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Chemoradiation improves OS, PFS in older patients with glioblastoma
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CHICAGO — The addition of concomitant and adjuvant temozolomide to hyperfractionated radiation therapy significantly improved PFS and OS among older patients with newly diagnosed glioblastoma, according to phase 3 study results presented during the plenary session of the ASCO Annual Meeting.
Patients with MGMT–methylated tumors derived the greatest benefit from temozolomide (Temodar, Merck), results showed.
Although glioblastoma occurs primarily in older adults, no clear guidelines for treatment have been defined.
“The peak age of incidence of glioblastoma is 64 years, and the incidence appears to be increasing with our aging population,” James R. Perry, MD, FRCPC, Crolla Family endowed chair in brain tumor research at the Odette Cancer and Sunnybrook Health Sciences Centres in Toronto, said during a press conference. “The current best practice is surgical resection, followed by radiotherapy combined with chemotherapy.”
A recent trial conducted by the EORTC suggested a survival benefit could be gained through the addition of temozolomide to radiation therapy in newly diagnosed patients; however, the researchers observed a trend of decreasing benefit with increasing age, and the potential OS benefit of the combination in older patients remained unknown.
“The studies that we have in older patients over 65 years have only compared radiation schedules head-to-head, or radiation alone vs. temozolomide alone,” Perry said. “There has never been a trial of combined chemotherapy with radiation in elderly patients.”
Perry and colleagues conducted a global randomized clinical trial of 562 older patients (median age, 73 years; range, 65-90; 61% men), whom they randomly assigned to 40 Gy radiation therapy in 15 fractions, with or without 3 weeks of concomitant temozolomide and monthly adjuvant temozolomide (n = 281 for both).
Patients assigned adjuvant temozolomide received treatment for up to 12 cycles or until progression.
Patients assigned temozolomide achieved a median OS of 9.3 months, compared with 7.6 months for patients assigned radiation alone (HR = 0.67; 95% CI, 0.56-0.8). Similarly, the combination arm had a median PFS of 5.3 months, compared with 3.9 months for radiation alone (HR = 0.5; 95% CI, 0.41-0.6).
A total of 462 patients provided an adequate tissue sample for MGMT analysis, which has been conducted in 354 patients to date. Patients with MGMT–methylated tumors (n = 165) assigned temozolomide had a median OS of 13.5 months, compared with 7.7 months for those assigned radiation alone (HR = 0.53; 95% CI, 0.38-0.73).
Unmethylated patients assigned the combination had a median OS of 10 months, compared with 7.9 months in patients assigned radiation (HR = 0.75; 95% CI, 0.56-1.01).
A quality-of-life analysis showed no differences in physical, cognitive, emotional or social functioning between arms. Patients assigned temozolomide reported more nausea, vomiting and constipation than those assigned to radiation alone.
The researcher reported high patient adherence to therapy, with more than 97% of patients able to complete 3 weeks of chemoradiation.
“This is quite important, because the elderly often have difficulties with mobility, or with distance from treatment centers,” Perry said. “They sometimes don’t have a caregiver who is able to bring them back and forth to treatment, so the shorter radiation schedule is an advantage.”
Thirty-nine percent of patients assigned temozolomide and 41% of patients assigned radiation alone received systemic therapy after progression.
“Oncologists now have evidence to consider radiotherapy with temozolomide in all newly diagnosed elderly patients with glioblastoma,” Perry said. – by Cameron Kelsall
Reference:
Perry JR, et al. Abstract LBA2. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: This study received funding from the Canadian Cancer Society Research Institute and through an unrestricted grant from Schering-Plough/Merck. Perry reports stock and ownership interests in DelMar Pharmaceuticals and VBL Therapeutics. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Andrew B. Lassman, MD
The take-home message of this trial is that regardless of the age of the adult patient, it is now becoming the standard of care to give radiotherapy plus temozolomide to patients with newly diagnosed glioblastoma. The second important takeaway is that the benefit of temozolomide was most pronounced among those with glioblastomas that demonstrated methylation of the promoter for a gene called MGMT. However, there was also a benefit regardless of MGMT methylation.
The context for why this is important is twofold. One, the prior practice changing trial that led to our current standard of care of radiotherapy and temozolomide in patients with glioblastoma excluded patients aged older than 70 years. In addition, that prior trial suggested the benefit of temozolomide decreased with age. Therefore, it was unclear whether temozolomide prolonged survival when combined with radiotherapy in patients over 70.
The other important aspect of this study was the length of the radiotherapy course. In this trial it was 3 weeks, whereas it was 6 weeks in the prior landmark trial by Stupp and colleagues. Six weeks of radiotherapy can be a rough treatment in older patients, and there had been previous studies demonstrating that a shortened course, using a technique called hypofractionation, was not inferior to a 6-week course in older patients.
What remains unclear is whether radiotherapy itself can be omitted in elderly patients with MGMT–methylated tumors. This trial included two arms, both of which had radiation. The question was whether adding temozolomide to radiation was beneficial, and the answer was yes. The flip question of randomly assigning patients to get temozolomide alone or with radiotherapy remains unanswered.
References:
Roa W, et al. J Clin Oncol. 2004;doi:10.1200/JCO.2004.06.082.
Stupp R, et al. N Engl J Med. 2005;10;352:987-996.
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Julie M. Vose, MD, MBA, FASCO
This is a really important study for a number of reasons. We are testing a very important question worldwide, and we are testing it in the older population that actually gets the disease. It is so important to make sure that our clinical trials are extending to the patients who are going to benefit from them.
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Stephanie Weiss, MD
This study is likely to change the practice patterns for older individuals with glioblastoma. Survival is particularly poor for the elderly, and because conventional treatment has potential side effects and requires 6 weeks of daily medical visits for chemoradiotherapy — often a significant portion of the patient’s remaining life — both patients and their physicians often take a fatalistic view, opting to forgo therapy as a quality-of-life decision.
A 2004 study showed that a time-shorted 3-week course of radiation was equally effective as conventional radiotherapy for the elderly population. Wide adoption of this strategy was blunted, however, because shortly after it appeared a major trial was published in The New England Journal of Medicine demonstrating that the addition of temozolomide chemotherapy to conventional radiotherapy improved median survival time. More impressively, there was a meaningful improvement in 2- and 5-year OS. Although elderly patients were excluded from that trial, the lack of chemotherapy in the short-course radiotherapy scheme doomed it as a “palliative” strategy for older patients deemed too frail to undergo definitive therapy.
The present study compares the 3-week radiotherapy regimen with and without temozolomide in a fashion similar to The New England Journal of Medicine trial. Again, there was a modest but significant median survival benefit with combined therapy, and a more impressive “tail effect.” Although overall numbers are still low, survival at 2-years more than tripled with the addition of temozolomide, from 2.8% to 10.4%.
For a subgroup whose tumor harbored a methylated MGMT promoter — a marker associated to response to therapy — results are more impressive, with the addition of temozolomide near doubling survival time.
Importantly, although patients receiving temozolomide more frequently experienced nausea, vomiting and constipation, comprehensive objective measures of patient quality of life were comparable for both groups.
This study demonstrates that our best therapies can be effective and tolerable and offer a meaningful benefit to older patients. These individuals with newly diagnosed glioblastoma should not be routinely dismissed to palliative therapies any more than younger patients.
References:
Roa W, et al. J Clin Oncol. 2004;doi:10.1200/JCO.2004.06.082.
Stupp R, et al. N Engl J Med. 2005;10;352:987-996.
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