Meta-Analysis Reveals Chemotherapy Benefit for Adults with Glioma
Abstract & Commentary
Synopsis: A meta-analysis of published (and 1 unpublished) clinical trials of adjuvant chemotherapy after surgery and radiation revealed a significant, albeit modest enhancement of survival in patients with high-grade glioma. Whether examined as a total population of more than 3000 adult high-grade glioma patients or by subsections defined by age, gender, histology, or volume of residual disease after surgery, chemotherapy produced the same modest response, which by meta-analysis reached a significant level. Thus, the idea that high-grade gliomas will respond to chemotherapy and improve survival by a few months may be expected. However, additional studies are called for to determine if such enhancement in survival is of sufficient quality to warrant the risks and costs associated with treatment.
Source: Glioma Meta-Analysis Trialists Group. Lancet. 2002;359:1011-1018.A number of individual clinical investigations spanning the past 3 decades have indicated modest, if any benefit, of adjuvant chemotherapy after surgery and radiation for adults with high-grade gliomas. Thus, the UK Medical Research Council Clinical Trials Unit charged an international group of investigators (the Glioma Meta-Analysis Trialists Group) to carefully review all published and unpublished clinical trials to determine, en masse, if there is discernible benefit demonstrated by meta-analysis. Data from 3004 patients participating in 12 clinical trials that were considered suitable for this analysis were reviewed and updated. Several additional reports were examined, but these were excluded for any of a number of reasons, most notably that they did not compare directly the effects of the addition of chemotherapy upon surgery plus radiation. In the various studies, the doses of radiation and the fields treated were variable, as were the chemotherapy regimens used. In all studies, at least 1 of the drugs used was a nitrosourea. Typically the dose of radiation selected ranged from 40 to 60 Gy.
Overall, the results indicated significant prolongation of survival associated with chemotherapy, with a hazard ratio of 0.85 (95% CI, 0.78-0.91) or a 15% relative decrease in the risk of death. This effect is equivalent to an absolute increase in 1-year survival of 6% (from 40-46%) and a 2-month increase in median survival. Surprisingly, there was no evidence that the effect of chemotherapy differed in any group of patients defined by age (< 40, 40-59, > 60), sex, histology, performance status, or extent of resection.
Comment by William B. Ershler, MD
Despite the infiltrative nature of high-grade gliomas that make them nearly impossible to resect and the virtual certainty that disease will recur, even after radiation therapy, the benefits of adjuvant chemotherapy in patients has been difficult to establish. Many clinical trials have been published demonstrating marginal, but not significant, enhancement in event free survival. Thus, typically, standard of care remains cytoreductive surgery followed by radiation. Yet, survival remains low, less than 1 year in most series.
The current report provides some evidence that chemotherapy may add some time beyond surgery and radiation. Although the improvement in survival was quite modest, the finding reached a level of unquestionable statistical significance. Thus, the report is yet another example of the power of carefully performed meta-analysis. In not one of the published clinical trials was there a significant enhancement of survival demonstrable, but when subjected to this type of analysis, such was unequivocally the case.
Of course, one might argue that the addition of 2 months of life for patients with high-grade gliomas by chemotherapy needs to be balanced by any impairment in quality-of-life for the several months in which the patient is treated. Yet, with the clear demonstration that chemotherapy provides survival benefit, these quality of life issues should be carefully examined and treatment regimens developed that are both tolerable and effective. Furthermore, it is now clear that gliomas are not absolutely resistant to cytoreductive chemotherapy, and new agents, particularly those that are, or can be made to be lipid soluble (and thus able to permeate the brain substance), need to be developed and tested in this population.
Dr. Ershler of INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studios in Aging, Washington, D.C.
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