Does Aggressive Surgery Only Benefit Patients with Less Advanced Ovarian Cancer?
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman is on the speaker's bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Synopsis: Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.
Source: Crawford SC, et al. Does Aggressive Surgery Only Benefit Patients With Less Advanced Ovarian Cancer? Results From an International Comparison Within the SCOTROC-1 Trial. J Clin Oncol. 2005;23:8802-8811.
The positive relationship between the amount of surgical residual following primary extirpation of advanced ovarian cancer and survival thereafter has been one frequently cited to justify aggressive surgical evaluation. This bias was initially suggested 3 decades ago and although it has never been proven by a randomized trial, several retrospective, prospective and meta-analyses of clinical trials appear to support the contention. Crawford and colleagues, applying the results from a recently reported randomized controlled clinical trial of post-operative chemotherapy, evaluated this question across a large cohort of ovarian cancer patients with stage IC to IV disease.
The cohorts consisted of 1077 women enrolled in the Scottish Randomized Trial in Ovarian Cancer (SCOTROC-1) trial and randomized to receive combination paclitaxel and carboplatin or docetaxel and carboplatin following surgery. Women were recruited from centers both within the United Kingdom (UK) and outside the UK. The trial was powered to address a 25% improvement in the median progression-free survival (PFS) for the docetaxel/carboplatin combination. The primary end point, reported previously, demonstrated that median PFS would not be different between the cohorts; thus, it has been widely interpreted that the 2 regimens are equivalent. The primary aim of the current study was to evaluate PFS by surgical outcome, in particular, among patients recruited from within and outside the UK. The premise for this division was based on an observation that less aggressive surgery might be occurring within the UK centers, explaining the disparate survival results observed in these sites compared to other European countries. Three main observations were noted: first, compared to non-UK centers, patients treated within the participating UK sites were significantly less likely to be optimally debulked (≤ 2 cm residual). Second, optimal cytoreduction was associated with an increased PFS; however, the effect was greatest among the patients with less extensive disease at presentation. And third, patients treated within UK sites and with no visible residual disease had a poorer survival than similar residua patients treated outside the UK. This latter observation appeared to be related to the performance of retroperitoneal lymphadenectomy. Crawford et al concluded that the increase in PFS with optimal cytoreduction is limited to patients with less advanced disease at presentation and likely reflects underlying characteristics of tumor biology and that lymphadenectomy may have beneficial effects on PFS in patients without disease residual.
The mantra to be aggressive surgically in newly diagnosed advanced staged ovarian cancer patients is a majority consensus throughout the United States and much of the world. Several factors have supported this strategy. First, there are several data sets in the literature that appear to document better outcomes in patients left post-operatively with less residual disease. "Optimal" has been variably defined over the years (by convention it is usually referred to as no individual nodule larger than 1 cm in greatest dimension) but it is hard to accurately estimate. While many have documented that inherent biology may dictate which patients are "debulkable," others have argued that surgical aggressiveness can even overcome this characteristic. Even patients with parenchymal stage IV disease (eg, hepatic metastases) appear to benefit from an aggressive intraperitoneal resection compared to those who are left with bulky intraperitoneal disease. Crawford et al strongly advocate primary surgery for all newly diagnosed patients.
Second, despite the lack of randomized clinical trials, very large data sets subjected to meta-analysis document a near linear relationship between the degree of cytoreduction and survival. However, when studying a cohort of patients deemed "optimal," there is wide variation in survival depending on the amount of disease present before attempting cytoreduction. Third, there is a concern that not operating when the diagnosis has been suspected may select a higher proportion of resistant cells ultimately reducing survival. This argument has been advanced against the use of neoadjuvant chemotherapy in patients with advanced disease at presentation.
Fortunately, this issue is being studied in a randomized clinical trial, which should shed light in this contentious area. And fourth, based a recent randomized clinical trial documenting the merits of retroperitoneal lymphadenectomy on PFS, many authors are now advocating systematic surgical evaluation in all patients with advanced disease but particularly in those deemed optimal.1-3
Circumstantial evidence abounds, and the current trial appears to fuel the fire. However, there are important nuances brought to light by the SCOTROC-1 trial that have bearing on our enthusiasm for taking an aggressive position. Biology may be important after all. In the current trial, only those patients in the first two quartiles of initial disease volume appeared to benefit from optimal surgery. Currently, studies evaluating the genetic and proteomic signature of patients are underway and preliminarily appear to identify several factors which, if validated, could be used to identify those patients in whom an aggressive surgical attempt should be made and those who are unlikely to benefit from such a procedure. In addition, attention again is directed to the retroperitoneum as a potential haven for metastatic disease. Given the ability to evaluate this area in most patients undergoing surgical extirpation, it is reasonable to add this procedure to those cytoreduced to no visible or minimal visible disease. While a randomized trial would provide the statistical proof necessary to satisfy all in this debate, studies like the current one help to refine the process of providing the appropriate surgery for the appropriate patient with advance ovarian cancer.
1. Berchuck A, et al. Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays. Am J Obstet Gynecol. 2004;190:910-925.
2. Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction of ovarian cancer: is there a correlation with "biological aggressiveness" and survival? Gynecol Oncol. 2001;82:435-441.
3. Panici PB, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst. 2005;97:560-566.