PDF hosted at the Radboud Repository of the Radboud University

Nijmegen

The following full text is a publisher's version.

For additional information about this publication click this link.

http://hdl.handle.net/2066/209059

Please be advised that this information was generated on 2022-09-25 and may be subject to

change.

IMPROVING PERSONALISED CARE IN HEAD AND NECK CANCER PATIENTS Janneke Ham

IMPROVING PERSONALISEDCARE IN HEAD AND NECKCANCER PATIENTS

Janneke Ham

UITNODIGINGvoor het bijwonen vande openbare verdedigingvan het proefschrift

IMPROVING PERSONALISEDCARE IN HEAD AND NECK CANCER PATIENTS

op dinsdag 5 november 2019om 16.30 uur preciesin de Aula van de Radboud Universiteit, Comeniuslaan 2,Nijmegen.

Janneke HamJanneke_ham@hotmail.com

PARANIMFENChantal DriessenChantal.driessen@radboudumc.nlLaura Derksen - van Nunspeetlderksen2014@outlook.com

IMPROVING PERSONALISEDCARE IN HEAD AND NECKCANCER PATIENTS

Janneke Ham

Improving personalised care in head and neck cancer patients

© J.C. Ham, 2019

All rights are reserved. No part of this book may be reproduced, distributed, stored in

a retrieval system, or transmitted in any form or by any means, without prior written

permission of the author.

ISBN: 978-94-6380-535-3

Design and lay-out: wenz iD || Wendy Schoneveld

Print: ProefschriftMaken || Proefschriftmaken.nl

IMPROVING PERSONALISED CARE INHEAD AND NECK CANCER PATIENTS

Proefschrift

ter verkrijging van de graad van doctor

aan de Radboud Universiteit Nijmegen

op gezag van de rector magnificus prof. dr. J.H.J.M. van Krieken,

volgens besluit van het college van decanen

in het openbaar te verdedigen op dinsdag 5 november 2019

om 16.30 uur precies

door

Johanna Catharina Ham

geboren op 2 september 1983

te Gouda

Promotoren: Prof. dr. W.T.A. van der Graaf

Prof. dr. C.M.L. van Herpen

Manuscriptcommissie: Prof. dr. J. Bussink (voorzitter)

Prof. dr. H. Vermeulen

Prof. dr. R. de Bree (UMC Utrecht)

Contents

Chapter 1 Introduction and outline of the thesis 7

Chapter 2 Prophylactic antibiotics reduce hospitalisations and cost in

locally advanced head and neck cancer patients treated with

chemo radiotherapy. A randomised phase 2 study

19

Chapter 3 Health-related quality of life of patients treated with

chemo radio therapy plus or minus prophylactic antibiotics to

reduce the number of pneumonias for locally advanced head

and neck cancer, the PANTAP study

35

Chapter 4 Pathogens and resistance patterns in locally advanced head and

neck cancer (LAHNC) patients treated with chemoradiotherapy

receiving prophylactic antibiotics

55

Chapter 5 Genetic variants as predictive markers for ototoxicity and

nephrotoxicity in patients with locally advanced head and

neck cancer treated with cisplatin-containing chemoradiotherapy

(the PRONE study).

69

Chapter 6 Methotrexate plus or minus cetuximab as first-line treatment in a

recurrent or metastatic (R/M) squamous cell carcinoma population

of the head and neck (SCCHN), unfit for cisplatin combination

treatment, a phase Ib – randomized phase II study COMMENCE

85

Chapter 7 Summary, general discussion and future perspectives 103

Chapter 8 Nederlandse samenvatting 119

Appendix PhD Portfolio

Research data management

List of publications

Dankwoord

Curriculum Vitae

130

131

132

134

138

Introduction and outline of the thesis

C H A P T E R 1

8

C h a p t e r 1

Head and neck cancer in general

Head and neck cancer is the seventh most common type of cancer worldwide. (1) In

2015 the incidence of head and neck cancer was 930,000 worldwide with 379,000

deaths. (2) Two-thirds of the head and neck cancer occurs in developing countries due

to the prevalence of risk factors such as smoking and alcohol consumption, while

nasopharyngeal carcinoma is more common in endemic areas of northern Africa and

Asia, due to the Epstein-Barr virus (EBV). (3) The incidence of head and neck cancer is

3-fold higher among men than women. (3) In the Netherlands, over 3000 new patients

with head and neck cancer were diagnosed in 2017. (4) Head and neck cancer

encompasses tumours that arise in the paranasal sinuses, nasal cavity, oral cavity,

pharynx (oropharynx, hypopharynx and nasopharynx), larynx, and salivary glands.

Because the incidence of the subtypes of head and neck cancer is less than 6 per

100.000, head and neck cancer belong to the rare cancers. Squamous cell carcinomas

are the most frequent type of head and neck cancer (more than 90%), Notable, other

malignancies can also present in the head and neck region, like salivary gland cancers,

melanomas and sarcomas. (5) The term ‘head and neck cancer’ most often refer to

squamous cell cancer of the oral cavity, oropharynx, hypopharynx or larynx.

AetiologyRisk factors for squamous cell carcinoma of the head and neck (SCCHN) are tobacco

and alcohol use. (5, 6) Compared to non-smokers and non-drinkers, those who smoke

more than two packs of cigarettes and drink more than four alcoholic beverages a day

have a 35-fold increased risk of head and neck cancer. (7, 8) Tobacco consumption

during treatment is associated with poorer outcomes. Continued alcohol and tobacco

use after treatment is a risk factor for developing second primary cancers and leads

to decreased 5-year survival. (6) In oropharyngeal cancer, the human papillomavirus

(HPV) has been recognized as another risk factor. (7, 9, 10)The incidence of non-HPV

oropharyngeal cancer is declining, while the incidence of HPV-positive oropharyngeal

cancer increases. (11, 12) There are nearly 200 genotypes of HPV, of which several

high-risk HPV genotypes are considered causative agents in oropharyngeal cancer,

including HPV16, 18, 31, 33, 45, 52, and 58. (13) Of these, HPV16 is most commonly

detected in oropharyngeal cancer with a meta-analysis of global data demonstrating

that 82% of all HPV-positive SCCHN worldwide were attributable to HPV16. (14) (7)

HPV-positive oropharyngeal cancer is associated with younger age at sexual debut,

lifetime number of sexual partners, male sex, and white race, but not with tobacco or

9

Introduction

1

alcohol consumption. HPV positive tumours are associated with a better response to

therapy and much better prognosis. (7)

DiagnosisEarly recognition of signs and symptoms of SCCHN is important, because advanced

stage of disease requires more intensive (multimodality) and toxic treatment and

nevertheless has a worse prognosis. Symptoms of head and neck cancer consist of

hoarseness, sore throat, tongue pain, poorly fitting dentures, otalgia, dysphagia or

stridor. (5) Symptoms are sometimes non-specific and not immediately recognized by

patient or doctor, leading to a delay in diagnosis and treatment. About 60% of patients

with SCCHN present with advanced stage disease, i.e. large primary tumour and/or

lymph node metastases. Distant metastasis at initial diagnosis however is uncommon

(in about 10% of the patients). (5)

Accurate staging is very important for the development of the best treatment plan as

well as the prognosis. Staging methods include physical examination, a

laryngopharyngoscopy under general anesthesia, radiographic imaging of the tumour

(by CT-scan or MRI) and lymph nodes (by ultrasound) and chest imaging for possible

Figure 1. Anatomy of the head and neck, in all of these sides head and neck cancer can originate.

10

C h a p t e r 1

metastasis or detection of lung cancer as second primary tumour. (5) The diagnosis is

confirmed by pathology findings obtained from the tumour and/or draining lymph

nodes. Currently, the 8th edition of the Tumour, Node, Metastasis (TNM) classification

by the American Joint Committee on Cancer (AJCC) is used for staging. (15)

Treatment of locally advanced disease

Treatment of head and neck cancers differs depending on the subtype, stage and the

primary site of the tumour, the age, co-morbidities and condition of the patient. Surgery,

radiotherapy, and chemotherapy/targeted therapy are the main treatment modalities

for curative management of locally advanced SCCHN (i.e., stage III or IV (without distant

metastases)). Surgery is standard treatment for SCCHN, but is frequently limited by the

anatomical extent of tumour and desire to achieve organ preservation. (5) Therefore,

radiotherapy or concomitant chemoradiotherapy is the treatment of choice for locally

advanced SCCHN located in the pharynx and larynx. In SCC of the oral cavity primary

surgery is standard treatment followed by adjuvant radiotherapy or concomitant

chemoradiotherapy in part of the patients. A meta-analysis by Pignon et al. showed an

absolute overall survival benefit for chemoradiotherapy of 6.5% at 5 years compared

with radiotherapy alone. (16) The benefit of chemoradiotherapy was shown for stage III

and stage IV (without distant metastases) disease, each primary site and for primary as

well as postoperative treatment in case of extra-nodal spread, vascular or perineural

invasion, or microscopically irradical tumour resection. (17) The survival advantage is

predominantly attributed to improved locoregional control, but has an non-significant

effect on the development of distant metastases. (5) Especially for oropharyngeal and

laryngeal cancers, concomitant chemoradiation improved overall survival significantly

compared with (neo-)adjuvant chemotherapy followed by radiotherapy and the effect

of chemotherapy was significantly higher with platinum than with other types of mono-

chemotherapies. (18)

Various chemoradiotherapy regimens are being used, of which cisplatin-containing

regimens are generally viewed as the standard. Chemoradiotherapy with cisplatin is

most often applied at a dose of 100mg/m2 every 3 weeks for 3 cycles (RTOG-regimen,

(19)) or at a dose of 40mg/m2 every week for 6 or 7 cycles. (20) Concomitant chemo-

radio therapy with two-drug combinations has also been tested, but did not perform

better than chemoradiotherapy with one single agent.(5) In patients not eligible for

chemotherapy, cetuximab, an IgG1 chimeric monoclonal antibody directed against the

epidermal growth factor receptor (EGFR), in combination with radiotherapy can be

11

Introduction

1considered. In a phase III study by Bonner et al. radiotherapy plus cetuximab showed improved locoregional control and overall survival compared with radiotherapy alone (overall survival at 3 years 55% with cetuximab and radiotherapy compared with 45% with radiotherapy alone, p=0.03). (21)

Toxicity of concomitant chemoradiotherapy Concomitant chemoradiotherapy is known for high rates of acute and late side effects. Acute toxicities consist of mucositis, dermatitis, dysphagia, nausea, vomiting, ototoxicity, nephrotoxicity and bone marrow suppression. The incidence of these toxicities depends on the applied cisplatin schedule and radiotherapy technique, but incidences of 8-68% of nephrotoxicity, 40% of haematological toxicity, and 77% of mucositis are common.(22-24) Dysphagia and aspiration are both frequently underreported during and after chemoradiotherapy. (25) The reported rate of aspiration is between 13-69%. (26, 27). Compared with radiotherapy alone, the incidence of grade 3 or 4 acute toxicities is 47% with radiotherapy alone versus 77% with chemoradiotherapy. (23) Nephrotoxicity as well as ototoxicity are mainly cisplatin-induced. (20, 28) Nephrotoxicity can be characterized by an impaired glomerular filtration rate and/or tubulopathy, while ototoxicity mainly manifests itself by hearing loss, starting with a loss of high tones. (29, 30). Both ototoxicity and nephrotoxicity are dose- and schedule dependent and can be dose-limiting for prescribing cisplatin. (20, 28, 29)Especially in LAHNC patients treated with chemoradiotherapy, infectious complications are seen relatively frequent, due to mucositis, dysphagia and aspiration. But also febrile neutropenia, as a side-effect of the platinum-based chemotherapy, can be a problem. Different prophylactic treatments are investigated to overcome these problems, like granulocyte colony-stimulating factors (G-CSFs) for the prevention of chemotherapy-induced febrile neutropenia(31) and Selective Digestive Decontamination (SDD) with the oral, non-absorbable antimicrobial substances with or without systemtic antibiotics to reduce the risk of gastrointestinal tract derived infections in patients recieving high-dose chemotherapy before autologous stem cell transplantation or to prevent aspirtion pneumonia in the Intensive Care population. (32, 33)Even 5 years after the end of concomitant chemoradiotherapy, LAHNC patients have toxicities grade 3 in 52% and grade 4 in 25%. (34) Late toxicities comprise fibrosis of the subcutaneous tissue, xerostomia, dysphagia, swallowing problems and osteoradionecrosis. The late toxicities are significantly correlated with tumour site (tumours in the oropharynx and oral cavity have more grade 3 and grade 4 toxicities than tumours in the hypopharynx) and with T-stage (higher T-stage have more toxicities). (34)

12

C h a p t e r 1

Concomitant chemoradiotherapy, as well as the disease itself, has a huge impact on

Health Related Quality of Life (HRQoL). During treatment, there is a significant

worsening of HRQoL. Four to six weeks after treatment, HRQoL declines even further,

but improves gradually in the period thereafter. (35-37). One year after the end of

treatment, most patients reported that HRQoL had recovered to baseline. (37, 38) The

global health status, a score of the EORTC QLQ-C30 with higher scores indicating better

functioning, is shown to be predictive of survival with increased mortality risk among

SCCHN patients with lower functioning prior to the start of curative treatment. (39)

Treatment of recurrent or metastatic disease

Despite aggressive treatment for locally advanced disease, a substantial number of

SCCHN patients will develop disease recurrence, with up to 60% risk of local failure

and up to 30% risk of distant failure. (40) (5) In case of locoregional recurrence only,

surgical treatment or re-irradiation with curative intent is possible in a minority of the

patients. However, patients with incurable recurrent or metastatic (R/M) disease have

a poor prognosis with a median overall survival of less than 1 year, frequently even

less than 6 months. (41) The combination of cisplatin, cetuximab and 5-FU (the

“EXTREME” regimen) was the first combination systemic therapy showing an overall

survival benefit compared to cisplatin and 5-FU alone (10.1 months versus 7.4 months).

(42) Although the investigators reported that the toxicity profile of the EXTREME

regimen was manageable, the grade 3 or 4 toxicity rate was 82%. Most frequently

reported grade 3 or 4 toxicities were neutropenia (22%), anemia (13%, thrombocytopenia

(11%) and skin reactions (9%). However, adverse events of any grade (including grade

1 and 2) were not reported in the article, but also long lasting grade 1 or 2 toxicities

can have an impact on HRQoL. Also, in clinical practice this regimen is often too toxic

for this vulnerable patient group, and frequently refused by the patient. Single agent

therapy or combination therapy with methotrexate, docetaxel, paclitaxel, carboplatin

or cetuximab has shown a better tolerance but did not show clinical benefit in terms

of overall survival, (40, 41).

13

Introduction

1Outline thesis

As described above, the primary treatment of HNSCC with concomitant

chemoradiotherapy with cisplatin is challenging for patients as it often coincides with

serious side effects. Also the current standard with cetuximab and platinum/5FU in

the metastatic setting treatment can induce high grade toxicities. Therefore, the aim

of my thesis is to perform studies in HNSCC patients in the curative and palliative

setting with a focus on reduction of early and late toxicity while maintaining treatment

efficacy to obtain knowledge that may improve personalised care and shared decision

making in future patients with head and neck cancer.

In the phase II study “Efficacy and cost efficacy of Prophylactic treatment with Antibiotics

during concomitant chemoradiotherapy in patients with locally advanced head and

neck cancer to prevent Aspiration Pneumonia – PANTAP”, described in Chapters 2-4,

the effect of prophylactic antibiotics in LAHNC patients treated with chemoradiotherapy

will be studied. Because aspiration and aspiration pneumonia have a negative influence

on HRQoL and put an enormous burden on the healthcare-system, it was hypothesized

that prophylactic antibiotics could reduce the number of aspiration pneumonias.

Secondary endpoints of this randomised phase II study are hospitalisation rate, adverse

events, costs and HRQoL. Furthermore, a cost-effectiveness analysis will be performed.

The PANTAP study was awarded with a grant from The Netherlands Organisation for

Health Research and Development (ZonMw).

Patients in the PANTAP study are included prior to the start of chemoradiotherapy,

and are randomised between day 21 and 28 after the start of chemoradiotherapy,

unless they have an infection or are on any antibiotic treatment 14 days prior to

randomization. Patients are randomised between standard of care or prophylactic

amoxicillin/clavulanic acid from day 29 after the start of chemoradiotherapy until 14

days after the end of the chemoradiotherapy. In Chapter 2 I describe the main results

of the PANTAP study: the effect of prophylactic antibiotics on aspiration pneumonias,

hospitalisations, adverse events and the results of the cost-effectiveness analysis. In

Chapter 3 I present the effects of prophylactic antibiotics on HRQoL, while in Chapter 4 I describe the results of the results of the sputum cultures collected during the

PANTAP study.

As ototoxicity and nephrotoxicity are two of the well-known acute and late treatment

toxicities related to chemoradiotherapy with cisplatin in the LAHNC population, it would

be of great value if we could define predictive biomarkers to adjust the treatment

timely, if necessary. In Chapter 5 results will be described of the PRONE study (“Genetic

14

C h a p t e r 1

variants as Predictive markers for Ototoxicity and Nephrotoxicity in patients with locally

advanced head and neck cancer treated with cisplatin-containing chemoradiotherapy”)

on genetic variants to predict ototoxicity and nephrotoxicity in patients treated with

chemoradiotherapy.

For patients with recurrent or metastatic disease there are currently limited treatment

options available and their prognosis is poor, especially in patients not eligible for the

EXTREME regimen. Therefore, “a phase Ib-II study of the Combination of Cetuximab

and Methotrexate in recurrent or metastatic squamous cell carcinoma of the head and

neck - COMMENCE”, was developed were patients with recurrent or metastatic

squamous cell carcinoma of the head and neck and ineligible for or refusing the

EXTREME regimen are randomly assigned to either methotrexate or cetuximab added

to methotrexate. In Chapter 6 I will first describe the results of a phase Ib study with

the combination of cetuximab and methotrexate with feasibility as primary objective.

Therafter, I will describe the COMMENCE study, a randomised phase II, with PFS as

the primary endpoint. Because especially frail or older patients are not eligible for the

EXTREME regimen, and are therefore candidates for the COMMENCE study, important

secondary objectives include the incidence and severity of adverse events and HRQoL.

In Chapter 7, I will summarize the results of these studies and discuss future

perspectives.

15

Introduction

1References

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer. 2015;136(5):E359-86.

2. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA oncology. 2017;3(4):524-48.

3. Marur S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clinic proceedings. 2008;83(4):489-501.

4. IKNL. https://www.cijfersoverkanker.nl 2017 [5. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet (London, England).

2008;371(9625):1695-709.6. Penfold CM, Thomas SJ, Waylen A, Ness AR. Change in alcohol and tobacco consumption after a diagnosis

of head and neck cancer: Findings from Head and Neck 5000. Head & neck. 2018;40(7):1389-99.7. Fung N, Faraji F, Kang H, Fakhry C. The role of human papillomavirus on the prognosis and treatment of

oropharyngeal carcinoma. Cancer metastasis reviews. 2017;36(3):449-61.8. Dal Maso L, Torelli N, Biancotto E, Di Maso M, Gini A, Franchin G, et al. Combined effect of tobacco smoking

and alcohol drinking in the risk of head and neck cancers: a re-analysis of case-control studies using bi-dimensional spline models. European journal of epidemiology. 2016;31(4):385-93.

9. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. The New England journal of medicine. 2010;363(1):24-35.

10. Argiris A, Li S, Ghebremichael M, Egloff AM, Wang L, Forastiere AA, et al. Prognostic significance of human papillomavirus in recurrent or metastatic head and neck cancer: an analysis of Eastern Cooperative Oncology Group trials. Annals of oncology : official journal of the European Society for Medical Oncology. 2014;25(7):1410-6.

11. Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region. Head & neck. 2013;35(5):747-55.

12. Nasman A, Attner P, Hammarstedt L, Du J, Eriksson M, Giraud G, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? International journal of cancer. 2009;125(2):362-6.

13. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. The Lancet Oncology. 2010;11(11):1048-56.

14. Ndiaye C, Mena M, Alemany L, Arbyn M, Castellsague X, Laporte L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. The Lancet Oncology. 2014;15(12):1319-31.

15. Huang SH, O’Sullivan B. Overview of the 8th Edition TNM Classification for Head and Neck Cancer. Current treatment options in oncology. 2017;18(7):40.

16. Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2009;92(1):4-14.

17. Cooper JS, Pajak TF, Forastiere A, Jacobs J, Fu KK, Ang KK, et al. Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy? Head & neck. 1998;20(7):588-94.

18. Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2011;100(1):33-40.

19. Al-Sarraf M, Pajak TF, Marcial VA, Mowry P, Cooper JS, Stetz J, et al. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer. 1987;59(2):259-65.

20. Espeli V, Zucca E, Ghielmini M, Giannini O, Salatino A, Martucci F, et al. Weekly and 3-weekly cisplatin concurrent with intensity-modulated radiotherapy in locally advanced head and neck squamous cell cancer. Oral oncology. 2012;48(3):266-71.

21. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England journal of medicine. 2006;354(6):567-78.

16

C h a p t e r 1

22. Driessen CM, Janssens GO, van der Graaf WT, Takes RP, Merkx TA, Melchers WJ, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head & neck. 2016;38 Suppl 1:E559-65.

23. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. The New England journal of medicine. 2003;349(22):2091-8.

24. Driessen CM, Uijen MJ, van der Graaf WT, van Opstal CC, Kaanders JH, Nijenhuis T, et al. Degree of nephrotoxicity after intermediate- or high-dose cisplatin-based chemoradiotherapy in patients with locally advanced head and neck cancer. Head & neck. 2016;38 Suppl 1:E1575-81.

25. Denaro N, Merlano MC, Russi EG. Dysphagia in Head and Neck Cancer Patients: Pretreatment Evaluation, Predictive Factors, and Assessment during Radio-Chemotherapy, Recommendations. Clinical and experimental otorhinolaryngology. 2013;6(3):117-26.

26. Langerman A, Maccracken E, Kasza K, Haraf DJ, Vokes EE, Stenson KM. Aspiration in chemoradiated patients with head and neck cancer. Archives of otolaryngology--head & neck surgery. 2007;133(12):1289-95.

27. Nguyen NP, Smith HJ, Dutta S, Alfieri A, North D, Nguyen PD, et al. Aspiration occurence during chemoradiation for head and neck cancer. Anticancer research. 2007;27(3B):1669-72.

28. Zuur CL, Simis YJ, Lansdaal PE, Hart AA, Rasch CR, Schornagel JH, et al. Risk factors of ototoxicity after cisplatin-based chemo-irradiation in patients with locally advanced head-and-neck cancer: a multivariate analysis. International journal of radiation oncology, biology, physics. 2007;68(5):1320-5.

29. Arany I, Safirstein RL. Cisplatin nephrotoxicity. Seminars in nephrology. 2003;23(5):460-4.30. Theunissen EA, Bosma SC, Zuur CL, Spijker R, van der Baan S, Dreschler WA, et al. Sensorineural hearing

loss in patients with head and neck cancer after chemoradiotherapy and radiotherapy: a systematic review of the literature. Head & neck. 2015;37(2):281-92.

31. Renner P, Milazzo S, Liu JP, Zwahlen M, Birkmann J, Horneber M. Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients. The Cochrane database of systematic reviews. 2012;10:Cd007913.

32. Murner CM, Stenner-Liewen F, Seifert B, Mueller NJ, Schmidt A, Renner C, et al. Efficacy of selective digestive decontamination in patients with multiple myeloma undergoing high-dose chemotherapy and autologous stem cell transplantation. Leukemia & lymphoma. 2019;60(3):685-95.

33. Liberati A, D’Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. The Cochrane database of systematic reviews. 2009(4):CD000022.

34. Rutten H, Pop LA, Janssens GO, Takes RP, Knuijt S, Rooijakkers AF, et al. Long-term outcome and morbidity after treatment with accelerated radiotherapy and weekly cisplatin for locally advanced head-and-neck cancer: results of a multidisciplinary late morbidity clinic. International journal of radiation oncology, biology, physics. 2011;81(4):923-9.

35. Epstein JB, Robertson M, Emerton S, Phillips N, Stevenson-Moore P. Quality of life and oral function in patients treated with radiation therapy for head and neck cancer. Head & neck. 2001;23(5):389-98.

36. de Graeff A, de Leeuw JR, Ros WJ, Hordijk GJ, Blijham GH, Winnubst JA. Long-term quality of life of patients with head and neck cancer. The Laryngoscope. 2000;110(1):98-106.

37. List MA SA, Haraf D, Schumm P, Kies M, Stenson K, Vokes EE. Quality of life and performance in advanced head and neck cancer patients on concomitant chemoradiotherapy: a prospective examination. JCO. 1999.

38. Klein J, Livergant J, Ringash J. Health related quality of life in head and neck cancer treated with radiation therapy with or without chemotherapy: a systematic review. Oral oncology. 2014;50(4):254-62.

39. Osthus AA, Aarstad AK, Olofsson J, Aarstad HJ. Prediction of survival by pretreatment health-related quality-of-life scores in a prospective cohort of patients with head and neck squamous cell carcinoma. JAMA otolaryngology-- head & neck surgery. 2013;139(1):14-20.

40. Sacco AG, Cohen EE. Current Treatment Options for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(29):3305-13.

41. Argiris A, Harrington KJ, Tahara M, Schulten J, Chomette P, Ferreira Castro A, et al. Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck. Frontiers in oncology. 2017;7:72.

42. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. The New England journal of medicine. 2008;359(11):1116-27.

17

Eur J Cancer. 2019 May;113:32-40

Janneke C. Ham, Chantal M. Driessen, Mathijs P. Hendriks, Edward Fiets, Bas Kreike,

Ann Hoeben, Marije Slingerland, Claudia C. van Opstal, Bart Jan Kullberg,

Marianne A. Jonker, Eddy M. Adang, Johannes H. Kaanders, Winette T. van der Graaf *,

Carla M. van Herpen*

*Shared last authors

Prophylactic antibiotics reduce hospitalisations

and cost in locally advanced head and neck

cancer patients treated with chemoradiotherapy.

A randomised phase 2 study

C H A P T E R 2

20

C h a p t e r 2

Abstract

BackgroundPlatinum-based chemoradiotherapy for locally advanced head and neck cancer (LAHNC)

induces a high rate of acute toxicity, including dysphagia and aspiration pneumonia.

We hypothesised that prophylactic antibiotics can prevent pneumonia and

hospitalisations and can be cost-effective.

Patient and MethodsIn this multicentre randomised trial, patients with LAHNC treated with

chemoradiotherapy received prophylactic amoxicillin/clavulanic acid from day 29 after

the start of treatment until 14 days after completion of chemoradiotherapy or standard

care without prophylaxis. The primary objective was to observe a reduction in

pneumonias. Secondary objectives were to evaluate the hospitalisation rate, adverse

events, costs and health-related quality of life.

ResultsOne hundred six patients were included; of which, 95 were randomised: 48 patients

were allocated to the standard group and 47 patients to the prophylaxis group. A

pneumonia during chemoradiotherapy and follow-up until 3.5 months was observed

in 22 (45.8%) of 48 patients in the standard group and in 22 (46.8%) of 47 patients in

the prophylaxis group (p=0.54). Hospitalisation rate was significantly higher in the

standard group versus the prophylaxis group, 19 of 48 pts (39.6%) versus 9 of 47 pts

(19.1%), respectively (p=0.03). Significantly more episodes with fever of any grade were

observed in the standard group (29.2% vs 10.2%, p=0.028). A significant difference in

costs was found, with an average reduction of €1425 per patient in favour of the

prophylaxis group.

ConclusionAlthough prophylactic antibiotics during chemoradiotherapy for patients with LAHNC

did not reduce the incidence of pneumonias, it did reduce hospitalisation rates and

episodes with fever significantly and consequently tended to be cost-effective.

21

Prophylactic antibiotics in LAHNC patients treated with CRT

2

Introduction

Head and neck cancer affects almost 600 000 patients at a global level yearly. A

substantial part of the patients has locally advanced disease at diagnosis. Concomitant

platinum-based chemoradiotherapy is the treatment of choice for locally advanced

head and neck carcinoma (LAHNC) and can be applied as primary or as postoperative

treatment (1). However, chemoradiotherapy induces a high rate of acute toxicities such

as mucositis and dysphagia.

Dysphagia can lead to aspiration, which is defined as passage of material below the

level of the vocal cords (2). Dysphagia and aspiration during and after chemoradiotherapy

for head and neck cancer are usually underreported (3-5). In patients with LAHNC, the

incidence of aspiration at diagnosis ranges from 9-53% (3, 6), and the aspiration rate

during and after chemoradiotherapy is between 13-69% (5-7). Aspiration pneumonia,

defined as pneumonia secondary to inhalation of food particles, saliva or other foreign

substances (4), often leads to (prolonged) hospitalisation and is a major cause of

morbidity and mortality (8). Xu et al. demonstrated a 5-year cumulative incidence of

aspiration pneumonia in head and neck cancer patients of 23.8%, with a hospital

admission rate of 84% and 47% requiring an admission to an intensive care . The

mortality rate after aspiration pneumonia varies between studies from 17% to 32.5%

(4, 9). Because of this high incidence of aspiration pneumonia in patients with LAHNC

treated with chemoradiotherapy, we hypothesised that prophylactic antibiotics could

lower the number of pneumonias and hospitalisations. To our knowledge, this is the

first prospective study that investigates the effect of prophylactic antibiotics in patients

with LAHNC treated with chemoradiotherapy. The primary aim of this multicentre

randomised study was to investigate the efficacy of prophylactic antibiotics versus

standard treatment to prevent aspiration pneumonia during chemoradiotherapy in

patients with LAHNC. Secondary aims were to investigate the effect on the number of

hospitalisations and cost-effectiveness and to evaluate the adverse events and health-

related quality of life (HRQoL).

Methods

Patients and study designPatients with LAHNC who were treated with chemoradiotherapy, as primary or as

postoperative treatment, were eligible. Participating patients were included and

registered before the start of chemoradiotherapy. Exclusion criteria for registration

22

C h a p t e r 2

included an allergy to amoxicillin, the use of maintenance antibiotics or immuno-

deficiency. Patients were randomised between day 21 and 28 after the start of

treatment if there were no additional exclusion criteria including pneumonia, other

infections or use of antibiotic treatment within the last 2 weeks before randomisation.

Patients were allocated equally to the two treatment groups by minimisation, which is

a method of adaptive stratification allowing higher numbers of stratification factors,

for smoking, Chronic Obstructive Pulmonary Disease (Global Initiative for Chronic

Obstructive Lung Disease (GOLD) 0-2 or GOLD 3-4), weight loss (more than 10% versus

less than 10%), primary site of the tumour (oral cavity, oropharyngeal or hypopharyngeal

and laryngeal cancer), participating centre and human papillomavirus positivity (10).

The trial was approved by the Medical Ethical Research Committee, in accordance with

the Declaration of Helsinki, and registered at clinicaltrials.gov (NCT01598402). All patients

signed written informed consent.

Laboratory and adverse events, scored by the Common Terminology Criteria for

Adverse Events version 4.0, were registered every week during chemoradiotherapy

and one week, three weeks and 3.5 months after completing chemoradiotherapy.

Sputum cultures were obtained on day 29 and at 1 week, 3 weeks and 3.5 months after

chemoradiotherapy. HRQoL questionnaires, among which was the EuroQol-5D (EQ-5D),

were collected at baseline, day 28 (one day before starting prophylactic antibiotics),

the last day of radiotherapy and 3.5 months after the end of chemoradiotherapy. For

the EQ-5D, utilities were calculated, resulting in a score between zero and one. A score

of one means perfect health, whereas zero means death (11).

The primary end-point was to evaluate the number of definite or suspected

pneumonias. A definite pneumonia was defined as an infiltrate on chest radiography

or the presence of 3 or more of the following 4 features: sustained fever (temperature

>38.0 °C), rales or rhonchi on chest auscultation, sputum Gram stain showing

substantial leukocytes (i.e. more than 5 leucocytes per high-power field, x100) or

sputum culture growing a respiratory pathogen. A suspected pneumonia was defined

as 2 of the 4 features (12).

Secondary end-points were the number and duration of hospitalisations, toxicity,

HRQoL and adverse events, cost-effectiveness and all-cause mortality.

Prophylactic antibioticsThe prophylaxis group received amoxicillin/clavulanic acid, oral suspension 625 mg

three times a day (tid), from day 29 after the start of chemoradiotherapy until 14 days

after completion, in addition to standard care. The standard group received no

23

Prophylactic antibiotics in LAHNC patients treated with CRT

2

prophylactic antibiotics. In case of a (suspected) lower airway infection, blood and

sputum cultures were taken and chest radiography was performed, mostly followed

by hospitalisation and intravenous antibiotics.

ChemoradiotherapyChemotherapy consisted of cisplatin, given at a dose of 100 mg/m2 every 3 weeks for

3 cycles or 40-50 mg/m2 weekly for 6 or 7 cycles. Radiotherapy was given as per local

practice with intensity-modulated radiation therapy and an accelerated (68Gy in 34

fractions of 2Gy in 5.5 weeks) or conventional scheme (70Gy in 35 fractions of 2Gy in

7 weeks) (13) (1). If a postoperative patient was not eligible for cisplatin, carboplatin

was given weekly.

Statistical analysisUnder the assumption that the percentage of definite and/or suspected pneumonia

in the standard group was 50% (6) and in the intervention group was 25% (a reduction

of 50%(14)), 46 patients in each group were needed to have a power of 80% to detect

a lower percentage in the prophylaxis group based on a one-sided binomial test at 5%

significance level. A 15% adjustment for data attrition resulted in a sample size of 53

patients in each group. No power analysis was performed for the secondary endpoints.

Efficacy analysis was conducted in the intention-to-treat population, that is, all

randomised patients. Non-parametric tests were performed using the one-sided Fisher

exact test to test for significant decrease in pneumonias in the prophylaxis group, the

chi-squared test for differences in hospitalisation and adverse events and Mann-

Whitney tests for differences in costs. For the analysis of the EQ-5D questionnaire, an

independent t-test was used.

Economic evaluationAn economic evaluation was performed alongside the clinical trial and was based on

the general principle of a cost-effectiveness analysis. On patient level, volumes of care

were measured prospectively. Per group, full cost prices were determined using activity-

based costing. The Dutch guidelines for cost analyses were used (15). The effects were

measured using the earlier described EQ-5D HRQoL questionnaire.

Only three groups of medication were analysed: analgetics, antiemetics and proton

pump inhibitors. The costs of the prophylactic treatment in the prophylaxis group were

determined for amoxicillin/clavulanic acid suspension used for 4 weeks, with a total

price of €20.16 per patient.

24

C h a p t e r 2

Results

Patient characteristics Between January 2012 and July 2015, a total of 106 patients were included in 6 centres.

At randomisation, 95 patients were randomised; 48 patients were allocated to the

standard group and 47 patients to the prophylaxis group. Eleven patients could not

be randomised (Figure 1).

One patient in the prophylaxis group refused further participation after randomisation

and was included into the intention-to-treat analysis for the primary objective as well

as the cost-effectiveness, but no further information for secondary objectives was

available for this patient.

The standard group and the prophylaxis group were well-balanced in terms of baseline

characteristics (Table 1). The median age of patients was 58.5 years in the standard

group and 57.0 years in the prophylaxis group.

Treatment

Prophylactic antibioticsIn the prophylaxis group, 29 patients (61.7%) completed the amoxicillin/clavulanic acid

prophylaxis as planned, that is, 625 mg tid from day 29 after the start of

chemoradiotherapy until 14 days after completion. Reasons for early discontinuation

in the other 18 patients were toxicity in 9 patients, mainly due to gastrointestinal

complaints, refusal of antibiotics in 3 patients, non-compliance to the prescribed

schedule in 4 patients and switch to alternative antibiotic treatment due to

hospitalisation or febrile neutropenia during the course of prophylaxis in 2 patients.

ChemoradiotherapyThe chemoradiotherapy was delivered as stated in Table 1. In 4 patients of each

treatment group the chemotherapy was adapted because of toxicity according to the

treating physician. One patient in the standard group had a delay in radiotherapy

during treatment, and one patient stopped prematurely. In the prophylaxis group, only

one patient needed a delay in radiotherapy while on treatment.

25

Prophylactic antibiotics in LAHNC patients treated with CRT

2

Efficacy of prophylactic antibiotics

PneumoniaNo decrease was found in the incidence of (definite or suspected) pneumonia in the

standard group compared with the prophylaxis group, 45.8% versus 46.8%, respectively

(p=0.54). In the standard group, 8 patients developed a definite pneumonia compared

with 4 patients in the prophylaxis group (Table 2). There was no difference in the use

of proton pump inhibitors between the two groups (39.6% versus 34.0% in the standard

group and prophylaxis group, respectively, p=0.576).

Patient selection. IC, informed consent.

Figure 1. CONSORT Flow Diagram.

26

C h a p t e r 2

Table 1. Patient characteristics. TNM, Tumour-node-metastasis; CRT, chemoradiotherapy

Patient characteristics Standard group(N=48)

Prophylaxis group(N=47)

Age, yr (range) 58.5 (43-68) 57.0 (23-68)Sex, no. (%) Female 14 (29.2) 11 (23.4) Male 34 (70.8) 36 (76.6)WHO (%) 0 35 (72.9) 32 (68.1) 1 11 (22.9) 11 (23.4) Unknown 2 (4.2) 4 (8.5)Tumour site (%) Oral cavity 14 (29.2) 13 (27.7) Oropharynx 20 (41.7) 20 (42.6) Hypopharynx 5 (10.4) 11 (23.4) Larynx 8 (16.7) 3 (6.4) Unknown primary 1 (2.1) 0TNMT 1 5 (10.4) 4 (8.5) 2 9 (18.8) 10 (21.3) 3 15 (31.3) 13 (27.7) 4 18 (37.5) 19 (40.4) x 1 (2.1) 1 (2.1)N 0 15 (31.3) 12 (25.5) 1 5 (10.4) 7 (14.9) 2a 4 (8.3) 3 (6.4) 2b 16 (33.3) 13 (27.7) 2c 7 (14.6) 10 921.3) 3 1 (2.1) 1 (2.1) x 0 1 (2.1)M 0 46 (95.8) 45 (95.7) x 2 (4.2) 2 (4.3)Indication CRT (%) Primary treatment 26 (54.2) 34 (72.3) Postoperative treatment 22 (45.8) 13 (27.7)Chemotherapy administered (%) Cisplatin 100 mg/m2 thrice weekly 10 (20.8) 12 (25.5) Cisplatin 40-50 mg/m2 weekly 32 (66.7) 30 (63.8) Carboplatin AUC 1.5 weekly 2 (4.2) 1 (2.1) Adapted chemotherapy 4 (8.3) 4 (8.4)Radiotherapy administered (%) Conventional 22 (45.8) 21 (44.7) Accelerated 26 (54.2) 26 (55.3) Total dose given at primary tumour and pathological lymph

nodes (median, range)68.0 (60-70) 68.0 (60-70)

Total dose given at elective neck levels (median, range) 50.3 (46-66) 50.3 (46-60)Tube feeding at Randomisation (%) No 39 (81.3) 38 (80.9) Yes 9 (18.8) 9 (19.1)

27

Prophylactic antibiotics in LAHNC patients treated with CRT

2

HospitalisationThe hospitalisation rate was significantly different between both groups; in the standard

group, 19 patients (39.6%) were hospitalised versus 9 (19.1%) in the prophylaxis group

(p=0.03). The median duration of hospitalisation was 5.0 days in both groups (p=0.96)

(Table 2). The main reasons for hospitalisations in both groups were related to the

chemoradiotherapy and were frequently multifactorial determined by a combination

of, for example, pneumonia, dehydration, fever, pain, mucositis or dyspnoea (Table 3).

ToxicityA significant difference in episodes of fever (higher than 38.0 °C) was found between

the standard group and the prophylaxis group (29.2% versus 10.9%, respectively,

p=0.028), with no difference in the frequency of neutropenia. With respect to other

adverse events, no significant differences were found between both groups (Table 4).

Table 2. Efficacy outcomes on definite and suspected pneumonias, number and duration of hospitalisation and costs. p <0.05: significantly different

Efficacy outcomes Standard group(N=48)

Prophylaxis group(N=47)

p

Incidence of pneumonia 22 (45.8) 22 (46.8) 0.544Type of pneumonia Definite (%) 8 (16.7) 4 (8.5) 0.232 Suspected (%) 14 (29.2) 18 (38.3) 0.346Hospitalised patients 19 (39.6) 9 (19.1) 0.030Total days of hospitalisation 0.96 Median (range) 5.0 (2-41) 5.0 (1-9)CostsHospitalisation 0.032 Mean per patient €2076.48 €682.17 Whole group €99671.00 €32062.00Pain medication 0.382 Mean per patient €78.34 €46.13 Whole group €3760.22 €2167.94Anti-emetics 0.388 Mean per patient €306.17 €288.15 Whole group €14696.31 €13543.16Proton pump inhibitors 0.597 Mean per patient €0.81 €0.65 Whole group €39.27 €30.58Prophylactic antibiotics 0.00 Mean per patient €0.00 €20.16 Whole group €0.00 €947.52Total costs 0.046 Mean per patient €2461.80 €1037.26 Whole group €118166.79 €48751.20

28

C h a p t e r 2

MortalityOne patient, who was included but not randomised because of antibiotic use 14 days

before randomisation, died during the 3.5-month of follow-up due to progressive

disease. All other patients were alive at the end of follow-up.

Economic evaluation and quality of lifeThe difference in costs of hospitalisation plus the medication used was significant

between the standard group and the prophylaxis group, in favour of the prophylaxis

group (p=0.046), with a mean difference of €1425 per patient (Table 2). The EQ-5D

HRQoL showed no significant differences. Because no differences were found between

the two groups regarding the number of pneumonias and HRQoL measured by the

EQ-5D, the cost-effectiveness decision rule became ‘cost-minimisation’, meaning that

the treatment with the lowest costs is to be preferred. Following that rule, the

prophylaxis group turned out to be cost-effective.

The full report on HRQoL of this study will be published separately.

Sputum cultures During the entire study period, there was no significant difference in the number of

patients with positive sputum cultures between the standard group and the prophylaxis

group (29 patients [60.4%] in the standard group and 32 [68.1%] in the prophylaxis

group, p=0.441). Before the start of prophylactic antibiotics (day 29), after the end of

chemoradiotherapy and 3 weeks after the end of chemoradiotherapy, no significant

Table 3. Reasons for hospitalisation in both treatment groups. In the standard group two patients had a combination of 2 reasons for hospitalisation, and in the prophylaxis group one patients had a combination of 2 reasons for hospitalisation.

Reason for hospitalisation Standard group(19/48 patients hospitalised)

Prophylaxis group (9/47 patients hospitalised)

Pneumonia 1 2Fever 5 1Candida mucositis 1Nausea and vomiting 2Dehydration 7 4Pain 1Dysphagia 1Dyspnoea 2Hypercalcemia 1Fatigue 1Other 2

29

Prophylactic antibiotics in LAHNC patients treated with CRT

2

differences were found in the number of performed cultures, in the number of positive

cultures for bacteria and/or fungi or in the number of cultures with resistant bacteria.

At the end of follow-up, 3.5 months after the end of chemoradiotherapy, more positive

cultures were found significantly in the prophylaxis group, although more resistant

bacteria were cultured significantly in the standard group. However, only few sputum

cultures were performed in both groups, probably because patients did not have any

complaints anymore (Table 5).

Discussion

In this prospective randomised controlled trial investigating the role of antibiotic

prophylaxis in patients with LAHNC treated with chemoradiotherapy, no decrease in

the incidence of pneumonia in the group treated with prophylactic antibiotics versus

standard care was found but there was a significant reduction in hospitalisation rate,

episodes with fever and costs.

Table 4. Reported adverse events by the local investigator. CTCAE, Common Terminology Criteria for Adverse Events

Standard group (N=48) Prophylaxis group (N=46) pCTCAE 4.0 Any grade Grade 3-4 Any grade Grade 3-4Allergic reaction 1 (2.1) 0 (0) 1 (2.2) 0 (0)Fatigue 40 (83.3) 1 (2.1) 31 (67.4) 1 (2.2)Fever 14 (29.2) 1 (2.1) 5 (10.9) 0 (0) 0.028Weight loss 41 (85.4) 1 (2.1) 36 (78.3) 3 (6.5)Rash/desquamation 16 (33.3) 1 (2.1) 13 (28.3) 2 (4.3)Dermatitis radiation 33 (68.8) 4 (8.3) 31 (67.4) 9 (19.6)Anorexia 28 (58.3) 17 (35.4) 23 (50.0) 5 (10.9)Constipation 22 (45.8) 0 (0) 19 (41.3) 0 (0)Diarrhoea 11 (22.9) 2 (4.2) 9 (19.6) 0 (0)Oral mucositis 41 (85.4) 20 (41.7) 33 (71.7) 15 (32.6)Nausea 25 (52.1) 2 (4.2) 25 (54.3) 0 (0)Vomiting 20 (41.7) 3 (6.3) 14 (30.4) 0 (0)Dry mouth 33 (68.8) 0 (0) 32 (69.6) 0 (0)Dysphagia 40 (83.3) 21 (43.8) 33 (71.7) 13 (28.3)Foetor ex ore 2 (4.2) 0 (0) 2 (4.3) 0 (0)Cough 15 (31.3) 0 (0) 13 (28.3) 0 (0)Dyspnoea 8 (16.7) 0 (0) 3 (6.5) 1 (2.2)Pneumonitis 1 (2.1) 0 (0) 1 (2.2) 1 (2.2)Creatinine increased 35 (72.9) 2 (4.2) 30 (65.2) 0 (0)Tumour pain 7 (14.6) 0 (0) 14 (30.4) 0 (0)Pain head/neck 24 (50.0) 2 (4.2) 20 (43.5) 1 (2.2)

30

C h a p t e r 2

Tabl

e 5.

Num

ber o

f spu

tum

cul

ture

s pe

rfor

med

, and

the

perc

enta

ge o

f cul

ture

s po

sitiv

e fo

r bac

teri

a w

ith re

sist

ant b

acte

ria

Day

29

Aft

er e

nd o

f CRT

3 w

eeks

aft

er C

RT3.

5 m

onth

s af

ter

CRT

Sput

um c

ultu

res

Stan

dard

gr

oup

(N=4

8)

Prop

hyla

xis

grou

p (N

=47)

p valu

eSt

anda

rd

grou

p (N

=48)

Prop

hyla

xis

grou

p (N

=47)

p valu

eSt

anda

rd

grou

p (N

=48)

Prop

hyla

xis

grou

p (N

=47)

p valu

eSt

anda

rd

grou

p (N

=48)

Prop

hyla

xis

grou

p (N

=47)

p valu

e

Perf

orm

ed (%

)34

(70.

8)31

(66.

0)0.

609

37 (7

7.1)

29 (6

1.7)

0.10

437

(77.

1)35

(74.

5)0.

766

15 (3

1.2)

12 (2

5.5)

0.53

7

Neg

ativ

e (%

)23

(67.

6)15

(48.

4)0.

116

20 (5

4.1)

9 (3

1.0)

0.06

118

(48.

6)15

(42.

9)0.

622

8 (5

3.3)

1 (8

.3)

0.01

4

Pos

itive

(%)

11 (3

2.4)

16 (5

1.6)

17 (4

5.9)

20 (6

9.0)

19 (5

1.4)

20 (5

7.1)

7 (4

6.7)

11 (9

1.7)

Perc

enta

ge o

f po

sitiv

e cu

lture

s w

ith r

esis

tant

(%)

14.3

40.0

0.25

238

.561

.50.

239

27.3

42.9

0.42

083

.320

.00.

036

31

Prophylactic antibiotics in LAHNC patients treated with CRT

2

A reduction in episodes of fever as well as a reduction in hospitalisations is important,

first, not only for the patients who already undergo an intensive treatment but also

for the oncology services as patients with LAHNC treated with chemoradiotherapy are

referred relatively often to acute and emergency departments where these unplanned

admissions are an extra burden. In this patient population, different attempts have

been made in the past to reduce acute admissions, such as an intensive nurse-led

intervention or the use of percutaneous endoscopic gastrostomies to prevent aspiration

pneumonias (16, 17). To the best of our knowledge, the use of antibiotic prophylaxis

has not been investigated before in a randomised way in this patient population, and

the positive effect on the incidence of fever and hospitalisation is a novel and relevant

result. Despite the fact that the difference in hospitalisation rate was not totally well

understood, prophylactic antibiotics seem to improve general well-being with effect

on multiple aspects, such as fever, mucositis, pain and dyspnoea.

There may be different reasons why the primary endpoint of the study, a significant

reduction in the incidence of pneumonias, was not reached. First, the hypothesis that

prophylactic antibiotics could lower the number of pneumonias in patients with

LAHNC by 50% was possibly overestimated. This estimation was based on a Cochrane

review on prophylactic antibiotics in adult Intensive Care Unit patients who showed

a significant reduction of 50% in respiratory tract infections and mortality in adult

patients, half of which received mechanical ventilation support. Second, in the

prophylaxis group, only 61.7% completed the amoxicillin/clavulanic acid prophylaxis

as planned, predominantly caused by poor compliance, which is partly due to this

specific patient population. Whether this has influenced a lack of difference in

incidence of pneumonias is unclear as it did not prevent the prophylaxis group from

having a lower rate of episodes with fever. Third, non-significantly, more patients in

the prophylaxis group received chemoradiotherapy as primary treatment, whereas,

in the standard group, relatively more patients received chemoradiotherapy as

postoperative treatment. However, in both groups, aspiration can occur. Finally, other

risk factors, such as alcoholic consumption, poor oral hygiene, and the use of sleeping

pills, for aspiration pneumonia were not used as stratification factors and could have

been confounders in this study (18).

There was a positive outcome for the secondary end-point cost. Antibiotic prophylaxis

intervention was cost-effective, with an average cost-saving of €1425 per patient. For

the Netherlands, with an estimation of 300 patients with LAHNC treated with

chemoradiotherapy each year, this could lead to a reduction of about €425,000 per

year. To prevent the emergence of bacterial resistance, prudent use of antibiotics,

32

C h a p t e r 2

particularly broad-spectrum agents such as amoxicillin/clavulanic acid, is warranted

(19). Although we did not observe any increase in bacterial resistance due to the use

of prophylactic antibiotics, we realise that the study included a low number of patients

to look for this end-point. Although the number of positive sputum cultures 3.5 months

after the end of chemoradiotherapy was significantly higher in the prophylaxis group,

the absolute number of cultures was too low to draw any meaningful conclusions. In

addition, the long-term (> 1 year) effects on resistance and related costs are unknown.

In conclusion, this randomised study suggests that the use of prophylactic antibiotics

by patients with LAHNC during chemoradiotherapy does not reduce the number of

pneumonias but does reduce the number of patients with fever and hospitalisations

and costs and can, therefore, be considered in this population.

Conflict of interest statementNone declared

FundingThis work was supported by The Netherlands Organisation for Health Research and

Development: ZonMw, project number 171101011. ZonMw only provided a grant to

perform the study, and was not involved in preparing the study protocol, performing

the analyses or writing the manuscript

AcknowledgementsThe authors would like to thank all collaborating hospitals.

33

Prophylactic antibiotics in LAHNC patients treated with CRT

2

References

1. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091-8.

2. Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. Dysphagia 1996;11(2):93-8.

3. Denaro N, Merlano MC, Russi EG. Dysphagia in Head and Neck Cancer Patients: Pretreatment Evaluation, Predictive Factors, and Assessment during Radio-Chemotherapy, Recommendations. Clin Exp Otorhinolaryngol 2013;6(3):117-26.

4. Xu B, Boero IJ, Hwang L, Le QT, Moiseenko V, Sanghvi PR, et al. Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. Cancer 2015;121(8):1303-11.

5. Rutten H, Pop LA, Janssens GO, Takes RP, Knuijt S, Rooijakkers AF, et al. Long-term outcome and morbidity after treatment with accelerated radiotherapy and weekly cisplatin for locally advanced head-and-neck cancer: results of a multidisciplinary late morbidity clinic. Int J Radiat Oncol Biol Phys 2011;81(4):923-9.

6. Langerman A, Maccracken E, Kasza K, Haraf DJ, Vokes EE, Stenson KM. Aspiration in chemoradiated patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2007;133(12):1289-95.

7. Nguyen NP, Smith HJ, Dutta S, Alfieri A, North D, Nguyen PD, et al. Aspiration occurence during chemoradiation for head and neck cancer. Anticancer Res 2007;27(3B):1669-72.

8. Nguyen NP, Moltz CC, Frank C, Vos P, Smith HJ, Karlsson U, et al. Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol 2004;15(3):383-8.

9. Chen SW, Yang SN, Liang JA, Lin FJ. The outcome and prognostic factors in patients with aspiration pneumonia during concurrent chemoradiotherapy for head and neck cancer. Eur J Cancer Care (Engl) 2010;19(5):631-5.

10. Scott NW, McPherson GC, Ramsay CR, Campbell MK. The method of minimization for allocation to clinical trials. a review. Control Clin Trials 2002;23(6):662-74.

11. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy 1990;16(3):199-208.

12. Schouten JA, Hulscher ME, Trap-Liefers J, Akkermans RP, Kullberg BJ, Grol RP, et al. Tailored interventions to improve antibiotic use for lower respiratory tract infections in hospitals: a cluster-randomized, controlled trial. Clin Infect Dis 2007;44(7):931-41.

13. Driessen CM, Janssens GO, van der Graaf WT, Takes RP, Merkx TA, Melchers WJ, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck 2016;38 Suppl 1:E559-65.

14. Liberati A, D’Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. Cochrane Database Syst Rev 2009(4):CD000022.

15. Oostenbrink JB, Koopmanschap MA, Rutten FF. Standardisation of costs: the Dutch Manual for Costing in economic evaluations. Pharmacoeconomics 2002;20(7):443-54.

16. Terzo L, Fleming M, Yechoor A, Camporeale J, Troxler M, Roth E, et al. Reducing Unplanned Admissions: Focusing on Hospital Admissions and Emergency Department Visits for Patients With Head and Neck Cancer During Radiation Therapy. Clin J Oncol Nurs 2017;21(3):363-369.

17. Brown TE, Banks MD, Hughes BG, Lin CY, Kenny LM, Bauer JD. Comparison of Nutritional and Clinical Outcomes in Patients with Head and Neck Cancer Undergoing Chemoradiotherapy Utilizing Prophylactic versus Reactive Nutrition Support Approaches. J Acad Nutr Diet 2018, 627-6.

18. Kawai S, Yokota T, Onozawa Y, Hamauchi S, Fukutomi A, Ogawa H, et al. Risk factors for aspiration pneumonia after definitive chemoradiotherapy or bio-radiotherapy for locally advanced head and neck cancer: a monocentric case control study. BMC Cancer 2017;17(1):59.

19. Schuts EC, Hulscher M, Mouton JW, Verduin CM, Stuart J, Overdiek H, et al. Current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis. Lancet Infect Dis 2016;16(7):847-856.

Oral Oncology. 2019 96;105-112

Janneke C. Ham, Carla M.L. van Herpen, Chantal M.L. Driessen,

Winette T.A. van der Graaf, Olga Husson

Health-related quality of life of patients

treated with chemoradiotherapy plus or minus

prophylactic antibiotics to reduce the number

of pneumonias for locally advanced head and

neck cancer, the PANTAP study.

C H A P T E R 3

36

C h a p t e r 3

Abstract

ObjectivesThe recent PANTAP trial showed that administration of prophylactic antibiotics in locally

advanced head and neck carcinoma (LAHNC) patients treated with chemoradiotherapy

reduced fever, hospitalization and costs. The current study describes the effect of

prophylactic antibiotics on health-related quality of life (HRQoL), another secondary

endpoint of the trial.

Materials and MethodsIn this multicenter randomized trial, LAHNC patients treated with chemoradiotherapy

received prophylactic antibiotics or standard care. HRQoL was assessed at baseline

(before chemoradiotherapy), day 28 of chemoradiotherapy (one day before starting

prophylactic antibiotics), the final day of radiotherapy, and 3.5 months after the end

of chemoradiotherapy, using the European Organisation for Research and Treatment

of Cancer (EORTC) QLQ-C30, EORTC H&N35 module, and the Performance Status Scale

for Head & Neck cancer patients (PSS-HN).

ResultsNinety-five patients were randomized: 48 patients were allocated to the standard group

and 47 patients to the prophylaxis group. Thirty-four patients in the standard group

(70.8%) and 28 patients in the prophylaxis group (59.6%) completed the questionnaires

at baseline and at follow-up. No significant differences in HRQoL were found at baseline

and at day 28. At the end of radiotherapy, the prophylaxis group performed better on

almost all functional subscales of the EORTC QLQ-C30 and reported less symptoms.

At the end of follow up, almost no differences were seen between the two treatment

groups.

ConclusionProphylactic antibiotics during chemoradiotherapy for LAHNC patients improved

HRQoL at the end of the radiotherapy, however no differences were found 3.5 months

after the end of chemoradiotherapy.

37

Quality of life of patients treated with prophylactic antibiotics

3

Introduction

Head and neck cancer is the sixth most common type of cancer with an annual

incidence of 686,328 new cases worldwide (1, 2). Locally advanced head and neck

cancer (LAHNC) itself, as well as the side effects of treatment, can negatively influence

health-related quality of life (HRQoL). Social and emotional interactions are important

aspects of an individual’s HRQoL and largely depend on structural and functional

capacity of organs in the head and neck region that are affected by the tumour and its

treatment (3). Rettig et al. showed that HRQoL begins to decline in the 2-5 years before

a diagnosis of LAHNC with a steep reduction in the 24 months before diagnosis (4). At

presentation, disease-related symptoms may comprise of hoarseness, pain, otalgia,

dysphagia, cough and stridor (5), which likely to account for decreased HRQoL prior to

diagnosis.

The treatment for LAHNC often consists of concomitant platinum-based chemo-

radiotherapy. However, this treatment is associated with a high rate of acute toxicities.

Radiotherapy causes mucositis, dermatitis, dysphagia, anorexia and pain (6,7), whereas

chemotherapy may cause nausea, neutropenia and thrombocytopenia and worsen

radiotherapy-related toxicities, in particular mucositis and dysphagia (6). In a previous

study, the incidence of grade 3 or 4 acute toxicities among LAHNC patients treated

with radiotherapy alone was 47%, while this was 77% among patients treated with

concomitant chemoradiotherapy (6). Due to these acute adverse events, there is a

significant deterioration of HRQoL during treatment(8), that may be worse for patients

treated with chemoradiotherapy compared to those treated with radiotherapy alone

(9). Immediately (4-6 weeks) after radiotherapy HRQoL declines even further (10, 11),

however gradual improvement is during the following period (4, 9-12). In general, most

HRQoL domains recover to baseline levels around 12 months after treatment (9, 13).

Dysphagia and aspiration during- and after chemoradiotherapy for head and neck

cancer are usually underreported (14-16). In LAHNC patients, the incidence of aspiration

at diagnosis ranges from 9-53% (14, 17), and the aspiration rate during and after

chemoradiotherapy is between 13-69% (16-18). As a consequence, aspiration

pneumonia during chemoradiotherapy is a relatively frequent complication (46%) (19).

In the recently conducted PANTAP-trial, prophylactic antibiotics during

chemoradiotherapy in LAHNC did not result in a reduction in the number of patients

with a pneumonia (45.8% of the patients in the standard group versus 46.8% of the

patients in the prophylaxis group), however prophylactic antibiotics led to a significant

reduction in the rate of hospitalization, episodes of fever and costs per patient (19, 20).

38

C h a p t e r 3

It could be hypothesized that prophylactic antibiotics have a protective effect on HRQoL

as they may reduce acute toxicities such as mucositis and pain, which were previously

shown to have a negative impact on HRQoL (21). One of the secondary objectives of

the PANTAP trial, and the aim of the current study, was to assess the effects of

prophylactic antibiotics during chemoradiotherapy on the HRQoL among LAHNC

patients compared with those who did not receive prophylactic antibiotics. We

hypothesized that the group receiving prophylactic antibiotics would report a better

HRQoL at the end of radiotherapy due to the positive effects of prophylactic antibiotics.

In addition, our study aims to describe HRQoL changes during treatment in both

treatment groups.

Methods

Patients and study designThe PANTAP-study was a randomized, multicenter phase II study for patients with

LAHNC who were treated with chemoradiotherapy, either as primary treatment or

postoperative treatment. Chemotherapy consisted of cisplatin, given at a dose of 100

mg/m2 every 3 weeks for 3 cycles, or 40-50 mg/m2 given every week for 6 or 7 cycles.

Radiotherapy was given with intensity-modulated radiation therapy and an accelerated

(68Gy in 34 fractions of 2Gy over 5.5 weeks) or conventional scheme (70Gy in 35

fractions of 2Gy over 7 weeks) (6, 7). Patients were enrolled before start of the

chemoradiotherapy. Exclusion criteria for registration included an allergy to amoxicillin,

the use of maintenance antibiotics or immunodeficiency. Patients were randomized

after 21-28 days of chemoradiotherapy, unless complications such as pneumonia,

other infections or antibiotic treatment had occurred within the 14 days preceding

randomization. Patients were randomized to receive either standard care alone, (the

standard group), or to receive prophylactic oral amoxicillin/clavulanic acid 625 mg three

times daily from day 29 until 14 days after the end of chemoradiotherapy in addition

to standard care (the prophylaxis group). Patients were allocated equally to the two

treatment groups by minimization, which is a method of adaptive stratification allowing

a higher numbers of stratification factors: smoking, Chronic Obstructive Pulmonary

Disease (Gold 0-2 or Gold 3-4), weight loss (more than 10% versus less than 10%),

primary site of the tumour (oral cavity, oropharyngeal, or hypopharyngeal and laryngeal

cancer), participating centre, and human papillomavirus positivity (22).

The primary endpoint was to evaluate the number of patients who developed

pneumonia. Secondary endpoints were to determine the number and duration of

39

Quality of life of patients treated with prophylactic antibiotics

3

hospital admissions, to assess toxicity and adverse events including side effects of

amoxicillin/clavulanic acid, to evaluate cost-effectiveness, and to explore HRQoL.

The study protocol was approved by the local ethical committee and registered at

clinicaltrials.gov (NCT01598402).

AssessmentsHRQoL was assessed at baseline, day 28 of chemoradiotherapy (one day before starting

prophylactic antibiotics), on the final day of radiotherapy, and 3.5 months after the

end of chemoradiotherapy. Questionnaires included the 30-item core European

Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire

(EORTC QLQ-C30) (23), the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC

H&N35) (23), and the Performance Status Scale for Head & Neck cancer patients (PSS-

HN)(24).

The EORTC QLQ-C30 is a 30-item questionnaire that assesses HRQoL in cancer patients

across five functioning scales (physical functioning, role functioning, emotional

functioning, cognitive functioning, social functioning), three multi-item symptom scales

(fatigue, pain, nausea and vomiting), six single-item symptom scales (dyspnoea,

insomnia, appetite loss, constipation, diarrhoea, and financial problems) and global

QoL (23). Patients provide their answers on a 4-point scale (from 1 [not at all] to 4 [very

much]), except for global QoL, which has a 7-point scale (from 1 [very poor] to 7

[excellent]). By linear transformation the raw scores are standardized, so that overall

scores range from 0 to 100. A higher score on the functioning scales and on global QoL

represent a better level of quality of life and functioning, and a higher score on the

symptom scales means a worse level of symptoms (25). According to EORTC Quality

of Life Group guidelines, clinically important differences between the two treatment

groups were divided into four classes based on size: large (representing unequivocal

clinical relevance), medium (likely to be clinically relevant, but to a lesser extent), small

(subtle but, nevertheless, clinically relevant) and trivial (circumstances unlikely to have

any clinical relevance, or where there was no difference). For each subscale criteria to

fit each of the four classes were composed (26). Within each treatment group clinical

relevant differences over time were defined as a difference of at least 10 points (27).

The EORTC H&N35, a disease-specific HRQoL questionnaire, comprises 35 questions

assessing symptoms and side effects of treatment, social function and body image/

sexuality, and incorporates seven multi-item scales (pain, swallowing, senses (taste

and smell), speech, social eating, social contact, sexuality), and 11 single item scales

(teeth, opening mouth, dry mouth, sticky saliva, coughing, felt ill, pain killers, nutritional

40

C h a p t e r 3

supplements, feeding tube, weight loss, weight gain). After linear transformation, all

symptom scales range in score from 0-100, where a higher score means more

complaints (23). A difference of at least 10 points between the two treatment groups,

as well as within the groups, was considered to be a clinically significant difference (27).

The PSS-HN was designed to measure unique disabilities of head and neck cancer

patients. Surgery and/or systemic therapies in head and neck cancer patients often

introduce cosmetic and functional deficits leading to problems with speech and

eating(28). The PSS-HN was developed as a simple and practical assessment and

consists of three subscales: ‘normalcy of diet’, ‘understandability of speech’, and ‘eating

in public’. Each is rated from 0 to 100, with higher scores indicating better performance,

and 100 representing normal function (24). The ‘normalcy of diet’ subscale assesses

the extent to which the patient is able to eat a regular diet. The ‘understandability of

speech’ subscale rates the degree to which a listener is able to understand the patient’s

speech. The ‘eating in public’ subscale scores swallowing-related QoL issues by

documenting the patient’s ability to share a meal with others, and in which type of

environment. The PSS-HN has been shown to have adequate inter-rater reliability and

to be sensitive to differences in performance and change over time(24). There are no

studies performed to determine clinically relevant differences on the three subscales,

as with the QLQ-C30 and QLQ-H&N35, however, a score of 50 or less on the different

scales seems to correlate with a lower Karnofsky performance scale (24). Norman’s

rule of thumb was used for the PSS-HN, whereby a ±0.5 standard deviation difference

(i.e. 12.8 points) indicated a clinically relevant difference (29,30).

StatisticsDifferences between the groups were calculated at every time point. Independent

t-tests were performed to find any statistical significant differences between the two

treatment groups for each symptom or functioning scale. For HRQoL during treatment

compared with baseline (both groups) no statistical tests were performed and therefore

results are descriptive. As described above, for all the separate questionnaires, we

have not only reported statistical significant differences, but also (minimal) clinically

important differences, because statistical significance does not provide information

about clinical meaningfulness i.e. whether the observed effect is larger than the

smallest clinically important effect (31,32).

The change in HRQoL and symptom burden (separate models for each scale) by

treatment group was analyzed using linear mixed-effects models (i.e. covariance

pattern model with an unstructured error variance matrix and maximum likelihood

41

Quality of life of patients treated with prophylactic antibiotics

3

estimation) (33). This technique uses data efficiently by including incomplete cases in

the analysis. As a result, bias is limited and statistical power is preserved. Time was

analyzed as a regular categorical predictor with four levels (i.e. four time points). The

interaction of treatment group and time was tested separately. Analyses were

performed in IBM SPSS 22.0 with a significance level of α=0.05.

Results

PatientsA total of 106 patients were included from six centres between January 2012 and July

2015. At randomization, 48 patients were allocated to standard group and 47 patients

to the prophylaxis group. Nine included patients could not be randomized (e.g. due to

the use of antibiotics 14 days prior to randomization). Both groups were well balanced

with respect to baseline clinical and sociodemographic characteristics (Table 1).

Table 1. Patient characteristics at baseline (no statistically significant differences between the study groups).

All patients Patients with complete HRQoL questionnaires

Standardgroup (N=48)

Prophylaxis group (N=47)

Standard group (N=34)

Prophylaxis group (N=28)

Age- yr (range) 58.5 (43-68) 57.0 (23-68) 58.5 (48-68) 58.1 (29-68)Sex – no. (%) Female 14 (29.2) 11 (23.4) 10 (29.4) 7 (25.0) Male 34 (70.8) 36 (76.6) 24 (70.6) 21 (75.0)WHO– no. (%) 0 35 (72.9) 32 (68.1) 26 (76.5) 19 (67.9) 1 11 (22.9) 11 (23.4) 7 (20.6) 7 (25.0) Unknown 2 (4.2) 4 (8.5) 1 (2.9) 2 (7.1)Tumor site– no. (%) Oral cavity 14 (29.2) 13 (27.7) 9 (26.5) 6 (21.4) Oropharynx 20 (41.7) 20 (42.6) 14 (41.2) 14 (50.0) Hypopharynx 5 (10.4) 11 (23.4) 4 (11.8) 7 (25.0) Larynx 8 (16.7) 3 (6.4) 7 (20.6) 1 (3.6) Unknown primary 1 (2.1) 0 0 0Indication CRT– no. (%) Primary treatment 26 (54.2) 34 (72.3) 19 (55.9) 20 (71.4) Postoperative treatment 22 (45.8) 13 (27.7) 15 (44.1) 8 (28.6)

42

C h a p t e r 3

HRQoL completion rate and baseline scoresOnly patients who completed the questionnaires at baseline as well as at follow up

were included in analyses (complete case analysis). Therefore, a total of 34 patients in

the standard group (70.8%) and 28 patients in the prophylaxis group (59.6%) were

included in final analyses. At baseline 34 patients in the standard group and 28 patients

in the prophylaxis group completed the questionnaires, before the start of prophylactic

antibiotics (at day 28) 34 and 26 patients respectively, at the end of radiotherapy 25

and 19 patients and at the end of follow up 34 and 28 patients respectively. However,

this could be different patients who completed the questionnaires at any time point.

At baseline, we found small clinically relevant differences between the two treatment

arms in some of the EORTC QLQ-C30 scales. However, none of these were statistically

significant.

Three items on the EORTC-HN35 were clinically relevant different with a difference of

more than 10 points. The prophylaxis group scored higher on ‘swallowing’ (28.7 vs.

16.3) and ‘social eating’ (24.2 vs. 13.1) than the standard group and lower on ‘painkillers’

(37.0 vs. 48.5) than the standard group. However, only the differences on ‘swallowing’

(p=0.024) and ‘social eating’ (p=0.027) were statistically significant in favour of the

standard group (Table 2).

The scores on the EORTC QLQ-C30 were comparable with EORTC reference data from

patients with stage III or IV head and neck cancer (34).

HRQoL between treatment groups during treatmentAt day 28 of chemotherapy, before the start of prophylactic antibiotics, there was no

statistically significant difference between the standard and prophylaxis group (Table 3).

After radiotherapy, at which point the prophylaxis group were still taking antibiotics

and acute toxicities of treatment are generally the highest, the prophylaxis group

reported fewer symptoms on almost all subscales of the QLQ-C30, QLQ-H&N35 and

PS-HN, though almost no items were significantly different to the 0.05 level (Table 3).

‘Cognitive functioning’ and ‘social functioning’ from the EORTC QLQ-C30 and ‘social

contact’ from the QLQ-H&N35 were significantly different in favour of the prophylaxis

group (Figure 1).

At 3.5 months after the end of chemoradiotherapy, the standard group scored lower

on ‘social eating’ (17.6 vs. 34.3, p=0.017) and ‘teeth’ (10.1 vs. 26.9, p=0.019) to a strong

clinically relevant level compared to the prophylaxis group in favour of the standard

group (Table 3).

43

Quality of life of patients treated with prophylactic antibiotics

3

Table 2: Baseline scores in HRQoL measured by the EORTC QLQ-C30 and QLQ-H&N35.

BaselineEORTCstage III-IV (mean)₣

Standard group(N=34)

Prophylaxis group(N=28)

∆ p

PSS-HNNormalcy of diet (N) NA 77.5 (32) 68.8 (25) -8.7 .253Eating in public (N) NA 93.8 (32) 84.0 (25) -9.8 .126Understandability of speech(N) NA 89.8 (32) 90.0 (25) 0.2 .977

QLQ-C30Physical functioning (N) 81.2 89.4 (34) 89.0 (28) -0.4 .895Role functioning (N) 78.8 74,0 (34) 79.8 (28) 5.8 .413Emotional functioning(N) 71.2 77.7 (34) 82.1 (28) 4.4 .382Cognitive functioning(N) 86.4 89.7 (34) 94.0 (28) 4.3* .267Social functioning(N) 82.2 79.4 (34) 88.7 (28) 9.3* .104Global health status(N) 63.1 72.2 (33) 72.0 (28) -0.2 .968Fatigue(N) 27.6 16.7 (34) 21.0 (28) 4.3 .415Nausea/vomiting(N) 5.2 0.5 (33) 5.4 (28) 4.9* .075Pain(N) 24.9 18.1 (34) 18.5 (28) 0.4 .962Dyspnoea(N) 18.0 8.8 (34) 6.0 (28) -2.8 .548Insomnia(N) 28.5 27.5 (34) 23.8 (28) -3.7 .629Appetite loss(N) 19.4 10.8 (34) 19.0 (28) 8.2 .230Constipation(N) 11.7 12.7 (34) 10.7 (28) -2 .719Diarrhea(N) 6.1 1.0 (34) 6.0 (28) 5* .068Financial problems(N) 18.8 18.6 (34) 11.9 (28) -6.7* .289

QLQ-H&N35a

Pain(N) NA 18.8 (34) 25.3 (27) 6.5 .203Swallowing(N) NA 16.3 (34) 28.7 (27) 12.4† .024‡Senses problems(N) NA 16.2 (34) 7.4 (27) -8.8 .090Speech problems(N) NA 16.5 (33) 14.0 (27) -2.5 .643Social eating(N) NA 13.1 (33) 24.4 (26) 11.3† .027‡Social contact (N) NA 4.0 (33) 7.7 (27) 3.7 .302Sexuality(N) NA 20.6 (30) 13.8 (23) -6.8 .428Teeth(N) NA 13.7 (34) 14.7 (25) 1 .891Opening mouth(N) NA 26.5 (34) 24.4 (26) -2.1 .800Dry mouth(N) NA 17.6 (34) 18.5 (27) 0.9 .886Sticky saliva(N) NA 21.6 (34) 20.5 (26) -1.1 .887Coughing(N) NA 24.5 (34) 22.2 (27) -2.3 .704Felt ill(N) NA 6.9 (33) 6.2 (26) -0.7 .890Pain killers(N) NA 48.5 (33) 37.0 (27) -11.5† .110Nutritional supplements(N) NA 27.3 (33) 37.0 (27) 9.7 .427Feeding tube(N) NA 9.1 (33) 7.7 (26) -1.4 .851

(N) after each subscales means the number of available questionnaires. *= small clinically important difference; †=clinically relevant difference of more than 10 points; ‡= statistically significant. ₣: EORTC reference data from patients with stage III or IV head and neck cancer (34). NA = not availableaWeight gain and weight loss not reported due to difficult interpretation

44

C h a p t e r 3

Table 3. Scores in HRQoL at four time points during the study measured by the EORTC QLQ-C30 and QLQ-H&N35.

Baseline Day 28Standard group(N=34)

Prophylaxis group(N=28)

∆ p Standard group(N=34)

Prophylaxis group(N=28)

∆

PSS-HNNormalcy of diet (N) 77.5 (32) 68.8 (25) -8.7 .253 45.5 (31) 37.6 (25) -7.9Eating in public (N) 93.8 (32) 84.0 (25) -9.8 .126 67.5 (30) 56.8 (22) -10.7Understandability of speech(N)

89.8 (32) 90.0 (25) 0.2 .977 79.8 (31) 80.0 (25) 0.2

QLQ-C30Physical functioning (N) 89.4 (34) 89.0 (28) -0.4 .895 82.0 (34) 84.2 (26) 2.2Role functioning (N) 74.0 (34) 79.8 (28) 5.8 .413 62.3 (34) 64.7 (26) 2.4Emotional functioning(N) 77.7 (34) 82.1 (28) 4.4 .382 81.4 (34) 78.2 (26) -3.2Cognitive functioning(N) 89.7 (34) 94.0 (28) 4.3* .267 81.9 (34) 86.5 (26) 4.6*Social functioning(N) 79.4 (34) 88.7 (28) 9.3* .104 73.0 (34) 75.6 (26) 2.6Global QoL(N) 72.2 (33) 72.0 (28) -0.2 .968 57.4 (34) 59.6 (26) 2.2Fatigue(N) 16.7 (34) 21.0 (28) 4.3 .415 41.5 (34) 41.9 (26) 0.4Nausea/vomiting(N) 0.5 (33) 5.4 (28) 4.9* .075 27.0 (34) 15.4 (26) -11.6¥Pain(N) 18.1 (34) 18.5 (28) 0.4 .962 28.9 (34) 34.0 (26) 5.1Dyspnoea(N) 8.8 (34) 6.0 (28) -2.8 .548 7.8 (34) 11.5 (26) 3.7Insomnia(N) 27.5 (34) 23.8 (28) -3.7 .629 22.2 (33) 18.7 (25) -3.5Appetite loss(N) 10.8 (34) 19.0 (28) 8.2 .230 49.0 (34) 50.7 (25) 1.7Constipation(N) 12.7 (34) 10.7 (28) -2 .719 22.5 (34) 23.1 (26) 0.6Diarrhea(N) 1.0 (34) 6.0 (28) 5* .068 9.8 (34) 7.7 (26) -2.1Financial problems(N) 18.6 (34) 11.9 (28) -6.7* .289 15.7 (34) 12.8 (26) -2.9

QLQ-H&N35aPain(N) 18.8 (34) 25.3 (27) 6.5 .203 39.2 (34) 44.3 (25) 5.1Swallowing(N) 16.3 (34) 28.7 (27) 12.4† .024‡ 45.9 (34) 46.7 (25) 0.8Senses problems(N) 16.2 (34) 7.4 (27) -8.8 .090 51.0 (34) 40.7 (25) -10.3†Speech problems(N) 16.5 (33) 14.0 (27) -2.5 .643 25.7 (34) 28.4 (26) 2.7Social eating(N) 13.1 (33) 24.4 (26) 11.3† .027‡ 35.9 (34) 39.4 (26) 3.5Social contact (N) 4.0 (33) 7.7 (27) 3.7 .302 12.7 (34) 9.6 (26) -3.1Sexuality(N) 20.6 (30) 13.8 (23) -6.8 .428 38.0 (32) 41.7 (22) 3.7Teeth(N) 13.7 (34) 14.7 (25) 1 .891 13.7 (34) 14.5 (23) 0.8Opening mouth(N) 26.5 (34) 24.4 (26) -2.1 .800 37.3 (34) 34.7 (25) -2.6Dry mouth(N) 17.6 (34) 18.5 (27) 0.9 .886 52.0 (34) 50.7 (25) -1.3Sticky saliva(N) 21.6 (34) 20.5 (26) -1.1 .887 58.8 (34) 68.0 (25) 9.2Coughing(N) 24.5 (34) 22.2 (27) -2.3 .704 35.3 (34) 38.7 (25) 3.4Felt ill(N) 6.9 (33) 6.2 (26) -0.7 .890 32.4 (34) 25.3 (26) -7.1Pain killers(N) 48.5 (33) 37.0 (27) -11.5† .110 76.5 (34) 88.5 (26) 12Nutritional supplements(N)

27.3 (33) 37.0 (27) 9.7 .427 72.7 (33) 76.0 (25) 3.3

Feeding tube(N) 9.1 (33) 7.7 (26) -1.4 .851 23.5 (34) 38.5 (26) 15†

(N) after each subscales means the number of available questionnaires. At baseline, 34 questionnaires in the standard group (70.8%) and 28 in the prophylaxis group (59.6%) could be analysed, at day 28, 70.8% and 55.3%, at the end of radiotherapy 52.1% and 40.4% and at follow up 70.8% and 69.6% in the standard group and prophylaxis group, respectively.*= small clinical important difference; ¥ = medium clinical important difference; ₣ = large clinical important difference; †=clinical relevant difference of more than 10 points; ‡= statistically significant (p<0.05); #clinical relevant difference of more than 12.8 pointsaWeight gain and weight loss not reported due to difficult interpretation

45

Quality of life of patients treated with prophylactic antibiotics

3

After RT FUp Standard

group(N=34)

Prophylaxis group(N=28)

∆ p Standard group(N=34)

Prophylaxis group(N=28)

∆ p

.294 39.2 (24) 28.9 (18) -10.3 .210 72.0 (32) 56.9 (26) -15.1# 0.090

.274 69.6 (23) 68.8 (16) -0.8 .946 87.5 (32) 72.9 (24) -14.6# .094

.981 71.9 (24) 84.7 (18) 12.8# .175 91.9 (31) 90.0 (25) -1.9 .607

.539 76.0 (25) 83.2 (19) 7.2* .167 87.1 (34) 84.6 (28) -2.5 .473

.708 55.3 (25) 68.4 (19) 13.1* .127 73.5 (34) 73.8 (28) 0.3 .965

.536 78.7 (25) 83.8 (19) 5.1 .335 85.9 (33) 81.3 (28) -4.6 .304

.382 77.3 (25) 89.5 (19) 12.2¥ .047‡ 88.4 (33) 91.7 (28) 3.3* .389

.693 66.7 (25) 86.0 (19) 19.3₣ .023‡ 84.3 (33) 83.3 (28) -1 .851

.679 50.3 (25) 59.6 (19) 9.3* .194 71.7 (33) 64.9 (28) -6.8* .179

.950 46.7 (25) 38.6 (19) -8.1* .267 28.9 (34) 27.0 (28) -1.9 .736

.091 29.3 (25) 27.2 (19) -2.1 .808 6.9 (34) 5.4 (28) -1.5 .659

.440 35.3 (25) 37.7 (19) 2.4 .782 17.6 (34) 18.5 (28) 0.9 .897

.390 8.0 (25) 8.8 (19) 0.8 .864 7.8 (34) 11.9 (28) 4.1* .384

.642 22.7 (25) 15.8 (19) -6.9* .443 16.7 (34) 28.4 (27) 11.7* .158

.854 53.3 (25) 42.1 (19) -11.2 .284 22.5 (34) 33.3 (28) 10.8 .176

.927 29.3 (25) 29.8 (19) 0.5 .955 6.9 (34) 9.5 (28) 2.6 .583

.618 10.7 (25) 15.8 (19) 5.1* .390 1.0 (33) 4.8 (28) 3.8* .136

.614 20.0 (25) 12.3 (19) -7.7* .343 17.2 (33) 21.4 (28) 4.2* .552

.418 46.2(24) 41.2 (18) -5 .501 26.5 (34) 28.7 (27) 2.2 .704

.907 53.8 (24) 47.2 (18) -6.6 .396 22.7 (34) 29.9 (27) 7.2 .263

.159 46.5 (24) 40.7 (18) -5.8 .468 28.4 (34) 30.9 (27) 2.5 .729

.690 42.4 (25) 26.9 (19) -15.5† .051 14.4 (34) 19.0 (28) 4.6 .354

.487 41.9 (25) 38.7 (19) -3.2 .643 17.6 (34) 34.3 (27) 16.7† .017‡

.479 22.1 (25) 9.4 (19) -12.7† .041‡ 6.3 (34) 8.8 (28) 2.5 .446

.711 43.5 (23) 42.2 (17) -1.3 .908 29.6 (31) 27.8 (24) -1.8 .845

.888 26.4 (24) 21.6 (17) -4.8 .616 10.1 (33) 26.9 (26) 16.8† .019‡

.764 47.2 (24) 35.2 (18) -12 .165 30.4 (34) 34.6 (27) 4.2 .583

.881 52.8 (24) 48.1 (18) -4.7 .643 54.9 (34) 56.8 (27) 1.9 .835

.255 66.7 (24) 70.4 (19) 3.7 .682 45.1 (34) 43.2 (27) -1.9 .789

.627 29.2 (24) 29.6 (18) 0.4 .951 24.5 (34) 29.6 (27) 5.1 .431

.329 41.7 (25) 24.1 (19) -17.6† .054 12.7 (34) 14.8 (28) 2.1 .740

.224 76.0 (25) 84.2 (19) 8.2 .515 29.4 (34) 28.6 (28) -0.8 .943

.783 72.0 (25) 57.9 (19) -14.1† .340 41.2 (34) 46.4 (28) 5.2 .684

.227 36.0 (25) 50.0 (18) 14† .371 26.5 (34) 32.1 (28) 5.6 .632

46

C h a p t e r 3

On the bottom three symptom subscales, showing an increase in symptoms during radiotherapy, with improvement of symptoms at follow up, except for some specific subscales like dry mouth. The prophylaxis group felt less ill during chemoradiotherapy.

Figure 1. On the top three functional items of the QLQ-C30 showing a decrease during chemoradiotherapy, and an increase at follow up, whereas the prophylaxis group in general had a less steeper decline after radiotherapy compared with the standard group.

47

Quality of life of patients treated with prophylactic antibiotics

3

HRQoL during treatment compared with baseline in both groupsThe standard group had a lower score to a clinically relevant level on all functional

subscales of the EORTC-QLQ-C30, except for ‘emotional functioning,’ at the end of

radiotherapy compared to baseline, while the prophylaxis group had a lower score to

a clinically relevant level only on ‘role functioning’ and ‘global QoL’ (Fig. 1). Scores on

all functional subscales returned to baseline values at 3.5 months follow up for both

treatment groups. In both groups, patients experiences a clinically relevant increase

in symptoms after chemoradiotherapy compared to baseline that persisted until 3.5

months follow up on the items ‘senses problems’, dry mouth’, ‘sticky saliva’, and

‘feeding tube’ (Table 3). On the other symptom subscales of the EORTC QLQ-C30 and

QLQ-H&N35, there was a clinically meaningful increase in scores during

chemoradiotherapy measured at day 28 and at the end of radiotherapy compared

with baseline, which recovered to baseline levels at 3.5 months follow up for both

groups (Table 3).

Course of HRQoLAt a group level, the EORTC QLQ-C30 functioning scales ‘physical functioning’, ‘role

functioning’, and ‘global QoL’ significantly decreased between baseline and the end of

chemoradiotherapy, indicating problems increased by the end of chemoradiotherapy.

These changes were similar in both treatment groups (Table 4). Patients scored

statistically significantly higher on ‘fatigue’, ‘pain’, ‘constipation’, and ‘diarrhea’ of the

EORTC QLQ-C30 at the end of radiotherapy compared to baseline and 3.5 months

follow-up, with no difference between the two treatment groups. Patients also scored

significantly higher on ‘Nausea and vomiting’ at the end of radiotherapy compared with

all other timepoints. The symptoms of the EORTC QLQ-H&N35 ‘pain’, ‘swallowing’, ‘sticky

saliva’, changed significantly between the end of radiotherapy and baseline and end

of radiotherapy and end of follow-up, with significantly higher scores at the end of

radiotherapy. The symptoms ‘senses problems’, ‘speech problems’, ‘social eating’,

‘sexuality’, ‘dry mouth’, ‘coughing’, ‘felt ill’ and the need of ‘a feeding tube’ scores all

significantly higher at the end of radiotherapy compared with baseline. On the ‘cognitive

functioning’ and ‘social functioning’ scales of the EORTC QLQ-C30 and the ‘social contact’

and ‘feeling ill’ symptom scales of the EORTC QLQ-H&N35 the standard group

experienced significantly more problems over time compared to the prophylaxis group

(Table 4).

48

C h a p t e r 3

Tabl

e 4.

Lin

ear m

ixed

-eff

ects

mod

el o

f the

func

tiona

l sca

les

of th

e EO

RTC

QLQ

-C30

(4a)

and

the

EORT

C Q

LQ-H

&N35

(4b)

.

4A.

Physical functioning

Role functioning

Emotional functioning

Cognitive functioning

Social functioning

Global QoL

Fatigue

Nausea

Pain

Dyspnoea

Insomnia

Appetite loss

Constipation

Diarrhea

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Tim

e va

riab

les

Tim

e

T3

vers

us T

16.

69*

13.1

4*-1

.45

4.74

4.90

13.0

6*-1

9.27

*-2

1.17

*-1

9.30

*-3

.92

6.52

-27.

01*

-19.

17*

-9.0

5*

T3

vers

us T

21.

88-2

.92

-5.6

5-3

.05

-7.8

1-0

.04

1.59

-11.

20*

-4.5

61.

501.

304.

67-6

.64

-7.0

4

T3

vers

us T

42.

347.

19-2

.34

2.36

-0.4

55.

92-1

3.32

*-2

1.17

*-1

9.30

*2.

0411

.16

-12.

72-2

0.36

*-1

0.24

*Tr

eatm

ent

Arm

B v

ersu

s A

rm A

-6.1

6-1

0.30

-5.6

7-1

1.91

*-1

6.37

*-7

.78

6.71

4.02

-3.0

6-2

.03

4.63

8.66

0.64

-3.5

8

4B.

Pain

Swallowing

Senses problems

Speech problems

Social eating

Social contact

Sexuality

Teeth

Opening mouth

Dry mouth

Sticky saliva

Coughing

Felt ill

Pain killers

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Beta

Tim

e va

riab

les

Tim

e

T3

vers

us T

1-1

5.44

*-2

0.60

*-3

5.79

*-1

4.33

*-1

6.95

*-2

.52

-29.

21*

-3.0

8-1

2.26

-28.

47*

-49.

40*

-11.

05*

-19.

98*

-14.

59

T

3 ve

rsus

T2

3.04

-2.7

3-0

.15

-0.2

4-1

.88

-0.8

2-1

.30

-4.4

3-2

.33

6.01

-0.5

35.

92-0

.14

1,97

T

3 ve

rsus

T4

-12.

31*

-19.

26*

-11.

30-9

.52

-6.5

6-1

.20

-15.

286.

68-1

.66

10.9

9-2

6.22

*-2

.78

-10.

48-5

5.98

*Tr

eatm

ent

Arm

B v

ersu

s A

rm A

4.03

4.63

7.81

13.3

61.

1911

.51*

0.50

5.83

5.95

7.38

-3.4

4-2

.87

16.2

4*-6

.97

The

item

fina

ncia

l pro

blem

s of

the

EORT

C Q

LQ-C

30 a

nd th

e ite

ms

nutr

ition

al s

uppl

emen

ts, f

eedi

ng tu

be, w

eigh

t los

s an

d w

eigh

t of t

he E

ORT

C H

&N

-35

are

not r

epor

ted,

be

caus

e th

ey a

re b

ased

on

sing

le it

em-q

uest

ions

, and

in th

at w

ay d

iffic

ult t

o in

terp

ret a

nd b

ecau

se o

f the

sm

all n

umbe

r of

pat

ient

s ea

sy to

var

y in

out

com

e.*:

Indi

catin

g a

clin

ical

ly s

igni

fican

t diff

eren

ce (<

0.05

).

49

Quality of life of patients treated with prophylactic antibiotics

3

Discussion

HRQoL was an important secondary objective of the PANTAP-study, which showed that

prophylactic administration of amoxicillin/clavulanic acid reduced the number of

hospital admissions, episodes of fever and healthcare costs without lowering the

incidence of pneumonias. This study showed that prophylactic antibiotics also seemed

to improve most aspects of HRQoL at the end of radiotherapy compared to standard

care alone, although not all subscales were statistically significantly different.

At baseline some small clinically relevant differences were found between the two

treatment groups, though most disappeared before the start of the prophylactic

antibiotics at day 28. However, at the end of radiotherapy, when patients in the

prophylaxis group were still taking the prophylactic antibiotics, the prophylaxis group

reported a better HRQoL on most items compared to the standard group. At the end

of follow up, 3.5 months after the end of chemoradiotherapy, few differences still existed

between the two treatment groups. This suggests the advantage of the prophylaxis,

with respect to the HRQoL, is experienced between the start of the antibiotics and the

end of radiotherapy, as seen in the decreased decline in functional subscales. During

the study, HRQoL deteriorated from baseline to day 28 and the end of radiotherapy;

patients experienced a significantly higher symptom burden at the end of radiotherapy

compared to baseline on 10 of the 18 symptoms covered by the EORTC QLQ-H&N35

reflects the high level of toxicity at the end of chemoradiotherapy. This confirms findings

in the literature that show a decline in HRQoL during and at the end of (chemo)

radiotherapy (9,11). This deterioration can be explained by treatment toxicities.

Interestingly, we observed no difference in reported levels of diarrhoea in the

prophylaxis group compared to the standard group. This is surprising given the

relatively long use of antibiotics in the prophylaxis group.

At follow-up, 3.5 months after the end of chemoradiotherapy, most subscales returned

to baseline-values or better, which has been previously described in other studies

(4,9,12). Only the ‘senses problems’, ‘dry mouth’, and ‘sticky saliva’ symptom scales saw

no improvement at follow up. This is also agrees with previous studies by Vergeer et

al. and Jellema et al. that showed dry mouth, sticky saliva and diminished taste can be

long lasting or even permanent (10,35), due to permanent damage to the salivary

glands caused by the radiotherapy. The fact that patients in the prophylaxis group

scored significantly higher on the subscales ‘social eating’ and ‘teeth’ at follow-up,

cannot be explained by the use of prophylactic antibiotics. This may be due to statistical

issues related to the small number of completed questionnaires.

50

C h a p t e r 3

Slightly more patients included in the prophylaxis group had hypopharyngeal cancer,

although not statistically different. Hypopharyngeal cancer is associated with a greater

risk of aspiration and pneumonia. This may have influenced the number of aspiration

pneumonias in both groups. But as the number of pneumonias were not different

between the two groups, it likely would not have had any consequence on the HRQoL

outcomes.

To the best of our knowledge, the PANTAP study is the first study to investigate the

effect of prophylactic antibiotics on the occurrence of pneumonias, the number of

hospital admissions and healthcare costs in LAHNC patients treated with

chemoradiotherapy. The strength of the current study is the focus on the effect of

prophylactic antibiotics on HRQoL in this patient group. As far as we know, only one

other study has looked at the effect of antibiotics on HRQoL. Braimah et al. investigated

the effect of oral antibiotics on HRQoL after mandibular third molar surgery and

showed that extended oral use of amoxicillin/clavulanic acid was correlated with a

better, though not statistically significant, HRQoL (36).

A limitation of this study is the relative low compliance of completed HRQoL

questionnaires, particularly at the end of radiotherapy. In addition, fewer questionnaires

were completed by the prophylaxis group (at baseline 70.8% versus 59.6% for standard

versus prophylaxis groups, respectively). Because of this, the number of included

questionnaires was too low to perform multivariate analyses and no conclusions could

be drawn on the impact of pneumonia or hospital admission on HRQoL. The explorative

nature of this study also made it impossible to correct for multiple comparisons or

confounders such as comorbidity. Furthermore, the last follow-up questionnaire was

at 3.5 months after the end of chemoradiotherapy, limiting our ability to assess the

long-term effects of prophylactic antibiotics on HRQoL. However, as HRQoL largely

returned to baseline values at 3.5 months follow up with almost no differences between

the groups, no large clinically relevant differences would be expected in future.

In conclusion, prophylactic antibiotics in LAHNC patients treated with chemoradiotherapy

may mitigate deterioration of HRQoL at the end of the radiotherapy compared to

standard care alone. However, no differences were found between groups at the end

of follow up. This study should be replicated with larger numbers and more potential

covariates. However, given the fact that prophylactic antibiotics, compared to standard

treatment, reduced the number of hospital admissions and costs and also seemed to

help maintain HRQoL at the end of the chemoradiotherapy, prophylactic antibiotics in

this patients group can be considered.

51

Quality of life of patients treated with prophylactic antibiotics

3

Declaration of Competing InterestNone declared.

AcknowledgementsWe would like to thank all the patients for their collaboration and all collaborating

hospitals.

FundingThis work was supported by The Netherlands Organisation for Health Research and

Development: ZonMw, project number 171101011

52

C h a p t e r 3

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7-30.2. Ferlay J SI, Ervik M, Dikshit R, Eser S, Mathers C, et al. . GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality

Worldwide; IARC Cancerbase No. 11. In; 2012.3. Bottomley A, Tridello G, Coens C, Rolland F, Tesselaar ME, Leemans CR, et al. An international phase 3 trial

in head and neck cancer: quality of life and symptom results: EORTC 24954 on behalf of the EORTC Head and Neck and the EORTC Radiation Oncology Group. Cancer 2014;120(3):390-8.

4. Rettig EM, D’Souza G, Thompson CB, Koch WM, Eisele DW, Fakhry C. Health-related quality of life before and after head and neck squamous cell carcinoma: Analysis of the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey linkage. Cancer 2016;122(12):1861-70.

5. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 2008;371(9625):1695-709.6. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and

radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091-8.7. Driessen CM, Janssens GO, van der Graaf WT, Takes RP, Merkx TA, Melchers WJ, et al. Toxicity and efficacy

of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck 2016;38 Suppl 1:E559-65.

8. Kelly C, Paleri V, Downs C, Shah R. Deterioration in quality of life and depressive symptoms during radiation therapy for head and neck cancer. Otolaryngol Head Neck Surg 2007;136(1):108-11.

9. Klein J, Livergant J, Ringash J. Health related quality of life in head and neck cancer treated with radiation therapy with or without chemotherapy: a systematic review. Oral Oncol 2014;50(4):254-62.

10. Vergeer MR, Doornaert PA, Rietveld DH, Leemans CR, Slotman BJ, Langendijk JA. Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: results of a nonrandomized prospective study using a standardized follow-up program. Int J Radiat Oncol Biol Phys 2009;74(1):1-8.

11. Epstein JB, Robertson M, Emerton S, Phillips N, Stevenson-Moore P. Quality of life and oral function in patients treated with radiation therapy for head and neck cancer. Head Neck 2001;23(5):389-98.

12. de Graeff A, de Leeuw JR, Ros WJ, Hordijk GJ, Blijham GH, Winnubst JA. Long-term quality of life of patients with head and neck cancer. Laryngoscope 2000;110(1):98-106.

13. List MA, Siston A, Haraf D, Schumm P, Kies M, Stenson K, et al. Quality of life and performance in advanced head and neck cancer patients on concomitant chemoradiotherapy: a prospective examination. J Clin Oncol 1999;17(3):1020-8.

14. Denaro N, Merlano MC, Russi EG. Dysphagia in Head and Neck Cancer Patients: Pretreatment Evaluation, Predictive Factors, and Assessment during Radio-Chemotherapy, Recommendations. Clin Exp Otorhinolaryngol 2013;6(3):117-26.

15. Xu B, Boero IJ, Hwang L, Le QT, Moiseenko V, Sanghvi PR, et al. Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. Cancer 2015;121(8):1303-11.

16. Rutten H, Pop LA, Janssens GO, Takes RP, Knuijt S, Rooijakkers AF, et al. Long-term outcome and morbidity after treatment with accelerated radiotherapy and weekly cisplatin for locally advanced head-and-neck cancer: results of a multidisciplinary late morbidity clinic. Int J Radiat Oncol Biol Phys 2011;81(4):923-9.

17. Langerman A, Maccracken E, Kasza K, Haraf DJ, Vokes EE, Stenson KM. Aspiration in chemoradiated patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2007;133(12):1289-95.

18. Nguyen NP, Smith HJ, Dutta S, Alfieri A, North D, Nguyen PD, et al. Aspiration occurence during chemoradiation for head and neck cancer. Anticancer Res 2007;27(3B):1669-72.

19. Ham J, Driessen C, Hendriks MP, Fiets WE, Kreike B, Hoeben A, et al. Prophylactic antibiotics to prevent pneumonia in patients treated with chemoradiotherapy (CRT) for locally advanced head and neck carcinoma (LAHNC). Journal of Clinical Oncology 2016;34(15_suppl):6079-6079.

20. Ham J, Driessen C, Hendriks MP, Fiets WE, Kreike B, Hoeben A, et al. Cost-effectiveness of prophylactic antibiotics to prevent pneumonia in patients treated with chemoradiotherapy (CRT) for locally advanced head and neck carcinoma (LAHNC). Journal of Clinical Oncology 2017;35(15_suppl):6075-6075.

21. Husson O, Haak HR, Buffart LM, Nieuwlaat WA, Oranje WA, Mols F, et al. Health-related quality of life and disease specific symptoms in long-term thyroid cancer survivors: a study from the population-based PROFILES registry. Acta Oncol 2013;52(2):249-58.

22. Scott NW, McPherson GC, Ramsay CR, Campbell MK. The method of minimization for allocation to clinical trials. a review. Control Clin Trials 2002;23(6):662-74.

23. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.

53

Quality of life of patients treated with prophylactic antibiotics

3

24. List MA, D’Antonio LL, Cella DF, Siston A, Mumby P, Haraf D, et al. The Performance Status Scale for Head and Neck Cancer Patients and the Functional Assessment of Cancer Therapy-Head and Neck Scale. A study of utility and validity. Cancer 1996;77(11):2294-301.

25. Fayers PM AN, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 2001.

26. Cocks K, King MT, Velikova G, Martyn St-James M, Fayers PM, Brown JM. Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 2011;29(1):89-96.

27. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.

28. List MA, Ritter-Sterr C, Lansky SB. A performance status scale for head and neck cancer patients. Cancer 1990;66(3):564-9.

29. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003;41(5):582-92.

30. Norman GR, Sridhar FG, Guyatt GH, Walter SD. Relation of distribution- and anchor-based approaches in interpretation of changes in health-related quality of life. Med Care 2001;39(10):1039-47.

31. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 1989;10(4):407-15.

32. King MT. The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. Qual Life Res 1996;5(6):555-67.

33. Liu LC, Hedeker D. A mixed-effects regression model for longitudinal multivariate ordinal data. Biometrics 2006;62(1):261-8.

34. Scott NW FP, Aaronson NK, Bottomley A et al. EORTC QLQ-C30 reference values manual. 2008.35. Jellema AP, Slotman BJ, Doornaert P, Leemans CR, Langendijk JA. Impact of radiation-induced xerostomia

on quality of life after primary radiotherapy among patients with head and neck cancer. Int J Radiat Oncol Biol Phys 2007;69(3):751-60.

36. Braimah RO, Ndukwe KC, Owotade JF, Aregbesola SB. Impact of oral antibiotics on health-related quality of life after mandibular third molar surgery: An observational study. Niger J Clin Pract 2017;20(9):1189-1194.

Submitted

Janneke C. Ham, Winette T.A. van der Graaf, Chantal M.L. Driessen,

Sophie C.M. Tops-van Kuppevelt, Heiman F.L. Wertheim, Carla M.L. van Herpen,

Bart Jan Kullberg

Pathogens and resistance patterns in locally

advanced head and neck cancer (LAHNC)

patients treated with chemoradiotherapy

receiving prophylactic antibiotics.

C H A P T E R 4

56

C h a p t e r 4

Abstract

ObjectivesIn locally advanced head and neck cancer (LAHNC) patients treated with concomitant

chemoradiotherapy, a randomised study to antimicrobial prophylaxis lead to a

reduction in the hospitalisation rate but not to a reduction in the number of pneumonias

(the PANTAP study). Here, we aim to study the effect of prophylactic antibiotics on

sputum cultures.

MethodsLAHNC patients treated with concomitant chemoradiotherapy were randomised

between standard care or antimicrobial prophylaxis with amoxicillin/clavulanic acid

from day 29 until 14 days after the end of chemoradiotherapy. Sputum cultures were

collected at day 29, at the end of chemoradiotherapy (ranging from day 40 to 47), and

3 weeks and 14 weeks after the end of chemoradiotherapy. Sputum culture positivity,

the spectrum and resistance pattern of microorganisms cultured were studied.

ResultsForty-eight patients were allocated to receive standard care and 47 to receive

prophylactic antibiotics. There were no differences in the number of cultures performed

between the treatment groups, nor in the number of sputum cultures positive for

bacteria and/or fungi. At the end of the chemoradiotherapy, 9.1% of the cultured

bacteria in the standard care group were resistant to amoxicillin/clavulanic acid

compared with 53.3% in the prophylaxis group (p=.006).

ConclusionsIn LAHNC patients treated with chemoradiotherapy and receiving prophylactic

antibiotics, there is no increase in appearance of atypical bacteria or fungi, and only

at the end of chemoradiotherapy, more bacteria were resistant to amoxicillin/

clavulanic acid.

57

Pathogens and resistance in patients receiving prophylactic antibiotics

4

Introduction

Head and neck cancer is the seventh most common type of cancer worldwide.(1) The

treatment for locally advanced head and neck cancer (LAHNC) often consists of

concomitant platinum-based chemoradiotherapy, which induces a high rate of toxicity,

like mucositis, dermatitis, anorexia, pain, and dysphagia (2). At presentation, up to 40%

of patients have dysphagia, and during chemoradiotherapy, the aspiration rate is

between 13 and 69% (3-6). Aspiration pneumonia is a relatively frequent complication

in LAHNC patients treated with chemoradiotherapy, with a 5-year cumulative incidence

of 23.8%, leading to a substantial higher risk of death (7, 8). Recently, we performed

the PANTAP-study to investigate the use of antimicrobial prophylaxis during

chemoradiotherapy in LAHNC patients to prevent aspiration pneumonia (9). Secondary

objectives were to investigate the number of hospitalisations, adverse events including

side effects of amoxicillin/clavulanic acid, quality of life, to evaluate cost-effectiveness

and to determine the influence of receiving antimicrobial prophylaxis on the sputum

cultures with respect to the microbial isolates and resistance.

As reported elsewhere, hospitalisation rate was significantly reduced in the prophylaxis

group, as well as the number of febrile episodes, leading to a significant reduction in

costs of €1425 per patient in favour of the prophylaxis group. No significant difference

was found in the incidence of aspiration pneumonias between the standard group and

the prophylaxis group (9).

Except for the difference in number of febrile episodes (episodes of fever of any grade

in 29.2% of patients in the standard group compared to 10.9% in the prophylaxis group,

p=0.028), no other significant differences were found in numbers of adverse events,

such as neutropenia, diarrhoea or rash.

However, to prevent antibiotic resistance, antimicrobial prophylaxis should only be

prescribed when relevant clinical benefit has been demonstrated, and it has been

shown that even a single dose of amoxicillin leads to selection of resistant strains in

the oral microflora (10). Therefore, the aim of this study was to investigate the effect

of the antimicrobial prophylaxis on sputum culture positivity, and the spectrum and

resistance pattern of microorganisms cultured.

58

C h a p t e r 4

Patients and methods

A multicenter randomised trial was performed in LAHNC patients, who were treated

with concomitant chemoradiotherapy. Patients were included into the study before

the start of chemoradiotherapy. Selection criteria included an indication for

chemoradiotherapy, no known allergy to amoxicillin, no use of maintenance antibiotics

and no HIV/immunodeficiency. Chemoradiotherapy was given as primary treatment

or as postoperative treatment and consisted of 6 to 7 weeks of radiotherapy (35

fractions of 2.0 Gy) with concomitant weekly or 3-weekly platinum based chemotherapy.

Randomisation took place between days 21 to 28 of chemoradiotherapy, unless there

were a pneumonia or other infections or antibiotic treatment within 14 days prior to

randomisation.

Antimicrobial prophylaxis The standard group received standard care (no antimicrobial prophylaxis), including

blood and sputum cultures and a chest radiography in case of a (suspected) lower

airway infection, mostly followed by hospitalisation and intravenous antibiotics. The

prophylaxis group received amoxicillin/clavulanic acid suspension 625mg three times

daily on top of the standard care. In case of hepatic injury or an allergic reaction,

treatment with amoxicillin/clavulanic acid had to be stopped and could be replaced by

clindamycin 450 mg three times daily and metronidazol 500 mg three times daily. The

antimicrobial prophylaxis was prescribed from day 29 after the start of

chemoradiotherapy until 14 days after the end of the chemoradiotherapy. The total

duration of antibiotic treatment was 25-32 days, depending on which cisplatin regimen

was given (i.e. 6 or 7 cycles of cisplatin).

Sputum Sputum samples were collected at day 29 (before the start of antimicrobial prophylaxis),

at the end of chemoradiotherapy (within 1 week), 3 weeks and 14 weeks after

chemoradiotherapy. When clinically indicated, additional sputum samples were taken.

Gram stains were performed, and substantial leukocytosis was defined as ≥5 leucocytes

per high-power field. Sputum was streaked on two agar plates (Columbia Blood agar

and chocolate agar), incubated at 36 °C for 2 days and bacterial identification was done

by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-

TOF MS, Bioptyper version 3, Bruker, Bremen, Germany). Antibiotic susceptibility testing

was done according to (Clinical & Laboratory Standards Institute (CLSI) guidance (11).

59

Pathogens and resistance in patients receiving prophylactic antibiotics

4

Statistical analysisThe chi-square test was performed to test for significant differences between the

treatment groups. P-values were tested two-sided and were considered as statistically

significant when <0.05. SPSS statistics version 22 was used for performing the analyses.

Results

Between January 2012 and July 2015, 106 patients were included in this study. The main

results of the PANTAP trial have been published elsewhere (9). In summary, a total of

95 patients were randomised; 48 patients received standard care and 47 patients

received antimicrobial prophylaxis. Seven patients could not be randomised due to

infections or use of antibiotics within 14 days before randomisation, and 4 patients due

to other reasons. The baseline characteristics were well balanced (Table 1).

Antimicrobial prophylaxis Twenty-nine patients (61.7%) in the prophylaxis group completed the amoxicillin/

clavulanic acid prophylaxis as planned. Reasons for early discontinuation in the other

18 patients were toxicity in 9 patients, mainly due to gastro-intestinal complaints,

refusal of antibiotics in 3 patients, noncompliance to the prescribed schedule in 4

patients, and switch to alternative antibiotic treatment due to hospitalization or febrile

neutropenia during the course of prophylaxis in 2 patients. The mean duration of

antimicrobial prophylaxis was 21.7 days (range 0-34 days).

Sputum culture results At baseline, i.e. 29 days after the start of chemoradiotherapy, at the end of

chemoradiotherapy and 3 weeks after the end of chemoradiotherapy, no differences

were found in the number of sputum culture samples that were positive for bacteria

and/or fungi in the prophylaxis group compared to the standard care group. At 14

weeks after the end of chemoradiotherapy, sputum cultures were performed in only

31.2% of patients in the standard group and in 25.5% in the prophylaxis group. In these

sputum samples, more cultures were positive for bacteria and/or fungi in the

prophylaxis group (Table 2).

60

C h a p t e r 4

Table 1. Patient characteristics.

Standard group(N=48)

Prophylaxis group(N=47)

Age- yr (range) 58.5 (43-68) 57.0 (23-68)Sex – no. (%) Female 14 (29.2) 11 (23.4) Male 34 (70.8) 36 (76.6)WHO performance status (%) 0 35 (72.9) 32 (68.1) 1 11 (22.9) 11 (23.4) Unknown 2 (4.2) 4 (8.5)Tumour site (%) Oral cavity 14 (29.2) 13 (27.7) Oropharynx 20 (41.7) 20 (42.6) Hypopharynx 5 (10.4) 11 (23.4) Larynx 8 (16.7) 3 (6.4) Unknown primary 1 (2.1) 0TNM ClassificationT 1 5 (10.4) 4 (8.5) 2 9 (18.8) 10 (21.3) 3 15 (31.3) 13 (27.7) 4 18 (37.5) 19 (40.4) x 1 (2.1) 1 (2.1)N 0 15 (31.3) 12 (25.5) 1 5 (10.4) 7 (14.9) 2a 4 (8.3) 3 (6.4) 2b 16 (33.3) 13 (27.7) 2c 7 (14.6) 10 (21.3) 3 1 (2.1) 1 (2.1) x 0 1 (2.1)M 0 46 (95.8) 45 (95.7) x 2 (4.2) 2 (4.3)Indication for CRT (%) Primary treatment 26 (54.2) 34 (72.3) Postoperative treatment 22 (45.8) 13 (27.7)Chemotherapy (%) Cisplatin 100 mg/m2 three-weekly 10 (20.8) 12 (25.5) Cisplatin 40-50 mg/m2 weekly 32 (66.7) 30 (63.8) Carboplatin AUC 1.5 weekly 2 (4.2) 1 (2.1) Adapted chemotherapy 4 (8.3) 4 (8.4)Radiotherapy (%) Conventional 22 (45.8) 21 (44.7) Accelerated 26 (54.2) 26 (55.3) Total dose given at primary tumour and

pathological lymph nodes (median, range)68.0 (60-70) 68.0 (60-70)

Total dose (Gy) given at elective neck levels (median, range)

50.3 (46-66) 50.3 (46-60)

Tube feeding at randomisation (%) 9 (18.8) 9 (19.1)

WHO performance status range between 0-5 , with a score of 0 meaning “Able to carry out all normal activity without restrictions ”and a score of 5 “death”, TNM=tumour, node, metastasis, CRT=chemoradiotherapy.

61

Pathogens and resistance in patients receiving prophylactic antibiotics

4

Tabl

e 2.

Spu

tum

cul

ture

resu

lts re

gard

ing

the

num

ber o

f per

form

ed sp

utum

cul

ture

s, n

umbe

r of b

acte

rial

and

fung

al sp

ecie

s, n

umbe

r of c

ultu

res w

ith

resi

stan

t bac

teri

a.

Day

29

At

the

end

of C

RT3

wee

ks a

fter

CRT

14 w

eeks

aft

er C

RTSt

anda

rdG

roup

(N=4

8)

Prop

hyla

xis

grou

p(N

=47)

p- valu

eSt

anda

rdG

roup

(N=4

8)

Prop

hyla

xis

grou

p(N

=47)

p- valu

eSt

anda

rdG

roup

(N=4

8)

Prop

hyla

xis

grou

p(N

=47)

p- valu

eSt

anda

rdG

roup

(N=4

8)

Prop

hyla

xis

grou

p(N

=47)

p- valu

e

Perf

orm

ed (%

)34

(70.

8)31

(66.

0).6

0937

(77.

1)29

(61.

7).1

0437

(77.

1)35

(74.

5).7

6615

(31.

2)12

(25.

5).5

37

Neg

ativ

e23

(67.

6)15

(48.

4).1

1620

(54.

1)9

(31.

0).0

6118

(48.

6)15

(42.

9).6

228

(53.

3)1

(8.3

).0

14

Pos

itive

11 (3

2.4)

16 (5

1.6)

17 (4

5.9)

20 (6

9.0)

19 (5

1.4)

20 (5

7.1)

7 (4

6.7)

11 (9

1.7)

F

or b

acte

ria

(%)*

7 (2

0.6)

10 (3

2.3)

.285

13 (3

5.1)

13 (4

4.8)

.424

11 (2

9.7)

14 (4

0.0)

.360

6 (4

0.0)

5 (4

1.7)

.930

F

or fu

ngi (

%)*

5 (1

4.7)

8 (2

5.8)

.264

8 (2

1.6)

10 (3

4.5)

.244

8 (2

1.6)

9 (2

5.7)

.683

4 (2

6.7)

8 (6

6.7)

.038

Num

ber o

f bac

teri

al s

peci

es7

1422

1513

2112

9N

umbe

r of

fung

al s

peci

es

59

811

910

59

Num

ber

of r

esis

tant

ba

cter

ia#

1 4

5 9

3 6

7

1

Num

ber

of c

ultu

res

wit

h re

sist

ant

bact

eria

/num

ber

of p

osit

ive

cult

ures

(%

)

1/7

(14.

3)4/

10 (4

0.0)

.252

5/13

(3

8.5)

8/13

(61.

5).2

393/

11

(27.

3)6/

14 (4

2.9)

.420

5/6

(8

3.3)

1/5

(20.

0).0

36

B

acte

ria

resi

stan

t to

ceft

riax

one

01

12

11

00

B

acte

ria

resi

stan

t to

amox

icill

in1

35

92

66

1

B

acte

ria

resi

stan

t to

amox

icill

in/c

lavu

lani

c ac

id

0 (0

.0)

3 (2

1.4)

.521

2 (9

.1)

8 (5

3.3)

.006

2 (1

5.4)

6 (2

8.6)

.444

6 (5

0.0)

0

(0.0

).0

19

F

ungi

and

bac

teri

a re

sist

ant t

o am

oxic

illin

/cl

avul

anic

aci

d

5 (4

1.7)

12 (5

2.2)

10 (3

3.3)

19 (7

3.1)

11 (5

0.0)

16 (5

1.6)

11 (6

4.7)

9/18

(50.

0)

*Som

e po

sitiv

e cu

lture

s co

ntai

ned

bact

eria

as

wel

l as

fung

i.#

Resi

stan

t bac

teri

a w

ere

defin

ed a

s ba

cter

ia w

ith r

esis

tanc

e to

cef

tria

xone

, am

oxic

illin

or

amox

icill

in/c

lavu

lani

c ac

id.

62

C h a p t e r 4

BacteriaBefore the start of antimicrobial prophylaxis, 7 of 34 sputum cultures (20.6%) in the

standard care group were positive for bacteria compared with 10 of 31 (32.3%) sputum

cultures in the prophylaxis group (p=.285). At the end of chemoradiotherapy, when

patients in the prophylaxis group were still on prophylactic antibiotics, 13 of 37 (35.1%)

sputum cultures in the standard care group versus 13 of 29 (44.8%) in the prophylaxis

group grew bacteria (p=.424). At three weeks after the end of chemoradiotherapy, 11

of 37 (29.7%) and 14 of the 35 (40.0%) sputum cultures yielded bacteria in the standard

care group and prophylaxis group, respectively (p=.360). At the end of follow up, 14

weeks after the end of chemoradiotherapy, 6 of 15 (40.0%) sputum cultures performed

in the standard care group versus 5 of 12 (41.7%) in the prophylaxis group were positive

(p=.930) (Table 2). In some patients more than one pathogen was found in the sputum

cultures (Figure 1). Detailed culture results are presented Supplemental Table 1.

Fungi There were no significant differences in the numbers of fungi cultured from the sputum

samples in the two groups, except at the end of follow up. At baseline, 14.7% of the

sputum cultures performed in the standard group contained fungi or yeast compared

with 25.8% of sputum cultures in the prophylaxis group (p=.264). At the end of

chemoradiotherapy, fungi were found in 21.6% of sputum cultures in the standard

group and in 34.5% in the prophylaxis group (p=.244), at 3 weeks after chemoradiotherapy

this was 21.6% versus 25.7% (p=.683), and 14 weeks after chemoradiotherapy 26.7%

versus 66.7% (p=.038) (Table 2). Fungal isolates are specified in Supplemental Table 1.

Susceptibility testing for fungi was not performed. More non-albicans Candida species

were found in the prophylaxis group. There was no significant difference between the

use of fluconazole or other antifungals between the treatment groups; 13 of 48 (27.1%)

patients in the standard group and 19 of 47 (40.4%) in the prophylaxis group (p=.169)

had used fluconazole. All non-albicans Candida isolates were found in patients using

fluconazole, except for the patient with a Candida inconspicua.

Antimicrobial susceptibility Table 2 provides the incidence of resistance to amoxicillin, amoxicillin/clavulanic acid

and ceftriaxone. At the end of the chemoradiotherapy, when patients in the prophylaxis

group were still on prophylactic, 2 of 22 bacterial isolates in the standard care group

were resistant to amoxicillin/clavulanic acid, compared with 8 of 15 isolates in the

prophylaxis group (p=.006). At 3 and 14 weeks after the end of chemoradiotherapy,

63

Pathogens and resistance in patients receiving prophylactic antibiotics

4

after discontinuation of antimicrobial prophylaxis, no differences were found in the

prevalence of resistance against amoxicillin/clavulanic acid, except at 14 weeks after

the end of chemoradiotherapy, where a higher rate of resistance to amoxicillin/

clavulanic acid in the standard group was suggested. However, only few sputum

cultures were performed at that time point (Table 2).

Susceptibility of bacterial isolates during pneumoniaIn each study arm, 22 patients developed a pneumonia. No trends toward selection of

resistant organisms were observed in sputum cultures of patients with pneumonia,

when compared to the baseline pathogens before the start of antimicrobial prophylaxis

(Table3).

Discussion

To the best of our knowledge, the PANTAP study has been the first to investigate not

only the efficacy of antimicrobial prophylaxis in LAHNC patients receiving

chemoradiotherapy, but also the bacterial isolates and antimicrobial susceptibility.

A reduction in hospital admissions and episodes with fever were observed in the

prophylaxis group, while no differences in incidence of pneumonia and adverse effects

were found (9).

T1=Day 29, T2=At end of CRT, T3=3 weeks after CRT, T4=14 weeks after CRT

Figure 1. Type of pathogens found in the sputum cultures during the study.

64

C h a p t e r 4

With respect to the numbers of sputum culture samples positive for bacteria, there

were slightly more positive sputum cultures in the prophylaxis group compared with

the standard group during the study, although not statistically significantly different.

At the end of the chemoradiotherapy and 3 weeks after chemoradiotherapy, more

Serratia and Enterobacter species were found in the prophylaxis group, possibly at least

in part due to selection by amoxicillin/clavulanic acid. However, several of these isolates

had been present before the start of the prophylactic antibiotics.

After the end of chemoradiotherapy, when patients randomised to the prophylaxis

group were still on antimicrobial prophylaxis, significantly more bacteria isolated from

the prophylaxis group were resistant to amoxicillin/clavulanic acid. Three weeks and

14 weeks after the end of chemoradiotherapy no differences were found in resistance

to amoxicillin/clavulanic acid between the two treatment groups.

With respect to fungi, no significant differences were found between the two groups,

except at the end of follow up when only few sputum culture samples were obtained.

This is a remarkable finding, as selection of Candida species in the oral flora was

anticipated during amoxicillin/clavulanic acid use.

Amoxicillin/clavulanic acid as prophylactic antibiotic was chosen because the organisms

causing aspiration pneumonia were anticipated to be, streptococci, enterobacteriacae,

and anaerobe bacteria, as previously demonstrated by Lakshmaiah et al. (12).

Amoxicillin/clavulanic acid seemed well chosen as prophylactic antibiotic as a significant

reduction in episodes of fever was found with only slightly more sputum cultures

Table 3. Antimicrobial resistance of bacteria from initial sputum cultures and during pneumonia.

Standard group At the time of pneumoniaInitial sputum culture (N) Susceptible Resistant# Negative Not performedSusceptible (4) 3/22 1/22 - -Resistant# (1) - 1/22 - -Negative (10) 5/22 2/22 3/22 -Not performed (7) 2/22 2/22 2/22 1/22

Prophylaxis group At the time of pneumoniaInitial sputum culture (N) Sensitive Resistant# Negative Not performedSensitive (4) 3/22 1/22 - -Resistant# (3) - 2/22 1/22 -Negative (11) 3/22 3/22 5/22 -Not performed (4) 1/22 - 3/22 -

In both groups, 22 pneumonias were observed. # Resistant bacteria were defined as bacteria with resistance for amoxicillin, amoxicillin/clavulanic acid or ceftriaxone.

65

Pathogens and resistance in patients receiving prophylactic antibiotics

4

positive for bacteria and/or fungi and no excess of fungi were isolated.

A pilot study among head and neck cancer patients applying an antimicrobial lozenge

containing bacitracin, clotrimazole, and gentamicin found elimination of Candida in all

patients, and reduction in gram-negative flora in most patients (13). However, in a

successive phase 3 trial, this antimicrobial lozenge did not lead to a reduction in

mucositis (14).

A limitation of the current study, is that no sputum culture samples were obtained

from all patients at all time points. From around 30% of patients in both treatment

groups, no sputum culture was performed at the specific time points, mainly due to

the patients’ incapability to produce sputum. At 14 weeks after the end of

chemoradiotherapy, sputum samples could be obtained from 30% of patients only. In

addition, culture results may at least in part have represented oral colonization rather

than lower airway flora. This is supported by the spectrum of bacterial and fungal

isolates, and by the fact that squamous cell epithelia was present in more than the half

of the sputum culture samples.

Another potential limitation of this study is the limited duration of follow up until 14

weeks after chemoradiotherapy, and no conclusions can be drawn about the longer-

term effects of prophylactic antibiotics on the colonising flora.

In conclusion, this study showed that with the use of 5-6 weeks of antibiotic treatment,

while there is a significant reduction in hospital admissions and cost, there was a

transient increase of resistant bacterial flora at the end of chemoradiotherapy, but no

significant impact on resistant flora at subsequent follow-up during 14 weeks.

AcknowledgementsWe would like to thank all the patients for their collaboration and all collaborating

hospitals.

FundingThis work was supported by The Netherlands Organisation for Health Research and

Development: ZonMw, project number 171101011

Transparency declarationNone to declare

66

C h a p t e r 4

Supp

lem

ent t

able

1. S

peci

ficat

ion

of th

e ba

cter

ia a

nd fu

ngi c

ultu

red.

Day

29

At

end

of C

RT3

wee

ks a

fter

CRT

14 w

eeks

aft

er C

RTSt

anda

rd

Gro

up (N

=48)

Prop

hyla

xis

grou

p (N

=47)

St

anda

rd G

roup

(N

=48)

Prop

hyla

xis

grou

p (N

=47)

St

anda

rd G

roup

(N

=48)

Prop

hyla

xis

grou

p (N

=47)

St

anda

rd

Gro

up (N

=48)

Prop

hyla

xis

grou

p (N

=47)

To

tal o

f sp

ecie

s7

1422

1513

2112

9

Gra

m p

ositi

ve

cocc

iSt

aphy

loco

ccus

au

reus

(1)

Stap

hylo

cocc

us

aure

us (3

)H

aem

olyt

ic

stre

ptoc

occi

(3),

Stap

hylo

cocc

us

aure

us (4

)

Stap

hylo

cocc

us

aure

us (1

)St

aphy

loco

ccus

au

reus

(1),

Hae

mol

ytic

st

rept

ococ

ci (1

)

Stap

hylo

cocc

us

aure

us (3

), Vi

rida

ns

stre

ptoc

occu

s (1

)

Stap

hylo

cocc

us

aure

us (3

)St

aphy

loco

ccus

au

reus

(3),

Stre

ptoc

occu

s an

gino

sus

(1)

Ente

roba

cter

acea

e an

d no

n-fe

rmen

ters

Kleb

siel

la

pneu

mon

iae

(1)

Ente

roba

cter

sp

ecie

s (2

), Ps

eudo

mon

as

spec

ies

(2)

Ente

roba

cter

cl

oaca

e (3

), Kl

ebsi

ella

pn

eum

onia

e (1

), Es

cher

ichi

a co

li (1

),Ac

hrom

obac

ter

xylo

soxi

dans

(1)

Sten

othr

opho

mon

as

mal

toph

ilia

(2),

Ente

roba

cter

cl

oaca

e (5

), Ci

trob

acte

r sp

p. (1

), Es

cher

ichi

a co

li (1

)

Ente

roba

cter

sp

ecie

s (2

), Se

rrat

ia s

peci

es (1

),Ps

eudo

mon

as

spec

ies

(2),

Sten

otro

phom

onas

m

alto

phili

a (1

)

Ente

roba

cter

sp

ecie

s (4

), Kl

ebsi

ella

ox

ytoc

a (1

)Se

rrat

ia s

peci

es

(3),

Pseu

dom

onas

ae

rugi

nosa

(3)

Ente

roba

cter

cl

oaca

e (3

)Se

rrat

ia s

peci

es

(2),

Haf

nia

alve

i (1)

Kleb

siel

la

spec

ies

(2)

Pseu

dom

onas

ae

rugi

nosa

(1),

Oth

er G

ram

ne

gativ

e ba

cter

iaH

aem

ophi

lus

spp

(4),

Nei

sser

ia

men

ingi

tidis

(1)

Hae

mop

hilu

s sp

p (6

), Ac

inet

obac

ter

Iwof

fii (1

),

Hae

mop

hilu

s sp

p (6

), M

orax

ella

ca

tarr

halis

(1)

Hae

mop

hilu

s in

fluen

zae

(7),

Hae

mop

hilu

s sp

p (2

), Ag

greg

atib

acte

r se

gnis

(1),

Acin

etob

acte

r ha

emol

ytic

us (1

), M

orax

ella

ca

tarr

halis

(1)

Aggr

egat

ibac

ter

segn

is (1

), H

aem

ophi

lus

spp

(4),

Mor

axel

la

cata

rrha

lis (1

)

Hae

mop

hilu

s sp

p (2

), Ac

inet

obac

ter

baum

anii

(1),

Hae

mop

hilu

s in

fluen

zae

(2)

Tota

l of f

ungi

59

811

910

59

Cand

ida

spp

C. a

lbic

ans

(5)

C. a

lbic

ans

(6),

C. tr

opic

alis

(1),

C. g

labr

ata

(1)

C. a

lbic

ans

(7)

Cand

ida

NO

S (1

)C.

alb

ican

s (7

), C.

trop

ical

is (1

)C.

gla

brat

a (2

) C.

par

apsi

losi

s (1

)

C. a

lbic

ans

(8)

C. a

lbic

ans

(4),

C. tr

opic

alis

(2),

C. g

labr

ata

(1),

C. p

arap

silo

sis

(1),

Cand

ida

NO

S (1

)

C. a

lbic

ans

(3)

C. a

lbic

ans

(3),

C. g

labr

ata

(1),

C. k

efyr

(1),

C.

inco

nspi

cua

(1),

Cand

ida

NO

S (1

)

Oth

er fu

ngi

Aspe

rgill

us

fum

igat

us (1

)As

perg

illus

fu

mig

atus

(1)

Yeas

t NO

S (1

)Ye

ast N

OS

(1)

Peni

cilli

um

spec

ies

(1)

Aspe

rgill

us

fum

igat

us (1

), Sa

ccha

rom

yces

ce

revi

siae

(1)

67

Pathogens and resistance in patients receiving prophylactic antibiotics

4

References

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359-86.

2. Bentzen SM, Trotti A. Evaluation of early and late toxicities in chemoradiation trials. J Clin Oncol 2007;25(26):4096-103.

3. Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer. J Clin Oncol 2006;24(17):2636-43.

4. Langerman A, Maccracken E, Kasza K, Haraf DJ, Vokes EE, Stenson KM. Aspiration in chemoradiated patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2007;133(12):1289-95.

5. Nguyen NP, Frank C, Moltz CC, Vos P, Smith HJ, Bhamidipati PV, et al. Aspiration rate following chemoradiation for head and neck cancer: an underreported occurrence. Radiother Oncol 2006;80(3):302-6.

6. Nguyen NP, Smith HJ, Dutta S, Alfieri A, North D, Nguyen PD, et al. Aspiration occurence during chemoradiation for head and neck cancer. Anticancer Res 2007;27(3B):1669-72.

7. Xu B, Boero IJ, Hwang L, Le QT, Moiseenko V, Sanghvi PR, et al. Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. Cancer 2014.

8. Chen SW, Yang SN, Liang JA, Lin FJ. The outcome and prognostic factors in patients with aspiration pneumonia during concurrent chemoradiotherapy for head and neck cancer. Eur J Cancer Care (Engl) 2010;19(5):631-5.

9. Ham JC, Driessen CM, Hendriks MP, Fiets E, Kreike B, Hoeben A, et al. Prophylactic antibiotics reduce hospitalisations and cost in locally advanced head and neck cancer patients treated with chemoradiotherapy: A randomised phase 2 study. Eur J Cancer 2019;113:32-40.

10. Khalil D, Hultin M, Rashid MU, Lund B. Oral microflora and selection of resistance after a single dose of amoxicillin. Clin Microbiol Infect 2016;22(11):949.e1-949.e4.

11. Institute CLS. In.12. Lakshmaiah KC, Sirsath NT, Subramanyam JR, Govind BK, Lokanatha D, Shenoy AM. Aspiration in head

and neck cancer patients: a single centre experience of clinical profile, bacterial isolates and antibiotic sensitivity pattern. Indian J Otolaryngol Head Neck Surg 2013;65(Suppl 1):144-9.

13. El-Sayed S, Epstein J, Minish E, Burns P, Hay J, Laukkanen E. A pilot study evaluating the safety and microbiologic efficacy of an economically viable antimicrobial lozenge in patients with head and neck cancer receiving radiation therapy. Head Neck 2002;24(1):6-15.

14. El-Sayed S, Nabid A, Shelley W, Hay J, Balogh J, Gelinas M, et al. Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system. J Clin Oncol 2002;20(19):3956-63.

Genetic variants as predictive markers for

ototoxicity and nephrotoxicity in patients with

locally advanced head and neck cancer treated

with cisplatin-containing chemoradiotherapy

(the PRONE study).

Cancers. 2019 Apr 17;11(4).

Chantal M.L. Driessen*, Janneke C. Ham*, Maroeska te Loo, Esther van Meerten,

Maurits van Lamoen, Marina H. Hakobjan, Robert P. Takes, Winette T.A. van der Graaf,

Johannes H. Kaanders, Marieke J.H. Coenen, Carla M.L. van Herpen

*Driessen and Ham contributed equally to this manuscript

C H A P T E R 5

70

C h a p t e r 5

Abstract

Ototoxicity and nephrotoxicity are potentially irreversible side effects of

chemoradiotherapy with cisplatin in locally advanced head and neck cancer (LAHNC)

patients. Several predictive genetic variants have been described, but as yet none in

LAHNC patients. The aim of this study is to investigate genetic variants as predictors

for ototoxicity and nephrotoxicity in LAHNC patients treated with cisplatin-containing

chemoradiotherapy. Our prospective cohort of 92 patients was genotyped for 10

genetic variants and evaluated for their association with cisplatin-induced ototoxicity

(ACYP2, COMT, TPMT and WFS1) and nephrotoxicity (OCT2, MATE and XPD). Ototoxicity

was determined by patient-reported complaints as well as tone audiometrical

assessments. Nephrotoxicity was defined as a decrease of ≥25% in creatinine clearance

during treatment compared to baseline. A significant association was observed between

carriership of the A allele for rs1872328 in the ACYP2 gene and cisplatin-induced

clinically determined ototoxicity (p=0.019), and not for ototoxicity measured by tone

audiometrical assessments (p=0.449). Carriership of a T allele for rs316019 in the OCT2

gene was significantly associated with nephrotoxicity at any time during

chemoradiotherapy (p=0.022), but not with nephrotoxicity at the end of the

chemoradiotherapy. In conclusion, we showed prospectively that in LAHNC patients

genetic variants in ACYP2 are significantly associated with clinically determined

ototoxicity. Validation studies are necessary to prove the added value for individualized

treatments plans in these patients.

71

Genetic predictors for ototoxicity and nephrotoxicity

5

Introduction

Head and neck cancer is a common type of cancer worldwide(1, 2). The most frequently

used treatment for patients with locally advanced head and neck cancer (LAHNC) is

concomitant chemoradiotherapy with cisplatin, which improves loco-regional control

as well as overall survival compared to radiotherapy alone (3, 4). Chemoradiotherapy

can also be applied as adjuvant treatment in case of a high recurrence risk after surgery.

Concomitant chemoradiotherapy with cisplatin however, induces a high rate of acute

toxicities such as mucositis, dysphagia and dermatitis, most of which will recover with

time, but can also induce irreversible ototoxicity and nephrotoxicity (3, 5-7).

Ototoxicity, characterized by sensorineural hearing loss, can be an adverse effect of

either systemically administered cisplatin or radiotherapy to the inner ear. Both

chemotherapy and radiotherapy cause lesions in the cochlea, which may lead to

ototoxicity (8). Ototoxicity caused by cisplatin begins with high frequency loss and is

often bilateral, permanent and can be progressive also after the end of administration

of cisplatin (8, 9). Chemotherapy with cisplatin is most often applied either at a dose of

100mg/m2 every 3 weeks for 3 cycles (high dose) or at a dose of 40mg/m2 every week

for 6 or 7 cycles (intermediate dose (5, 6). The incidence of ototoxicity in patients treated

with high dose cisplatin is 79%.(10) Besides ototoxicity, another common side effect of

cisplatin is nephrotoxicity that also can be irreversible. However, unlike ototoxicity, part

of the nephrotoxicity can be reduced by hyperhydration with high natriumchloride. The

occurrence and the severity of nephrotoxicity is also related to the cisplatin dose; 100%

of the patients treated with high dose cisplatin experienced nephrotoxicity of any grade

compared with 75% of the patients with intermediate dose cisplatin (7).

With the aim to prevent ototoxicity and nephrotoxicity, several studies have been

performed to identify risk factors and predictive markers. Known clinical risk factors

for ototoxicity after chemoradiation in LAHNC patients are the cumulative dose of

cisplatin and cumulative radiation dose to the cochlea, younger age, good pretreatment

hearing, administration of furosemide and low levels of serum albumin and hemoglobin

(11, 12). However, cisplatin-induced toxicity can only partly be predicted by these

factors. Recently, various studies found genetic variants, i.e. single nucleotide

polymorphisms (SNPs), that are associated with cisplatin-induced side-effects. Genetic

variants in ACYP2 (Acylphosphatase 2) and WFS1 (Wolframin ER transmembrane

glycoprotein) were identified as predictive markers for hearing loss (13-17). The ACYP2

gene is expressed in the cochlea (14). Mutations in WFS1 can cause progressive deafness

after administration of cisplatin (18). Cisplatin-induced ototoxicity could be related to

72

C h a p t e r 5

increased levels of S-adenosylmethionine through reduced TPMT (thiopurine

S-methyltransferase) or COMT (catechol O-methyltransferase) activity. However, their

predictive value for ototoxicity is controversial (19, 20). With respect to nephrotoxicity,

genetic variants in OCT2 (organic cation transporter 2), MATE1 (multidrug and toxin

extrusion 1) and XPD (xeroderma pigmentosum group D), are believed to be of

predictive value (21-24). OCT2 and MATE1 are expressed in the human kidney at the

basolateral membrane of renal proximal tubules, and are involved in the secretion of

various cationic substances from the circulation into tubular cells. In that way OCT2

and MATE1 are involved in the cellular uptake of cisplatin (21, 23). XPD is part of the

nucleotide excision repair pathway and is involved in removal of cisplatin and

radiotherapy induced DNA damage (24, 25).

However, most of the above-mentioned studies showed correlations in a limited

number of patients and thus confirmation of the association between the SNPs and

cisplatin related side effect is needed. Furthermore, the studies were performed in

patients with other cancers than LAHNC. Therefore, the aim of this study is to investigate

the relationship between the different SNPs and cisplatin-induced ototoxicity and

nephrotoxicity in LAHNC patients.

Materials and methods

Patients and treatmentA cohort of Dutch patients with pathologically proven LAHNC and treated with cisplatin-

based chemoradiotherapy was prospectively recruited at the Radboud university

medical center and the Erasmus University Medical Center in the Netherlands. Eligibility

criteria included a minimum age of 18 years and a WHO performance score of 0 or 1.

Patients with renal dysfunction defined as a creatinine clearance below 60 mL/min.

were not considered eligible. Before inclusion, written informed consent was obtained

from all patients. The local ethical committee waived the study from ethical approval.

Patients were treated with cisplatin-based chemoradiotherapy for either primary

treatment or adjuvant treatment. Concomitant chemoradiotherapy was administered

in three different treatment schedules; 1. Conventional radiotherapy in combination

with cisplatin 100 mg/m2 on days 1, 22 and 43; 2. Accelerated radiotherapy combined

with cisplatin 40 mg/m2 on a weekly basis for 6 weeks; 3. Conventional radiotherapy

combined with cisplatin 40 mg/m2 on a weekly basis for 7 weeks. Intensity-modulated

radiation therapy (IMRT) was mandatory. Dose to gross tumor volume was 68-70 Gy

and dose to elective nodal areas 46-50.3 Gy.

73

Genetic predictors for ototoxicity and nephrotoxicity

5

Cisplatin was given by infusion in combination with standard prehydration,

posthydration and anti-emetics. If during the treatment the creatinine clearance was

below 60 mL/min because of dehydration, cisplatin was only administered if the

creatinine clearance recovered to 60 mL/min after rehydration. Dose modifications

and discontinuation of cisplatin were performed according to standard local practice.

MeasurementsTone audiometry was performed according to standard procedures under standardized

conditions. Air-conduction and thresholds were determined at 1, 2, 4, 8, 10, 12.5 and

16 kHz. Bone-conduction thresholds were measured, from 1 kHz to 8 kHz. According

to the study protocol, audiometry was carried out at baseline, during chemoradiotherapy

after 100 mg/m2 or 120 mg/m2 cisplatin as total dosage at that moment and within 2

months after completion of treatment.

Ototoxicity was scored utilizing two different approaches. In the first approach,

clinically determined ototoxicity, physicians asked their patients to the hearing loss

according to the CTCAE 4.03. In the second approach, hearing loss was classified using

the tone audiometric data from baseline and end of treatment based on the ear with

the worst hearing loss. Hearing loss was defined by threshold shifts at 2,4 or 8 kHz of

≤ 25 dB (grade 1), threshold shift of 26-40 dB (grade 2) or threshold shift of ≥ 40 dB

(grade 3) (15).

Additionally, weekly laboratory tests were performed including the creatinine clearance

by use of calculation of the Modification of Diet in Renal Disease (MDRD). Nephrotoxicity

was defined as a decrease of 25% or more in creatinine clearance by the MDRD at any

point during treatment compared to baseline, based on the international accepted

Risk, Injury, Failure, Loss and End Stage Renal Disease (RIFLE) criteria (7).

Blood or saliva (Oragene saliva collection kit (DNA Genotek, Kanata, Ontario, Canada))

were used for DNA extraction.

GenotypingGenotyping of genetic variant in TPMT (rs12201199, rs1800460, rs1142345) and COMT

(rs9332377) were performed using Taqman SNP genotyping according to the

instructions of the manufacturer (ThermoFisher, Nieuwerkerk aan den IJssel, The

Netherlands). The other genetic variants (COMT rs4646316, ACYP2 rs1872328, OCT2/

SLC22A2 rs316019, WFS1 rs62283056, XPD/ERCC2 rs13181 and MATE1 rs2289669) were

genotyped using Kompetitive Allele Specific PCR (KASPTM) (KASPar-On_Demand assays

(Laboratory of the Government Chemist (LGC) Genomics, Hoddesdon, UK)) according

74

C h a p t e r 5

to the instructions of the manufacturer (13, 26). Analysis of the Taqman and KASP assay was carried out on a 7500FAST Real-Time PCR System (ThermoFisher). Genotypes were scored using 7500 software (v2.0.6, ThermoFisher). Negative controls as well duplicates (8%) were included as quality controls for genotyping.

StatisticsA sample size calculation showed that inclusion of 100 patients in our study would give 80% power to identify a statistically significant association between a SNP and ototoxicity, assuming a 40% ototoxicity rate, an alpha of 0.05, an allelic OR of 3, and a minor allele frequency of 10% (19, 20). The association between the SNPs and clinically relevant hearing loss (“yes” versus “no”) and between the SNPs and nephrotoxicity (“yes” versus “no”) were analyzed with a Pearson’s chi-square or Fisher-exact tests. P-values were tested two-sided and were considered as statistically significant when <0.05. SPSS version 22 was used for performing the analyses. Meta-analysis of the data of ototoxicity and ACYP2 was performed using a fixed-effects model in review Manager version 5.3 (The Cochrane Collaboration, Oxford, UK).

Results

Between August 2013 and February 2017, 103 patients were included in this study. One patient withdrew consent. In 10 cases no blood or saliva samples were available for DNA analysis. Thus, in total 92 patients were included in the final analysis. Fifty-seven patients were treated with intermediate dose cisplatin 40mg/m² weekly for 6 or 7 weeks, and 35 patients were treated with high dose cisplatin 100mg/m² on days 1, 22 and 43. Baseline characteristics are shown in Table 1.

OtotoxicityIn all 92 patients, data on clinically-determined ototoxicity were available, whereas hearing loss after treatment based on tone audiometric measurements was available for 79 patients. Of the 92 patients, six patients reported new grade 2 hearing loss and one patient reported grade 3 hearing loss at end of treatment (Table 2). Of these 7 patients, 4 were treated with cisplatin 40 mg/m2 and 3 were treated with cisplatin 100 mg/m2. Based on audiometric measurements, of the 79 patients included in the analysis, 52 patients (65.8%) had grade 1 hearing loss, whereas 16 patients (20.3%) and 11 patients (13.9%) had grade 2 and 3 hearing loss, respectively (Table 2). Nine of the 11 patients with grade 3 hearing loss were treated with cisplatin 100 mg/m2. There was no statistically difference in cumulative cisplatin dose in patients with or without

75

Genetic predictors for ototoxicity and nephrotoxicity

5

hearing loss when measured clinically or audiometrically (p=0.231 and p=0.142).

Unfortunately, bone conduction was only available in 55 patients. Of these 41 patients

(74%) showed no hearing loss, 11 patients (20%) showed mild hearing loss, 3 patients

(6%) suffered moderate-profound hearing loss (Table 2).

NephrotoxicityOf the 92 patients, 53 patients (58%) had nephrotoxicity any time during treatment

(Table 2). Cumulative cisplatin dose was not different between those patients

intentionally treated with high dose or intermediate dose cisplatin (p=0.107). In 86

patients end of treatment creatinine clearance was available. Of these patients, 8 (9%)

had nephrotoxicity relative to baseline. All these 8 patients (100%) were treated with

cisplatin 100 mg/m2.

Table 1. Patient characteristics of the 92 patients analyzed.

Number of patients (%)Age mean (range) 57.8 (28-69)Gender

Male 67 (72.8)Female 25 (27.2)

WHO score 0 63 (68.5)1 28 (30.4)2 1 (1.1)

Treatment indication

Primary treatment 62 (67.4)

Postoperative treatment 29 (31.5)

Primary treatment tumor, postoperative 1 (1.1)

treatment for lymph nodes

Primary site

Oral cavity 21 (22.8)

Oropharynx 42 (45.7)

Hypopharynx 10 (10.9)

Larynx 13 (14.1)

Unknown primary 4 (4.3)

Nasal vestibule 2 (2.2)

Cisplatin dose

40 mg/m2 57 (61.3)

100 mg/m2 35 (37.6)

Cumulative cisplatin dose (median, range) 240mg (80-300)

WHO: World Health Organisation

76

C h a p t e r 5

SNP and ototoxicityNine patients were heterozygous GA for the ACYP2 variant rs1872328; all other patients

(n=83) were homozygous GG. Forty-three percent of the patients reporting clinically

hearing loss grade 2 or 3 (3 out of 7 patients) were carrying an A allele, whereas 7% of

the patients without clinically hearing loss (grade 0 or 1) were carrier of the A allele.

Association analysis showed a statistically significant difference between the groups

(p=0.019, OR 9.9 95%CI [1.8-54.7]). We found no differences between carriership of the

A allele and ototoxicity based on tone audiometrical measurements (Table 3). A meta-

analysis of the cohorts of the previous published studies performed in humans also

indicated a significant association of the ACYP2 variant with ototoxicity. For this analysis

we used the data of the audiometrical assessments in our patients to compare with

the other studies (Figure 1).

For the tested genetic variants in TPMT, COMT and WFS1 no statistically differences were

found in either clinically or tone audiometrically assessed hearing loss (Table 3). Also,

the association analysis in patients with hearing loss using bone conduction as

outcome, showed no statistically significant difference.

Table 2. Ototoxicity and nephrotoxicity. MDRD: Modification of Diet in Renal Disease.

Number of Patients (%)Ototoxicity clinically at the end of treatment (n=92)

None (grade 0 or grade 1) 85 (92.4)

Hearing loss without hearing aid indicated (grade 2) 6 (6.5)

Hearing loss with hearing aid indicated (grade 3) 1 (1.1)

Ototoxicity by tone audiometry (n=79)

Grade 1 (≤25 dB loss) 52 (65.8)

Grade 2 (26-40 dB loss) 16 (20.3)

Grade 3 (≥40 dB loss) 11 (13.9)

Ototoxicity by audiometry, only bone conduction (n=55)

Grade 1 (≤25 dB loss) 41 (74.5)

Grade 2 (26-40 dB loss) 11 (20)

Grade 3 (≥40 dB loss) 3 (5.5)

Nephrotoxicity any time during study (n=92)

MDRD < 25% decrease 39 (42.4)

MDRD ≥25 % decrease 53 (57.6)

Nephrotoxicity at the end of study (n=86)

MDRD < 25% decrease 78 (84.8)

MDRD ≥25 % decrease 8 (8.7)

77

Genetic predictors for ototoxicity and nephrotoxicity

5

Meta-analysis of published cohorts in humans and present study using a fixed-effects model. 95% CI, 95% confidence interval of odds ratio; M-H, Mantel-Haenszel method.

Figure 1. Forest plot of meta-analysis of ACYP2 rs1872328.

Table 3. Significance levels for genetic variants related to ototoxicity.

Genotype Clin

ical

no o

toto

xici

tyN

(%)

Clin

ical

otot

oxic

ity

N (%

)

p-va

lue

Aud

iom

etri

cal

otot

oxic

ity

Gra

de 1

N (%

)

Aud

iom

etri

cal

otot

oxic

ity

Gra

de 2

N (%

)

Aud

iom

etri

cal

otot

oxic

ity

Gra

de 3

N (%

)

p-va

lue

TPMT:rs12201199

AA 77 (91.6) 7 (8.3) p=1.0 47 (66) 14 (20) 10 (14) p=0.863

AT/TT 8 (100) 0 (0) 5 (63) 2 (25) 1 (12)

TPMT:rs1142345

TT 77 (91.6) 7 (8.3) p=1.0 47 (66) 14 (20) 10 (14) p=0.863

TC/CC 8 (100) 0 (0) 5 (63) 2 (25) 1 (12)

TPMT:rs1800460

CC 77 (91.6) 7 (8.3) p=1.0 47 (66) 14 (20) 10 (14) p=0.863

CT/TT 8 (100) 0 (0) 5 (63) 2 (25) 1 (12)

COMT:rs4646316

CC 50 (94) 3 (6) p=0.452 31 (66) 11 (23) 5 (11) p=0.459

CT/TT 35 (90) 4 (10) 21 (66) 5 (15) 6 (19)

COMT:rs9332377

CC 66 (93) 5 (7) p=0.657 40 (66) 11 (18) 10 (16) p=0.410

CT/TT 19 (90) 2 (10) 12 (67) 5 (28) 1 (5)

ACYP2:rs1872328

GG 79 (95) 4 (5) p=0.019* 48 (67) 15 (21) 9 (12) p=0.499

GA 6 (67) 3 (33) 4 (57) 1 (14) 2 (29)

WFS1:rs62283056

GG 54 (89) 7 (11) p=0.091 35 (66) 12 (23) 6 (11) p=0.600

GC/CC 31 (100) 0 (0) p=0.091 17 (66) 4 (15) 5 (19)

*=significantly different (p<0.05).

78

C h a p t e r 5

SNP and nephrotoxicityData on the OCT2 gene were available in 92 patients. Eighteen patients were

heterozygous GT for the OCT2 variant rs316019; 2 patients were homozygous TT and

all other 72 patients were homozygous GG. Thirty percent of the patients with

nephrotoxicity during treatment were carrying a T allele, whereas 10% of the patients

without nephrotoxicity, which was significantly different (p=0.049, OR 3.78 95%CI [1.1-

12.4]). No association was found between carriers of the T allele and nephrotoxicity at

end of treatment compared to baseline (p=0.845). Nephrotoxicity was not significantly

associated with the analyzed genetic variants in MATE1 and XDP (Table 4).

Discussion

Since a high percentage of LAHNC patients treated with cisplatin-based chemo-

radiotherapy develop irreversible ototoxicity and nephrotoxicity, it would be worthwhile

to add predictive biomarkers for toxicity to treatment decision-making to avoid these.

In this study we investigated whether germline genetic variants were associated with

ototoxicity and nephrotoxicity. We focused on 10 SNPs in 7 genes which were

previously reported to be related to these adverse effects (15, 16, 19, 21). We could

confirm the association between a genetic variant in ACYP2 and clinical reported

hearing loss, but not with tone audiometrical measurements. Moreover, we found an

association with OCT2 and nephrotoxicity during treatment with cisplatin, but not with

Table 4. Significance levels for genetic variants related to nephrotoxicity. *=significantly different (p <0.05).

Genotype No

neph

roto

xici

ty

duri

ng t

reat

men

tN

(%)

Nep

hrot

oxic

ity

duri

ng t

reat

men

tN

(%)

p-va

lue

No

neph

roto

xici

tyat

end

of

trea

tmen

tN

(%)

Nep

hrot

oxic

ity

at e

nd o

f tr

eatm

ent

N (%

)

p-va

lue

OCT2/SLC22A2:rs316019 GG 35 (48.6) 37 (51.4) p=0.049* 61 (91.0) 6 (9.0) p=1.00 GT/TT 5 (24.0) 16 (76.0) 18 (89.5) 2 (10.5)MATE1:rs2289669 GG 15 (42.9) 20 (57.1) p=1.00 29 (90.6) 3 (9.4) p=1.00 GA/AA 25 (43.1) 33 (56.9) 50 (90.9) 5 (9.1)XPD/ERCC2:rs13181 TT 20 (55.6) 16 (44.4) p=0.085 32 (96.9) 1 (3.1) p=0.146 TG/GG 20 (35.7) 36 (64.3) 46 (86.8) 7 (13.2)

79

Genetic predictors for ototoxicity and nephrotoxicity

5

nephrotoxicity at end of treatment, which makes it not useful in clinical practice.

With our findings we are the fifth to report on the association between genetic variation

in the ACYP2 gene and cisplatin-induced ototoxicity (13-16). The initial studies of Xu and

Vos reported that the A allele of the genetic variants rs1872328 in the ACYP2 gene was

only present in patients with ototoxicity, i.e. 13.8% and 6.5%, respectively, carried the

A allele. More recent studies, also identified the A allele in patients without hearing

loss, but only in a low percentage (1%) (15). In contrast to these studies we found that

57% of the patients without audiometrical measured ototoxicity carried the A allele and

43% of the patients with mild to moderate audiometrical measured ototoxicity. A study

by Fang et al. described an increased risk of esophageal carcinoma associated with the

genetic variant rs11125529 in the ACYP2 (27). Although another variant of the A allele

was found and a Chinese population was studied, a genetic variant of the A allele could

be related to head and neck cancer and therefore found more often in our cohort.

We could not find an association between the other variants investigated and

ototoxicity. This is in line with previous studies that showed equivocal results (15, 19,

20) (Table 5). A possible confounder in ototoxicity rate in our patient population is

radiation in the head and neck region, because radiation can induce conductive hearing

loss as a result of inflammation and edema as well as sensorineural hearing loss caused

by radiation on the inner ear (11). Although some patients in the studies by Xu et al.

and Ross et al. received cranial radiation as well (14, 19).

There is a great variance in the applied scoring systems for ototoxicity between the

studies, as the initial studies were done in children, most systems are only validated

in children (28). We decided to perform two analyses, one based on clinical hearing

loss and the other on objective audiometrical assessments. For the audiometrical

assessments we used the same scoring system as Drogemoller, because this system

can be applied to adults, in contrast to the Chang scoring system which is only used

for children (13, 15). We are the first to use clinically-determined ototoxicity as well, as

this is a clinically relevant outcome measure reflecting the patients’ perspective.

However, it remains a subjective outcome, which can be influenced by the interpretation

of different investigators. Interestingly we could detect an association between the

genetic variant in ACYP2 when using the clinical measure but not for audiometrically

determined ototoxicity. The reason for the discrepancy between clinical and

audiometrical determined ototoxicity is speculative. Audiometrical determined

ototoxicity is obviously more objective, but clinical assessed ototoxicity is probably

more relevant for the patient. In the meta-analysis that we performed, our study had

the same direction of effect (OR>1) as the other studies.

80

C h a p t e r 5

Cisplatin-induced sensorineural hearing loss can best be evaluated with bone

conduction measurements as this specifically measures the hearing of the inner ear/

cochlea (29).

Theunissen et al. argued that air conduction thresholds represent the functionality of

the whole auditory system, including both air and bone conduction, and felt that the

grading criteria should comprehend the overall hearing loss due to treatment as this

is eventually the clinically relevant hearing loss the patient experiences.

However, to address the underlying mechanism of cisplatin-associated hearing loss

and the relation with genetic variants, we decided to perform an association analysis

using both air and bone conduction hearing tests, but we did not find any association

between the studied genetic variants and the two ototoxicity outcomes.

With respect to SNPs as predictive markers for nephrotoxicity, the genetic variant in

OCT2 was found to be significant associated with nephrotoxicity at any point during

chemoradiotherapy, but not with nephrotoxicity at end of treatment. To our knowledge,

only two studies have been performed to assess the relationship between OCT2 and

cisplatin-induced nephrotoxicity in humans (21, 30). Filipski et al. investigated the effect

of the rs316019 variant in OCT2 in 78 cancer patients receiving cisplatin. Renal function

was determined 1 day before and 1-8 days after the first dose cisplatin. Iwata et al.

investigated the rs316019 variant of OCT2 in 53 patients receiving cisplatin during more

cycles. Remarkably, both Iwata et al. and Filipski et al. showed that the presence of T

of the genetic variant rs316019 in OCT2 was ameliorating cisplatin-induced

nephrotoxicity, whereas our study found the opposite. The variation in the results

might be related to the different endpoints for nephrotoxicity that have been used.

Based on the previous studies and ours, we believe that at the moment the use of this

SNP is not relevant for clinical practice.

In our study, patients treated with high dose cisplatin and intermediate dose cisplatin

were taken together, because of the small number of patients treated with the high

dose schedule. Therefore we cannot draw conclusion regarding association between

SNPs and toxicity for specific cisplatin dosages, while we know from previous studies

that high dose cisplatin induces higher rates of ototoxicity as well as nephrotoxicity.

These data could be of particular interest, as several studies demonstrated the ability

to enhance chemosensitivity to cisplatin in HNC, thus reducing the dosage needed,

through the down-regulation of molecules related to cell death (31, 32).

A limitation of our study is that we were not able to reach the planned sample size of

100 patients, due to lack of DNA of 10 patients, resulting in a somewhat smaller patient

cohort. Furthermore, because of the relative small patient population, we did not

81

Genetic predictors for ototoxicity and nephrotoxicity

5correct for multiple testing and could not perform subgroup analyses. Therefore this

study should be viewed as the first steps in the link between the studied genes and

toxicities in LAHNC patients.

Conclusions

This is the first study to the association of ACYP2 and cisplatin-induced ototoxicity in

LAHNC patients and the fifth to describe the possible predictive value of ACYP2

regarding (clinical determined) cisplatin-induced ototoxicity. These findings should be

validated in a large cohort, to finally determine the predictive value of ACYP2 in

ototoxicity. As personalized medicine is getting more important, these findings could

eventually provide better tailored, individualized treatment for LAHNC patients

considering both oncologic efficacy as well as toxicity and quality of life, as other

treatment regimens are available such as radiotherapy with cetuximab or carboplatin.

AcknowledgementsThis work was supported by the Dutch Cancer Society [grant number KUN2013-5881]

Conflict of interestNone to declare

Table 5. Overview of performed studies to ototoxicity and cisplatin.

Discovery Xu[14]

Replication Xu[14]

Vos[13]

Thiesen[16]

Drogemoller[15]

Our study

Patients Children with brain tumours

Children with brain tumours

Children (3-43 yrs) with osteosarcoma

Children with different tumours

Testicular cancer

Head and neck cancer

Number of patients

238 68 156 149 229 92

Cummulative dose cisplatin (median, range)

287 mg/m2

(unknown)Unknown* 480 mg/m2

(140-720)378 mg/m2

(60-800)400 mg/m2

(200-920)240mg/m2

(80-300)

Concomitant drugs

Vincristine, amisfostine, cyclofosfamide

Vinblastin, carboplatin

Vincristine, carboplatinin some pts

Vincristine, carboplatin

Etoposide, bleomycine

-

Radiation Craniospinal Focal in some pts

0 Some pts 0 IMRT

* But same cisplatin dose as discovery cohort. IMRT: Intensity-modulated radiation therapy.

82

C h a p t e r 5

References

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359-86.

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66(1):7-30.3. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and

radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091-8.4. Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer

(MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92(1):4-14.5. Espeli V, Zucca E, Ghielmini M, Giannini O, Salatino A, Martucci F, et al. Weekly and 3-weekly cisplatin

concurrent with intensity-modulated radiotherapy in locally advanced head and neck squamous cell cancer. Oral Oncol 2012;48(3):266-71.

6. Driessen CM, Janssens GO, van der Graaf WT, Takes RP, Merkx TA, Melchers WJ, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck 2016;38 Suppl 1:E559-65.

7. Driessen CM, Uijen MJ, van der Graaf WT, van Opstal CC, Kaanders JH, Nijenhuis T, et al. Degree of nephrotoxicity after intermediate- or high-dose cisplatin-based chemoradiotherapy in patients with locally advanced head and neck cancer. Head Neck 2016;38 Suppl 1:E1575-81.

8. Theunissen EA, Bosma SC, Zuur CL, Spijker R, van der Baan S, Dreschler WA, et al. Sensorineural hearing loss in patients with head and neck cancer after chemoradiotherapy and radiotherapy: a systematic review of the literature. Head Neck 2015;37(2):281-92.

9. Theunissen EA, Zuur CL, Bosma SC, Lopez-Yurda M, Hauptmann M, van der Baan S, et al. Long-term hearing loss after chemoradiation in patients with head and neck cancer. Laryngoscope 2014;124(12):2720-5.

10. Zuur CL, Simis YJ, Lansdaal PE, Hart AA, Schornagel JH, Dreschler WA, et al. Ototoxicity in a randomized phase III trial of intra-arterial compared with intravenous cisplatin chemoradiation in patients with locally advanced head and neck cancer. J Clin Oncol 2007;25(24):3759-65.

11. Zuur CL, Simis YJ, Lansdaal PE, Hart AA, Rasch CR, Schornagel JH, et al. Risk factors of ototoxicity after cisplatin-based chemo-irradiation in patients with locally advanced head-and-neck cancer: a multivariate analysis. Int J Radiat Oncol Biol Phys 2007;68(5):1320-5.

12. Blakley BW, Gupta AK, Myers SF, Schwan S. Risk factors for ototoxicity due to cisplatin. Arch Otolaryngol Head Neck Surg 1994;120(5):541-6.

13. Vos HI, Guchelaar HJ, Gelderblom H, de Bont ES, Kremer LC, Naber AM, et al. Replication of a genetic variant in ACYP2 associated with cisplatin-induced hearing loss in patients with osteosarcoma. Pharmacogenet Genomics 2016;26(5):243-7.

14. Xu H, Robinson GW, Huang J, Lim JY, Zhang H, Bass JK, et al. Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss. Nat Genet 2015;47(3):263-6.

15. Drogemoller BI, Brooks B, Critchley C, Monzon JG, Wright GEB, Liu G, et al. Further Investigation of the Role of ACYP2 and WFS1 Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients. Clin Cancer Res 2018.

16. Thiesen S, Yin P, Jorgensen AL, Zhang JE, Manzo V, McEvoy L, et al. TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity. Pharmacogenet Genomics 2017;27(6):213-222.

17. Wheeler HE, Gamazon ER, Frisina RD, Perez-Cervantes C, El Charif O, Mapes B, et al. Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity. Clin Cancer Res 2017;23(13):3325-3333.

18. Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 1998;20(2):143-8.

19. Ross CJ, Katzov-Eckert H, Dube MP, Brooks B, Rassekh SR, Barhdadi A, et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 2009;41(12):1345-9.

20. Hagleitner MM, Coenen MJ, Patino-Garcia A, de Bont ES, Gonzalez-Neira A, Vos HI, et al. Influence of genetic variants in TPMT and COMT associated with cisplatin induced hearing loss in patients with cancer: two new cohorts and a meta-analysis reveal significant heterogeneity between cohorts. PLoS One 2014;9(12):e115869.

21. Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther 2009;86(4):396-402.

83

Genetic predictors for ototoxicity and nephrotoxicity

5

22. Powrozek T, Mlak R, Krawczyk P, Homa I, Ciesielka M, Koziol P, et al. The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients. Clin Transl Oncol 2016;18(2):125-31.

23. Yonezawa A, Inui K. Organic cation transporter OCT/SLC22A and H(+)/organic cation antiporter MATE/SLC47A are key molecules for nephrotoxicity of platinum agents. Biochem Pharmacol 2011;81(5):563-8.

24. Lopes-Aguiar L, Costa EF, Nogueira GA, Lima TR, Visacri MB, Pincinato EC, et al. XPD c.934G>A polymorphism of nucleotide excision repair pathway in outcome of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation. Oncotarget 2017;8(10):16190-16201.

25. Rouillon C, White MF. The evolution and mechanisms of nucleotide excision repair proteins. Res Microbiol 2011;162(1):19-26.

26. He C, Holme J, Anthony J. SNP genotyping: the KASP assay. Methods Mol Biol 2014;1145:75-86.27. Fang Q, Hui L, Min Z, Liu L, Shao Y. Leukocyte telomere length-related genetic variants in ACYP2 contribute

to the risk of esophageal carcinoma in Chinese Han population. Oncotarget 2017;8(15):25564-25570.28. Crundwell G, Gomersall P, Baguley DM. Ototoxicity (cochleotoxicity) classifications: A review. Int J Audiol

2016;55(2):65-74.29. Theunissen EA, Dreschler WA, Latenstein MN, Rasch CR, van der Baan S, de Boer JP, et al. A new grading

system for ototoxicity in adults. Ann Otol Rhinol Laryngol 2014;123(10):711-8.30. Iwata K, Aizawa K, Kamitsu S, Jingami S, Fukunaga E, Yoshida M, et al. Effects of genetic variants in SLC22A2

organic cation transporter 2 and SLC47A1 multidrug and toxin extrusion 1 transporter on cisplatin-induced adverse events. Clin Exp Nephrol 2012;16(6):843-51.

31. Khan Z, Khan AA, Prasad GB, Khan N, Tiwari RP, Bisen PS. Growth inhibition and chemo-radiosensitization of head and neck squamous cell carcinoma (HNSCC) by survivin-siRNA lentivirus. Radiother Oncol 2016;118(2):359-68.

32. Santarelli A, Mascitti M, Rubini C, Bambini F, Giannatempo G, Lo Russo L, et al. Nuclear Survivin as a Prognostic Factor in Squamous-Cell Carcinoma of the Oral Cavity. Appl Immunohistochem Mol Morphol 2017;25(8):566-570.

Submitted

Janneke C. Ham, Esther van Meerten, W. Edward Fiets, Laurens V. Beerepoot,

Frank J.F. Jeurissen, Marije Slingerland, Marianne A. Jonker, Olga Husson,

Winette T.A. van der Graaf, Carla M.L. van Herpen

Methotrexate plus or minus cetuximab as

first-line treatment in a recurrent or metastatic

(R/M) squamous cell carcinoma population

of the head and neck (SCCHN), unfit for cisplatin

combination treatment, a phase Ib – randomized

phase II study COMMENCE

C H A P T E R 6

86

C h a p t e r 6

Abstract

BackgroundMethotrexate in recurrent or metastatic (R/M) squamous cell carcinoma of the head

and neck (SCCHN) has limited progression-free survival (PFS) benefit. We hypothesized

that adding cetuximab to methotrexate improves PFS.

MethodsIn the phase-Ib-study, patients with R/M SCCHN received methotrexate and cetuximab

as first-line treatment. The primary objective was feasibility. In the phase-II-study

patients were randomized to this combination or methotrexate alone (2:1). The primary

endpoint was PFS. Secondary endpoints were overall survival (OS), toxicity, and quality

of life (QoL).

ResultsIn six patients in the phase-Ib-study, no dose limiting toxicities were observed. In the

phase II study 30 patients received the combination and 15 patients methotrexate. In

the phase-II-study median PFS was 4.5 months in the combination group versus 2.0

months in the methotrexate group (HR 0.37; p=0.002). OS, toxicity and QoL were not

significantly different.

ConclusionCetuximab with methotrexate improved PFS without increased toxicity in R/M SCCHN-

patients.

87

Methotrexate and cetuximab in recurrent or metastatic SCCHN

6

Introduction

Head and neck cancer is the seventh most common cancer type worldwide (1). Cure

rates of patients with locoregionally advanced squamous cell carcinoma of the head

and neck (SCCHN) vary between 30-60%, and in case of metastases or local recurrence,

palliative treatment is often the only option (2). In this setting, the only approved

treatment with significant overall survival (OS) benefit at the time this study was

initiated was cetuximab added to platinum/5FU (OS of 10.1 months versus 7.4 months

with platinum/5FU alone), but its toxicity is considerable (3). Other treatment options

were single agent methotrexate (MTX) or docetaxel in patients unfit for platinum, or

combination therapies of platinum combined with 5FU or taxane (4). MTX has a

response rate (RR) of 10-25%, and a mean OS of 6-8 months (5-10), while combination

therapy with platinum and 5FU or taxane has RRs of 45-50%, but without OS benefit

compared with single agent treatment, and with more toxicity (4, 8, 10, 11).

The epidermal growth factor receptor (EGFR) has shown to be up-regulated in 90-100%

of the head and neck cancers (12). Cetuximab is a recombinant, human/mouse chimeric

monoclonal antibody that binds specifically to EGFR and inhibits receptor activation

by competing with epidermal growth factor. It is approved in the United States as single

agent after failure to platinum-based therapy, based on a single-arm phase II study

with a RR of 13% and median OS of 6 months (13).

No data are available on the combination of MTX and cetuximab. This combination

could be beneficial for patients unfit for or unwilling to get platinum-based therapy in

the recurrent or metastatic (R/M) setting. The aim of this study was to investigate in

first-line R/M SCCHN patients the feasibility of adding cetuximab to MTX and to

investigate whether the combination can improve progression-free survival (PFS) versus

MTX alone. Secondary aims were to investigate the OS, RR, toxicity and health-related

quality of life (HRQoL).

Methods

PatientsPatients aged ≥ 18 years with previously untreated R/M SCCHN, who were unfit for or

unwilling to get platinum-based chemotherapy, were eligible. Other inclusion criteria

were at least one measurable lesion as determined by RECIST v1.1., time between prior

treatment for locally advanced disease and inclusion in the study of at least 3 months,

WHO performance status 0-2, and adequate organ function and laboratory tests. Main

88

C h a p t e r 6

exclusion criterion was prior treatment with EGFR-inhibitors or MTX.

The study was approved by the Medical Ethical Research Committee of Radboudumc,

the Netherlands and in accordance with the Declaration of Helsinki. All patients signed

written informed consent. The ClinicalTrials.gov Identifier is: NCT02054442.

Study design of the Commence studyFirst, a phase Ib open-label non-dose-escalating study was performed to determine

the safety and tolerability of the combination of cetuximab and MTX. Six patients should

be treated first and if 0-1 dose limiting toxicities (DLT) in these six patients would occur,

a phase II study could start.

In the phase II study, patients were randomized between cetuximab and MTX or MTX

alone. Participating institute, performance status (0 or 1 versus 2) and local or

locoregional recurrence independently of distant metastatic disease (yes versus no)

were used as stratification factors.

During treatment patients were seen every week for the first 4 weeks and thereafter

every 2 weeks. At these visits adverse events (AEs) (scored by Common Terminology

Criteria for Adverse Events (CTCAE) version 4.0), and laboratory measures were

recorded. Patients were monitored for AEs during, and for 30 days after the last

administration of study medication.

Tumor assessment, i.e. CT or MRI of the head and neck, and CT-scan of the thorax, was

performed at baseline and every 8 weeks. HRQoL was assessed at baseline, after 8

weeks, after 24 weeks, after 1 year and at progressive disease using the 30-item core

European Organization for the Research and Treatment of Cancer Quality-of-Life

Questionnaire (EORTC QLQ-C30)(14), the EORTC QLQ Head and Neck Cancer-Specific

Module (EORTC H&N35) (14), and the Performance Status Scale for Head & Neck cancer

patients (PSS-HN) (15).

In oropharyngeal cancer patients human papillomavirus (HPV) positivity was determined

with immunohistochemical staining p16 (16).

TreatmentIn the phase Ib study, all patients were treated with cetuximab and MTX. The dosage

of MTX was 40 mg/m2 weekly, delivered in 5-10 minutes iv. The dosage of cetuximab

was 400 mg/m2 in a 2-hour infusion for the first infusion, followed by 250 mg/m2 in 1

hour, weekly.

Treatment was continued until progressive disease (PD), unacceptable toxicity or

refusal by the patient.

89

Methotrexate and cetuximab in recurrent or metastatic SCCHN

6

In case, despite standard precautions, grade 1 or 2 cetuximab-related hypersensitivity

reaction occurred, infusion rate was reduced or stopped temporarily. In case of

cetuximab-related grade 3 or 4 toxicity, cetuximab had to be discontinued permanently,

but continuation of MTX was allowed. In case of MTX-related grade 4 toxicity in patients

treated with the combination, cetuximab could be continued. If the absolute neutrophil

count was <1.5 x 109/l and/or thrombocytes <100 x 109/l, MTX had to be postponed for

1 week and if recovered, folinic acid needed to be prescribed.

EndpointThe primary endpoints in phase Ib were toxicity and the incidence of DLTs after start

of treatment. The primary endpoint of the phase II part of the study was PFS, defined

as the time from randomization to PD or death. Secondary endpoints for the phase Ib

and phase II study were OS (time from randomization to death), RR according to RECIST

v1.1 (i.e. complete or partial response), the clinical benefit rate (i.e. complete or partial

response or stable disease), toxicity according to CTCAE v4.0, HRQoL and HPV-status

in relation to these outcomes.

Statistical analysisIn the phase Ib study, a minimum of 6 patients were needed, depending on the

occurrence of DLT’s. The results are summarized using simple descriptive statistical

methods.

In the phase II study, 57 patients were needed in each treatment group to achieve 80%

power at a 0.05 significance level to detect a hazard ratio of 0.6 assuming that the

addition of cetuximab to MTX would improve PFS by 2 months from 3 months in the

MTX alone group to 5 months in the combination group.

Unfortunately, due to financial constraints in the Netherlands in July 2015, after

inclusion of six patients in the phase Ib study and 12 patients in the phase II study, the

study had to be amended to a design with a total of 45 patients with a 2:1 randomization

in the phase II study (30 patients in the MTX with cetuximab group and 15 patients in

the MTX alone group). Kaplan-Meier curves were plotted and PFS and OS were

compared by the log-rank test. Cox-regression models were fitted to estimate and test

hazard ratios. Non-parametric tests were performed using the chi-square test to test

for differences in patient characteristics and occurrence of AEs between the treatment

groups. All statistical tests were two-sided, with an alpha level of 5% considered as

statistically significant. HRQoL was only investigated and described exploratively.

90

C h a p t e r 6

Results

Patient characteristicsFrom February to June 2014, six patients were included in the phase Ib study in the

Radboudumc, the Netherlands. All patients received the combination of cetuximab

with MTX. The phase II study started in July 2014, but was on hold from July 2015 until

August 2016 due to amendment of the study design. Last patient was included in

January 2018. Forty-five patients were included in the phase II study in 6 participating

hospitals in the Netherlands, of which 30 patients were allocated to cetuximab and

MTX and 15 patients to MTX alone (Figure 1).

The baseline characteristics were well balanced between the two treatment groups

(Table 1).

Figure 1. CONSORT Flow Diagram of the enrollment of patients in the phase II study.

91

Methotrexate and cetuximab in recurrent or metastatic SCCHN

6

EfficacyIn the phase Ib study, median PFS was 5.8 months (range 1.9-13.0 months) and median

OS 10.6 months (range 3.0-17.9 months). The cut-off date for the efficacy analysis of

the phase II study was 1 October 2018. Median follow-up was 19.3 months, with a

minimum follow-up of 8.9 months. Median PFS was 4.5 months (range 0.9-23.2+

months) in the cetuximab and MTX group and 2.0 months (range 0.9-9.0 months) in

the MTX alone group (hazard ratio for progression, 0.37; 95% CI, 0.19 to 0.71; p= 0.002)

(Figure 2a). One patient in the combination group, who had a resection of one lymph

node metastasis which was growing during treatment without any progression of other

lesions, was still on treatment with no signs of progressive disease. The main reason

for discontinuation of treatment was PD in both groups.

The median OS in the phase II study was 8.0 months (range 0.9-23.8+ months) in the

cetuximab and MTX group compared with 4.7 months (range 0.9-20.7+) in the MTX

alone group (hazard ratio for death 0.67; 95% CI, 0.34 to 1.22; p=0.248) (Figure 2b).

Table 1. Patient characteristics.

Phase 1(N=6)

Phase 2MTX+cetuximab (N=30)

Phase 2MTX (N=15)

P value#

Age (median,range) 65.0 (58-71) 68.5 (46-80) 64.0 (49-77)Sex .806 Male (%) 5 (83.3) 23 (76.7) 11 (73.3) Female (%) 1 (16.7) 7 (23.3) 4 (26.7)WHO .606 0 4 (66.7) 6 (20.0) 5 (33.3) 1 2 (33.3) 21 (70.0) 9 (60.0) 2 0 3 (10.0) 1 (6.7)Tumor site .205 Oral cavity 1 (16.7) 11 (36.7) 2 (13.3) Oropharynx 2 (33.3) 8 (26.7) 7 (46.7) HPV positive 0 4 1 HPV negative 2 3 5 HPV unknown 0 1 1 Hypopharynx 1 (16.7) 7 (23.3) 2 (13.3) Larynx 2 (33.3) 4 (13.3) 4 (26.7)Loco-regional recurrence* .429 Yes 6 (100) 25 (83.3) 11 (73.3) No 0 (0) 5 (16.7) 4 (26.7)Distant metastases Yes 5 (83.3) 21 (70) 7 (46.7) .128 No 1 (16.7) 9 (30) 8 (53.3)

* Loco-regional recurrence means local recurrence and/or metastases in locoregional lymphnodes. # The P-values are for the differences between the treatment groups in the phase II study.

92

C h a p t e r 6

Eight and two patients were still alive in the combination group and MTX group,

respectively. The addition of cetuximab to MTX improved the clinical benefit rate

significantly from 40.0% to 76.7% (p=0.015). The RR showed no significant differences

with 13.3% PR in the MTX and cetuximab group and 6.7% PR in the MTX alone group.

ToxicityIn the phase Ib study no DLT’s occurred and one serious adverse event (SAE) was

reported, not related to the study medication. Three patients reported grade 3 toxicity

(two patients had a hypophosphatemia and one syncope), no grade 4 toxicity was

observed.

In the phase II study, the overall incidence of grade 3 or 4 AEs was 46.7% in the MTX

and cetuximab group compared with 53.3% in the MTX group (p=0.673). Only the

Figure 2. Kaplan-Meier estimates of Progression Free Survival (A) and Overall Survival (B) according to the two treatment groups.

93

Methotrexate and cetuximab in recurrent or metastatic SCCHN

6

incidence of all grade skin AEs was significantly higher in the combination group

compared with the MTX group (86.7% versus 40.0%, p=0.001). The incidence of

dysphagia (6.7% in the combination group versus 16.7% in the MTX group, p=0.032)

and dyspnea (3.3% in the combination group versus 10.0% in the MTX group, p=0.005)

were significantly higher in the MTX group (Table 2).

Table 2. Most relevant and common (related and not related) adverse events according to the CTCAE 4.0.

MTX + cetuximab (N=30) MTX (N=15) P value# Any grade Grade 3-4 Any grade Grade 3-4

Any event 30 (100) 14 (46.7) 15 (100) 8 (53.3) .673Skin reactions* 26 (86.7) 3 (10.0) 6 (40.0) 0 (0) .001Mucositis 14 (46.7) 1 (3.3) 5 (33.3) 1 (6.7) .393Xerostomia 3 (10.0) 0 (0) 0 (0) 0 (0) .205Dysphagia 5 (16.7) 2 (6.7) 7 (46.7) 2 (13.3) .032Dyspnea 3 (10.0) 1 (3.3) 7 (46.7) 2 (13.3) .005Cough 9 (30.0) 0 (0) 5 (33.3) 0 (0) .820Pneumonia 5 (16.7) 2 (6.7) 2 (13.3) 0 (0) .771Pneumonitits 1 (3.3) 1 (3.3) 0 (0) 0 (0) .475Infusion reaction 6 (20.0) 0 (0) 0 (0) 0 (0) .063Vomiting 4 (13.3) 0 (0) 1 (6.7) 0 (0) .502Diarrhea 10 (33.3) 0 (0) 1 (6.7) 0 (0) .050Anorexia 7 (23.3) 0 (0) 4 (26.7) 2 (13.3) .806Weight loss 3 (10) 1 (3.3) 0 (0) 0 (0) .205Anemia 3 (10) 0 (0) 0 (0) 0 (0) .205Thrombocytopenia 3 (10) 1 (3.3) 2 (13.3) 0 (0) .737Leucocytopenia 2 (6.7) 0 (0) 0 (0) 0 (0) .306Neutropenia 3 (10.0) 0 (0) 0 (0) 0 (0) .205Hypercalcemia 1 (3.3) 0 (0) 3 (20.0) 1 (6.7) .064Hypomagnesemia 4 (13.3) 0 (0) 0 (0) 0 (0) .138Hypophosphatemia 1 (3.3) 1 (3.3) 0 (0) 0 (0) .475Hyponatremia 2 (6.7) 2 (6.7) 1 (6.7) 0 (0) 1.00Hypokalemia 1 (3.3) 0 (0) 0 (0) 0 (0) .475Hepatotoxicity 6 (20.0) 4 (13.3) 1 (6.7) 1 (6.7) .245Pain tumor 6 (20.0) 0 (0) 2 (13.3) 0 (0) .581Pain non-tumor 12 (40.0) 0 (0) 5 (33.3) 0 (0) .664Tumor hemorrhage 4 (13.3) 0 (0) 0 (0) 0 (0) .138Fatigue 16 (53.3) 2 (6.7) 9 (60.0) 2 (13.3) .671Depression 3 (10.0) 0 (0) 2 (13.3) 0 (0) .737Malaise 9 (30.0) 0 (0) 4 (26.7) 0 (0) .816Cardiac event 2 (6.7) 0 (0) 0 (0) 0 (0) .306

*: skin reactions included fissures, rash acneiform, rash macula-papular, paronychia, blisters, nail changes, xerodermia, lymph edema and toxicity of the eyes. #: The P values are for the differences between the treatment groups for any grade toxicity, except for the difference in any event, where the P value is for the difference between grade 3-4 toxicity.

94

C h a p t e r 6

The total number of SAEs was 14 (in 12 out of 30 patients) in the combination group,

compared to 8 ( 5 out of 15 patients) in the MTX group. None of the SAEs in the MTX

group was related to MTX, while 3 of the 14 in the combination group were considered

as possibly related to MTX or cetuximab. These 3 (possibly) related SAEs were pneumonia

(grade 3), pneumonitis (grade 3) and an infusion-related reaction (grade 1).

HRQoLAt baseline, 93.3% and 86.7% of the patients completed the HRQoL questionnaires in

the cetuximab and MTX group and MTX group, respectively. Only small clinical

important differences were found between the two treatment groups at baseline. The

compliance of completing the questionnaires during the study as well as at PD was

low (Table 3). The HRQoL did not seem to deteriorate after the start of cetuximab and

MTX.

The 16 patients in the combination group who completed the questionnaires at 8 weeks

after start of treatment, did not differ much in baseline scores from the patients who

did not completed the questionnaires after 8 weeks. The only notable differences were

that patients who completed the questionnaires after 8 weeks, felt less ill at baseline

and had less problems of a dry mouth.

HPVFour out of 8 (50%) versus 1 out of 7 (14.3%) oropharyngeal carcinomas were HPV

positive in the combination group and MTX group, respectively. Because of the small

number of oropharyngeal cancers in both groups, no conclusions can be drawn about

the effect of HPV-status on PFS and OS.

Discussion

This phase Ib-randomized phase II study of first-line treatment of R/M SCCHN showed

a significant increase in PFS by adding cetuximab to MTX with 2.5 months. The clinical

benefit rate of 76.7% in the combination group was significantly higher compared with

40.0% in the MTX group.

The 2.5 months benefit in PFS by adding cetuximab to MTX, is in line with earlier studies

showing benefits of adding cetuximab to platinum-based therapy (3, 17), however, this

is the first study in combination with MTX. Although Vermorken et al. showed a clinically

significant difference in OS with adding cetuximab to platinum-5FU, there was

substantial toxicity, with grade 3/4 toxicity rate of 82%, whereas the patients in our

95

Methotrexate and cetuximab in recurrent or metastatic SCCHN

6

study treated with the combination of MTX and cetuximab reported grade 3/4 toxicity

in 46.7%. The PFS of 2.0 months in the MTX alone group was slightly less than expected

before the start of the study (power calculation was made with the consumption of a

PFS of 3.0 months in the MTX alone group). The PFS and OS are in line with other studies

comparing MTX with other chemotherapy regimens or tyrosine kinase inhibitors in

first and second line (Table 4).

The landscape of the treatment of R/M SCCHN patients is rapidly evolving due to the

introduction of immunotherapy. Nivolumab is already registered for patients with

R/M SSCHN after platinum-failure, showing an improved 2-year OS rate of 16.9%

versus 6.0% with investigator’s choice chemotherapy (HR 0.68; 95% CI, 0.54-0.86) (18).

Recently, the results of the KEYNOTE-048 phase III study were presented in which the

current standard cetuximab-platinum/5FU was compared with pembrolizumab

monotherapy or pembrolizumab combined with platinum/5FU in first-line R/M head

and neck cancer. This study showed that pembrolizumab alone improved OS compared

with standard chemotherapy (14.9 months versus 10.7 months, HR 0.61, p=0.0007)

in patients with ≥20 CPS (combined positive score; PD-L1 expression in tumour and/

or surrounding immune cells, divided by tumour cells) (19). Despite these

developments, there will always be patients who are not suitable for immunotherapy

because of auto-immune diseases or a PDL-1 negative cancer and who are too

vulnerable for treatment with platinum-based chemotherapy. For these patients, the

combination of MTX and cetuximab, as it has shown a PFS benefit at the price of

limited and well manageable toxicities, can be an interesting treatment option. New

studies in which this combination can be compared in first and/or second-line therapy

in patients unfit for, or after failure of immunotherapy would increase the insight in

this combination treatment.

Limitations of this study are the small number of patients included and the altered

study design. Therefore, the results and statistical analyses should be interpreted with

caution and should be seen as hypothesis generating for new studies in the future.

Another limitation is the small number of completed HRQoL questionnaires, which

made it difficult to draw firm conclusions about the effect of adding cetuximab to MTX

on HRQoL, while patient reported outcomes are getting more important. However, the

fact that the HRQoL did not deteriorate after the start of cetuximab and MTX, is in line

with Mesia et al., who showed that adding cetuximab to platinum-fluorouracil does

not adversely affect QoL in patients with R/M SCCHN (20). As shown by the rapid decline

in HRQoL at PD, a stable HRQoL after start of the treatment is of clinical relevance in

this patient group.

96

C h a p t e r 6

Table 3. Scores in HRQoL at baseline, after 8 weeks of treatment and at progressive disease measured by the EORTC QLQ-C30, QLQ-H&N35, PSS-HN and Visual Analog Scale (VAS)-score. (N) after each subscales means the number of available questionnaires.

BaselineMTX + cetuximab(N=28)

MTX(N=13)

∆

PSS-HNNormalcy of diet (N) 54.4 (27) 49.2 (12) 5.2Eating in public (N) 63.0 (23) 83.3 (12) -20.3Understandability of speech(N)

78.9 (26) 68.8 (12) 10.1

VAS-score (N) 2.3 (26) 3.4 (13) -1.1QLQ-C30Physical functioning 79.4 86.2 -6.8*Role functioning 82.7 78.2 4.5Emotional functioning 78.0 79.5 -1.5Cognitive functioning 88.7 92.3 -3.6*Social functioning 84.5 89.7 -5.2*Global health status 67.3 73.1 -5.8*Fatigue 23.4 22.2 1.2Nausea/vomiting 6.5 3.8 2.7Pain 22.0 23.1 -1.1Dyspnea 13.1 7.7 5.4*Insomnia 11.9 12.8 -0.9Appetite loss 17.3 17.9 -0.6Constipation 15.5 15.4 0.1Diarrhea 8.3 10.3 -2.0Financial problems 6.0 12.8 -6.8*QLQ-H&N35a

Pain 23.5 20.1 3.4Swallowing 24.3 21.2 3.1Senses problems 23.2 20.5 2.7Speech problems 24.8 22.2 2.6Social eating 25.4 16.0 9.4Social contact 10.5 4.6 5.9Sexuality 40.6 35.9 4.7Teeth 15.3 8.3 7.0Opening mouth 29.6 35.9 -6.3Dry mouth 26.2 33.3 -7.1Sticky saliva 35.9 44.4 -8.5Coughing 29.8 20.5 9.3Felt ill 13.1 10.3 2.8Pain killers 75.0 69.2 5.8Nutritional supplements 48.1 30.8 17.3Feeding tube 25.0 16.7 8.3

*= small clinical important difference; ¥ = medium clinical important difference; ₣ = large clinical important difference [21]; #=clinical relevant difference of more than 10 points between baseline and 8 weeks after the start of treatment within one group aWeight gain and weight loss not reported due to difficult interpretation

97

Methotrexate and cetuximab in recurrent or metastatic SCCHN

6

After 8 weeks At progressive diseaseMTX + cetuximab(N=16)

MTX(N=3)

∆ MTX + cetuximab(N=4)

MTX(N=2)

∆

70.8 (13) 53.3 (3) 17.5 30.0 (3) 40.0 (2) -10.081.8 (11) 41.7 (3) 40.1 62.5 (2) 62.5 (2) 0.075.0 (13) 66.7 (3) 8.3 83.3 (3) 50.0 (2) 33.3

2.3 (26) 3.4 (13) -1.1 3.2 (5) 3.3 (2) -0.1

75.2 73.3# 1.9 45.0 83.3 -38.372.9 83.3 -10.4 22.2 58.3 -36.180.0 94.4# -14.4 75.0 83.3 -8.382.3 94.4 -12.1 58.3 83.3 -25.079.2 77.8# 1.4 50.0 83.3 -33.364.6 83.3# -18.7 33.3 70.8 -37.528.8 11.1# 17.7 52.8 22.2 30.61.0 11.1 -10.1 20.8 0.0 20.818.8 11.1# 7.7 45.8 42.7 3.120.8 11.1 9.7 16.7 0.0 16.714.6 11.1 3.5 25.0 50.0 -25.021.4 0.0# 21.4 77.8 0.0 77.818.8 0.0# 18.8 8.3 0.0 8.38.3 0.0# 8.3 16.7 33.3 -16.66.3 0.0# 6.3 8.3 0.0 8.3

17.7 11.1 6.6 45.8 41.7 4.121.4 11.1# 10.3 27.1 37.5 -10.420.8 25.0 -4.2 37.5 50.0 -12.528.5 0.0# 28.5 41.7 33.3 8.411.5# 33.3# -21.8 63.9 16.7 47.26.3 2.2 4.1 46.7 33.3 13.426.9# 11.1# 15.8 58.3 50.0 8.311.1 0.0 11.1 22.2 0.0 22.225.0 11.1# 13.9 41.7 66.7 -25.020.0 33.3 -13.3 33.3 33.3 0.044.4 0.0# 44.4 50.0 50.0 0.035.4 0.0# 35.4 25.0 33.3 -8.316.7 0.0# 16.7 50.0 16.7 33.381.3 100.0# -18.7 100.0 100.0 0.033.3# 66.7# -33.4 25.0 0.0 25.025.0 66.7# -41.7 25.0 50.0 -25.0

98

C h a p t e r 6

In conclusion, in this small study the addition of cetuximab to MTX improved PFS in

patients with R/M SCCHN, and could be considered as treatment option in patients not

eligible or unfit for platinum-based therapy.

AcknowledgementsWe would like to thank all participating patients and their families, furthermore we

would like to thank all collaborating hospitals; Erasmus MC Cancer Institute, Medical

Center Leeuwarden, Elisabeth TweeSteden Hospital, Medical Center Haaglanden,

Leiden University Medical Center.

FundingThis work was supported by Merck B.V. (The Netherlands), an affiliate of Merck KGaA,

Darmstadt, Germany.

Role of Funding SourceMerck KGaA, Darmstadt, Germany provided a grant to perform the study, and provided

cetuximab as study medication. Merck KGaA, Darmstadt, Germany reviewed the

manuscript for medical accuracy only before journal submission. The authors are fully

responsible for the content of this manuscript, and the views and opinions described

in the publication reflect solely those of the authors

Table 4. Overview of studies, in which MTX monotherapy was compared with other chemotherapy regimens or oral tyrosine kinase inhibitors in R/M SSCHN patients.

Study Line of treatment

Regimen Number of patients

RR Median PFS (months)

Median OS (months)

Forastiere, 1992[8]

First Cisplatin + 5FUCarboplatin + 5FUMTX

878688

322110

4.25.14.1

6.65.05.6

Stewart, 2009[22]

Any Gefitinib 250mgGefitinib 500mgMTX

158167161

2.77.63.9

---

5.66.06.7

Kushwaha, 2015[6]

Any Gefitinib 500mgMTXMTX + 5FU

394038

7.75.07.9

---

8.87.88.1

Machiels, 2015[23]

Second Afatinib 40mgMTX

322161

106

2.61.7

6.86.0

Machiels, 2016[24]

Second CabazitaxelMTX

5348

00

1.91.9

5.03.6

This study First MTX + cetuximabMTX

3015

13.36.7

4.52.0

8.04.7

99

Methotrexate and cetuximab in recurrent or metastatic SCCHN

6

References

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359-86.

2. Brockstein BE. Management of recurrent head and neck cancer: recent progress and future directions. Drugs 2011;71(12):1551-9.

3. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359(11):1116-27.

4. Sacco AG, Cohen EE. Current Treatment Options for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. J Clin Oncol 2015;33(29):3305-13.

5. A phase III randomised trial of cistplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. Br J Cancer 1990;61(2):311-5.

6. Kushwaha VS, Gupta S, Husain N, Khan H, Negi MP, Jamal N, et al. Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil as palliative treatment in recurrent head and neck squamous cell carcinoma. Cancer Biol Ther 2015;16(2):346-51.

7. DeConti RC, Schoenfeld D. A randomized prospective comparison of intermittent methotrexate, methotrexate with leucovorin, and a methotrexate combination in head and neck cancer. Cancer 1981;48(5):1061-72.

8. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10(8):1245-51.

9. Schornagel JH, Verweij J, de Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, et al. Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J Clin Oncol 1995;13(7):1649-55.

10. Molin Y, Fayette J. Current chemotherapies for recurrent/metastatic head and neck cancer. Anticancer Drugs 2011;22(7):621-5.

11. Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23(15):3562-7.

12. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993;53(15):3579-84.

13. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25(16):2171-7.

14. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.

15. List MA, D’Antonio LL, Cella DF, Siston A, Mumby P, Haraf D, et al. The Performance Status Scale for Head and Neck Cancer Patients and the Functional Assessment of Cancer Therapy-Head and Neck Scale. A study of utility and validity. Cancer 1996;77(11):2294-301.

16. Farshadpour F, Konings S, Speel EJ, Hordijk GJ, Koole R, van Blokland M, et al. Human Papillomavirus and Oropharyngeal Squamous Cell Carcinoma: A Case-Control Study regarding Tobacco and Alcohol Consumption. Patholog Res Int 2011;2011:806345.

17. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23(34):8646-54.

18. Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol 2018;81:45-51.

19. B. Burtness1 KJH, R. Greil3, D. Soulières4, M. Tahara5, G. De Castro Jr.6, A. Psyrri7, N. Baste Rotllan8, P.C. Neupane9, Å. Bratland10, T. Fuereder11, B.G.M. Hughes12, R. Mesia13, N. Ngamphaiboon14, T. Rordorf15, W.Z. Wan Ishak16, A. Roy17, J. Cheng18, F. Jin19, D. Rischin20 KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). ESMO 2018 Congress 2018, abstract 2018.

100

C h a p t e r 6

20. Mesia R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2010;21(10):1967-73.

21. Cocks K, King MT, Velikova G, Martyn St-James M, Fayers PM, Brown JM. Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 2011;29(1):89-96.

22. Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27(11):1864-71.

23. Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015;16(5):583-94.

24. Machiels JP, Van Maanen A, Vandenbulcke JM, Filleul B, Seront E, Henry S, et al. Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy. Oncologist 2016;21(12):1416-e17.

101

Summary, general discussion

and future perspectives

C H A P T E R 7

104

C h a p t e r 7

Summary

Dysphagia and aspiration pneumonia are common toxicities of chemoradiotherapy for LAHNC. In a multicenter randomised phase II PANTAP-study the effect was studied of prophylactic amoxicillin/clavulanic acid during chemoradiotherapy for LAHNC on aspiration pneumonia, hospitalisation rate, HRQoL, adverse events and on sputum cultures and resistance. (Chapters 2-4) Patients were included before the start of chemoradiotherapy and randomised between day 22 and 28, unless they had received antibiotics or had an infection 14 days prior to randomisation. Patients were randomised between standard of care or prophylactic amoxicillin/clavulanic acid from day 29 after the start of chemoradiotherapy until 14 days after the end of chemoradiotherapy. One-hundred-and-six patients were included, of which 95 could be randomised; 48 patients were allocated to the standard group and 47 patients to the prophylaxis group. In Chapter 2 the main results of the PANTAP study are described; the use of prophylactic antibiotics did not reduce the incidence of definite or suspected aspiration pneumonias (45.8% versus 46.8%, p=0.544), but significantly reduced the hospitalisation rate (39.6% versus 19.1%, p=0.030), number of episodes with fever (29.2% vs 10.2%, p=0.028) and total costs per patient (€2462 versus €1037, p=0.046). In Chapter 3 the effect of prophylactic antibiotics on health related quality of life (HRQoL), one of the secondary endpoints of the study is described. Especially at the end of chemoradiotherapy, when the toxicity of treatment is most severe, patients treated with the prophylactic antibiotics performed better on all functional subscales (e.g. physical functioning, cognitive functioning, and social functioning) of the EORTC QLQ-C30 and reported less symptoms, except for the items ‘diarrhoea’ and ‘feeding tube’. Finally, the results of the effect of the prophylactic antibiotics on the number of positive sputum cultures, the bacterial spectrum including the resistance pattern, and the presence of fungi and yeast in these cultures are presented in chapter 4. No differences were found in the number of performed cultures between the two treatment groups, neither in the number of sputum cultures positive for bacteria and/or fungi. At the end of the chemoradiotherapy, 2 out of 22 of the cultured bacteria in the standard care group were resistant to amoxicillin/clavulanic acid compared with 8 out 15 bacteria in the prophylaxis group, p=.006. However, this difference was not determinative for a clinical difference in infections and/or pneumonias, and disappeared 3 weeks and 14 weeks after the end of chemoradiotherapy.In Chapter 5 the results are described of a second study in LAHNC patients treated with chemoradiotherapy, the PRONE study. As ototoxicity and nephrotoxicity are potentially irreversible side effects of cisplatin containing chemoradiotherapy, the

105

Summary and general discussion

7

PRONE study investigated genetic variants, which could serve as predictors for these toxicities in LAHNC patients. A significant association was observed between carriership of the A allele in the ACYP2 gene and cisplatin-induced clinically determined ototoxicity (p=0.019), which was not the case for ototoxicity measured by tone audiometrical assessments (p=0.449). Carriership of a T allele in the OCT2 gene was significantly associated with nephrotoxicity at any time during chemoradiotherapy (p=0.022), but not with nephrotoxicity at the end of the chemoradiotherapy. Validation studies are necessary to confirm these results, and until then the use of these predictive genetic variants is limited. In patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), first-line treatment consists of the combination of cetuximab and platinum-5FU, but this combination has substantial toxicity. Methotrexate as single agent is often well tolerated, but improvement in progression-free survival (PFS) is limited. In the phase Ib-II COMMENCE study, firstly the feasibility was studied and subsequently the efficacy of the combination of cetuximab and methotrexate. With this study we aimed to improve PFS without adding significant toxicities, especially in patients unfit for or refusing platinum-based therapy. In the phase II study patients were randomised between the combination of cetuximab and methotrexate versus methotrexate alone. In Chapter 6 the results of the COMMENCE study are presented. In the phase I study the combination of cetuximab and methotrexate showed to be feasible and in the phase II study the addition of cetuximab to methotrexate significantly improved PFS (4.5 months versus 2.0 months, p=0.002). Overall survival (OS) (8.0 versus 4.7 months, p=0.248) was not significantly different. The toxicity profile of the combination of methotrexate and cetuximab was predictable and manageable (46.7% grade 3-4 toxicity) and comparable to the known toxicity of single agent methotrexate. Unfortunately, due to an altered study design, less patients were included in the phase II study than originally planned and calculated in the power-analysis (45 patients instead of 114 patients). In conclusion: the results of the studies as described in this thesis show that the use of prophylactic antibiotics can be considered in patients with LAHNC treated with chemoradiotherapy. The prediction of ototoxicity and nephrotoxicity by genetic variants in LAHNC patients treated with cisplatin-containing chemoradiotherapy should be validated in a larger cohort before it can be implemented in daily clinical practice. At last, in patients with recurrent or metastatic SCCHN the combination of cetuximab and methotrexate improves PFS, without adding toxicity, but nevertheless the prognosis of these patients remains still disappointing. So small steps into improving personalised treatment are made, but definitely further research is necessary.

106

C h a p t e r 7

General discussion and Future perspectives

Treatment of locally advanced head and neck cancer (LAHNC) patients with concomitant

chemoradiotherapy can induce high rates of acute toxicities, e.g. mucositis in up to

70%, and late toxicities. Also, treatment of recurrent or metastatic squamous cell

carcinoma of the head and neck (SCCHN) with the current first line standard of care

with platinum, 5-FU and cetuximab, causes grade 3-4 toxicity in 82% of the patients.

(1) Especially in patients with recurrent or metastatic SCCHN, prognosis remains poor

with an overall survival (OS) of often only a couple of months, Health Related Quality

of Life (HRQoL) is very important. Treatment induced toxicities should be avoided as

much as possible. New treatment options with improved prognosis as well as reduced

toxicities are therefore highly desirable.

Recurrent or metastatic diseaseUnfortunately, in case of recurrent or metastatic disease, the prognosis is poor, with

a median overall survival of less than 1 year. (2) As stated before, in 2008 the

combination of platinum, 5-FU and cetuximab (EXTREME-regimen) showed an OS-

benefit (OS of 10.1 versus 7.4 months with platinum and 5-FU alone) (1). However, it

is an intensive treatment with significant toxicities and therefore can only be applied

to fit patients. For this reason, in the Netherlands, this EXTREME-regimen is not often

administered. An alternative is, for example, methotrexate as single agent, which never

showed to be beneficial in terms of OS, but can improve QoL in the first period after

start of treatment, has less adverse effects compared to cisplatin-based chemotherapy,

and has an overall response rate (ORR) of around 16%. (3-5). Based on this knowledge

and the lack of studies in the less fit metastatic HN cancer patients, the COMMENCE

study was initiated, to investigate the efficacy and toxicity of the combination with

methotrexate and cetuximab.

The efficacy of cetuximab as single agent, has only been investigated as second-line

treatment, with an ORR of 13%, a median PFS of 2.3 months, and a median OS of 5.9

months. Therefore, in the Netherlands, it is not allowed to prescribe cetuximab as

single agent nor as first-line, nor as second-line.

As investigated in the randomised phase II COMMENCE study, in which 45 patients

received cetuximab and methotrexate and 15 patients methotrexate alone, the

combination resulted in a PFS of 4.5 months and an OS of 8.0 months, both improved

compared to methotrexate alone. However, an OS of 8.0 months is still disappointing,

especially when the OS in untreated patients is around 6 months. And although the

107

Summary and general discussion

7

grade 3-4 toxicity rate with cetuximab and methotrexate was almost the half of the

toxicity rate of the EXTREME-regimen, it was still 46.7%. As the toxicity rate of

methotrexate singe agent treatment was more or less the same as that of the

combination treatment with cetuximab and methotrexate, but with improved PFS and

OS, I believe the combination treatment could be an alternative for recurrent or

metastatic SCCHN patients who are not eligible for the EXTREME schedule or are not

willing to receive it. Notably, this study was performed in a time period in which there

was no access to immunotherapy.

New treatment modalities with improved PFS and OS but without much toxicity are

therefore highly desirable. Immune checkpoint pathways, which are normally used by

tumour cells to suppress the immune system, can be blocked by immune checkpoint

inhibitors (ICI), causing an activation of the immune response in order to eliminate

cancer cells. Examples of ICI are antibodies against cytotoxic T-lymphocyte antigen-4

(CTLA-4) and to the programmed cell death protein 1 (PD-1) receptor. They were first

introduced in melanoma patients, with approval of ipilimumab for metastatic

melanoma by the U.S. Food and Drug Administration (FDA) in 2011.(6)

In recurrent or metastatic SCCHN patients, immunotherapy was firstly investigated as

second-line therapy. In the Checkmate-141 phase III study, in recurrent or metastatic

SCCHN patients, who had progressive disease <6 months after platinum containing

treatment (either as palliative treatment or as primary treatment in combination with

radiotherapy) nivolumab (an IgG4 fully human antibody targeting PD1) was compared

with investigators choice (docetaxel, methotrexate or cetuximab). (7) After a minimal

follow up of 24 months, median OS with nivolumab was 7.7 months compared with

5.1 months with investigators choice -treatment (HR = 0.68). The ORR was 13.3% in the

nivolumab group versus 5.8% in the investigators choice group. (8) Therefore nivolumab

was approved in the United States in 2016 for the treatment of this patient population,

followed by European approval following in 2017 (2), and approval by the “Commissie

BOM” in the Netherlands in 2018.

Thereafter, studies with immunotherapy as first-line treatment for recurrent or

metastatic SCCHN were performed. In the 3-armed Keynote-048 phase III study patients

were randomised between (i) pembrolizumab (a humanised monoclonal anti-PD-1

antibody) as single agent or (ii) combination pembrolizumab with platinum-5FU or (iii)

the EXTREME regimen. Chemotherapy was given for up to 6 cycles, pembrolizumab

for a maximum of 24 months. Primary outcomes were PFS and OS in the total

population as well as in a subgroup with a PD-L1 combined positive score (CPS) of ≥

20. CPS is a scoring method for PD-L1 expression, and is defined by the total number

108

C h a p t e r 7

of PD-L1 positive cells (tumour, lymphocytes, and macrophages) divided by the total

number of tumour cells.(9) Pembrolizumab significantly improved OS compared with

the EXTREME regimen in the subgroups with a PD-L1 CPS ≥ 20 (14.9 months versus

10.7 months, HR 0.61) and ≥ 1 (12.3 months versus 10.3 months, HR 0.78) and was

non-inferior in the total population. Pembrolizumab in combination with platinum-5FU

significantly improved OS in the total population (13.0 months with pembrolizumab

plus platinum-5FU versus 10.7 months with the EXTREME-regimen, HR 0.77). Toxicities

of pembrolizumab with platinum-5FU were comparable with the EXTREME-regimen.

Pembrolizumab as single agent was less toxic than the EXTREME-regimen. (10) In June

2019, the FDA approved pembrolizumab for use in combination with platinum and

5FU for all patients and as a single agent for patients whose tumours express PD-L1

CPS ≥1. The European Medicines Agency (EMA) did not yet approve pembrolizumab

as first-line treatment, but only in patients progressing on or after platinum-containing

chemotherapy. In the Netherlands it is expected that “Commissie BOM” will approve

pembrolizumab as single agent as first-line treatment in recurrent or metastatic SCCHN

patients with tumours expressing PD-L1 CPS ≥20.

The CheckMate 651, in which nivolumab with ipilimumab is compared with the

EXTREME regimen, and the Kestrel study, in which durvalumab versus durvalumab

+tremelimumab versus EXTREME regimen is investigated, are two other ongoing first-

line studies with ICI in recurrent or metastatic SSCHN patients (NCT02741570,

NCT02551159).

A big advantage of immunotherapy is that it is relatively well tolerated, with reduced

incidence of adverse events compared with chemotherapy regimens. In the Checkmate

141 study with nivolumab the incidence of grade 3-4 toxicity was 13.1% versus 35.1%

in the chemotherapy or cetuximab -group, and HRQoL remained stable after the start

of nivolumab, while patients receiving chemotherapy had a clinically meaningful

deterioration in HRQoL from baseline to weeks 9 and 15. (7, 11)

However, despite these promising results and new treatment options, ORRs are still

only 13.8% with nivolumab and 17% with pembrolizumab in the total population,

compared with 36% with the EXTREME regimen. (8, 10) Despite the reduced RR with

immunotherapy compared with chemotherapy, in patients who respond, the OS is

significantly longer. Therefore, it would be of great clinical value if it is possible to

predict responders and non-responders before start of the treatment, especially as a

high response rate is important in patients with symptoms due to their local recurrent

tumour or metastases, and it would be of great value to predict which patient should

prescribed immunotherapy and which the EXTREME regimen. Ferris et al. tried to study

109

Summary and general discussion

7

differences in responses between PD-L1 expressors (≥1%) and non-expressors (<1%)

and also between HPV-positive and HPV-negative tumours. Nivolumab showed OS

benefit in comparison with investigators choice treatment in both PD-L1 expressors

and PD-L1 non-expressors. However, nivolumab provided a 45% reduction in the risk

of death compared with investigators choice treatment in PD-L1 expressors, while in

non-expressors nivolumab the reduction in the risk of death was only 27%. (8) ORR

was improved with nivolumab compared with investigator’s choice treatment in PD-L1

expressors (17.7% versus 1.6%), while the ORR was similar in PD-L1 non-expressors

between nivolumab and investigators choice treatment (11.8% versus 12.5%). In the

KEYNOTE-048 Burtness et al. investigated the use of the PD-L1 CPS as predictive marker

to differentiate which patients need pembrolizumab in combination with chemotherapy

and those who can benefit with pembrolizumab as single agent. (10) As described

above, pembrolizumab as single agent was superior compared with the EXTREME-

regimen in patients with a PD-L1 CPS ≥ 20 (HR 0.61, p=0.0007), while pembrolizumab

in combination with platinum-5FU was superior to the EXTREME regimen in the total

population (HR 0.77, p=0.0034). Further studies are necessary to determine which

predictive markers are the best for this group of patients.

With regard to the HPV status, the same OS benefit (40% reduction in the risk of death

with nivolumab versus investigators choice treatment) was observed in HPV-positive

and HPV-negative tumours. The ORR was improved with nivolumab compared with

investigator’s choice treatment in HPV-positive tumours, as HPV-positive tumours

frequently have higher PD-L1 expression, while ORR was similar in both treatment

groups in HPV-negative tumours. (8)

As we know from treatment with immunotherapy in other types of cancer, and also

from treatment with nivolumab in the CheckMate 141, time to response with

immunotherapy is often more than 8 weeks (2.1 months in the CheckMate 141). Some

patients do not have that time because of very aggressive tumour behaviour or because

of a poor condition and performance status. Therefore, it is of clinical value and cost-

effective, if it is possible to predict who can benefit from potential effect from

immunotherapy, and for whom the possible treatment effect will be too late.

At this moment, in the Netherlands, only nivolumab is approved for recurrent or

metastatic head and neck cancer, and only as second-line treatment after platinum

failure. However, as the KEYNOTE-048 study showed improved outcomes with

pembrolizumab in first-line, it is expected that pembrolizumab will be approved soon,

at least in patients with CPS ≥ 20.

In patients who are ineligible for (e.g. have auto-immune diseases) or refuse

110

C h a p t e r 7

immunotherapy and platinum-based chemotherapy, but with a great motivation to

start treatment, treatment with cetuximab and methotrexate could be a meaningful

treatment option, certainly as first-line treatment. Treatment with the combination of

cetuximab and methotrexate was not investigated in second-line, but currently there

is no data at all of chemotherapy in combination with or without cetuximab as second-

line after immunotherapy.

Other treatment options for recurrent or metastatic disease are targeted therapies

such as tyrosine kinase inhibitors (TKI) against EGFR, HER2, PIK3CA or mammalian

targets of rapamycin (mTOR). EGFR for example is overexpressed in around 90% of

the SCCHN patients, but many patients are or become refractory to anti-EGFR

treatment, due to different intrinsic or acquired mechanisms. In tumours refractory

to EGFR-inhibition, there is activation of the PIK3CA, AKT and mTOR pathway leading

to enhanced cell survival. The exact incidence of the alterations in the different

pathways is unknown and TKI’s against EGFR (erlotinib, gefitinib), HER2 (lapatinib) or

EGFR and pan-HER (afatinib) only showed modest activity in recurrent or metastatic

disease (12). In a phase III trial, in which patients were randomised between gefitinib

250mg, gefitinib 500mg and methotrexate, gefitinib 500mg improved ORR, however,

this was not significantly different, while the OS was the same in the three treatment

groups. (13) In the phase 3 LUX-Head&Neck 1 study, afatinib was compared to

methotrexate as second-line treatment after platinum-failure, with a significant longer

PFS in the afatinib group (2.6 versus 1.7 months). Two phase II trials did not demonstrate

a benefit in OS or PFS of adding PX-866, an agent targeting PI3K isoforms, to either

cetuximab or docetaxel. (14, 15) Also, two mTOR inhibitors, everolimus and

temsirolimus, had disappointing results as single agent therapies as well as combination

therapies in phase I and phase II studies. (12)

Locally advanced diseaseChemoradiotherapy is the treatment of choice for LAHNC, as primary treatment or as

post-operative treatment in case of extracapsular extension and/or microscopically

involved surgical margins. (16) The addition of chemotherapy led to an absolute OS

benefit of 4.5% in all patients treated with the combination of chemotherapy to

radiotherapy (i.e. induction, concomitant, or adjuvant chemoradiotherapy) and 6.5%

in case of concomitant chemoradiotherapy. (17) However, the benefit of chemoradio-

therapy in terms of OS is at the expense of extra toxicity. Chemoradiotherapy is

characterized by a high incidence of toxicities, like dysphagia, aspiration pneumonia,

nephrotoxicity and ototoxicity. The incidence of grade 3-4 acute toxicities was 47% with

111

Summary and general discussion

7

radiotherapy alone versus 77% with chemoradiotherapy. (18) It is therefore important

to find ways to reduce the toxicities without reducing efficacy.

As immunotherapy is getting more and more important in the recurrent or metastatic

setting, with improved OS in part of the patients and with reduced toxicity, it is a logical

next step to study its contribution in LAHNC patients. Currently several studies are

running with immunotherapy in combination with radiotherapy or chemoradiotherapy

in LAHNC patients. These studies are performed as concomitant therapy with

chemotherapy as definitive treatment (NCT03040999), or as adjuvant treatment

(NCT02641093). Furthermore, a study in which chemoradiotherapy will be compared

with immunotherapy-radiotherapy (so without chemotherapy) is in preparation.

(NCT03383094)

Despite all these new developments, cisplatin-based chemoradiotherapy is still

considered as the standard in most LAHNC patients. Because the high acute and late

toxicity rate of cisplatin-based chemoradiotherapy, studies which investigate other

effective, but less toxic treatments are of utmost importance to improve personalised

care.

Alternatives of cisplatin in combination with radiotherapyDifferent kinds of therapies are combined with radiotherapy to improve efficacy and/

or to reduce toxicity. In a meta-analysis by Pignon et al. no significant difference in

efficacy was seen between single agent chemotherapy and poly-chemotherapy. In the

mono-chemotherapy group, efficacy of chemotherapy was significantly improved with

platinum (i.e. cisplatin or carboplatin) compared with other types of chemotherapy.

(17) A meta-analysis of the comparison between cisplatin and carboplatin, revealed

better 5-year OS with cisplatin (HR=0.67, 95% CI, 0.49 to 0.91; P=0.01). Cisplatin-based

chemoradiotherapy was associated with fewer haematological toxicities, but with more

gastrointestinal toxicities and nephrotoxicity compared with carboplatin-based

chemoradiotherapy. (19)

If a patient is not eligible for cisplatin-based chemoradiotherapy, due to performance-

status, age, renal function or hearing loss, cetuximab added to radiotherapy has shown

to be beneficial as primary treatment in terms of locoregional control (LRC) and OS.

(20) However, there are no good head to head studies comparing cisplatin-radiotherapy

and cetuximab-radiotherapy. A retrospective study of Bauml et al. showed that

cetuximab added to radiotherapy as primary treatment had inferior OS compared with

cisplatin-radiotherapy, regardless of the use of high-dose or intermediate-dose

cisplatin. (21) A recent study by Do et al. confirms these findings in a small retrospective

112

C h a p t e r 7

study, in which cetuximab-radiotherapy had reduced OS rate, LR rate, and 2-year organ

preservation rate compared with cisplatin-radiotherapy. (22) Recently, in HPV positive

patients, who in general have a better prognosis, cetuximab-radiotherapy was

associated with worse OS and PFS compared to treatment with cisplatin-based

radiotherapy. (23) The goal of this de-escalate study in HPV-positive oropharyngeal

cancer was to improve patient’s quality of life and reduce acute and long-term toxicity,

but without compromising efficacy. Unfortunately, not only the efficacy was worse, but

also no differences in the overall rates of grade 3-5 toxicities were observed between

the cetuximab-radiotherapy and cisplatin-radiotherapy group.

Another interesting alternative for cisplatin-based chemotherapy can be poly ADP-

ribose polymerase (PARP) inhibitors in combination with radiotherapy. As PARP-

inhibitors increase the level of double-strand breaks by the inability to repair

radiotherapy-induced single-strand breaks, they can increase cell death induced by

radiotherapy.(24) This is currently tested in phase I studies in head and neck cancer

patients, either alone or in combination with cisplatin. (25) (NCT02229656,

NCT02308072).

Prediction of cisplatin-toxicityAnother way to personalize treatment is to predict the risk of the most clinically relevant

toxicities of cisplatin in each individual patient. Chemotherapy with cisplatin is most

often applied either at a dose of 100mg/m2 every 3 weeks for 3 cycles (high dose) or

at a dose of 40mg/m2 every week for 6 or 7 cycles (intermediate dose).(26) Several

studies showed that intermediate dose cisplatin reduced the rate of acute toxicities,

especially ototoxicity and nephrotoxicity, compared with high dose cisplatin without

reduced efficacy. (27, 28) Although chemoradiotherapy with cisplatin still is the best

treatment option, if it is possible to predict the cisplatin-induced toxicities, shared

decision making is important to weigh up the toxicity and the efficacy. For example,

treatment with an intermediate dose instead of high dose cisplatin can be considered,

treatment with cetuximab or carboplatin instead of cetuximab, or even radiotherapy

alone without concomitant chemotherapy. Personal circumstances and physical

condition can be taken into account and justify to administer a possible less effective

treatment with the benefit of less toxicity.

Genetic variants to predict ototoxicity and nephrotoxicity were studied in the Prone

study, in which only a significant correlation between the SNP ACYP2 and clinically

determined ototoxicity was found. As clinically determined ototoxicity the is probably

113

Summary and general discussion

7

more clinically relevant than audiometrically determined ototoxicity, in new studies

there should be more attention to clinically determined ototoxicity measured by the

Common Terminology Criteria for Adverse Events (CTCAE). However, for clinical

practice, at this moment there are no reliable predictive tests for ototoxicity as well as

nephrotoxicity, so larger multinational cohort studies are necessary to eventually can

improve personalised care. In these studies, HRQoL should be an important aspect,

because ototoxicity as well as nephrotoxicity can have a (huge) impact on HRQoL.

AntibioticsIn LAHNC patients treated with concomitant chemoradiotherapy there is a high rate

of hospitalisation. To the best of our knowledge, the use of prophylactic antibiotics to

prevent aspiration pneumonias or mucositis in patients with LAHNC has never been

investigated before. In our PANTAP study almost 40% of the patients in the standard

group were hospitalised. (29) Reasons for hospitalisation were for example mucositis,

pain, fever, and dehydration, but frequently multifactorial. Besides that, there is a high

incidence of dysphagia and aspiration in these patients with a reported aspiration rate

of 13-69% (30, 31), therefore the PANTAP-study was performed, to investigate if

prophylactic antibiotics could lower the number of aspiration pneumonias, which was

the primary endpoint. Although this primary endpoint was negative, the reduced

number of hospital admissions is clinically relevant from the patient’s perspective.

Although pneumonias were the primary outpoint, the effect of prophylactic antibiotics

could potentially have a positive effect on other side effect of the treatment, which

often lead to hospitalisation (e.g. mucositis, fever, pain). Besides the fact that a lower

hospitalisation rate is an advantage for the patient, reducing the number of admissions

to the emergency department and to the in-patient ward is not only effective in

reducing costs, but also for the burden on health care services. It would be of great

value if there would be biomarkers, which can predict which patients would benefit

most from prophylactic antibiotics. Because of the relative small number of patients,

no subgroup analyses could be performed, but it would be very interesting to

investigate if for example patients with chronic obstructive pulmonary disease (COPD)

or aspiration before the start of chemoradiotherapy, could benefit more from

prophylactic antibiotics. However, in the PANTAP study for these patient characteristics

was stratified.

Although prophylactic antibiotics to prevent aspiration pneumonia was never described

before, we only found results of a pilot study which was performed in head and neck

cancer patients with an antimicrobial lozenge instead of systemic antibiotics that

114

C h a p t e r 7

showed elimination of Candida in all patients and reduction in gram-negative flora in

most patients.(32) However, a subsequent randomized phase 3 study failed to show

a reduction in mucositis with the use of antimicrobial lozenge.(33) Until new studies

are performed or new insights in the treatment with prophylactic antibiotics are

presented, we suggest that in patients with high risk of aspiration pneumonia, e.g.

COPD Gold 3-4, aspiration before start of the chemoradiotherapy and patients who

continue smoking, administration of prophylactic antibiotics can be considered. Before

initiating any new supportive care studies in this patient group, it should be considered

that the primary endpoint, pneumonia, is a challenging one.

As mentioned above, new studies are currently being performed or in preparation with

new treatment modalities including immunotherapy in LAHNC patients. If in future,

immunotherapy possibly will replace chemotherapy in this setting, you could argue

that prophylactic antibiotics will be of less importance. However, as aspiration and

aspiration pneumonia will remain to be a critical issue in LAHNC patients due to the

primary tumour localization and radiotherapy treatment, which will be a cornerstone

of the treatment, all means to prevent (aspiration) pneumonia, are still important.

Whether oral amoxicillin/clavulanic acid will be the best choice in this respect, can be

discussed. Reasonable alternatives are selective digestive decontamination (SDD) or

selective oropharyngeal decontamination (SOD), as used at intensive care units (ICU),

to prevent infectious complications. SDD means the prophylactic treatment of patients

with an oropharyngeal paste and enteral suspension containing antimicrobials as well

as an intravenous antibiotic during the first 4 days of ICU admission. The purpose of

the treatment is to eradicate potential pathogenic microorganisms from the oropharynx

and digestive tract of patients at risk for nosocomial infections. SOD consists of SDD

without the enteral suspension and without intravenous antibiotics.(34)

Especially SOD could be an interesting treatment alternative in LAHNC patients to

prevent pneumonia, but further studies are logically necessary.

Prevention of head and neck cancer Instead of reducing toxicities and improving outcomes, primary prevention of head

and neck cancer would be even better. Alcohol and tobacco and HPV in oropharyngeal

cancer are the major risk factors for head and neck cancer. Prevention and cessation

of smoking and alcohol use are two principal strategies to reduce alcohol and tobacco

addiction. Although for alcohol drinking, a long time period (36-39 years) of

discontinuation is required to equal the risk of laryngeal and pharyngeal cancers to

that of never drinkers, already after 5 years of drinking cessation a reduction of around

115

Summary and general discussion

7

15% in the alcohol-related elevated risk of these cancers was seen. (35) Therefore, also

alcohol drinking cessation should be encouraged. As for smoking, active programs at

secondary schools are in high need to show its terrible late effects to lower the

incidence of young people starting with this potentially lethal addictions.

As HPV vaccination in women, is safe and effective in preventing cervical cancer, HPV

vaccination in male to prevent oropharyngeal cancer could be worthwhile.

Unfortunately, in a recent review by Harder et al., no data were identified about the

efficacy of HPV vaccination in men to prevent head and neck squamous cell cancer.

However, HPV vaccination in males is moderately effective against persistent anogenital

HPV infection and high-grade anal intraepithelial lesions. Vaccine effectiveness drops

markedly in individuals who are already infected with the corresponding HPV type.

This supports a recommendation for early vaccination of boys also with the goal of

establishing optimal vaccine-induced protection before the onset of sexual activity.

(36) Recently, the “Gezondheidsraad” in the Netherlands has advised to vaccinate boys

as well as girls, from an age of 9 years old.

Conclusion

Despite the progressions made in the treatment of patients with SCCHN over the last

decades, there are still a lot of challenges to improve the care for these patients.

Improving personalised care should consist of both improvements in efficacy and

prognosis by developing new treatment modalities and similarly reducing toxicities

leading to improving health-related QoL.

116

C h a p t e r 7

References

1. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359(11):1116-27.

2. Argiris A, Harrington KJ, Tahara M, Schulten J, Chomette P, Ferreira Castro A, et al. Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck. Front Oncol 2017;7:72.

3. Schornagel JH, Verweij J, de Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, et al. Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J Clin Oncol 1995;13(7):1649-55.

4. Kushwaha VS, Gupta S, Husain N, Khan H, Negi MP, Jamal N, et al. Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil as palliative treatment in recurrent head and neck squamous cell carcinoma. Cancer Biol Ther 2015;16(2):346-51.

5. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10(8):1245-51.

6. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013;342(6165):1432-3.7. Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for Recurrent

Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016;375(19):1856-1867.8. Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab vs investigator’s

choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol 2018;81:45-51.

9. Kulangara K, Zhang N, Corigliano E, Guerrero L, Waldroup S, Jaiswal D, et al. Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer. Arch Pathol Lab Med 2018.

10. B. Burtness KJH, R. Greil, D. Soulieres, M. Tahara, et al. KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In: European Society for Medical Oncology Munich; 2018.

11. Harrington KJ, Ferris RL, Blumenschein G, Jr., Colevas AD, Fayette J, Licitra L, et al. Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol 2017;18(8):1104-1115.

12. Sacco AG, Cohen EE. Current Treatment Options for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. J Clin Oncol 2015;33(29):3305-13.

13. Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27(11):1864-71.

14. Jimeno A, Shirai K, Choi M, Laskin J, Kochenderfer M, Spira A, et al. A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Ann Oncol 2015;26(3):556-61.

15. Jimeno A, Bauman JE, Weissman C, Adkins D, Schnadig I, Beauregard P, et al. A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Oral Oncol 2015;51(4):383-8.

16. Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27(10):843-50.

17. Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92(1):4-14.

18. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091-8.

19. Guan J, Li Q, Zhang Y, Xiao N, Chen M, Zhang Y, et al. A meta-analysis comparing cisplatin-based to carboplatin-based chemotherapy in moderate to advanced squamous cell carcinoma of head and neck (SCCHN). Oncotarget 2016;7(6):7110-9.

20. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354(6):567-78.

21. Bauml JM, Vinnakota R, Anna Park YH, Bates SE, Fojo T, Aggarwal C, et al. Cisplatin versus cetuximab with definitive concurrent radiotherapy for head and neck squamous cell carcinoma: An analysis of veterans health affairs data. Cancer 2018.

117

Summary and general discussion

7

22. Ly Viet Do MD, Zayd Parekh, Richard Trevino, Richard Eng, Karen Fann et al. Outcomes of concurrent radiation with cisplatin versus cetuximab in locally-advanced head and neck squamous cell carcinoma (LAHNSCC). . Journal of Clinical Oncology;36(no. 15_suppl).

23. 1.Mehanna H KA, Hartley A, et al. Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy. Presented at: ESMO 2018; October19-23; Munich, Germany. LBA9_PR; 2018.

24. Chalmers AJ, Lakshman M, Chan N, Bristow RG. Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. Semin Radiat Oncol 2010;20(4):274-81.

25. Khan K, Araki K, Wang D, Li G, Li X, Zhang J, et al. Head and neck cancer radiosensitization by the novel poly(ADP-ribose) polymerase inhibitor GPI-15427. Head Neck 2010;32(3):381-91.

26. Espeli V, Zucca E, Ghielmini M, Giannini O, Salatino A, Martucci F, et al. Weekly and 3-weekly cisplatin concurrent with intensity-modulated radiotherapy in locally advanced head and neck squamous cell cancer. Oral Oncol 2012;48(3):266-71.

27. Driessen CM, Janssens GO, van der Graaf WT, Takes RP, Merkx TA, Melchers WJ, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck 2016;38 Suppl 1:E559-65.

28. Driessen CM, Uijen MJ, van der Graaf WT, van Opstal CC, Kaanders JH, Nijenhuis T, et al. Degree of nephrotoxicity after intermediate- or high-dose cisplatin-based chemoradiotherapy in patients with locally advanced head and neck cancer. Head Neck 2016;38 Suppl 1:E1575-81.

29. Ham JC, Driessen CM, Hendriks MP, Fiets E, Kreike B, Hoeben A, et al. Prophylactic antibiotics reduce hospitalisations and cost in locally advanced head and neck cancer patients treated with chemoradiotherapy: A randomised phase 2 study. Eur J Cancer 2019;113:32-40.

30. Langerman A, Maccracken E, Kasza K, Haraf DJ, Vokes EE, Stenson KM. Aspiration in chemoradiated patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2007;133(12):1289-95.

31. Nguyen NP, Smith HJ, Dutta S, Alfieri A, North D, Nguyen PD, et al. Aspiration occurence during chemoradiation for head and neck cancer. Anticancer Res 2007;27(3B):1669-72.

32. El-Sayed S, Epstein J, Minish E, Burns P, Hay J, Laukkanen E. A pilot study evaluating the safety and microbiologic efficacy of an economically viable antimicrobial lozenge in patients with head and neck cancer receiving radiation therapy. Head Neck 2002;24(1):6-15.

33. El-Sayed S, Nabid A, Shelley W, Hay J, Balogh J, Gelinas M, et al. Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system. J Clin Oncol 2002;20(19):3956-63.

34. Plantinga NL, Bonten MJ. Selective decontamination and antibiotic resistance in ICUs. Crit Care 2015;19:259.35. Ahmad Kiadaliri A, Jarl J, Gavriilidis G, Gerdtham UG. Alcohol drinking cessation and the risk of laryngeal

and pharyngeal cancers: a systematic review and meta-analysis. PLoS One 2013;8(3):e58158.36. Harder T, Wichmann O, Klug SJ, van der Sande MAB, Wiese-Posselt M. Efficacy, effectiveness and safety

of vaccination against human papillomavirus in males: a systematic review. BMC Med 2018;16(1):110.

C H A P T E R 8Nederlandse samenvatting

120

C h a p t e r 8

Nederlandse samenvatting en discussie

Hoofd-hals kankerKanker in het hoofd-hals gebied kan voorkomen in de voorhoofdholtes, neusbijholte,

mondholte, keelholte, strottenhoofd of speekselklieren. Er kunnen verschillende types

kanker in het hoofd-hals gebied voorkomen, waarbij het meest voorkomende type

plaveiselcel kanker is. Met de term ‘hoofd-hals kanker’ wordt dan ook meestal

plaveiselcel kanker in de mondholte, keelholte of strottenhoofd bedoeld.

Hoofd-hals kanker is de zevende meest voorkomende type kanker wereldwijd.

Wereldwijd waren er in 2015 930.000 patiënten die de diagnose hoofd-hals kanker

kregen; in Nederland waren dat in 2017 meer dan 3000 patiënten.

In de Westerse wereld ontstaat hoofd-hals kanker in twee derde van de patiënten als

gevolg van roken en alcohol gebruik, en komt driekeer zo vaak voor bij mannen als bij

vrouwen. Een andere risicofactor, met name voor kanker in de keelholte, is het humaan

papillomavirus (HPV). Hoofd-hals kanker veroorzaakt door HPV komt meestal voor op

jongere leeftijd, heeft een betere prognose en reageert over het algemeen beter op

behandeling.

Symptomen van hoofd-hals kanker kunnen zijn heesheid, keel- or oorpijn, moeite met

slikken of een niet goed passend kunstgebit. Symptomen worden echter zowel door

patiënt als de huisarts niet altijd goed herkend, waardoor de diagnose regelmatig pas

laat gesteld wordt. Hierdoor is de kanker vaak al in een gevorderd stadium, met een

slechtere prognose, waardoor er een intensievere behandeling nodig is met meer

bijwerkingen.

Een gevorderd stadium (in ongeveer 60% van de patiënten) kan bestaan uit een grote

tumor, en/of uit uitzaaiingen in de lymfeklieren in de hals. Daarnaast zijn er in 10% van

de patiënten al uitzaaiingen op afstand op het moment dat voor het eerst de diagnose

hoofd-hals kanker wordt gesteld.

De diagnose wordt gesteld door lichamelijk onderzoek (inclusief een uitgebreid

onderzoek door een KNO-arts of kaakchirurg), een CT-scan van de hals of MRI-scan

van de tumor, een echo van de lymfeklieren in de hals en een CT van de longen, omdat

roken een risicofactor is voor zowel hoofd-hals kanker als voor longkanker. Door middel

van een biopt van de tumor en/of punctie van de lymfeklieren wordt het uiteindelijke

tumor stadium bepaald. Zowel de behandeling als de prognose hangen af van dit tumor

stadium.

121

Nederlandse samenvatting

8

Behandeling gevorderde ziekte zonder uitzaaiingenDe behandeling hangt niet alleen af van de locatie van de oorspronkelijke tumor en

het stadium van de ziekte, maar ook van de leeftijd, co-morbiditeit en conditie van de

patiënt. Operatie, bestraling en chemotherapie zijn de drie voornaamste mogelijkheden

van behandeling. Operatie heeft in een aantal patiënten de voorkeur, bijvoorbeeld bij

kanker in de mondholte. Bij een aantal patiënten zou een operatie een grote impact

op hun leven hebben, bijvoorbeeld door het kwijtraken van hun stembanden en

daarmee hun stem-functie. In deze patiënten is aangetoond dat bestraling, al dan niet

gecombineerd met chemotherapie, een even goede prognose oplevert en de functie

van de stembanden kan behouden. In de literatuur is een absolute overlevingswinst

van 6,5% aangetoond van behandeling met chemotherapie en bestraling ten opzichte

van alleen bestraling bij patiënten met een lokaal uitgebreid hoofd-halskanker.

Als chemotherapie is cisplatin het meest effectief gebleken. Dit kan in verschillende

schema’s en met verschillende doseringen worden toegediend. Het wereldwijd meest

gebruikte schema is een driewekelijkse kuur met een dosering van cisplatin van 100mg/

m2 (hoge dosis), waarbij in totaal 3 kuren worden toegediend. Een veel gebruikt

alternatief is een wekelijkse kuur met een dosering van 40mg/m2 cisplatin (gemiddelde

dosis), waarbij 6-7 kuren in totaal worden gegeven. Als alternatief voor cisplatin kan

carboplatin of eventueel cetuximab, een monoklonaal antilichaam, worden

gecombineerd met bestraling. De bestraling wordt dagelijks toegediend gedurende

6-7 weken, waarbij er in sommige (kortere) schema’s twee keer per dag wordt bestraald

op één dag in de week.

Gecombineerde behandeling met chemotherapie en bestraling kent echter veel

bijwerkingen, zowel op de korte termijn, als op de lange termijn. Bijwerkingen

gedurende de behandeling kunnen zijn slijmvlies aantasting, moeite en/of pijn met

slikken, misselijkheid, gehoorverlies, nierschade of onderdrukking van het beenmerg.

Hoe vaak deze bijwerkingen voorkomen hangt af van welke dosering cisplatin en welke

schema gebruikt wordt. Nierschade wordt gemeld in 8-68% van de patiënten, beenmerg

onderdrukking in 40%, en aantasting van het slijmvlies in 77% van de patiënten. Moeite

en/of pijn met slikken worden vaak niet goed gerapporteerd. Moeite met slikken kan

verslikken tot gevolg hebben, wat kan leiden tot een longontsteking. Het voorkomen

van verslikken wordt in de literatuur beschreven in 13-69% van de patiënten.

Naast deze bijwerkingen op de korte termijn, kunnen er ook 5 jaar na de behandeling

bijwerkingen ontstaan of sommige bijwerkingen kunnen blijvend zijn, zoals

verlittekening van het behandelde gebied, het hebben van een droge mond en moeite

en/of pijn met slikken.

122

C h a p t e r 8

De behandeling zelf, maar ook de bijwerkingen op korte en lange termijn, hebben een

grote impact op de ervaren kwaliteit van leven van patiënten. Tijdens behandeling

daalt de kwaliteit van leven, waarbij deze 4-6 weken na het afronden van de behandeling

zelfs nog verder daalt, terwijl na 1 jaar na afronden van de behandeling de kwaliteit

van leven vaak weer op hetzelfde niveau is als voorafgaand aan de behandeling.

Behandeling uitgezaaide ziekteOndanks deze intensieve behandeling voor gevorderde hoofd-hals kanker, krijgt een

substantieel deel van de patiënten de ziekte terug; tot 60% van de behandelde

patiënten krijgt lokaal de ziekte terug en tot 30% ontwikkelt uitzaaiingen elders in het

lichaam. Helaas is lokale behandeling met operatie of opnieuw bestraling in geval van

lokale ziekte terugkeer, slechts in een zeer klein percentage van de patiënten mogelijk.

Voor het grootste deel van de patiënten, is er op het momenten dat de ziekte

terugkeert geen genezing meer mogelijk. De gemiddelde overleving op het moment

van ziekte terugkeer is minder dan 1 jaar. Indien patiënten nog fit genoeg zijn kan

chemotherapie worden gegeven, waarbij er in het algemeen een combinatie van

verschillende middelen (cisplatin, cetuximab en 5FU ; het “EXTREME-schema”) wordt

gegeven omdat deze combinatie van chemotherapie het eerste schema was dat winst

in overleving heeft aangetoond (van gemiddeld 7.4 maanden naar 10.1 maanden).

Deze behandeling gaat echter gepaard met veel bijwerkingen. Hierdoor blijkt ook vaak

in de dagelijkse praktijk dat dit schema niet haalbaar is in deze vaak kwetsbare

patiëntengroep. Een alternatief is methotrexaat, waarvan geen overlevingswinst is

vastgesteld, maar waarvan wel bekend is dat het de tijd tot toename van ziekte uitstelt

en over het algemeen goed verdragen wordt zonder veel bijwerkingen. Uiteraard kan

in plaats van behandeling met chemotherapie, ook alleen ondersteunende zorg een

goede optie zijn.

Resultaten van onderzoek beschreven in dit proefschriftZoals eerder gezegd, zijn slikklachten en verslikken met een longontsteking als gevolg,

veel voorkomende bijwerkingen van gecombineerde chemotherapie en radiotherapie

voor patiënten met gevorderde hoofd-hals kanker. Daarom hebben wij de PANTAP-

studie bedacht en uitgevoerd, waarin het profylactisch voorschrijven van een

antibioticum aan patiënten met gevorderde hoofd-hals kanker die behandeld werden

met gecombineerde chemotherapie en bestraling werd vergeleken met standaard zorg

in het voorkómen van longontsteking (al dan niet het gevolg van verslikken). In deze

studie hebben we naast het effect op de longontsteking gekeken naar het effect van

123

Nederlandse samenvatting

8

de profylactische antibiotica op het aantal en de duur van de ziekenhuisopnames, de

ervaren kwaliteit van leven, bijwerkingen, kosten en of bacteriën in slijmkweken

ongevoelig werden voor het antibioticum. Patiënten werd gevraagd deel te nemen aan

de studie vooraf aan de start van de behandeling met chemotherapie en bestraling

waarbij ze, indien ze toestemden, werden gerandomiseerd (=geloot) voor wel of geen

profylactische antibiotica. Deze antibiotica moesten ze gebruiken vanaf 29 dagen na

start van de behandeling met chemotherapie en bestraling tot 14 dagen na het einde

van de behandeling. In totaal hebben 106 patiënten deelgenomen aan de studie,

waarbij er 48 patiënten geloot hebben om geen antibioticum te krijgen, en 47 patiënten

om wel antibioticum te gebruiken. De overige 11 patiënten konden om verschillende

redenen niet geloot worden tussen wel of geen antibioticum, meestal omdat ze al voor

dag 29 van de behandeling een antibioticum hadden gekregen.

In hoofdstuk 2 worden de voornaamste resultaten van de PANTAP-studie beschreven;

er werd geen verschil gevonden in het aantal longontstekingen tussen patiënten die

wel of geen profylactisch antibioticum hadden gebruikt. Wel was er een duidelijke

afname in het aantal ziekenhuisopnames in de groep patiënten die wel het antibioticum

had gekregen, evenals een afname in het optreden van koorts. Hierdoor waren de

gemiddelde kosten voor een patiënt die wel antibioticum had gekregen duidelijk lager

(€1425 minder) dan voor een patiënt die geen antibioticum had gekregen. In hoofdstuk

3 wordt het effect van de profylactische antibiotica op de kwaliteit van leven beschreven.

Vooral aan het einde van de gecombineerde behandeling met chemotherapie en

bestraling, is de kwaliteit van leven op veel verschillende aspecten beter voor de groep

die profylactisch antibioticum kregen. Als laatste worden de resultaten van de

slijmkweken en het effect van het antibioticum hierop beschreven in hoofdstuk 4. Er

was geen verschil in het aantal kweken waarin bacteriën of schimmels werden gekweekt

tussen beide groepen. Er waren echter wel meer bacteriën ongevoelig voor antibiotica

direct aan het einde van de gecombineerde behandeling met chemotherapie en

bestraling in de patiënten die werden behandeld met profylactisch antibiotica, maar

dit verschil was niet meer aantoonbaar 3 en 14 weken na het afronden van de bestraling

en chemotherapie behandeling.

In hoofdstuk 5 worden de resultaten beschreven van de PRONE-studie. Aangezien

behandeling met het cytostaticum cisplatin als onderdeel van de gecombineerde

behandeling met bestraling en chemotherapie kan leiden tot zowel gehoorverlies als

nierschade, heeft deze studie onderzocht of er genen zijn die kunnen voorspellen welke

patiënten wel en welke patiënten geen last van deze bijwerkingen kregen. Gehoorverlies

is op twee manieren te bepalen; enerzijds door wat de patiënt ervaart en rapporteert,

124

C h a p t e r 8

anderzijds door een gehoormeting. Een variatie in het ACYP2-gen bleek voorspellend

voor gehoorverlies zoals deze wordt ervaren door de patiënt, maar niet voorspellend

voor schade gemeten bepaald door gehoormetingen. Een variatie in het OCT2-gen

bleek nierschade te kunnen voorspellen gedurende de behandeling, maar had geen

voorspellende waarde voor nierschade aan het einde van de behandeling, wat

uiteindelijk het meest relevant is.

Tot slot heeft de COMMENCE-studie, beschreven in hoofdstuk 6, onderzocht of de

combinatie van methotrexaat met cetuximab effectiever is dan behandeling met alleen

methotrexaat in patiënten met teruggekeerde ziekte. Aangezien de

standaardbehandeling met het EXTREME-schema, dat bestaat uit drie verschillende

chemotherapie-middelen, meestal te intensief is voor deze patiënten en veel

bijwerkingen kent, onderzocht de COMMENCE studie of behandeling met een nieuwe

combinatie van twee middelen, methotrexaat en cetuximab, zowel effectief was als

goed verdragen werd. In eerste instantie werd gekeken of deze nieuwe combinatie

veilig kon worden toegediend. Nadat dit het geval bleek te zijn in de eerste 6 patiënten,

werd de studie vervolgens uitgebreid naar een studie waarin twee behandelingen

werden vergeleken, namelijk methotrexaat en cetuximab met methotrexaat alleen.

Dertig patiënten zijn vervolgens behandeld met methotrexaat en cetuximab en 15

patiënten met methotrexaat alleen. Met de combinatie behandeling duurde het langer

totdat de ziekte weer toenam in vergelijking met methotrexaat alleen (4,5 maanden

versus 2,0 maanden). Er was geen verschil in overleving tussen de beide groepen en

ook geen verschil in bijwerkingen.

Nieuwe ontwikkelingenHet is van belang te weten dat de COMMENCE studie is uitgevoerd in de periode

voordat er de mogelijkheid was om immunotherapie toe te dienen aan patiënten met

teruggekeerde hoofd-hals kanker die niet meer kunnen genezen. Inmiddels is er in

Nederland goedkeuring om patiënten die toename van ziekte hebben, nadat ze

behandeld zijn met cisplatin of carboplatin (bijvoorbeeld volgens het EXTREME-schema),

te behandelen met immunotherapie. Dit laat in een relatief kleine groep patiënten een

duidelijke overlevingswinst zien met daarbij relatief weinig bijwerkingen. Want ondanks

dat slechts 13.3% van de patiënten in deze studie, die tot registratie leidde, baat heeft

bij de behandeling, is de 1-jaars overleving van deze groep patiënten die respondeert

wel duidelijk beter (1-jaars overleving van 36.0% in plaats van 16.6%). Daarnaast is er

recent een studie verricht, waarbij patiënten die nog nooit behandeld waren voor

teruggekeerde hoofd-hals kanker, werden geloot tussen het EXTREME-schema,

125

Nederlandse samenvatting

8

immuuntherapie alleen, of immuuntherapie gecombineerd met cisplatin of carboplatin

en 5-FU. In die studie is onderscheid gemaakt naar patiënten met een hoge en lage

Combined Positive PDL1 Score (CPS), waarvan gedacht wordt dat patiënten met een

hoge CPS beter op immuuntherapie reageren. Daarin bleek dat patiënten met een

hoge CPS een duidelijk betere overleving hadden met immuuntherapie vergeleken

met de groep die alleen chemotherapie kreeg volgende het EXTREME-schema (14.9

maanden versus 10.7 maanden). In de gehele groep, met ook patiënten met een lage

CPS, bleek de combinatie van immuuntherapie en chemotherapie beter dan het

EXTREME-schema (een overleving van 13.0 maanden versus 10.7 maanden). Het is dan

ook waarschijnlijk dat deze behandeling voor patiënten met een hoge CPS binnenkort

wordt goedgekeurd in Nederland. Desalniettemin, zullen er ook patiënten blijven die

niet in aanmerking komen voor immunotherapie, en die niet fit genoeg zijn voor het

intensieve EXTREME-schema, voor wie de combinatie van methotrexaat en cetuximab

dan een waardevol alternatief kan zijn.

Gezien de ontwikkelingen van immunotherapie bij patiënten met teruggekeerde hoofd-

hals kanker, is het een logische stap om ook immunotherapie toe te voegen aan de

behandeling van patiënten met lokaal gevorderde ziekte. Dit om te streven naar

enerzijds minder bijwerkingen van de chemotherapie en anderzijds om de kans op

terugkeer van ziekte zo klein mogelijk te maken. Deze studies worden momenteel

uitgevoerd.

Ook als immuuntherapie in de toekomst chemotherapie zou kunnen gaan vervangen

in combinatie met bestraling bij de eerste behandeling van patiënten met een

gevorderd hoofd-hals carcinoom, zal het voorkomen van longontstekingen (al dan niet

door verslikken) en het voorkomen van ziekenhuisopnames een belangrijke rol blijven

spelen. Daarmee blijft de vraag of een profylactisch antibioticum standaard toegevoegd

zou moeten worden aan de gecombineerde behandeling (immunotherapie en

bestraling). Zeker in patiënten met een hoog risico op longontstekingen, zoals patiënten

met een onderliggende longziekte of patiënten die roken, is dit een goed te verdedigen

beleid. Bij voorkeur zou hier meer onderzoek naar gedaan moeten worden, waarbij

ook onderzocht kan worden of andere antibiotica dan die in onze studie werden

gegeven, of combinatie van middelen wellicht effectiever kan zijn met minder invloed

op het ongevoelig worden van bacteriën voor antibiotica.

Wat betreft het voorspellen van bijwerkingen van cisplatin, zoals gedaan is in de PRONE-

studie, was dit het eerste onderzoek uitgevoerd in patiënten met hoofd-hals kanker.

Voor de huidige praktijk kunnen we hier helaas dus nog geen consequenties aan

verbinden, en zal vervolgonderzoek nodig zijn in grotere groepen patiënten.

126

C h a p t e r 8

Waar nog veel winst te behalen is, is in het voorkómen van hoofd-hals kanker. Zo is

stoppen met roken en stoppen met alcohol duidelijk effectief gebleken in het

voorkómen van een tweede hoofd-hals kanker in patiënten die eerder al een hoofd-

hals kanker hadden ontwikkeld. Het is daarom van groot belang om jongeren al op

jonge leeftijd op de risico’s van roken en alcohol te wijzen en om hiermee het ontstaan

van hoofd-hals kanker te voorkómen.

Daarnaast worden meisjes inmiddels ingeënt om baarmoederhalskanker als gevolg

van HPV te voorkomen, maar kiest helaas nog lang niet 100% van de meisjes ervoor

om zich te laten vaccineren. Jongens worden nog niet gevaccineerd waardoor zij nog

steeds het risico lopen om besmet te worden met HPV, en als gevolg hiervan hoofd-

hals kanker te ontwikkelen. Daarom heeft onlangs de Gezondheidsraad gepleit om

niet alleen meisjes, maar ook jongens te gaan vaccineren tegen HPV.

ConclusieIn dit proefschrift zijn de resultaten van onderzoeken beschreven bij patiënten met

hoofd-hals kanker, waarvan enerzijds het doel was bijwerkingen te verminderen en

aandacht te geven aan behoud van kwaliteit van leven en anderzijds de effectiviteit

van behandelingen te verbeteren. De in dit proefschrift nieuw verworven inzichten

dragen bij aan de wereldwijde vooruitgang die er de laatste jaren is gemaakt in de

behandeling van patiënten met hoofd-hals kanker. Er zijn echter nog veel uitdagingen

om de zorg voor deze patiënten te verbeteren. Verbeteringen betreffen idealiter zowel

een meer gepersonaliseerde zorg voor deze patiënten als ook effectievere

behandelingen met minder bijwerkingen om betere uitkomsten zowel op de korte als

langere termijn te bewerkstelligen.

127

PhD Portfolio

Research data management

List of publications

Dankwoord

Curriculum Vitae

A P P E N D I X

130

A p p e n d i x

PhD Portfolio

Name PhD candidate: J.C. HamDepartment: Medical OncologyGraduate School: Radboud Institute for Health Sciences

PhD period: 01-07-2014 till 01-09-2016 and 24-11-2017 till 01-03-2018 and 01-07-2018 till 01-01-2019.

Promotor(s): Prof. Winette van der Graaf, Prof. Carla van Herpen Co-promotor(s): -

Year(s) ECTSTRAINING ACTIVITIESa) Courses & Workshops - ICH-GCP re-registration 2018 0.5 - GCP R2 training 2018 0.5 - Scientific Integrity Course 2016 1.0 - Refresher course in statistics for PhD candidates 2016 1.0 - Academic Writing 2015 1.0 - Presentation Skills 2015 1.0 - RIHS introduction course for PhD students 2015 2.0 - BROK course (ICH-GCP examination and

registration-NFU certificate)2014 2.0

- EORTC-PHARMED-PHARMATRAIN Course in Modern Development of Oncological treatments

2014 3.0

b) Seminars & lectures^ - NA NA NAc) Symposia & congresses^ - European Society of Medical Oncology (ESMO) congress, Munchen

(poster)2018 2.0

- American Society of Clinical Oncology (ASCO) congress, Chicago (poster)

2016 3.0

- 5th Trends in Head and Neck Oncology (THNO), Lisbon (oral) 2015 2.0 - Nederlanse Werkgroep Hoofd-Hals Tumoren (NWHHT) congress,

Leiden (oral)2015 1.0

- EGFR Advisors’ Network (EAN) meeting for squamous cell carcinoma of the head and neck (SCCHN), Berlin

2015 2.0

- Nederlanse Werkgroep Hoofd-Hals Tumoren (NWHHT) congress, Groningen (oral)

2014 1.0

d) Other - Journal club Medical Oncology - Poster presentation at the American Society of Clinical Oncology

(ASCO) congress, Chicago, but poster was presented by last author.

2014-20192017

5.01.0

TEACHING ACTIVITIESe) Lecturing - NA NA NAf) Supervision of internships / other - NA NA NA

TOTAL 29.0

131

A

PhD Portfolio - Research data management

Research data management

This thesis is based on the results of human studies, which were conducted in

accordance with the principles of the Declaration of Helsinki. The medical and ethical

review board Committee on Research Involving Human Subjects Region Arnhem

Nijmegen, Nijmegen, the Netherlands has given approval to conduct these studies.

 

The patient data for the analyses of the studies as presented in chapter 2, 3, and 4 are

stored in clinical data management system “Trias” at the Integraal Kankercentrum

Nederland (IKNL). The patient data for the analyses of the studies as presented in

chapter 5 are stored in clinical data management system “OpenClinica” at our

Radboudumc Technology Center Clinical Studies. The patient data for the analyses of

the studies as presented in chapter 6 are stored on the departments’ H-drive (H:\

Afdelingsmappen\Medische oncologie - ONCO\Hoofd-hals onderzoek\PRONE studie)

in SPSS format.

The data will be saved for 15 years after termination of the study. Using these patient

data in future research is only possible after a renewed permission by the patient as

recorded in the informed consent. The datasets analyzed during these studies are

available from the corresponding author on reasonable request.

132

A p p e n d i x

List of publications

Ham JC, van Herpen CML, Driessen CML, van der Graaf WTA, Husson O. Health-related quality of life of patients treated with chemoradiotherapy plus or minus prophylactic antibiotics to reduce the number of pneumonias for locally advanced head and neck cancer, the PANTAP study. Oral Oncol 2019;96:105-112.

Ham JC, Driessen CM, Hendriks MP, Fiets E, Kreike B, Hoeben A, et al. Prophylactic antibiotics reduce hospitalisations and cost in locally advanced head and neck cancer patients treated with chemoradiotherapy: A randomised phase 2 study. Eur J Cancer 2019;113:32-40.

Driessen CM, Ham JC, Te Loo M, van Meerten E, van Lamoen M, Hakobjan MH, et al. Genetic Variants as Predictive Markers for Ototoxicity and Nephrotoxicity in Patients with Locally Advanced Head and Neck Cancer Treated with Cisplatin-Containing Chemoradiotherapy (The PRONE Study). Cancers (Basel) 2019;11(4).

Caetano-Pinto P, Jamalpoor A, Ham J, Goumenou A, Mommersteeg M, Pijnenburg D, et al. Cetuximab Prevents Methotrexate-Induced Cytotoxicity in Vitro through Epidermal Growth Factor Dependent Regulation of Renal Drug Transporters. Mol Pharm 2017;14(6):2147-2157.

Ham JC, Tops BBJ, Driessen CML, van Raaij AWM, Slootweg PJ, Melchers WJG, et al. Using a semi-conductor sequencing-based panel for genotyping of HPV-positive and HPV-negative oropharyngeal cancer: a retrospective pilot study. Clin Otolaryngol 2017;42(3):681-686.

Ham JC, Verhoef CG, van Herpen CM. Acute erythema of the face after methotrexate. Neth J Med 2016;74(1):49-50.

Brouwers MC, Ham JC, Wisse E, Misra S, Landewe S, Rosenthal M, et al. Elevated lactate levels in patients with poorly regulated type 1 diabetes and glycogenic hepatopathy: a new feature of Mauriac syndrome. Diabetes Care 2015;38(2):e11-2.

Ham JC, Bloks WAM, Drenth JPH. Gecompliceerde levercyste?! Lever. 2013; Nr 4.Ham JC, Rondeel JMM, Ladde BE, van der Steeg WA. De kunst van het kijken (Gelatineuse beenmerg-transformatie). Nederlands Tijdschrift voor Hematologie. 2013; 10: 193-4.

Ham JC, Ruijs GJ, van Marwijk Kooy MR. [A man with neutropenic fever]. Ned Tijdschr Geneeskd 2013;157(12):A5997.

133

A

List of publications

Van Dijk PR, Ham JC, Bloembergen P, Groeneveld PHP. Capnocytophaga canimorsus

bacteriëmie: niet alleen door een bijtwond. Tijdschrift voor infectieziekten, 2013; 8: 22-26.

Ham JC, Hoogendijk-van den Akker JM, Verdonck LF. A hemodialysis patient with higher-

risk myelodysplastic syndrome treated with standard-dose azacitidine. Leuk Lymphoma

2012;53(12):2521-2.

Ham JC, Janssen JJ, Boers JE, Kluin PM, Verdonck LF. Allogeneic stem-cell transplantation

for blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol 2012;30(8):e102-3.

Ham JC, Janssen JJWM, Boers JE, Kluin PhM, Verdonck LF. Blastair plasmacytoïd

dendritische celneoplasma; casuïstiek en behandeling. Nederlands tijdschrift voor

Hematologie 2010; 6: 245-248.

134

A p p e n d i x

Dankwoord

Een proefschrift maak je nooit alleen. Daarom ben ik veel mensen dank verschuldigd,

die op enige wijze hebben bijgedragen aan het tot stand komen van dit proefschrift.

In de eerste plaats uiteraard de patiënten en hun familie, die geheel belangeloos

hebben ingestemd met deelname aan de beschreven studies. Door hun deelname aan

studies zijn wij in staat om de zorg voor patiënten met hoofd-hals kanker te verbeteren.

Niet iedereen kan ik met naam bedanken die heeft bijgedragen aan dit proefschrift.

Toch wil ik enkele mensen specifiek noemen en bedanken.

Allereerst mijn promotoren.

Prof. dr. van der Graaf, beste Winette, tijdens mijn promotietraject ben je twee keer

van werklocatie veranderd, maar desondanks wist je altijd tijd te maken om praktisch

en inhoudelijk advies te geven en mee te denken over lopend onderzoek en te schrijven

artikelen. Jouw commentaar maakte het artikel altijd beter. Ik heb daar veel van geleerd.

Prof. dr. van Herpen, beste Carla, je bent altijd laagdrempelig bereikbaar om mee te

denken en advies te geven. Wat enorm veel kennis van zowel kliniek als onderzoek

heb je! Op beide gebieden heb ik dan ook enorm veel van je geleerd en doe dat nog

steeds.

De leden van de manuscriptcommissie, prof. dr. Bussink, prof. dr. Vermeulen en prof. dr. de Bree, wil ik bedanken voor het kritisch beoordelen en goedkeuren van

mijn manuscript.

Alle mede-auteurs wil ik heel hartelijk bedanken voor hun bijdragen aan de artikelen

die samen dit proefschrift vormen. De studies beschreven in dit proefschrift zijn

uitgevoerd in meerdere hoofd-hals centra in Nederland, en zonder hun bijdrage

was het nooit gelukt om deze studies te voltooien. Met name Dr. Esther van Meerten

wil ik bedanken voor de bijdrage aan de COMMENCE studie. Binnen het Radboudumc

wil ik graag Dr. Marianne Jonker bedanken. Ondanks het feit dat je vaak niet

betrokken was bij de opzet van de studies, heb je wel veel geholpen bij de statistische

analyses van zowel de PANTAP-studie als de COMMENCE-studie. Dr. Olga Husson,

zonder jouw aanstekelijke enthousiasme over kwaliteit-van-leven-onderzoek, zou het

artikel over QoL van de PANTAP-studie nooit van de grond zijn gekomen. Prof. dr. Kullberg, uw bijdrage aan het microbiologie stuk van de PANTAP-studie was

135

A

Dankwoord

onmisbaar. De datamanagers van het IKNL wil ik bedanken voor hun inzet voor de

PANTAP studie.

Alle leden van de werkgroep Hoofd Hals Oncologie van het Radboudumc, bedankt

voor de ontzettend fijne samenwerking afgelopen jaren. Dankzij de korte lijnen in de

keten en de onderlinge prettige samenwerking, wordt er topzorg geleverd aan

patiënten met hoofd-hals kanker.

Dankzij de subsidie van ZonMw was het mogelijk om de PANTAP-studie uit te voeren.

Ik wil alle medisch oncologen van de afdeling Medische Oncologie van het Radboudumc

bedanken voor hun inzet en bijdrage om mij te vormen tot de oncoloog die ik nu ben.

De fellows, met jullie heb ik tijdens mijn opleiding intensief en heel fijn samengewerkt.

Mede-promovendi, fijn dat we samen in zowel de villa interna en later in de villa

externa, menige frustratie over het doen van onderzoek konden delen. De research-verpleegkundigen en het ondersteunend personeel wil ik graag bedanken voor het

begeleiden van alle patiënten in de studies en voor het vele werk dat jullie mij uit

handen namen. Dames van het secretariaat, bedankt voor jullie ondersteuning en

opbeurende woorden.

Mijn paranimfen. Lieve Laura, we hadden al jaren samen gestudeerd, maar pas toen

we begonnen aan onze co-schappen in Zwolle werd jij één van mijn beste vriendinnetjes.

Ondanks dat we inmiddels verder bij elkaar vandaan wonen dan we zouden willen,

kunnen we nog eindeloos praten over patiëntenzorg, onze beide gezinnen en alles wat

ons dagelijks bezig houdt. Ik hoop dat nog heel lang samen vol te kunnen houden en

vind het heel fijn dat jij vandaag naast me staat! Lieve Chantal, ik mocht van jou het

lopende onderzoek bij patiënten met hoofd-hals kanker overnemen. Wat een enorme

uitdaging was dat, want jij bent zowel een goede clinicus, goede onderzoeker, als enorm

sociaal mens, waardoor het een hele uitdaging was om jou op een goede manier op te

volgen. Maar jouw enthousiasme voor patiënten met hoofd-hals kanker heeft ook zeker

mij aangestoken. Hoewel helaas straks niet meer in hetzelfde ziekenhuis, hoop ik dat

we nog vaak samen mogen sparren! Dank je wel dat je vandaag naast me wil staan!

Lieve vrienden en vriendinnen, veel te bang om iemand te vergeten, noem ik jullie

niet allemaal bij naam. Afgelopen jaren heb ik jullie minder gezien dan ik wilde, maar

dit heeft uiteindelijk wel geresulteerd in dit boekje en het afronden van mijn

136

A p p e n d i x

specialisatie. Desondanks waren jullie altijd geïnteresseerd in waar ik precies mee bezig

was. Dank jullie wel daarvoor! Hopelijk kan ik vanaf nu weer wat makkelijker borrelen,

uit eten, thee drinken en naar feestjes komen, ik kijk er naar uit!

Beste Leni, Wim, Rianne, René, Annelies, Ferdinand, Wim en natuurlijk Jill, Siebe, Jette en Cato, heel fijn om jullie als schoonfamilie te hebben!

Lieve opa en oma van Velzen, ondanks dat jullie er beiden helaas niet meer zijn, zijn

jullie nog steeds mijn grote voorbeeld. Als ik ook maar 1% van jullie doorzettingsvermogen

heb geërfd, maakt me dat ontzettend trots.

Lieve Marieke, Anita, Thijs, Pieter, Bram en Daniel, van drie kleine zusjes door de

jaren heen uitgegroeid tot drie hardwerkende, ambitieuze vrouwen met allemaal een

prachtig gezin. Daardoor zien en spreken we elkaar minder dan we zouden willen,

maar weten dat we altijd op elkaar kunnen bouwen, vertrouwen en voor elkaar klaar

staan. Weet dat ik dat enorm waardeer, dank jullie wel!

Lieve papa en mama, er zijn geen woorden die jullie onvoorwaardelijke steun,

vertrouwen en liefde goed beschrijven. Jullie zijn er altijd voor mij en ons. Heel veel

dank voor alles wat jullie gedaan hebben.

Lieve Jasper, door jou is alles relatief. Hard werken is opeens nog minder leuk. Maar

wat geef jij mij veel liefde, plezier, relativiteit en positiviteit. Ik vind het geweldig om je

groot te zien worden, en hoop dat je samen met je broertje geweldige avonturen

tegemoet gaat.

Liefste Niek, uiteraard zijn de laatste woorden voor jou. Je bent altijd geïnteresseerd

in wat ik doe, vangt alles thuis op als ik weer eens iets voor werk of promotie moet

doen, stimuleert me om verder te gaan, maar zet me tegelijkertijd ook met beide benen

op de grond. Ik hou van jou!

137

A

138

A p p e n d i x

Curriculum Vitae

Janneke Ham werd op 02 september 1983 geboren te Gouda. Ze behaalde haar

gymnasium diploma in 2001 aan het Christelijk gymnasium te Utrecht. Omdat ze twee

keer uitgeloot werd voor Geneeskunde, startte ze met de studie Bewegings-

wetenschappen aan de RijksUniversiteit te Groningen. Na twee jaar kon zij in 2003,

eveneens aan de RijksUniversiteit Groningen, starten met de studie Geneeskunde,

waarbij ze de laatste twee jaar van Bewegingswetenschappen combineerde met de

eerste drie jaar van Geneeskunde. In 2006 behaalde ze haar doctoraal diploma

Bewegingswetenschappen en in 2009 haar Master diploma Geneeskunde. Na haar

artsenexamen werkte ze 11 maanden als arts-assistent op de afdeling Interne

Geneeskunde van de Isala Klinieken in Zwolle onder de supervisie van Dr. M.A. Alleman.

In 2010 werd zij aangenomen voor de opleiding Interne Geneeskunde in het Universitair

Medisch Centrum Groningen door Prof. R.O.B. Gans, waarbij ze de eerste drie jaar

perifeer bleef werken in de Isala Klinieken te Zwolle met als opleider Dr. P.H.P.

Groeneveld. In 2013 vervolgde zij haar opleiding in het Radboudumc te Nijmegen met

als opleiders Interne Geneeskunde Prof. dr. J. de Graaf en Prof. dr. J.A.W. Smit en de

laatste maanden Dr. G.M.M Vervoort. In 2014 startte zij met de differentiatie Medische

Oncologie met als opleiders Prof. dr. W.T.A. van der Graaf, en later Prof. dr. J.J.M. van

der Hoeven en Dr. I.M.E. Desar. In 2014 startte zij ook met haar promotietraject

“Improving personalised care in head and neck cancer patients” onder leiding van Prof.

dr. W.T.A. van der Graaf en Prof. dr. C.M.L. van Herpen. In de periode tussen 2014 en

2019 wisselde zij haar opleiding tot internist-oncoloog en het promotietraject af. In

2019 heeft zij haar opleiding tot internist-oncoloog afgerond. Momenteel werkt zij als

junior staflid op de afdeling Medische Oncologie van het Radboudumc.

Janneke is getrouwd met Niek de Groot, samen hebben ze een zoon Jasper (2017) en

verwachten ze in 2019 hun tweede kindje.

IMPROVING PERSONALISED CARE IN HEAD AND NECK CANCER PATIENTS Janneke Ham

IMPROVING PERSONALISEDCARE IN HEAD AND NECKCANCER PATIENTS

Janneke Ham

UITNODIGINGvoor het bijwonen vande openbare verdedigingvan het proefschrift

IMPROVING PERSONALISEDCARE IN HEAD AND NECK CANCER PATIENTS

op dinsdag 5 november 2019om 16.30 uur preciesin de Aula van de Radboud Universiteit, Comeniuslaan 2,Nijmegen.

Janneke HamJanneke_ham@hotmail.com

PARANIMFENChantal DriessenChantal.driessen@radboudumc.nlLaura Derksen - van Nunspeetlderksen2014@outlook.com