Intraperitoneal Chemotherapy for Ovarian Cancer

Epithelial ovarian cancer is the second most common gynecologic malignancy, but is the leading cause of death from gynecologic cancer in the United States. In 2007, an estimated 22,430 new cases of ovarian cancer and 15,280 deaths from ovarian cancer will occur in the United States (1). Most patients with ovarian cancer present with either stage III or stage IV disease.

Patients with early stage disease need to have comprehensive surgical staging to assess risks and to direct adjuvant chemotherapy. In addition, for advanced ovarian cancer, primary surgical cytoreduction plays an important role. The goal of cytoreductive surgery is to achieve optimal tumor reduction, ideally with individual aggregates of residual disease less than 1 cm. Postoperative intravenous (IV) chemotherapy in advanced stage ovarian cancer has been the standard treatment. Recent trials have suggested that patients with optimally debulked stage III ovarian cancer may be candidates to receive part of their chemotherapy intraperitoneally. Patients with newly diagnosed ovarian cancer may solicit input from their generalist obstetrician–gynecologist regarding treatment options. The purpose of this Committee Opinion is to provide the generalist obstetrician–gynecologist with information regarding the use of intraperitoneal (IP) chemotherapy in the treatment of ovarian cancer and a summary of recent trial results.

Intraperitoneal chemotherapy as a therapeutic strategy for patients with ovarian cancer was based on pharmacologic modeling studies performed in the late 1970s (2). The rationale was based on the findings of high intraperitoneal concentration of drugs and longer half–life of the drug in the peritoneal cavity, which resulted in a prolonged exposure of the chemotherapy agents. One of the concerns of the use of IP chemotherapy has been uniform distribution of the drug, which may not occur because of adhesions that result from surgery.

To study these concerns, randomized clinical trials of IV chemotherapy versus IP chemotherapy began approximately 20 years ago. The results of Gynecologic Oncology Group (GOG) Protocol 172 were published in early 2006 (3). This trial compared IV chemotherapy with an experimental regimen containing both IV and IP chemotherapy in women with optimally debulked stage III ovarian cancer. The treatment regimen was administered every 3 weeks for six cycles (see box). The results of this trial are summarized in Table 1.

The survival advantage of approximately 16 months in GOG Protocol 172 was considered to be a significant advance. The results of this trial and six other randomized trials prompted the National Cancer Institute (NCI) to issue a Clinical Announcement pertaining to IP chemotherapy for epithelial ovarian cancer (4). Seven randomized trials found that women who received adjuvant IP chemotherapy had greater overall survival rates than women who did not receive such treatment.

However, in GOG Protocol 172, the complication rate of the experimental IV/IP regimen was significantly greater than the complication rate of IV therapy alone. The IV/IP chemotherapy group had more severe toxicities, which included pain and fatigue and hematologic, gastrointestinal, metabolic, and neurologic toxicities. Quality of life was lower in the IV/IP chemotherapy group during the first year after initial treatment. In addition, only 42% of the patients randomized to IV/IP chemotherapy completed the recommended six cycles. The most common reason for discontinuation of IP therapy was catheter–related problems (34%) (5). Nine percent of patients refused additional IP treatment.

There has not been widespread acceptance of IV/IP therapy because of toxicities, catheter problems, and a complicated treatment regimen. Acceptance of the IV/IP regimen is further complicated because the IV–only regimen used in GOG Protocol 172 was not the current preferred treatment of IV administration of paclitaxel, 175 mg/m² over 3 hours, and IV administration of carboplatin (area under the curve, 7.5). Intravenous administration of paclitaxel, 175 mg/m² over 3 hours, and IV administration of carboplatin (area under the curve, 7.5) was one of the treatments compared with 24–hour IV administration of paclitaxel and cisplatin in GOG Protocol 158. The paclitaxel (given over 3 hours) and carboplatin treatment arm of GOG Protocol 158 demonstrated improved survival compared with 24–hour IV administration of paclitaxel and cisplatin, which was the IV–only regimen used in GOG Protocol 172 (6). Women in GOG Protocol 172 and GOG Protocol 158 had optimally debulked stage III ovarian cancer. Robust exploratory cross–trial comparisons of IV administration of carboplatin and IV administration of paclitaxel compared with IV/IP regimens suggest similar efficacy (7). A recent international consensus conference recommended IV administration of carboplatin and paclitaxel as the standard regimen against which new treatments should be compared (8).

Patients with optimally debulked stage III epithelial ovarian cancer who would be potential candidates for IP chemotherapy should be well counseled regarding the risks and benefits of IV plus IP chemotherapy versus IV chemotherapy alone. Clinically, many patients are being treated with IP chemotherapy, but probably are not using the GOG Protocol 172 dosing regimen. Consequently, women may be treated with IV/IP chemotherapy regimens that have no scientific evidence of better outcomes. The NCI Clinical Announcement summary stated that despite the positive findings of the trials, the ideal combination of drugs for IV/IP therapy had not been identified. The NCI Clinical Announcement suggested consideration of IP cisplatin therapy, 100 mg/m², and IV–only taxane administration or by IV plus IP administration. The Gynecology Oncology Group is currently evaluating other IV/IP chemotherapy regimens to identify a less toxic, more tolerable, and less complicated treatment regimen.

In summary, combination IV/IP chemotherapy may be an option for well counseled, carefully selected patients with optimally debulked stage III ovarian cancer when provided by a physician with the requisite training and experience in administering this treatment. However, given the balance of efficacy, quality of life, and toxicity, the decision to use IP chemotherapy must be individualized.

References

1. American Cancer Society. Cancer facts and figures 2007. Atlanta (GA): ACS; 2007. Available at: http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf. Retrieved August 22, 2007.
2. Dedrick RL, Myers CE, Bungay PM, DeVita VT Jr. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 1978;62:1–11.
3. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. Gynecologic Oncology Group. N Engl J Med 2006;354:34–43.
4. National Cancer Institute. Clinical announcement on intraperitoneal chemotherapy in ovarian cancer. Cancer Therapy Evaluation Program. Bethesda (MD): NCI; 2006. Available at: http://ctep.cancer.gov/highlights/clin_annc_010506.pdf. Retrieved September 28, 2007.
5. Walker JL, Armstrong DK, Huang HQ, Fowler J, Webster K, Burger RA, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. Gynecol Oncol 2006;100:27–32.
6. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke–Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. Gynecologic Oncology Group. J Clin Oncol 2003;21:3194–200.
7. Ozols RF, Bookman MA, du Bois A, Pfisterer J, Reuss A, Young RC. Intraperitoneal cisplatin therapy in ovarian cancer: comparison with standard intravenous carboplatin and paclitaxel. Gynecol Oncol 2006;103:1–6.
8. du Bois A, Quinn M, Thigpen T, Vermorken J, Avall–Lundqvist E, Bookman M, et al. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Gynecologic Cancer Intergroup; AGO–OVAR; ANZGOG; EORTC; GEICO; GINECO; GOG; JGOG; MRC/NCRI; NCIC–CTG; NCI–US; NSGO; RTOG; SGCTG; IGCS; Organizational team of the two prior International OCCC. Ann Oncol 2005;16(suppl 8):viii7–viii12.