Neoadjuvant Chemotherapy for Ovarian Cancer

Primary debulking surgery by a gynecologic oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumor load. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in stage IIIC and IV patients. Interval debulking is defined as an operation performed after a short course of induction chemotherapy. Based on the randomized European Organization for Research and Treatment of Cancer–Gynecological Cancer Group (EORTC-GCG) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on Gynecologic Oncology Group (GOG) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery.

The importance of cytoreductive surgery in the treatment of advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] stage III and IV) was first suggested as early as 1934 by Meigs.[1] But this procedure was long disputed until, in the 1970s, Aure et al[2] and Griffiths et al[3] showed that the amount of residual tumor following primary surgery was an important prognostic factor in advanced ovarian carcinoma. Unfortunately, no prospective randomized controlled trials have investigated the role of primary cytoreductive surgery in advanced ovarian carcinoma. Despite this lack of randomized controlled trials, primary cytoreductive surgery should be the standard of care in advanced ovarian cancer.[4] In the 1980s, the European Organization for Research and Treatmentof Cancer-Gynecological Cancer Group (EORTC-GCG) launched a randomized study of the role of interval debulking surgery in women who did not or could not have a successful primary debulking operation (reduction of disease to < 1 cm). During the same time period, several institutions started using neoadjuvant chemotherapy in patients with advanced ovarian cancer (without a primary attempt at debulking) followed by an interval debulking surgery. We will try to define the current role of primary or neoadjuvant chemotherapy followed by interval debulking surgery in the primary management of advanced ovarian cancer. Definitions Agreement about the terminology for surgical procedures is essential for a clear understanding. The following standard definitions were recommended during the 1998 consensus meeting on advanced ovarian cancer[5]: Primary cytoreductive surgery: an operation to remove as much of the tumor and its metastases as possible before subsequent therapy is initiated. Interval cytoreductive surgery: an operation performed in patients after a short course of induction chemotherapy- usually two or three cycles of chemotherapy-to remove as much primary and metastatic disease as possible, in order to facilitate response to subsequent chemotherapy and to improve survival. Secondary cytoreductive surgery: an operation performed in patients who have either persistent disease at the completion of a planned course of chemotherapy or who subsequently experienced clinical relapse. Surgery in Primary Management of Advanced Ovarian CancerPrimary Debulking Surgery

• Conclusion-Although evidence from retrospective studies suggests that neoadjuvant chemotherapy followed by interval debulking surgery is a valid alternative in a selected group of patients with stage III or IV ovarian carcinoma, this needs to beconfirmed in a prospective randomized trial. Therefore, the EORTCGCG, in cooperation with the National Cancer Institute of Canada, launched a prospective randomized trial to compare primary debulking surgery with neoadjuvant chemotherapy (Figure 3). To be eligible, patients must have biopsy- proven stage IIIC or IV epithelial ovarian cancer or peritoneal or fallopian tube carcinoma (with the biopsy taken at laparoscopy or laparotomy, or image-guided). The study is expected to close in the summer of 2006, with a target accrual of 704 patients.

Laparoscopy to Select Patients for Neoadjuvant Chemotherapy
Nelson et al[53] proposed computed tomographic (CT) criteria to predict operability in patients with suspected ovarian masses. Tumor localization on the spleen or tumors larger than 2 cm on the diaphragm, liver surface, mesentery, or gall bladder on CT were regarded as inoperable. However, 6 out of 18 patients (33%) judged to be inoperable based on these criteria were optimally debulked. Therefore, we do not believe that operability can be judged based on CT findings. Others proposed newer CT criteria, CA-125, or microarrays analyses to predict operability.[54-56]

We concluded that CT with peritoneography was superior to standardCT but still less sensitive than laparoscopy to evaluate operability.[57] The technique of an open laparoscopy decreases the risk of a "blind" insertion of a Veress needle or trocar. During open laparoscopy, a small incision in or underneath the umbilicus is made. Consecutively, the different layers of the abdominal wall are opened (ie, a mini-laparotomy), and a blunt trocar is introduced under direct vision. Between 1995 and 2002, we performed an open laparoscopy in 173 patients to establish the diagnosis of stage III or IV ovarian carcinoma and found that open laparoscopy was the best technique to evaluate the operability. This procedure also provides the opportunity to perform biopsies and to exclude other primary tumors metastatic to the pelvis (eg, intestinal tumors, pancreatic tumors, and so forth).[58] The possible development of port site metastases might prevent some surgeons from performing laparoscopy. We explored this issue further and completely excised all port sites at the time of primary debulking surgery or interval debulking surgery in the last 71 cases. Twenty-two of these sites contained malignant cells. The total number of port site metastases (clinically detected or diagnosed at microscopic examination of the excised port site) in the whole series of 173 patients was 30 (17%). It should be noted that, in this series, all port site metastases disappeared during the neoadjuvant chemotherapy or were excised at the time of surgery. None of the patients developed a subsequent recurrence in the port sites during follow- up, and none of the patients had a port site metastasis at the time of death. Therefore, we believe that port site metastases in advanced ovarian cancer are frequent but not of prognostic significance.

• Conclusion-Open laparoscopy is an important tool in the evaluation of the operability of patients with ovarian cancer. To date, this technique has produced no proven detrimental effects on the prognosis of these patients.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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