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Background There is no community standard for the treatment of glioblastoma in patients 70 years of age or older. We conducted a randomized trial that compared radiotherapy and supportive care with supportive care alone in such patients.
Methods Patients 70 years of age or older with a newly diagnosed anaplastic astrocytoma or glioblastoma and a Karnofsky performance score of 70 or higher were randomly assigned to receive supportive care only or supportive care plus radiotherapy (focal radiation in daily fractions of 1.8 Gy given 5 days per week, for a total dose of 50 Gy). The primary end point was overall survival; secondary end points were progression-free survival, tolerance of radiotherapy, health-related quality of life, and cognition.
Results We randomly assigned 85 patients from 10 centers to receive either radiotherapy and supportive care or supportive care alone. The trial was discontinued at the first interim analysis, which showed that with a preset boundary of efficacy, radiotherapy and supportive care were superior to supportive care alone. A final analysis was carried out for the 81 patients with glioblastoma (median age, 73 years; range, 70 to 85). At a median follow-up of 21 weeks, the median survival for the 39 patients who received radiotherapy plus supportive care was 29.1 weeks, as compared with 16.9 weeks for the 42 patients who received supportive care alone. The hazard ratio for death in the radiotherapy group was 0.47 (95% confidence interval, 0.29 to 0.76; P=0.002). There were no severe adverse events related to radiotherapy. The results of quality-of-life and cognitive evaluations over time did not differ significantly between the treatment groups.
Conclusions Radiotherapy results in a modest improvement in survival, without reducing the quality of life or cognition, in elderly patients with glioblastoma. (ClinicalTrials.gov number, NCT00430911
[ClinicalTrials.gov]
.)
Methods
Patients
Patients 70 years of age or older were eligible to participate in the study if they had histologically proven, newly diagnosed glioblastoma multiforme or anaplastic astrocytoma on the basis of the World Health Organization (WHO) classification and a Karnofsky performance score of 70 or more. Written informed consent was obtained from all patients, and the study was approved by the ethics committee of the Salpêtrière Hospital in Paris.
Treatment
After undergoing surgery, patients were randomly assigned to receive supportive care alone (the supportive care group) or supportive care in combination with radiotherapy (the radiotherapy group). Randomization was performed at the data center of the Delegation for Clinical Research of the Assistance Publique–Hôpitaux de Paris, and patients were stratified according to the treatment center. Randomization and initiation of assigned treatments were required within 4 weeks after surgery. Supportive care consisted of treatment with corticosteroids and anticonvulsant agents, physical and psychological support, and management by a palliative care team. Radiotherapy, delivered by means of linear accelerators with a nominal energy of 6 mV or more, consisted of fractionated focal irradiation, at a dose of 1.8 Gy per fraction, given once daily 5 days per week, for a total dose of 50 Gy. The dose was defined according to the guidelines of the International Commission on Radiation Units and Measurements. The clinical target volume included the area of contrast enhancement on magnetic resonance imaging (MRI) and a tumor margin of 2 cm.
Surveillance and Follow-up
The baseline examination included computed tomographic (CT) or MRI studies; complete blood counts and blood chemical tests; neurologic examination; assessment of the Karnofsky performance status; evaluation of the health-related quality of life with the use of a questionnaire developed by the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30, version 2.0), which has a specific module for brain cancer (QLQ-BN20); and a neuropsychological evaluation that included the Mini–Mental State Examination (MMSE), the Mattis Dementia Rating Scale (MDRS), and the Neuropsychiatric Inventory. Patients were assessed every month during the first 3 months and then every 6 weeks by means of CT or MRI, neurologic examination, MMSE, and the health-related EORTC questionnaire (QLQ-C30). The MDRS and Neuropsychiatric Inventory were administered at days 60 and 135 and then every 3 months.
Tumor progression was defined as an increase in tumor size by 25% or more or the appearance of new lesions on CT or MRI. Patients with tumor progression received supportive care. Toxic effects were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.
Assessment of Health-Related Quality of Life
The QLQ-C30 questionnaire7 comprises five scales that measure functioning (physical, role [work and household activities], emotional, cognitive, and social), three symptom scales (fatigue, vomiting, and pain), and six single-item scales (dyspnea, insomnia, anorexia, constipation, diarrhea, and financial difficulties). The QLQ-BN20 questionnaire8 includes 20 items covering functional deficits, symptoms, toxic effects of treatment, and uncertainty about the future. The two questionnaires were scored according to the EORTC scoring manual.9 For both questionnaires, scores can range from 0 to 100, with higher scores on the global health status and functioning scales and lower scores on the symptom scales and single-item measures indicating better performance.
Neuropsychological Evaluation
The MMSE was used as a measure of general cognitive status. Higher scores on this 30-point scale indicate better cognitive function. The Neuropsychiatric Inventory is a 12-item rating instrument that covers a range of psychological and behavioral symptoms (delusions, hallucinations, agitation or aggression, depression or dysphoria, anxiety, euphoria or elation, apathy or indifference, dysinhibition, irritability or lability, aberrant motor behavior, and problems with sleeping or appetite).10 The scores range from 0 to 144 for the patient's rating (obtained from the caregivers), with 0 indicating the optimal rating. The MDRS examines attention, memory, initiation and maintenance of verbal and motor responses, and conceptualization and construction (design copying).11 Scores range from 0 to 144, with higher scores indicating better cognitive function.
Statistical Analysis
The primary end point was survival; the secondary end points were progression-free survival, tolerance of treatment, health-related quality of life, and cognitive functioning. Comparisons between the two groups were made on an intention-to-treat basis.
The trial was initially designed to have 80% statistical power to detect a 100% increase in the median overall survival from 16 to 32 weeks (hazard ratio for death, 0.5) in the radiotherapy group as compared with the supportive care group, with a two-sided significance level of 0.05. Seventy-four patients with a minimum follow-up of 1 year were required for this analysis. However, after the inclusion of the 72nd patient, an amendment to the protocol was made to permit an interim analysis. This was done because the investigators, who had no access to any part of the outcome data at that point, were concerned about the possibility of a premature, inconclusive termination of the study.
A procedure of sequential planning, associated with the continuation of recruitment, was instituted with a triangular sequential design for two-sided alternatives. This sequential design permitted discontinuation of the trial according to preset boundaries (Figure 1) if radiotherapy was found to be significantly superior to supportive care (the upper boundary) or if there was no significant difference between the two groups (the lower boundary). After termination of the trial, we performed a final analysis, using the sequential method, of the data from all the patients who had undergone randomization by the time the efficacy boundary was crossed.
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Monitoring of the trial and data collection were performed by the Delegation for Clinical Research of the Assistance Publique–Hôpitaux de Paris. Site visits were performed at all centers. All histologic specimens were subject to a central review.
Results
Patients
From February 2001 to January 2005, a total of 85 patients from 10 institutions were randomly assigned to receive supportive care (the supportive care group) or supportive care plus radiotherapy (the radiotherapy group). The first interim analysis was carried out after inclusion of the 85th patient (in January 2005). In this analysis, the log-rank statistic for the difference in survival between the two groups crossed the upper boundary for efficacy (Figure 1), and the trial was discontinued because of the superiority of radiotherapy over supportive care.
Histologic slides were submitted for 84 of the 85 patients (99%), and a central pathological review confirmed the diagnosis of malignant astrocytoma in 83 of these patients (99%). The tumors included glioblastoma in 81 of the 84 patients (96%) and anaplastic astrocytoma in 2 patients (2%). On central review, one patient was found to have had a stroke. Owing to the very small number of anaplastic astrocytomas, this analysis focuses solely on the 81 patients with glioblastoma. The characteristics of the two groups of patients with glioblastoma were similar at baseline (Table 1). The median age in the supportive care group was 73 years and the median age in the supportive care plus radiotherapy group was 75, and 39 of the 81 patients (48%) had undergone debulking surgery.
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The median time from diagnosis to the start of radiotherapy was 5.3 weeks (range, 2.6 to 10.0) — about 1 week more than was expected. Table 2 summarizes the details of treatment. One patient who was assigned to the radiotherapy group did not receive radiation because another tumor (duodenal cancer) developed before the start of radiotherapy; this patient received supportive care only. Six patients received 90% or less of the planned radiation dose because of tumor progression (in five patients) and sudden death related to a pulmonary embolus (in one patient).
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At a median follow-up of 21 weeks, 73 patients (90%) had died. The hazard ratio for death in the radiotherapy group was 0.47 (95% confidence interval [CI], 0.29 to 0.76; P=0.002 by the log-rank test), indicating a 53% relative reduction in the risk of death for patients who received radiotherapy plus supportive care as compared with those who received only supportive care. The median survival benefit was 12.2 weeks; the median survival was 29.1 weeks (95% CI, 25.4 to 34.9) with radiotherapy plus supportive care and 16.9 weeks (95% CI, 13.4 to 21.4) with supportive care alone (Figure 2). The median progression-free survival was 14.9 weeks (95% CI, 10.9 to 22.1) with radiotherapy plus supportive care and 5.4 weeks (95% CI, 4.4 to 7.6) with supportive care alone (Figure 3). The hazard ratio for disease progression in the radiotherapy group was 0.28 (95% CI, 0.17 to 0.47; P<0.001 by the log-rank test).
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Performance Status and Quality of Life
The Karnofsky performance status declined over time, but there were no significant differences between the two groups (P=0.22). The rate of compliance with the health-related quality-of-life assessment decreased over time in both the group that received supportive care alone and the group that received radiotherapy plus supportive care, from 93% and 90% at baseline to 60% and 67% at day 135, respectively (see Tables 1 and 2 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). Few patients were alive after the first four follow-up evaluations (up to day 135). For this reason, analyses of health-related quality of life were restricted to evaluations at days 1, 30, 60, 90, and 135. Table 3 shows changes in the mean health-related quality-of-life scores over time. In both groups, scores were significantly worse over time on the physical (P<0.001), cognitive (P=0.01), social (P=0.02), fatigue (P=0.008), and motor dysfunction (P=0.001) scales, whereas scores on the other scales, particularly the global score for health-related quality of life, did not change significantly (Fig. 1 of the Supplementary Appendix). Global assessments of deterioration over time also did not differ significantly between the two groups. Only the scale that assessed uncertainty about the future showed a different pattern of scores over time in the two groups, but no pattern exhibited a clear trend.
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The MMSE scores declined over time in both groups (P=0.007), with no significant differences between the two groups (P=0.13). Analyses of the Neuropsychiatric Inventory and MDRS scores were also restricted to 135 days of follow-up (Table 3 of the Supplementary Appendix). The global scores on the Neuropsychiatric Inventory did not change significantly over time (P=0.18), and there were no significant differences in these scores between the two groups (P=0.84). The MDRS score did not change significantly over time, except for progressive deterioration on the initiation (P=0.03) and construction (P=0.05) subscales in both groups (Table 4 of the Supplementary Appendix).
Safety
All patients in the radiotherapy group tolerated the treatment. One patient had transient early delayed somnolence (abnormal sleepiness) shortly after the completion of radiotherapy. Complications of corticosteroid treatment included diabetes in seven patients in the supportive care group and in two patients in the radiotherapy group and myopathy in three patients in the supportive care group and in six patients in the radiotherapy group.
Treatment after Disease Progression
After disease progression, supportive care was given, with a few exceptions. Two patients in the radiotherapy group and one patient in the supportive care group received temozolomide. One patient in the supportive care group underwent reoperation.
Discussion
This study shows that the addition of radiotherapy to supportive care prolongs survival and does not reduce the health-related quality of life or cognitive function of patients with newly diagnosed glioblastoma who are 70 years of age or older. The 16.9-week median survival of patients in our study who received only supportive care is consistent with the median survival reported more than two decades ago for younger patients treated with supportive care alone.12,13 Conversely, the 12.2-week survival benefit with radiotherapy in the older patients in our study is about half the survival gain reported in the two earlier studies (22 and 24 weeks), which compared conventional radiotherapy (a total dose of 45 to 60 Gy, given in fractions of 1.7 to 2.0 Gy) with supportive care in a younger population.12,13
We selected a conventional 50-Gy schedule to minimize the age-related risk of radiation-induced neurotoxicity.5 With this schedule, there were no cases of delayed neurotoxicity,14 but the short survival of the patients in our study may have precluded the development of late toxicity. The optimal dose of radiotherapy in elderly patients remains undetermined. It is unclear whether a total dose of 60 Gy would increase the survival benefit of radiotherapy in older patients, as it does in younger patients.15,16 In our trial, the 29.1-week median survival and 15% rate of discontinuation of radiotherapy compare favorably with the 22.1-week survival and 26% rate of discontinuation reported in a prospective study in which a dose of 60 Gy was delivered in 30 fractions over a period of 6 weeks in older patients.17 In that study, an abbreviated course of radiotherapy (40 Gy in 15 fractions over a period of 3 weeks), as compared with the 60-Gy schedule, resulted in a similar median survival (24.3 weeks vs. 22.1 weeks), but a lower rate of premature discontinuation of radiotherapy (10% vs. 26%).17
Since the goal of the treatment of glioblastoma in older patients is palliation, the quality of life is relevant. The evaluation of health-related quality of life in patients with malignant glioma is notoriously difficult.18,19,20 The main limitation is that severely ill patients with a rapidly progressive, fatal disease are not always compliant with such evaluations. To our knowledge, only one prospective study in the elderly attempted to evaluate health-related quality of life sequentially in patients with glioblastoma, but the data could not be analyzed because the compliance rate was too low (15 to 21% immediately after radiotherapy).17 In our study, the rate of compliance with the questionnaires was similar to that in the few reported studies of patients with glioblastoma.19,20,21 We were able to conduct a meaningful analysis of the data obtained from the first four follow-up evaluations (135 days of follow-up). Thereafter, the number of patients was too small for a reliable analysis.
At baseline, scores for the health-related quality of life did not differ significantly between the two groups and were similar to scores reported previously.20 During and after treatment, scores on several evaluation scales (physical, cognitive, social, fatigue, and motor dysfunction) progressively declined in both groups, although the global score for health-related quality of life did not change significantly over time in either group. We did not observe the mild-to-moderate improvement on several scales that was reported in younger patients after radiotherapy, with or without chemotherapy.20
The evaluation of neuropsychiatric symptoms and cognitive function is associated with the same compliance limitation as the health-related quality-of-life analysis. The Neuropsychiatric Inventory did not show a time or treatment effect, particularly in the case of depression. In contrast, the cognitive evaluation (the MMSE and the initiation subscale of the MDRS) showed significant deterioration over time in both groups. However, as compared with supportive care alone, radiotherapy plus supportive care did not have a detrimental effect on cognitive function.
The population of elderly patients with cancer is underrepresented in clinical trials.22,23 Likely causes of this underrepresentation are study-imposed restrictions, coexisting conditions, concern about the toxic effects of treatment, patient and family preferences, and the reluctance of physicians to enroll elderly patients in clinical trials.24 Nevertheless, our study shows that these barriers may be overcome,25 even in trials that involve a rapidly progressive, fatal disease, such as glioblastoma, and a palliative-care comparison group.
In conclusion, radiotherapy increases the median survival of elderly patients with glioblastoma who have a good performance status at the start of treatment. As compared with supportive care, radiotherapy in such patients does not cause further deterioration in the Karnofsky performance status, health-related quality of life, or cognitive functions, but the survival benefit is modest.
Supported by a grant (PHRC AOM 98071, P000502) from the Programme Hospitalier de Recherche Clinique.
No potential conflict of interest relevant to this article was reported.
This article is dedicated to each patient in this trial and to their families who went through the informed-consent process and agreed to participate in a study with a palliative care group. Knowing the situation, they chose to participate in solidarity with future patients.
We thank Lucette Lacomblez and Michele Levy-Soussan for assistance with the design of the study (cognitive evaluation and supportive care program); Alain Mallet, Jacques Medioni, and Philippe Broet for their help with the statistical design of the study; and the neuropsychologists and supportive care team members who participated in the study.
Source Information
From Groupe Hospitalier Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris; INSERM Unité 711; and Université Pierre et Marie Curie, Paris (F.K.-G., K.M., J.-J.M., A.B., J.-Y.D.); Hôpital de la Timone, Marseille, France (O.C., M.B.); Hôpital Saint-Julien, Nancy, France (L.T., V.B.); Université Claude Bernard Lyon 1, INSERM Unité 842, and Hospices Civils de Lyon, Lyon, France (S.C.-C., J.H.); Centre Antoine Lacassagne, Nice, France (M.F., P.-Y.B.); Institut Bergonie, Bordeaux, France (G.K.); Centre Hospitalo-Universitaire Côte de Nacre, Caen, France (J.-S.G.); Centre Paul Papin, Angers, France (E.J.); Polyclinique de Courlancy, Reims, France (P.C.); Centre Hospitalo-Universitaire, Angers, France (P.M.); and Centre Hospitalo-Universitaire, Bordeaux, France (H.L.).
Address reprint requests to Dr. Delattre at Service de Neurologie Mazarin, Hôpital de la Salpêtrière, 47 Blvd. de l'Hôpital, 75013, Paris, France, or at jean-yves.delattre{at}psl.aphp.fr.
References
In addition to the authors, the following investigators participated in the Radiotherapy for Glioblastoma in the Elderly Study: Groupe Hospitalier Pitié–Salpêtrière, Paris — L. Lacomblez, M. Levy-Soussan, A. Mallet, C. Houssard, D. Delgadillo, M. Poitou, K. Hoang-Xuan, M. Sanson, A.F. Carpentier, F. Laigle-Donadey, S. Taillibert, P. Cornu, A. Omuro, L. Capelle, A.-L. Boch, H. Duffau, J.-M. Simon; Hôpital Européen Georges Pompidou, Paris — J. Medioni; Hôpital Paul Brousse, Villejuif — P. Broet; Hôpital de la Timone, Marseille, France — A. Schmitt; Hôpital Saint-Julien, Nancy, France — E. Garat, P. Mathieu; Institut Fédératif des Neurosciences, Hospices Civils de Lyon, Lyon, France — N. Camille, J.-P. Collin; Centre Antoine Lacassagne, Nice, France — B. Bailet, C. Ciais, F. Fauchon, C. Lebrun; Institut Bergonie, Bordeaux, France — G. Guesdan, N. Stadelmaier, I. Lombard; Centre Hospitalo-Universitaire Côte de Nacre, Caen, France — P. Delassus, C. Lalevec; Centre Hospitalo-Universitaire, Angers, France — G. Aubin, D. Fournier, and G. Hayek.
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Related Letters:
Prophylactic Radiotherapy for Glioblastoma in the Elderly
Hanna S., Vordermark D., Tartarone A., Ardito R., Romano C., Delattre J.-Y.
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Full Text |
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N Engl J Med 2007;
357:195-196, Jul 12, 2007.
Correspondence
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