Towards a Genomic Definition of Completeness of Resection

The relationship between extent of surgical resection (EOR) and survival of patients with high grade gliomas has been a point of debate over the past several decades. As ethical considerations generally preclude the prospective randomization of patients to a complete versus intentionally subtotal tumor resection, the issue of whether EOR is causally related to survival likely will not be addressed by a prospective, randomized trial. Yet, a growing body of large retrospective analyses have provided compelling evidence that more extensive resections are associated with better outcomes, so long as surgical morbidity is temporary and/ or minimized. 1 – 9 That said, there remain important questions as to whether there are biological considerations that underlie the relationship between EOR and outcome. Are there molecular and/or genetic differences between tumors that appear to be more “resectable” than others at initial presentation? Is the observed relationship between EOR and outcome dependent upon the molecular class of the tumor, 10 and/or on specific hallmark mutations present in gliomas? Independent of the questions regarding the biological underpinnings of EOR and outcome, are more fundamental questions regarding the meaning of EOR itself. The analysis of EOR has not been uniform for the various grades of gliomas. For example, a complete resection in the setting of a WHO grade II glioma specifically relates to the complete removal of tumor-associated T2 or FLAIR abnormality on an MRI. Conversely, complete resection of a WHO grade IV glioma (GBM) relates to the removal of contrast-enhancing tumor tissue but ignores the surround T2/ FLAIR portions of the disease, which are known to include infiltrating glioma cells. These contradictions have been recognized by the Response Assessment in NeuroOncology working group, which has proposed language that more clearly describes the completeness of resection in terms of the pre-operative target tissue (ie, enhancing vs. non-enhancing). 11 In a new retrospective analysis of EOR and outcome published in this volume ofNeuroOncology, Cahill and colleagues 12 have evaluated the impact of IDH-1 mutational status. They evaluated the EOR results for 335 patients with newly diagnosed high grade (WHO grade III or IV) gliomas where tumor tissue was also subjected to determination of IDH1 status by immunohistochemistry and sequencing and they have used these data to address some of the questions noted above. Specifically, they found that there might be a biological basis to the resectablity of gliomas, as IDH-1 mutation was an independent predictor of the success of obtaining a complete resection of enhancing disease (CRET). They also found that IDH-1 status might have an impact on what the goal for resection should be. Patients with IDH-1 wild-type tumors saw a benefit from maximal resection of the enhancing disease, but no further benefit from removal of non-enhancing disease. Most interestingly, patients with IDH-1 mutant tumors did best if all enhancing and non-enhancing disease was removed at surgery. The relationship between completeness of resection and survival was strongest in this group of patients. The impact of IDH-1 status on the survival benefit of a complete resection was an unexpected finding as, currently, we have no understanding of the specific mechanistic link that would suggest that IDH-1 mutation would alter the link between resection of non-enhancing tumor tissue and survival. With the usual caveats regarding the retrospective nature of the study and possibility for selection bias left aside, there are several important considerations and implications that arise from these findings, many of which are discussed by the authors. One of the most interesting issues relates to the question of whether EOR has truly a causal impact on survival, or whether it is largely a surrogate measure of IDH-1 mutation (ie, mutant tumors are likely to be completely resected more often than wild-type tumors), which in itself is an independent predictor of survival. From this observation it becomes evident that future, prospective analyses of the impact of EOR on outcome will need to include IDH-1 status as a covariate. Most problematic, however, is how do we apply this information to neurosurgical oncology practice? We typically do not know the IDH-1 status of a tumor at the time of initial resection, unless a previous biopsy was performed. So, does this study provide sufficient evidence to change standard practice to require a biopsy to obtain sufficient tissue to determine IDH-1 status, which would be used to formulate the goals for a subsequent resection? If the initial procedure is a resection, and the tumor is found to have an IDH-1 mutant genotype, should any residual T2/FLAIR disease be removed in a secondary procedure, prior to use of radiation therapy and/or chemotherapy? Naturally, one single-center, retrospective study is not likely to provide sufficient justification to make radical changes to standard practice. Instead, it should be viewed as a hypothesis generating study, and there will be opportunities to apply this type of analysis to much larger surgical outcome datasets. The authors should be congratulated for uncovering what is likely the first