 1 996;20: 1 08-1 3 .

35. Barret J, Mavroudis D: Cel l u lar component therapy: stem cel ls, graft-faci l itating cel ls, and graft-versus­tumor cel ls. In Atkinson K, ed. C l in ical Bonemarrow and B lood Stem Cel l Transplantation, 3nd edn.,

Cambridge University Press, 2000, 1 259-68.

I 8 1

5 Fatigue and relating factors in high-risk breast cancer

patients treated with adjuvant standard or high-dose

chemotherapy: a longitudinal study

P. Nieboer1 , C. Buijs1 , S. Rodenhuis2, C. Seynaeve3, L.V.A.M. Beex4, E. van der Wal l5,

D.J. Richel6, M.A. Nooij7, E .E. Voest8, P. Hupperets9, N.H. Mulder1 , W.T.A. van der Graafl ,

E.M. TenVergert1 , H. van Tinteren2, E .G.E. de Vries1

1Department of Medical Oncology, U niversity Medical Center Groningen 2Department of Medical Oncology, The Netherlands Cancer Institute Amsterdam

3Department of Medical Oncology, Erasmus Medica.l Center/Daniel den Hoed Cancer

Center Rotterdam 4Department of Medical Oncology, University Medical Center Nijmegen 5Department of Medical Oncology, Free U niversity Hospital Amsterdam

6Department of Medical Oncology, Medical Spectrum Enschede 7Department of Medical Oncology, Leiden U niversity Medical Center

8Department of Medical Oncology, University Medical Center Utrecht

9Department of Medical Oncology, U niversity Hospital Maastricht

J Clin Oneel 2005; 23: 8296-9302

Chapter 5

Summary

Determine whether standard or high-dose chemotherapy leads to changes in fatigue, hemoglobin (Hb), mental health, muscle and joint pain, and menopausal status from pre- to post-treatment and to evaluate whether fatigue is associated with these factors in disease-free breast cancer patients.

Eight hundred eighty-five patients were randomly assigned between two chemotherapy regimens both followed by radiotherapy and tamoxifen. Fatigue was assessed using vitality scale (score � 46 defined as fatigue), poor mental health using mental health scale (score � 56 defined as poor mental health) both of Short-Form 36, muscle and joint pain with Rotterdam Symptom Checklist, and Hb levels were assessed before and one, two and three years after chemotherapy.

Fatigue was reported in 20% of 430 evaluable patients (202 standard-dose, 228 high-dose) with at least a three-year follow-up, without change over time or difference between treatment arms. Mean Hb levels were lower following high-dose chemotherapy. Only 5% of patients experienced fatigue and anemia. Mental health score was the strongest fatigue predictor at all assessment moments. Menopausal status had no effect on fatigue.

Linear mixed effect models showed that the higher the Hb level (p=0.0006) and mental health score (p<0.0001 ), the less fatigue was experienced. Joint (p<0.0001 ) and muscle pain (p=0.0283) were associated with more fatigue.

In three years after treatment, no significant differences in fatigue were found between standard and high-dose chemotherapy. Fatigue did not change over time. The strongest fatigue predictor was poor mental health.

a4 I

Fatigue and relating factors in high-risk breast cancer patients

Introduction

Adjuvant chemotherapy is being increasingly administered to women with breast cancer, because it delays disease recurrence and improves long-term survival. High-dose chemotherapy strategies aim at further improving disease-free and overall survival in high-risk breast cancer patients. Studies carried out thus far have yielded varying results. 1 ·3 In the Dutch randomized study, patients treated with adjuvant standard-dose or high-dose chemotherapy followed by autologous peripheral stem cell transplantation were compared.2 This study showed an advantage for high­dose chemotherapy, particularly for patients with HER2/neu negative tumors and those with more than nine positive axillary lymph nodes.2

Relatively little is known, however, about the long-term effects of both standard and high-dose adjuvant therapy in terms of the patient's wel l-being. A growing body of evidence indicates that breast cancer survivors experience a variety of problems. A recent review reported that many cancer survivors report fatigue after the completion of cancer treatment.4 This symptom is reported to be highly distressing to the patients and a limiting factor in the quality of life. Studies in which fatigue has been investigated in treated, disease-free breast cancer patients are rare.5·1 1 Moreover, these small, cross-sectional studies mainly consist of heterogeneous samples of cancer survivors with regard to tumor stage or previous treatment. A better understanding of long-term fatigue in cancer survivors is, thus, fundamental to the development of appropriate intervention strategies. 1 2

A low hemoglobin (Hb) level is generally considered to be a possible reason for fatigue. Several studies in cancer patients investigated the relationship between Hb level and fatigue, but the results, mainly performed during cancer treatment, are not unequivocal. 13•15 Other reasons for the existence of fatigue in cancer patients are depression and pain. Servaes et al.,4 for example, concluded that the influence of these factors on fatigue are highly consistent across several studies. The shifts in menstrual status, caused by the therapy from premenopausal at diagnosis to postmenopausal, may also have an impact on fatigue experienced by breast cancer patients.

The purpose of this prospective, longitudinal study is to analyze whether standard or high-dose chemotherapy leads to changes in fatigue, Hb, mental health, pain (i.e., muscle and joint), and menopausal status from pre- to post-treatment and to evaluate whether fatigue is associated with these factors in disease-free breast cancer patients.

I 85

Chapter 5

Patients and Methods

Study Population E l igible patients participated in the Dutch randomized multicenter adjuvant breast cancer c l in ical

trial and the accompanying qual ity of l i fe study. Recruitment detai l s and study procedures of the

Dutch adjuvant breast cancer c l in ical tria l have been publ ished p reviously.2 The present analysis

i ncluded patients with at least three years of fol low-up and who were without c l in ical evidence

of disease recurrence.

Clinical Trial Patients younger than 56 years of age with stage II and I l l breast cancer were el ig ible, if they had

four or more positive axi l lary lymph nodes, a normal chest x-ray, normal bone-scan, normal l iver

sonogram, a WHO performance status of O or 1 , and no prior treatment other than surgery. The

study compared standard-dose chemotherapy consisti ng of f ive cycles of five fl uorouraci l

500 mglm2, epi rubicin 90 mg/m2 and cyclophosphamide 500 mglm2 (FEC) with four cycles of FEC

p lus one cycle of h igh-dose chemotherapy consisti ng of cyclophosphamide 6 g/m2, thiotepa

480 mglm2 and carboplati n 1 600 mg/m2 admin istered over fou r days, fol lowed by peripheral

stem-cel l reinfusion on day seven. After chemotherapy, treatment in both arms consisted of local

radiotherapy and 40 mg tamoxifen da i ly, during two years, and from 1 998 onwards, during five

years. 12 Fol lowing chemotherapy, patients were seen on an outpatient basis at a three-month

i nterval during the first two years and biannua l ly thereafter. Patients el igible for the c l in ical tria l

were also asked to participate i n the qual i ty of l i fe study.

The study was approved by the Medica l Eth ical Committees of a l l partic ipati ng centers. A l l

patients gave informed consent.

Quality of Life Assessments Participating patients were asked to complete a qual ity of l ife questionnaire at several fol low-up

points. This questionnaire i ncluded questions about the socio-demographic characteri stics of the

patients i nc lud ing age, whether they have a partner, level of education, number of chi ldren l iving

at home, and paid employment. Furthermore, the Rotterdam Symptom Checkl ist, the Short-Form

36 (SF-36), the self-report vers ion of the Karnofsky Performance Index, Visual Analogue Scale

evaluation of overal l health-related qual ity of l ife, and a questionnaire about costs made by the

patients were i ncluded. 1 6•1 7 The questionnaire was sent to the participants by mai l before random

assignement, directly after chemotherapy, after radiotherapy, and every half-year thereafter. The

data obtained at random assignment and after one, two and three years were analyzed. A l l

Fatigue and relating factors in high-risk breast cancer patients

patients had completed chemotherapy and radiotherapy at the one-year time point. Fatigue and mental health were assessed by the SF-36.

Standard procedures were employed to compute the score for the subscale vitality and mental health of the SF-36. The subscale vitality is composed of four items: felt full of pep, had a lot of energy, felt worn out, and felt tired. The subscale mental health is composed of five items: been a very nervous person, felt so down in the dumps nothing could cheer you up, felt calm and peaceful, felt downhearted and blue, and been a happy person. These items were assessed in a six-point Likert scale to determine how the patients experienced these symptoms during the last four weeks. 1 7 The scores range from O to 1 00, with higher scores representing higher functional level (ie, less fatigue/vitality and better mental health status). General Dutch population norms are available for the SF-36. 1 8 The mean vitality score for Dutch women (reference value) is 66 and the standard deviation (SD) is 20. Fatigue was defined in this study as a vitality score of one or more SD below the mean of the reference value. Consequently, patients who scored $; 46 on the vitality scale were defined as having fatigue, and patients with a score above 46 as having no fatigue.

The mean mental health score reference value for Dutch women is 74 (SD = 1 8). 1 8 Poor mental health was defined as one or more SD below the mean of the reference value, and therefore, mental health scores of $; 56 were defined as poor mental health. The Rotterdam Symptom Checklist measures both physical and psychosocial dimensions and consists of a 35-item symptom checklist to be answered in a 4-point Likert scale (1 = not at all, 2 = a little bit, 3 = quite a bit, 4 = very much). 1 9 Muscle pain and joint pain are two of the items. Answers to these questions were condensed into two groups. Scores of 1 (= not at all) and 2 (= a little bit) were categorized as having only limited muscle or joint pain. Patients with scores 3 (= quite a bit) and 4 (= very much) were considered to experience muscle or joint pain.

Hematological Determinations

Hb level was determined by using automated Counter particle counts. Peripheral blood counts were evaluated annually after peripheral stem-cell transplantation. A normal Hb level for women was defined as Hb more than 1 2 g/dL.20 Hb levels $; 1 2 g/dl were defined as anemia.

Determination of Menopausal Status

To monitor menopausal status, the date of last menstruation was noted and follicle-stimulating hormone and 1 7 beta-estradiol serum levels were measured at least every year during tamoxifen treatment and also after discontinuation of tamoxifen, if any uncertainty regarding postmenopausal status remained.

I a1

Chapter 5

Statistical Analysis Normal d i stribution d ifferences between treatment groups were tested us ing the independent

sample t-test. If the variables did not fit the normal d istribution, the Mann-Whitney test was used.

The correlation between fatigue and Hb level s was tested us ing the Spearman rank correlation r. The relationsh i p between anemia-no anemia and fatigue-no fatigue was eval uated us ing the x2

test. D ifferences i n fat igue between the standard-dose and the h igh-dose chemotherapy were

a l so evaluated us ing the x2 test. Mu lt iple logi stic regression analyses with fatigue as dependent

variable and Hb, mental health score, jo int pa in, muscle pain, menopausal status, and treatment

group as i ndependent variables were performed. Mu ltiple l i near regression analyses with fatigue

as continuous variable were also performed on the previously mentioned i ndependent variables.

L inear mixed effect models (LME) were used to investigate changes in fatigue over time. T ime was

defi ned as the time in years relative to random ass ignment. Random effects were estimated for

the i ntercept and changes over t ime. Variables included i n the model were H b, menta l health,

muscle pain, jo int pai n, menopausal status, and treatment group. F ina l ly, an i nteraction term of

group with t ime was entered into the model to determi ne whether treatment groups showed

differences with regard to changes in fatigue over time. The LME analyses were performed on a l l

data col lected on the different t ime points, thus us ing a l l i nformation ava i l ab le, and test ing

whether changes in Hb were associated with changes in fatigue over time.

Data analysis was carried out with the help of Statistical Package for Social Sciences (SPSS version

1 2 .0; SPSS I nc, Chicago, I L) ) and S-pl us 6 (Vers ion 3 .3; Stati stica l Sciences, Seattle, WA) .

P val ues � 0.05, tested two s ided, were cons idered statist ica l ly s ignificant. In case of mult iple

testing, which was executed to examine the relationsh ip between fatigue with H b levels, P values

were adjusted accord i ng to the Bonferron i step-down procedure to reduce the r isk of type I

errors.21 The s ign ificance level for two tests was adj usted, and therefore, the P value of � 0 .025

was considered statistical ly sign ificant.

Results

Patients

Between August 1 993 and Ju ly 1 999, 885 patients entered into the study. After incl usion of the

fi rst 47 patients, the next 838 patients were approached to participate in the qual ity of l ife study.

Of these 838 patients, 27 refused part ic ipation and seven did not participate because of logistic

reasons. Consequently, 804 patients completed one or more qual ity of l ife questionnaires. At the

t ime of analysis, March 2002, 43 0 patients had a fol low-up of at least three years and were

88 I

Fatigue and relating factors in high-risk breast cancer patients

disease-free. Of these, 202 patients (47%) were randomly assigned into the standard-dose and 228 patients (53%) into the high-dose chemotherapy arm. There was no difference in mean age between the groups (45.8 years [SD 6.4] in the standard-dose, 45. 1 years [SD 6.5] in the high­dose chemotherapy group).

Fourteen patients randomly assigned to the high-dose chemotherapy treatment did not receive this treatment for various reasons, with most of them receiving a fifth course of FEC chemotherapy instead.2 None of the patients who were randomly assigned to standard treatment received high­dose chemotherapy outside of the protocol.

In accordance with the published clinical data, all analyses were done according to the intention­to-treat principle.2

Differences between the two treatment groups and change over time.

Vitality scores The mean vitality scores of the two treatment groups are shown in Table 1. No statistical difference between the treatment groups was found. Figure 1 A illustrates the change in scores over time for both treatment groups and did not reveal any changes in time in either group. The percentage of patients with fatigue in both groups is shown in Table 1 . The number of patients with fatigue in both groups did not change over time and no statistical differences were found between the treatment groups.

Of the 430 patients, 262 patients (61 %) did not report fatigue at any of the four time points and only twelve patients (3%) reported fatigue at all four points. Twenty percent of the patients (n=42) reported fatigue once, 1 0% (n=42) twice, and 6% (n=2 7) reported fatigue three times.

Hb The mean Hb levels at the four time points (random assignment, one, two and three years) for the two treatment arms are shown in Table 1 . Figure 1 B illustrates the change in Hb levels over time for both treatment groups. The mean Hb level at one year was lower than at random assignment in the high-dose chemotherapy group. Thereafter, the mean Hb level recovered to the level measured at random assignment. In the standard-dose chemotherapy group the mean Hb level increased slowly after random assignment to a higher level compared with the level at random assignment (p<0.001 ). The standard-dose chemotherapy group had a slightly higher mean Hb level than the high-dose chemotherapy group at all three time points after random assignment. The difference was most pronounced one year after random assignment.

I ag

Chapter 5

Table 1 . Comparisons between the standard-dose and the high-dose chemotherapy groups

No. of patients Standard-dose High-dose P value SD HD Chemotherapy, % Chemotherapy, %

Mean vitality score At random assignment 196 220 64 67 0.106 1 year 186 206 67 64 0.324 2 years 18 1 207 68 65 0 .215 3 years 170 195 67 64 0.369

Fatigue, vitality score s; 46 At random assignment 19 16 0.291 1 year 19 2 1 0.53 1 2 years 17 21 0 .291 3 years 19 22 0.536

Mean hemoglobin levels, g/dl At random assignment 200 226 12.9 12.9 0.848 1 year 198 212 13 12.3 0.001 2 years 182 212 13.1 12 .8 0.001 3 years 133 159 13.3 13 0 .004

Anemic, s; 12 g/dl At random assignment 21 20 0.881 1 year 13 41 < 0.001 2 years 11 24 0.001 3 years 9 13 0.333

Mean mental health score At random assignment 196 220 68 70 0.27 1 year 186 206 78 77 0.44 2 years 181 207 79 80 0.62 3 years 170 195 79 80 0.60

Poor mental health (mental health score s; 56) At random assignment 25 23 0.76 1 year 7 11 0 . 15 2 years 8 8 0.99 3 years 15 12 0.33

Muscle pain At random assignment 196 220 19 15 0.29 1 year 185 209 21 20 0.91 2 years 180 206 19 28 0.06 3 years 168 191 23 29 0.19

Joint pain At random assignment 196 221 6 2 0.04 1 year 183 208 10 11 0 .83 2 years 179 207 15 16 0.61 3 years 169 193 17 23 0.18

Menopausal status At random assignment

pre-/ post-/ uncertain 159/65/7 183/39/6 3 years

pre-/ post-/ uncertain 30/141/3 1 4/194/30

Abbreviations: SD, standard-dose; HD, high-dose.

90 I

Fatigue and relating factors in high-risk breast cancer patients

1 00

80

� 60 en

]j 40 ·s:

20

0 0

C

1 00

� 80

en 60

Q)

]j 40 Q)

20

0 0

Vitality

---- conventional-dose

- high-dose

2

time (years)

Mental health

--- conventional-dose

--..- high-dose

2

time (years)

3

1 3 .4

1 3 . 2

A

Hemoglobin

1 3 . 0 ----�---

B

� 1 2 . 8 ..c :::c:

3

1 2 .6

1 2 .4 ___....,_ high-dose

1 2 . 2+------.------.-------, 2 3

time (years)

Figure 1 . Mean vital ity scores, mean hemoglobin levels, and mean mental health scores of the SF-36 subscales in the standard-dose and the high-dose treatment groups at random assignment and the three years thereafter (higher vita l ity scores represent less fatigue and h igher menta l health scores better mental health) .

I 91

92

Chapter 5

The percentage of patients with anemia (Hb level � 1 2 g!dL) i n both treatment groups is shown

in Table 1 . Anemia was seen more often in the h igh-dose chemotherapy group one and two years

after random assignment (three and two ti mes h igher, respectively).

Mental Health Scores

The mean mental hea lth scores and the percentage of patients with poor mental health in both

treatment groups are shown in Table 1 . The mean mental health scores in both groups i ncreased

after random assignment and remained stable thereafter. The percentage of patients with a poor

mental health decreases after random assignment. No statistical ly s ign ificant d ifferences in scores

were found between the treatment groups. Figure 1 C i l l ustrates the change in mental health scores

over time for the two treatment groups.

Muscle and Joint Pain

The percentages of patients with muscle pa i n and jo int pai n i n both treatment groups are

presented in Table 1 . There were no statistica l ly significant d ifferences between the standard and

h igh-dose groups. The percentage of patients with muscle pa i n in the standard-dose group

remained stable over t ime wh i le in the h igh-dose chemotherapy group th is percentage i ncreases

over ti me. The percentage of patients suffering from joint pai n i ncreases in time in both treatment

groups (p=0.001 ) .

Menopausal Status

S ixty percent ( 1 03 patients in the standard-dose and 1 54 in the h igh-dose groups) of the patients

were premenopausa l at random assignment and were postmenopausal after three years. S ixteen

percent (33 patients in the standard-dose and 35 patients i n the h igh-dose groups) were

postmenopausa l at random assignment and only 34 patients (30 patients i n the standard-dose

and four patients in the h igh-dose groups; 8%) were sti l l premenopausal at three years after

random assignment. The other patients had an uncerta in menopausa l status (36 patients i n the

standard-dose and 3 5 patients i n the h igh-dose groups). Fewer patients i n the standard-dose

chemotherapy group than in the h igh-dose chemotherapy group were premenopausal at random

ass ignment and postmenopausal three years after random ass ignment (p<0.001 ).

Factors predicting fatigue

Hb

There was no statistical difference i n the mean Hb levels of patients with fatigue or without fatigue

at any of the time points (Table 2) . Table 2 a lso shows the n umber of anemic patients with or

without fatigue. More patients with fatigue had anemia compared to patients without fatigue both

Table 2. Mean Hb levels, percentage anemia, mental health scores, muscle and joint pain in patients with and without fatigue

No. of Mean Hb P value Patients with P value Mean mental P value Patients with P value Patients with P value patients g/dl anemia health score muscle pain joint pain

No. % No. % No. %

Random assignment

Fatigue 72 1 2.8 0 . 163 21 29 0.025 47 <0.00 1 21 29 0.002 9 1 3 <0.0001 No fatigue 340 1 3 .0 60 18 74 49 14 6 2 ---1 year

Fatigue 79 1 2.4 0.09 24 30 0 .515 58 <0.001 41 52 <0.001 16 20 0.003 "TI No fatigue 307 1 2.7 82 27 82 39 1 3 26 8 co· C

2 years (D

a.

Fatigue 67 1 3.0 0.696 1 2 18 0 .984 63 <0.00 1 39 54 <0.001 26 36 <0.001 (D

No fatigue 292 1 2.9 52 18 84 53 1 7 34 1 1 5·

3 years

Fatigue 56 1 3 .0 1 1 20 61 38 51 30 40 (JI

0 . 1 37 0 .0 16 <0.001 <0.00 1 <0.001 :5· No fatigue 204 1 3.2 1 7 8 83 57 20 43 15 ;;;r co·

r

Abbreviation: Hb, hemoglobin. �

<ii'

94

Chapter 5

at randomization (p=0.025) and three years later (p=0.01 6). Anemia was frequently encountered

in the patients with fatigue ( 1 8 to 29% at the four d ifferent time points); however, among the

patients without fatigue, anemia was a lso often observed (8 to 2 7%). Three to 8% of a l l patients

(at the d ifferent ti me points) had both fatigue and anemia. Spearman analysis of the relationsh ip

between fatigue and Hb levels d id not reveal significant correlations a t any of the four time points

(rta=0.005, rtl =0.035, rt2 =0.039, rt3 =0.07 a l l p>0.05) .

Mental Health The mean menta l health scores of patients with fatigue were a lways lower compared to the

patients without fatigue at a l l time poi nts (Table 2 ) . Spearman analysis showed sign ificant

correlations between fatigue and mental health scores at all four measurement ti mes (rtO = 0.69,

rt, = 0 .66, rt2 = 0 .693, rt3 = 0.686 a l l p<0.001 ).

Muscle and Joint Pain Table 2 shows that patients with fatigue had s ign ificantly more muscle pain compared with the

patients without fatigue at a l l four ti me poi nts.

Menopausal Status Patients with fatigue did not differ from patients without fatigue on menopausal status (data not

shown).

Multivariate Analyses

Table 3 presents the resu lts of the mu ltip le logistic regression of treatment and factors on higher

vita l ity score (no fatigue). No effect of treatment arm was seen on fatigue at any of the four time

poi nts. A sign ificant relation between Hb levels and fatigue was only seen at random assignment.

At a l l four ti me poi nts the strongest predictor of fatigue was the mental health score. The relation

between muscle pain and fatigue was sign ificant at one and two years after random assignment.

No effect of menopausa l status on fatigue was observed (Table 3) . The resu lts of the l i near

regression were consistent with the resu lts of the logistic regression as presented in Tab le 3 .

On this ana lysis, about 30% to 35% of the variance in h igh vita l ity score (no fatigue) could be

expla i ned by the combi nation of H b, menta l hea lth score, muscle pain, jo int pai n, treatment

group, and menopausal status.

Fatigue and relating factors in high-risk breast cancer patients

Table 3. Multiple logistical regression of effect of hemog lobin , mental health score, muscle pain , joint pain , treatment group, and menopausal status on high vital ity score (no fatigue)

Variable

Random assignment

Hemoglobin

Mental health score

Muscle pain

Joint pain

Treatment group

Menopausal status

1 year

Hemoglobin

Mental health score

Muscle pain

Joint pain

Treatment group

Menopausal status

2 years

Hemoglobin

Mental health score

Muscle pain

Joint pain

Treatment group

Menopausal status

3 years

Hemoglobin

Mental health score

Muscle pain

Joint pain

Treatment group

Menopausal status

Odds Ratio

3.5

12.4

0.9

0.3

1 .2

1 .0

1 . 1

15.7

0 . 1

1.4

1.0

1 .0

0.9

13 .7

0.3

0.5

0.8

1 .23

2.0

10.0

0.4

0.5

1 .0

1 .0

95% CI P value Variance explained (%)

33

1 .7 to 7. 1 0.001

6.5 to 23.4 <0.00 1

0.4 to 1.8 0.669

0.08 to 1 .0 0.059

0.6 to 2.2 0.509

0.7 to 1 .4 0.923

35

0.5 to 2.2 0 .789

6.3 to 38.6 <0.001

0 .07 to 0.2 <0 .001

0.5 to 3 .6 0 .478

0.5 to 1 .9 0.942

0.7 to 1.4 0.973

31

0.7 to 2 0.724

5.3 to 35.4 <0.00 1

0.1 to 0.6 <0.001

0.2 to 1 .2 0 . 1 35

0.4 to 1 .4 0.404

0.8 to 1 .8 0.278

30

0.7 to 5.5 0 . 176

4.8 to 24.7 <0.00 1

0.2 to 1 .0 0.062

0.2 to 1.3 0 . 172

0.5 to - 2 0.927

0.7 to 1.5 0 .871

Notes: Hb s 12 g/dL versus > 12 g/dL, mental health score s 56 versus > 56, muscle pain yes or no, joint pain yes or no, treatment group high-dose versus standard-dose, menopausal status. Mental health-a high score is associated with less fatigue; muscle pain-a low score is assocoated with less fatigue.

I 95

Chapter 5

LME Analyses

The LME analyses showed that the higher the level of Hb (p=0.0006) and mental health scores (p<0.0001 ), the less fatigue. The presence of joint pain (p<0.0001) and muscle pain (p=0.0283) was associated with more fatigue. Treatment group and menopausal status were not associated with fatigue. There were no differences between treatment groups over the years.

Because only two of the patients did not receive tamoxifen, the effect of tamoxifen on fatigue could not be studied.

Fifty-three patients did not receive radiotherapy. There was no difference in fatigue between the patients who did and did not receive radiotherapy.

All analyses were also performed without the 1 4 patients randomly assigned to the high-dose arm, who did not receive this treatment. Excluding these patients, however, did not affect any outcome of this study (data not shown).

Discussion

This prospective longitudinal study evaluates fatigue, using the vitality scores of the SF-36, in patients treated for high-risk breast cancer and who were disease-free till at least three years after random assignment. The patients received either standard-dose or high-dose chemotherapy followed by stem cell reinfusion. The relationships between fatigue and Hb levels, mental health scores, muscle/joint pain, and menopausal status are described.

Fatigue occurred in 20% of the patients. Fatigue did not change over time in either group, and no differences between the treatment groups were found. Only 5% of all patients experienced both fatigue and anemia. The strongest predictor for fatigue was poor mental health. The presence of joint pain and muscle pain were associated with fatigue. Menopausal status was not associated with experiencing fatigue.

Compared to other studies, this three-year follow-up period for fatigue is long and the use of a prospective design is unique. Moreover, these studies usually consisted of heterogeneous samples of cancer survivors with regard to tumor stage or previous treatment.22 Most other studies in disease-free breast cancer patients after adjuvant therapy observe a somewhat higher percentage of patients with fatigue: 30% as compared with the 20% found here. Different from our study, these studies, however, are cross-sectional. Lindley et al.23 reported fatigue in 31 % of 86 breast cancer patients who survived for two to five years following adjuvant chemotherapy and/or tamoxifen. Broekel et al. 7 compared fatigue in 61 breast cancer patients more than one year after

Fatigue and relating factors in high-risk breast cancer patients

adjuvant chemotherapy, with women without a history of cancer. Patients reported more severe fatigue and worse quality of life due to fatigue. Bower et al.6 studied fatigue measured with the RAN D 36-item health survey, which is almost identical to the SF-36, in a large sample of disease­free breast cancer patients (n=1 ,957). Most patients did not experience prominent or disabling fatigue. However, approximately one-third indicated that they felt tired and lacked energy. Energy levels were relatively low at one year after diagnosis, increased at two years after diagnosis, and remained relatively stable for three, four and five years after diagnosis. These findings could not be confirmed here. There are, however, some differences between the study presented here and Bower's study, which may explain these differences, namely, a longitudinal versus Bower's cross­sectional design and two randomized versus diverse types of treatments. Furthermore, the mean age of the patients in this study is 45 years compared with 55 years in Bower's study. All patients in this study had a disease-free follow up of three years compared to one to five years post-therapy (mean, three years; SD, one year) in Bower's study. Bower et al.6 used a slightly higher cutoff level of 50 for fatigue. If this cutoff point is used in the present study, the percentage of patients reporting fatigue will rise accordingly. However, this does not alter the results of the comparisons and correlations. Interestingly, in our study, only 3% of the patients reported fatigue (vitality score � 46) at all four time points.

Interpreting the results of the above studies remains difficult because fatigue is commonly reported by both patients and healthy individuals.24 Prevalence rates of fatigue in healthy individuals range from 7 to 46%.23 Almost any disease, physical or mental, can be accompanied by fatigue.25 In the context of breast cancer, investigators have proposed that fatigue may be caused by the disease itself, the treatment of the disease, physical symptoms or conditions resulting from the disease or its treatment, and/or psychological responses to the disease.6

In this study, no difference in fatigue was observed between the standard-dose and high-dose chemotherapy groups. This is in contradiction with the expectations. In a recent study of breast cancer patients Brandberg et al.26 reported no differences in fatigue between the tailored chemotherapy and the high-dose adjuvant chemotherapy group one year after treatment. However, the tailored arm in the Brandberg study actually received more chemotherapy than the high-dose arm. Other data directly comparing fatigue in high-dose and real standard-dose chemotherapy for breast cancer are not yet available.

Anemia is a possible explanation for fatigue. This is of special interest because erythropoietin has become available as a supportive treatment option. Turner et al.27-30 reviewed several studies examining the effect of erythropoietin on Hb and quality of life in patients with various tumor types during, and several weeks after, chemotherapy. Erythropoietin administration unequivocally

I 91

Chapter 5

increased the Hb values, decreased the necessity for blood transfusions, and improved quality of life. 1 5 In these studies, no statements were made about the long-term effect of erythropoietin on Hb levels and fatigue. We used multiple regression analysis to study the association of Hb values on four different time points and found Hb to be significantly associated with fatigue only at random assignment, and not at any of the other time points. The fact that Hb is only a predictor at random assignment is most likely because the breast operation before random assignment is often accompanied by significant blood loss. The present study also evaluated the association of Hb and fatigue, taking all time points into account, using LME analysis. In this analysis, the Hb level was found to be a significant predictor of fatigue. This is probably because the LME analysis was performed on all measurements combined over all different time points, which may lead to smal ler confidence intervals associated with the effect estimates. Additionally, in the LME analysis, fatigue was analyzed as a continuous variable, and thus, as a dichotomous variable fatigue versus no fatigue as in the logistic regression analysis. Both these factors might explain the supposedly contradictory results of both types of analysis . In the present study, only 5% of all patients experienced both fatigue and anemia during the three years fol low-up.

Sixteen percent of the patients in the present study experienced poor mental health at three years after therapy. Although we are aware of the fact that depression is not identical to poor mental health, a comparison was made between evidence of depression after breast cancer found in the literature and the data from the current study. In a recent review studying the relation between breast cancer (treatment) and depression, prevalence rates for depression between 1 0% and 32% are mentioned.3 1 However, in a cross-sectional study by Ganz et al.32 in 864 disease-free breast cancer patients, 3. 1 years after diagnosis, the frequency of depression was similar to general population samples. The differences in these percentages may be partly because of the lack of uniform criteria and diagnostic tools. In the present study, the strongest predictor for fatigue was poor mental health. Servaes et al.4 reviewed several studies in which strong correlations between fatigue and depression were observed. Possible explanations for the positive association between fatigue and depression are because the cancer, as well as its treatment, can induce fatigue leading to depression, or that fatigue develops as a consequence of depression.7•33 Joint pain was observed in 20% of the patients and muscle pain in 2 7% of the patients at three years. Ganz et al.34

observed percentages of joint pain between 33% and 55% of the patients and muscle stiffness between 38% and 55% of the patients in different age groups in 577 breast cancer survivors, aged 50 years or younger at diagnosis, at a mean follow-up of six years. In their study, the majority of the women were premenopausal at diagnosis. There were substantial shifts in menstrual status at an average of six years later: the majority of the patients who were 2:'. 40 years old at diagnosis were postmenopausal at the time of the survey. In the study presented here, 1 9% of the patients

Fatigue and relating factors in high-risk breast cancer patients

with a known menopausal status were postmenopausal at diagnosis and 92% were postmenopausal at three years. This might be an explanation for the high percentage of pain in both studies. These differences in percentage between the study of Ganz and the study here might be explained by the prospective design here versus the Ganz's cross-sectional design. In addition, their population was slightly younger and included any rate of bother (the study here included quite a bit and very much).

This study found, like others did previously, that fatigue was associated with pain.22•24 In a number of studies, patients consistently identify pain as provoking increased feelings of fatigue and, conversely, that relief of pain alleviates fatigue.

After the start of this quality of life study, more refined instruments have been developed to assess fatigue in cancer patients. As is the case in many other studies, this study design did not have an age-matched control group of healthy women without a cancer history.22 Fortunately, normal values of the SF-36 in Dutch women are available to put the results in perspective. 1 8 The mean vitality scores in both groups at all four time points were at most two points lower than the normal value, which is 66 for Dutch women (Table 1 ). This small difference has no clinical relevance.

In conclusion, the present study shows that long-term fatigue occurs in 20% of the women adjuvantly treated for breast cancer. Fatigue scores did not differ between the two treatment groups nor from norm population scores and did not change over time. Anemia plays a small causative role in fatigue, but less than expected. The strongest relationship was found between fatigue and poor mental health.

Many of the processes underlying long-term fatigue in this group of cancer patients are still unknown. Development of effective clinical strategies to manage fatigue continues to be a challenge for future research.

Acknowledgments

This study was supported by a grant from the Dutch Health Insurance Council.

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patients: structure and appl ication of the Rotterdam Symptom Checklist. Br J Cancer 1 990;62 : 1 034-8.

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1 8. Aaronson N K, Mul ler M, Cohen PD, et al : Translation, val idation, and norming of the Dutch language

version of the SF-36 Health Survey in community and chronic disease populations. J Cl in Epidemiol

1 998;5 1 : 1 055-68.

Fatigue and relating factors in high-risk breast cancer patients

19. Fal lowfield L, Gagnon D, Zagari M, et a l : Multivariate regression analyses of data from a randomised,

double-bl ind, placebo-control led study confirm qual ity of l ife benefit of epoetin alfa in patients receiving

non-platinum chemotherapy. Br J Cancer 2002;87: 1 34 1 -53.

20. Geneve WHO: Technica l Report 503. Nutritional anemias. 1 972 .

21 . Norman G R, Streiner DL: B iostatistics: the bare essentials. 2002.

22. Jacobsen PB, Hann DM, Azzarel la LM, et a l : Fatigue in women receiving adjuvant chemotherapy for

breast cancer: characteristics, course, and correlates. J Pa in Symptom Manage 1 999; 1 8:233-42 .

23. Lindley C, Vasa S, Sawyer WT, Winer EP: Qual ity of l ife and preferences for treatment fol lowing

systemic adjuvant therapy for early-stage breast cancer. J Cl in Oncol 1 998; 1 6:1 380-7.

24. Stone P, R ichards M, Hardy J: Fatigue in patients with cancer. Eur J Cancer 1 998;34: 1 670-6.

25. Sobrero A, Pugl isi F, Guglielmi A, et al: Fatigue: a main component of anemia symptomatology. Semin

Oneal 2001 ;28: 1 5-8.

26. Brandberg Y, Michelson H, N i lsson B, et al: Qual ity of l ife in women with breast cancer during the first

year after random assignment to adjuvant treatment with marrow-supported h igh-dose chemotherapy

with cyclophosphamide, thiotepa, and carboplatin or ta i lored therapy with Fl uorouraci l , epirubicin,

and cyclophosphamide: Scandinavian B reast Group Study 9401 . J Cl in Oneal 2003;21 :3659-64.

27. Abels RI, Larholt KM, Krantz KD, Bryant EC: Recombinant human erythropoieti n (rHuEPO) for the

treatment of the anemia of cancer. Oncologist 1 996; 1 : 1 40-50.

28. Demetri G D, Kris M, Wade J, Degos L, Cel la D: Qual ity-of-l ife benefit in chemotherapy patients treated

with epoetin a lfa is independent of d isease response or tumor type: results from a prospective

community oncology study. Procrit Study Group. J Cl in Oneal 1 998; 1 6:341 2-25.

29. Kurz C, Marth C, Windbichler G, et a l : Erythropoietin treatment under polychemotherapy in patients

with gynecologic mal ignancies: a prospective, randomized, double-b l ind placebo-control led

mu lticenter study. Gynecol Oneal 1 997;65:461 -6.

30. Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B: Effects of epoetin alfa on hematologic

parameters and qual ity of l ife in cancer patients receiving nonplati num chemotherapy: resu lts of a

randomized, double-b l ind, placebo-control led tria l . J Cl in Oncol 2001 ; 1 9:2865-74.

31 . Somerset W, Stout SC, Mi l ler AH, Musselman D: Breast cancer and depression. Oncology (Huntingt)

2004; 1 8: 1 02 1 -34.

32. Ganz PA, Rowland JH, Desmond K, Meyerowitz B E, Wyatt GE: Life after breast cancer: understanding

women's health-related qual ity of l ife and sexual functioning. J Clin Oncol 1 998; 1 6:501 -1 4.

33. Visser MR, Smets EM: Fatigue, depression and qual ity of l ife in cancer patients: how are they related?

Support Care Cancer 1 998;6: 1 01 -8.

34. Ganz PA, Greendale GA, Petersen L, Kahn B, Bower J E: Breast cancer in younger women: reproductive

and late health effects of treatment. J C l in Oncol 2003;21 :41 84-93 .

1 10 1

6 Screening for infectious foci in breast cancer patients prior to

high-dose chemotherapy and stem cell transplantation

P. Nieboer1 , J .L.N. Roodenburg2, B. F.A.M van der Laan3, E.G.E. de Vries 1 , N.H. Mulder1 , W.T.A. van der Graafl

1 Department of Medical Oncology, University Medical Center Groningen 2Department of Oral and Maxillofacial Surgery, University Medical Center Groningen

3Department of Otorhinolaryngology, University Medical Center Groningen

Anticancer Res 200 3; 23 : 1 779-1 784

Chapter 6

Summary

Cancer patients treated with high-dose chemotherapy (HOC) fol lowed by peripheral stem-cel l

transplantation are at risk for infections during neutropenia. Our standard policy was to screen

for potential infectious foci prior to HOC. Screening for infectious foci consisted of chest and

sinus roentgenograms and a visit to the ear-nose-throat surgeon (ENT surgeon) and the

maxi l lofacial surgeon . The purpose of this study was to evaluate this approach.

Between 1993 and 2000, 73 breast cancer patients received HOC. Al l chest roentgenograms

were normal. ENT screening yielded in three (symptomatic) patients a potential infectious focus.

In 32 patients (44%) a potential dental infectious focus was diagnosed and treated. During

neutropenia after HOC clinical infections occurred in 1 5 patients (21 %). In only five patients

(7%) the infectious focus was probably the upper respiratory tract. Potential ENT infectious foci

were infrequent and a l l were symptomatic. Potential dental infectious foci were seen quite often;

whether they would have had clinica l impact if left untreated remains speculative.

Screening for infectious foci prior to high-dose chemotherapy

Introduction

High-dose chemotherapy (HOC) followed by autologous transplantation has been applied extensively to a broad category of solid tumour patients, including patients with breast cancer and relapsed germ-cell tumours. 1 Following HOC, all patients have a period of profound neutropenia and mucositis during which there is a high incidence of fever and infections. Infections in these granulocytopenic patients usually originate from the gastrointestinal tract (including the oral cavity), the respiratory tract (including sinus), skin and venous access devices.2'3 Colonisation of the gastrointestinal tract and especially the oral cavity is likely to be the initial step preceding systemic infections. The approach for preventing infections from the gastrointestinal and respiratory tract remains controversial. Standardised clinical practice to prevent infections during neutropenia varies between the use of prophylactic oral antibiotics and fungostatics and the additional use of a protected environment such as laminar air-flow rooms and reduced microbial diets.4 Haematological recovery following HOC is accelerated by peripheral stem-cell transplantation (PSCT) compared to bone-marrow reinfusion and by the use of haematopoietic growth factors, all resulting in fewer infectious complications.5 As a consequence, protocols concerning the prevention of infections are applied less strictly and even out-patient protocols for HOC have been developed.6

In many oncological stem-cell transplantation centres, it is still policy to perform standard radiological examinations (chest roentgenogram, sinus roentgenogram and odontogram) searching for potential infectious foci and to refer patients prior to HOC to the ear-nose-throat surgeon (ENT surgeon) and maxillofacial surgeon for screening and, if necessary, eradication of potential infectious foci_3,7•9 Eradication of potential infectious foci prior to myeloablative chemotherapy is supposed to result in fewer systemic infections during neutropenia.2, 1 0

There are no data available of the incidence of infectious foci in solid tumour patients prior to high-dose chemotherapy. Therefore the yield and efficacy of screening procedures can not be determined. At present HOC is considered standard-therapy in only a few indications in solid tumours. However, in the next few years mature results of large randomised trials will show the value of HOC in the adjuvant setting in breast cancer. Therefore it is important to have insight into the incidence of potential infectious foci in these patients and, if necessary, to adjust screening programs for infectious foci.

The present study evaluated the incidence of potential infectious foci in the upper respiratory and gastrointestinal tract as diagnosed by radiological examinations, history taking and physical examinations performed by the ENT surgeon and maxillofacial surgeon in 73 breast cancer

1 1 05

Chapter 6

patients, prior to HDC. Al l patients were treated with identical courses of standard chemotherapy fol lowed by an identical high-dose regimen in an adjuvant setting.

Patients and methods

Patients

Patients i ncluded i n this research were treated i n the U n iversi ty Hospital Gron ingen, The Netherlands and participated in a national randomised adjuvant breast cancer study. The study was approved by the Medical Ethical Committee of the Un iversity Hospital Gron i ngen; al l patients gave i n formed consent. Chemotherapy-naive breast cancer patients with four or more tumour­involved axi l lary lymph nodes (stage II and I l l ), < 55 years of age with negative chest X-ray, l iver ultrasound and bone scan were randomised between treatment with f ive courses of standard chemotherapy and four courses of standard chemotherapy fol lowed by HDC and PSCT. 1 1

Between 1993 and 2000, 82 patients were randomised to receive the high-dose arm. U ltimately, 73 patients actual ly received H DC and were i ncluded i n this study. The reasons for cross-over from the high-dose arm to the standard arm were psychosocial in eight patients and catheter­related insertion problems i n one. No patient randomised for the standard arm received the high-dose arm.

Standard chemotherapy regimens, mobilisation and harvest of stem-cells

The patients received four courses of standard chemotherapy (FEC = 5-fluorouraci l 500 mg/m2, epirubici n 90 mg/m2 and cyclophosphamide 500 mg/m2) . Peripheral stem-cel ls were mob i l ised fo l lowing the thi rd or fourth course of FEC wi th dai l y subcutaneous recombi nant human granulocyte-colony stimulati ng growth factor (G-CSF, f i lgrastim, 5 µg/kg/day) from day two of the course.

High-dose chemotherapy and supportive care

Fol lowing haematological recovery from standard-dose chemotherapy, patients received HDC admin istered over four days (in total CTC = carboplatin 1600 mg/m2, thiotepa 480 mg/m2 and cyclophosphamide 6000 mg/m2) through a double- lumen Hickman catheter. Stem-cel ls were rei nfused three days after completion of chemotherapy. Al l patients received selective gut decontamination consist ing of oral ciprofloxacin (250 mg twice dai ly) and oral amphotericin B (500 mg four times dai ly) starti ng the day before H DC. Amphoterici n B was routi nely admi n istered i ntravenously starting two days after rei nfusion of stem-cel ls, escalati ng to a dose

106 I

Screening for infectious foci prior to high-dose chemotherapy

0.3 mg/kg body weight. Ciprofloxacin was replaced by sulfamethoxazole/trimethroprim (800/1 60 mg three times daily) from three days following PSCT. In case of a rise in temperature above 38.5°C, patients with neutropenia (defined as an absolute neutrophil count < 500 cells/mm3)

were either treated based on previous positive surveillance cultures or were empirically treated with cefuroxim and netilmycin until culture results were obtained.

Screening for infectious foci

Chest roentgenograms were performed in all patients. All patients were referred after four courses of standard chemotherapy and prior to HDC to the maxillofacial surgeon, who performed history and physical examination especially directed at dental problems. Odontograms were performed and assessed by the maxillofacial surgeon in all patients. The first 59 patients in the study were also referred after four courses of standard chemotherapy and prior to HDC to the ENT surgeon, who performed history and physical examination especially directed at ear-nose-throat problems. Sinus roentgenograms were performed and assessed by the radiologist in these 59 patients. Abnormalities in history, during physical examination and on the roentgenograms, possibly indicating an infectious focus, were evaluated and treated appropriately.

Definitions of infectious complications following (high-dose) chemotherapy

Fever was defined as a temperature of 38.5°C or higher. All positive results of blood cultures were deemed significant unless it was documented in the medical record that a culture was thought to be contaminated. The site of infection was classified as lower respiratory tract (pneumonia or bronchitis), upper respiratory tract (sinusitis or rhinitis), urinary tract, skin and/or soft tissue, blood (septicaemia), catheter-related (positive blood cultures from the catheter, catheter-site cellulitis or tunnel infection) and other. The diagnosis of pneumonia was made on the basis of fever with a radiographically compatible pulmonary infiltrate. The diagnosis of catheter-related bacteremia was made if both peripheral cultures and catheter-derived blood cultures were positive with the same organism. Isolated fever was defined as the presence of fever without an identifiable focus of infection.

Infections following the four courses of standard FEC chemotherapy were also evaluated. Infections during neutropenia from standard chemotherapy are sometimes an indicator for increased risk of severe infectious problems during the HOC. If severe infections during standard chemotherapy occurred, this could have led to reconsideration of the procedure of HOC.

1 107

Chapter 6

Results

Chest roentgenograms In all 73 patients the chest roentgenogram was normal immediately prior to HOC.

ENT examinations Sinus roentgenograms were abnormal in four out of 59 evaluated patients (7%). One patient received oral antibiotics for sinusitis after the second course of FEC chemotherapy. She was diagnosed with a maxillary cyst during screening. To exclude an infectious focus, translabial anthroscopic evaluation was performed during which fluid was obtained which tested negative on bacteriological examination. Three other patients had radiological evidence of major mucosa! thickening of the maxillary sinus. One of these three patients had a recent history of sinusitis and was treated with a short course of oral antibiotics. The other two patients had never been symptomatic and were assessed as requiring no treatment. During history and physical examination, one patient was found to have a symptomatic rhinitis during ENT examination which was assessed as requiring pre-HOC treatment with a short course of antibiotics.

In summary, three patients (5%) were found to have a (symptomatic) potential infectious focus on pre-HOC ENT examination; two of them also had abnormalities on the sinus roentgenograms.

Examinations by the maxillofacial surgeon In 32 (44%) out of 73 evaluated patients a potential infectious focus was diagnosed by the maxillofacial surgeon after history taking and physical examination especially directed at dental problems and after assessment of odontograms. Significant problems included poor oral hygiene, periapical pathology, periodontal disease, severe dental caries, defective restorations and ill­fitting protheses. All (potential) foci were treated several weeks before HOC. Twenty patients (2 7%) were seen by the dental hygienist because of acute and chronic periodontitis, two patients were treated for oropharyngeal fungal infection and in 1 7 patients (23%) one or more teeth were extracted. Reasons for extraction varied from loose teeth, unerupted molars, non-vital teeth and possibly infected apical lesions. The urgency of the treatment made it impossible to do apectomies in cases of periapical lesions. Impacted teeth were removed if there was a (possible) connection with the oral cavity, with a risk of pericoronitis. The number of teeth extracted varied: total extraction (two patients), six teeth (one patient), four teeth (two patients), three teeth (two patients), two teeth (six patients) and one tooth (four patients). Morbidity from these extractions was severe: several patients report the extractions to be one of the most unpleasant parts of the transplantation procedure.

1 08 I

Screening for infectious foci prior lo high-dose chemotherapy

Infections following (high-dose) chemotherapy

Four patients (5.5%) were treated with antibiotics for documented or suspected infections following the four courses of standard FEC chemotherapy (four infectious complications during 292 cycles). The first patient received a short course of oral antibiotics because of isolated fever after the second course of chemotherapy. The second patient had non-neutropenic fever after the first course of FEC chemotherapy and was treated with oral antibiotics for bronchitis. The third patient was found to have sinusitis after the second FEC chemotherapy and was treated with oral antibiotics. The fourth patient received oral antibiotics after the third course of FEC chemotherapy for bronchitis. None of these patients were hospitalised because of these infectious complications. In none of the patients, HDC was postponed or cancelled for infectious complications during standard chemotherapy.

Table 1 shows the clinical and microbiologically documented infections during neutropenia following HDC. Coagu/ase-negative staphylococci catheter-related bacteremia was the most common diagnosis. Four cases of severe septicaemia occurred. One of the two patients suffering from a septicaemia from streptococcus mitis died of irreversible septic shock. The origin of the bacteremia remained unclear in both patients. Two patients suffered from septicaemia with streptococcus pneumoniae, one of them originating from a radiologically-documented

Table 1. Cl in ical ly and microbiologically infectious compl ications during neutropenia in 73 patients who underwent HOC and PSCT

Type of diagnosis, infection

Microbiological

Bacterial

Coagulase-negative staphylococci

Streptococcus pneumoniae Streptococcus mitis

Clinical

No fever, no documented infection

Isolated fever

Lower respiratory infection

Pneumoniae

Skin infection

Catheter-related infection

Number (%) of patients

1 1 ( 1 5)

7 ( 1 0) 2 (3) 2 (3)

34 (47)

25 (34)

2 (3)

1 ( 1 )

Bacteremia Coagulase-negative staphylococci 7 ( 1 0) Catheter-site cellulitis 2 (3)

Septicaemia 4 (5)

1 109

1 1 0

Chapter 6

pneumonia. One additional patient had pneumonia radiologically, but cultures remained negative. In all of these five patients, the preceding screening investigations by the ENT surgeon and maxillofacial surgeon had been without abnormalities.

Discussion

Patients treated with HOC followed by PSCT are at high risk for developing infections during the phase of neutropenia. These infections are major causes of morbidity, mortality and costs. The susceptibi lity to infections is proportional to the degree of marrow suppression. When the granulocyte count fa l ls below 500 cells/mm3 and remains depressed for several weeks, the incidence of infectious complications is almost 100%. Although the duration of profound neutropenia has been shortened since bone-marrow transplantation has been replaced by PSCT, 1 2

identification of potential infectious foci prior to HDC is still seen as relevant, as i t is considered to result in a lower incidence of neutropenic infections after HOC. However the data concerning the incidence of infectious foci before HOC in solid tumour patients are scarce.8• 1 3 Apart from intravenous catheters, the upper gastrointestinal tract and upper respiratory tract are the most common sites of infections. Therefore, screening is focused on these tracts. The oral cavity is the most important source of bacteremia during leukopenia in patients with acute haematological diseases.2• 14 Oral infections during neutropenia most likely represent an acute exacerbation of pre­existing chronic periodontal disease.

The number of days with profound neutropenia is higher after treatment with HDC for haematological diseases than for solid tumours. This is explained by differences in high-dose regimens, pre-existing neutropenia, usage of growth factors and possibly the underlying disease. Moreover, patients with haematological diseases are assumed to have more infectious foci than patients with solid tumours, mostly as a consequence of immune suppression by the underlying disease. 1 0• 1 5 The incidence of infectious complications in breast cancer patients treated with common HOC regimens is the same or lower compared to haematological patients. 1 6• 1 7 In a study by van der Wall et al. in breast cancer patients, using the same HOC regimen as in our study, most infections were catheter-related and positive blood cultures of Gram-negative organisms were not observed. 18 This is in accordance with the data from the present study. No gram-negative bacteremia was encountered. The most common infectious complication was catheter-related bacteremia with coagulase-negative staphylococci. Only four patients with a bacteremia other than coagulase-negative staphylococci were encountered. Two had positive blood cultures with streptococcus pneumoniae; in one of them the chest roentgenogram was consistent with pneumonia. Two patients had a bacteremia with streptococcus mitis. The origin was not clear in these patients, but possibly it was the upper respiratory tract. One additional patient had

Screening for infectious foci prior to high-dose chemotherapy

pneumonia radiologically, but remained culture-negative. All five patients had a normal pre­HOC screening by the ENT surgeon and maxillofacial surgeon.

In our study of 73 uniformly treated breast cancer patients a potential infectious focus was diagnosed by the maxillofacial surgeon in a high percentage. In 23% of patients one or more teeth were extracted and two patients were treated for oropharyngeal fungal infection. There were no complications due to the treatment of the dental focus. It is common clinical practice to evaluate and treat pre-existing periodontal disease.7 I ts extreme consequence has been the suggestion to extract all teeth in the patient with leukopenia.1 9 In haematological patients time pressure is high; therefore the start of chemotherapeutic treatment is required faster and extractions are performed relatively often. In solid tumour patients it is common practice to treat dental problems temporary and delay definitive dental treatment until full haematological recovery from HOC. Nevertheless it was considered to be indicated to extract one or more teeth in 23% of our study population before HOC. In two patients all the teeth were extracted resulting in severe psychological and physical patient morbidity.

Because of the high incidence of potential infectious foci in our study population, we conclude that screening by the maxillofacial surgeon seems indicated in all patients prior to HOC. However, not all oral abnormalities should be treated invasively. Apicoectomy and extraction of teeth is probably performed too often in case of periapical radiolucency. Peters et al., however described, in 276 patients evaluated before transplantation, that non-treatment of asymptomatic oral radiolucencies in 14 out of 23 patients did not increase the incidence of infectious complications following autologous transplantation.20 In a study by Toljanic et al. in 48 patients, it was demonstrated that patients with chronic dental pathology could safely proceed with intensive chemotherapy without dental intervention, as conversion of chronic dental disease to an acute state during chemotherapy occurred only in 4% of patients. 1 3

Chest and sinus roentgenograms are often made routinely in transplantation centres prior to HOC to exclude possible infectious foci. In our study population, chest roentgenograms were normal in all patients prior to HOC. The sinus roentgenogram was abnormal in four patients and two of these patients were supposed to need treatment prior to HOC. Both patients were symptomatic. Consultation by the ENT surgeon resulted in one additional patient needing pre-HD treatment. This patient was also symptomatic. The benefit of routine chest and sinus roentgenograms and consultation by the ENT surgeon to screen for potential infectious foci prior to HOC is so low that it can be omitted in asymptomatic breast cancer patients. However this does not preclude other reasons to perform chest roentgenograms such as control of position and complications of a centrally-positioned intravenous catheter.

1 11 1

Chapter 6

The following approach to roentgenological screening and screening by the ENT surgeon and

maxillofacial surgeon prior to HOC and PSCT in breast cancer patients seems rational. Routine

chest and sinus roentgenograms can be omitted in asymptomatic patients. If there is suspicion of

sinusitis or other abnormalities based on history taking and physical examination, appropriate

radiological examinations and an ENT surgeon consultation should be performed and potential

foci of infection should be removed whenever possible prior to HOC. Our finding of the high

incidence of potential infectious dental foci emphasises the value of screening by the

maxillofacial surgeon in patients with solid tumours prior to HDC. However, whether in this

group of patients all these infectious foci would have led to clinical infections during neutropenia

remains speculative. Since there is no possibility to predict the risk, we keep to the protocol of

screening and treatment of potential dental foci in HDC and PSCT patients.

Acknowledgements

This work was in part supported by a grant from the Dutch College for Health Care Assurances

(CVZ), The Netherlands. The authors thank GCM Sieling and BE Oosterhuis for data management.

References

1 . Nieboer P, de Vries EGE, Mulder N H, et a l : Long-term haematologic recovery fo l lowing h igh-dose

chemotherapy with autologous bone marrow transplantation or peripheral stem cel l transplantation in

patients with sol id tumors. Bone Marrow Transplant 2001 ;27:959-66.

2. Greenberg MS, Cohen SG, McKitrick JC, Cass i leth PA: The oral flora as a source of septicemia in patients

with acute leukemia. Oral Surg Oral Med Oral Pathol 1 982;53 :32-6.

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3. Wright WE, Hal ler JM, Harlow SA, Pizzo PA: An ora l disease prevention program for patients receiving

radiation and chemotherapy. J Am Dent Assoc 1 985;1 1 0 :43-7.

4. Dykewicz CA: Hospital infection control in hematopoietic stem cel l transplant recipients. Emerg Infect

Dis 2 001 ; 7:263-7.

5. To LB, Roberts MM, Haylock DN, et a l : Comparison of haematological recovery times and supportive

care requ irements of autologous recovery phase peripheral b lood stem cel l transplants, autologous

bone marrow transplants and a l logeneic bone marrow transplants. Bone Marrow Transplant

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6. Westermann AM, Holtkamp MM, Li nthorst GA, et al: At home management of aplastic phase fol lowing

h igh-dose chemotherapy with stem-cel l rescue for hematological and non-hematological mal ignancies.

Ann Oncol 1 999; 1 0 :51 1 -7.

7. Consensus statement: ora l compl ications of cancer therapies. National Institutes of Health Consensus

Development Panel . NCI Monogr 1 990;3-8.

Screening for infectious foci prior to high-dose chemotherapy

8. Peterson DE: Pretreatment strategies for i nfection prevention in chemotherapy patients. NCI Monogr

1 990;61 -71 .

9. Son is ST, Woods PD, White BA: Ora l compl ications of cancer therapies. Pretreatment oral assessment.

NCI Monogr 1 990;29-32.

1 0. Son is S, Kunz A: Impact of improved dental services on the frequency of oral compl ications of cancer

therapy for patients with non-head-and-neck mal ignancies. Oral Surg Oral Med Ora l Pathol

1 988;65 : 1 9-22.

1 1 . De Vries EGE, ten Vergert EM, Mastenbroek CG, Dalesio 0, Rodenhu is S: Breast cancer stud ies in the

Netherlands. Lancet 1 996;348:407-8.

1 2. De Graaf H, Mulder N H, Wi l lemse PHB, et a l : The additive effect of periphera l b lood stem cel ls,

harvested with low- dose cyclophosphamide, to autologous bone marrow reinfusion on hematopoietic

reconstitution after ablative chemotherapy in breast cancer patients with loca l ized disease. Anticancer

Res 1 995; 1 5 :285 1 -6.

1 3. Toljanic JA, Bedard J F, Larson RA, Fox JP: A prospective pi lot study to evaluate a new dental assessment

and treatment paradigm for patients scheduled to undergo intensive chemotherapy for cancer. Cancer

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1 4. Peterson DE, Minah G E, Overholser CD, et al: Microbiology of acute periodontal infection in

myelosuppressed cancer patients. J C l in Oncol 1 987;5 : 1 46 1 -8.

1 5. Peterson DE, Sonis ST: Oral compl ications of cancer chemotherapy: present status and future studies.

Cancer Treat Rep 1 982;66: 1 25 1 -6.

1 6. Reich G, Mapara MY, Reichardt P, Dorken B, Maschmeyer G: Infectious compl ications after h igh-dose

chemotherapy and autologous stem cel l transplantation: comparison between patients with lymphoma or multiple myeloma and patients with sol id tumors. Bone Marrow Transplant 2001 ;2 7:525-9.

1 7. Sezer 0, Eucker J , Bauhuis C, et al: Patients with mal ignant lymphomas experience a higher rate of documented infections than patients with breast cancer after high-dose chemotherapy with autologous

peripheral stem cel l transplantation. Ann Hematol 2000;79:62 7-30.

1 8. van der Wal l E, Nooijen WJ, Baars JW, et al: H igh-dose carboplatin, thiotepa and cyclophosphamide

(CTC) with peripheral blood stem cel l support in the adjuvant therapy of h igh-risk breast cancer: a

practical approach. Br J Cancer 1 995; 71 :857-62.

1 9. Chapman RM, Crosby WH: Letter: E lective dental extraction in leukemia. N Engl J Med 1 976;295: 1 1 4.

20. Peters E, Monopol i M, Woo SB, Son is S: Assessment of the need for treatment of postendodontic

asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral

Pathol 1 993;76:45-8.

I 113

7 Factors influencing catheter-related infections in the Dutch

multicenter study on high-dose chemotherapy followed by peripheral

stem-cell transplantation in high-risk breast cancer patients

P. Nieboer1 , E.G.E. de Vries1 , N.H. Mulder1 , S. Rodenhuis2, M. Bontenbal3, E. van der Wall4, Q.G. van Hoesel5, W.M. Smit6, P. Hupperets7, E.E. Voest8,

M.A. Nooij9, H.M. Boezen1 , W.T.A. van der Graaf

1University Medical Center Groningen, University of Groningen 2Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam

3Erasmus Medical Center Rotterdam 4VU Medical Center Amsterdam

5University Medical Center Nijmegen 6Medical Spectrum Twente Enschede

7University Hospital Maastricht 8University Medical Center Utrecht 9Leiden University Medical Center

Submitted

Chapter 7

Summary

Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate.

Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated.

Median catheter dwell time was 25 days (range 1-141 ). Catheter-related infections were seen in 28 .3%. Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Factors predictive for catheter-related infections were duration of neutropenia > 10 days (p=0.004) and use of the catheter for both stem-cell apheresis and high-dose chemotherapy (p=0.007). In a multivariate analysis duration of neutropenia > 10 days (p=0.001) was predictive for catheter-related infections; a trend was found for use of a non-tunneled catheter (p=0.055).

A high incidence of catheter-related infections after high-dose chemotherapy was seen, related to duration of neutropenia > 10 days, use of a non-tunneled catheter and use of the catheter for both stem-cell apheresis and high-dose chemotherapy. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.

Factors influencing catheter-related infections

Introduction

High-dose chemotherapy fol lowed by autologous stem-cel l transplantation is increasingly being used in the treatment of patients with hematological diseases and has in the last two decades also been used in the treatment of solid tumor patients. Large phase I l l studies have mostly been executed in the adjuvant setting in breast cancer patients. The precise place of high-dose chemotherapy is unresolved. 1 In selected patients however, high-dose chemotherapy results in improved disease-free survival and probably also in overal l survival.2-6 High-dose chemotherapy­related mortality, original ly reported to be around 20%,7 is consistently below 1 % in more recent studies. This improvement is mostly due to advances in supportive care, the introduction of peripheral stem-cel l reinfusion instead of bone-marrow reinfusion, the choice of cytostatic agents used for the high-dose chemotherapy regimen, the use of hematopoietic growth factors and the growing experience with the procedure.

It is common practice to insert a large-bore central venous catheter at some time prior to the high-dose chemotherapy regimen. This catheter facilitates the administration of the high-dose chemotherapy, reinfusion of stem-cel ls, the drawing of blood samples and the infusion of drugs, blood products and total parenteral nutrition (TPN). The catheter can also be used for the apheresis of peripheral stem-cel ls, prior to the high-dose regimen. Catheter-related complications, especial ly infections, result however in considerable morbidity and may even be fatal. Relatively litt le is known concerning risk factors of catheter-related infections. I t is important to have insight in the complications of central venous catheters, the pros and cons, preferably in a l arge group of uniformly treated cancer patients. This could result in changes in the use of central venous catheters during high-dose chemotherapy.

In the present study we analyzed the complication rate of central venous catheters and evaluated risk factors associated with infectious complications in a large group of breast cancer patients receiving high-dose chemotherapy fol lowed by peripheral stem-cel l transplantation.

Patients and methods

Patients Al l patients included in this study participated in a Dutch national randomized adjuvant breast cancer study of which the clinical results have been published.3•5 Patients were treated in ten centers in the Netherlands. The study was approved by a l l Medical Ethical Committees; a l l patients gave informed consent. Chemotherapy-naive breast cancer patients with four or more tumor-involved axi l lary lymph nodes (stage II and Il l), < 56 years of age with negative chest

\ 1 1 7

1 18

Chapter 7

X-ray, l iver ultrasound and bone scan were randomly assigned to treatment with five courses of standard chemotherapy (FEC; 5-fluorouraci l 500 mg/m2, epirubicin 90 mg/m2 and cyclophosphamide 500 mg/m2) and four courses of FEC fol lowed by high-dose chemotherapy (CTC; carboplatin 1 600 mg/m2, thiotepa 480 mg/m2 and cyclophosphamide 6000 mg/m2

del ivered over four days) fol lowed by peripheral stem-cel l transplantation. Peripheral stem-cel ls were mobi l ized fol lowing a course of FEC with dai ly subcutaneous recombinant human granulocyte-colony stimulating growth factor (G-CSF) after which stem-cel l apheresis was performed. Stem-cel ls were reinfused three days after completion of high-dose chemotherapy.

Supportive care Al l patients received selective bowel decontamination consisting of oral drugs to prevent infections with gram-negative bacteria and fungal infections. Centers were al lowed to select these drugs according to their local protocol. In three centers, in addition amphotericin B was routinely administered intravenously. In eight centers gram-positive prophylaxis, mostly penici l l in, was administered. In case of fever, patients with neutropenia were either treated based on previous positive survei l lance cultures or were empirical ly treated with a broad-spectrum antibiotic, unt i l definitive culture results were obtained. Centers were al lowed to select these antibiotics according to their local protocol.

Catheters and (infectious) complications For this retrospective study, a l l medical records of the patients randomly assigned to the high-dose arm were reviewed with a standard check-l ist. We also retrieved data from the avai lable case record forms of the prospective cl inical study.5 We col lected information on the fol lowing: patient demographics, type of central venous catheter, catheter dwel l time, use of TPN, results of blood cultures, grade of mucosit is, duration of fever and neutropenia, catheter-related infectious compl ications and mortal i ty.

Mucositis and other non-hematological toxicities were graded according to the WHO criteria.8

Fever was defined as an axi l lary temperature of 38.5 °C or higher, neutropenia was defined as an absolute neutrophi l count < 500 cel ls/mm3 • Al l positive results of blood cultures were deemed significant, unless it was clearly documented i n the medical record that a culture was thought to be contaminated and no change in antibiotic treatment was made. Criteria for the diagnosis of a catheter-related infection were defined as fol lows: documented: a) a cl inical infection with positive blood cultures from the catheter with or without positive peripheral blood cultures; b) a positive catheter tip culture in the appropriate cl inical setting; suspected: a cl inical infection with no other apparent focus and c l inical improvement after removal of the central venous catheter or after appropriate antimicrobial therapy directed at usual organisms responsible for catheter-

Factors influencing catheter-related infections

related infections. Patients were followed from insertion of the central venous catheter until it was removed.

Statistics Differences in distributions of categorical variables between groups were tested using Chi-square tests. Differences between groups in distributions of continuous variables were tested using t-tests or Mann-Whitney U-tests, as appropriate.

Factors influencing catheter-related infections were tested using Chi-square tests and Kaplan­Meier survival curves and tested with log-rank tests. Analyses were performed from first day of high-dose chemotherapy.

The independent associations of duration of neutropenia, type of central venous catheter and use of catheter for both stem-cell apheresis and high-dose chemotherapy with catheter-related infections were estimated using multiple logistical regression analysis. To determine the most important predictors of catheter-related infections, forward stepwise logistic regression analysis was performed.

P values < 0.05 were considered significant. SPSS for Windows 1 2 .0 (SPSS Inc, Chicago, I L) was used for all statistical analysis.

Results

Patients Between August 1993 and July 1999, 885 patients were included in the Dutch national randomized study study, 3,5 of which 442 were assigned to receive high-dose chemotherapy. No patient assigned to the standard arm received the high-dose arm. In two patients data were lacking on infectious complications and in three patients data were lacking on bacterial cultures. In 99% of patients (43 7 patients) sufficient data could be retrieved from the medical records and case record forms. Ultimately, 392 patients actually received high-dose chemotherapy. Reasons not to proceed with the high-dose regimen were an infected central venous catheter prior to high-dose chemotherapy in three patients, venous access problems in one patient and catheter-unrelated in the remaining patients.5 Median age at start of high-dose chemotherapy was 45 years (range 23-55).

High-dose chemotherapy and peripheral stem-cell transplantation The mean duration of neutropenia induced by the high-dose chemotherapy was ten days (range 1-28). The median number of days with fever was four (range 0-23) . 295 patients (75%) were

I 11s

1 20

Chapter 7

treated with broad-spectrum antibiotics for suspected or documented infections. The maximal mucositis grade was 0-1 in 56.3% and � 2 in 43.7%. In 1 08 patients (29.3%), TPN was given on one or more days through the central venous catheter, mostly because of sign i f icant weight loss. The median number of red cell blood transfusions was four units (range 0-59), the median number of platelet transfusions was three un its (range 0-48). L i fe-threaten i ng hemorrhagic compl ications were not observed.

Central venous catheters All patients received a central venous catheter. 36.1 % of patients received a non-tunneled central venous catheter (subclavian catheter mostly), 62.8% of pat ients received a tunneled central venous catheter (Hickman catheter mostly), in 1.1 % of patients the type of central venous catheter used was l imited documented. The median number of days the catheter stayed in situ (catheter dwell t ime) was 25 (range 1-141 ). Al l patients received high-dose chemotherapy, stem-cells and therapeuti c support such as antiemetics, f lu ids, ant ibiot ics and platelets and red cell blood transfusions through the catheter.

In 20.4% of the patients a documented catheter-related infection and in another 7.9% of the patients a suspected catheter-related in fection was encountered (total catheter-related in fection rate 28.3%). In 95 patients (25.8%), the catheter was prematurely removed as a consequence of documented or suspected i nfection. The most common pathogen found was coagulase-negative staphylococcus, present i n 104 (56%) of 186 posit ive blood cultures (113 patients). No systemic fungal i n fection was observed. One out of the total o f four deaths with i n 100 days after the reinfusion of stem-cel ls was possibly partly due to a catheter-related in fection (catheter-related sepsis with staphylococcus simulans).

Factors predicting catheter-related infection (Figures 1 -3) The results of the Kaplan-Meier survival analysis of variables affecting catheter-related i nfections are shown in Figures 1-3. Duration of neutropen ia was a predictive factor for the occurrence of catheter-related i n fections with less catheter-related i n fectious complications when the duration of neutropenia was ::;; 10 days (Figure 1, p=0.004). In 62 patients (16.8%), the central venous catheter was i nserted prior to the procedure of stem-cell apheresis and i ntended to remai n in situ for the high-dose chemotherapy period. In th is subgroup the median catheter dwell time was 71 versus 22 days when the catheter was used only for the high-dose chemotherapy (p<0.001) and catheter-related in fection rate was 41.9% versus 25.5% when the catheter was not used for the stem-cel l apheresis (p=0.009). In 3 7.1 % of these patients, the catheter had to be removed (several before start of h igh-dose chemotherapy) for catheter-related i n fectious compl icat ions versus 23.5% when the catheter was not used for the stem-cell apheresis (p=0.007). The use of the

Factors influencing catheter-related infections

catheter for both stem-cel l apheresis and h igh-dose chemotherapy was significantly associated

with h igher catheter-related i nfection rate (Figure 2, p=0.007). The use of a H ickman catheter

resu l ted in non-sign ificant less catheter-related i nfections versus a non-tunneled catheter

(Figure 3, p=0. 1 5) . Del ivery of TPN, maximum mucositis grade, age, number of reinfused CD34+

cel l s, experience with the procedure of h igh-dose chemotherapy (first half of patients randomly

assigned versus second half of patients randomly assigned to the study), gram-pos i tive

prophylaxis, number of platelets and red b lood cel l s transfusions were not factors predi cting

i nfection of the central venous catheter.

Catheters at risk:

1 ,0

c: 0,8

n � .5

-� 0,6

= � 0 � 0,4

8.

0,2

0,0

Neutropenia s 10 days Neutropenia > 1 0 days

0

224 39

duration of neutropenia :;;: 10 days

duration of neutropenia > 10 days

p=0.004

1 0 20 30 40 50

days with catheter

2 18 1 02 27 8 2 39 32 1 2 5 1

Figure 1 . Proportion of catheters without infection over time for patients with duration of neutropen ia s 10 days versus > 10 days (shown for first 50 days fol lowing first day of infusion of high-dose chemotherapy) .

1 121

1 22

Chapter 7

1 ,0

HOC only

c:: 0,8

.5

0 £ -� 0,6 I!? stem-cell pheresis and HOC £

0 0

0,4

0,2

0,0 p=0.007

0 1 0 20 30 40 50

days with catheter

Catheters at risk: HOC only 295 288 1 56 37 1 3 3 Apheresis + HOC 57 56 38 22 7 2

Figure 2. Proportion of catheters without infection over time for patients with catheters used for both stem-cell apheresis and h igh-dose chemotherapy versus catheters used for high-dose chemotherapy only (shown for first 50 days fol lowing first day of infusion of high-dose chemotherapy).

Factors influencing catheter-related infections

1 ,0

Hickman catheters

C: 0,8

0

.E

0 non-tunneled catheters ·;;: 0,6

0 C: 0 0,4 0

0,2

0,0 p=0.15

0 1 0 20 30 40 50

days with catheter

Catheters at risk: Hickman catheters 220 2 12 1 35 51 17 5

Non-tunneled catheters 1 32 1 28 59 8 3 0

Figure 3. Proportion of catheters without infection over time for patients with H ickman catheters versus non-tunneled catheters (shown for first 50 days following first day of infusion of h igh-dose chemotherapy) .

1 1 23

1 24

Chapter 7

Table 1. Multivariate analysis of factors infl uencing catheter-related infections (n=392)

Variable OR 95% Cl lower 95% Cl upper P value

Neutropenia 3.3 1 .6 6.7 0 .00 1

Stem-cell apheresis+HDC 0.7 0 .4 1 .4 0 .32

Type catheter 0.5 0 .3 1 .0 0.055

Abbreviations and notes: Neutropenia, absolute neutrophil count < 500 cells/mm3 for > 10 days versus s 10 days; Stem-cell apheresis + HOC, catheter used for high-dose chemotherapy only versus for both stem-cell apheresis and high-dose chemotherapy; type catheter, Hickman catheters versus non-tunneled catheters; OR, Odds ratio; C l , Confidence Interval.

Multivariate analysis of variables influencing catheter-related infection (Table 1 )

To investigate independent factors with respect to catheter-related infection rate, a multip le logistic regression analysis was performed. Duration of neutropenia > 10 days was a significant independent predictor for catheter-related infections (Odds ratio (OR) = 3.3 [95% confidence interval (Cl) = 1.6-6.7], p=0.001 ). A trend was found for use of a Hickman catheter predicting less infections (OR = 0.5 [95% Cl = 0.3-1.0] , p=0.055). To determine the most important predictor of catheter-related infections, forward stepwise logistic regression analysis was performed showing that besides duration of neutropenia > 10 days (p=0.001 ), use of a non-tunneled catheter (p=0.01) was the major predictor of catheter-related infections.

Discussion

In this large study of 392 breast cancer patients, randomly assigned to high-dose chemotherapy fol lowed by autologous peripheral stem-cel l transplantation, systematical ly studying catheter­related infections, we found a high incidence of catheter-related infections. Documented catheter-related infections were seen in 20.4%, and suspected catheter-related infections in another 7.9% of the patients receiving a central venous catheter. No systemic fungal infections occurred. Factors predictive for catheter-related complications were duration of neutropenia > 10 days and use of catheter for both stem-cel l apheresis and high-dose chemotherapy. In a multivariate analysis duration of neutropenia > 10 days was predictive for catheter-related infections and a trend was seen for use of a non-tunneled catheter.

Currently, central venous catheters represent the most frequently used intravenous line for patients treated with high-dose chemotherapy fol lowed by autologous stem-cel l transplantation. Multiple blood tests, infusions and transfusions are easily administered through a l arge-bore catheter, also al lowing high f low and easy removal in case of complications. However, the price that has to be paid is the high complication rate, with infections observed in 13 to 24%.9-1 2 We found a

Factors influencing catheter-related infections

relatively high incidence (28.3%) of catheter-related infections compared to other studies, probably partly explained by a more clinical and practical definition of a catheter-related infection. Van der Wall et al. used an identical high-dose regimen during which neutropenic fever occurred in 27 of 28 patients (96%). 1 3 In four patients in their study, fever was accompanied by positive blood cultures. In 13 patients (46%), cultures drawn from the Hickman catheter yielded gram-positive organisms. Blood cultures with gram-negative or fungal organisms were not encountered.

We found a relation between duration of neutropenia > 10 days and catheter-related infections and between use of the catheter for both stem-cell apheresis and high-dose chemotherapy and catheter-related infections. Neutropenia has been described in hematological, pediatric and mixed populations of patients as an independent risk factor for catheter-related infections, 14-1 7

but to our knowledge not in a uniformly treated population of solid tumor patients as in our study. The infectious complication rate if the catheter was used for stem-cell apheresis and stayed in place for the high-dose regimen (n=62) was very high (41.9% versus 25.5% of patients). There are some studies, mostly performed in children, studying complications of a single catheter used for both stem-cell apheresis and high-dose chemotherapy, but comparative studies are not available. 1 8•23 Most of these studies indicate that use of a single catheter is safe and effective, but sometimes as low as 31% of patients are able to complete the whole procedure with only one catheter. 1 8 In our study the catheter for dual purpose had to be removed before the end of the procedure because of infectious complications in 37. 1 % of patients. Tunneled catheters have less infectious complications than non-tunneled catheters, as shown in a recent systematic review. 1 2 Although in the multivariate analysis we found a trend and not a significant influence of type of catheter on catheter-related infections, the forward stepwise analysis showed that use of a non-tunneled catheter was a significant predictor of infection.

In our study population, the central venous line was intended to be used for stem-cell apheresis, delivery of chemotherapy, TPN and blood products, drawing of blood samples, delivery of large amounts of fluids in case of dehydration and intravenous fungostatics (amphotericin). Many of these indications are probably not absolute, giving the opportunity to diminish the number of catheters inserted and infectious complications associated.

The use of one catheter for both stem-cell apheresis and high-dose chemotherapy can potentially be avoided. In four centers that performed the stem-cell apheresis through peripheral veins, this could be done successfully in 119 of 164 patients (73%). When peripheral veins are not suitable for stem-cell apheresis, a double-lumen internal jugular vein catheter or a femoral catheter can

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Chapter 7

be inserted as a bedside procedure, to be immediately removed after enough stem-cells have been collected.

Since in general anthracyclines, which are known irritants for veins, are not part of high-dose regimens, it seems possible to deliver chemotherapy through peripheral veins. An alternative would be to deliver the high-dose chemotherapy on a central venous catheter, to be immediately removed after the high-dose chemotherapy has been delivered.

Stem-cell transplantation patients often have poor food-intake during and after high-dose chemotherapy for about two to three weeks. In many transplantation centers it has been standard policy to administer TPN in all patients or in patients losing more than 1 0% of body weight. Roberts et al. showed that in 55 breast cancer or hematopoietic cell transplantation patients, prophylactic TPN did result in a higher body mass post-transplant, but did not impact length of stay or survival when compared with oral diet.24 They observed however a trend for more infections in the TPN group. This could not be confirmed in the present study.

The central catheter is also used for the delivery of blood products. In the future, the threshold for red cell blood transfusions and platelet transfusions could probably be set lower. Ballen et al. showed in 26 Jehovah's witnesses, that autologous stem-cell transplantation could safely be performed without the use of blood products but with the use of G-CSF, erythropoietin and interleukin-1 1 .25 In addition, most transfusions can also be administered on peripheral veins.

Drawing of blood samples is easily performed via a central catheter. However, nearly all routine blood values (hematological values, kidney- and liver-functions) can be performed -if necessary­on capillary blood samples, thus diminishing the necessity of the catheter for drawing blood samples. The disadvantage of this procedure is that infections of fingers can occur and no blood cultures can be collected.

In case of dehydration, related to insufficient intake due to chemotherapy-related mucositis, it is easy to deliver large amounts of fluids via a central catheter. Newer chemotherapy regimens with less mucositis-inducing agents, utilization of recombinant keratinocyte growth factor, newer anti­emetics such as NK1-antagonists causing less nausea and vomiting, will diminish the need for the catheter for this purpose. Furthermore, large amounts of fluids can easily be administered through a peripheral vein.

In our study, no invasive fungal infections were encountered. This is in accordance with the experience that most serious invasive fungal infections occur in hematological patients and especially after allogenic transplantation.26 Newer antifungals such as oral broad-spectrum

Factors influencing catheter-related infections

triazoles, liposomal amphotericin B and echinocandinds are available. Consequently, the need for a central line to deliver amphotericin B will most likely disappear.

There are also other methods to diminish the risk of catheter-related infections. Aseptic techniques for handling the catheters,27 skin desinfection,28 impregnating catheters with antibiotics or the use of anticoagulation29-33 have been proven of value. A study of 356 non-tunneled catheters in cancer patients showed that impregnation of central venous catheters with minocycline and rifampicin was efficacious (3 versus 14 infections in impregnated versus non-impregnated catheters) and safe in reducing catheter-related infections.34 Catheter-related infections may be caused by fibrin deposition associated with these catheters and interventions to decrease fibrin deposition could reduce infections. In a recent study in 208 patients33 the use of low-dose unfractionated heparin resulted in significant less catheter-related infections (6.8% versus 16.6%). Another alternative is a peripherally inserted catheter or a totally implanted Venous Access Port (VAP). In a study of 351 peripherally inserted catheters in a heterogeneous group of cancer patients while on chemotherapy, a low infection rate of 7.4% of catheters was found.35 In the largest published series of totally implanted VAPs in 376 patients, used for high-dose chemotherapy, reinfusion of stem-cells, medications, blood products and TPN, a very low incidence rate of infectious complications was shown.36 Only two port pocket infections and three bacteremias were encountered, which not required removal of the catheter. All catheter­related infections could successfully be treated with antibiotics. In a very recent study in 419 pediatric patients with a central venous catheter (246 VAPs and 173 Hickman catheters), the use of a VAP was associated with less catheter-related infections.37 In a randomized study of infectious morbidity in 1,431 patients with solid tumors requiring 1,630 cathetersN APs38, 43% of catheters were infected versus 6% of the VAPs. Although a totally implanted VAP seems to be safe and effective, the device cannot be easily removed when an infectious catheter-related complication occurs, it requires surgical support for placing and it is relatively expensive and cannot be used for stem-cell apheresis.

In conclusion, we showed that there is a high incidence of catheter-related complications to be expected during the work-up for and during and after high-dose chemotherapy in solid tumor patients. Several aspects of the central venous catheter and high-dose chemotherapy, related to the chance of infection of the catheter, can however be potentially influenced. As is shown in our study, fewer days of neutropenia, use of a Hickman catheter and not using the catheter for both stem-cell apheresis and the procedure of high-dose chemotherapy could reduce the number of catheter-related infectious periods. Given the very high infectious complication rate of the central venous catheter for high-dose chemotherapy, we suggest to carefully reconsider in every patient

1 1 21

Chapter 7

the indication for and type of the central venous catheter and the duration of letting the catheter in si tu. This could lead to a substantial reduction of catheter-related infectious complications in this setting.

Acknowledgments

This work was supported by a grant from the Dutch College for Healthcare Assurances (CVZ).

References

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3. Rodenhuis S, Bontenbal M, van Hoesel QG et a l : Efficacy of h igh-dose a lkylating chemotherapy in

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5. Rodenhuis S, Bontenbal M, Beex L V et a l : H igh-dose chemotherapy with hematopoietic stem-cel l

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1 1 . Ray S, Stacey R, Imrie M, Fi lshie J: A review of 560 H ickman catheter insertions. Anaesthesia 1 996;5 1 :

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1 2. Maki DG, Kluger DM, Crnich CJ: The risk of bloodstream infection in adults with d ifferent intravascular

devices: a systematic review of 200 publ ished prospective studies. Mayo Clin Proc 2006;8 1 : 1 1 59-

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1 3. Van der Wal l E, Nooijen WJ, Baars JW et a l : High-dose carboplatin, th iotepa and cyclophosphamide

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a practical approach. Br J Cancer 1 995;71 :857-862.

14. De Gaetano Donati K., Tacconel l i E, Tumbarel lo M et a l : Central venous catheter-related sepsis: one

year experience in a large un iversity hospita l . l nfez Med 1 999;7:227-230.

1 5. Lai CH, Wong WW, Ch in C et a l : Central venous catheter-related Stenotrophomonas maltoph i l ia

bacteraemia and associated relapsing bacteraemia in haematology and oncology patients. C l in

Microbial Infect 2006; 1 2 :986-991 .

1 6. Nosari A, N ichelatti M, De Gasperi A et a l : I ncidence of sepsis in central venous catheter-bearing

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1 7. Offidani M, Corvatta L, Ol ivieri A et a l : I nfectious compl ications after autologous periphera l blood

progenitor cel l transplantation followed by G-CSF. Bone Marrow Transplant 1 999;24: 1 079-1 087.

1 8. Johansson E, Sol ien HA, N i l sson AS, Engerval l P: Vascu lar access devices used during harvest of peripheral blood stem cel ls: h igh compl ication rate in patients with a long-term dia lysis central venous

catheter. Bone Marrow Transplant 1 999;24:793-797.

1 9. Lazarus HM, Trehan S, Mi l ler R et al: Multi-purpose si lastic dual-lumen central venous catheters for both

col lection and transplantation of hematopoietic progenitor cel ls. Bone Marrow Transplant 2000;25 :779-

785.

20. Leibundgut K, Mul ler C, Mul ler K et a l : Tunneled, double l umen Broviac catheters are usefu l , efficient

and safe in chi ldren undergoing peripheral blood progenitor cel l harvesting and transplantation. Bone

Marrow Transplant 1 996; 1 7:663-667.

21 . Madero L, Diaz MA, Benito A et al: Non-tunneled catheters for the col lection and transplantation of

peripheral blood stem cel ls in chi ldren. Bone Marrow Transplant 1 997;20:53-56.

22. Micel i MH, Dong L, Coria P et a l : Leaving previously implanted central venous catheters (ports) in

place does not i ncrease morbid ity i n patients undergoing autologous peripheral stem cel l

transplantation. Bone Marrow Transplant 2005;36: 1 3 1 -1 34.

23. Restrepo A, Devore P, Encarnacion CE et al : Performance of a hybrid central venous catheter uti l i zed

for both peripheral blood stem cel l harvest and transplant support of patients undergoing autologous

peripheral blood stem cel l transplantation. Bone Marrow Transplant 2002;30:389-395.

24. Roberts S, Mi l ler J , P ineiro L, Jennings L: Total parenteral nutrition vs oral diet in autologous

hematopoietic cel l transplant recipients. Bone Marrow Transplant 2003;32: 71 5-72 1 .

25. Bal len KK, Becker PS, Yeap BY et a l : Autologous stem-cel l transplantation can be performed safely

without the use of blood-product support. J Cl in Oneal 2004;22:4087-4094.

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26. Martino R, Subira M: I nvasive fungal infections in hematology: new trends. Ann Hematol 2002;81 :233-

243.

27. Raad I I , Hohn DC, G i lbreath BJ et a l : Prevention of central venous catheter-related infections by using

maximal steri le barrier precautions during insertion. I nfect Control Hosp Epidemiol 1 994; 1 5:23 1 -238.

28. Maki DG, Ringer M, Alvarado CJ: Prospective randomised tria l of povidone-iodine, a lcohol, and

chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet

1 991 ;338:339-343 .

29. Henrickson KJ, Axtel l RA, Hoover SM et a l : Prevention of central venous catheter-related infections

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heparin flush solution: A randomized, multicenter, double-bl ind trial . J Cl in Oncol 2000; 1 8 : 1 269-1 278.

30. Darouiche RO, Raad I I , Heard S O et a l : A comparison of two antimicrobial-impregnated central venous

catheters. Catheter Study Group. N Engl J Med 1 999;340 : 1 -8.

31 . Maki DG, Stolz SM, Wheeler S, Mermel LA: Prevention of central venous catheter-related bloodstream

i nfection by use of an antiseptic-impregnated catheter. A randomized, control led tria l . Ann I ntern Med

1 997; 1 2 7:25 7-266.

32. Raad I , Darouiche R, Dupuis J et a l : Central venous catheters coated with minocycl ine and rifampin for

the prevention of catheter-related colonization and b loodstream i nfections. A randomized, double­

b l ind tria l . The Texas Medical Center Catheter Study G roup. Ann Intern Med 1 997; 1 2 7:267-274.

33. Abdelkefi A, Torjman L, Ladeb S et a l : Randomized tria l of prevention of catheter-related bloodstream

i nfection by continuous i nfusion of low-dose unfractionated heparin in patients with hematologic and

oncologic d isease. J Clin Oncol 2005;23:7864-7870.

34. Hanna H, Benjamin R, Chatzin i kolaou I et al: Long-term s i l icone central venous catheters impregnated

with minocycl i ne and rifampin decrease rates of catheter-related bloodstream i nfection in cancer

patients: a prospective randomized c l inical tria l . J C l in Oncol 2004;22:31 63-3 1 71 .

35. Walshe LJ, Malak SF, Eagan J, Sepkowitz KA: Compl ication rates among cancer patients with

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36. B iffi R, Pozzi S, Agazzi A et a l : Use of total ly implantable central venous access ports for high-dose

chemotherapy and peripheral blood stem cel l transp lantation: resu lts of a monocentre series of 3 76

patients. Ann Oneal 2004; 1 5 :296-300.

37. Adler A, Yaniv I, Steinberg R et al: I nfectious compl ications of implantable ports and H ickman catheters

in paediatric haematology-oncology patients. J Hosp I nfect 2006;62 :358-365.

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access devices in patients with cancer. Ann Intern Med 1 993;1 1 9: 1 1 68-1 1 74.

8 Summary and future perspectives

Chapter 8

Summary

Drug resistance is a major problem in the treatment of malignancies. Based on a steep dose­response relationship for certain chemotherapeutic drugs in vitro on tumor cell survival, high-dose chemotherapy was considered of interest for the treatment of malignancies. Introduction of autologous bone-marrow and subsequently peripheral stem-cell transplantation allowed the administration of high doses of bone-marrow toxic chemotherapy while thereafter the bone­marrow was rescued. Initially there were high expectations for the application in solid tumors. Nowadays, following numerous phase 2 and a number of phase 3 studies its precise role in solid tumors is still unknown. Therefore, the meta-analysis of especially high-dose chemotherapy in the adjuvant breast cancer setting is eagerly awaited. High-dose chemotherapy induces considerable morbidity. The balance between side effects and survival benefit will finally determine the indication(s) for this treatment modality in solid tumors. This thesis aims to give in depth insight in a number of short-term and long-term side effects that are consequences of high-dose chemotherapy.

Chapter 2. In this chapter we give an overview of the available data on high-dose chemotherapy and autologous stem-cell transplantation in solid tumor patients. Initially, phase 1 and 2 studies were promising with high (but short) tumor response rates. However, the subsequent randomized phase 3 studies, mostly executed in breast cancer patients, failed to show a major effect of high­dose chemotherapy on survival. We highlight in chapter 2 various drawbacks of the clinical study designs of the randomized studies in solid tumors. The power of most studies is insufficient to detect a small, but clinically significant effect. The follow-up of the currently available studies in the adjuvant breast cancer setting is relatively short and compares unfavorable to the more than 20 years of follow-up available for other adjuvant chemotherapy regimens. An insufficient number of patients and/or a short follow-up could be an argument for the missed effect, but do not explain that the expected major effect from the in vitro studies is not observed. There could be a number of other reasons as well, that may explain the lack of major improvement by high­dose chemotherapy. Tissue cultures poorly predict clinical results: the condition in humans is clearly different from the condition in tissue culture. High intracellular chemotherapy levels are much easier to obtain in tumor tissue cultures than in human tumors. Although with hematopoietic stem-cells the bone-marrow toxicity can partially be bypassed, the final drug dose is still restricted by potential toxicity to other organs. We currently know that in many tumors, apart from active cycling cells (as also present in tissue culture), there are "dormant" tumor stem­cells. Such cells are difficult to recognize in vitro. These tumor stem-cells may well possess completely different characteristics from other more mature malignant cells. Dormancy is a state that renders a cell resistant to chemotherapy. This may explain the fact that high-dose

1 32 I

Summary and future perspectives

chemotherapy can induce a high tumor response rate and prolongs disease-free survival, but does not completely eradicate tumor stem-cells and thus does not protect from relapse definitively. This translates in lack of overall survival. Tumors are heterogeneous in nature compared to cell lines. Therefore the high-dose treatment may be adequate for only a part of the tumor cell population.

In the initial high-dose studies the transplant-associated death rate was 7-1 0%. These figures are nowadays improved to 1 -2% post transplant (first 1 00 days) mortality. This reduction in death rate might translate in better results of high-dose chemotherapy regimens in the future. Maturation of the results from recent studies indicating a more modest benefit balanced versus long-term side effects will ultimately determine the role of high-dose chemotherapy in certain solid tumors. In case of well-defined indications for high-dose chemotherapy, further selection of patients based on patient and tumor characteristics will most likely play a role.

For some tumor types, such as Ewing sarcoma, the role of high-dose chemotherapy is still not fully elucidated and is one of the questions to be answered in the ongoing large international "Euro Ewing" study.

Chapter 3. In chapter 3 we present long-term peripheral blood counts and factors influencing long-term trilineage recovery in 1 31 solid tumor patients. All patients included had survived relapse-free for more than one year after high-dose chemotherapy followed by autologous bone­marrow transplantation or peripheral stem-cell transplantation. Peripheral blood counts were examined six months and yearly following transplantation. Median follow-up was 4. 1 years (range 1 - 1 0+ years). We demonstrate that it takes several years for white blood counts, hemoglobin and platelets to normalize completely. Three years after transplantation 91 % of patients had normal white blood counts, 94% normal hemoglobin and 75% normal platelets. Tri lineage recovery was complete in 70% (n=83) at three years and in 85% (n=50) at five years. After five years, 1 5% of the patients in our study had still low values in one or more hematopoietic cell lineages. Recovery of hemoglobin occurred before white blood cell and platelet recovery. Approximately 25% of patients displayed an elevated MCV (mean corpuscular volume) throughout the follow-up period. These long-term results were independent of age, high-dose regimen and stem-cell source (bone-marrow or peripheral blood). They were also independent of number of reinfused stem-cells, possibly due to the use of a relatively high number of CD34+ cells reinfused. Double (n=1 2) versus single (n=1 1 9) transplantations showed a significant slower trilineage recovery and a higher MCV. No secondary graft failure, myelodysplasia or leukemia was encountered in this study.

1 1 33

Chapter 8

In conclusion, hematological recovery after high-dose chemotherapy fol lowed by autologous bone-marrow transplantation or peripheral stem-cell transplantation occurs slowly. Slower recovery is seen after double transplantations. The results suggest lasting implications for the bone-marrow after autologous transplantation. The impairment of hematological recovery after high-dose chemotherapy might thus have clinical implications in subsequent chemotherapy or radiotherapy in case of relapse after transplantation.

Chapter 4. In this chapter we present short-term and long-term hematological data of 98 patients with hematological malignancies, which are in complete remission for over one year after high­dose chemotherapy and peripheral stem-cell transplantation. We also investigated factors that could influence hematological reconstitution after peripheral stem-cel l transplantation. Short­term (granulocytes ;;:: 0.5 x109/L and untransfused platelets ;;:: 20 x1 09/L) hematological recovery following high-dose chemotherapy and peripheral stem-cell transplantation was reached in approximately two weeks. In contrast to short-term recovery, long-term (white blood count � 4 x1 09/L, platelets ;;:: 1 50 x 1 09/L and hemoglobin � 7.45 mmol/L for females and � 8.7 mmol/L for males) hematological recovery was slow. One year after peripheral stem-cell transplantation, ful l hematological recovery was demonstrated for hemoglobin in 47% of patients, for the white blood cell count in 94% and for platelets in 64%; 39% had a trilineage recovery. Roughly 25% of patients displayed an elevated MCV throughout the follow-up period. None of the patients developed manifest myelodysplasia or secondary acute myeloid leukemia in the year following transplantation. In the multivariate analysis, long-term recovery was influenced by age (p=0.002), number of reinfused CD34+ cells (p=0.01 6), hemoglobin at start of high-dose chemotherapy (p=0.001 ), and platelets at start of high-dose chemotherapy (p=0.008). Other factors such as radiotherapy, number of preceding conventional-dose chemotherapy cycles and sex did not influence hematological recovery in the multivariate analysis. The number of stem-cells required for optimal short-term recovery is considered to be 2.5-5 x 1 06 CD34+ cel ls/kg body weight. We showed, however, that for long-term recovery this threshold of 2.5-5 x 1 06 CD34+ cells/kg body weight does not apply. When more than 10 x 1 06 CD34+ cells/kg body weight were reinfused, long-term recovery was stil l accelerated. While more mature stem-cel ls are necessary for the short-term recovery with a clear threshold, long-term recovery is apparently more dependent on more immature stem-cel ls.

We conclude that these results, which suggest a limited bone-marrow reserve, could have important implications for clinical practice in high-dose chemotherapy and peripheral stem-cel l transplantation in patients with hematological malignancies. One year following peripheral stem­cel l transplantation, 61 % of patients still have subnormal blood counts. Long-term recovery is

134 I

Summary and future perspectives

dependent on age, blood counts at start of high-dose chemotherapy and number of reinfused CD34+ cells without a threshold, all reflecting the residual function of bone-marrow before high­dose chemotherapy. Reinfusing more CD34+ cells could accelerate long-term hematological recovery.

Chapter 5. Fatigue is commonly reported by both patients and healthy Dutch people. Prevalence rates of fatigue in healthy individuals range from 7 to 46%. In the context of breast cancer, investigators have proposed that fatigue may be caused by the disease itself, the treatment of the disease, physical symptoms or conditions resulting from the disease or its treatment, and/or psychological responses to the disease. In chapter 5 we evaluated in a prospective longitudinal study in 885 breast cancer patients whether standard or high-dose chemotherapy affected changes in fatigue, hemoglobin, mental health, muscle and joint pain, and menopausal status. We also evaluated whether fatigue was associated with these factors. Patients were randomly assigned between two chemotherapy regimens both followed by radiotherapy and tamoxifen. The patients received either standard-dose or high-dose chemotherapy followed by stem-cell reinfusion. Fatigue was assessed using vitality scale (score :5: 46 defined as fatigue), poor mental health using mental health scale (score :5: 56 defined as poor mental health) both of Short-Form 36 Health Survey, muscle and joint pain with Rotterdam Symptom Checklist, and hemoglobin levels were assessed in disease-free patients before and one, two and three years after chemotherapy. Fatigue was reported in 20% of 430 evaluable patients (202 standard-dose, 228 high-dose) with at least a three-year follow-up, without change over time or difference between treatment arms. Mean hemoglobin levels were lower following high-dose chemotherapy. Only 5% of patients experienced both fatigue and anemia. Mental health score was the strongest fatigue predictor at all assessment moments. Menopausal status had no effect on fatigue. "Linear mixed effect models" showed that the higher the hemoglobin level (p=0.0006) and mental health score (p<0.0001 ), the less fatigue was experienced. Joint (p<0.0001 ) and muscle pain (p=0.0283) were associated with more fatigue. In three years after treatment, no significant differences in fatigue were found between standard and high-dose chemotherapy and the norm population. Fatigue did not change over time. Sixteen percent of the patients in the present study experienced poor mental health at three years after therapy. Joint pain was observed in 20% of the patients and muscle pain in 2 7% of the patients at three years.

In conclusion, we found that long-term fatigue occurs in 20% of the women adjuvantly treated for breast cancer. Fatigue scores did not differ between the two treatment groups or from norm population scores and did not change over time. Anemia plays a small causative role in fatigue, but less than expected. The strongest relationship was found between fatigue and poor mental health.

j 1 35

Chapter 8

Chapter 6. Patients treated with h igh-dose chemotherapy fol lowed by periphera l stem-cel l

transplantation are at h igh r isk for developing i nfections duri ng the phase of neutropen ia. Apart

from i ntravenous catheters, the gastroi ntesti nal tract and upper respi ratory tract are the most

common s i tes of i nfections. Therefore, our pol icy was to screen a l l patients before the high-dose

chemotherapy for an i nfectious focus, in these tracts. In chapter 6 we evaluated pre-treatment

screen i ng by the ear-nose-throat surgeon and the maxi l lofacia l surgeon and i nfectious

compl ications occurri ng i n 73 consecutive patients with breast cancer, treated with high-dose

chemotherapy and peripheral stem-cel l transplantation. Screen ing for infectious foci consisted of

chest and s inus roentgenograms and examinations by the ear-nose-throat surgeon and the

maxi l lofacia l surgeon. All chest roentgenograms were normal . Three patients (5%) were found to

have a (symptomatic) potentia l i nfectious focus by the ear-nose-throat surgeon; two of them a lso

had abnormal ities on the s i nus roentgenograms. In 32 (44%) out of 73 eva luated patients a

potentia l i nfectious focus was d iagnosed and treated by the max i l lofaci a l surgeon. In 23% of

patients one or more teeth were extracted. During neutropenia after h igh-dose chemotherapy

c l in ical infections occurred in 1 5 patients (2 1 %). In only five patients (7%) the probab le focus was

in the upper resp i ratory tract; a l l five patients had a normal pre-high-dose chemotherapy

screen i ng by the ear-nose-throat surgeon and maxi l lofacial surgeon. The most common i nfectious

compl i cati on was catheter-related bacteremia with coagulase-negative staphylococci.

Because of the h igh incidence of potential infectious foci in our study popu lation, we conclude

that screening by the maxi l lofacial surgeon seems i nd icated in all breast cancer patients prior to

high-dose chemotherapy. It has been the impression that the pol i cy towards extraction of teeth

has been too aggressive i n the past, resu lting from the experience with early schedu les with longer

duration of ap las ia after h igh-dose chemotherapy. Routi ne chest and s inus roentgenograms and

consultation by the ear-nose-throat surgeon can be omitted in asymptomatic patients. If there is

suspicion of si nusit is or other abnormal ities, appropriate radi ological examinations and an ear­

nose-throat surgeon consu ltation should be performed; potentia l foci of i nfection shou ld be

removed whenever possib le prior to h igh-dose chemotherapy.

Chapter 7. Neutropenia fo l lowi ng (h igh-dose) chemotherapy leads to a h igh i ncidence of

infectious compl ications, of which centra l venous catheter-related i nfections predomi nate.

Currently, centra l venous catheters represent the most frequently used intravenous l i nes for

patients undergo ing the procedure of h igh-dose chemotherapy fol lowed by autologous stem-cel l

transplantation. Mu ltiple b lood tests and transfusions are eas i ly performed through a large-bore

catheter, a l so a l lowi ng high flow and easy removal in case of compl ications. However, the price

that has to be paid is the h igh compl ication rate due to these catheters. In chapter 7 we analyzed

the incidence and risk factors of central venous catheter-related i nfectious compl ications in 392

1 36 I

Summary and future perspectives

breast cancer patients assigned in the Dutch randomized adjuvant breast cancer trial ("N4+ trial") to high-dose chemotherapy and peripheral stem-cell transplantation. Mean duration of neutropenia (neutrophil count < 500 cells/mm3) after high-dose chemotherapy was ten days (range, 1 to 28 days). The mean catheter dwell time was 25 days (range, 1 to 1 4 1 days). Documented catheter-related infections were seen in 20.4% and suspected catheter-related infections in 7.9% of the patients (total catheter-related infection rate 28.3%). Coagulase-negative staphylococci were found in 1 04 of 1 86 positive blood cultures (56%). No systemic fungal infections occurred. One patient died possibly from catheter-related sepsis. Duration of neutropenia was a predictive factor for the occurrence of catheter-related infections with less catheter-related infectious complications when the duration of neutropenia was � 1 0 days (p=0.004). The use of the catheter for both stem-cell pheresis and high-dose chemotherapy was significantly associated with higher catheter-related infection rate (p=0.007). Duration of neutropenia > ten days was a significant independent predictor for catheter-related infections in a multivariate analysis (Odds ratio (OR) = 3.3 [95% confidence interval (Cl) = 1 .6-6 .7] , p=0.001 ). A trend was found for use of a Hickman catheter predicting less infections (OR = 0.5 [95% Cl = 0.3-1 .0] , p=0.055). To determine the most important predictor of catheter-related infections, forward stepwise logistic regression analysis was performed showing that besides duration of neutropenia > 1 0 days (p=0.001 ), use of a non-tunneled catheter (p=0.01 ) was the major predictor of catheter-related infections.

In conclusion, we showed that there is a high incidence of catheter-related complications during the procedure of high-dose chemotherapy for solid tumor patients, related to duration of neutropenia > 10 days, use of a non-tunneled catheter and use of the catheter for both stem-cell pheresis and high-dose chemotherapy. Therefore, we suggest to carefully reconsider in every patient the indication for and optimal timing of the central venous catheter, to remove it as quickly as possible when no longer absolutely needed. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications in this setting.

Future perspectives

In the last decade, the perception of the role of high-dose chemotherapy in many solid tumor types has changed from optimism to nihilism. From a concept with a strong rationale derived from preclinical model systems and considered highly interesting by the scientific community, it is now a therapy with low priority in research settings. It is, however, highly questionable if high­dose chemotherapy in solid tumors is really irreversibly "dead". It is however clear that the optimistic view induced by the positive results from the early phase 2 studies was unrealistic.

1 1 37

Chapter 8

Most of the phase 3 studies of high-dose chemotherapy in solid tumor patients were executed in

breast cancer patients in the adjuvant and metastatic setting. All of these studies are regarded as

negative or as showing limited activity. However, this deserves some additional attention. Nearly

900 patients with metastatic disease have been treated in six randomized studies and although

all of these studies show excellent objective response rates and five of the six studies also show

a better relapse-free survival for the high-dose arm, overall survival is not different between the

two treatment arms. Over 5,500 patients have at present been treated in the 14 reported

randomized studies in high-risk breast cancer. Many of the studies show a trend for better relapse­

free survival or show less relapses for the high-dose arm. Overall survival again is not different

between the two treatment arms in any of the studies. However, a l l of the studies are

underpowered for overall survival. They are unable to detect smaller, but clinically important,

differences and are reported much too early for a reliable overall survival analysis. Definitive

data with longer follow-up and data from other large comparative studies in breast cancer will

soon be available, giving the opportunity to perform meta-analyses and define groups of patients

benefiting from high-dose chemotherapy.

High-dose chemotherapy cannot eradicate macroscopic disease in breast cancer in most patients.

However, the concept that it may potentially eradicate micrometastases in high-risk breast cancer

or in metastatic breast cancer when any macrometastatic disease is either resected or irradiated

is still viable. The Dutch National Study of high-dose chemotherapy in the adjuvant treatment of

high-risk breast cancer ("N4+ trial") is the largest published randomized study of high-dose

chemotherapy with 885 patients. An alkylator-based regimen was used as high-dose

chemotherapy (CTC; carboplatin, thiotepa and cyclophosphamide). Treatment-related mortality

was less than 1 % of the patients. It is the study with the best patient compliance compared to the

other high-dose studies; no patient randomly assigned to the standard-dose chemotherapy was

treated with high-dose chemotherapy. The study had a symmetrical design, with the high-dose

chemotherapy being the only difference between the two treatment arms. Furthermore it was the

only study with a pathology review. At a median follow-up of 84 months, relapse-free survival

was not different between the high-dose treatment and the standard-dose treatn:ient (p=0.076).

However, in a HER2/neu subgroup analysis, there was a clear difference in relapse-free survival

for the HER2/neu negative patients (p=0.002). For the HER2/neu positive patient no difference in

relapse-free survival was found (p=0.22). These findings are in line with data from phase 2 studies

that also suggested that HER2/neu-amplified tumors do not benefit from high-dose chemotherapy.

An even more important outcome of the subgroup analysis was a difference in overall survival

for the HER2/neu negative patients at five years (p=0.02). Formal proof has to be obtained with

a prospective study comparing HER2/neu negative and positive patients, as this HER2/neu

13a I

Summary and future perspectives

subgroup analysis was not foreseen in the design of the study and was performed in a retrospective way.

As HER2/neu and hormone receptor measurements are currently standard diagnostic procedures, new subgroups of patients have been identified which benefit from different therapeutic strategies. For instance, it has become clear that HER2/neu positive patients have decreased sensitivity to alkylators (like cyclophosphamide) and increased sensitivity to anthracyclines (like doxorubicin and epirubicin) and triple-negatives (tumors that are estrogen-receptor, progesterone-receptor and HER2/neu-receptor negative) seem to form a separate unfavorable subgroup. If there is a role for high-dose chemotherapy it is likely that there will be a subgroup, probably those with HER2 negative tumors that will especially benefit. Adequate studies that include these subgroups are desirable. Subgroups can be defined with immune-histochemistry (staining for the estrogen­receptor, progesterone-receptor and HER2/neu-receptor), FISH or CISH (HER2/neu) and in the near future possibly micro-array techniques will be a part of the standard diagnostic procedure with regard to the choice of adjuvant treatment. Computer-based programs such as adjuvantonline (www.adjuvantonline.com) will increasingly support patients and clinicians in defining subgroups of breast cancer patients benefiting from a specific established therapy, taking into account available prognostic and predictive factors. Data from clinical studies are compatible with the existence of a subgroup of breast cancers that is exquisitely sensitive to (high-dose) alkylating chemotherapy, probably the triple-negatives. Future regimens will include the taxanes and presumably also the tyrosine kinase inhibitors and drugs inhibiting angiogenesis like antibodies against VEGF (vascular endothelial growth factor). Several of these new "smart drugs" are expected to become part of standard treatment in the next decade.

In contrast to the many studies in breast cancer, very few randomized trials have been conducted studying the value of high-dose chemotherapy in other solid tumors. Small cell lung cancer is a very chemosensitive tumor and therefore par excellence a tumor to be investigated in high-dose regimens. However, in the absence of large randomized trials until now, the value of high-dose chemotherapy is still unsettled. The two available phase 3 trials in patients with ovarian cancer have failed to demonstrate a significant benefit in terms of overall survival. However, since a total of only 259 patients have been included in these two trials, no definitive conclusions about high-dose chemotherapy can be drawn. Germ cell tumors are the most chemo-sensitive tumors in adults. High-dose chemotherapy has been administered in a variety of clinical circumstances, such as "salvage" therapy of cisplatin-refractory disease, consolidation therapy or up-front for poor-risk patients. Currently there are data from only three randomized phase 3 studies available, respectively executed in patients with poor-prognosis, patients with "high-volume" disease and

j 1 39

Chapter 8

as "salvage" therapy, with a total of 614 patients included. All three studies failed to show an impact on complete tumor response and overall survival. The results of an ongoing study of high­dose chemotherapy in Ewing sarcoma (the "Euro Ewing" study) are eagerly awaited.

The procedure of high-dose chemotherapy has become feasible due to improved supportive care. All high-dose regimens have significant acute and late toxicities, directly related to the type of drug and schedule. Mortality originally reported as high as 20% is reported as low as 1-2% in more recent transplantation regimens. This is mostly due to advances in supportive care, shorter duration of aplasia due to the introduction of peripheral stem-cell reinfusion instead of bone­marrow reinfusion and the use of hematopoietic growth factors, the choice of cytostatic agents used for the high-dose chemotherapy regimen and the growing experience with the procedure. Improved supportive care has even made outpatient treatment feasible. It should be realized that a high mortality rate during high-dose chemotherapy will translate into a persistent diminished overall survival compared to standard-dose chemotherapy; a factor that is most likely partly responsible for the lack of effect of high-dose chemotherapy in the earlier studies. It is hoped for (and by some expected) that with longer follow-up of the most recent high-dose chemotherapy studies, such as the Dutch N4+ study, differences in overall survival will ultimately be found.

A greater chance of cure or long-term survival after high-dose chemotherapy implicates the need for attention for the long-term effects of high-dose chemotherapy. The effects of high-dose chemotherapy on the bone-marrow are more lasting than expected and long-term follow-up is important to confirm that bone-marrow reserve after stem-cell transplantation is sufficient in periods of hematological stress. Several factors have shown to influence this long-term hematological recovery and some of them are under the influence of the clinician. Quicker hematological recovery could translate into a diminished number of (mostly infectious) complications. Many cancer survivors report fatigue long after the completion of cancer treatment. This symptom is reported to be highly distressing to the patients and a limiting factor in the quality of life. Many of the processes underlying long-term fatigue are still unknown. It is important to define subgroups of patients that are the most at risk of developing long-term fatigue. Development of effective clinical strategies to manage fatigue continues to be a challenge for future research.

Acute problems during the procedure of high-dose chemotherapy are mostly infectious of nature. The source of these infections is especially the gastrointestinal tract and central venous catheters. It is important to define and treat risk factors of infectious complications. A uniform policy of necessary screening of patients scheduled for high-dose chemotherapy should be defined. Many "standard" investigations could be omitted, but some are still necessary pre-treatment to avoid

Summary and future perspectives

infectious complications. Infections originating from the gastrointestinal tract are related to the severity of mucositis. The number of infections could possibly be diminished now that a keratinocyte growth factor, namely palifermin, is available and proven effective. The central venous catheter is the most common source of infection during the period of neutropenia. Given the very high infectious complication rate of the central venous catheter, we suggest to carefully reconsider in every patient the indication for the central venous catheter. When a catheter is placed, it should be removed as early as possible when there is no absolute need for the central catheter anymore. The time of insertion is most critical for later development of catheter-related infections and should be performed according to a strict aseptic protocol. There are also other methods to diminish the risk of catheter-related infections. Aseptic techniques for handling the catheters and skin desinfection have a proven value. Other options to reduce catheter-related infections are to impregnate them with antibiotics or to use a peripherally inserted catheter or a totally implanted Venous Access Port (VAP).

In conclusion, it should be possible to further improve the side-effects of high-dose chemotherapy. Improvements in supportive care will directly translate into better outcome for patients treated with high-dose chemotherapy. High-dose chemotherapy still has not been deleted definitively from the therapeutic arsenal of medical oncologists. Meta-analyses will indicate the role of this strategy in the next years, even in the era of innovative drugs such as trastuzumab, the aromatase inhibitors, tyrosine kinase inhibitors such as lapatinib (targeting HER1 and HER2) and the angiogenesis inhibitors.

1 14 1

9 Samenvatting en toekomstige ontwikkelingen

Chapter 9

Samenvatting

Resistentie tegen chemotherapie is een groot probleem bij de behandeling van tumoren. De

belangstelling voor hoge dosis chemotherapie bij de behandeling van kanker ontstond toen bleek

dat in het laboratorium een relatief geringe stijging in de dosering van sommige

chemotherapeutica een grote toename veroorzaakte in aantal gedode tumorcellen. Om de

problemen van potentieel lethale beenmergdepressie na hoge dosis chemotherapie bij de mens

te ondervangen, ontstond de praktijk van autologe beenmerg- en later perifere

stamceltransplantaties. Aanvankelijk waren er hooggespannen verwachtingen van de toepassing

ervan bij solide tumoren. Na vele fase 2 en een aantal fase 3 studies is de precieze indicatie

echter nog zeker niet vol ledig uitgekristalliseerd. Om deze reden wordt dan ook met spanning

uitgekeken naar de meta-analyse van de adjuvante hoge dosis chemotherapie studies bij

borstkanker. Omdat hoge dosis chemotherapie gepaard gaat met aanzienlijke morbiditeit, zal de

balans tussen bijwerkingen en overlevingsvoordeel uiteindelijk bepalen of er een indicatie is

voor deze vorm van behandeling bij solide tumoren. Dit proefschrift beoogt inzicht te geven in

een aantal neveneffecten van hoge dosis chemotherapie op de korte- en lange-termijn.

Hoofdstuk 2. In dit hoofdstuk geven we een overzicht van de beschikbare gegevens omtrent

hoge dos is chemotherapie en autologe stamceltransplantatie bij patienten met een solide tumor.

Aanvankelijk waren de fase 1 en 2 studies veelbelovend met een hoog percentage (maar

kortdurende) tumor responsen. In de vervolgens uitgevoerde gerandomiseerde fase 3 studies, met

name uitgevoerd bij patienten met borstkanker, kon een belangrijk effect van hoge dosis

chemotherapie op overleving niet worden aangetoond. In hoofdstuk 2 bespreken we

verschillende problemen rond de opzet van die gerandomiseerde studies bij solide tumor

patienten. De "power" van de meeste studies is onvoldoende om een k lein, maar klinisch

belangrijk effect aan te tonen. De follow-up van de patienten in de nu beschikbare adjuvante

borstkankerstudies is te kort om nu al over de precieze rol te kunnen beslissen. Studies met een

te k lein aantal patienten en/of een te korte fol low-up kunnen reden zijn voor het feit dat een

significant effect (nog) niet gezien wordt. Toch kan hiermee nog niet verklaard worden dat het

verwachte grote effect van hoge dosis chemotherapie op basis van de in vitro studies helemaal

niet wordt gezien. Hiervoor kunnen een aantal verklaringen zijn. Een celkweek is een slechte

voorspel ler van een k linisch resultaat: de situatie in de mens is natuurlijk volledig anders dan die

in een celkweek. Het bereiken van langdurig hoge spiegels van cytostatica in een tumorcelkweek

is onvergelijkbaar eenvoudiger dan in tumorweefsel in de mens. Hoewel door het toepassen van

re·infusie van hematopoietische stamcel len de toxiciteit op het beenmerg gedeeltelijk kan worden

omzeild, wordt de uiteindelijke dosis van het chemotherapeuticum nog steeds beperkt door

toxiciteit op andere organen. We weten tegenwoordig dat in vele tumoren naast de actief delende

1 44 I

Samenvatting en toekomslige ontwikkelingen

cel len (die ook aanwezig zijn in de celkweek) "s lapende" tumorstamcel len aanwezig zij n . Deze

cel len zijn moei l ij k in vitro te determ ineren. Deze tumorstamcel len hebben waarsch ij n l i jk

vol ledig andere eigenschappen dan de andere rijpere mal igne cel len en z i jn ongevoel i ger voor

chemotherap ie. Dit zou kunnen verklaren dat hoge dos is chemotherapie vergeleken met

standaard chemotherapie meer tumorcel len doodt en een langere progressievrije overlev ing kan

laten zien, maar de tumorstamcel len n iet a ltijd vol ledig el im i neert en dus n iet altijd defin itief

beschermt tegen een recidief. Dit vertaalt zich vervolgens dan in gebrek aan effect op overleving.

Tumoren bevatten heterogene cel popu laties in vergel ij king met cel l ijnen. Daarom zal hoge dos is

chemotherapie waarsch ijn l ij k maar voor een deel van de tumorcelpopu latie effectief zij n .

I n d e eerste hoge dosis studies was d e sterfte 7-1 0%. Tegenwoordig wordt een post-transplantatie

sterfte (eerste 1 00 dagen na de transplantatie) gezien van 1 -2%. Deze vermindering in sterfte kan

zich in de toekomst verta len in betere resu ltaten van hoge dosis schema's. Meer u itgerijpte

resultaten van studies d ie nu nog s lechts een beperkt voordeel tonen, afgewogen tegen lange­

termijn bijwerkingen zul len u iteindelijk de rol van hoge dosis chemotherapie b ij bepaa l de types

sol ide tumoren bepalen. In het geval van goed gedefi n ieerde indicaties voor hoge dosis

chemotherapie, zal verdere selectie van patienten gebaseerd op karakteristieken van patient en

tumor een belangrijke rol spelen.

Voor sommige tumortypes, zoals het Ewing sarcoom, is de rol van hoge dosis chemotherapie

nog n iet vol ledig uitgekrista l l iseerd en vormt dit een van de vragen die gesteld wordt i n de thans

lopende internationale "Euro Ewi ng" studie.

Hoofdstuk 3. In hoofdstuk 3 warden de lange-termijn perifere b loedbeelden en factoren d ie

herstel van dat bloedbeeld kunnen be"invloeden u itgezocht i n 1 3 1 patienten met sol ide tumoren.

Al deze patienten waren m i nstens een jaar z iektevrij na de behandel ing met hoge dos is

chemotherapie gevolgd door beenmerg- of stamceltransplantatie. De b loedbeelden werden

bekeken een half jaar na transplantatie en daarna jaarl ijks . De mediane fol low-up was 4, 1 jaar

(u iteen lopend van een tot meer dan tien jaar) . Het bl i jkt vele jaren te duren voordat het aantal

witte bloedcel len, het hemoglobi negehalte en het aantal b loedplaatjes vol ledig norma l i seren.

Orie jaar na transplantatie heeft 91 % van de patienten een normaal aantal witte bloedcel len,

94% een normaa l hemoglobinegehalte en 75% een normaal aantal b loedplaatjes. Norm a l iseren

van zowel leukopoiese, erythropoiese a ls trombopoiese trad op bij 70% (n=83) na drie jaar en

bij 85% (n= 50) na vijf jaar. Na vijf jaar had 1 5% van de patienten nog lage waarden in ofwel

witte of rode bloedcel len of bloedplaatjes. Het herstel van het hemoglobinegehalte trad op voor

het herstel van witte bloedcel len en b loedplaatjes. Ongeveer 25% van de patienten had een

verhoogd MCV (median corpuscular volume) tijdens de hele fol low-up periode. Al ie gevonden

1 1 45

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lange-termij n resu ltaten waren onafhankel ij k van leeftijd, type hoge dosis schema en bron van

de stamcel len (d.w.z. beenmerg of perifeer b loed). Ze waren ook onafhankel ijk van het aantal

gere'infundeerde stamce l len, waarsch ij n l ij k samenhangend met de relatief grote hoeveel heid

CD34+ stamcel len die werd teruggegeven . Vergeleken met enkelvoudige transplantaties (n=1 1 9)

werd na dubbele transplantaties (n=1 2) een sign ificant trager herstel van het bloedbeeld en een

hoger MCV gezien. U itputting of falen van het transplantaat, myelodysplasie en acute leukemie

werd in deze studie n iet gezien.

Samenvattend werd gevonden dat het herstel van het bloedbeeld na hoge dosis chemotherapie

en beenmerg- of stamceltransplantatie traag plaatsvindt. Nog trager herstel van het bloedbeeld

wordt gezien na dubbele transplantaties. Deze resu ltaten suggereren langdurige effecten van

autologe stamceltransplantatie op het beenmerg. Het trage hematologische herstel na hoge dosis

chemotherapie kan dus mogel i jk kl i n ische gevolgen hebben als opn ieuw chemotherapie of

radiotherapie gegeven wordt bij een recid ief na transplantatie.

Hoofdstuk 4. In dit hoofdstuk presenteren we korte- en lange-termij n hematologische data van

98 patienten met hemato logische mal igniteiten, die a l ien mi nstens een jaar in complete remissie

waren na hoge dosis chemotherapie en perifere stamceltransplantatie. We onderzochten tevens

factoren die het hematologische herstel konden be'invloeden. Korte-termijn hematologisch herstel

(gedefinieerd als aantal granulocyten � 0,5 x1 09/L, spontaan aantal bloedplaatjes � 20 x1 09/L) trad

op in ongeveer twee weken. Het lange-termijn herstel (gedefi n ieerd a ls aantal witte bloedcel len

� 4 x1 09/L, aanta l b loedplaatjes � 1 50 x 1 09/L en hemoglob i negehalte � 7,45 mmol/L voor

vrouwen en � 8, 7 m mol/L voor mannen) duurde echter veel !anger. Een jaar na perifere

stamceltransplantatie werd een vol ledig normaal hemoglobi negehalte gezien bij 47% van de

patienten, een vol ledig normaal aantal witte b loedcel len bij 94% en een vol ledig normaal aantal

b loedplaatjes b ij 64%, terwij l 39% een vo l led ig normaal b loedbeeld had in a l le 3 cel l ij nen.

Ongeveer 25% van de patienten l iet een verhoogd MCV zien tijdens de fol low-up periode. Geen

van de patienten ontwikkelde een manifeste myelodysplasie of secundaire acute leukemie in het

jaar na de transplantatie. In een mu ltivariate analyse werd het lange-termij n herstel van

bloedbeeld be'invloed door leeftijd (p=0,002), aanta l teruggegeven CD34+ cel len (p=0,01 6),

hemoglobinegehalte bij start hoge dos is chemotherapie (p=0, 00 1 ) en aantal b loedplaatjes b ij

start hoge dosi s chemotherapie (p=0,008). Factoren a l s radi otherapie, aanta l voorafgaande

conventioneel gedoseerde kuren chemotherapie en geslacht bleken geen sign ificante i nvloed te

hebben op het hematolog ische herstel i n de mu ltivariate analyse. Het aantal stamcel len nodig

voor een opti maal korte-termijn herstel i s ongeveer 2, 5-5 x 1 06 CD34+ cel len per k i lo

l ichaamsgewicht. Wij toonden echter aan dat deze grens van 2,5-5 x 1 06 CD34+ cel len per k i lo

Samenvatting en toekomstige ontwikkelingen

l ichaamsgewicht n iet gold voor het lange-termijn herste l . B ij teruggave van meer dan 2,5-5 x 1 06

CD34+ cel len per ki lo l ichaamsgewicht, was het lange-termijn herstel namel ij k sne l ler. Terwij l

meer u itgerijpte stamcel len noodzakel i jk zij n voor het korte-term ij n herstel met een du idel ij ke

grenswaarde, is lange-termijn herstel b l ij kbaar meer afhanke l ijk van onrijpe stamcel len.

Wij concluderen dat deze resu ltaten, die een beperkte reserve van het beenmerg suggereren,

mogel ij k gevolgen kunnen hebben voor de k l in ische procedure van hoge dosis chemotherapie

en perifere stamceltransp lantatie bij patienten met hematologische mal ign iteiten. Een jaar na de

transplantatie heeft 6 1 % van de patienten nog afwijkende waarden in het bloedbeeld. Lange­

termijn herstel van het bloedbeeld is afhankel i jk van leeftijd, bloedwaarden bij start van hoge

dosi s chemotherapie en aantal teruggegeven CD34+ cel len zonder grenswaarde, wat een

afspiegel ing kan zij n van de restfunctie van het beenmerg voorafgaand aan hoge dos is

chemotherapie. Door meer CD34+ cel len terug te geven kan het lange-termijn herstel van het

bloedbeeld worden versneld .

Hoofdstuk 5. Moeheid wordt vaak gemeld door kankerpatienten maar ook door gezonde

Nederlanders. De prevalentie van moeheid b ij gezonden varieert van 7 tot 46%. Onderzoekers

suggereren dat in de context van borstkanker moeheid veroorzaakt kan worden door de ziekte

zelf, door de behande l ing ervan, door ziekte-gerelateerde l ichamel i jke symptomen, door

omstandigheden veroorzaakt door ziekte of behandel i ng en/of door een psychologische reactie

erop. In hoofdstuk 5 hebben we in een prospectieve longitudinale studie bij 885 patienten met

borstkanker gekeken of standaard dosis of hoge dosis chemotherapie veranderingen veroorzaakt

wat betreft moeheid, hemoglobinegehalte, geeste l ij ke gezondheid, spier- en gewrichtspijn en

menopauzale status. We hebben ook gekeken of moeheid geassocieerd was met deze factoren.

Patienten werden gerandomiseerd tussen twee chemotherapie schema's, beide gevolgd door

radiotherapie en tamoxifen. Patienten ontvingen standaard dosis chemotherapie of hoge dosis

chemotherapie gevolgd door stamcelre·infusie. B ij ziektevrije patienten werd voorafgaand aan

en een, twee en drie jaar na de chemotherapie de mate van moeheid bepaald middels een

moeheidsschaal (een score � 46 gedefinieerd als moeheid), de mate van geeste l i jke gezondheid

m iddels een geestel ijke gezondheidsschaal (score � 56 gedefin ieerd als s lechte geestel ij ke

gezondheid) beide onderdeel van de Short-Form 3 6 Health Survey, spier- en gewrichtspijn

m iddels de Rotterdam Symptom Checkl ist en het aantal rode b loedcel len door het meten van het

hemoglobinegehalte in het b loed. Moeheid werd gerapporteerd door 20% van de 430

evalueerbare patienten met m instens dr ie jaar fol low-up (202 standaard dosis, 228 hoge dosi s),

zonder veranderingen in de loop van de tijd en zonder versch i l len tussen de beide

behandel ingsarmen. Het gemiddeld hemoglobinegehalte was lager na hoge dosis chemotherapie.

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Slechts 5% van de patienten was zowel moe als anemisch. De score ten aanzien van geestelijke gezondheid bleek de beste voorspeller van moeheid op alle tijdspunten. Menopauzale status had geen invloed op moeheid. "Linear mixed effect models" lieten zien dat hoe hoger het hemoglobinegehalte (p=0,0006) en de geestelijke gezondheidsscore (p<0,0001 ), hoe minder moeheid werd ondervonden. Gewrichts- (p<0,0001 ) en spierpijn (p=0,0283) waren geassocieerd met meer moeheid. In de drie jaar na de behandeling werden geen verschillen gevonden in moeheid tussen standaard chemotherapie, hoge dosis chemotherapie en de normpopulatie. Moeheid veranderde niet in de loop van de tijd. In de studie had 1 6% een slechte geestelijke gezondheidsscore drie jaar na de therapie. Gewrichtspijn werd gezien bij 20% van de patienten en spierpijn bij 2 7% drie jaar na de therapie.

Concluderend vonden we dat lange-termijn moeheid werd gevonden bij 20% van de vrouwen die adjuvant behandeld waren voor borstkanker. Moeheidsscores verschilden niet tussen de twee behandelingsgroepen en ook niet van de normpopulatie; ze veranderden ook niet in de tijd. Anemie speelt een kleine veroorzakende rol bij moeheid, maar minder dan verwacht. De belangrijkste relatie was die tussen moeheid en geestelijke gezondheidsscore.

Hoofdstuk 6. Patienten behandeld met hoge dosis chemotherapie gevolgd door perifere stamceltransplantatie hebben een hoog risico om een infectie te ontwikkelen tijdens de periode van neutropenie. Naast intravasculaire katheters zijn de tractus digestivus en bovenste luchtweg de meest voorkomend bron van infectie. Daarom screenden wij alle patienten voorafgaand aan de hoge dosis chemotherapie, op zoek naar een mogelijk infectieus focus op deze plaatsen. In hoofdstuk 6 hebben we gekeken naar de screening door de KNO-arts en kaakchirurg voorafgaand aan hoge dosis chemotherapie en hebben we de infectieuze complicaties geevalueerd bij 73 achtereenvolgende patienten, behandeld met hoge dosis chemotherapie en perifere stamceltransplantatie. De screening bestond uit rontgenfoto's van thorax en sinussen en onderzoek door de KNO-arts en kaakchirurg. Alie thoraxfoto's bleken normaal te zijn. Bij drie patienten (5%) vond de KNO-arts een (symptomatisch) potentieel infectieus focus; twee hiervan hadden ook afwijkingen op de rontgenfoto van de sinussen. Bij 32 (44%) van de 73 geevalueerde patienten vond de kaakchirurg een potentieel infectieus focus waarvoor een behandeling werd uitgevoerd. Bij 23 patienten werden een of meer tanden of kiezen getrokken. Klinische infecties tijdens de neutropenie na hoge dosis chemotherapie traden op bij 1 5 patienten (2 1 %). Bij slechts vijf patienten (7%) was het vermoedelijke focus gelegen in de bovenste luchtwegen. Voorafgaand aan de hoge dosis chemotherapie hadden deze vijf patienten een screening ondergaan door de KNO-arts en kaakchirurg waarbij geen afwijkingen waren geconstateerd. De meest voorkomende infect ieuze complicatie was een katheter-gerelateerde bacteriemie met coagulase-negatieve staphylococcen.

1 48 I

Samenvatting en toekomstige ontwikkelingen

Vanwege de hoge i ncidentie van potentieel i nfectieuze foci i n onze studiepopulatie, concluderen

wij dat screen ing door de kaakchi rurg ge"indiceerd is bij a l le borstkankerpatienten voorafgaand

aan de hoge dosis chemotherapie. De indruk bestaat echter dat er een behoudender beleid ten

aanzien van extracties van gebitselementen gevoerd kan worden, nu de aplasieduur na hoge

dosis chemotherapie korter is. Routine rontgenfoto's van thorax en s inussen en consulten door

KNO-arts kunnen achterwege worden gelaten b ij asymptomatische patienten. Als er een

verdenking op sinusitis of andere afwijkingen bestaat, d ient rontgenologisch onderzoek te worden

u i tgevoerd en d ient een KNO-arts te worden geconsu lteerd; mogel ij ke bronnen van i nfectie

d ienen zoveel mogel ij k te worden verwijderd voorafgaand aan de hoge dosis chemotherapie.

Hoofdstuk 7. Neutropenie na (hoge dosis) chemotherapie geeft aan leiding tot een hoge incidentie

van infectieuze compl i caties, waarb ij de centraal veneuze katheter-gerelateerde infecties de

belangrijkste z ijn . Tegenwoordig zijn centraal veneuze katheters de belangrijkste intraveneuze

toegangsweg voor patienten die de procedure van hoge dos is chemotherapie gevolgd door

perifere stamceltransplantatie ondergaan. B loedafnames en transfusies zijn eenvoudig u itvoerbaar

via een katheter met een grote d iameter. Er is gemakkel ijk veel infuus door te geven en ze zijn

relatief eenvoudig te verwijderen a ls er compl icaties optreden. Een nadeel is echter het hoge

aanta l katheter-gerelateerde compl icaties. In hoofdstuk 7 hebben we de i ncidentie en

risicofactoren geanalyseerd van centraal veneuze katheter-gerelateerde infectieuze compl icaties

bij 392 borstkankerpatienten, die gerandomiseerd waren voor een behandel i ng met hoge dosis

chemotherapie en perifere stamceltransplantatie a ls onderdeel van de Nederlandse

gerandomiseerde adj uvante borstkankertr ial ("N4+ stud ie"). De gemiddelde neutropen ieduur

(aantal neutrofielen onder de 500 cel len/mm3) na hoge dos is chemotherapie was t ien dagen

(varierend van 1 tot 28 dagen) . Gemiddeld werd de katheter 25 dagen gebru i kt (varierend van 1

tot 1 41 dagen). Bewezen katheter-gerelateerde i nfecties werden gezien b ij 20,4% en

vermoedel ij ke katheter-gerelateerde i nfecties bij 7,9% van de patienten (totaa l percentage

katheter-gerelateerde i nfecties 28,3%). Coagu lase-negatieve staphylococcen werden gevonden

in 1 04 van de 1 86 positieve b loedkweken (56%). Systemische sch immel infecties werden niet

gezien. Een patient overleed mogel i jk aan een katheter-gerelateerde sepsis . De duur van de

neutropenie was voorspel lend voor het optreden van katheter-gerelateerde i nfectieuze

compl icaties; er waren m inder compl icaties als de duur van de neutropenie s; 1 0 dagen was

(p=0,004). Als de katheter zowel voor de pherese als voor de hoge dosis chemotherapie werd

gebru ikt was dit ook s ignificant geassocieerd met meer katheter-gerelateerde infecties (p=0,007) .

I n een mu ltivariate ana lyse werd gez ien dat duur van de neutropenie > 1 0 dagen een

onafhankel ijke voorspel ler was voor katheter-gerelateerde infecties (Odds ratio (OR) = 3 . 3 [95%

betrouwbaarheidsi nterval = 1 .6-6 . 7] , p=0,001 ) . Een trend werd gezien voor minder infecties bij

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Chapter 9

gebruik van een getunnelde Hickman katheter (OR = 0.5 [95% betrouwbaarheidsinterval = 0.3-1.0] , p=0,055). Om de meest belangrijke voorspeller van katheter-gerelateerde infecties te vinden werd een "forward stepwise regressie analyse" uitgevoerd; deze liet zien dat naast duur van de neutropenie > 10 dagen (p=0,001 ), het gebruik van een niet-getunnelde katheter (p=0,01) de belangrijkste factor was, voorspellend voor katheter-gerelateerde infecties.

Concluderend hebben we laten zien dat er een hoge incidentie is van katheter-gerelateerde infecties tijdens de procedure van de hoge dosis chemotherapie bij patienten met solide tumoren, gerelateerd aan duur van de neutropenie > 10 dagen, gebruik van de katheter voor zowel pherese als hoge dosis chemotherapie en het gebruik van een niet-getunnelde katheter. Daarom is onze suggestie om bij elke patient de indicatie voor en optimale timing van de centraal veneuze katheter zorgvuldig te overwegen en deze direct te verwijderen als de katheter niet meer absoluut noodzakelijk is. Selectief gebruik en de keuze van een katheter kan leiden tot een aanzienlijke reductie van het aantal katheter-gerelateerde complicaties.

Toekomstige ontwikkelingen

In de laatste tien jaar is de vis ie op hoge dosis chemotherapie bij veel types solide tumoren omgeslagen van optimisme naar pessimisme. Van een concept met een sterke onderbouwing vanuit preklinische modellen en een voor dit concept uiterst gemotiveerde groep medisch oncologen, is het nu geworden tot een therapie met lage prioriteit in de onderzoekssetting. Het is echter op dit moment nog onzeker of hoge dosis chemotherapie werkelijk "dood" is. Wat wel duidelijk is, is dat de optimistische visie die was veroorzaakt door de positieve resultaten van de eerste fase 2 studies gebleken is onrealistisch te zijn.

De meeste van de fase 3 studies met hoge dosis chemotherapie bij sol ide tumor patienten werden uitgevoerd bij borstkankerpatienten in de adjuvante en gemetastaseerde setting. De resultaten van al deze studies zi jn beoordeeld als negatief of als hebbende een beperkt voordeel voor de hoge dosis. Deze conclusies verdienen echter nadere bestudering. Bijna 900 patienten met gemetastaseerde ziekte zijn behandeld in zes gerandomiseerde studies en hoewel al deze studies een uitstekende reactie van de tumor laten z ien en vijf van de zes studies een betere recidiefvrije

overleving tonen, is de overleving niet verschillend tussen de hoog en standaard gedoseerde chemotherapeutische behandelingsarmen. Meer dan 5.500 patienten zij n nu adjuvant behandeld i n de 14 gepubliceerde gerandomiseerde studies bij hoog r is ico borstkanker. Veel van deze studies laten een trend zien voor betere recidiefvrije overleving of laten minder recidieven zien voor de hoge dosis arm. De overleving is echter in geen van de studies verschillend tussen de beide behandelingsarmen. Al deze studies hebben echter niet genoeg power en een te korte

1 so I

Samenvatting en toekomstige ontwikkehngen

follow-up om een verschil in overleving aan te kunnen tonen. Ze zijn niet in staat om kleine, maar klinisch belangrijke verschillen te detecteren en zijn veel te vroeg gepubliceerd voor een betrouwbare analyse van de overleving. Definitieve gegevens met een langere follow-up duur en gegevens van andere vergelijkende studies in borstkankerpatienten zullen spoedig komen, alsmede een meta-analyse. Op deze wijze kan wellicht een groep van patienten gedefinieerd worden die wel baat heeft bij hoge dosis chemotherapie.

Hoge dosis chemotherapie is bij borstkanker niet altijd in staat om macroscopische ziekte te eradiceren. Echter, het concept dat hoge dosis chemotherapie bij hoog risico patienten of bij gemetastaseerde ziekte, waarbij de macroscopische ziekte verwijderd of bestraald is, in staat is micrometastasen te eradiceren, is nog steeds houdbaar. De Nederlandse nationale studie met hoge dosis chemotherapie als adjuvante behandeling van patienten met een hoog risico op recidief van hun borstkanker ("N4+ studie") is de grootste gepubliceerde gerandomiseerde studie met hoge dosis chemotherapie waarin 885 patienten ingesloten zijn. Voor de hoge dosis chemotherapie werd een schema gebruikt dat vooral gebaseerd is op alkylerende cytostatica (CTC; carboplatine, thiotepa en cyclofosfamide). Sterfte gerelateerd aan de behandeling was minder dan 1 % van de patienten. Het is de studie met de beste compliance van patienten vergeleken met de andere hoge dosis studies; geen enkele patient gerandomiseerd voor de standaard dosis chemotherapie werd behandeld met hoge dosis chemotherapie. De studie heeft een symmetrische opzet, met de hoge dosis chemotherapie als enige verschil tussen de beide behandelingsarmen. Verder is het de enige studie met een centrale beoordeling van de pathologie. Na een mediane follow-up van 84 maanden is de recidiefvrije overleving niet verschillend tussen de hoge dosis en de standaard dosis behandeling (p=0,076). Echter, in een HER2/neu subgroep analyse werd een duidelijk verschil gevonden in recidiefvrije overleving ten gunste van de hoge dosis chemotherapie voor de HER2/neu negatieve patienten (p=0,002). Bij de patienten met HER2/neu positieve tumoren werd geen verschil gevonden (p=0,22). Deze uitkomsten ondersteunen gegevens van fase 2 studies die ook suggereren dat patienten met HER2/neu positieve tumoren geen voordeel hebben van hoge dosis chemotherapie. Een nog belangrijker uitkomst van de subgroepanalyse was dat er een voordeel van hoge dosis chemotherapie werd gezien in overleving na vijf jaar voor de HER2/neu negatieve patienten (p=0,02). Formeel moet het bewijs nog geleverd worden met een prospectieve studie die patienten met HER2/neu negatieve en positieve tumoren vergelijkt, aangezien deze HER2/neu subgroep analyse niet in de opzet van de studie zat en retrospectief is uitgevoerd.

Doordat HER2/neu bepalingen en hormoonreceptorbepalingen een standaard onderdeel zijn geworden van het diagnostisch traject, zijn nieuwe subgroepen patienten ge'identificeerd die baat kunnen hebben bij verschillende therapeutische strategieen. Het is bijvoorbeeld duidelijk

j 1 51

1s2 I

Chapter 9

geworden, dat patienten met H ER2/neu positieve tumoren een verminderde gevoel igheid hebben

voor een schema met een a lkyleerder (zoal s cyclofosfamide) en een toegenomen gevoel igheid

hebben voor anthracyc l i nes (zoals doxorubicine of epi rubici ne) en dat ten aanzien van prognose

de "triple-negatives" (tumoren die zowel ER negatief, PgR negatief als H ER2/neu negatief zijn)

sowieso een aparte ongunstige subgroep vormen. Als er een rol is voor hoge dosis chemotherapie,

dan is het waarschij n l ij k in de subgroep met een HER2/neu negatieve tumor. Adequate studies

voor deze subgroepen zijn nod ig. Subgroepen kunnen ge'identificeerd worden met

immuunhistochemie (kleuringen voor de ER receptor, PgR receptor en H ER2/neu receptor), F ISH

of CISH (HER2/neu) en in de nabije toekomst zul len waarsch ij n l ij k m icro-array techn ieken

onderdeel van een standaard d iagnostische procedure worden d ie de keuze voor het type

adj uvante therapie ondersteu nt. Computergebaseerde program ma's zoals adj uvanton l i ne

(www.adj uvanton l i ne.com) zu l len patienten en de c l i n icus gaan helpen om subgroepen te

defi nieren van borstkankerpatienten die baat hebben b ij een specifieke, bewezen therapie, daarbij

de beschikbare prognostische en predictieve factoren betrekkend. Gegevens van k l in ische studies

laten zien dat er een subgroep borstkankerpatienten is d ie u i termate gevoel ig is voor (hoog

gedoseerde) chemotherapie met a lkyleerders, waarschij n l ij k de trip le-negatives. Toekomstige

regimes zul len taxanen gaan bevatten en zeer waarsch ij n l ij k ook tyrosine kinase remmers en

middelen die de angiogenese remmen zoa ls anti l ichamen tegen b ijvoorbeeld VEG F (vascular

endothel ia l growth factor) . Van versch i l lende van deze "smart drugs" wordt verwacht dat ze in

de komende t ien jaar onderdeel gaan u itmalen van de standaardbehandel ing.

In tegenstel l i ng tot de vele studies bij borstkanker, zij n er maar wein ig gerandomiseerde studies

u itgevoerd naar de waarde van hoge dos is chemotherap ie b ij andere sol ide tumoren. Het

kleince l l ig longcarcinoom is een voor chemotherapie zeer gevoel ige tumor en daarom bij uitstek

gesch ikt om te onderzoeken met een hoge dosi s schema. Echter, door de afwezigheid van grote

gerandomiseerde studies is de waarde van hoge dosi s chemotherapie nog onbekend. De twee

besch ikbare studies b ij patienten met eierstokkanker laten geen s ign ificant voordeel zien wat

betreft overleving. Echter, omdat s lechts 259 patienten z i jn ge'inc ludeerd in deze 2 stud ies,

kunnen defi n itieve concl us ies n iet getrokken worden. Kiemceltumoren zijn van a l le sol ide

tumoren het meest gevoe l ig voor chemotherapie. Hoge dos i s chemotherapie is gegeven i n

versch i l lende kl in ische omstandigheden, zoa ls a l s "salvage" therapie bij c isp latine refracta i re

patienten, consol idatie therapie en als pri maire therapie bij hoog r is ico patienten. Op d it moment

zijn de gegevens van drie gerandomiseerde fase 3 studies, respectievel ijk u itgevoerd bij patienten

met s lechte prognose, b ij patienten met "h igh-volume" z iekte en als "salvage" therap ie

besch i kbaar met i n totaa l 6 1 4 ge'inc ludeerde patienten. Deze dr ie studies laten geen verschi l

zien i n complete tumor respons e n overlevi ng. Het resu ltaat van d e lopende studie met hoge

Samenvatting en toekomstige ontwikkelingen

dosis chemotherapie bij het Ewing sarcoom (de "Euro Ewing" studie) wordt met belangstelling tegemoet gezien.

De procedure van hoge dosis chemotherapie is mogelijk geworden door de verbeterde ondersteunende maatregelen (supportive care). Alie hoge dosis schema's hebben acute en late bijwerkingen, direct gerelateerd aan het type chemotherapie en schema. De sterfte die in de eerste studies tot wel 20% was, is 1 -2% in de meest recente studies. Dit is voornamelijk het gevolg van verbeterde supportive care, de verkorte aplasieduur door de introductie van perifere stamceltransplantatie in plaats van beenmergre·infusie en het gebruik van hematopoietische groeifactoren, de keuze van de cytostatica die gebruikt worden voor de hoge dosis chemotherapie en de groeiende ervaring met de procedure. Verbeterde supportive care heeft het zelfs mogelijk gemaakt de behandeling buiten het ziekenhuis te geven. Het is belangrijk te beseffen dat een hoge sterfte tijdens hoge dosis chemotherapie zich blijft vertalen in een verminderde overleving vergeleken met standaard dosis chemotherapie. Dit is een factor die deels verantwoordelijk is voor het ontbreken van een effect op overleving van hoge dosis chemotherapie in de eerste studies. Het is te hopen (en volgens sommigen ook te verwachten) dat met een langere follow­up van de meest recente hoge dosis studies, zoals de Nederlandse N4+ studie, de verschillen uiteindelijk wel gevonden zullen worden.

Een grotere kans op genezing of lange-termijn overleving na hoge dosis chemotherapie vergroot de noodzaak om ook aandacht te besteden aan de lange-termijn effecten. Het duurt lang voordat het bloedbeeld volledig is hersteld na hoge dosis chemotherapie. Lange-termijn follow-up is nodig om bevestigd te krijgen dat de beenmergreserve na stamceltransplantatie voldoende blijft in periodes van hematologische stress. Verschillende factoren be'invloeden dit lange-termijn hematologische herstel en sommige van deze factoren kunnen be'invloed worden door de clinicus. Een sneller hematologisch herstel kan zich vertalen in een verminderd aantal (meestal infectieuze) complicaties. Veel overlevers van kanker melden moeheid, lang nadat de therapie is afgerond. Dit symptoom geeft veel onrust en vermindert de kwaliteit van leven. Veel van de processen die ten grondslag liggen aan lange-termijn moeheid zijn onbekend. Het is belangrijk om subgroepen te herkennen die het meeste risico hebben op het ontwikkelen van lange-termijn moeheid. Ontwikkeling van effectieve strategieen om moeheid te be'invloeden blijft een uitdaging voor toekomstig onderzoek.

Acute problemen tijdens de procedure van hoge dosis chemotherapie zijn vooral infectieus van aard. De bron van deze infecties is meestal de tractus digestivus en de centraal veneuze katheter. Het is belangrijk om risicofactoren voor infectieuze complicaties te definieren en te behandelen. Een eenduidig beleid met betrekking tot het noodzakelijk screeningsonderzoek voor patienten die

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Chapter 9

hoge dosis chemotherapie gaan krijgen dient gedefi n ieerd te warden . Vele "standaard"

onderzoeken kunnen achterwege warden gelaten, maar sommige onderzoeken zij n nog steeds

noodzakel ijk voorafgaand aan behandel ing om infectieuze compl icaties te voorkomen. lnfecties

vanuit de tractus digestivus hebben een relatie met de ernst van de mucositis . Het aantal i nfecties

kan mogel i jk verminderd warden nu er een groeifactor besch ikbaar is, namel i jk pal ifermin, die

de mucositis na hoge dosis chemotherapie reduceert. De centraal veneuze katheter is de meest

voorkomende bron van infecties tijdens de periode van neutropenie. Gezien het zeer hoge

percentage infectieuze comp l icaties van de centraal veneuze katheter, verdient het de voorkeur

bij e lke patient zorgvuldig de indicatie voor de centraal veneuze katheter te bekij ken. Als een

katheter is gep laatst, dient deze zo snel mogel i jk verwijderd te warden a l s er geen absol ute

noodzaak meer voor is . Het tijdstip van plaatsen van de katheter is zeer kritisch voor het later

ontwikkelen van katheter-gerelateerde infecties en dit dient daarom uitgevoerd te warden volgens

een strikt aseptisch protocol . Er zij n ook andere manieren om de kans op katheter-gerelateerde

infecties te verminderen. Aseptische technieken bij hanteren van de katheter en huid-desinfectie

hebben bewezen waarde. Andere moge l ij kheden om katheter-gerelateerde infecties te

vermi nderen zij n impregnatie van de katheter met antib iotica en gebru i k van een perifeer

geplaatste katheter of vol ledig ge·imp lanteerde katheter (VAP).

Concluderend is het mogel ij k om de bijwerkingen van hoge dosis chemotherapie op een aantal

fronten te verbeteren. Verbeteringen in supportive care zul len zich rechtstreeks vertalen in betere

uitkomsten voor patienten behandeld met hoge dosis chemotherapie. Hoge dosis chemotherapie

is zeker n iet defi n itief u it het kl i n isch oncologisch arsenaal verwijderd. De komende jaren zal de

precieze rol op basis van onder andere meta-analyses duide l ij k warden. Er za l dan gekeken

moeten warden wat de rol ervan is naast de veelheid aan nieuwe middelen zoals trastuzumab,

de aromatase remmers, tyrosi ne kinase remmers zoa ls lapati n ib (werkend op zowel HER1 als

HER2) en de angiogenese remmers.

List of Publications

1 56

N ieboer P, Ku ipers EJ, Hazenberg HJ . Feces op occu lt bloed obsoleet. Ned Tijdschr Geneeskd

1 996; 1 40:2 -4.

N ieboer P, van Erve RHGP, Driessen APPM. Fracturen door osteoporose b ij man nen. Ned

Tijdschr Traum 1 998;6 : 1 59-64.

N ieboer P, Gietema JA, de Vries-Hospers HG, van der Graaf WT A. An unusual presentation of

sepsis caused by coagu lase-negative staphylococci . Neth J Med 1 999;55:55-9.

N ieboer P, van der Werf TS, Beentjes JAM, Tu l leken J E, Zij l stra JG, L igtenberg JJM.

Catecholamine-dependency in a polytrauma patient: relative adrenal i nsufficiency? I nt Care Med

2000;26: 1 2 5-7.

N ieboer P, Vel lenga E, Adriaanse R, van de Loosdrecht AA. Central d iabetes ins ip idus precedi ng

acute myeloid leukemia with t(3 ; 1 2) (q26;p1 2) . Neth J Med 2000;56:45-7.

N ieboer P, de Knegt RJ, van Du l lemen HM, van der G raaf WTA. Rectal sydrome as fi rst

presentation of metastatic breast cancer. Am J Gastroenterol 2000;95 :2 1 38-9.

Ligtenberg JJM, N ieboer P, Beentjes JAM, van der Werf TS, Tul leken J E, Zij lstra JG. A new therapy

for a new syndrome. I nt Care Med 2000;26: 1 01 3 .

N ieboer P, de Vries EGE, Mulder N H, Sleijfer DTh, W i l lemse PH B, Hospers GAP, G ietema JA,

S lu iter WJ , van der Graaf WTA. Long-term haematologica l recovery fo l lowi ng h igh-dose

chemotherapy with autologous bone marrow transplantation or periphera l stem cel l

transp lantation in patients with sol id tumors. Bone Marrow Transplant 2001 ;2 7:959-66.

N ieboer P, Mulder N H, van der Graaf WTA, Wi l lemse PHB, Hospers GAP. Dacarbazine (DTIC)

and carboplati n as an outpatient treatment for d issem inated mal ignant melanoma. Anticancer

Res 2001 ; 2 1 :3 1 1 5-6.

Van Steijn J HM, N ieboer P, Hospers GAP, de Vries EG E, Mu lder N H . Del i ri um after i nterleukin-

2 and a lpha-interferon therapy for renal cel l carc inoma. Anticancer Res 200 1 ;21 :3699-3 700.

Van Steijn JHM, van der Graaf WTA, van der S l u i s A, N ieboer P. How to d iagnose card iac

tamponade. Neth J Med 2002;60:334-8.

N ieboer P, Roodenburg J LN, van der Laan B FAM, de Vries EGE, Mu lder N H, van der Graaf WT A.

Screen i ng for i nfectious foci in breast cancer patients prior to h igh-dose chemotherapy and stem

cel l transplantation. Anticancer Res 2003:2 3 : 1 779-84.

List of Publications

Rentinck MEM, Nieboer P, Sleijfer DTh, van der Graaf WTA. Chemotherapy for metastatic seminoma in elderly patients. Anticancer Res 2003;23:3093-96.

Nieboer P, de Vries EGE, Vellenga E, van der Graaf WT A, Mulder NH, Sluiter WJ, de Wolf JThM. Factors infuencing haematological recovery following high-dose chemotherapy and peripheral stem-cell transplantation for haematological malignancies: 1-year analysis. Eur J Cancer 2004;40: 1199-1207.

Nieboer P, de Vries EGE, Mulder NH, van der Graaf WT A. Relevance of high-dose chemotherapy in solid tumours. Cancer Treat Rev 2005;31 :210-25.

Nieboer P, Buijs C, Rodenhuis S, Seynaeve C, Beex LVAM, van der Wall E, Richel DJ, Nooij MA, Voest EE, Hupperets P, Mulder NH, van der Graaf WTA, TenVergert EM, van Tinteren H, de Vries EGE. Fatigue and relating factors in high-risk breast cancer patients treated with adjuvant standard or high-dose chemotherapy: a longitudinal study. J Clin Oncol 2005;23:8296-304.

Waanders F, van Hengel P, Krikke A, Wesseling J, Nieboer P. Sarcoidosis mimicking metastatic disease, a case report and review of the literature. Neth J Med 2006;64:342-45.

De Boer J , Jager PL, Wiggers T, Nieboer P, Wymenga ANM, Pras B, Hoogenberg K, Sleijfer DTh, van der Graaf WTA. The therapeutic challenge of a nonresectable solitary fibrous tumour in a hypoglycemic patient. Int J Clin Oncol 2006;11 :478-81.

Duiverman ML, Cohen D, van Oven W, Nieboer P. Diabetes de novo in a patient treated with olanzapine: a case report and proposal for hyperglycaemia screening. Neth J Med 2007;65 :346-48.

Nieboer P, de Vries EGE, Mulder NH, Rodenhuis S, Bontenbal M, van der Wall E, van Hoesel QG, Smit WM, Hupperets P, Voest EE, Nooij MA, Boezen HM, van der Graaf WT A. Factors influencing catheter-related infections in the Dutch multicenter study on high-dose chemotherapy followed by peripheral stem-cell transplantation in high-risk breast cancer patients. 2007; submitted.

Buijs C, Mom CH, Willemse PHB, Boezen HM, Maurer JM, Wymenga ANM, de Jong RS, Nieboer P, de Vries EGE, Mourits MJE. Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: a double-blind, randomized cross-over study. 2007; submitted.

J 1 57

Dankwoord

Het is gelukt! ! Een mijlpaal is bereikt: mijn proefschrift is af.

Een proefschrift schrijf je niet alleen. Zonder de hulp van velen zou dit boekje niet tot stand zijn gekomen. lk wil bij deze graag van de gelegenheid gebruik maken om iedereen die meegeholpen heeft, te bedanken voor de "supportive care". Hopelijk zonder anderen tekort te doen, wil ik een aantal mensen in het bijzonder noemen.

Allereerst wil ik mijn drie promotoren bedanken, Prof.cir. E.G.E. de Vries, Prof.cir. W.T.A. van der Graaf en Prof.cir. N.H. Mulder. lk dank jullie alle drie voor het vertrouwen dat jullie in mij hadden. Hoewel ik zelf in het begin ernstige twijfels had over mijn wetenschappelijke ambities en mogelijkheden, ben ik nu erg blij dat jullie me over de streep hebben weten te trekken om dit boekje te schrijven. Verder dank ik jullie voor het enthousiasme waarmee jullie me hebben begeleid, jullie opbouwende kritieken en met name voor het geduld dat jullie met me hadden bij de totstandkoming van dit proefschrift.

Beste Liesbeth. lk sta nog steeds versteld van je ongeevenaarde werktempo, je gedrevenheid en de enorme hoeveelheid ideeen die je hebt. Het is inmiddels legendarisch hoe snel je artikelen kunt reviseren. Dit heeft menig promovendus tot wanhoop gebracht. Maar het heeft er bij mij toe geleid om naast baan en gezin dit proefschrift af te ronden. lk hoop dat onze samenwerking hiermee niet is afgelopen. lk heb veel van je geleerd.

Beste Winette. Het is maar weinigen gegeven om naast een goed en betrokken clinicus ook een uitmuntend onderzoeker te zijn. Je vertrek uit het UMCG betekent een aderlating voor de afdeling medische oncologie in Groningen. lk dank je voor het feit dat je mij, ook in moeilijke tijden, altijd hebt geholpen en voor me klaar stond. lk mis je nu je in het verre Nijmegen zit, maar ik weet je te vinden voor een advies.

Beste Nanno. lk maak nog dagelijks gebruik van je wijze lessen en denk met veel plezier terug aan de wekelijkse bijeenkomsten, waarin je mij als fellow de zin en onzin van medisch oncologisch handelen probeerde bij te brengen. Je enorme kennis van zaken maakt dat ik af en toe de behoefte heb om "even je hersenen te lenen".

Prof.cir. S. Rodenhuis, Prof.dr. D.J. Richel en Prof.cir. T.S. van der Werf wil ik danken voor hun bereidheid plaats te nemen in de leescommissie. Sjoerd, Dick en Tjip, dank voor de snelle beoordeling van mijn proefschrift.

lk zou "de anderen" op de afdeling medische oncologie van het UMCG tekort doen als ik hen ook niet zou bedanken. Prof.dr. D.Th. Sleijfer, beste Dirk. Je hebt me geleerd dat een probleem

1 so I

Dankwoord

altijd opgelost dient te warden en nooit terzijde mag warden geschoven. lk heb (op een na) al je wijze adviezen opgevolgd. Prof.dr. P.H.B. Willemse, beste Pax, Dr. J.A. Gietema, beste Jourik, Dr. G.A.P. Hospers, beste Geke, mede dankzij jullie is de opleiding tot medisch oncoloog in het UMCG van hoog niveau. Dank voor de fijne manier van samenwerken, die overigens na dit boekje zeker niet zal stoppen.

Willy, Gretha, Bianca en Sylvia. Hartelijk dank voor jullie secretariele (maar met name ook geestelijke) ondersteuning.

Al ie co-auteurs en alle mee-denkers wil ik hartelijk danken voor hun respectievelijk enthousiast meeschrijven en meedenken.

Voor een deel van mijn onderzoek heb ik een rondgang gemaakt door Nederland, langs alle centra die hebben meegedaan aan de zogenaamde 4+ studie. Dit is een studie naar de meerwaarde van hoge dosis chemotherapie bij borstkanker. De bereidheid in alle ziekenhuizen om mij te helpen met het verzamelen van de gegevens was opvallend. lk wil iedereen daar hartelijk voor bedanken: de oncologen ter plaatse, de onderzoekers, de research­verpleegkundigen en de datamanagers. Een deel van het onderzoek, waarvan de resultaten in dit boekje zijn beschreven, werd mogelijk door een doelmatigheidsproject, gefinancierd door CVZ (College voor Zorgverzekeringen), die ik daarvoor hartelijk wil bedanken.

Gerry Sieling, Bregtje Oosterhuis en Jos Dijkstra wil ik danken voor het verzamelen van patienten­gegevens en het bijhouden van de verschil lende databases.

Astrid Appelhof zorgde ervoor dat het boekje ook echt een boekje werd. Daarvoor mijn dank.

Mijn paranimfen Bas Nieboer en Harald Faber wil ik bedanken voor hun hulp en ondersteuning voorafgaand aan en tijdens "de dag". lk laat de regie graag even aan jullie over.

De internisten van de Maatschap lnterne/MDL, de secretaresses, endoscopie- en poli-assistentes van het Wilhelmina Ziekenhuis in Assen bedank ik voor het begrip en de morele steun bij de laatste loodjes van dit proefschrift.

Janjaap, Maarten, rest van mijn familie, schoonfamilie, vrienden en vriendinnen. Jullie wil ik bedanken voor de steun die jullie elk op geheel eigen wijze hebben gegeven. Binnenkort weer wat meer tijd voor andere dingen!

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Lieve vader en moeder, dank voor j u l l ie steun en betrokkenheid. J u l l ie zij n onmisbaar voor me

en hebben me gesteund in mi jn streven dokter, i ntern i st, oncoloog en uitei ndel i jk Dr. te warden.

Daarom draag ik dit boekje aan j u l l ie op.

Het gevaar van een dankwoord i s dat iemand vergeten wordt. Ik w i l daarom iedereen bedanken

die op de een of andere mani er heeft meegewerkt aan m ij n proefschrift.

En tot s lot. Tanja, dankjewel dat je er altijd bent voor m ij . Bart en Mare, i k leer iedere dag van

ju l l ie. Ik heb j u l l ie drie l ief.