What is consistent in the literature is that patients who receive neoadjuvant chemotherapy are significantly more likely to undergo optimum surgical cytoreduction and often have shorter operating times, less blood loss, shorter intensive care unit stays, and shorter overall hospital stays, as less aggressive surgery is necessary to achieve optimum surgical cytoreduction. Additionally, patients are often much better prepared emotionally to undergo surgery when they have received neoadjuvant chemotherapy then when surgery is the first step in their treatment.
Timing and Sequence of Treatment
Timing of surgery following initiation of neoadjuvant chemotherapy is the major variable in the management of women with advanced-stage ovarian cancer. Prospective randomized European trials have used three cycles of neoadjuvant chemotherapy, followed by surgery and postoperative administration of three more cycles of chemotherapy. A Japanese trial is employing four cycles of neoadjuvant chemotherapy, followed by surgery and four more cycles of chemotherapy.
At Yale University, we have administered six cycles of chemotherapy, as long as the serum CA-125 levels are declining or normalized, before surgery is performed. As it is routine that some evidence of cancer persists even after six cycles, three additional cycles of the same chemotherapy is recommended following surgery.
Clinical Reports on Neoadjuvant Chemotherapy
More than 30 retrospective reports from institutions around the world are now available regarding the role of neoadjuvant chemotherapy in the management of advanced-stage ovarian cancer. Many of these articles have recently been reviewed. Unfortunately, no published prospective randomized trials are currently available to answer questions about selection of patients, dosage, and number of treatments of neoadjuvant chemotherapy prior to surgery in the management of advanced-stage disease.
Almost all of the published neoadjuvant chemotherapy clinical trials suffer from the same difficulty—the patients described in these trials are not randomized to their treatment regimens. Patients with the most advanced disease routinely received neoadjuvant chemotherapy. Patients most likely to be optimally surgically cytoreduced underwent conventional treatment—ie, cytoreductive surgery followed by adjuvant chemotherapy.
Recently, a meta-analysis on neoadjuvant chemotherapy was performed. The meta-analysis included 22 published series of patients, involving 18 different chemotherapy regimens and 13 different chemotherapeutic agents. Unlike the two recently published large Gynecologic Oncology Group (GOG) studies investigating conventional treatment of stage III and IV ovarian cancer, where the chemotherapy dose and duration was the same for all patients, there was no standardization of the chemotherapy regimens, doses, or the duration of neoadjuvant chemotherapy treatment prior to surgery in the reports entered into the meta-analysis.[1,2,24]
The authors of the meta-analysis used a relatively simple but less precise method for this meta-analysis. They pooled the data together, using each study as a data point instead of pooling individual patients together from each study. They then used a simple linear regression analysis instead of a survival analysis. Their pooled analysis may have generated possible leads regarding the role of neoadjuvant chemotherapy in the management of advanced-stage ovarian cancer, but the results were far from definitive. They did recognize that neoadjuvant chemotherapy patients treated with a combined platinum/taxane regimen did better than patients treated with other regimens—a finding consistent with the GOG 111 trial and the Yale data.[18,25]
A subsequent review of neoadjuvant chemotherapy reports in advanced-stage ovarian cancer by the authors who reported the meta-analysis above, classified all of the reported study’s results into one of three categories. The first group reportedly demonstrated inferior survival after neoadjuvant chemotherapy compared to survival after primary cytoreductive surgery. The second group showed no difference in survival outcome between neoadjuvant chemotherapy and a less than maximal primary cytoreductive surgical effort. The third category was associated with very favorable survival results for the neoadjuvant chemotherapy–treated patients, but was criticized by the authors for “the generous nature” of the patient inclusion criteria. These authors noted in their conclusion that “additional research is needed to characterize the appropriate proportion of patients in which an attempt at primary surgery should be deferred in favor of initial chemotherapy.”