Concept of optimal surgical cytoreduction in advanced ovarian cancer: a brief critique and a call for action.

It would not be an exaggeration to state that the goal of attempting to surgically maximally cytoreduce diffuse intraperitoneal ovarian cancer represents one of the most unique standardof-care management strategies in oncology. One can only imagine the response of a hospital quality committee upon learning a general surgeon had performed over the past year a dozen such procedures, including removal of multiple metastatic peritoneal implants and retroperitoneal lymph nodes of varying size, along with masses adherent to the diaphragm and within the liver, in patients with pancreatic cancer. Thus, the first question to be answered in this article relates to the fundamental justification for this approach in disease management. It has been known for more than 30 years that women with advanced ovarian cancer who initiate systemic therapy with an apparent small total quantity of residual disease after surgical cytoreduction experience a superior outcome compared with patients with larger amounts of macroscopic cancer. In fact, such retrospective data are so strong that randomized clinical trials in ovarian cancer will either include this feature as one important stratification factor, or will simply restrict entry of patients into the study based on a perceived objective measure of this parameter (for example, largest single residual malignant mass 1 cm in maximum diameter). Yet, despite the overwhelming evidence that the size of residual tumor masses after surgery is a highly relevant prognostic feature of advanced ovarian cancer, there remain profoundly limited evidence-based data to support the conclusion that it is the surgical procedure itself that is actually responsible for the superior outcome associated with smaller disease, or if the technical ability to cytoreduce the cancer simply identifies a biologically more favorable patient subgroup. It is reasonable to speculate that the multiple factors (both currently defined and still unknown) that likely determine the manner in which a cancer progresses throughout the peritoneal cavity and that might substantially influence a surgeon’s ability to remove the majority of visible tumor may also define such critically important features as the presence of de novo, or development of acquired, cytotoxic drug resistance. In fact, to the best of my knowledge, of the three completed phase III trials that have at least attempted to partially address the issue of the relevance of a surgical cytoreductive procedure, compared with the cancer’s inherent biology in defining outcome in advanced ovarian cancer, one study suggested a role for surgery, while two trials (one with an inadequate sample size) failed to reveal a survival advantage from the procedure. It must be noted that these randomized trials were conducted to define a role for an interval cytoreductive surgery. To date, the benefits of primary surgical cytoreduction in ovarian cancer have not been defined through a well-designed and conducted prospective phase III trial. However, in the absence of such definitive data, it is possible to provide a rational hypothesis for why surgical cytoreduction in advanced ovarian cancer might at least be partially (even if not exclusively) responsible for the superior outcome associated with the presence of small volumes of intraperitoneal metastatic cancer. By decreasing the total quantity of disease, or removing cancer in specific locations (such as a lesion causing bowel obstruction) before the initiation of systemic therapy there may be an improvement in the patient’s nutritional and immunological status, which might enhance still poorly defined internal mechanisms to fight the cancer, as well as to permit the individual to successfully tolerate the adverse effects of subsequently delivered cytotoxic therapy. Further, the removal of large malignant masses may substantially increase the probability that optimal concentrations of highly active cytotoxic antineoplastic agents will be delivered to the residual cancer cell population. In addition, to the extent that the effectiveness of chemotherapy depends on the presence of welloxygenated tissue that will permit more effective killing by drugs most active against cycling cells, surgical cytoreduction may be a clinically relevant management approach. Thus, assuming the overall morbidity associated with primary surgery is limited, it is not difficult to make a strong argument that the potential (but not definitively proven) survival benefits associated with primary surgical cytoreduction outweigh the risks of the performance of this procedure in the majority of women with advanced ovarian cancer. However, one must now deal with the question of what it means to achieve an optimal surgical cytoreduction, and the level of evidence required to suggest it is appropriate in routine clinical JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 25 NUMBER 27 SEPTEMBER 2