A scheme for the management of patients with advanced-stage epithelial ovarian cancer is presented in

Figure 118-6. The components of this approach are discussed below.

Cytoreductive Surgery in Ovarian Cancer
Patients who have advanced-stage epithelial ovarian cancer documented at initial exploratory laparotomy should undergo cytoreductive surgery to remove as much of the tumor and its metastases as possible in order to facilitate the effectiveness of subsequent therapies. The operation usually includes the performance of a total abdominal hysterectomy and bilateral salpingo-oophorectomy, a complete omentectomy, and resection of metastatic lesions on the peritoneal surfaces or from the intestines. In addition, the pelvic tumor may directly involve the rectosigmoid colon, the terminal ileum, and the cecum. In some patients, most or all of their disease is confined to the pelvic viscera and the omentum, so that removal of these organs results in the extirpation of all gross tumor, a situation that is associated with a reasonable chance of complete response.

The rationale for cytoreductive surgery relates to three general theoretical considerations: (1) potential physiologic benefits from excising the tumor; (2) improved tumor perfusion and increased growth fraction, that may increase the likelihood of a response to chemotherapy or radiation therapy; and (3) enhanced immunologic competence of the patient.

The principal goal of cytoreductive surgery is to remove all of the primary cancer and, if possible, its metastases. If resection of all metastases is not feasible, the goal is to reduce the tumor burden by resection of all individual tumors to an optimal status. The definition of “optimal” was initially proposed by Griffiths, who found that the survival of patients whose metastatic disease was resected to less than 1.5 cm in maximum dimension was significantly longer than the survival of those whose residual lesions were larger than 1.5 cm. The optimal category of patients had a higher subsequent response rate to chemotherapy and longer disease-progression-free interval. Subsequently, Hacker and colleagues showed that patients whose largest residual lesions were less than 5 mm (defined as minimal residual disease, MRD) survived much longer than did those with larger non-resectable tumor deposits, and this finding has been confirmed by Van Lindert. The median survival of patients in this category was 40 months, compared with 18 months for patients whose disease was greater than 1.5 cm. It has been suggested that the performance of a complete retroperitoneal lymphadenectomy might also improve the survival of patients with advanced stage disease. Resectability of the metastatic tumor is often determined by the size of nodules, the extent of carcinomatosis, and the location of the disease.

The ability of cytoreductive surgery to influence survival is limited by the size, extent, and location of metastases prior to cytoreduction, and presumably by the presence of drug-resistant cells. For example, in patients whose metastatic disease was very large (ie, greater than 10 cm before cytoreductive surgery), survival was shorter than when less bulky disease was resected. Thus, the value of cytoreductive surgery seems to be more limited in patients with very large metastases, regardless of the extent of tumor removal. This may result from the presence of resistant clones among large masses of tumor cells. Patients with gross ascites also seem to do less well, regardless of the extent of surgical resection. In some patients, very extensive upper abdominal masses, particularly on the diaphragm or in the parenchyma of the liver, will preclude an adequate surgical excision of metastatic disease. Extensive disease involving the base of the small bowel mesentery, the large bowel mesentery, the lesser omentum, and the porta hepatis, as well as diffuse extraperitoneal metastasis, may prevent the optimal resection of tumor. Thus, the efficacy of cytoreductive surgery is limited. From these and other data, definitions of the patients’ status based on the extent of residual disease are presented in

Table 118-5.

An analysis of the retrospective data available suggests that these operations are feasible in 70 to 90% of patients when performed by gynecologic oncologists. Major morbidity is in the range of 5% and operative mortality is 1%. Intestinal resection in these patients does not appear to increase the overall morbidity of the operation. The median survival and progression-free interval of patients after cytoreductive surgery relate to the extent of residual disease at the completion of the laparotomy. A meta-analysis has been performed with 81 cohorts of patients that included 6,885 women with stage III or stage IV disease. A statistically significant positive correlation was found between percent maximal cytoreduction and log median survival time that remained significant after controlling for all other variables (p < .001). Each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. Cohorts with 25% or less maximal cytoreduction had a median survival time of 22.7 months compared to 33.9 months in cohorts with greater than 75% maximal cytoreduction.

In a study by Van der Burg and colleagues, a prospective randomized trial of “interval” debulking operations was performed on patients with advanced-stage epithelial ovarian cancer. The patients were referred after having undergone an exploratory laparotomy during which the patient’s tumor was not debulked. The patients were then randomized to receive either (1) chemotherapy for three cycles followed by another operation, then an interval debulking operation, followed by more chemotherapy; or (2) chemotherapy with no interval debulking. The patients who underwent the interval debulking had a longer disease-free and overall survival as compared with those patients who did not. These data support the role of debulking surgery in advanced-stage epithelial ovarian cancer and suggest that the sooner the operation can be performed during the course of treatment, the more likely it is that the surgery will improve the survival. Therefore, primary cytoreductive or interval surgery should be the standard of care in patients with advanced epithelial ovarian cancer. If the primary operation either was not done or was unsuccessful, interval debulking should be performed.