Commentary (Konner/Abu-Rustum): Neoadjuvant Chemotherapy for Ovarian Cancer

The review by Vergote et al[1] presents a well-organized and comprehensive summary of the data addressing neoadjuvant chemotherapy for ovarian cancer. The timing of debulking surgery for this disease is a common and clinically important question, but one that lacks definitive trial data. The assembled data suggest a rationale for decisionmaking. The European Organization for Research and Treatment of Cancer (EORTC) and Gynecologic Oncology Group (GOG) 152 trials present compelling evidence supporting a "maximal surgical effort" by an experienced gynecologic surgeon, preferably at a specialty hospital, at some point during primary therapy. Without clear indications for delaying surgery, initial debulking should at present be the default. What those indications are and precisely how stringently to define them remain at issue. The results of the randomized study sponsored by the EORTC-Gynecological Cancer Group (GCG) and the National Cancer Institute of Canada will be of clear interest. In the several-year interim before we yield answers from this trial, however, the treatment paradigmfor newly diagnosed ovarian cancer is poised to evolve in significant ways. Intraperitoneal Chemotherapy
At the 2005 American Society of Clinical Oncology (ASCO) meeting, Armstrong et al presented survival data from GOG 172,[2] a large randomized trial comparing upfront chemotherapy delivered intravenously vs combined intravenous and intraperitoneal (IP) delivery. The control group (n = 210) received IV paclitaxel, 135 mg/m² over 24 hours on day 1, and cisplatin, 75 mg/m² IV on day 2, while the experimental arm (n = 205) received paclitaxel, 135 mg/m² IV over 24 hours on day 1, cisplatin, 100 mg/m² IP on day 2, and paclitaxel, 60 mg/m² IP on day 8. Despite the fact that one-half of patients in the IP arm received three or fewer of the intended six cycles oftherapy (mostly owing to toxicity), a survival advantage of 17 months (overall survival = 66.9 vs 49.5 months, P = .0076) was nonetheless seen for the IP group. When these data are formally published and further disseminated, IP therapy is poised to become a widely accepted standard of upfront care for optimally debulked stage III cancers. This will complicate the roles of neoadjuvant chemotherapy and interval debulking. Although the data suggest that fewer than six cycles of IP therapy may indeed be beneficial, it may also be the case that more is better. This may influence the optimal number of cycles of neoadjuvant therapy that are recommended; giving one to two, rather than three to four, would allow the patient to receive more IP treatments. Clear criteria as to what degree of response is hoped for with initial therapy may allow this schedule to be individually tailored. Role of Laparoscopy
The value of laparoscopy with regard to assessing resectability remains controversial. As with resectability by other modalities, what appears unresectable to one operator may not appear so to another. From our experience with laparoscopy in this setting (and in advanced ovarian cancer in general), the use of this approach may exaggerate the extent of disease and unnecessarily exclude patients from cytoreductive surgery. Important shortcomings include the magnification during laparoscopy, the difficulty in completely aspirating ascites to clearly visualize deep peritoneal surfaces and the retroperitoneum, as well as the limitations in evaluating the bowel and its mesentery in the setting of bulky omental disease. Clearly, laparoscopy is useful for tissue diagnosis. In the majority of cases, however, this can be performed percutaneouslywith image-guided biopsy or aspiration. In the unlikely scenario that IP therapy proves useful for bulky peritoneal disease, as some authors have proposed, then perhaps an IP catheter can be placed at the time of the open laparoscopy procedure recommended by Vergote et al.[1] Bevacizumab Therapy
Another treatment that may become part of upfront therapy in this setting is the incorporation of bevacizumab (Avastin) in combination with a platinum agent and a taxane. Two trials[3,4] presented as abstracts at ASCO 2005 demonstrate activity of this drug in recurrent ovarian cancer. Burger et al[3] presented results from GOG 170-D, where bevacizumab was given as a single agent at 15 mg/kg IV every 3 weeks to 62 patients. The overall response rate was 17.7%, and the stable disease rate was 54.8%, with a response duration of 10.2 months. In a study by Garcia et al,[4] bevacizumab (10 mg/kg) was given every 2 weeks along with cyclophosphamide (50 mg po daily), yielding an overall response rate of 21% and a 7.5-month median time to progression. As a follow-up, the GOG 218 (182R) trial, which is planned and may open this year, will compare upfront IV carboplatin and IV paclitaxel with or without bevacizumab, in patients with stage IV or suboptimal stage III disease. A third arm will receive the three drugs, followed by a bevacizumab-only maintenance phase. Due to concerns about wound healing, bevacizumab will not be given before the second cycle during this study. Should the addition of bevacizumab confer a survival benefit, it would become the standard of care. In that scenario, the safety of performing an interval debulking after bevacizumab will have to be considered carefully, if at all. What is a safe interval? Moreover, will bevacizumab's benefit be undermined if it is withheld from several of the six cycles of chemotherapy, eg, followingopen laparoscopy (if it is performed) and both before and after interval debulking? Conclusions
In summary, primary cytoreductive surgery remains the standard, preferred approach for women with presumed advanced-stage ovarian or peritoneal cancer and is best performed by experienced gynecologic oncologists in high-volume centers. Every effort should be made to completely resect all visible peritoneal and retroperitoneal disease. This may necessitate collaboration with more experienced surgical subspecialists (such as hepatobiliary or thoracic surgeons), particularly for extensive upper abdominal and perihepatic disease. Gynecologic oncologists should continue to advance their expertise and training in radical abdominal and retroperitoneal surgery and adapt surgical techniques and approaches routinely used by other surgical oncologists in order to achieve the best approach and skills necessary to adequately resect advanced ovarian cancer.

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.

References:

1. Vergote I, Van Gorp T, Amant F, et al: Neoadjuvant chemotherapy for ovarian cancer. Oncology 19:1615-1622, 2005.
2. Armstrong DK, Bundy BN, Baergen R, et al: Randomized phase III study of intravenous (IV) paclitaxel and cisplatin vs IV paclitaxel, intraperitoneal (IP) cisplatin and IP paclitaxel in optimal stage III epithelial ovarian cancer: A Gynecologic Oncology Group trial (GOG 172) (abstract 803). Proc Am Soc Clin Oncol 21:201a, 2002.
3. Burger RA, Sill M, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study (abstract 5009). J Clin Oncol 23:457s, 2005.
4. Garcia AA, Oza AM, Hirte H, et al: Interim report of a phase II clinical trial of bevacizumab (Bev) and low dose metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary peritoneal carcinoma: A California Cancer Consortium Trial (abstract 5000). J Clin Oncol 23:455s, 2005.