Drs. Hess and Alberts have provided us with a thoughtful review of the issues surrounding the use of intraperitoneal (IP) chemotherapy for women with epithelial ovarian cancer, including the three National Cancer Institute (NCI)-sponsored phase III clinical trials whose outcomes led to the 2006 NCI clinical announcement. Dr. Alberts deserves substantial credit for his leadership in the development of a combined IP/intravenous (IV) approach to chemotherapy over the past 2 decades.
Two meta-analyses of ovarian cancer treatment have recently been published.[1,2] Both support an important role for IP chemotherapy for women with optimally debulked ovarian cancer as well as the importance of chemotherapy combining platinums and taxanes in improving survival. As Drs. Hess and Alberts make clear, the significant improvement in survival associated with IP chemotherapy does come with greater toxicity. In general, however, this increase in toxicity is manageable and short-term. In the Gynecologic Oncology Group (GOG)-172 trial, for example, at 1 year after the end of treatment, women on the IV and the IV/IP arms of the trial had similar health-related quality of life (HRQOL), although women on the IV/IP arm did have a slightly higher incidence of chronic peripheral neuropathy. Administration of IP cisplatin must be accompanied by aggressive IV hydration, as well as dose-reduction at the first report of any grade of neurotoxicity.
What steps do we need to take to ensure that women benefit from the conclusions of clinical tresearch in ovarian cancer? First, primary care physicians evaluating a woman should inquire as to family history of disease, including cancer. Those with a family history suggestive of BRCA1 or BRCA2 mutations, such as an excess of breast and/or ovarian cancerespecially cases diagnosed at a young ageor Lynch syndrome (excess of colon cancer and endometrial cancer among women, excess of colon cancer among men, especially cases diagnosed at a young age), should be referred to a cancer genetics clinic for counseling. Prophylactic bilateral salpingo-oophorectomy (BSO) may be appropriate for women found to have inherited germline defects consistent with BRCA1 or BRCA2 mutations, while prophylactic total abdominal hysterectomy (TAH)/BSO may be appropriate for those found to have an inherited germline defect consistent with Lynch syndrome.
Women reporting a constellation of symptoms including bloating, increased abdominal size, and urinary symptoms should be promptly evaluated, with ovarian cancer considered in the differential diagnosis. Serum CA-125 measurement and transvaginal ultrasound (TVUS) should be included in the work-up of such patients. Those women with CA-125 and TVUS findings suspicious for malignancies should be referred to a gynecologic oncologist. The Gynecologic Cancer Foundation website provides a guide to gynecologic oncologists in the United States.
If the patient is thought to be a reasonable surgical candidate, then she should undergo a primary surgical exploration. If the diagnosis of invasive ovarian cancer is made, then she should undergo TAH/BSO, surgical staging, and cytoreduction. Women who wish to retain fertility and have what appears to be disease limited to one ovary may undergo unilateral -salpingo-oophorectomy (USO) and surgical staging. Women found to have stage III/IV ovarian cancer should receive at least six courses of chemotherapy with a platinum and a taxane. Women with optimally debulked stage III disease should be counseled about the potential benefits of a combined IV/IP approach to chemotherapy.
As Drs. Hess and Alberts note, the NCI has worked with the GOG and the Southwest Oncology Group (SWOG), as well as numerous centers with expertise in IP chemotherapy for ovarian cancer, to make available educational material on IP chemotherapy for doctors, nurses, and patients. In addition, the NCI hosts a website listing centers in the United States and elsewhere with expertise in the multidisciplinary management of ovarian cancer, including IP chemotherapy.
Numerous questions concerning IP chemotherapy remain unanswered. We do not know the optimal IV/IP chemotherapy regimen, as the three NCI-sponsored trials all used different experimental regimens. The most recent trial, GOG-172, which demonstrated the longest survival advantage of the three, used both IP cisplatin and IP paclitaxel, while the two previous trials used only cisplatin IP in addition to IV agents. We do not know the optimal or minimal number of IP courses. We need to know how best to decrease the toxicity that has been observed with IP chemotherapy. In addition, we need to establish whether there is a role for IP chemotherapy among women with optimally debulked stage IV disease (staged as IV on the basis of pleural effusions, not parenchymal liver metastasis) or for women who have minimal to no residual disease following primary surgery and IV chemotherapy.
1. Jaaback K, Johnson N: Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev 2006(1):CD005340.
2. Kyrgiou M, Salanti G, Pavlidis N, et al: Survival benefits with diverse chemotherapy regimens for ovarian cancer: Meta-analysis of multiple treatments. J Natl Cancer Inst 98:1655-1663, 2006.
3. Goff BA, Mandel LS, Melancon CH, et al: Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 291:2755-2756, 2004.
4. Gynecologic Cancer Foundation website. Available at www.thegcf.org. Accessed January 23, 2007.
5. Gynecologic Oncology Group website. Available at www.gog.org. Accessed January 23, 2007.
6. NCI Cancer Therapy Evaluation Program: Institutions with expertise in the multi-disciplinary management of ovarian cancer, including effective surgical cytoreduction and administration of intraperitoneal chemotherapy and commitment to NCI-supported clinical trials. Available at http://ctep.cancer.gov/highlights/. Accessed January 23, 2007.