Regardless of how much progress we make in this area, we will never be completely rid of physician bias or the fact that there will always be variability in gynecologic oncologists’ surgical skills and intraoperative decision-making.— David M. Gershenson, MD
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Ever since the landmark studies of Griffiths and colleagues in the 1970s,1 primary cytoreductive surgery followed by chemotherapy with the objective of achieving minimal residual disease has been the standard approach for women with advanced-stage epithelial ovarian cancer. However, what is largely buried in one of those reports is a subgroup of nine women who had unresectable disease at primary surgery and subsequently received primary chemotherapy followed by interval debulking surgery.1 Optimal residual disease was possible in seven of the nine women.
Beginning in the late 1970s, neoadjuvant chemotherapy followed by interval debulking surgery began to be employed selectively in two U.S. centers—Yale and MD Anderson—and initial reports appeared in the early 1990s.2,3 Previously, in the late 1980s, four other reports from the Netherlands, Great Britain, and Italy also described patients who had been treated with this alternative approach. Over the next 2 decades, a flood of retrospective studies and a few nonrandomized trials of neoadjuvant chemotherapy and interval debulking surgery appeared. During this period, most of the women who underwent this approach did so based on imaging evidence of extensive tumor, comorbidities, advanced age, or some combination thereof.
Trial Data Behind Consensus Recommendations
Fast forward to 2016. The clinical practice guideline issued by a joint Society of Gynecologic Oncology (SGO)/ASCO expert panel—summarized in this issue of The ASCO Post—is thoughtful, comprehensive, and balanced.4 The recommendations are primarily based on the findings of four randomized controlled trials. Of the four, the two trials that had been published at the time of this guideline essentially reached the same conclusion: The neoadjuvant chemotherapy arm was noninferior to the primary cytoreductive surgery arm with respect to the primary outcome of overall survival.5,6
The publication of the European Organisation for Research and Treatment of Cancer (EORTC) trial in 2010 evoked a flurry of criticism in the form of editorials, single-institution reports, and meta-analyses. More recently, similar questions have been raised about the CHORUS study. The predominant condemnation of these trials is related to questioning the adequacy of the surgical effort. This appraisal is based on the following findings: (1) the median overall survival durations in these trials are inferior to those previously reported in other trials; (2) the median operative times were significantly shorter; and (3) the rates of upper abdominal procedures were lower.
Bias Against Neoadjuvant Chemotherapy
Interestingly, a survey of SGO members, published the same year as the EORTC study, found that 60% of respondents used neoadjuvant chemotherapy in less than 10% of advanced-stage ovarian cancer cases, and 82% did not consider currently available evidence as sufficient to justify neoadjuvant chemotherapy followed by interval debulking surgery.7 Following the publication of the EORTC trial, what impressed me most was the exposure of bias on the part of the antagonists to neoadjuvant chemotherapy and interval debulking surgery. At times, it appeared that many, if not most, gynecologic oncologists were so uncompromising about the principle of primary cytoreductive surgery that they were unwilling even to consider there may be a role for neoadjuvant chemotherapy.
It very much reminded me of the controversy regarding the optimal method of delivery in the setting of breech presentation—vaginal vs cesarean section—within the discipline of obstetrics and gynecology. Several experienced obstetricians were completely resistant to considering there may be appropriate indications for cesarean delivery in an effort to improve fetomaternal outcomes. However, this controversy galvanized the obstetric community to launch a series of randomized controlled trials, which have resulted in improved criteria for breech delivery management.
As exceptional as these guidelines are, they represent a snapshot in time. As the state of our knowledge continues to grow, I hope that SGO/ASCO will plan to update them every 3 to 5 years. In 2016, however, here is what we know about the role of primary cytoreductive surgery vs neoadjuvant chemotherapy and interval debulking surgery and what we don’t know but need to know.
What We Know
Patients who have optimal residual disease following surgery have significantly better outcomes than patients who have suboptimal residual disease.
For women with a high probability of achieving optimal cytoreduction with acceptable morbidity, primary cytoreductive surgery is preferable to neoadjuvant chemotherapy and interval debulking surgery. However, we still do not understand the interaction between tumor biology and surgical effort.
All patients deemed to be eligible for neoadjuvant chemotherapy and interval debulking surgery should have histologic confirmation of ovarian or peritoneal cancer prior to initiating treatment.
In the two published randomized controlled trials, the neoadjuvant chemotherapy arm was noninferior to the primary cytoreductive surgery arm in terms of the primary outcome of overall survival.
Interval debulking surgery following neoadjuvant chemotherapy is associated with significantly less perioperative and postoperative morbidity and mortality, shorter operative times, shorter hospitalizations, higher rates of optimal debulking, and possibly less cost compared with primary cytoreductive surgery.
What We Need to Know
Over the past few decades, criteria used to determine the optimal approach have included age, comorbidities, performance status (American Society of Anesthesiologists score), nutritional status, imaging evaluation, serum CA-125, and, more recently, laparoscopic assessment. However, none of these criteria is either independent or perfect. We clearly need development and validation of better tools with which to predict the two most important factors: (1) the probability of optimal debulking, and (2) the estimated risks of primary cytoreductive surgery compared with neoadjuvant chemotherapy. In addition, novel imaging modalities and histologic subtype should be a focus in future studies. Ultimately, we hopefully will have the tools to personalize surgical treatment, just as we are attempting to individualize systemic therapy.
We do not know the optimal number of neoadjuvant chemotherapy cycles and the timing of surgery. Based on consensus opinion, three to four cycles seems to be appropriate. However, I am not optimistic that future randomized controlled trials will focus on this aspect.
I agree with the recommendation for a well-designed U.S. trial, which would hopefully resolve the issue of substandard surgery and possibly provide additional information on the issue of tumor biology vs surgical skill and aggressiveness. There is some sense that the National Cancer Institute has little interest in supporting clinical trials focused on surgical questions. However, the issue of primary cytoreductive surgery vs neoadjuvant chemotherapy is among the most important unresolved topics within our discipline, and such a trial is frankly long overdue.
We do not know the optimal neoadjuvant chemotherapy regimen. Future studies will hopefully enhance our knowledge.
Our Principal Goal: Improving Outcomes
And, finally, the neoadjuvant chemotherapy setting is ideal for testing novel therapeutics, as illustrated by the recently developed NRG Oncology trials. One word of caution: Regardless of how much progress we make in this area, we will never be completely rid of physician bias or the fact that there will always be variability in gynecologic oncologists’ surgical skills and intraoperative decision-making. But, if we as gynecologic cancer specialists can maintain our focus on developing a much-improved algorithm that will allow us to optimally triage women to primary cytoreductive surgery vs neoadjuvant chemotherapy based on the prediction of optimal cytoreduction while minimizing potential morbidity and mortality, we will significantly improve outcomes for women with advanced ovarian cancer. And, after all, isn’t that our principal goal? ■
Disclosure: Dr. Gershenson reported no potential conflicts of interest.
4. Wright AA, Bohlke K, Armstrong DK, et al: Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 143:3-15, 2016.
6. Kehoe S, Hook J, Nankivell M, et al: Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): An open-label, randomised, controlled, non-inferiority trial. Lancet 386:249-257, 2015.
7. Dewdney SB, Rimel BJ, Reinhart AJ, et al: The role of neoadjuvant chemotherapy in the management of patients with advanced stage ovarian cancer: Survey results from members of the Society of Gynecologic Oncologists. Gynecol Oncol 119:18-21, 2010.
Alexi A. Wright, MD, MPH
All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy to determine whether they are candidates for primary cytoreductive surgery.— Alexi A. Wright, MD, MPH,...