Conventional therapy for advanced-stage ovarian cancer—ie, aggressive cytoreductive surgery followed by aggressive chemotherapy—was established more than 3 decades ago [Editor’s note: See Dr. Schwartz’s article, “Cytoreductive Surgery in the Management of Ovarian Cancer,” in last month’s issue of ONCOLOGY]. Since that time, no prospective randomized trials have been reported to confirm the efficacy of this treatment strategy. Recent large retrospective studies have demonstrated that the greatest survival benefit is accrued to those who have no gross disease left after the initial surgical cytoreduction. This represents only 23% of stage III patients and 8% of stage IV patients.[1,2] Alternative strategies for patients who do not appear to be surgically cytoreducible to no macroscopic residual disease need to be identified.
One such strategy—chemotherapy administered prior to aggressive surgical cytoreduction, ie, neoadjuvant chemotherapy—is now being evaluated in three prospective randomized trials. Retrospective reports utilizing neoadjuvant chemotherapy suggest that a major benefit to this approach is a significantly higher rate of surgical cytoreduction to no visible disease. Additional benefits include a patient in a better nutritional state preoperatively than with conventional treatment. Surgery performed following neoadjuvant chemotherapy is routinely shorter in time, associated with less blood loss, shorter intensive care unit stays and shorter hospitalizations.
Survival data suggest no difference in the progression-free or overall survival for stage III disease patients treated with neoadjuvant chemotherapy or conventional therapy. Some reports suggest improved survival with stage IV patients treated with neoadjuvant chemotherapy compared with conventional therapy.
This article will review the current status of neoadjuvant chemotherapy for the management of women with advanced-stage ovarian cancer.
History of Neoadjuvant Chemotherapy for Ovarian Cancer
Neoadjuvant chemotherapy as used in this article refers to the administration of chemotherapy for advanced-stage ovarian cancer prior to attempted surgical cytoreduction. This approach was first used at Yale University in 1979. The diagnosis of ovarian cancer was based on a computed tomography (CT) scan consistent with advanced-stage ovarian cancer and cytology consistent with a nonmucinous epithelial ovarian cancer.
The initial approach used at Yale University was to reserve neoadjuvant chemotherapy for women who were medically impaired such that their performance status would not allow them to undergo aggressive cytoreductive surgery. A decade after its use in that regard, it was recognized that there were ovarian cancer patients who, by CT criteria, were unlikely to be optimally surgically cytoreduced. Those patients were then offered neoadjuvant chemotherapy as the initial step in the management of their disease.
Neoadjuvant chemotherapy alone is insufficient for the initial treatment of advanced-stage ovarian cancer—it is only one event in the treatment course. Aggressive cytoreductive surgery is the necessary next step. Surgeons who are unprepared for aggressive cytoreductive surgery should not be performing the surgery following neoadjuvant chemotherapy. Such surgery should be done by a gynecologic oncologist prepared to do radical surgery necessary to remove all gross disease present following neoadjuvant chemotherapy. Today, it is believed that the major value of neoadjuvant chemotherapy is in preparing patients for aggressive cytoreductive surgery so that those patients can be optimally cytoreduced.
Patient Selection for Cytoreductive Surgery
Many attempts have been made to identify the patients unlikely to be optimally surgically cytoreduced. Diagnostic imaging has been employed. In 1993, Nelson et al published the Yale criteria for when patients are unlikely to be optimally cytoreduced. These criteria included a preoperative CT scan revealing the presence of an omental cake extending to the spleen, the diaphragm coated by cancer that extends to the liver serosa, greater than 2-cm lesions in the suprarenal para-aortic lymph nodes and in the portahepatis, parenchymal liver disease, pulmonary metastases, and enlarged pericardial lymph nodes. Since that time, numerous studies have been reported, some of which support the “Nelson criteria” and others that fail to support these criteria.[8-12]
A presurgical serum CA-125 level had been proposed as a means of identifying which patients could not be optimally surgically cytoreduced.[13-16] In the Memorial Sloan-Kettering Cancer Center experience prior to the year 2000, patients whose serum CA-125 values were less than 500 U/mL could be optimally cytoreduced in 75% of cases, whereas those who had CA-125 values over 500 U/mL could not be optimally cytoreduced in 78% of cases. Since the year 2000, the gynecologic oncologists at that institution have employed a more radical approach to the surgical management of ovarian cancer. In their most recently reported experience, the serum CA-125 level no longer reflects their ability to optimally cytoreduce the patient. A similar observation had been made by the Yale investigators.
Because of the failure of either diagnostic imaging or serum CA-125 levels to consistently reflect the likelihood of suboptimally cytoreducing patients, laparoscopy has been utilized, to attempt to identify which patients can be optimally cytoreduced.[19-21] Currently, cytoreduction scores are being evaluated by physicians who are performing laparoscopy on their patients to identify those likely to be optimally cytoreduced. An attempt to use microarray techniques to identify advanced-stage ovarian cancer patients who might be optimally cytoreduced had a predictive accuracy of 72.7%, supporting the hypothesis that optimal surgical cytoreduction is due, at least in part, to biologic characteristics of the cancer. At present, there is no absolute way to identify which patients with advanced-stage ovarian cancer will or will not be able to be optimally cytoreduced at the time of their initial operation.
What the Literature Suggests About Neoadjuvant Chemotherapy
Gynecologic oncologists have broadly accepted the concept that all patients with advanced-stage ovarian cancer must initially be aggressively operated on to optimally surgically cytoreduce the cancer and then receive platinum-based combination chemotherapy. Any change to this approach should only be done under dire circumstances, such as extremely advanced disease in a patient with a very poor performance status or in a situation where change in treatment would significantly improve survival.
The currently available published data suggests that for most series, patients with stage IIIC disease do as well with neoadjuvant chemotherapy followed by aggressive cytoreductive surgery as they do with conventional treatment. However, it is routine in these retrospective, nonrandomized series that patients with the most advanced disease and the least likelihood to be optimally cytoreduced received neoadjuvant chemotherapy, whereas those with the least advanced disease and best chances to be optimally surgically cytoreduced underwent surgery first. For stage IV disease, there is retrospective evidence that patients do better with neoadjuvant chemotherapy.