Phase I Trial of Sequential High-Dose Chemotherapy with ......Vol. 4, /689-1695, July 1998 Clinical Cancer Research 1689 Phase I Trial of Sequential High-Dose Chemotherapy with Escalating

Vol. 4, /689-1695, July 1998 Clinical Cancer Research 1689

Phase I Trial of Sequential High-Dose Chemotherapy with Escalating

Dose Paditaxel, Melphalan, and Cyclophosphamide, Thiotepa, and

Carboplatin with Peripheral Blood Progenitor Support in

Women with Responding Metastatic Breast Cancer’

Linda T. 2 Kyriakos Papadopoulos,

Casilda Balmaceda, Trish McGovern,

Jane Dunleavy, Elizabeth Kaufman,

Blanche Fung, Thomas Garrett, David Savage,

Amy Tiersten, Janet Ayello, Emilia Bagiella,

Daniel Heitjan, Karen Antman, and

Charles HesdorfferDivision of Medical Oncology and Hematology, Department of

Medicine Columbia University College of Physicians and Surgeons,

New York, New York 10032

ABSTRACT

A single high-dose cycle of chemotherapy with stem cell

support can produce disease-free survival of 15-20% for at

least 3 years in women with responding stage IV breast

cancer. North American Autobogous Bone Marrow Trans-

plant Registry data suggest that a complete response (CR) is

the single most important prognostic factor associated with

prolonged disease-free survival. Therefore, if sequential

high-dose chemotherapy can increase the CR rate, then

perhaps an increased proportion of patients will remain

disease free.

Women with at least a partial response (PR) to induc-

tion chemotherapy received three separate high-dose cycles

of chemotherapy with peripheral blood progenitor support

and granulocyte colony-stimulating factor. The first inten-

sification was a dose escalation of paditaxel (400-825 mg/

m2), the second intensification was melphalan (180 mglm2),

and the third intensification consisted of 6000 mg/m2 cyclo-

phosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125

mg/m2/day), and 800 mg/m2 carboplatin (200 mglm2/day;

CTCb).

Thirty-six women were enrolled and 31 completed all

three cycles. After the paditaxel infusion most patients de-

veloped reversible predominantly sensory neuropathy. Of

Received 12/5/97; revised 4/15/98; accepted 4/17/98.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby marked

advertisement in accordance with 18 U.S.C. Section 1734 solely to

indicate this fact.

‘ Supported in part by USPHS Grant P30-CA13696-2l, NCI R21

CA66244-0l , and P20CA66244-0l . L.T.V. is a Michael Cohen Scholar.2 To whom requests for reprints should be addressed, at Blood andMarrow Transplant Unit, Division of Medical Oncology, MHB 6N-435,177 Fort Washington Avenue, New York, NY 10032. Phone: (212)305-2486; Fax: (212) 305-6798.

the 19 patients with measurable disease, 6 converted to CR,

7 converted to a PR* (the complete resolution of all soft

tissue or visceral disease with sclerosis of prior lytic bone

lesions), and 2 had a further PR for an overall response rate

of 79%. Two patients had no further response and disease in

two patients progressed, and thus they were taken off the

study before CTCb. Seventy-eight percent are progression-

free at a median follow-up of 14 months (range, 3-24+).

Three sequential cycles of high-dose chemotherapy are

feasible and were administered in this study with no mor-tality. Single agent pacitaxel at doses up to 825 mg/m2 werewell tolerated with moderate reversible toxicity.

INTRODUCTION

Although breast cancer is considered a highly curable

disease if detected early in its course, disseminated breast cancer

is associated with a grave prognosis with a median survival of

less than 3 years (1, 2). North American Autologous Bone

Marrow Transplant Registry data and multiple single institution

Phase II trials confirm that a single high-dose cycle of chemo-

therapy can produce disease-free survivals of 15-20% for at

least 3 years (3). Furthermore, progression-free survival can be

stratified by response to chemotherapy with patients with tu-

mors responding completely associated with a higher probabil-

ity of remaining progression-free than those with partial or

nonresponding tumors.

Fifteen to twenty percent of patients whose tumors respond

completely to either conventional or high-dose chemotherapy

remain disease-free for up to 10 years (3, 4). The percentage of

patients achieving a CR3 to cytotoxic chemotherapy in Phase II

trials is higher for high-dose chemotherapy than for conven-

tional dose chemotherapy; however, an increased response rate

may not always translate into a similarly increased disease-free

survival rate (5).

In the only published randomized trial of high-dose therapy

versus conventional dose therapy for metastatic breast cancer,

Bezwoda et a!. (6) randomized patients between high-dose

cyclophosphamide, mitoxantrone, and etoposide for two cycles,

compared with conventional dose cyclophosphamide, mitox-

antrone, and vincristine. The disease-free and overall survival of

the women randomized to the high-dose chemotherapy was

significantly improved over their counterparts in the lower dose

3 The abbreviations used are: CR, complete response; PR, partial re-sponse; PR*, complete resolution of all soft tissue or visceral disease

with sclerosis of prior lytic bone lesions; G-CSF, granulocyte colony-

stimulating factor; DLT, dose-limiting toxicity; ANC, absolute neutro-

phil count.

Research. on July 26, 2021. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

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1690 Escalating Dose Paclitaxeb in Metastatic Breast Cancer

arm. However, an I 1-fold increase in response rate translated

into only a 2-fold improvement in disease-free survival.

Several arguments favor evaluation of sequential high-dose

chemotherapy as compared with a single high-dose cycle. First,

in the analysis of registry data, a CR is the single most important

prognostic factor associated with prolonged disease-free sur-

vival (3). Hence, if sequential high-dose chemotherapy could

increase the CR rate, then perhaps an increased proportion of

patients would remain disease-free. Secondly, the curative

chemotherapy regimens for tumors such as testis, lymphoma,

and for breast cancer in the adjuvant setting require repetitive

chemotherapy cycles. In a review of the several sequential

high-dose chemotherapy trials completed over the past 8 years,

the CR rate ranged from 23-93% with as many as 35% disease-

free at 44 months of follow-up (7).

Paclitaxel is one of the most active agents against breast

cancer to emerge in the past 20 years. Preclinical data in breast

cancer cell lines and MCA-4 transplanted tumors in C3Hf/Kam

mice support a dose-concentration/response effect in breast can-

cer (8, 9). The relative importance of dose has not been ade-

quately evaluated clinically because of the narrow therapeutic

index with dose-limiting schedule-dependent myclosuppression

or neurotoxicity. The Denver group escalated the dose of pacli-

taxcl in combination with cisplatin and cyclophosphamide in a

Phase I trial in heavily pretreated patients with advanced cancer

(10). They reported responses, even in heavily pretreated breast

cancers, as well as severe central nervous system toxicity and an

adult respiratory distress syndrome-type pulmonary process

with one toxic death at the 825 mg/rn2 dose of paclitaxel. The

contribution of paclitaxel or the other agents to either response

or toxicity is difficult to evaluate.

On the basis of these data, determining the feasibility of

escalating the dose of single agent paclitaxel as a part of a

planned sequential high-dose chemotherapy regimen is a rca-

sonablc research strategy in women with responding metastatic

breast cancer.

PATIENTS AND METHODS

Patient Eligibility. Women ages 18-60 years with re-

sponding (PR or CR) histologically documented stage IV breast

cancer were eligible if hepatic (bilirubin level � 2 times normal,

aspartatc aminotransferase � I .5 times normal), renal (creati-

nine < 1.5 times normal), and cardiac (left ventricular ejection

fraction �45%) functions and performance status (Eastern Co-

operative Oncology Oroup 0-1 ) were adequate. Exclusion en-

tcria included central nervous system metastases, progression

while on prior taxanc chemotherapy, a disease-free interval less

than 12 months since completion of any ta.xane-containing ad-

juvant therapy, pre-existing grade III or IV neuropathy (National

Cancer Institute Common Toxicity Criteria), prior mitomycin C

or cisplatin chemotherapy, or a cumulative dose of more than

450 mg/rn2 anthracyclines. All patients gave written informed

consent. This study was approved by the Institutional Review

Board of the Columbia Presbyterian Medical Center.

Patients with completely rcsectcd or radiated metastatic

disease were eligible provided that their metastases were not

previously refractory to chemotherapy. For patients with bone as

the only site of metastases, radiological evidence of tumor

Table I Treatment schema

At least three cycles of conventional dose induction chemotherapy

CR or PR

Harvest stem cells

Intensifications, each with PBSC” + G-CSF support

I: Paclitaxel (400-825 mg/rn2)II: Mebphalan ( 180 mg/rn2)III: Cycbophosphamide (6000 mg/m2), thiotepa (500 mg/m2), and

carboplatin (800 mg/rn2)

Post-HDC consolidation therapy

Surgery and/or radiotherapy if feasible

Antihorrnonal therapy for 5 yr if tumor expresses ER or PR+

a PBSC, peripheral blood stem cell; HDC, high-dose chemother-

apy; ER, estrogen receptor; PR, progesterone receptor.

response (i.e. , sclerosis of lytic lesions) coupled with symptomatic

improvement and, where applicable, falling tumor markers was

sufficient. Progression of disease between cycles or life-threatening

(grade IV) toxicity resulted in removal from study. Evaluation by a

reference neurologist and nerve conduction studies were performed

at baseline and before each cycle of therapy and posttherapy.

Treatment. The treatment plan is outlined in Table 1.

Induction chemotherapy was delivered by the referring oncolo-

gist. After documentation of a PR for patients with measurable

disease or after at least three cycles of chemotherapy for patients

whose metastases had been resected or radiated, peripheral

blood hematopoietic progenitor cells were mobilized with

chemotherapy and O-CSF (5 p.g/kg/day s.c.) and a minimum of

3 X 106 CD34+(CD45+/CD14-) mononuclear cells/kg were

harvested and cryopreserved using previously published stand-

ard techniques ( 1 1).

Intensification 1: Paditaxel with Peripheral Blood Stem

Cell Support. After standard premedication with dexametha-

sone, cimetidine, and diphenhydramine, paclitaxel was admin-

istered as a continuous infusion over 24 h. Approximately

one-third of stem cells were infused 72 h later. The paclitaxel

dose was escalated from 400 to 825 mg/rn2 in cohorts of three

to six patients. If DLT developed in two cases, then the prior

dose was designated the maximum tolerated dose. If only one of

the first three patients had DLI, then two additional patients

were treated at that dose. If no DLT was observed, the dose was

escalated. A minimum of 2 weeks must have elapsed after

treatment of the last patient at the prior dose level before

enrollment of patients on the next dose level.

Intensification 2: Melphalan with Peripheral Blood

Stem Cell Support. After recovery from the first intensifica-

tion, patients received melphalan at 90 mg/m2/day for 2 con-

secutive days (180 mg/rn2 total). On day 3, one-third of stem

cells were infused after hydration with 1 liter of isotonic fluid.

Intensification 3: CTCb with Peripheral Blood Stem

Cell Support. With recovery to an ANC � l000/p.L, and in

the absence of platelet refractoriness or disease progression,

patients were admitted for cyclophosphamide (6000 mg/rn2;

1500 mg/m2/day), thiotepa (500 mg/rn2; 125 mg/m2/day), and

carboplatin (800 mg/rn2; 200 mg/m2/day) over 96 h from day

-7 to -3. Mesna (7500 mg/rn2; 1500 mg/m2/day) was admin-

istered by continuous infusion over 120 h. Concomitant use of



No.________

36

34 100

16 47

6 181 3

10 29

1 3

7 21

11 32

16 47

19 56

15 44

6 1828 82

13 46

8 29

3 11

0 0I 4

3 11

9 327 25

5 18

3 11

4 14

8 29

19 681 4

15 54

8 29

3 11

2 7

Clinical Cancer Research 1691

barbiturates, acetaminophen, or steroids during chemotherapy

was precluded to avoid affecting p450 drug metabolism. The

remaining peripheral blood stern cells were infused on day 0.

All patients had complete blood counts and chemistries

checked daily. Prophylactic ciprofloxacin 500 mg twice a day,

fluconazole, acyclovir (if HSV+), and rifampin were begun

when the ANC fell below 500/p.l. G-CSF (5 p.g/kg/day s.c.) was

begun after each stem cell infusion and was continued until the

ANC �l000/p.l for 2 consecutive days.

Patients were discharged home after the stem cell infusion

after the first and second intensifications. At the first neutro-

penic fever, the ciprofloxacin and rifampin was discontinued

and broad spectrum i.v. antibiotics were instituted. Patients were

transfused with irradiated (2,500 rads) products for hemoglobin

<8 gm/dl or platelets <20,000/p.l.

Postintensification Therapy. After recovery from three

intensifications, sites of prior bulk disease were excised or

radiated when feasible. Patients with estrogen or progesterone

receptor positive tumors received antihormonal agents after

completing high-dose therapy when appropriate.

Definition of Terms and Response. DLT was defined as

life-threatening (grade IV) or lethal (grade V) organ damage in

two of three to six patients at a given dose level. Hernatological

recovery was measured from day 0 to ANC �500/p.l, and a

platelet count >20,000/p.l unsupported by transfusion.

Tumors were assessed by physical exam and imaging stud-

ies at entry and 4 to 6 weeks after discharge from the hospital.

A CR or PR is defined as the complete disappearance or

>50% reduction in the sum of the products of the largest

biperpendicular diameters of all measurable disease for at least

4 weeks. PR* is the complete resolution of all soft tissue or

visceral disease with sclerosis of prior lytic bone lesions. Stable

disease is a <25% reduction in the bidimensional measurements

of the lesions. Disease progression is an increase of 25% in

tumor size or the appearance of new lesions.

Statistical Analysis. Descriptive statistics are reported as

medians. Disease-free survival and overall survival are defined

as time from the discharge from the hospital after the third

intensification until disease progression or death, respectively,

and curves were estimated by the Kaplan-Meier product limit

method (12).

RESULTS

Patient Characteristics

From March 1994 until January 1997, 36 women entered

this study. Patient characteristics are listed in Table 2. The

median age for all patients was 43 years with a range of 29-59.

Twenty-eight women were initially diagnosed with local-

ized breast cancer. Primary invasive breast cancer was meta-

chronous and bilateral in two patients and diagnosed during or

immediately after pregnancy in four. One patient had a prior

ductal carcinoma in situ, whereas 6, 16, and 5 patients had stage

I, stage II, and stage III breast cancer, respectively. Nine patients

were node-negative at diagnosis, but eight patients had four or

more lymph nodes involved with breast cancer. Most patients

had received adjuvant chemotherapy (23) or tamoxifen (3).

Fifteen of 23 patients (65%) had received an anthracycline-

containing regimen.

Table 2 Patient characteristics

Variable

Patients enteredPatients receiving any protocol therapy

Hormone receptor status

ER/PR+”

ER+/PR-

ER-/PR+

ER/PR-

UnknownPredominant metastatic site

BoneSoft tissueViscera

Age (yr)<45

�45

Initial diagnosis stage IV breast cancer

Prior primary breast cancer

Primary tumor size (n = 28)

Tl

13

14

DCIS

Unknown

No. of involved axiblary nodes

01-3

4-9

10+

Unknown

Type of surgeryLumpectomy + node dissection + RTModified radical mastectomyRadical mastectomy

Adjuvant therapyDoxorubicin-containing regimen

Non-doxorubicin regimen

TamoxifenNone

Time from diagnosis to metastases1-23 mo24+ mo

%

7 25

21 75

a ER, estrogen receptor; PR, progesterone receptor; DCIS, ductal

carcinoma in situ; RI, radiation therapy.

Nineteen patients had undergone a modified radical mas-

tectomy, eight patients had lumpectomy and radiation therapy,

and one patient had a radical mastectomy. The median disease-

free interval from diagnosis to stage IV disease was 37 months

(range, 3-125).

Initial Presentation of Stage IV Breast Cancer

Six patients (18%) had advanced breast cancer as their

initial diagnosis. Metastatic sites included ipsilateral supracla-

vicular lymph node (5) and bone (1).

Treatment

The majority of patients had one chemotherapy regimen for

metastatic breast cancer (range, 1-5). Of the 36 patients entered,

2 were removed from the study for inadequate stem cell collec-

tions and 2 were removed because of disease progression; I

patient refused to continue because she felt so well with good



1692 Escalating Dose Paclitaxeb in Metastatic Breast Cancer

Table 3 Paclita xel dose escalation levels

Paclitaxeb dose (mg/rn2) No. of patients

400 5

480 3575 3

690 5

725 9

775 6

825 3

disease control after two high-dose cycles. Thirty-one patients

completed all three high-dose cycles of chemotherapy. There

were no toxic deaths and veno-occlusive disease of the liver was

not observed. Thus, 34 patients were at least partially evaluable

for toxicity. Of the 23 patients with hormone receptor-positive

tumors, 13 received tamoxifen, 9 received anastrazole, and 1

required no further therapy.

Intensification 1: Paclitaxel with Peripheral Blood Stem

Cell Support

Thirty-four patients were treated with paclitaxel according

to the dose escalation scheme presented in Table 3.

Myelosuppression was variable with a median time to

ANC �500/p.l of 6 days and with only two patients decreasing

their platelets to <20,000/pA (Table 4). The median duration of

ANC �500/p.l was 4 days (range, 0-6) and did not seem to be

dQse related. Forty-one percent (14 of 34 patients) were read-

mitted with neutropenia/fever (12), or severe mucositis (2).

Positive blood cultures were obtained in two patients. Polymi-

crobial sepsis (pseudomonas aeroginosa, serratia marcescans,

klebsiella pneumonia, staph epidermidis, and xanthomonas mal-

tophilia) in one patient was attributed to contaminated IV solu-

tion, and the other bacterernia was due to xanthomonas malto-

philia.

Cardiac. Two patients developed transient atrial fibrilla-

tion at the 400 and 725 mg/rn2 dose level.

Hepatic. Transient elevations in total bilirubin ranging

from 1.2- 3.9 rng/dl (median, 1.5) was observed in 65% (22 of

34) of patients occurring on day -3 to day +5. Of 34 patients,

32 developed a mild (National Cancer Institute criteria grade I)

to moderate (grade II) transaminitis over the same interval.

Neurological. Neurotoxicity was predominantly sensory,

however, 5 of 18 patients treated at paclitaxel doses �725

mg/rn2 developed weakness. Both the motor and sensory

changes were reversible. Nerve conduction studies revealed

statistically significant decreased amplitude in sensory (median,

ulnar and sural) as well as motor (peroneal >> tibial) nerves

across all dose levels suggesting an axonal neuropathic process.

Gait difficulties resembling ataxia were observed in patients

receiving doses �725 mg/m2. One patient receiving paclitaxel

at 775 mg/rn2 developed an unexplained Horner’s syndrome

between the second and third intensifications (evaluation in-

eluded magnetic resonance imaging and lumbar puncture). An-

other patient treated at 690 mg/rn2 developed a peroneal nerve

palsy 3 months after completing paclitaxel. This patient entered

the program with a left peroneal nerve palsy attributed to a

decompression injury. She completed the first intensification

Table 4 Hemat obogical and toxicity data

Variable Paclitaxel Melphalan CTCb

No. of patients 34 34 31

Hematological parametersCD34 + cells/kg infused

Median 1.06 1.13 1.69Range 0.45-1.86 0.78-2.08 0.67-3.06

Days to:

ANC � 500//p.l

Median 6 10 10Range 0-9 9-13 8-11

pbts � 20kJ/�b

Median 0 13 13Range 0-7 0-17 9-20

Units transfused

PRBC”

Median 0b 1 3

Range 0-I 0-8 1-6Platelets

Median 0� 12 36Range 0-6 0-30 6-66

Grade III or IV toxicitiesStomatitis/esophagitis 10 5 20

Nausea/vomiting 4/4 4/2 13/6

Diarrhea 0 1 10

LiverVOD 0 0 0Elevated bilirubin 14 5 12

Bacteremia 2 2 6

C. difficile 0 0 4Cardiac

Arrhythmia 2 0 0

Myocarditis 0 0 1

Mortality 0 0 0

a PRBC, packed red blood cells; VOD, veno-occlusive disease.b Three patients were transfused with one unit of PRBC each.C One patient received a platelet transfusion.

with a maximal sensory neurotoxicity of 3 + , which resolved by

the end of the third intensification. One month later, she devel-

oped a right peroneal nerve palsy which has not changed at 11

months of follow-up.

Other. Myalgias requiring varying types of analgesia

(acetaminophen to morphine sulfate) were observed in all pa-

tients. Obstipation lasting up to I week was observed in patients

treated at dose levels �725 mg/rn2; however, no bowel obstruc-

tion was observed and this problem resolved with the use of

laxatives.

Intensification 2: Melphalan with Peripheral Blood Stem

Cell Support

Thirty-four patients received the second intensification a

median of 22 days (range, 15-77) after the first intensification.

Sixteen patients were initially treated as inpatients and, once

deemed feasible, the remainder received melphalan as outpa-

tients.

The median time to ANC �500/p.l was 10 days (range,

9-13) and platelets to >20,000/p.l was 13 days (range 0-17;

Table 4). Twenty-one of 34 patients were readmitted with neu-

tropenia/fever (18), or severe mucositis (3). Two patients were

bacteremic with Escherichia coli and Streptococcus sanguis,

respectively.



� 1 #{149} I

‘�- .6

Cl)

E .4C-)

.2

0�I #{149}I #{149}I #{149}I ‘ ‘� #{149}I

0 5 10 15 20

Time (months)

Fig. I Kaplan-Meier curves of progression-free (0) and overall sur-vival (El).


Six patients (32%) converted from a PR to a CR, seven

T able 5 Tumo r responses

Paclitaxel (mg/rn2) No.

Pre-HDC” Post-HDC

SD PDCR PR Ineval CR PR PRb Ineval

400 5 0 3 2 3 0 0 2 0 0480 3 0 2 1 1 0 0 1 1 0575 3 0 2 1 0 1 0 2 0 0690 5 0 5 0 0 0 3 0 1 1

725 9 2 5 2 3 1 2 2 0 1

775 6 1 2 3 1 0 2 3 0 0

825 3 0 1 2 1 0 0 2 0 0

Totals 34 3 20 Il 9 2 7 12” 2 2

a HDC, high-dose chemotherapy; Ineval, inevaluabbe; SD, stable disease; PD, progressive disease.

b Includes one patient who refused to complete the third intensification.

Intensification 3: CTCb with Peripheral Blood Stem Cell

Support

Two patients did not receive the third intensification be-

cause of progressive disease in the chest wall (1) and visceral/

soft tissue sites (1). Thirty-one patients proceeded to the inpa-

tient third intensification. The median interval between the

second and third intensifications was 30 days (range, 17-63).

The median time to ANC �500/p.l was 10 days (range,

8-I 1 ) and platelets to >20,000/p.l was 13 days (range, 9-20).

Toxicities included bacteremia (6), transient myocarditis (1),

grade III or IV nausea (13), vomiting (6), diarrhea (10), stoma-

titis/esophagitis requiring analgesia (20), or Clostridium difficile

(4; Table 4). Six patients (19%) developed dermatomal herpes

zoster 4-6 months after completion of therapy.

Treatment Response

Of the 36 patients entered, 2 were removed from the study

for inadequate stem cell collections (and returned to their refer-

ring physicians), and 1 patient refused to continue because she

felt so well with a PR* after two high-dose cycles. Thus, 33

patients were evaluable for response, time to progression, and

survival and are included in all analyses. The one patient who

refused to complete the final intensification is included in the

toxicity analysis for the first two intensifications; however, she

is excluded from the response, time to progression, and survival

analyses.

The patients received a median of six cycles of induction

chemotherapy before the first intensification: 16 patients under-

went induction with paclitaxel; 10 patients with a doxorubicin-

based regimen; 5 patients with both paclitaxci and doxorubicin;

1 with cyclophosphamide, methotrexate, and 5-fluorouracil; and

2 with vinorelbine. After completion of induction, three patients

were in CR and 20 patients were in PR. Six patients had disease

confined to bone and five patients had their only sites of meas-

urable disease resected after an initial PR to induction therapy

and, hence, are inevaluable for treatment response to high-dose

therapy.

Of the 3 1 patients who completed three cycles of high-dose

therapy, 17 are evaluable for response (3 patients who had prior

PRs did not complete all cycles). Of these, two with progressive

disease are included and one who refused additional therapy was

excluded.

patients (37%) converted to a PR*, two additional patients had

a further PR (70% shrinkage in liver metastases), two patients

had no further response to therapy, and two patients had pro-

gressive disease before the third intensification and did not

complete the third cycle. The PR to CR/PR* rate is 69% for an

overall response rate of 79% (Table 5).

Two patients who presented with stage IV disease under-

went a mastectomy after completion of the high-dose chemo-

therapy and were found to have a pathological CR. Other sites

of disease in these patients were ipsilateral supraclavicular

lymph node (1) and lungs (1).

At 14 months median follow-up, the progression-free sur-

vival is 78%. For those who achieved a CR, 7 of 9 patients

remain progression-free. One relapse occurred at 9 months and

the other patient developed a contralateral inflammatory breast

cancer 7 months after completing therapy. Of seven patients

with resolution of all soft tissue disease but persistently abnor-

mal bone scans (PR*), three have relapsed at 5, 7, and 1 1

months and four remain progression-free at 6-1 1 + months.

One of the four patients with a PR after completing therapy is

alive with disease and the other three have subsequently died.

All five patients who had their disease resected before transplant



1694 Escalating Dose Pacbitaxel in Metastatic Breast Cancer

Table 6 Trials of sequential high-dose chemotherapy

No. CR DFSC FlUInstitution” Regimen” pts (%) (%) mos. Reference

MDAH CEPI x 2 58 55 10 >24 (16)Seattle CEP1 X 2 45 51 17 24 (17)DFCI L/CTCb 67 59 34 9-39 (5)

MSKCC I X 2 42 39 50 13 (18)

Chicago CT/L 27 56 56 >24 (19)

Columbia PIUCTCb 33 69 78 14

a MDAH, M. D. Anderson Hospital; DFCI, Dana-Farber Cancer

Institute; MSKCC, Memorial Sloan-Kettering Cancer Center.b C, cycbophosphamide; E, etoposide; Pb, Cisplatin; L, melphalan;

T, thiotepa; Cb, carboplatin; P. paclitaxel.C DFS, disease-free survival; FlU, follow-up.

(stage IV with no evidence of disease) are disease-free (Fig. 1).

With the exception of the contralateral breast cancer, all failures

occurred at sites of prior bulk disease.

DISCUSSION

Multiple single institution studies and Autologous Blood

and Marrow Transplant Registry data identify CR as the most

significant factor associated with prolonged disease-free sur-

vival after high-dose therapy. Strategies used to increase the CR

rate include the incorporation of new drugs or new schedules of

established drugs into accepted chemotherapy treatment regi-

mens, use of repetitive cycles of high-dose chemotherapy, and

novel post-transplant consolidation strategies with various types

of immune modulation (13-15).

This study has adopted the strategies of repetitive dosing

and of incorporation of new active agents. Several institutions

have piloted sequential cycles of high-dose chemotherapy for

patients with breast cancer as long as a decade ago, although the

testing of this strategy only really became feasible with the

advent of hematopoietic growth factors and mobilization of

large numbers of blood derived stem cells which tended to result

in more rapid marrow recovery (5, 16-19; Table 6).

Paclitaxel, one of the most active drugs to emerge in the

last 20 years, has been escalated in combination with other

agents by several other investigators (10, 20-22) who have

reported coma and a dose-limiting adult respiratory distress

syndrome-like capillary leak syndrome at doses of 825 mg/rn2

leading to the death of one patient.

We have administered this dose of paclitaxel as a single

agent with only moderate and largely reversible toxicity. All,

intensifications but two were given on time, and these delays

were due to iatrogenic polymicrobial sepsis and a patient who

was considering whether to forgo further high-dose therapy and

not due directly to toxicity of therapy.

Conventional dose paclitaxel has been associated previ-

ously with a diffuse sensory polyneuropathy. With higher doses,

the sensory neuropathy seemed to be most evident within the

first week after paclitaxel and then rapidly improved before the

second intensification, resolving completely as long as 9 or 10

months later. We observed motor weakness in 5 of the 18

patients treated at the 725 and 775 mg/rn2 dose levels, although

none was observed in the 3 patients treated at the 825 mg/rn2

dose level. Whether the development of a grade IV peroneal

nerve palsy at 3 months after the completion of therapy was a

delayed toxicity of high-dose paclitaxel therapy remains un-

known. Although Yubero et al. (23) reported that neurotoxicity

of high-dose paclitaxel correlated with prior neurotoxic chem-

otherapy, no correlation between dose or number of prior cycles

of paclitaxel, prior neuropathy, or presence of liver metastases

was observed in our study.

Several issues remain to be addressed including whether

paclitaxel represents the best agent to incorporate into this

high-dose regimen, its optimum schedule, and whether pacli-

taxel is best administered as a single agent or in combination

with other active agents. Because of the small numbers of

patients treated at each dose level and the substantial concurrent

therapy, an analysis of dose response would be unreliable. Other

issues relate to the sequence of the high-dose regimens and the

potential induction or loss of drug resistance (24). Finally, the

pattern of myelosuppression and hematological recovery sug-

gests that peripheral blood progenitor support may not be re-

quired at these doses of paclitaxel.

This study demonstrates that three sequential cycles of

high-dose chemotherapy are feasible and can be safely admin-

istered without mortality. In addition, single agent paclitaxel at

doses up to 825 mg/rn2 is well-tolerated with moderate revers-

ible toxicity. The observation of transient muscle weakness

observed at the higher dose levels suggested that further dose

escalations would be hazardous, and thus we proceeded with the

Phase II trial using 825 mg/m2. The sequence of high-dose

paclitaxel, melphalan, and cyclophospharnide, thiotepa, and car-

boplatin resulted in a high complete remission rate. Whether this

alone is sufficient to extend disease-free survival requires fur-

ther follow-up.

ACKNOWLEDGMENTSWe thank the nursing and house staff for the excellent care ren-

dered our patients, and Dr. Phyllis Della LaUa and Tom Fisher for

assistance with collection of the microbiology data.

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1998;4:1689-1695. Clin Cancer Res L T Vahdat, K Papadopoulos, C Balmaceda, et al. support in women with responding metastatic breast cancer.thiotepa, and carboplatin with peripheral blood progenitorescalating dose paclitaxel, melphalan, and cyclophosphamide, Phase I trial of sequential high-dose chemotherapy with

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