Commentary (Ozols): Neoadjuvant Chemotherapy for Ovarian Cancer

Neoadjuvant, or induction, chemotherapy has been used extensively in selected carcinomas, particularly head and neck cancer (recently reviewed in ONCOLOGY)[1] and locally advanced breast cancer. Despite beneficial effects on morbidity, long-term survival has not been significantly improved by neoadjuvant chemotherapy. Ovarian cancer, because of its clinical presentation, is associated with factors to suggest that neoadjuvant chemotherapy would be beneficial. Ovarian cancer is diagnosed as International Federation of Gynecology and Obstetrics (FIGO) stage III disease with intraperitoneal carcinomatosis in 75% of patients. Standard therapy consists of initial cytoreduction (eg, removal of as much disease as possible), with the understanding that surgery has essentially no curative potential in advanced disease- at a minimum, microscopic disease will remain at numerous sites, including the peritoneum, lymph nodes, and mesentery. Cytoreductive surgery is followed by combination chemotherapy, with paclitaxel plus carboplatin being the most common regimen currently in use. Ovarian cancer is a chemosensitive disease, and following chemotherapy, approximately 75% of patients with advanced-stage disease will be in a clinical complete remission. Unfortunately, most patients will ultimately relapse, and less than 25% of patients with advanced-stage disease will be cured with current therapy. Key Prognostic Factors
While no prospective randomized controlled trial has established that effective initial cytoreduction (ie, no tumor nodule greater than 1 cm in diameter remaining) prolongs survival, numerous retrospective analyses, including meta-analyses, conclude that the less disease remaining after initial surgery, the better the outcome.[ 2] There is little benefit if any tumor nodule greater than 1 cm in diameter remains after cytoreduction. Such optimal cytoreduction is possible in approximately 75% of patients at the time of initial diagnosis, if performed at centers with expertise in the management of ovarian cancer. In addition to surgical resectability, the biology of the disease-which accounts for bulky disease in some patients-is also an important prognostic factor. Hoskins et al[3] reported inferior survival for stage III patients who had bulky upper abdominal disease and underwent successful cytoreduction, compared to patients who presented with smallvolume stage III disease and therefore did not require cytoreduction. Rationale for Neoadjuvant Therapy
The possibility that induction chemotherapy could affect subsequent rates of optimal cytoreduction remains a primary rationale for neoadjuvant chemotherapy in ovarian cancer. Because of the intrinsic sensitivity of this disease to chemotherapy, such induction chemotherapy may increase the number of patients who can be optimally cytoreduced after a specified number of chemotherapy cycles. Furthermore, if neoadjuvant chemotherapy does not result in significant cytoreduction, and the patient has primarily drug-resistant disease (which is the case in about 15% to 20% of all patients diagnosed), it is probable that initial cytoreduction- despite the claims that it may removedrug-resistant tumors-is unlikely to have had a significant impact on survival, since the remaining microscopic or macroscopic nodules also would likely be drug-resistant. Consequently, neoadjuvant chemotherapy could potentially make cytoreduction more effective in some patients with chemosensitive disease and obviate the need for such surgery in patients with chemoresistant disease. Despite the clear rationale, there has been reluctance to conduct the appropriate clinical trial to either prove or disprove the hypothesis. In addition, there has been controversy about clinical criteria used to identify patients with advanced disease, in whom cytoreduction has only a small chance of producing an optimal postoperative state and who would be potential candidates for neoadjuvant chemotherapy. In their review, Vergote et al[4] list six criteria that identify "candidates" for neoadjuvant chemotherapy, as cytoreductive surgery would be unlikely to result in an optimal postoperative state. These criteria are somewhat subjective, and certainly some aggressive surgeons would not rule out initial cytoreduction in all of these patients. While laparoscopy may be helpful in evaluating the operability of patients, noninvasive criteria are inherently more useful. Until criteria can be validated and agreed upon, the practicing gynecologic oncologist is left in a quandary as to how to clearly identify patients who should receive initial chemotherapy instead of cytoreduction. Data Limitations
The problem is even more fundamental since there are no data about the potential effects of induction chemotherapy in patients who, at the time of diagnosis, clearly are good candidates for cytoreductive surgery. And what if a patient responds to neoadjuvant chemotherapy with normalization of serum CA-125 and resolution of all objective intraperitoneal disease? Is there any need for surgery whatsoever in such patients? Perhaps the patient with advanced ovarian cancer with a small amount of intraperitoneal disease (who could be optimally cytoreduced at the time of diagnosis) would benefit the most from induction chemotherapy, possibly eliminating the need for any surgery. However, it is unlikely that such a hypothesis could be tested in a prospective randomized trial, given the belief that these patients with initially diagnosed small-volume ovarian cancer benefit from cytoreduction. Arguments against any potential benefit for induction chemotherapy in ovarian cancer are also based on its pattern of metastases. The entire peritoneal cavity as well as pelvic and retroperitoneal nodes are at risk and frequently involved with disease. Neoadjuvant therapy has no realistic chance of "downstaging" the disease unless all disease is eradicated and the patient achieves a complete remission. The results of the European Organization for Research and Treatment of Cancer/Gynecological Cancer Cooperative Group trial[5] suggest that interval debulking surgery after three cycles of chemotherapy improves survival in patients who did not undergo a "maximal surgical effort" at diagnosis, whereasthe Gynecologic Oncology Group trial[6] failed to demonstrate any benefit for interval debulking surgery following chemotherapy in patients who underwent an initial, but unsuccessful, cytoreduction by gynecologic oncologists. The immunologic effects and reduction of potentially drug-resistant clones by cytoreductive surgery have been postulated as other benefits of initial cytoreduction, but have not been validated in clinical trials. Conclusions
What then is the state of neoadjuvant therapy in advanced ovarian cancer? Only one randomized trial is currently addressing the issue and one clinical trial is rarely definitive. In addition, it is clear that more effective chemotherapy is also needed in order to make a significant impact on survival in this disease. The more effective systemic therapy is, the less will be the need for cytoreductive surgery. Germ-cell tumors of the ovary are a primary example of a cancer in which cytoreduction has been replaced by selective surgery that preserves fertility due to the curative role of platinum- based chemotherapy. Obviously, the treatment of epithelial ovarian cancer has not yet reached that point, but the debate over initial cytoreduction vs neoadjuvant chemotherapy will likely continue until more effective systemic therapy has settled the issue.In the meantime, clinical judgment will dictate who will undergo initial surgery and which patients should receive induction chemotherapy. The identification of validated criteria to identify patients in whom cytoreductive surgery should not be attempted, even by experienced gynecologic oncologists, remains an unmet need.

Disclosures:

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

References:

1. Argiris A, Jayaram P, Pichardo D: Revisiting induction chemotherapy for head and neck cancer. Oncology 19:759-770; 932-939, 2005.
2. Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 20:1248-1259, 2002.
3. Hoskins WJ, Bundy BN, Thigpen JT, et al: The influence of cytoreductive surgery on recurrence-free interval and survival in smallvolume stage III epithelial ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 47:159-166, 1992.
4. Vergote I, Van Gorp T, Amant F, et al: Neoadjuvant chemotherapy for ovarian cancer. Oncology 19:1615-1622, 2005.
5. van der Burg ME, van Lent M, Buyse M, et al: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 332:629-634, 1995.
6. Rose PG, Nerenstone S, Brady MF, et al: Gynecologic Oncology Group: Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 351:2489-2497, 2004.