These studies highlight the prognostic and therapeutic importance of molecularly stratifying low-grade gliomas based on IDH mutation and 1p-19q co-deletion, a practice that is now much more common than when the trial was initially designed.— Julie Miller, MD, PhD, and Tracy Batchelor, MD
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The optimal treatment strategy for low-grade glioma has yet to be established, and practice patterns vary in regard to the timing of treatment, as well as the chosen treatment modality. It was against this backdrop, at a time when the benefits of radiation and chemotherapy remained uncertain but concern about long-term risks of treatment was increasing, that the European Organisation for Research and Treatment of Cancer (EORTC) initiated a randomized phase III clinical trial to examine progression-free survival in low-grade glioma patients treated with either radiation therapy or temozolomide.
At the outset, the investigators worried that radiation therapy would result in more long-term side effects, specifically radiation-induced leukoencephalopathy and resultant cognitive and functional deficits. Given these concerns, measures of quality of life and neurocognitive function were incorporated into the trial design as secondary endpoints. Outcomes of the trial were reported by Baumert et al1 and Reijneveld et al2 in The Lancet Oncology and are reviewed in the December 10, 2016, issue of The ASCO Post.
Learning From Subgroup With IDH Mutations
Although the overall results do not demonstrate a significant difference in progression-free survival between the two treatment arms, further analysis suggests that a specific molecular subset of patients with IDH mutations experience a longer delay in disease progression when treated with radiation therapy as compared with temozolomide treatment. The importance of the IDH1 and IDH2 mutations on the disease course was not published until 4 years after the trial began. Analysis for IDH mutations was incorporated from that point forward, to assess differences between what we now understand to be critically diverse molecular subtypes, namely IDH-mutant/1p-19q co-deleted tumors, compared with IDH-mutant/1p-19q non–co-deleted tumors and IDH wild-type tumors.
In an exploratory analysis, the investigators noted that patients with IDH-mutant/1p-19q non–co-deleted tumors had better outcomes with radiation therapy vs temozolomide (hazard ratio [HR] = 1.86, 95% confidence interval [CI] = 1.21–2.87). It is worth noting that this study investigated radiation therapy alone compared with temozolomide alone, without the inclusion of an arm combining the two treatment modalities. This makes it more difficult to directly compare these findings to the recently published, long-term follow-up of the Radiation Therapy Oncology Group (RTOG) 9802 trial, which demonstrated that patients with grade II glioma treated with radiation therapy plus procarbazine, lomustine, and vincristine (PCV) experienced significantly longer progression-free and overall survival than similar patients treated with radiation therapy alone.3
Although it is not clear how equivalent or interchangeable temozolomide and PCV are, one might extrapolate from these two studies together that radiation therapy followed by chemotherapy is likely better than either treatment alone, particularly for IDH-mutant glioma. For a trial in patients with low-grade glioma, however, much longer follow-up is needed before firm conclusions can be made. Since this trial enrolled patients with both IDH-mutant and IDH wild-type low-grade tumors, it is likely that many of the progression events captured at the time of analysis, within the first 5 to 6 years, are driven largely by the IDH wild-type population. For that reason, a significant difference in progression-free and/or overall survival may emerge at a later analysis, after more events have occurred.
Long-Term Effects of Cranial Irradiation
There is much concern in the neuro-oncology community regarding the long-term sequelae of cranial irradiation, particularly in a population of patients with expected life expectancy of a decade or more. To assess how radiation treatment compares with chemotherapy in terms of health-related quality of life and neurocognitive function, the authors used a combination of two validated quality-of-life scales and the Mini-Mental State Examination. It is worth noting that this test can be administered quickly and has good inter-examiner reliability; however, it also has known limitations, including sensitivity to educational background and minimal ability to identify important deficits, such as executive dysfunction or neglect, which can have a major functional impact on a patient’s life.4
The investigators obtained a very good initial compliance rate at the time of randomization and established a useful baseline for health-related quality of life and neurocognitive function prior to beginning treatment. Notably, impaired cognitive function was present in approximately 13% to 14% of patients at the outset. Unfortunately, compliance with additional testing for both measures dropped significantly during the follow-up period. These data were collected for only 50% of patients at the 3-year time point.
Although no significant differences in either quality of life or neurocognitive function were noted between the two treatment arms, the poor compliance with testing is likely nonrandom and therefore may be preventing the investigators from capturing the true magnitude of overall change during the 3 years. Furthermore, the authors noted higher compliance in temozolomide-treated patients, as well as lower compliance in those with a lower performance status (World Health Organization performance status 2). One wonders whether there is indeed a more significant decrease in either measure in the radiation group that is not being observed in this study, because the people suffering from the side effects being assessed are the ones who are less willing or able to be tested. More detailed, prospective neuropsychologic testing may be required to better identify any key differences that exist between the two treatment arms.
Longer Follow-up Needed
Another difficulty in interpreting these data, which is acknowledged by the investigators, is the fact that the follow-up period of 3 years is likely too short to observe the full spectrum of delayed neurotoxicity from radiation treatment, which may not manifest for 5 or more years after treatment. Furthermore, the trial was powered to find a 10-point or greater difference in health-related quality-of-life scores, based on previous reports in the literature that this is a clinically meaningful difference. It is uncertain whether this difference is relevant in this particular patient population.
Overall, the short-term analysis of this study does not provide clear evidence that one therapy is inferior to the other in terms of either progression-free survival or cognitive function and quality of life. Clinicians should, however, interpret these results with caution until longer-term follow-up data become available. These studies highlight the prognostic and therapeutic importance of molecularly stratifying low-grade gliomas based on IDH mutation and 1p-19q co-deletion, a practice that is now much more common than when the trial was initially designed.
These data are suggestive that treatment should not necessarily be “one size fits all,” as there are clues that IDH-mutant/1p-19q co-deleted tumors may respond differently to different treatment modalities than IDH-mutant/1p-19 non–co-deleted tumors. Finally, the health-related quality of life assessments demonstrate that a significant number of patients suffer from cognitive issues at the time of diagnosis, and increased awareness of this finding may help oncologists work to address these deficits more effectively to help patients better maintain functionality and independence.
Clinical Implications
How do these two trials inform the neuro-oncologist’s practice? With the strictest interpretation of these data, the evidence supports the treatment of patients with IDH-mutant non–co-deleted gliomas with radiation therapy over temozolomide for optimal progression-free survival advantage, whereas all others may fare equally well with either choice. In the context of the results of RTOG 9802, however, the combination of radiation therapy followed by chemotherapy of some sort may provide the optimal treatment regimen for patients with IDH-mutant low-grade glioma. ■
Disclosure: Drs. Miller and Batchelor reported no potential conflicts of interest.
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