Adult Low-Grade Gliomas

Abstract

Adult diffuse low-grade gliomas (LGG) are a diverse group of WHO Grade II infiltrating tumors whose treatment remains controversial. Current treatment strategies include surgical, chemotherapeutic, and radiation modalities, and initial management ranges from watchful waiting to biopsy to maximal safe resection. As these tumors infiltrate diffusely into normal brain tissue, they are usually considered surgically incurable, and, as such, much controversy surrounds the extent of surgical resection at presentation. Surgeons attempt to balance potential long-term survival benefits of operation with the possibility of immediate functional morbidity, but current practice is based on data solely from uncontrolled surgical series. In the current issue of JAMA, Jakola and colleagues address this question in the first well-controlled study of initial management strategies for adult low-grade gliomas (Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012;308(18):1881-1888.). The authors take advantage of naturally occurring divergent practice preferences at 2 Norwegian academic hospitals that exclusively serve demographically similar, geographically neighboring referral bases. This approach allows a well-controlled comparison of early surgical resection vs biopsy and watchful waiting. The population-based parallel cohort study spans 12 years of data at the 2 hospitals, and no patients were lost to follow-up. Overall, 122 of 153 (80%) of patients underwent the initial treatment approach favored at their hospital. The primary outcome (overall survival) and secondary outcome (surgical morbidity) were reviewed retrospectively, and data were analyzed with both intention-to-treat and actual-treatment analyses. The primary finding was a statistically significant survival advantage in the hospital favoring early surgical resection of low-grade gliomas over the hospital favoring biopsy followed by a “wait and scan” approach (P = .01, Figure). This advantage was magnified if patients not undergoing the locally preferred strategy were excluded from analysis. Post-hoc analysis also showed that significance was retained after controlling for multiple demographic variables known to contribute to morbidity and mortality in these patients, as well as the possibility of unmeasured differences in care quality between centers or unknown confounders specific to their referral bases. Surgical complications were comparable at the 2 institutions, though more patients undergoing biopsy underwent delayed malignant transformation.Figure: Survival curves for patients at the surgical resection preferred hospital (gray line with 95% confidence intervals in shading) vs biopsy preferred hospital (blue line).Despite the strong evidence presented in favor of early surgical resection, these results should be interpreted with caution. Specifically, the retrospective nature of the study limits the ability to control for patient-, surgeon-, and hospital-specific confounders. Also, while the study clearly demonstrates overall survival benefit for early resection, no attempt is made to assess less standardized intermediate outcomes such as progression-free survival or postoperative neurological and functional status, which often play a major role in guiding the initial treatment strategy. The authors also acknowledge the possibility of sampling error in biopsy vs resection specimens in properly classifying tumors as truly low-grade. One hypothesis arising from these results is that maximal resection increases survival primarily by reducing the overall burden of viable tumor cells capable of undergoing malignant transformation, which has been supported by other recent publications as well. However, regardless of the biological mechanism underlying these findings, this study significantly strengthens the data in support of early resection of newly diagnosed LGG over watchful waiting.