THE EFFECT OF DEBULKING SURGERY AFTER INDUCTION CHEMOTHERAPY ON THE PROGNOSIS IN ADVANCED EPITHELIAL OVARIAN CANCER

Background. Although the value of primary cytoreductive surgery for epithelial ovarian cancer is beyond doubt, the value of debulking surgery after induction chemotherapy has not yet been defined. In this randomized study we investigated the effect on survival of debulking surgery. Methods. Eligible patients had residual lesions measuring more than 1 cm in diameter after primary surgery. After three cycles of cyclophosphamide and cisplatin, these patients were randomly assigned to undergo either debulking surgery or no surgery, followed by further cycles of cyclophosphamide and cisplatin. The study end points were progression-free survival and overall survival. At surgery 65 percent of the patients had lesions measuring more than 1 cm. In 45 percent of this group, the lesions were reduced surgically to less than 1 cm. Results. Of the 319 patients who underwent randomization, 278 could be evaluated (140 patients who underwent surgery and 138 patients who did not). Progressionfree and overall survival were both significantly longer in the group that underwent surgery (P 0.01). The difference in median survival was six months. The survival rate at two years was 56 percent for the group that underwent surgery and 46 percent for the group that did not. In the multivariate analysis, debulking surgery was an independent prognostic factor (P 0.012). Overall, after adjustment for all other prognostic factors, surgery reduced the risk of death by 33 percent (95 percent confidence interval, 10 to 50 percent; P 0.008). Surgery was not associated with death or severe morbidity. Conclusions. Debulking surgery significantly lengthened progression-free and overall survival. The risk of death was reduced by one third, after adjustment for a variety of prognostic factors. (N Engl J Med 1995;332:629-34.) From the Rotterdam Cancer Institute, Daniel den Hoed Kliniek, Rotterdam, the Netherlands (M.E.L.B., M.L.); the International Institute for Drug Development, Brussels, Belgium (M.B.); the Medical Academy, Gdansk, Poland (A.K.); Ospedale San Gerardo, Monza, Italy (N.C.); the University of Brescia, Brescia, Italy (G.F., S.P.); the Central Hospital of Asturias, Oviedo, Spain (A.J.L.); the Regina Elena Cancer Institute, Rome (M.N.); and the European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium (J.R.). Address reprint requests to Dr. van der Burg at the Rotterdam Cancer Institute, Daniel den Hoed Kliniek, P.O. Box 5201, 3008 AE Rotterdam, the Netherlands. *Other principal investigators who contributed to the study are listed in the Appendix. T HE value of cytoreductive surgery in the management of ovarian cancer has been debated for years. The reasons for cytoreductive surgery are manifold. Large tumors with relatively poor central blood supplies and the areas with the lowest growth rates are both rather insensitive to cytotoxic drugs. 1 In betterperfused small, residual tumors, the growth rate and the diffusion of chemotherapeutic agents are higher — factors that are apt to increase the efficacy of chemotherapy. The removal of large tumors also reduces the likelihood that drug-resistant clones will appear as a result of spontaneous mutations. 2 Moreover, small tumors require fewer cycles of chemotherapy, thus decreasing the probability of drug-induced resistance. Several nonrandomized studies showed improved survival of patients with residual tumors less than 1 cm in diameter after primary surgery, as compared with patients with larger lesions. 3-5 In a case–control study of patients with minimal residual disease, Eisenkop et al. reported that patients whose small lesions were all resected survived significantly longer than patients in whom such lesions were not resected. 6 On the other hand, Hacker et al. 7 and Hoskins et al. 8 reported that despite optimal cytoreduction, the survival of patients with large intraabdominal metastases before resection was significantly worse than that of patients with small initial intraabdominal lesions. These results suggest that in addition to residual disease after cytoreduction, intrinsic tumor factors are of prognostic importance. They also raise the question of whether cytoreduction has a significant effect on survival among patients with the same size tumors and the same intrinsic prognostic factors. The value of debulking surgery after induction chemotherapy is even more difficult to assess. Several studies indicated that patients in whom cytoreduction was optimal after induction chemotherapy had approximately the same survival rate as patients in whom cytoreduction was optimal at primary surgery. 9-12 Neijt et al., however, reported just the opposite. 4,13 Patients with optimal cytoreduction at intervention surgery had poorer rates of survival than patients with optimal cytoreduction at primary surgery. Moreover, the survival of patients with optimal cytoreduction at intervention surgery was the same as that of patients with suboptimal cytoreduction. All these studies, however, included only small numbers of patients with different prognoses. In 1987 the Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) initiated a randomized phase 3 study to establish the effect on survival of debulking surgery after induction chemotherapy.