An International Phase 3 Trial in Head and Neck Cancer: Quality of Life and Symptom Results

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1 An International Phase 3 Trial in Head and Neck Cancer: Quality of Life and Symptom Results EORTC on Behalf of the EORTC Head and Neck and the EORTC Radiation Oncology Group Andrew Bottomley, PhD 1 ; Gloria Tridello, PhD 1,2 ; Corneel Coens, MSc 1 ; Frederic Rolland, MD 3 ; Margot E.T. Tesselaar, MD, PhD 4 ; C. Rene Leemans, MD, PhD 5 ; Pierre Hupperets, MD, PhD 6 ; Lisa Licitra, MD 7 ; Jan B. Vermorken, MD, PhD 8 ; Danielle Van Den Weyngaert, MD, PhD 9 ; Gilles Truc, MD 10 ; Isabelle Barillot, MD 10 ; and Jean-Louis Lefebvre, MD, PhD 11 BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) phase 3 randomized clinical trial compared 2 schemes of combined chemotherapy for patients with resectable cancers of the hypopharynx and larynx: sequential induction chemotherapy and radiotherapy versus alternating chemoradiotherapy. The current study reports detailed effects of both treatment arms on health-related quality of life (HRQOL) and symptoms. METHODS: A total of 450 patients aged 35 years to 76 years (World Health Organization performance status (WHO PS) 2) with untreated, resectable advanced squamous cell carcinoma of the larynx (tumor classification of T3-T4) or hypopharynx (tumor classification of T2-T3-T4) with regional lymph nodes in the neck classified as N0 to N2 with no metastases were randomized in this prospective phase 3 trial into either the sequential arm (control) or the alternating arm (experimental). QOL assessment was performed at randomization; at baseline; at 42 days; and at 6, 12, 24, 36, and 48 months. RESULTS: There were no observed differences with regard to the primary endpoint of Fatigue and secondary endpoint of Dyspnea. Significant differences were found in the secondary endpoints of Swallowing and Speech problems at 42 days after randomization in favor of patients in the sequential arm. Explanatory and sensitivity analysis revealed that the primary analysis favored the sequential arm, but the majority of differences in HRQOL did not exist at the end of treatment, and returned to baseline levels. CONCLUSIONS: In the current study, a trend toward worse scores was noted in the patients treated on the alternating chemoradiotherapy arm but very few differences reached the level of statistical significance. The HRQOL scores of the majority of patients returned to baseline after therapy. Cancer 2014;120: VC 2013 American Cancer Society. KEYWORDS: hypopharynx cancer, larynx cancer, chemotherapy, radiotherapy, alternating chemoradiotherapy, health-related quality of life, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). INTRODUCTION According to the American Cancer Society, 1 the number of estimated new cases of throat cancer diagnosed in the United States in 2010 was 12,720 cases of laryngeal cancer and 12,660 cases of pharyngeal cancer, and the number of deaths was approximately 3600 from laryngeal cancer and 2410 from pharyngeal cancer. These numbers are falling by approximately 2% to 3% each year, mainly because fewer people are smoking. Nevertheless, patients with such cancers can have major impairment in their health-related quality of life (HRQOL). Cancers of the hypopharynx and larynx affect HRQOL in a negative manner and can induce symptoms that may interfere with daily life. Both disease and treatment can affect important functions such as eating, swallowing, and speaking as well as physical appearance. 2,3 The measurement of HRQOL and symptoms among patients with head and neck cancer may help in making decisions regarding treatment, identifying patients with major physical and/or Corresponding author: Andrew Bottomley, PhD, Quality of Life Department, European Organization for Research and Treatment of Cancer, 83/11 Ave E, Mounier, 1200 Brussels, Belgium; Fax: (011) ; andrew.bottomley@eortc.be 1 Quality of Life Department, European Organization for Research and Treatment of Cancer, Brussels, Belgium; 2 Pediatric Hematology Oncology Department, University Hospital of Verona, Verona, Italy; 3 Medical Oncology Department, Centre R. Gauducheau, Saint-Herblain, France; 4 Division of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands; 5 Otolaryngology - Head and Neck Surgery Department, Vrije Universiteit University Medical Center, Amsterdam, the Netherlands; 6 Oncology and Radiotherapy Department, Radiotherapy Institute Limburg, University Hospital of Maastricht, Maastricht, The Netherlands; 7 Medical Oncology, Fondazione IRCCS, National Tumor Institute, Milan, Italy; 8 Medical Oncology Department, Antwerp University Hospital, Antwerp, Belgium; 9 Radiotherapy Department, Middelheim University Hospital, Middelheim, Antwerp, Belgium; 10 Radiotherapy Department, Centre G.F. Leclerc, Dijon, France; 11 Head and Neck surgery Department, Oscar Lambret Center, Lille, France. We thank all the patients and their families who agreed to be involved in this clinical trial. We are very grateful to the staff and researchers who helped collect data or commented on the draft of our article, specifically Dr. Bjordal for assistance in writing the protocol quality of life (QOL) section along with the QOL Department, Ms. Melodie Cherton and Ms. Cheryl Whittaker of the European Organization for Research and Treatment of Cancer QOL Department for proofreading, and Mr. Efstathios Zikos for his support in writing parts of an early draft of this report. DOI: /cncr.28392, Received: May 8, 2013; Revised: June 28, 2013; Accepted: July 1, 2013, Published online October 25, 2013 in Wiley Online Library (wileyonlinelibrary.com) 390 Cancer February 1, 2014

2 Quality of Life in Head and Neck Cancer/Bottomley et al psychological or psychosocial morbidity, and even help make rehabilitation planning possible. Therefore, they are critical to providing a complete picture of treatments with new therapies from clinical trials. However, although the majority of clinical trials focus on clinical endpoints of survival or disease-free survival, not all undertake a detailed evaluation of HRQOL. Indeed, there has been a lack of randomized controlled trials (RCTs) in the literature regarding head and neck cancer, and it is critical that this be addressed. QOL is an important endpoint because patients often may have the above-mentioned debilitating problems with swallowing, speech, and hearing, as well as the psychological effects of loss of function and change in body image. Therefore, any study that sheds further light on the HRQOL of patients can only be of value for patients and clinicians. Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported to be valuable alternatives to total laryngectomy in patients with advanced cancer of the larynx or hypopharynx, but to the best of our knowledge little is known about the impact on HRQOL. Therefore, in the current study, we report the analysis of HRQOL and symptoms when patients with resectable tumors of the hypopharynx and larynx undergo either sequential induction of chemotherapy and radiotherapy or alternating chemoradiotherapy. MATERIALS AND METHODS Study Design The European Organization for Research and Treatment of Cancer (EORTC) study was an international, multicenter, phase 3 RCT. Patients with untreated, resectable, advanced squamous cell carcinoma of the larynx (tumor classification T3-T4) or hypopharynx (T2-T3- T4) with regional lymph nodes in the neck classified as N0 to N2 with no metastases were randomized in this prospective phase 3 trial to receive either sequential chemotherapy and radiotherapy or alternating chemoradiotherapy. Patients were stratified for site of the primary cancer, stage of disease (TNM), and performance status (WHO PS). The details of trial conduct and clinical outcome were previously reported. 4 The protocol was reviewed by the EORTC protocol review committee and approved by the ethics committee at each institution. All patients provided written informed consent and the study was conducted in accordance with the Declaration of Helsinki. Two HRQOL measures were selected for the trial: the EORTC Quality of Life Questionnaire C30 (EORTC QLQ-C30, version 3) 5 and the EORTC Quality of Life Head and Neck cancer-specific questionnaire (QLQ- H&N35). 6 Both tools have robust psychometric properties resulting from rigorous testing and development and external validity and, in the case of the core tool, from its use in hundreds of international cancer RCTs. 7 The EORTC QLQ-C30 is a core measure designed to be supplemented with disease-specific questionnaires. Although this core measure standard is used in most EORTC studies, it lacks some key HRQOL dimensions related to the HRQOL and symptoms patients with head and neck cancer can experience. Therefore, the core tool was supplemented with the EORTC head and neck module. This module has undergone a 3-phase validation 8 and is now fully validated and extensively used in head and neck cancer research, having being cited > 136 times and is classified as one of the most widely used tool in trials of patients with head and neck cancer. 9 Both instruments were available in the languages of all participating countries. 10 The EORTC QLQ-C30 measure comprises 5 functioning scales (Physical, Role, Emotional, Cognitive, and Social), 3 symptom scales (Fatigue, Nausea/ Vomiting, and Pain), 6 single-item scales (Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, and Financial Impact), and the overall HRQOL scale. The EORTC QLQ-H&N35 is designed for use with patients undergoing surgery, chemotherapy, or radiotherapy, and is composed of 18 scales assessing the symptoms and side effects of treatment (eg, Trouble With Eating), social function (eg, trouble having social contact with friends), and body image/sexuality (eg, less interest in sex). The HRQOL Fatigue scale was selected as the primary HRQOL endpoint and 3 HRQOL scales (Swallowing, Breathing, and Speech Problems) were selected as secondary HRQOL endpoints. Assessment was performed as stated in the protocol at randomization; at baseline; at 42 days; and at 6, 12, 24, 36, and 48 months. The questions on both HRQOL measures were scaled and scored using the recommended EORTC Quality of Life Group procedures. 11 Raw scores were transformed to a linear scale ranging from 0 to 100, with a higher score representing a higher level of functioning or higher level of symptoms. Provided at least one-half of the items in the scale were completed, the scale score was calculated using only those items for which values existed. The primary HRQOL analysis was performed on a priori selected HRQOL scores: Fatigue, Swallowing, Dyspnea, and Speech Problems. No directionality was established Cancer February 1,

3 for each scale given the limited experience we had in this area when planning this trial. The results of the current study are presented in accordance with recent guidelines for reporting HRQOL RCTs. 12 Critically, to interpret clinical significance (a key issue in HRQOL RCTs), differences of at least 10 points (on a scale of 0-100) were classified as the minimum clinically meaningful change in the mean value of a HRQOL parameter. 13 For example, a mean increase of 10 points on a functional scale would indicate a moderate improvement, whereas a mean decrease of 10 points would be interpreted as moderate worsening. Likewise, an increase in a symptom score indicates deterioration whereas a reduced score means improvement of the specific symptom. Mean changes of < 10 effect points were considered as no change or to be clinically smaller. Mean changes of >-20 points were classed as large effects. All patients were informed that their HRQOL would be assessed regularly. They completed the EORTC QLQ-C30 (version 3) and QLQ-H&N35 questionnaires at randomization; at baseline; at 42 days; and at 6, 12, 24, 36, and 48 months. The questionnaires were handed out to the patients by the investigator or a study nurse before clinical evaluation. Statistical Analysis Compliance levels were calculated following a standard EORTC procedure (number of forms received divided by the number expected) at each assessment point. According to the protocol, the time windows for acceptable HRQOL forms were defined as follows: baseline HRQOL assessments had to be completed 2 weeks before randomization; thereafter, adjacent time windows were used to gather the maximum information available ( 3 days before the 42-day boundary after randomization; 2 weeks before and after the assessment at 6 months; and 1 month before and 1 month after for the assessment at 12, 24, 36, and 48 months). A linear mixed model was fitted to compare HRQOL between the 2 treatment groups at each time point up to 2 years after randomization. The variables entered in the model were interaction between treatment and number of assessments, site of the primary tumor (hypopharynx, epilarynx, or endolarynx), N category (0-1 vs 2-3), T category (2 vs 3 vs 4), and performance status at baseline (2 or 1 vs 0). Because of the low number of patients with a performance status of 2, patients with performance statuses of 2 and 1 were pooled into 1 category. HRQOL scales were analyzed on an exploratory basis and the level of statistical significance was set at P The difference in mean scores that was considered to be clinically relevant was a 10-point difference. All data analyses were performed using SAS statistical software (version 9; SAS Inc, Cary, NC). RESULTS A total of 450 patients were recruited from 19 institutions in 6 countries and were randomly assigned in this trial (224 patients were assigned to the sequential arm and 226 were assigned to the alternating arm). Patient ages ranged from 35 years to 76 years, with a median age of 55 years in both treatment arms. The main clinical endpoint of the study was survival with a functional larynx between the 2 treatment groups and HRQOL was the secondary endpoint. In brief, the clinical results demonstrated that the median follow-up was 6.5 years. Survival with a functional larynx was found to be similar between the sequential and alternating treatment arms (hazards ratio of death and/or event, 0.85; 95% confidence interval [95% CI], ), as were median overall survival (4.4 years and 5.1 years, respectively) and median progression-free survival (3.0 years and 3.1 years, respectively). 4 HRQOL: Compliance and Baseline Scores Compliance for all 450 patients was found to be too restrictive and new time windows were defined; only time points at baseline; 42 days; and 6, 12, and 24 months were considered and centers with high compliance were therefore selected. The selected centers were found to have treated more patients with advanced stages of disease and more patients with the epilarynx as their primary tumor site (P <.05), but no differences in other patient characteristic stratification factors or overall survival were noted. Among the selected centers, 24 patients did not complete any HRQOL forms and consequently only 270 patients were eligible for analysis. The resulting compliance was 62.2% at baseline, 55.5% at 42 days, 57% at 6 months, 63.3% at 1 year, and 54.7% at 2 years (Table 1). A significant difference in baseline compliance was detected between the 2 randomized treatment arms (P 5.01), demonstrating better compliance in the sequential arm. In addition, the lowest scale rates in item compliance (individual questions on a returned form could be left blank) was found for the Less Sexuality scale on the H&N35, with 17% of the head and neck questionnaires insufficiently completed. A logistic regression model was performed to detect clinical factors related to compliance. Men and patients with cancer of the epilarynx demonstrated lower 392 Cancer February 1, 2014

4 Quality of Life in Head and Neck Cancer/Bottomley et al TABLE 1. HRQOL: Compliance and Baseline Scores a Forms Received Forms Expected % Compliance According to Protocol Baseline At 42 d At 6 mo At 1 y At 2 y At 3 y At 4 y According to analysis plan Baseline Sequential Alternating At 42 d Sequential Alternating At 6 mo Sequential Alternating At 1 y Sequential Alternating At 2 y Sequential Alternating Abbreviations: HRQOL, health-related quality of life. a Compliance was low (<50% for all time points). Extending time windows included forms that fell outside the time windows and improved compliance. Compliance percentages before and after extended time windows are shown. compliance, whereas higher compliance was found for the increasing number of expected assessments. HRQOL Scales and Sensitivity Analyses The primary HRQOL analysis was conducted on a priori selected HRQOL scores: Fatigue, Swallowing, Dyspnea, and Speech Problems. No statistically significant differences were observed in the primary endpoint of Fatigue at any time point or considering the overall randomization, whereas the secondary scales revealed a trend in favor of the sequential arm. Considering the secondary scales of Swallowing and Speech Problems, a statistically significant and clinically meaningful difference was found in mean scores for Swallowing (P <.001; ) and Speech Problems (P <.001; ) at 42 days, whereas no statistically significant differences were detected for the scores in Dyspnea at any time point (Table 2) (Figs. 1 and 2). The above scores indicate that participants in the alternating arm experienced more issues with Swallowing and Speech than those in the sequential arm. Further analysis using a Cochran-Mantel-;Haenszel test calculated the percentage of patients who experienced a clinically relevant worsening in the post-baseline time points for both treatments. It was found that there was a TABLE 2. HRQOL: Compliance Assessment Time Alternating Sequential Treatment Difference P Fatigue Estimate SE Estimate SE At baseline At 42 d At 6 mo At 12 mo At 24 mo Overall post-baseline.6126 Dyspnea At baseline At 42 d At 6 mo At 12 mo At 24 mo Overall post-baseline.4802 Swallowing At baseline a At 42 d <.0001 At 6 mo At 12 mo At 24 mo Overall post-baseline.0206 Speech Problems At baseline At 42 d a At 6 mo At 12 mo At 24 mo Overall post-baseline.1342 Abbreviation: SE, standard error. a Bold type indicates statistical significance. higher risk of problems with Fatigue and Speech in the alternating arm because the patients assigned to that arm demonstrated clinically worse score levels. However, score levels for the most part differed only in the first time point after randomization, but had a tendency to improve in the following time points, because the treatment difference disappeared at the later assessments. Furthermore, input scores were analyzed as a sensitivity analysis based on the clinically relevant worsening ( 10) confirming the results of the primary analysis. In addition, a model based on post-baseline assessments including baseline compliance as a covariate was performed and gave results similar to the main analysis. Other HRQOL Scales All remaining HRQOL scores were analyzed on an exploratory basis. A statistically significant difference (P <.05), considering the overall post-baseline score level in the 2 treatments, was found for Nausea/Vomiting (16.1; 95% CI, ), Pain (22.8; 95% CI, ), Dry Mouth (63.5; 95% CI, ), Trouble with Social Eating (30.9; 95% CI, ), and Sticky Saliva (61.6; 95% CI, ) (Fig. 3). The overall Cancer February 1,

5 Figure 1. Fatigue and dyspnea scores are shown over time by treatment arm. C30 indicates European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30; 95% CI, 95% confidence interval. Figure 2. Swallowing and speech scores are shown over time by treatment arm. HN35 indicates European Organization for Research and Treatment of Cancer Quality of Life Head and Neck cancer-specific questionnaire; 95% CI, 95% confidence interval significant difference was due to large score differences during the 42-day time point. For all these scales, patients in the alternating treatment arm demonstrated the worst findings, thereby supporting the results of the primary analysis. DISCUSSION This randomized, phase 3 clinical trial had the primary aim of investigating survival and the secondary endpoint of examining HRQOL differences between sequential induction chemotherapy and radiotherapy versus alternating chemoradiotherapy in the treatment of patients with resectable cancers of the hypopharynx and larynx. The clinical results demonstrated no significant differences between treatment arms in terms of overall survival or progression-free survival, 4 but some insights were gained in terms of HRQOL. Baseline HRQOL scores were found to be similar in both treatment arms, which is comparable to the reference values in patients with head and neck cancer (Table 3). 14 However, some differences were observed between the treatment scores and reference data in the scales of Sense Problems, Dry Mouth, Sticky Saliva, Nutritional Supplement, Feeding Tube, and Weight Loss. The difference between treatment mean scores and references scores was clinically significant (> 10) and favored the sequential and alternating arms. Small differences that did not reach the minimally significant differences score (> 10) were observed for the scales of Social Eating and Opening of the Mouth. The difference observed between the reference 394 Cancer February 1, 2014

6 Quality of Life in Head and Neck Cancer/Bottomley et al Figure 3. Score over time is shown per treatment arm for selected scales: Nausea/Vomiting, Pain, Dry Mouth, Trouble with Social Eating, and Sticky Saliva. C30 indicates European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30; 95% CI, 95% confidence interval; HN35, European Organization for Research and Treatment of Cancer Quality of Life Head and Neck cancer-specific questionnaire. Cancer February 1,

7 TABLE 3. Baseline QOL Scores and Reference Data 13 Reference Data: Head and Neck Cancer Stage III-IV (N51722), Mean (SD) EORTC Alternating Arm (N5152), Mean (SD) EORTC Sequential Arm (N5142), Mean (SD) Reference Data: Head and Neck Cancer at All Stages (N52929), Mean (SD) QLQ-C30 Global QoL 63.1 (22.4) 72.1 (28.4) 69.2 (26.2) 64.1 (22.7) Physical Functioning 81.2 (20.2) 84.3 (29.6) 88.8 (27.4) 81.2 (20.4) Role Functioning 78.8 (27.9) 84.2 (35.8) 82.4 (32.2) 78.9 (28.1) Emotional Functioning 71.2 (24.1) 68.8 (33.3) 66.0 (29.8) 72.5 (24.1) Cognitive Functioning 86.4 (19.1) 85.7 (27.1) 89.4 (25.0) 85.9 (19.7) Social Functioning 82.2 (24.7) 86.2 (34.5) 83.9 (31.0) 82.6 (24.7) Fatigue 27.6 (25) 22.9 (33.3) 19.6 (29.8) 26.9 (24.9) Nausea and Vomiting 5.2 (13.3) 4.1 (2.1) 4.7 (23.8) 5.3 (13.7) Pain 24.9 (26.3) 19.8 (34.5) 20.9 (32.2) 23.2 (26.1) Dyspnea 18.0 (26.6) 18.8 (34.5) 20.2 (31.0) 18.2 (26.9) Insomnia 28.5 (32.4) 29.8 (40.7) 28.7 (36.9) 27.3 (31.8) Appetite Loss 19.4 (29.3) 13.6 (40.7) 14.2 (36.9) 17.7 (28.2) Constipation 11.7 (23.2) 8.1 (30.8) 11.8 (28.6) 11.1 (22.6) Diarrhea 6.1 (16.7) 5.3 (23.4) 7.0 (21.4) 6.1 (16.9) Financial Difficulties 18.8 (30.2) 15.0 (38.2) 13.6 (34.6) 18.2 (29.6) H&N35 Pain 29.9 (25.1) 23.8 (30.8) 21.5 (27.4) 27.1 (24) Swallowing 27.5 (26.1) 23.3 (33.3) 24.4 (29.8) 23.9 (25.3) Senses 20.0 (30.0) 8.8 (29.6) 8.5 (27.4) 19.3 (28.8) Speech 27.1 (27.2) 29.3 (37.0) 34.4 (32.2) 28.0 (27.6) Social Eating 23.9 (26.7) 12.8 (32.1) 14.5 (28.6) 20.9 (25.1) Social Contact 13.2 (19.1) 8.5 (21.0) 8.5 (19.0) 13.0 (18.9) Sexuality 32.3 (36.1) 22.9 (53.1) 22.7 (47.7) 31.3 (35.2) Teeth 27.8 (35.0) 22.9 (43.2) 10.0 (38.1) 25.5 (33.2) Opening mouth 22.4 (31.9) 6.3 (30.8) 11.6 (27.4) 19.5 (29.5) Dry mouth 31.1 (34.2) 15.1 (37.0) 14.4 (33.4) 30.7 (33.4) Sticky Saliva 32.4 (35.4) 18.6 (39.4) 18.8 (35.7) 30.5 (33.9) Coughed 34.9 (32.1) 38.8 (40.7) 37.7 (35.7) 33.9 (32.2) Felt ill 21.7 (29.2) 11.4 (34.5) 13.8 (31.0) 21.6 (28.9) Painkillers 52.8 (49.9) 46.1 (72.7) 49.3 (65.5) 49.5 (50) Nutritional supplementation 27.0 (44.4) 7.5 (54.2) 7.8 (47.7) 26.7 (44.2) Feeding tube 18.3 (38.7) 2.2 (27.1) 3.2 (23.8) 19.7 (39.8) Weight loss 41.3 (49.2) 22.0 (61.7) 17.5 (54.8) 38.9 (48.8) Weight gain 25.9 (43.8) 29.8 (67.8) 29.4 (59.6) 27.3 (44.6) Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; QLQ C30, Quality of Life Questionnaire C30; H&N35, European Organization for Research and Treatment of Cancer Quality of Life Head and Neck cancer-specific questionnaire; QOL, quality of life; SD, standard deviation. Bold type indicates clinically relevant difference between trial data and reference data (>10pts). and current data could be attributed to the large differences in sample size between the 2 groups. In contrast to the initial experimental assumption, the results of the current study revealed that patients treated with alternating chemoradiotherapy experienced worse HRQOL than patients receiving sequential chemotherapy. Patients receiving alternating chemoradiotherapy demonstrated worse score levels, but very few differences were found to be clinically or statistically significant. The difference observed between the 2 treatments was evident for the most part at the 42-day time point. Patients in the sequential arm demonstrated statistically and clinically significantly better scores 42 days after randomization in the scales of Swallowing and Speech Problems, in contrast to the alternating arm scores. Nevertheless, the treatment difference observed in the first time point disappeared completely during the following assessments. This is in accordance with previous results reported from other clinical trials, 15 in which the negative treatment effect in patients QOL disappeared at the end of the treatment. However, there is a limitation herein in the time comparison, in particular at the 42-day time point, in that at 42 days in the sequential arm, the patient had received only 2 cycles of chemotherapy (including weeks of a no treatment window at weeks 2-3 and 5-6), but patients in the alternating arm had received 2 cycles of chemotherapy and 40 grays of radiotherapy (with a continuous treatment protocol). The side effects and their subsequent impact on patients HRQOL are therefore different and so comparison at this time point is not ideal. 396 Cancer February 1, 2014

8 Quality of Life in Head and Neck Cancer/Bottomley et al It is important to note that these results are based on a selected number of centers with the best compliance. Consequently, this can have an impact on the generalizability of the results. The compliance according to the protocol design was low at all time points (< 50%) (Table 1), partly due to the finding that the time windows were too strict and had to be extended. Compliance clearly increased after the extension of the time windows but still was too low and therefore only 9 centers with high compliance (> 45%) were selected for the current analysis. Due to attrition, the data available at later time points were too sparse to draw meaningful conclusions, and only permitted significant analysis up to 24 months. Similar constraints have been observed in another published RCT of patients with head and neck cancer 15 in which, despite high baseline compliance (97%), the researchers were forced to limit data analysis to 6 months of follow-up only. The compliance problems stem partly from the design of the study itself. The narrow time windows, intensive collection schedule, and limited correlation between the clinical and HRQOL assessment schedules were part of the original design, which, being a long-term study, dates from The assumptions were too optimistic and the expectations perhaps too high, possibly due to the limited level of experience with HRQOL data collection in this setting in the mid-1990s. Significant differences in compliance were found at baseline. Because the baseline assessment was gathered before randomization, no plausible explanation for this difference could be found except pure random chance. Sensitivity analyses specifically correcting for baseline differences did not reveal this to have an impact on the results of the current study. Despite these limitations, all significant differences found between the 2 treatment arms disappeared at the end of treatment and returned to the pretreatment levels, a result that is supported by the extensive sensitivity analyses, addressing the issues of missing data and baseline differences. This point is important and also supported in part by other literature regarding longer-term survival in patients with head and neck cancer, 16,17 in whom initial treatment can have short-term negative effects on HRQOL but HRQOL can later return to pretreatment levels. The current study had several major strengths. To the best of our knowledge, it is one of the first RCTs to examine this population in such detail with HRQOL tools. The trial was randomized, used robust HRQOL head and neck-specific measures, was independently recommended, and was translated rigorously 18 in a largescale international randomized clinical trial. We used a rigorous analysis technique for the analysis and detailed exploration of missing data, and standardized reporting of the study findings to ensure consistency of reporting. 19 However, despite these strengths, it is clear that neither the clinical results nor the HRQOL findings have provided an answer to the question of what is the optimal approach for larynx preservation, and this is something that needs further investigation by other international groups. Nevertheless, we hope our trial has shed some light on the treatment that patients with head and neck cancer face and the possible impact such patients may experience during the acute as well as the longer-term stages of this cancer diagnosis and treatment. It could also be argued that the current study could be viewed as a trial that can help to inform and empower patients. For example, patients can now know that they now have a choice as to which therapy they undergo, either alternating or sequential, because neither clinical data nor QOL data have demonstrated any major long-term advantage for one form of treatment over the other. Therefore, patient choice, which is often lacking in this population, is something of a key outcome and of importance given these results. FUNDING SUPPORT The cancer trial registry number for this trial is NCT This publication was supported by grants 2U10 CA through 5U10 CA from the National Cancer Institute. This research project was supported by the Fonds Cancer (FOCA) (Belgium). CONFLICT OF INTEREST DISCLOSURES Dr. Tesselaar is a member of the advisory board of the Dutch Neuro Endocrine Cancer patient network. Dr. Licitra has received funds from her institution for clinical studies and research activities in which she is involved from EISAI, Exelixis, Lilly, Merck Serono, Amgen, Boehringer Ingelheim, and Pfizer. She has acted in a consultant/advisory role for BMS, GlaxoSmithKline, Lilly, Merck Serono, Amgen, Boehringer Ingelheim, Debiopharm, VentiRX, EISAI, and Pfizer. She also received travel coverage for medical meetings from Merck Serono and Debiopharm. Dr. Lefebvre is a member of the boards of and has acted as a member of the Speakers Bureaus for Merck Serono and Sanofi-Aventis. REFERENCES 1. American Cancer Society. Cancer Facts and Figures Atlanta, GA: American Cancer Society; Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet. 2008;371: Pauloski BR, Logemann JA, Rademaker AW, et al. Speech and swallowing function after oral and oropharyngeal resections: 1-year follow-up. 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