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Cytoreductive Surgery in the Management of Ovarian Cancer

Cytoreductive Surgery in the Management of Ovarian Cancer

ABSTRACT: The standard management for previously untreated advanced-stage epithelial ovarian cancer is optimum cytoreductive surgery followed by aggressive cytotoxic chemotherapy. This approach is based on a retrospective review of a single-institution experience published more than 30 years ago and has yet to be confirmed in a prospective randomized trial. Many subsequent studies have supported the observation that advanced ovarian cancer patients who have the longest survival invariably have no macroscopic disease left at the completion of the initial surgery. The combination of a platinum- and taxane-based chemotherapy regimen is now well established as the most active one for treating women with advanced ovarian cancer. However, the overwhelming majority of patients with advanced ovarian cancer will eventually experience disease recurrence and develop resistance to cytotoxic chemotherapy. Selected patients with recurrent ovarian cancer—ie, those with an isolated recurrence identified more than 6 months following completion of initial chemotherapy and who have an excellent performance status—are managed with cytoreductive surgery followed by a platinum-based regimen. As in previously untreated patients, patients who have no macroscopic residual tumor left after secondary debulking for recurrent ovarian cancer have a significantly better survival than those left with any gross tumor. This article will review the role of surgery in the initial management of advanced-stage and recurrent ovarian cancer, focusing on the definition of optimum surgical cytoreduction.

The standard management for advanced-stage ovarian cancer was established in the mid-1970s. At a 1974 National Cancer Institute Consensus Conference on Ovarian Cancer, Griffiths presented data supporting the role for aggressive cytoreductive surgery as the first step in the management of this disease, followed by cytotoxic chemotherapy.[1]

In a retrospective review, Griffiths demonstrated that women with advanced-stage disease who had no residual disease at the completion of the initial surgery had a 39-month average survival, whereas those with less than a 5-mm maximum diameter of residual disease had a 29-month average survival. Patients with 6- to 15-mm residual disease had an 18-month mean survival, and those with more than 1.5 cm residual disease had an 11-month mean survival.

Griffiths et al subsequently demonstrated that if one cytoreduced patients with advanced-stage tumors to less than a 1.5-cm maximum diameter of residual disease, those patients had the same survival as patients who at the time of beginning the initial surgery had metastatic implants with less than a 1.5-cm diameter.[2] The 5-year survival for both those cytoreduced to < 1.5 cm and those with only miliary disease < 1.5 cm initially present was approximately 20%. Thus, for at least 80% of the patients, the surgery and chemotherapy proved to be palliative, not curative.

Other Available Data

Numerous institutional series have confirmed that patients with the least residual disease at completion of their initial cytoreductive surgery experienced the longest survivals.[3-8] However, no prospective randomized American trials have been performed to confirm cytoreductive surgery as the most effective initial step in the treatment of advanced ovarian cancer, and few reports have used a definition of no macroscopic residual disease to define optimal surgical cytoreduction.[5,9,10]

In 1992, Hoskins et al attempted to confirm Griffiths’ observation that cytoreduction to 1 cm or less residual disease would achieve the same survival results as those accrued to patients who initially had less than 1-cm implants in the upper abdomen.[11] Hoskins et al retrospectively reviewed the results of the Gynecologic Oncology Group (GOG) trial 52, a study confined to optimally cytoreduced stage III ovarian cancers, all of which were treated with postoperative platinum-based chemotherapy. Optimal surgical cytoreduction was defined by the GOG as residual disease ≤ 1 cm in maximum diameter at the completion of the initial surgery.

Figure 1

Figure 1: Survival After Surgical Cytoreduction in Ovarian Cancer, First GOG Trial—(A) Progression-free survival (PFS) for patients with stage III ovarian cancer treated with intravenous cisplatin and paclitaxel. (B) Overall survival (OS) for patients with stage III ovarian cancer treated with intravenous cisplatin and paclitaxel. NP = no progression; P = progression. Reprinted, with permission, from Winter WE 3rd et al.[18] Copyright © 2007 by the American Society of Clinical Oncology. All rights reserved.

The study included patients with stage IIIA (ie, only microscopic disease in the upper abdomen), stage IIIB (disease ≤ 2 cm in the upper abdomen at the beginning of surgery), and stage IIIC (disease that was present in the upper abdomen > 2 cm at the initiation of the surgery). While patients who had stage IIIA or IIIB disease did well following surgery and postoperative chemotherapy, 90% of the optimally surgically cytoreduced patients who had stage IIIC disease—based on gross omental disease > 1 cm and gross disease anywhere else in the abdominal cavity prior to initiating cytoreduction—died within 5 years following the initial diagnosis.

Hoskins et al noted that the patients with the worst survival were those with gross omental disease in addition to visible disease elsewhere in the abdominal cavity and those who had clear cell or mucinous histologic types of cancer. Further, the authors noted that younger women were more likely to have stage IIIA or IIIB disease with histologically lower-grade tumors. Older women tended to have high-grade cancer. The study failed to confirm Griffiths’ observation that stage III patients who were optimally surgically cytoreduced achieved the same survival as those who initially had only miliary disease in the upper abdomen at the beginning of their laparotomy.[1]

Role of Disease Biology

An unanswered question in this setting concerns whether the inherent biology of the disease or the surgical skills of the physician are most important in determining the outcome of initial cytoreductive surgery. In an attempt to answer this question, Crawford et al reviewed the Scottish Randomized Trial in Ovarian Cancer (SCOTROC-1) data on 1,011 patients participating in a prospective randomized trial for International Federation of Gynecology and Obstetrics (FIGO) stage IC–IV patients who were to receive cytotoxic chemotherapy following surgery.[12] All patients were treated with carboplatin and randomized to also receive either paclitaxel or docetaxel (Taxotere). There was no difference in survival for the women receiving paclitaxel or docetaxel. Essentially all patients participating in either of the treatment groups had the same survival outcomes.

Data were collected prospectively on the surgical findings, and a prognostic score was created based on the following four significant patient characteristics: (1) FIGO stage, (2) preoperative serum CA-125 level, (3) presence or absence of an omental cake, and (4) clear cell histology vs other. (Gross omental disease and histology were also significant in the GOG study.[12]) The patients were then placed into one of four quartiles based on their prognostic score. The survival of patients in each quartile was determined based on whether there was no macroscopic residual disease, ≤ 2 cm residual disease, or > 2 cm residual disease at completion of the initial surgery. Residual disease was confirmed by postoperative, prechemotherapy computed tomography (CT) scans.

Figure 2

Figure 2: Survival After Surgical Cytoreduction in Ovarian Cancer, Second GOG Trial—(A) Progression-free survival (PFS) for patients with stage IV ovarian cancer treated with intravenous cisplatin and paclitaxel. (B) Overall survival (OS) for patients with stage IV ovarian cancer treated with intravenous cisplatin and paclitaxel. Reprinted, with permission, from Winter WE 3rd et al.[19] Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved.

The patients who benefited most from surgical cytoreduction to no residual disease were those in the first two quartiles.[13] The patients in the third or fourth quartile experienced no apparent survival benefit from having no macroscopic residual disease at the end of cytoreductive surgery, as there was no statistical difference in progression-free survival (PFS) for those with no residual disease compared to those with residual disease either less than or greater than 2 cm. These findings supported the view that the inherent biology of the disease is key in determining outcomes.

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