Results of Interval Debulking Surgery Compared with Primary Debulking Surgery in Advanced- Stage Ovarian Cancer

Abstract & Commentary

Synopsis: Survival rates were similar in patients with advanced-stage ovarian cancer who underwent IDS or PDS. The rates of surgical resection and morbidity were reduced after IDS. IDS can be safely used in unresectable advanced-stage ovarian cancer.

Source: Morice P, et al. J Am Coll Surg. 2003;197(6): 955-963.

In an effort to shed light on a controversial approach to advanced ovarian cancer management, Morice and colleagues present intriguing data on the use of interval debulking surgery following pre-operative chemotherapy. The retrospective study consisted of 2 cohorts, matched for stage, tumor grade, and histology. The first cohort consisted of 57 patients who were determined, largely at surgery, to be unresectable (to less than 2 cm residual disease) by standard debulking techniques. This group received a median 3 courses (range, 2-5) of platinum- and taxane-based chemotherapy followed by a second attempt at cytoreduction. Following this surgery, they were administered a median 5 (range, 3-7) courses of the same chemotherapy. The second cohort—the control group—consisted of 28 patients deemed resectable who underwent standard primary debulking surgery followed by a similar platinum- and taxane-based chemotherapy regimen.

In both cohorts, "optimal" cytoreduction was considered less than 2 cm of residual disease—an achievement made in 84% of the interval debulking surgery group and in 100% of the primary cytoreduction group. Similar rates of complete resection (ie, no gross residual) were achieved in each cohort (51% and 54%, respectively) as well. To document the effects of chemotherapy in the interval-debulking cohort, Morice et al recorded disease volumes in several specific peritoneal and extraperitoneal locations both before and after chemotherapy and compared this disease volume to that found in the control cohort at primary surgery. Following the initial chemotherapy, tumor reduction on specific intra-abdominal structures ranged from 30% on the diaphragmatic peritoneum to 60% on the bowel and rectum regions. In addition, despite the spectrum of disease at entry, the distribution and volume of disease found at cytoreductive surgery was markedly reduced for the interval-debulking group. The rates of bowel resection, large peritoneal, resection and postoperative morbidity were significantly reduced in the interval-debulking group, as well. After adjustment for tumor residual, no significant differences could be determined between the 2 cohorts with regards to disease-free and overall survival. Morice et al conclude that interval-debulking surgery is a viable therapeutic option for patients with unresectable advanced ovarian cancer and is associated with reduced surgical resection and morbidity compared to primary cytoreduction with equivalent survival.

Comment by Robert L. Coleman, MD

The merits of cytoreductive surgery and chemotherapy for patients with advanced ovarian cancer have been well documented. Typically, the sequence is surgery first and combination platinum- and taxane-based chemotherapy second. In a meta-analysis on the topic of primary cytoreduction, Bristow and colleagues documented that achievement of "optimal" status from surgery was associated with an 11-month (50%) increase in survival compared to "suboptimal" cytoreduction.1 In addition, each 10% increase in cytoreduction was associated with a 5.5% increase in survival. The result was most notable among institutions and surgeons familiar with the techniques of ovarian cancer resection and goals of debulking. In nearly all studies on this topic, those patients rendered completely disease-free (no gross residual) after primary surgery have the best subsequent performance whether it is reported by intermediate end points such as negative second-look operations and progression-free survival or by durable survival. In an attempt to achieve optimal resection, a variety of surgical techniques and strategies have been reported, such as the radical oophorectomy/posterior exenteration, diaphragmatic resection and stripping, peritoneal implant excision and suprarenal retroperitoneal dissection.2,3 While these procedures have increased initial cytoreduction rates in some cohorts they have often been associated with increased perioperative morbidity.

An alternative strategy is to "preload" the patient by offering chemotherapy ahead of a cytoreduction attempt. Since ovarian cancer is generally chemosensitive, the strategy has appeal, and most patients will experience a reduction in tumor volume (sometimes elimination of gross disease) before surgery is attempted. The limited number of articles on the topic of neoadjuvant chemotherapy would suggest, as the current article does, that more patients are rendered optimal with less morbidity.4-7 Unfortunately, there is a confusing assortment of terms that applies to this kind of treatment approach. "Neoadjuvant" chemotherapy, "induction" chemotherapy, and interval cytoreduction have all been used to describe a cohort of patients undergoing chemotherapy ahead of a definitive cytoreduction. To some degree, the disparity in terms may explain the differences seen in clinical trials with respect to survival outcomes. In general, "neoadjuvant" has been used to describe a cohort of patients administered chemotherapy without surgical exploration the diagnosis being determined by cytology or limited biopsy.

Those who have undergone a suboptimal surgical cytoreductive attempt and are to undergo a second exploration are treated with "induction" chemotherapy between the 2 surgeries. Interval cytoreduction, as used in the current study, refers to a cohort of patients undergoing surgical exploration to make the diagnosis and assess cytoreducibility. Chemotherapy is then given prior to a definitive surgical attempt. Retrospective studies involving patients in all 3 of these "designations" are significantly biased by patient selection and are difficult to interpret even when matched with historical or concomitantly treated "controls." What is generally apparent though, is that most patients do achieve some level of tumor reduction after chemotherapy, and surgery is facilitated with better odds of achieving an "optimal" status.

The answer as to whether the strategy makes a difference in a "hard point" such as survival is really the purview of randomized, prospective trials. Two have been completed and 1 published. Not surprisingly, the conclusions reached by these 2 trials are not uniform. In the trial reported by van der Burg et al, biopsy-proven ovarian cancer patients left with more than 1 cm residual disease following initial surgery were treated with 3 cycles of platinum-based chemotherapy before being randomized to either 3 more cycles of chemotherapy or to a second, interval cytoreduction attempt followed by 3 cycles of chemotherapy.8

This latter, experimental cohort demonstrated improved progression-free and overall survival compared to the conventionally treated suboptimally debulked patients. The benefit was significant and amounted to a gain of a median 5 and 6 months, respectively. In the second trial, conducted by the Gynecologic Oncology Group (GOG), all patients underwent a maximal effort at cytoreduction and were left with greater than 1 cm residual disease.9 All patients received platinum and paclitaxel chemotherapy, but the experimental group underwent a second cytoreduction attempt after 3 cycles if their disease had not progressed (77% of randomization cohort). No difference was observed for either progression-free or overall survival between the interval debulking cohort and the conventionally treated cohort. Operative morbidity was acceptable and similar between cohorts for both trials. Numerous differences between the trials are note-worthy, but unaddressed is the estimation of inherent tumor biology, which may more strongly influence survival and is likely unaffected by "brawn." Currently, a trial by the EORTC is attempting to address this question by randomizing patients ahead of any surgical debulking to either a conventional approach or to neoadjuvant chemotherapy followed by surgery. This ambitious project will help provide a frame of reference to when and where aggressive surgery should be performed and how it will influence the natural history of ovarian cancer. One point is clear, however—patients who never undergo surgery, either because of medical infirmity or incomplete chemotherapy response, fair poorly. Limited options are available for this group.

References

1. Bristow RE, et al. J Clin Oncol. 2002;20:1248-1259.

2. Bristow RE, et al. J Am Coll Surg. 2003;197:565-574.

3. Eisenkop SM, Spirtos NM. Gynecol Oncol. 2001;82: 435-441.

4. Shibata K, et al. Int J Gynecol Cancer. 2003;13: 587-592.

5. Mazzeo F, et al. Gynecol Oncol. 2003;90:163-169.

6. Kuhn W, et al. Cancer. 2001;92:2585-2591.

7. Ansquer Y, et al. Cancer. 2001;91:2329-2334.

8. van der Burg ME, et al. N Engl J Med. 1995;332: 629-634.

9. Rose PG, et al. Proc Am Soc Clin Oncol. 2022;201a.