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Tamoxifen, exemestane sequence improved survival
Exemestane use may increase osteoporosis and fracture risk, but seems bone sparing over time.
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Switching to exemestane after two to three years of tamoxifen treatment improved overall survival in patients with estrogen-sensitive breast cancer, according to results from the Intergroup Exemestane Study.
“We now have follow-up on one of the aromatase inhibitor trials, an average follow-up of 2.5 years off active drug treatment,” Stephen Jones, MD, medical director of the U.S. Oncology Research Network and an investigator for the study, said in an interview. “The treatment effect — the benefit of exemestane — clearly persists, so there is a large carryover effect. We did not know that before.”
The study involved 4,724 postmenopausal patients with unilateral invasive, estrogen-receptor positive or estrogen-receptor unknown breast cancer who were disease free after two to three years of tamoxifen treatment. The investigators randomly assigned 2,352 of the patients to switch to exemestane (Aromasin, Pfizer); the rest stayed on tamoxifen for the remainder of the five-year endocrine treatment period.
The researchers chose disease-free survival as their primary endpoint and overall survival as a secondary endpoint.
Largest crossover trial
At the median follow-up of 55.7 months, there were 809 events contributing to the analysis of disease-free survival (354 for exemestane, 455 for tamoxifen). Overall, the unadjusted hazard ratio for disease-free survival was 0.76 (95% CI 0.66-0.88) in favor of exemestane, the authors wrote in The Lancet. There were 222 deaths in the exemestane group vs. 261 deaths in the tamoxifen group.
“There is a 15% to 17% less chance of dying for the women who were crossed over to exemestane vs. staying on tamoxifen,” Jones said. “And this is the largest of these crossover trials with nearly 5,000 women.”
These results also showed that there were no severe toxicity data associated with exemestane, he said.
Tamoxifen use is associated with side effects such as uterine bleeding, endometrial thickening that requires procedures and endometrial polyps, Jones said. Exemestane use does not result in these side effects. “There is even half the rate of uterine cancer for the women who got crossed over to exemestane,” he said. “The numbers are small; there were not many [patients with] uterine cancers in the tamoxifen group, but it was roughly half the rate for exemestane.”
Increased fracture risk
Some data indicate that exemestane use increases osteoporosis and fracture risk. Jones participated in another study that compared exemestane and tamoxifen. In the bone substudy, the investigators measured the participants’ bone mineral density at six, 12 and 24 months. At 24 months, the bone mineral loss rate was 4% in the exemestane group, but that rate slowed to less than 1% per year thereafter, the researchers wrote.
“It appears that once you are on exemestane for a period of time, it is actually relatively bone sparing,” Jones said
A five-year course of tamoxifen remains the standard therapy for women with estrogen-receptor positive breast cancer, according to the American Society for Clinical Oncology’s 2002 technology assessment on aromatase inhibitors, published in the Journal of Clinical Oncology.
“I am actually one of those physicians who thinks, for a majority of women who are at a lower risk of recurrence, that … giving tamoxifen first and then an aromatase inhibitor may be the preferred strategy,” Jones said. “You have a couple of years of potential bone benefits, [and] you have the chance of using two effective drugs rather than one.” – by Colleen Owens
For more information:
- Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomized controlled trial. The Lancet. Published online Feb. 13, 2007.
- Winer EP. Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor–positive breast cancer: status report 2002. J Clin Oncol. 2002;20:3317-3327.