Debulking Surgery May Be of Benefit in Stage IV Ovarian Cancer

ABSTRACTS & COMMENTARY

In previous issues of Clinical Oncology Alert, we have highlighted reports suggesting that an aggressive approach to selected cases of stage IV lung and colon cancer may result in a better outcome. For example, the resection of solitary lung cancer metastases to the brain, liver, or adrenal glands can confer improved survival over palliative chemotherapy or radiotherapy alone. Now come independent data from three institutions suggesting that not only is an aggressive surgical approach feasible in many patients with advanced ovarian cancer, but survival may be better than with palliative chemotherapy alone.

The outlook for stage IV ovarian cancer patients remains poor, and despite the application of platinum-based chemotherapy, the median survival of those treated with chemotherapy alone is not much greater than a year.1 With this in mind, investigators have explored the role of surgical debulking for patients with advanced, metastatic disease. In 1992, Goodman et al reported their series of 35 women with stage IV ovarian carcinoma; however, in that study, only 16 women underwent primary surgical cytoreduction.2 Most of the remaining women received 2-4 cycles of chemotherapy before debulking surgery was attempted, and although there was a non-significant (six month) prolongation of median survival, a five-year survival of 5% was observed whether or not the women achieved optimal (< 2.0 cm residual) debulking.

Recently, Liu et al retrospectively reviewed the registry of the University of Pennsylvania Cancer Center from 1984 to 1995, and 47 patients with stage IV ovarian cancer were selected for inclusion in this study. These patients were so classified on the basis of malignant pleural effusion or metastasis to the liver parenchyma, abdominal wall, lung, supraclavicular lymph node, or a combination of these. Of these women, 90% had poorly-differentiated tumors. Of these patients, 14 (30%) were successfully debulked (i.e. the maximal residual disease was < 2.0 cm in diameter). Half of these women were classified as having stage IV disease because of a malignant pleural effusion alone. Two patients had resectable anterior abdominal wall metastasis, and the remaining five patients had unresectable distant metastasis that were, fortunately, < 2.0 cm in diameter, and therefore, only primary cytoreductive surgery was necessary. Some sort of bowel resection was necessary in 36% of patients, but in those who were successfully debulked, the operative mortality was zero. In this series, the median survival of the optimally-debulked patients was 37 months, as opposed to 17 months in the suboptimally-debulked group (P = 0.0295).

Another retrospective review, from Memorial Sloan-Kettering Cancer Center, analyzed the outcome of patients with stage IV ovarian cancer treated between 1987 and 1993. Ninety-seven patients were identified with this condition, and of these, 92 had undergone initial laparotomy. The five patients who did not undergo surgery were deemed ineligible due to the advanced nature of their disease. One of them did undergo interval surgical debulking after neoadjuvant chemotherapy. Of the 92 patients in which surgical debulking was attempted, 44.6% were optimally debulked (again, to < 2 cm maximum tumor diameter). Again, there was a significant improvement in survival in those who were optimally debulked. The median survival was 40 months in the optimally-debulked group, as opposed to 18 months in the other group. Although one might speculate that being classified as having stage IV disease solely on the basis of having a malignant pleural effusion might perhaps be different from having intraparenchymal metastasis, this was not borne out by the data. As long as the disease could be optimally debulked, one's survival was prolonged to the same degree as those with optimally-debulked intraparenchymal disease.

Further reinforcing the conclusions of these two studies was a third from MD Anderson Cancer Center. This report, also a retrospective review, examined the outcome of 108 women with stage IV ovarian cancer between the years 1978 and 1992 who had received platinum-based chemotherapy. Of these patients, 100 women underwent primary surgical debulking followed by chemotherapy. The remaining women were felt to have inoperable disease, and were treated with chemotherapy alone. Half of the women (54) were classified as having stage IV disease on the basis of pleural involvement, followed by liver metastasis (16 women) and sundry other sites such as mediastinal lymph nodes, axillary nodes, cervical nodes, subcutaneous tissue, and adrenal glands. Again, the criterion for optimal debulking was that the diameter of the largest residual tumor was < 2 cm. As with the previous studies, the median survival of the optimally debulked was 25 months, as opposed to 15 months if optimal debulking was not achieved. The median progression-free interval was 18 months in the optimally-debulked group, and 10 months in the other group, a difference that was not statistically significant. Another observation that was echoed in previous reports was that the size of extra-pelvic disease did not affect survival, provided that optimal surgical debulking was somehow achieved. Neither the site, nor the number of metastases influenced overall survival. Even if a malignant pleural effusion was the only site of extraperitoneal disease, such patients fared no better than others with bulkier disease. Multivariate analysis confirmed that only tumor histology and size of residual tumor correlated with survival; however, residual tumor size was still independently predictive of survival, even when patients were stratified by tumor histology. (Liu PC, et al. Gynecol Oncol 1997;64:4-8; Curtin JP, et al. Gynecol Oncol 1997;64:9-12; Munkarah AR, et al. Gynecol Oncol 1997;64:13-17.)

COMMENTARY

Standardized, evidence-based recommendations have not been formulated for management of metastatic ovarian carcinoma, and most of us would welcome some guidance in this area. Surgical debulking has been shown to be an important component in the management of stage III disease. It is a bit of surprise, however, that surgical debulking appears to have some survival effect in metastatic disease. The conclusions drawn in the three studies above appear credible. Each of the reports discussed is a retrospective review, a limitation that each set of authors has acknowledged; however, it is reassuring that all are unanimous in their conclusion that overall survival is superior when optimal debulking can be achieved. In fact, the median survival for these patients is similar to that of stage III patients who undergo debulking surgery followed by platinum-based chemotherapy.

It comes as no surprise that not everyone could be successfully debulked. The percentage of women who were optimally debulked ranged from 30.0% to 44.6%, and these are figures from some of the best tertiary cancer centers in the country. Although the exact surgical procedures were not explicitly stated, only bowel resection was specifically mentioned in which non-gynecologic tissue was removed. In many cases, patients were classified as having stage IV disease on the basis of a malignant pleural effusion. One has the impression that little or no effort was made in any of these studies to debulk extraperitoneal disease, although it is difficult to be certain. Therefore, one cannot conclude from these data that one is obliged to resect all bulky disease when outside the abdominal cavity. Rather, a more reasonable interpretation is that since there is no discernible advantage to debulking surgery when performed with suboptimal results, surgery is not recommended in this situation.

The critical role of surgery in this disease raises the question of whether a neoadjuvant chemotherapeutic approach would be beneficial to those with inoperable disease. Relatively little has been published that would address this question. One study, published only in abstract form, observed a significant survival benefit in women with inoperable stage III and IV ovarian cancer who were treated with neoadjuvant chemotherapy followed by surgery, as compared to women with less bulky, operable disease, who underwent the traditional program of surgery first followed by adjuvant chemotherapy, suggesting that the neoadjuvant approach may be superior to the conventional approach.3 However, to speculate further would exceed the scope of this commentary.

Of course, skeptics will rightly point out that the surgery may not be altering natural history. Without a randomized trial, one cannot be sure that it is not the ability to be debulked rather than the debulking itself that is the important determinant of outcome. Frankly, I don't think it matters. If the only way to identify patients with a superior outcome is to operate on them, we should do it.

Until additional data are available, we should consider debulking surgery for suitable women with stage IV ovarian cancer provided that optimal debulking can be achieved. If patients are not candidates for primary surgery (and there are no applicable investigational protocols), then consideration could be given to neoadjuvant chemotherapy at the discretion of the physician, followed by interval debulking surgery.

References

1. Repetto L, et al. Tumori 1990;76:274-277.

2. Goodman HM, et al. Gynecol Oncol 1992;46:367-371.

3. Shimizu Y, et al. Fourth International Congress on Anti-cancer Chemotherapy. February 2-5, 1993, Paris, France, p. 86.