Women who received estrogen-alone hormone replacement therapy (HRT) after a diagnosis of epithelial ovarian cancer lived longer than women who did not receive this form of adjuvant therapy, according to the results of a multinational randomized clinical trial.
Journal of Clinical Oncology, September 28, 2015 (see the journal abstract).
Surgery is one of the standard treatment options for women with ovarian cancer. Premenopausal women who undergo surgical treatment for the disease will experience premature menopause as a result of the loss of ovarian estrogen. This can cause some women to experience adverse health effects, including hot flashes as well as an increased risk of bone fractures and coronary heart disease. Hormone replacement therapy has been shown to reduce menopausal symptoms, which affect many women with ovarian cancer.
Although some women with ovarian cancer experience severe menopausal symptoms, some physicians have been reluctant to prescribe HRT out of a concern that the treatment might be harmful and could possibly cause a relapse and/or increase the risk of breast cancer. However, a small number of observational studies and clinical trials have indicated that women with ovarian cancer who receive HRT have similar survival outcomes as women who do not receive HRT.
In fact, some data have even suggested that HRT may have additional health benefits beyond the relief of menopausal symptoms for women diagnosed with ovarian cancer.
The randomized, controlled Adjuvant Hormone Therapy trial was launched in 1990 to assess survival outcomes in women with epithelial ovarian cancer who received HRT with estrogen alone. The primary endpoint of the study was overall survival (as measured from the time of random assignment to death from any cause). The main secondary endpoint was relapse-free survival (as measured from the time of random assignment to disease relapse or death from any cause).
Between 1990 and 1995, Rosalind A. Eeles, M.D., Ph.D., of The Institute of Cancer Research, London, and her colleagues enrolled 150 premenopausal and postmenopausal women from 19 centers in the United Kingdom, Spain, and Hungary in the trial. The researchers randomly assigned 75 patients to the group scheduled to receive HRT for 5 years and 75 patients to the group that was not scheduled to receive HRT.
The participants joined the trial within 9 months of being diagnosed with epithelial ovarian cancer. Women with all stages of cancer were eligible; a patient was ineligible if her ovarian function had been preserved or if she had a history of hormone-dependent malignancy.
The types of HRT used in the trial included conjugated estrogens (Premarin®), conjugated estrogens and norgestrel (Prempak®), estradiol patch, and estradiol implant.
Because of challenges in enrollment, the trial did not achieve its original goal of recruiting 570 patients, and accrual ended early. To make the trial results as clinically useful as possible, the researchers conducted extended follow-up studies of the participants.
A "snapshot" of the data as of September 2012 was analyzed. At that time, the median follow-up for patients who had not died was more than 19 years. Overall, 81 percent of the patients had died, including 71 percent of those in the hormone therapy group and 91 percent of those in the control group (the adjusted hazard ratio for death from any cause was 0.45). The majority of deaths were due to ovarian cancer.
The mean overall survival at 20 years after diagnosis was 8.5 years for patients in the hormone therapy groups and 5.7 years for women in the control group.
The study authors observed a similar effect for relapse-free survival. Eighty-one percent of patients in the trial relapsed, including 72 percent of those in the hormone therapy group and 91 percent of those in the control group. At 20 years after diagnosis, the estimated mean relapse-free survival was 7.5 years for patients in the hormone therapy group and 4.7 years in the control group.
Fourteen patients in the HRT group discontinued treatment for medical reasons or because of the side effects of treatment. The study authors collected information on adverse events in both groups, including myocardial infarction, fracture, transient ischemic attack (heart attack), cerebrovascular accident (stroke), and second cancer. The rates of these events were low, and there were no statistically significant differences between the treatment groups.
The median estimated time of treatment with HRT was 1.14 years. The effects of HRT on overall survival could be observed as soon as 4 or 5 years after some patients were randomly assigned to a group, and these effects seemed to persist long after most women had stopped taking HRT, the study authors reported. They noted that a similar persistence that extends beyond the time of treatment has been observed in breast cancer prevention trials evaluating hormonal treatments.
The low accrual for the study was a limitation. The study authors also noted that when the trial began in 1990, the data were collected based on the known prognostic and therapeutic options at the time. As a result, there are "several potentially relevant factors that cannot be assessed in these analyses, such as the use of post-relapse treatment," the authors wrote.
"These results show that women who have severe menopausal symptoms after ovarian cancer treatment can safely take hormone replacement therapy, and this may, in fact, infer benefits in terms of overall survival in addition to known advantages in terms of quality of life," the study authors wrote.
An accompanying editorial by two NCI researchers, Elise C. Kohn, M.D., of the Cancer Therapy Evaluation Program and Stanley Lipkowitz, M.D., Ph.D., of the Center for Cancer Research, congratulated the study authors for "recognizing the importance of this study and observing the accrued cohort for nearly two decades."
The surprise of the study, the editorialists wrote, was the persistence of treatment effects after treatment ended. "Only approximately one-third of patients continued HRT until death or last follow-up, and the benefits of HRT persisted throughout the duration of the study," they wrote.
In conclusion, the editorialists asked, "Where do we stand in 2015? To treat or not to treat?" Although there are unanswered questions, such as the mechanisms of how estrogen improves overall survival, Drs. Kohn and Lipkowitz wrote that the results of the current trial and those of previous studies "allow oncologists to feel comfortable offering patients HRT after the treatment of epithelial ovarian cancer to reduce vasomotor and other postmenopausal symptoms and should, therefore, improve the quality of life for patients with epithelial ovarian cancer."