Fertility Treatments Unlikely to Raise Ovarian Cancer Risk

Ovarian cancer risk was no greater for women who used any of four different groups of fertility drugs [gonadotrophins, clomifenes, human chorionic gonadotrophin, and gonadotrophin releasing hormone] than for those who had not used these drugs. Of the ovarian cancer cases that did occur in this cohort, 58 percent were serous tumors—occurring in the outer lining of the ovary—and the incidence of this particular tumor type appears significantly higher only among women who had taken clomiphene, which was the most commonly used fertility drug.

“During the last few decades, women taking fertility drugs in order to become pregnant have not had definitive evidence that such treatments would not increase their ovarian cancer risk. Now researchers from Denmark, who conducted the largest population-based cohort study thus far to address this question, have reported that fertility drugs do not increase a woman’s risk of ovarian cancer. The study, led by Dr. Allan Jensen of the Institute of Cancer Epidemiology in Copenhagen, appeared February 5 in the British Medical Journal.

The study involved 54,362 Danish women who were treated in fertility clinics between 1963 and 1998 and then followed for a median of 15 years; 156 of these women eventually developed invasive epithelial ovarian cancer.

Ovarian cancer risk was no greater for women who used any of four different groups of fertility drugs [gonadotrophins, clomifenes, human chorionic gonadotrophin, and gonadotrophin releasing hormone] than for those who had not used these drugs. Of the ovarian cancer cases that did occur in this cohort, 58 percent were serous tumors—occurring in the outer lining of the ovary—and the incidence of this particular tumor type appears significantly higher only among women who had taken clomiphene, which was the most commonly used fertility drug. The authors noted that this association ‘may be real and important,’ but they pointed out that long-term follow-up studies will be needed to confirm this finding. Also, because the usual peak age for ovarian cancer diagnosis is 63 and the average age of these women was only 47 by the end of the study, they will continue to monitor the cohort.

Nevertheless, ‘Some women who take fertility drugs will inevitably develop ovarian cancer by chance alone,’ explained Dr. Penelope Webb in an accompanying editorial, ‘but current evidence suggests that women who use these drugs do not have an increased risk of developing ovarian cancer.’”

Quoted Source: Fertility Treatments Unlikely to Raise Ovarian Cancer Risk, NCI Cancer Bulletin Vol. 6 / No. 4, National Cancer Institute, February 24, 2009.

Primary Citations:

Sometimes More Is Less: Evaluation of Experimental Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer; A Phase III Trial of the Gynecologic Cancer InterGroup

“… Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent [gemcitibine, liposomal doxorubicin or topotecan] provided no benefit in PFS [progression-free survival] or OS [overall survival] after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.”

“Michael A. Bookman,* Mark F. Brady, William P. McGuire, Peter G. Harper, David S. Alberts, Michael Friedlander, Nicoletta Colombo, Jeffrey M. Fowler, Peter A. Argenta, Koen De Geest, David G. Mutch, Robert A. Burger, Ann Marie Swart, Edward L. Trimble, Chrisann Accario-Winslow, and Lawrence M. Roth

From the Fox Chase Cancer Center, Philadelphia, PA; Gynecologic Oncology Group Statistical and Data Center, Buffalo, NY; Franklin Square Hospital; Baltimore, MD; Guy’s Hospital, London, United Kingdom; Arizona Cancer Center, Tucson, AZ; Australia New Zealand Gynaecological Oncology Group, Camperdown, Australia; European Institute of Cancer Research, Milano, Italy; Ohio State University, Columbus, OH; University of Minnesota School of Medicine, Minneapolis, MN; University of Iowa Hospitals and Clinics, Iowa City, IA; Washington University School of Medicine, St. Louis, MO; University of California, Irvine Medical Center, Orange, CA; University College London and Medical Research Council Clinical Trials Unit, London, United Kingdom; National Cancer Institute, Bethesda, MD; and Indiana University School of Medicine, Indianapolis, IN.

* To whom correspondence should be addressed. E-mail: michael.bookman@fccc.edu

Purpose: To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel.

Patients and Methods: Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons.

Results: Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup.

Conclusion: Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.”

Quoted Source Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup; Bookman MA et. al., J Clin Oncol. 2009 Feb 17. [Epub ahead of print].