Prospective Randomized Trials
No prospective randomized trials in the United States have evaluated neoadjuvant chemotherapy against conventional treatment for advanced ovarian cancer. One international prospective randomized trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) has completed accrual of patients. The EORTC 55791 trial randomized over 700 women to receive either neoadjuvant chemotherapy for three cycles, followed by cytoreductive surgery and then three additional cycles of chemotherapy, or surgery followed by six cycles of chemotherapy. For the latter arm, there was an option to perform interval cytoreduction following three cycles of chemotherapy if the surgeon declared that it was his or her intent to do so prior to performing the initial surgery.
A very similar trial, Chemotherapy or Upfront Surgery (CHORUS), is now accruing patients in a UK study. Over 300 patients have joined this trial, which has a total goal of accruing 550 patients. Finally, the Japanese Clinical Oncology Group is inviting patients to participate in a prospective randomized trial wherein 350 women will be randomized to receive either four cycles of carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel) followed by surgery and four additional cycles of treatment, or initial cytoreductive surgery followed by eight cycles of carboplatin and paclitaxel.
Future of Neoadjuvant Chemotherapy for Advanced Ovarian Cancer
Preliminary results from the EORTC 55791 study are expected to be available in the fall of 2008 (personal communication). The initially released results will focus on morbidity. Survival data should be available in the spring of 2009. If there is no difference in survival between conventional therapy and neoadjuvant chemotherapy in the EORTC data and the morbidity is improved among women receiving neoadjuvant chemotherapy, neoadjuvant chemotherapy may become an accepted standard technique for the management of patients with advanced-stage ovarian cancer. Indeed, the latter is already true in Ottawa, Canada.
Aletti et al have proposed a treatment strategy for patients with stage IV disease. Neoadjuvant chemotherapy would be offered to patients with multiple hepatic metastases or extensive pleural disease. Patients with a good performance status (American Society of Anesthesiologists [ASA] 1 or 2) would undergo attempted debulking. Those with poor performance status (ASA 3 or 4) would undergo laparoscopy. For the latter, those found to have extensive peritoneal or unresectable disease would receive neoadjuvant chemotherapy, while those who did not would undergo an attempt at primary debulking.
The Southwest Oncology Group recently provided preliminary data on survival for patients believed to be not optimally cytoreducible. These advanced-stage disease patients received neoadjuvant chemotherapy for three cycles and then underwent cytoreductive surgery. Those who were optimally cytoreduced received intraperitoneal chemotherapy to complete their treatment. The survival data were similar to results seen in patients who underwent surgery followed by chemotherapy in a conventional manner.
Laparoscopic surgery has become a routine part of the management of patients with gynecologic cancers. It is often used by European gynecologic oncologists to determine whether a patient can initially be optimally cytoreduced. Should neoadjuvant chemotherapy become an accepted standard of care, it is possible that among those who achieve a clinical complete response or who have limited and isolated tumor nodules noted on posttreatment CT scans, selected patients will then undergo laparoscopic surgery to remove residual disease as well as reproductive organs that are still in place.
The critical question regarding neoadjuvant chemotherapy for the management of advanced-stage ovarian cancer concerns the estimation of surgical cytoreducibility. The survival data, which have been available since 1974, strongly suggest that the best approach to the initial treatment of advanced-stage ovarian cancer is to resect all gross cancer. Estimating cytoreducibility by diagnostic imaging, serum biomarkers, laparoscopic, and molecular biologic techniques has proven to be less than completely reliable. Efforts must be made to identify patients with advanced disease who can be cytoreduced to no gross residual disease, as they benefit the most from this approach.
A second question is: How many cycles of chemotherapy should be given prior to performing the surgery? The excellent findings obtained by the Yale group were the result of giving six cycles of chemotherapy (carboplatin and paclitaxel) prior to patients undergoing cytoreductive surgery. The EORTC and CHORUS trials selected three cycles of chemotherapy prior to surgery. The Japanese Clinical Oncology Group trial uses four cycles of chemotherapy prior to surgery.
Finally, and perhaps most significantly, the management of residual disease—which may represent chemoresistant clones of cancer cells—identified at the time of surgery following neoadjuvant chemotherapy will remain an issue. The possibility exists that the cancer that persists after neoadjuvant chemotherapy for advanced-stage ovarian cancer represents ovarian cancer stem cells, which are known to be inherently chemotherapy-resistant. Strategies for treating ovarian cancer stem cells are currently being developed.
Medically compromised patients who are physically unable to tolerate aggressive cytoreductive surgery should undergo neoadjuvant chemotherapy first, followed by aggressive cytoreductive surgery if their medical condition improves. Likewise, patients with stage IV ovarian cancer do poorly with conventional therapy, and thus, neoadjuvant chemotherapy should become a standard alternative approach to treating this particular group of women.
All women with stage IIIC disease should be evaluated by a gynecologic oncologist. If the gynecologic oncologist feels the patient can be optimally cytoreduced to no macroscopic residual disease, surgery should be the first step in treatment. If it is expected that macroscopic disease will be left behind, the patient should be offered the choice of either neoadjuvant chemotherapy or conventional therapy.