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The role of initial maximal surgical cytoreduction in ovarian cancer still debated
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There is considerable excitement in the gynecologic cancer research community with the pending results of several randomized phase-3 trials that examine the utility of antiangiogenic therapy in the management of ovarian cancer and with the early results of a number of targeted antineoplastic agents, including drugs that are known to inhibit poly (ADP-ribose) polymerase — or PARP.
Almost lost in the discussions of future directions for research and clinical care in advanced ovarian cancer is the paradox of two rather divergent views regarding the role and importance of an initial attempt at maximal surgical cytoreduction in advanced-stage disease before the administration of cytotoxic chemotherapy.
Based exclusively on reported retrospective evaluations, one group of investigators has argued that aggressive surgery, including extensive attempts to resect all upper abdominal disease, is indicated to optimize an individual ovarian cancer patient’s opportunity to experience extended survival. These data reveal that women who initiate chemotherapy with no macroscopic cancer exhibit superior outcomes compared with individuals with any visible disease.
However, it must be emphasized that these reports are all based on uncontrolled analyses, and it remains essentially unknown how much the inherent tumor biology influenced the ultimate outcome vs. the surgical philosophy and basic expertise of the surgical teams. Simply stated, in the absence of data from a randomized phase-3 trial, one can rationally argue that the observed ability of skilled surgeons to remove all macroscopic cancer may closely correlate with clinically meaningful tumor growth patterns, the extent of spread and inherent chemosensitivity.
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As a result, the degree of surgical resection may be an important prognostic factor and, like tumor stage or grade, will help to define patients likely to have a relatively more favorable or unfavorable outcome. However, the evidence does not reveal if the “successful performance” of aggressive surgery actually alters that outcome.
The alternative surgical hypothesis argues that patients with large volume advanced ovarian cancer may be more rationally managed with chemotherapy administered before an attempt at surgical resection.
Existing data reveal that subsequent surgery performed after a response to chemotherapy is likely to be less extensive and potentially less morbid. Further, the 20% to 40% of patients documented to have chemoresistant cancer (no objective response or actual tumor growth) will be spared an attempt at aggressive surgery that is highly unlikely to be of clinical utility in this setting.
What we do know
In contrast to the previously noted experience with aggressive primary surgery, the concept of primary chemotherapy (neoadjuvant chemotherapy) followed by surgery (where clinically indicated) has been subjected to the test of a randomized phase-3 trial. Preliminary results of this landmark multinational study reveal equivalent survival for patients who were randomized to undergo primary surgery (control arm) vs. chemotherapy followed by surgery (experimental arm).
Further, treatment with the experimental regimen was associated with reduced surgery-related morbidity and mortality.
Thus, we have two very different concepts regarding the role of primary surgery in advanced ovarian cancer. One approach favors more aggressive and the other less aggressive surgery preceding chemotherapy. What is the best way forward? In the opinion of this commentator, there is only one answer to this question, and it is obvious.
There is a critical need for a well-designed phase-3 trial that directly compares aggressive initial surgery with neoadjuvant chemotherapy followed by surgical resection of the residual cancer. The primary study endpoint will be overall survival, with serious treatment-related morbidity and mortality being relevant secondary issues to evaluate.
Although there is no inherent reason to suspect the neoadjuvant chemotherapy approach will be associated with a superior survival outcome (in contrast to its potential to be equally effective but far less morbid), it is possible that patients who are able to have all residual disease surgically removed may benefit from the utilization of alternative innovative approaches, such as regional (intraperitoneal) drug administration. Of course, any such idea will need to be subjected to a randomized trial.
Although the world of surgery is not necessarily characterized by the utility of innovative clinical hypotheses being formally evaluated through the conduct of randomized phase-3 clinical trials, it will hopefully be the case that the gynecologic cancer surgical community will see the wisdom of further exploration of these important concepts in prospective well-designed and evidence-based clinical trials.
Our current and future patients deserve no less.
Maurie Markman, MD, is from the Department of Gynecologic Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, and a member of the HemOnc Today Editorial Board.
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