Secondary Surgical Cytoreduction for Advanced Ovarian Carcinoma

Abstract & Commentary

Synopsis: For patients with advanced ovarian carcinoma in whom primary cytoreductive surgery was considered to be maximal, the addition of secondary cytoreductive surgery to postoperative chemotherapy with paclitaxel plus cisplatin does not improve progression-free survival or overall survival.

Source: Rose PG, et al. N Engl J Med. 2004;351(24): 2489-2497.

Nearly 10 years ago, a randomized trial of interval cytoreduction for primary therapy of advanced ovarian cancer was published, suggesting the surgical intervention after 3 cycles of cisplatin and cyclophosphamide added significantly to progression-free (PFS) and overall survival (OS). Rose and colleagues, on behalf of the Gynecologic Oncology Group (GOG), reported final results on a similarly designed trial, which, unfortunately, leaves the question as to its benefit unresolved. In this trial, patients who were left with more than 1 cm of residual disease after an initial debulking effort were randomized to a second procedure if they were found not to progress during 3 cycles of paclitaxel and cisplatin adjuvant chemotherapy. Patients in both cohorts received a total of 6 cycles of chemotherapy. More than 400 patients were randomized. Relative to those patients receiving only one operation and adjuvant chemotherapy, those who had undergone the additional interval cytoreduction had similar PFS and OS. Hazard ratios for both events were statistically insignificant. Rose et al concluded that in the setting of a maximal initial attempt at cytoreduction plus paclitaxel and cisplatin chemotherapy no benefit was realized for an interval secondary procedure.

Comment by Robert L. Coleman, MD

Most health care providers with even a peripheral understanding of ovarian cancer would most likely be able to articulate the importance surgery and chemotherapy play in the disease’s management. These modalities represent the virtual 1-2 punch of initial therapy for most cases of advanced disease. And, in general, the more 1 and possibly, the more 2, that is realized, the better the outcome. However, as many as 20-50% of stage III and more stage IV patients are left with gross residual disease (> 1 cm) after primary exploration, usually the result of massive intraperitoneal carcinomatosis or intraparenchymal disease. Observational trials of chemotherapy before surgery for medically infirmed or other such non-surgical patients has demonstrated that a proportion achieve dramatic reduction in disease volume and in some cases, make those patients good candidates for debulking where favorable perioperative clinical courses are realized. Therefore, the question arose that if one could not achieve a complete resection initially, could this be achieved at a later point, particularly among those demonstrating a good response to chemotherapy, and thus improve their survival? Our initial insight into this question was "yes."1 However, these data came as much of the treated population was receiving taxane-based chemotherapy regimens and the results from a confirmatory trial, while launched, was years away. The current study by Rose et al, employing a more contemporary treatment program, did not confirm the earlier encouraging data and left us sorting through the details of each study to determine why.

As pointed out by Rose et al, one key difference, besides the treatment regimen, lies in the intent of the initial surgery. In the initial trial, a cohort of patients could have entered the trial after disease documentation from only a biopsy. In this group of patients, the interval surgery more accurately represented the initial debulking attempt and the chemotherapy, a neoadjuvant infusion. In addition, more stage IV patients were included in the initial trial, which may have contributed to the almost twice as frequent progression before interval surgery (9% vs 5%). Since these patients did not undergo surgery, a case selection bias of sensitive, but incompletely resected patients populated the initial trial. This is most evident by observing the significantly longer progression-free survivals in the initial trial compared to the GOG trial (18 mos vs 10.5 mos, interval reduction arm) but likely no difference in overall survival (26 mos vs 32 mos, interval reduction arm). In addition, consolidation therapy was allowed in the initial trial, but not in the GOG trial. Whether consolidation therapy truly affects the survival end points is unconfirmed at this time. However, at least one trial has suggested a progression-free survival advantage with the addition of 12 cycles of paclitaxel.2

So how does one interpret this clinical conundrum? A reasonable conclusion is that one maximal attempt at cytoreduction is warranted in the initial setting. Those left suboptimal don’t appear to gain measurably with a second attempt after induction chemotherapy. Unclear biological characteristics are more likely at work in this situation and are an active focus of research.3 Whether delaying surgery until the documentation of chemosensitivity (neoadjuvant chemotherapy) will ultimately help our patients both in morbidity and survival is the subject of an ongoing randomized European trial.

Dr. Coleman is Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston Texas.

References

1. van der Burg ME, et al. N Engl J Med. 1995; 332(10):629-634.

2. Markman M, et al. J Clin Oncol. 2003;21(13): 2460-2465.

3. Berchuck A, et al. Am J Obstet Gynecol. 2004; 190(4):910-925.