Maximum Safe Resection of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is the most frequent and deadliest form of primary brain tumor. In the United States alone, 12,000 new cases are diagnosed each year. Despite decades of refinement, the standard treatment, which consists of surgical resection followed by adjuvant chemotherapy and radiation, still results in a dismal mean survival time of only 14 months. Nonetheless, subsets of patients can be identified who have an improved natural history and response to treatment. For instance, age and preoperative performance status, the tumor’s radiographic characteristics, and the tumor’s genetic and epigenetic features have all been demonstrated to influence prognosis and predict response to treatment. The 5-year follow-up data from the original regimen of concomitant temozolomide, an alkylating agent, and focal radiation therapy for GBM, have shown that for patients who present with methylguanine methyltransferase promoter methylation, the overall survival is 13.8%, in comparison with 0% for patients without methylation who are treated with radiation therapy alone. The objectives of surgery for glioblastoma are multiple. Although the necessity of establishing the histologic diagnosis and relieving the tumor mass effect on the surrounding brain are generally accepted, the ability of tumor cytoreduction to facilitate adjuvant therapies and prolong survival are routinely challenged. The first attempt at rigorous quantification of survival benefits of microsurgical resection was produced by the MD Anderson Cancer Center neurosurgical group in 2001. The conclusion supported an all-or-none approach of tumor resection, whereby removal of 98% or more of the brain magnetic resonance imaging gadolinium-enhancing portion of the tumor was necessary to achieve a statistically significant increase in patient survival. A decade later, Sanai et al expanded on this conclusion and demonstrated the clinical value of total and subtotal extent of resection (EOR) on a percentile-by-percentile basis. Their analysis of 500 consecutive, newly diagnosed patients with GBM demonstrated that an EOR of 78% is the minimum associated with a survival benefit, and that this trend continues with more complete surgical resections. Although there is mounting evidence that suggests that EOR is associated with longer survival of patients with GBM, the concept of what can be safely resected is evolving. Improved imaging modalities, intraoperative neurophysiologic mapping, refined understanding of cortical and subcortical anatomy, and enhanced intraoperative techniques for tumor delineation, including ultrasound, magnetic resonance imaging, and optical adjuncts, have all contributed to the goal of maximizing tumor resection while keeping the surgically induced deficit at an acceptable level. But safety is crucial; the negative impact on survival of a new postoperative neurologic deficit has been clearly demonstrated. In the article that accompanies this editorial, Marko et al describe a personalized survival model for patients with GBM. They used an accelerated failure time modeling with data from 721 newly diagnosed patients with GBM to test factors that affect survival after surgical resection. Age, Karnofsky performance score (KPS), EOR, and the use of adjuvant chemotherapy and radiation were incorporated into a continuous, nonlinear, multivariable survival model for GBM. The median personalized predictive error was 4.37 months, representing greater than 20% improvement over other current methods. Thus, their model resolves some of the limitations of discontinuous survival models that are unable to describe the probabilistic nature of the continuous time process. A probabilistic approach to survival modeling provides a more accurate representation of the relationship between factors that influence the survival of patients with GBM after surgical resection, compared with what can be achieved by earlier all-or-none or EOR threshold models. The MD Anderson clinical outcome scale for patients with GBM was an attempt to stratify which patients would potentially benefit most from resection of 98% or more. Age, KPS, and radiologic tumor necrosis were singled out of a multivariable analysis for predictors of survival and were used to build the scale. The recursive partitioning analysis of Sanai et al singled out age, KPS, EOR, and tumor volume as each predictive of overall survival. Recursive partitioning analysis branching defined four risk groups with better to worse outcomes. Both efforts were meant to serve as decision-making tools so that the clinician could advise patients perioperatively. The article by Marko et al offers a better, broader, and more adaptable tool for this purpose. It allows for a continuous assessment of risks and benefits of treatment modalities for an individual patient and is tailored to the patient’s own demonstrated prognostic characteristics. In addition, it can be adjusted both preand postoperatively to aid in tumor board sessions and patient counseling. Fundamentally, it provides, for the first time, explicit evidence supporting a maximum safe resection approach to GBM surgery, in an oncologic sense. Instead of EOR thresholds that are aimed at a potential median survival benefit, this tool allows the clinician to project different scenarios of any combination of three treatment modalities, whereas EOR, radiation therapy, and temozolomide are modeled according to their combined influence on outcome. We believe that this has the potential to shift the paradigm of EOR toward the goal of maximum tumor cytoreduction in preparation for adjuvant therapy. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 8 MARCH 1