Many individuals within the medical community argue that cancer trials do not represent patients in the real world. For example, some cancer subtypes are prevalent in the elderly, yet patients older than 65 years may not be recruited for trials of intensive interventions. As a result, older adults may be treated with less-aggressive therapy that can affect survival. Elderly patients with glioblastoma may be disadvantaged if less-aggressive therapy is chosen as the median survival for all patients with this type of cancer is less than 2 years. Temozolomide, an oral chemotherapy drug from the alkylating class, in combination with a 6-week course of radiotherapy has been shown to improve survival in patients with glioblastoma. However, patients in the trial were aged 70 years and younger. Thus, questions remain about management of elderly patients with glioblastoma: What is the effect on survival of a shorter course of radiotherapy, the addition of temozolomide, and the presence of an O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation?
In this week’s issue of NEJM, Perry and colleagues compared short-course radiotherapy with a new chemoradiation strategy in patients with glioblastoma who were age 65 years and older. In a phase 3 trial, 562 patients from four continents were randomized to receive radiotherapy alone for 3 weeks or the same course of radiotherapy with concurrent temozolomide for 21 days. Following the 3-week course of chemoradiation, patients continued adjuvant temozolomide for 5 consecutive days every 28 days for 12 cycles or until disease progression. The final analysis included 271 patients in each arm.
The median age of trial participants was 73 years; 30% were older than 75 years. Median overall survival (the primary endpoint) was significantly longer in patients treated with radiotherapy plus temozolomide than in patients treated with radiotherapy alone (9.3 vs. 7.6 months; hazard ratio, 0.67; 95% CI 0.56–0.80; P<0.001). Similarly, chemoradiation was associated with significantly longer progression-free survival (HR, 0.50; 95% CI 0.41–0.60; P<0.001). Side effects such as nausea and constipation were worse in patients those treated with chemoradiotherapy. Analyses of other quality-of-life symptoms and functions were similar between the two treatment arms.
In analysis stratified by MGMT promoter methylation status, promoter methylation was associated with longer survival and better response to temozolomide. Among patients with methylated MGMT promoter status, combination therapy was associated with significantly longer median overall survival than radiotherapy alone (HR, 0.53; 95% CI 0.38 to 0.73; P<0.001). Additionally, exploratory analyses in this subgroup suggested that chemoradiation was associated with a persistent survival advantage at 24 months after randomization. Among patients with unmethylated MGMT status, a 2.3-month difference in survival between the two treatment arms was not statistically significant (P=0.055).
Contrary to the belief that increasing age may be associated with poorer outcomes, younger patients (aged, 65–70 years) derived less benefit from chemoradiation than patients aged 71–75 years and older than 76 years. The authors suggest that this finding might reflect the inclusion of younger patients more likely to have worse outcomes. However, no other differences among age groups were detected in characteristics such as performance status or cognitive scores.
Using these study results, physicians should be able to help navigate elderly patients with glioblastoma through the risks and benefits of proceeding with intensive treatment options. This trial provides a framework for designing trials on combination chemotherapy and radiotherapy that include elderly patients.
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Ramya Ramaswami is a 2016-2017 NEJM editorial fellow. She is a medical oncologist within the National Health Services of the United Kingdom. Ramya received her medical degree, postgraduate medical and oncology training from Imperial College London, and a masters in public health from Columbia University, Mailman School of Public Health. Her clinical and research interests include cancer prevention, viral driven cancers, as well as disparities and access issues in global oncology.