Department of Neurology and Brain Tumor Center Amsterdam ZH 2F.27
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Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033); a randomised, open-label, phase 3 intergroup study.
Corresponding author:
J.C. Reijneveld, M.D. Department of Neurology and Brain Tumor Center Amsterdam – ZH 2F.27 VU University Medical Center PO Box 7057 1007 MB Amsterdam The Netherlands Tel: 31-20-4442834 Fax: 31-20-4442800 E-mail: [email protected]
1 Authors
Jaap C Reijneveld, MD, Prof Martin JB Taphoorn, MD, Corneel Coens, MSc, Jacoline EC Bromberg, MD, Warren P Mason, MD, Prof Khê Hoang-Xuan, MD, Gail Ryan,FRANZCR, Mohamed Ben Hassel, MD, Roelien H Enting, MD, Alba A Brandes, MD, Antje Wick, MD, Prof Olivier Chinot, MD, Michele Reni, MD, Prof Guy Kantor, MD, Brian Thiessen, MD, Prof Martin Klein, PhD, Eugenie Verger, MD, Christian Borchers, MD, Prof Peter Hau ,MD, Prof Michael Back, MBBS, Prof Anja Smits, MD, Vassilis Golfinopoulos, MD, Thierry Gorlia, PhD, Andrew Bottomley, PhD, Prof Roger Stupp, MD, Brigitta G Baumert, MD.
Jaap C Reijneveld,MD 1, Prof Martin JB Taphoorn,MD 2, Corneel Coens,MSc 3, Jacoline EC Bromberg, MD 4, Warren P Mason, MD 5, Prof Khê Hoang-Xuan, MD 6, Gail Ryan,FRANZCR 7, Mohamed Ben Hassel, MD 8, Roelien H Enting, MD 9, Alba A Brandes, MD 10, Antje Wick, MD 11, Prof Olivier Chinot, MD 12, Michele Reni, MD 13, Prof Guy Kantor, MD 14, Brian Thiessen, MD 15, Prof Martin Klein,PhD 16, Eugenie Verger, MD 17, Christian Borchers, MD 18, Prof Peter Hau ,MD 19, Prof Michael Back, MBBS 20, Prof Anja Smits, MD 21, Vassilis Golfinopoulos, MD 22, Thierry Gorlia, PhD 23, Andrew Bottomley, PhD 3, Prof Roger Stupp, MD 24, Brigitta G Baumert, MD 25.
1 Dept. of Neurology & Brain Tumor Center Amsterdam, VU University Medical Center and Academic Medical Center, Amsterdam, The Netherlands 2 Dept. of Neurology, Medical Center Haaglanden and Leiden University Medical Center, the Hague, The Netherlands 3 Dept. of Quality of Life, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium 4 Dept. of Neuro-oncology, Erasmus MC University MC Cancer Center, Rotterdam, The Netherlands 5 Princess Margaret Hospital, University of Toronto, Toronto, Canada 6 APHP, Dept. of Neurology, Pitie-Salpetriere Hospital, UPMC, Sorbonne Universités, IHU, Paris, France 7 Dept. of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 8 Depts of Medical Oncology and Radiotherapy, Centre Eugène Marquis, Rennes, France 9 Dept. Neurology, University of Groningen, University Medical Center, Groningen, Netherlands 10 Dept. of Medical Oncology, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy 11 Neurology Clinic, University of Heidelberg Medical Center and NCT Neurooncology within DKTK of the German Cancer Research Center (DKFZ), Heidelberg, Germany 12 Aix Marseille Universite, APHM, Hopital de La Timone, Department of Neuro- Oncology, 13005, Marseille, France 13 IRCCS San Raffaele Scientific Institute, Milano, Italy 14 Dept. of Radiotherapy (Institut Bergonié, Comprehensive Cancer Center, Bordeaux) and University Bordeaux Segalen, France
2 15 BC Cancer Agency, Vancouver, Canada 16 Dept. of Medical Psychology & Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands 17 Dept. of Radiation-Oncology, Hospital Clinic Universitari, Barcelona, Spain 18 Dept of Neurology, University Hospital Tübingen,Germany / Center of Neuromedicine, North-West-Hospital Sanderbusch, Sande, Germany 19 Dept. of Neurology, University Hospital Regensburg, Germany 20 Dept. of Radiation Oncology, Royal North Shore Hospital, St. Leonards, New South Wales, Australia 21 Dept. of Neuroscience, Neurology, Uppsala University / University Hospital, Sweden 22 Medical Dept, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium 23 Dept of Statistics, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium 24 Depts. of Clinical Neurosciences, Neurosurgery and Oncology. University Hospital Lausanne, Lausanne, Switzerland 25 Department of Medical Oncology and Cancer Center, University Hospital Zurich, Zurich, Switzerland 26 Dept. of Radiation-Oncology (MAASTRO), Maastricht University Medical Center (MUMC) and GROW (School for Oncology), Maastricht, Netherlands and Dept. or Radiation-Oncology, MediClin Robert-Janker-Clinic & Clinical Cooperation Unit Neuro- oncology University Bonn Medical Centre, Germany
3 Summary
Background: Temozolomide chemotherapy versus radiotherapy in patients with a high- risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. Methods: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0–1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50∙4 Gy in 28 fractions of 1・8 Gy for 5 days per week up to 6・5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer’s [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819. Findings: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months’ follow-up (mean between group difference [averaged over all timepoints] 0・06, 95% CI –4・64 to 4・75, p=0∙98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. Interpretation: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not diff er in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. Funding: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer
4 Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
5 Research in context
Evidence before this study An international, randomised controlled trial of temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma showed that progression-free survival was not significantly different between the treatment groups. If these therapeutic options have a different effect on health-related quality of life (HRQOL), this might affect the choice of treatment. We searched PubMed for Articles published before March 27, 2016, using the search terms (((((“low-grade AND (glioma OR astrocytoma OR oligodendroglioma OR oligoastrocytoma))) AND (irradiation OR radiotherapy OR chemotherapy OR treatment)) AND (quality of life OR patient-reported outcome))) AND adult)”. We did not use language restrictions in our search, which yielded 102 references. One cross-sectional study reported that HRQOL of patients with low-grade glioma is already compromised at the time of diagnosis, whereas another reported that HRQOL levels did not return to levels similar to those in healthy controls, even after successful treatment. In this second study of 195 patients, 53% had previously undergone irradiation, but this factor was not significantly associated with the mental and physical component scores of the SF-36 questionnaire, and no patient had received any form of chemotherapy at the time of assessment. Another single-arm phase 2 study reported on an interim analysis of 66 patients with low-grade glioma who had postoperative residual disease, who had not previously received radiotherapy. During treatment with at least 12 cycles of temozolomide chemotherapy, HRQOL remained stable in many domains and even improved on some subscales during treatment. Several research groups have reported the eff ect of irradiation on HRQOL in patients with low-grade glioma, including an European Organisation for Research and Treatment of Cancer (EORTC) phase 3 trial that reported poorer HRQOL during the first 15 months after treatment in patients with low-grade glioma who had high-dose versus low- dose postoperative irradiation, suggesting that the eff ect is at least partly related to radiotherapy dose. Another study showed that scores for several HRQOL subscales even improved during the fi rst 3 years after treatment in a mixed cohort of 43 patients with newly diagnosed and recurrent low-grade glioma requiring radiotherapy. Unfortunately, these reports do not directly compare the effect of radiotherapy and any type of chemotherapy on HRQOL in patients with low-grade glioma.
Added value of this study To the best of our knowledge, our study is the fi rst randomised, international head-to- head comparison of the effect of temozolomide chemotherapy versus radiotherapy on HRQOL and global cognition in patients with low-grade glioma. Our analysis shows no significant difference in HRQOL or Mini-Mental State Examination scores between the two treatment modalities during the first 3 years of follow-up. Temozolomide was not associated with improved HRQOL and cognitive symptoms, which was our initial hypothesis.
Implications of all the available evidence HRQOL results do not support the choice for temozolomide alone over radiotherapy alone in patients with high-risk, low-grade glioma.
6 Introduction
The necessity, choice, and optimal timing of treatment of patients with diffuse low-grade glioma (LGG) after initial surgical biopsy or resection are a matter of continuous debate. (1) Early irradiation increases the length of progression-free survival (PFS), but this does not translate into prolonged overall survival (OS).(2) Furthermore, late toxicity caused by radiotherapy, including neurocognitive decline and secondary malignancies, might impair health-related quality of life (HRQOL) and outcome.(3) Several uncontrolled trials suggest activity of temozolomide (TMZ) chemotherapy against LGG. (4-6) In a prospective randomized phase 3 trial, investigators from the European Organisation for Research and Treatment of Cancer (EORTC) compared two distinct treatment strategies for patients with high-risk LGG; upfront treatment with standard fractionated radiotherapy versus low-dose TMZ chemotherapy for up to 1 years (EORTC study 22033-26033). At an initial analysis of the data with a median follow-up of almost 4 years, no statistical difference was noted in progression-free survival.(7) In particular for patients with cancer who cannot be cured of their disease but might have a slow-growing tumour (e.g. LGG), HRQOL is a highly relevant endpoint.(8) HRQOL is a multidimensional concept that incorporates physical, social and psychological aspects and has become a major secondary endpoint, and sometimes even a primary endpoint in cancer clinical trials.(9) Previous studies showed that HRQOL of LGG patients is already compromised at the time of diagnosis (10), and further deteriorates during the disease course.(11) However, the extent to which the disease itself, disease symptoms (eg. epilepsy and cognitive decline), and disease treatment (for both oncological and symptomatic) contribute to the gradual decline in HRQOL remains to be determined. If TMZ and irradiation had different impacts on HRQOL and global cognitive function, these treatment differences might affect clinical decision-making in LGG patients who require treatment. In this Article we report on a head-to-head comparison of TMZ and irradiation in terms of the effect on HRQOL and cognitive functioning in patients with LGG, which was a secondary endpoint in EORTC study 22033-26033.(7) The pre-trial hypothesis was that TMZ would have less negative effects on HRQOL and cognitive functioning than would radiotherapy, mainly by avoiding radiation-induced leukoencephalopathy and its cognitive sequelae.
Methods Study design and participants The EORTC–National Cancer Institute of Cancer (NCIC)–Canadian Cancer Trials Group (CTG)–Trans Tasman Radiation Oncology Group (TROG)–Medical Research Council (MRC)–Clinical Trial Unit (CTU) intergroup study, EORTC 22033-26033, was a prospective, randomised, open-label, phase 3 study, undertaken in 78 medical centres and large hospitals in 19 countries (appendix). This trial consisted of two steps: first, a registration step at any time after initial diagnosis, allowing for tissue collection and molecular analyses required for stratification, and a second randomisation step at the
7 timepoint when treatment was judged to be clinically indicated. Adult patients (aged ≥18 years) were eligible for registration if they had histologically verified supratentorial diff use (WHO grade II) low-grade glioma (astrocytoma, oligodendroglioma, or mixed oligoastrocytoma), WHO performance status score of 2 or lower, and had not previously received chemotherapy or radiotherapy. Additionally, eligible patients could not have a known HIV infection, or chronic hepatitis B or hepatitis C infection, or any medical condition that could interfere with oral medication intake. Availability of paraffin- embedded tumour tissue and a blood sample was required for central pathological review and molecular testing for chromosome 1p status. To be eligible for randomisation (the second step), patients had to require active treatment other than surgery, defined by at least one of the following criteria: age 40 years or older, radiological tumour progression, new or worsening symptoms, and refractory seizures. These criteria were established at the time of the protocol writing and based on a prognostic score developed by EORTC on the basis of two large, randomised, multicentre trials with more than 600 patients.(12) Other eligibility criteria for randomisation included: WHO performance status score of 2 or lower; Radiation Therapy Oncology Group (RTOG) neurological function score of 0–3; adequate haematological, renal, and hepatic function (absolute neutrophil count ≥1500 cells/μL, platelet count ≥100 000 cells/μL, serum creatinine concentration ≤1∙5 × the upper limit of normal [ULN], total serum bilirubin concentration ≤1∙5 × ULN, and liver function values [alanine aminotransferase, aspartate amino transferase, or alkaline phosphatase] ≤2∙5 × ULN), results of genetic testing available, and not candidate for treatment exclusively by surgery (protocol). The study was approved by the institutional review boards and ethics committees of all participating centres and the respective authorities. We completed the trial according to the Declaration of Helsinki. All patients provided written informed consent at the time of registration. Before randomisation, a separate written informed consent was obtained from all participants.
Randomisation and masking We randomly assigned patients (1:1) to receive either radiotherapy or temozolomide chemotherapy using a minimisation technique, stratified according to WHO performance status (0–1 vs 2), age (<40 years vs ≥40 years), presence versus absence of contrast enhancement on MRI, 1p status (deleted vs non-deleted vs indeterminate), and by their treating medical centre. Registration, randomisation, and data collection were centralised at the EORTC Headquarters in Brussels, Belgium. Patients had to begin their assigned treatment within 6 weeks after randomisation. Given the nature of the intervention, the trial was open label, and patients, treating physicians, and researchers were all aware of the assigned intervention.
Procedures For the temozolomide chemotherapy regimen, we postulated that the fact that low- grade gliomas have a low number of cells in the proliferation phase made more continuous administration theoretically attractive. At the time of the design of the trial, several studies (13)(23), had shown that continuous low-dose schedules were safe and
8 well tolerated, so we chose the 21 of 28 days drug regimen. Patients who were assigned to temozolomide chemotherapy therefore received 75 mg/m2 oral temozolomide daily for 21 of 28 days (one cycle), repeated for a maximum of 12 cycles or until disease progression or unacceptable toxicity occurred: in the case of an absolute neutrophil count lower than 1∙0 × 10⁹ cells per L (≥grade 3), platelet count
between 25 × 10⁹ and 75 × 10⁹ cells per L (≥grade 2), or common toxicity criteria non-haematological toxicity of grade 2 or worse (except alopecia, nausea, and vomiting), temozolomide treatment had to be withheld until recovery of toxicity to grade 1 or lower. Patients with recurrent severe toxicity (repeated grade 4 haematological toxicity or grade 3–4 non-haematological toxicity [except alopecia, nausea, and vomiting]) despite dose reduction, were to immediately and definitively discontinue temozolomide treatment. The choice of the radiotherapy regimen was based on two previous randomised studies of low-grade glioma that showed no significant survival difference between a dose of 45 Gy and 59∙4 Gy (the EORTC study(14;15) and between 50∙4 Gy and 64∙8 Gy (the NCCTG–RTOG–ECOG study (14;15). Since the dose prescription to different isodose concentrations might have resulted in slightly higher total doses than 45 Gy in the tumour itself, a total dose of 50∙4 Gy was selected for this trial. Patients who were assigned to the radiotherapy group therefore received 50∙4 Gy in 28 fractions of 1・8 Gy once daily, for 5 days per week up to a maximum treatment period of 6・5 weeks. Standard treatment comprised three-dimensional conformal radiotherapy, but intensity- modulated and stereotactically guided radiotherapy were also allowed if the same dose prescription as for non-stereotactic radiotherapy was used when this was the preferred approach of the local team. Expected acute toxicity from radiotherapy included headache, fatigue, hair loss, skin reaction, mucositis (if nasopharynx included), temporary reduced hearing (if ear canal included), and temporary loss of taste (if nasopharynx included). Individual reasons for treatment interruption, such as major worsening of neurological or mental status or any other medical condition that would preclude the continuation of radiotherapy and, conversely, the decision to resume radiotherapy after interruption, were taken on an individual basis by the local investigator. The maximum allowed overall treatment time for radiotherapy was 6∙5 weeks, and dose adjustments were not recommended irrespective of the duration of the treatment interruption. We did a baseline evaluation (within 6 weeks before randomisation and before the start of treatment) which included MRI, full clinical and neurological evaluation (including HRQOL, Mini-Mental State Examination [MMSE], and assessment of seizure frequency if applicable), and complete blood counts and blood chemistry. The extent of tumour resection was assessed by the neurosurgeon according to local practice and was based
9 on postoperative imaging. Once treatment had been initiated, all patients were assessed clinically and neurologically once every 3 months until disease progression, with no time constraint, and tumour assessment with MRI was completed once every 6 months. To assess HRQOL, we selected two of the most commonly used HRQOL assessments in brain cancer clinical trials (EORTC QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]), which are both well established and validated tools, and have been translated into all the required 17 languages for our trial. (9)(16) Both have robust psychometric properties that result from rigorous testing and from refinement through their use in several international clinical cancer trials.(17;18) The items from both measures were scaled and scored according to the scoring manual method, whereby responses were aggregated and transformed into a linear scale of 0–100 points, in which a higher score represented a higher degree of functioning (function scales) or a higher level of symptoms (symptom scales).(19) If at least half of the items in the scale were completed, the scale score was calculated with only those items for which values existed. We present the results in accordance with the 2003 guidelines for reporting HRQOL. (20) For the assessment of neurocognitive function, we used the MMSE, which is a brief standardised method used to grade patients’ cognitive function. It consists of 11 questions that test five areas of cognitive function: orientation, registration, attention and calculation, recall, and language.(21) We chose the MMSE mainly on practical grounds for its availability of the test, familiarity in participating investigators, and existing body of previous results. Importantly, at the time of the initial conception of our study, no consensus had yet been reached between brain tumour study groups in Europe and the USA for a common neurocognitive testing battery. Following the study by Brown and colleagues (22) the patient’s cognitive function was considered impaired if the MMSE score was 26 or lower and normal if it was between 27 and 30. We stopped data collection in the case of progression, death, loss to follow-up, or if the patient refused further participation. Only assessment forms completed before or on the day of progression of the disease, or before or on the final day of study for patients who did not progress were selected for the analysis. Timepoints for eligible follow-up assessment were set at 6 weeks before and 4 weeks after the scheduled follow-up assessment. Forms completed outside the eligible time windows or duplicates within a window were removed from the analysis. HRQOL and MMSE were mandatory aspects of our clinical trial protocol to ensure optimal compliance, and guidelines to administer questionnaires were provided to participating centres to ensure standardisation by all personnel.(23)
Outcomes The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, reported separately. (7) Secondary endpoints were overall survival, adverse events, HRQOL, and MMSE (used at all centres and the cognitive test battery for selected centres) outcomes, and neurocognitive functioning. In this Article, we report the results for HRQOL and neurocognitive functioning. Statistical analysis
10 To reduce multiplicity (thereby increasing type I errors), we preselected seven key HRQOL scales (from both EORTC QLQ-C30 and QLQ-BN20) for the primary analysis (global health or quality-of-life status, and role functioning, social functioning, communication deficit, visual disorder, motor dysfunction, drowsiness based on past clinical experience) and MMSE. The standard deviation of the selected HRQOL scales is about 20 points.(24) With the two-sided α set at 5% and a power of 80% to detect a diff erence of 10 points (effect size 0・5), a minimum of 128 patients (64 per treatment group) were needed. We used the Bonferroni approach: p<0∙00625=0∙05/8 to compare the two treatments. The remaining HRQOL variables and any other comparisons (eg, difference in HRQOL at specific timepoints or area under the curve [AUC] between the two groups [to establish whether or not the loss of HRQOL differed between the treatment groups during a specific time interval]) were studied at 5% significance on a post-hoc exploratory basis only. According to previous work by Osoba and colleagues (25) and King et al (26), changes in scores of 5–10 points represent a small difference and a change in 10–20 points represent a moderate difference, with 10 points being considered the threshold for clinically relevant changes. We therefore judged a difference to be clinically relevant if it was greater than 10 points. For MMSE, after the study by Brown and colleagues (22) the patient’s cognitive function was considered impaired if the MMSE score was 26 or lower and considered normal if the score was between 27 and 30. Analyses were done on the intention-to-treat population. A linear mixed-effects model was constructed with treatment, time, and time–treatment interactions as fixed effects, and a patient-specific random effect to account for the longitudinal nature of the HRQOL data. Furthermore, we considered that comparison of HRQOL between both groups at prespecified timepoints might not reveal all relevant information, because the treatment groups, differ in treatment duration and character (radiotherapy on weekdays during 6 weeks vs 12 cycles of temozolomide chemotherapy during 21 of 28 days [one cycle]). In our post-hoc exploratory AUC analysis, for each patient and for all primary HRQOL scales, two AUC values were calculated: one covering the time from inclusion to 15 months and the second from inclusion to 24 months, by calculation of the product of the HRQOL scores during the interval with the duration of that interval (15 months or 24 months after randomisation). We did sensitivity analyses on the per-protocol population (all patients who started their allocated treatment) to assess the robustness of the results. The change from baseline to the average, minimum, maximum, and last available HRQOL assessment were calculated per patient. Additionally, we calculated whether each patient had a 10 point or more deterioration from baseline at any follow- up visit and compared these findings between the two treatment groups using non- parametric rank tests for patients with baseline and at least one follow-up HRQOL assessment. The primary analysis was replicated with missing HRQOL data imputed with values predicted from a linear regression model that included additional factors (treatment group, assessment time, WHO performance status, age, sex, molecular testing, type of histology, and MRI contrast enhancement). Further details about our statistical analyses are in the appendix. We used SAS version 9.3 for all analyses. For MMSE analysis, we used the general mixed model for inference and to estimate timepoint CIs. This study is closed and is registered at EudraCT, number 2004-002714
11 Role of the funding source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (JCR), CC, AB, RS, and BGB had full access to all the data and had the final responsibility to submit for publication. Results
Between Dec 6, 2005, and Dec 21, 2012, of 707 registered patients, we randomly assigned 477 (67%) to receive radiotherapy (n=240) or temozolomide chemotherapy (n=237; figure 1). Baseline patient characteristics were well balanced between the groups, and are reported elsewhere.(7) At a median follow-up of almost 4 years (48 months; IQR 31–56), progression-free survival did not differ significantly between the two treatment groups (median 39 months [95% CI 35–44] for temozolomide vs 46 months [40–56] for radiotherapy; hazard ratio [HR] 1∙16, 95% CI 0∙9–1∙5, p=0∙22). 219 (91%) of 240 patients completed radiotherapy as planned (including one patient who is still on treatment) and 180 (76%) of 237 completed 12 cycles (range 1–14) of temozolomide chemotherapy (figure 1), including three (2%) who continued temozolomide for more than 12 cycles for unspecified reasons. The main safety and tolerability results and further details on the number of events in patients in each treatment group are presented elsewhere.(7) Overall HRQOL compliance in the intention-to-treat population is shown in table 1. Initial compliance for completion of HRQOL questionnaires was good, with 431 (90%) of 477 patients completing the questionnaires at baseline. Baseline compliance scores were similar between the two treatment groups. However, compliance decreased over time to slightly below 60% at 36 months. Beyond this timepoint the available data were too sparse to draw reliable results. The main documented reason for missing data was administrative failure (ie, not related to patient health or refusal to participate), accounting for 559 (59%) of all 951 reported reasons. Compliance at all timepoints was higher in the temozolomide group than in the radiotherapy group (table 1). For the EORTC QLQ-C30 functioning scales, symptom scales, and global health or quality-of-life status, baseline scores were lower than reference values reported from the general population (appendix).(27) The overall test for differences in HRQOL scores from baseline between the two treatment groups resulting from the longitudinal mixed-effects analysis was not significant (mean between group difference [averaged over all timepoints] 0・06, 95% CI –4・64 to 4・75, p=0∙98). Differences in the global health or quality-of-life status scale between the two treatment groups, assessed at each timepoint, were not significant, except at 3 months in which patients in the temozolomide group had a higher score than those in the radiotherapy group, although this difference was not clinically relevant (ie, difference <10 points; table 2). In both groups, the mean global health or quality-of-life status scores tended to be quite stable over time (table 2). Of the other pre-selected HRQOL endpoints, although not significant, the only indication for a different overall treatment effect was for communication deficit in favour of the temozolomide group (mean between group difference [averaged over all timepoints]
12 5∙91, 95% CI –11∙45 to –0∙36, p=0∙037). Although significant differences between groups were observed at months 9 (difference –5∙5, 95% CI –10∙2 to –0∙7, p=0・024), 12 (–5∙3, –10∙2 to –0∙4, p=0・034), 15 (–5∙6, –10∙6 to –0∙6, p=0・028), and 18 (–5∙7, – 10∙8 to –0∙6, p=0・027) for communication deficit, these differences were not clinically relevant (fi gure 2; for all timepoints see appendix). Additionally, the significant difference at 3 months for social functioning and motor dysfunction scales, both in favour of temozolomide, were not clinically relevant (data not shown) because the differences between groups were less than 10 points. We did not find any significant differences for the other prespecified HRQOL scales (role functioning, visual disorder, and drowsiness; data not shown). In our post-hoc exploratory analyses of the expected acute toxicity effects, hair loss (p<0∙0001) was significantly more prevalent in patients treated with radiotherapy than in those who received temozolomide (appendix). Hair loss was significantly different between groups at months 3, 6, 9, 12, and 15, of which months 3 and 6 were also clinically relevant (appendix). Nausea-vomiting scores were in favour of the radiotherapy group, with statistically significant differences at months 3, 6, and 9 (p=0∙0031), but these were not clinically relevant (appendix). Other significant differences were in favour of temozolomide at 3 months for emotional functioning, cognitive functioning, and fatigue; whereas significant differences in favour of radiotherapy were for appetite loss (at 9 months and 12 months) and constipation (at 6, 9, and 12 months; appendix). However, these differences were not clinically relevant. In our post-hoc sensitivity analysis of the per-protocol population, we investigated compliance of patients to check for systematic trends. We recorded large differences between the various institutions, but because of the large number of institutions (78 institutions), it was decided (by JCR, CC, AB, RS, and BGB) to group these together. A first grouping by country still yielded 19 levels, so we did a subsequent grouping by continent: continental Europe (Austria, Belgium, France, Germany, Hungary, Italy, Netherlands, Portugal, Spain, Sweden, and Switzerland), Asia and Oceania (Australia, New Zealand, and Singapore), North America (Canada [NCIC group], no USA centres participated), the Middle East (Egypt and Israel), and the UK. Non-compliance was associated with the participating institution (lower compliance in continental European centres than in all other centres combined; difference estimate 9・23, 95% CI 3・08– 15・38, p<0・0001) and treatment group (systematic higher compliance in the temozolomide group than in the radiotherapy group; data not shown). Additionally, compliance was lower in patients with WHO performance status 2 (mean 58% [SD 30・ 72] questionnaires completed; n=18]) than in those with WHO performance status 0 (72% [28・54]; n=294) or 1 (71% [30・13]; n=165; difference estimate –13∙46%, 95% CI –27∙23 to –0∙30, p=0∙048). We found no indication that patients’ global health or quality-of-life status scores decreased before dropping out of the study (mostly due to disease progression; data not shown). The primary analysis on global health or quality-of-life status was replicated in the per- protocol population (n=461) with similar results (p=0∙87; data not shown). Imputation also confirmed the result of no significant differences (data not shown; appendix). 203 (54%) of 375 patients with adequate data reported at least one clinically relevant worsening in global health or quality-of-life status during the course of the trial (data
13 not shown), but no statistically significant or clinically relevant treatment effects were recorded (appendix). In our post-hoc analys is of the standardised AUC scores, we recorded no differences in the seven key scales at 15 months and 24 months between the two treatment groups (data not shown). For both timepoints and both groups, the median standardised AUC per patient was about 71% of the total possible AUC (appendix). For the MMSE, overall baseline compliance was high (475 [97%] of 477 patients; table 1). Compliance was significantly higher in the temozolomide group than in the radiotherapy group at 3 months (158 [71%] of 221 patients in radiotherapy group vs 184 [81%] of227 patients in temozolomide group; difference 9・57%, 95% CI 1・72–17・ 40, p=0∙0026) and at 6 months (134 [63%] of 213 patients in radiotherapy group vs 160 [75%] of 214 patients in temozolomide group; difference 21・86%, 3・14–20・57, p=0∙00014). However, the baseline profile of patients who were non-compliant at 3 months or 6 months did not differ significantly between the groups (data not shown). On the basis of the absolute and relative compliance, our analysis was limited to the first 36 months of follow-up. At baseline, 32 (13%) 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. We recorded no significant difference between the radiotherapy and temozolomide groups for the change in MMSE scores in the longitudinal and overall analysis at any timepoint (fi gure 3, appendix).
Discussion Our analysis showed no significant difference in HRQOL or MMSE between radiotherapy or temozolomide chemotherapy treatment in patients with low-grade glioma during 36 months of follow-up. To our knowledge, our study is the first randomised, international, head-to-head comparison of the effect of these two treatment modalities in patients with low-grade glioma on progression-free survival and on HRQOL and MMSE. Temozolomide was not associated with improved HRQOL and self-reported symptoms, which was our initial hypothesis. A detrimental effect of radiotherapy was not shown. However, our study shows that HRQOL of patients with low-grade glioma is compromised in all patients already at the time of diagnosis and treatment initiation, and does not return to levels similar to those in healthy controls even after successful treatment. This observation is in agreement with previous reports and large cross-sectional studies, although detailed comparison is hampered by the use of different HRQOL measurement devices in these studies.(10;11;28-30) For social and professional integration, specific measures of additional psychological and social support might be needed for patients diagnosed with low-grade glioma. The major strengths of our study are the randomized nature of the trial and the large sample size, comprising a homogeneous group of patients with histologically verified diff use low-grade glioma with similar performance levels and prespecified criteria for start of treatment. Other strengths were the high compliance at baseline, the prospective study design with prespecified timepoints for HRQOL measurements and key scales for
14 the primary analysis, and the application of the EORTC QLQC-30 and BN20, which are extensively validated tools with robust validity and reliability for measurement of HRQOL in patients with brain cancer.(9;17;18) However, our study is subject to the limitations of quality-of-life studies in general, the most important being missing data.(8;31-33) compliance fell substantially during follow-up, restricting the primary analysis to the first 36 months, since beyond that timepoint, the available data are both too sparse to draw reliable results and the low compliance would be likely to cause selection bias. We therefore restricted our analysis to the first 36 months to maintain the statistical integrity of the results. Common reasons for missing data in brain tumour trials are administrative failure, patient refusal, and poor health status of the patient(8;34), which were also the case in our study. Compliance was systematically higher in the temozolomide group than in the radiotherapy group, which might be indicative of the more continuous administration nature of the treatment, although the protocol clearly prespecified the required visits in both groups. Furthermore, compliance was lower in patients being treated in continental European centres than other countries. Compliance was lowest in patients with poor performance status (WHO performance status 2), which might have resulted in an underestimation of the effect of both treatments on HRQOL in our study.(8;35) The design of this study did not include collection of HRQOL data after progression. However, an extension of the HRQOL data after progression would have been unlikely to yield reliable data in this setting, but we realise that this absence of data after progression is a limitation, since many side-effects continue beyond progression. (36) The question of how important the relative benefit of radiotherapy versus temozolomide is in terms of quality-adjusted life-years therefore remains unanswered. Furthermore, as is the case in many cancer trials (8), the patients in our trial might not be fully representative of the wider patient population with low-grade glioma, because patients with lower WHO performance scores or cognitive deficits preventing them from providing informed consent were excluded. A more specific limitation of our current study is the fact that we compared two treatment modalities that differed substantially in both duration and intensity. Because the linear mixed-model approach that we applied might not be adequate for such a comparison, we did post-hoc assessments of the standardised AUC score, which can be interpreted as the percentage of the maximum HRQOL (which is 100% as per definition) that a patient has experienced during a specified time interval. Both analyses of 15-month and 24-month intervals also did not show any significant benefit from temozolomide compared with radiotherapy in terms of HRQOL. Furthermore, a frequent observation throughout the study results was that statistically significant results were not clinically relevant because the magnitude of the treatment difference did not exceed the pre-set threshold of 10 points.(37) The use of the 10-point threshold itself might be nuanced—Maringwa and colleagues(38), found different thresholds for various QLQ-C30 scales depending on improvement or deterioration over time—but our trial was not statistically powered to attribute statistical significance to smaller differences. Long-term follow-up of the RTOG 9802 study (39), shows that the addition of procarbazine– lomustine–vincristine (PCV) chemotherapy to standard postoperative radio therapy in patients with high-risk low-grade glioma resulted in a substantial survival advantage, but HRQOL was not measured in this trial. A previous randomised controlled EORTC trial.(33) compared the same treatment
15 regimens in anaplastic oligodendroglial tumours, which showed that the addition of PCV chemotherapy only results in an increase in self-reported nausea or vomiting, loss of appetite, and drowsiness during and shortly after treatment, but not in substantial longer-term effects during the fi rst 2–5 years after treatment. Unfortunately, the sparse information about long-term follow-up (>12 years after treatment) did not allow for statistical comparison of HRQOL and cognitive functioning differences between the treatment groups.(40) Further studies will be necessary to establish whether the survival benefit of additional PCV chemotherapy has a serious trade-off in terms of loss of HRQOL compared with radiotherapy alone. Both temozolomide and radiotherapy might have different effects on mid-term and long-term HRQOL, which is relevant in a patient group with a median age of around 35 years at diagnosis and a median survival of about 6 years, which ranges widely from less than 2 years to more than 20 years. Therefore, long-term follow-up of HRQOL in our study will be pivotal, but we expect that collection of sufficient and unbiased long-term information from this trial might be difficult due to attrition. Additionally, previous studies (3;41) have shown that late cognitive sequelae in this patient group might not develop until after 6 years after completion of radiotherapy. In this study, MMSE scores did not differ between both groups during the first 3 years, but it is widely acknowledged that for adequate measurement of cognitive functioning, a panel of cognitive tests should be used.(42) Furthermore, repeated use of the MMSE test could lead to learning and practice effects that could theoretically render patient outcomes erroneously unaffected. However, some questions do allow for variations, and the assessing clinician can always downgrade the score based on their clinical judgment. Moreover, these limitations cancel each other out in aim to define a treatment effect on the basis of a randomized comparison, such as in this trial. In light of these reasons, the results of cognitive follow-up, which we assessed routinely through application of a standardized neuro psychological test battery in a subset of patients included in this EORTC trial, will be extremely important. We also plan an analysis on the effect of hippocampal sparing in the radiotherapy subgroup. In conclusion, the effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. Our results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. Contributors
JCR was involved in the literature search and data interpretation. MJBT, RS, and BGB were involved in the literature research, study design, and data interpretation. CC was involved in data analysis, data interpretation, and writing of the report. WPM was involved in the study design. JCR, MJBT, JECB, WPM, KH-X, GR, MBH, RHE, AAB, AW, OC, MR, GK, BT, MK, EV, CB, PH, MB, AS, RS, and BGB were involved in data collection and writing of the report. MK was involved in study design and data interpretation. VG was involved in the writing of the report. TG was involved in data analysis and writing of the report. AB was involved in data interpretation and writing of the report.
Declaration of interests
16 MJBT reports personal fees from Hoff mann La Roche, outside the submitted work. OC reports grants and non-fi nancial support from Roche, and reports personal fees from Roche, Ipsen, and AstraZeneca, outside the submitted work. MR reports grants from Celgene, Novartis, and Pharmamar, and reports personal fees from Celgene, Boehringer, Genentech, Lilly, and Merck-Serono, outside the submitted work. BT reports other from National Cancer Institute of Canada Clinical Trials Group, during the conduct of the study. VG reports grants from Merck & Co, during the conduct of the study. BGB reports personal fees from Merck & Co, outside the submitted work. JCR, CC, JECB, WPM, KH-X, GR, MBH, RHE, AAB, AW, GK, MK, EV, CB, PH, MB, AS, and TG declare no competing interests.
Acknowledgements This trial was partly supported by an unrestricted educational grant and free supply of temozolomide drug by Merck Sharpe & Dohme-Merck & Co. The European Organisation for Research and Treatment of Cancer (EORTC) is supported by National Cancer Institute grants (number 5U10 CA011488-35 to 2U10 CA011488-41). The UK participation was supported by the National Institute for Health Research through the National Cancer Research Network, and a grant to the Medical Research Council Clinical Trials Unit at University College London from Cancer Research UK (trial reference CRUK/07/032). The participation of the National Cancer Institute of Canada Clinical Trials Group has been supported by the Canadian Cancer Society Research Institute (grant numbers 015469 and 021039). The Trans Tasman Radiation Oncology Group (TROG) participation was supported by a National Health and Medical Research Council project grant (ID 509094). This publication was supported by the EORTC Cancer Research Fund. Translational research was funded in part by the Swiss Cancer League and the Swiss Bridge Award (to Monika E Hegi).
17 References
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21 Figure and table legends
Figure 1. Trial profile * At the date of database lock, 51 registered patients had not progressed or required anti-tumour therapy, and thus were not randomly assigned to a treatment.
Figure 2. Changes from baseline in communication deficit scores Error bars are SDs. 0 months is the baseline. A higher communication deficit score means more symptoms.
Figure 3. Changes from baseline in MMSE scores Error bars are 99% CIs. No significant difference was found between radiotherapy and temozolomide in the longitudinal and overall analysis or at any timepoint (p=0・47). 0 months is the baseline. MMSE=Mini-Mental State Examination.
Table 1. Compliance to health-related quality-of-life assessment in the intention-to-treat population Data are the number of patients from whom a completed questionnaire was received/number of patients from whom it was expected (%). HRQOL=health-related quality of life. MMSE=Mini- Mental State Examination.
Table 2. Changes in the mean global health or quality-of-life status scores from baseline in the intention-to-treat population Data are mean (SD), unless otherwise indicated. The scores listed in this table are mean global health or quality-of-life status scores. A higher score means better quality of life. Clinically relevant difference is at least 10 points.
22