“The results [of the study by Perry et al] underscore that chronologic age by itself should not be considered a barrier to more aggressive combination treatment.”— Isabel Arrillaga-Romany, MD, PhD (left), and Tracy T. Batchelor, MD, MPH
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In 2005, Stupp and colleagues published their landmark paper demonstrating in a randomized phase III trial that the addition of temozolomide to radiation increased overall survival in patients with newly diagnosed glioblastoma. Notably, patients over age 70 years were excluded from this study.1 Since then, concurrent radiation plus temozolomide followed by 6 months of adjuvant temozolomide has been considered the standard of care for the treatment of glioblastoma.
Though the median age at the time of glioblastoma diagnosis is 64, most randomized trials have excluded elderly patients, leaving unanswered questions about best treatment practices for approximately half of the glioblastoma patient population. The absence of specific data demonstrating the benefit of multimodality therapy for older patients and concerns that elderly patients with poor performance status and unfavorable overall prognosis would poorly tolerate combination therapy led investigators to consider alternative, less-aggressive treatment strategies.
Several studies have investigated these alternative treatment strategies. In patients greater than 60 years of age, a prospective randomized trial compared a short course (40 Gy in 3 weeks) to the standard course of radiation (60 Gy in 6 weeks) and found no significant difference in median overall survival (5.6 vs 5.1 months) but did show improved tolerability with the short course of radiation. Fewer patients in the short-course radiation arm required an increase in corticosteroid dose (23% vs 49%).2
Chemotherapy as a solo treatment strategy has also been evaluated in prospective trials. The ANOCEF trial in newly diagnosed glioblastoma patients older than 70 years and with baseline poor functional status (Karnofsky performance status < 70) treated patients with temozolomide alone. Compared to historical controls receiving supportive care, temozolomide improved survival and was well tolerated, with a more pronounced survival benefit observed in patients with a methylated O6-methylguanine-methyltransferase (MGMT) promoter vs unmethylated MGMT (median overall survival = 31 vs 19 weeks, respectively).3
The NOA-08 and Nordic Clinical Brain Tumor Study Group further supported the use of MGMT methylation as a predictive biomarker of response to treatment with temozolomide in elderly glioblastoma patients. The NOA-08 study enrolled newly diagnosed patients older than 65 years with Karnofsky performance status greater than 60 and randomized subjects to treatment with temozolomide only (dose-intensified regimen administered for 7 consecutive days out of 14 days, or 1 week on/1 week off) vs standard radiation (60 Gy in 30 fractions). In all patients, there was no significant difference in overall survival (8.6 vs 9.6 months) or progression-free survival (3.3 vs 4.7 months), though patients with MGMT promoter methylation did derive a therapeutic advantage from chemotherapy over radiation (event-free survival = 8.4 vs 4.6 months).4
The Nordic trial enrolled patients over age 60 years (median age = 70 years) with newly diagnosed glioblastoma and randomized subjects to standard radiation (60 Gy in 30 fractions), hypofractionated radiation (34 Gy in 10 fractions), or chemotherapy with temozolomide administered for 5 consecutive days over 28-day cycles.5 Here, in comparison with standard radiation, median overall survival was longer with temozolomide (6.0 vs 8.3 months, respectively) but not with hypofractionated radiation (7.6 months). Overall survival outcomes were similar for the temozolomide and hypofractionated radiation arms.
Again, methylation of the MGMT promoter proved a biomarker of response to treatment with temozolomide alone, with median overall survival of 9.7 months vs 6.8 months in those without tumor MGMT promoter methylation. Radiation did not confer the same survival advantage in patients with MGMT promoter methylation.5 Based on this limited evidence, treatment options for elderly patients with glioblastoma have included either radiation alone (and usually hypofractionated schedules) or temozolomide alone for patients with MGMT promoter methylation.
Short-Course Radiation Plus Temozolomide
Perry and colleagues’ phase III trial, published in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, was the first to prospectively investigate the efficacy and tolerability of combination multimodality treatment in newly diagnosed elderly glioblastoma patients aged 65 and over with an Eastern Cooperative Oncology Group performance status of 2 or below.6 Patients were randomized to radiation plus concurrent daily temozolomide (75 mg/m2/d) followed by adjuvant temozolomide (150–200 mg/m2/d for 5 consecutive days out of 28-day cycles for up to 12 cycles) vs radiation alone. Radiation for both arms was administered over 3 weeks for a total of 40 Gy.
Enrolled patients were determined by their treating physician not to be suitable for the standard course of radiation. Patients were randomized 1:1, and analysis of the primary objective of overall survival was conducted in the intention-to-treat population.
Several potentially practice-changing findings emerge from this investigation. First, all patients derived survival benefit from combination treatment with radiation and temozolomide vs radiation alone (median overall survival = 9.3 vs 7.6 months). Notably and not surprisingly, the survival advantage conferred by the addition of temozolomide to radiation was greatest in patients with methylation of the MGMT promoter (overall survival = 13.5 vs 7.7 months), but the advantage was still present in patients with unmethylated MGMT (overall survival = 10.0 vs 7.9 months).
Second, combination treatment was well tolerated in this elderly population, with a high and comparable treatment adherence rate between the two study groups. Last and importantly, the survival benefit of combination treatment did not come at a cost to quality of life: As measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) and the EORTC brain module (QLQ-BN20), administered weekly during radiation and every 3 months thereafter until disease progression, there was no significant difference between treatment groups.
Overall, these results support consideration of treatment with combined hypofractionated radiation (to at least 40 Gy) and temozolomide among elderly glioblastoma patients with a relatively good performance status, regardless of MGMT methylation status. Furthermore, the results underscore that chronologic age by itself should not be considered a barrier to more aggressive combination treatment.
In fact, given good tolerability of this regimen, we believe future work should consider taking treatment one step further to include a study arm with a standard dose of radiation combined with chemotherapy in a similarly designed protocol. There likely exists a population of elderly patients that would derive benefit from the full 6-week course of radiation in combination with temozolomide without a significant compromise to quality of life, though we do not yet understand well how to identify them. ■
Disclosure: Dr. Arillaga-Romany reported no conflicts of interest. Dr. Batchelor is a consultant for Merck & Co, Proximagen/Upsher, Roche, Amgen, and NXDC, and has received research support from Pfizer.
1. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005.
2. Roa W, Brasher PM, Bauman G, et al: Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: A prospective randomized clinical trial. J Clin Oncol 22:1583-1588, 2004.
3. Gállego Pérez-Larraya J, Ducray F, Chinot O, et al: Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: An ANOCEF phase II trial. J Clin Oncol 29:3050-3055, 2011.
4. Wick W, Platten M, Meisner C, et al: Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol 13:707-715, 2012.
5. Malmström A, Grønberg BH, Marosi C, et al: Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial. Lancet Oncol 13:916-926, 2012.
6. Perry JR, Laperriere N, O’Callaghan CJ, et al: Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 376:1027-1037, 2017.