The Role of Temozolomide in Elderly Patients with Glioblastoma
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- Abrey, L.E. Curr Neurol Neurosci Rep (2010) 10: 155. doi:10.1007/s11910-010-0106-6
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Brandes AA, Francheschi E, Tosoni A, et al.: Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer 2009, 115:3512–3518.
The administration of temozolomide concomitant with and adjuvant to radiotherapy was established as the standard of care for patients with newly diagnosed glioblastoma following the publication of a large randomized clinical trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) . However, this trial had as an eligibility criterion an upper age limit of 70 years, and thus the value of this therapy in older patients with glioblastoma could not be determined.
Management of older patients with glioblastoma is an area that has been relatively neglected. In particular, prospective clinical trials in this patient population are rare, despite the fact that glioblastoma occurs most commonly in patients aged 65 to 84 years and the median age for diagnosis of a glioblastoma is between 60 and 65 years. Advancing age is recognized as a poor prognostic factor in glioblastoma, and treatment of older patients often is approached in a somewhat nihilistic fashion; however, increasingly it has been recognized that elderly oncology patients may benefit from and desire the same aggressive management given to younger patients.
Recognizing the importance of these unanswered issues, Brandes et al. conducted a prospective clinical trial to examine the efficacy of concomitant and adjuvant temozolomide in elderly patients with glioblastoma; in addition, they assessed predictive markers of tumor response.
The primary goal of this study was to determine progression-free survival at 6 months, with the hypothesis that a 6-month progression-free survival rate of 50% would demonstrate adequate activity of the proposed regimen, meriting further study. Secondary end points included median overall and progression-free survival, assessment of toxicity, and investigation of MGMT methylation status in available tumor tissue.
This was a prospective, single-stage, phase 2 study. Patients ≥65 years old with a histologic diagnosis of glioblastoma, a Karnofsky performance score (KPS) ≥70, and a Mini-Mental Status Examination score ≥27 who had adequate organ function were permitted to enroll. Treatment consisted of conventional fractionated radiotherapy to a total dose of 60 Gy in 30 fractions. Temozolomide was administered at a dosage of 75 mg/m2 daily during radiotherapy. Standard adjuvant cycles of temozolomide, 150 mg/m2 daily for 5 days repeated every 28 days, began 4 weeks after completion of radiotherapy. National Cancer Institute Common Toxicity Criteria version 3.0 was used to monitor toxicity. MRI or CT imaging was assessed using Macdonald criteria approximately every 2 months. Survival was assessed using Kaplan-Meier methodology. MGMT status was assessed using methylation-specific polymerase chain reaction. The predetermined sample size was 53 patients.
Fifty-eight patients with a median age of 68 years (range, 65–82 years) and a median KPS of 80 were enrolled. Progression-free survival at 6 and 12 months was 79% and 35%, respectively. Median overall and progression-free survival of the entire group was 13.7 and 9.5 months.
Generally, the treatment was well tolerated, with the most common acute toxicity being myelosuppression. Fewer than 10% of patients interrupted or discontinued treatment for acute toxicity. However, a significant number of patients developed cognitive deterioration an average of 6 months after completion of radiotherapy; 31% of patients were reported to have grade 1 to 2 mental status deterioration, and 25% had grade 3 to 4 deterioration. Leukoencephalopathy (all grades) was reported in only 10%.
MGMT analysis was available and informative in 37 patients; 43% had methylated MGMT promoter, and 57% had an unmethylated promoter. On multivariate analysis, methylated MGMT promoter was shown to be a positive prognostic factor for both progression-free and overall survival. The only other variable that demonstrated independent prognostic significance for progression-free survival was KPS; no other variable predicted overall survival.
Radiotherapy has been established as the standard of care for older patients with glioblastoma . The current study of concurrent and adjuvant temozolomide met its primary end point, achieving a 6-month progression-free survival greater than 50%, even when considering the lower bound of the confidence interval (actual rate of 79% with a 95% CI of 69%–90%), suggesting that temozolomide has activity in elderly patients with glioblastoma. However, the authors also observed a significant rate of neurocognitive toxicity, which developed in 56% of patients and did not appear to be associated with more advanced age.
MGMT methylation status appeared to have a distribution and prognostic impact similar to that reported in younger glioblastoma patients . The ultimate conclusion from the authors was that a randomized study is required to determine the real benefit of this regimen in an elderly population, to fully account for any treatment-induced delayed toxicity.
This excellent study illustrates several critical issues in geriatric and neurologic oncology. Perhaps the most important is the demonstration that it is feasible to design and accrue patients to a prospective clinical trial in the elderly brain tumor population in a timely fashion. Although it is worth noting that most patients were between the ages of 65 and 70 (71%), the oldest patient enrolled was 82 years old. The overall study enrollment was completed at a single small center in just slightly more than 3 years. Given that patients over the age of 60 comprise at least half of the glioblastoma population, this proof of principle should motivate the conduct of other clinical trials in this age group.
The results of this study and others in the literature strongly suggest that temozolomide is an active drug in this patient population [4–7]. However, all these studies have been uncontrolled single-arm studies and likely have a bias in terms of patient selection and other criteria. An ongoing randomized clinical trial by the EORTC and NCIC (NCT00482677) will randomly assign older patients to receive a short course of radiotherapy alone or radiotherapy with concurrent and adjuvant temozolomide, with a primary end point of determining a difference in overall survival; quality of life and toxicity are secondary end points. However, early data from Brandes et al. suggest that adjuvant temozolomide in the elderly may have the same magnitude of benefit as concomitant and adjuvant temozolomide, which may be an important issue in light of the toxicity issues discussed in the following paragraph .
In elderly patients, improvements in survival may be attenuated by an increased risk of treatment-related toxicity. It is interesting to note that rates of acute toxicity do not appear to be higher than anticipated; however, the authors are to be commended on their observation of delayed cognitive decline, which represents an important quality-of-life issue in the elderly. It is possible that this decline represents a delayed treatment-related toxicity similar to that seen in patients with primary central nervous system lymphoma, which might be a result of enhanced toxicity from administering temozolomide during radiotherapy with a detrimental impact on neural tissue or stem cells. Alternatively, if survival truly is improved in subsets of patients, previously unseen toxicities may be observed that would not have emerged with shorter survival.
The molecular makeup of glioblastoma may vary across different age groups . This study suggests that MGMT methylation status is similar in terms of distribution and prognostic significance in the elderly; other groups have not shown similar results . However, the sample size analyzed here was small, and most patients with available tissue were between 65 and 70 years old.
Future studies will need to focus on optimizing our treatment regimens and understanding the molecular phenotype of glioblastoma in the elderly. In addition, it will be critical to assess the goals of care and the treatment wishes of elderly patients and their families. In practical terms, physicians managing elderly patients with glioblastoma today should be encouraged to offer these patients participation on available clinical trials. When this approach is not feasible or available, then it is crucial to discuss the potential benefit of adding temozolomide to standard radiotherapy in the context of the potential for delayed cognitive decline.
No potential conflict of interest relevant to this article was reported.