Dr. Edward Halperin challenges the premise that the "standard of care" treatment for malignant glioma patients, 6 weeks of cranial irradiation and nitrosourea chemotherapy, is appropriate for all patients. In particular, he maintains, those with the most unfavorable prognosis-the elderly and impaired glioblastoma multiforme patients-may have an equivalent outcome when treated with a more cost-effective, shorter course of hypofractionated irradiation without chemotherapy. There are three lines of evidence used to support his position:
The poor results for such patients entered into clinical trials evaluating variations of aggressive postoperative chemoradiation.
The seemingly equivalent outcomes of comparable patients reported in phase II trials of short-course irradiation without chemotherapy.
The underrepresentation of the most unfavorable glioblastoma multiforme patients in large randomized trials.
None of this evidence or the resulting conclusions should surprise us. There exist both randomized and nonrandomized data identifying subsets of patients with such malignancies as non-small-cell lung cancer, head and neck cancer, and certain pelvic malignancies with such unfavorable prognoses that brief, palliative irradiation regimens are equally efficacious as the standard, more aggressive multimodality approaches. For many malignancies, advanced age confers an unfavorable influence on prognosis because of its association with coexisting medical conditions or with an impaired ability to withstand aggressive therapy. For malignant gliomas, the influence of age on prognosis is even stronger. Using such assays of growth potential as the bromodeoxyuridine labeling index, Hoshino et al demonstrated an age-dependent relationship in the growth potential among histologically similar tumors, which may, in part, explain the poorer prognosis of older glioblastoma multiforme patients .
Two Questions-and Answers
Several questions related to both cost containment and appropriateness of care are posed by Dr. Halperin's essay and include: Is surgery necessary for elderly or impaired patients with imaging or metabolic studies highly suggestive of malignant glioma? Should the current postoperative standard of care for elderly or impaired malignant glioma patients be short-course hypofractionated irradiation? My answers to these questions are "No!" to the first and "Maybe?" to the second. However, as recently discussed in another editorial, there can be substantial therapeutic benefit to an aggressive debulking surgical procedure among patients who are neurologically impaired by a tumor's mass effect . With improved neurosurgical techniques, such as cortical mapping, and improved perioperative care more widely available, such palliative benefit is now available to an increasing number of unfavorable malignant glioma patients.
Regarding the appropriate postoperative standard of care for older patients, the time has clearly arrived to acknowledge the heterogeneity in both prognosis and response to various therapies among malignant glioma patients. In 1994, the Radiation Therapy Oncology Group (RTOG) departed from the practice of conducting a single trial for all newly diagnosed malignant glioma patients, and activated independent clinical trials for patients with aggressive oligodendroglioma, anaplastic astrocytoma, radiosurgery-eligible glioblastoma multiforme, and radiosurgery-ineligible glioblastoma multiforme. The majority of elderly and/or impaired patients discussed in Dr. Halperin's essay would either be eligible for the radiosurgery-ineligible glioblastoma multiforme trials or would fail to meet performance status criteria of any trial. There would, however, be a number of these patients who could be enrolled in the radiosurgery-eligible glioblastoma multiforme trial following an aggressive surgical debulking. For such patients, for whom a new modality could improve upon the disappointing outcome with standard therapy, a nihilistic approach to therapy is not appropriate.
There does exist a subset of glioblastoma multiforme patients with a level of neurologic impairment not reversible by surgery for whom short- course irradiation is appropriate. As mentioned by Dr. Halperin, the recursive partitioning analysis of prognostic factors among over 1,500 patients published by the RTOG identifies several subgroups with a particularly poor prognosis with standard therapy . This group includes older patients with low performance status and impaired mental status, and older patients undergoing biopsy only. Unless a promising clinical trial exists for such patients, short- course irradiation alone is appropriate therapy for such patients.
However, there is evidence that such an approach is not appropriate for all elderly glioblastoma multiforme patients. In a clinical trial referred to by Dr. Halperin as evidence that short- course irradiation is appropriate for elderly/impaired glioblastoma multiforme patients, Baumann et al compared the outcome of 29 such patients treated with 30.0 Gy/10 fractions to a historic cohort of patients treated with standard irradiation . While the outcome for patients with a low performance status was equivalent with either standard or short-course irradiation, there was a significant advantage to full-dose irradiation for patients over age 65 with a good performance status. Clearly, this is a group for whom efforts should continue to improve outcome through well-controlled trials of irradiation dose escalation, the testing of new systemic therapy approaches, and the refinement of neurosurgical techniques.