SAN FRANCISCO—An often troubling side effect of treatment for prostate cancer with bicalutamide is uncomfortable breast pain, as well as breast soreness and disfigurement caused by breast swelling. However, researchers presented data here at the American Urological Association Annual Meeting that administration of tamoxifen once a week may reduce the incidence and severity of those side effects, and perhaps do it without further adverse side effects.
Alan Eaton, a consultant surgeon in urology at Queen Elizabeth Hospital in the UK, presented the study, which showed that seven of 30 patients treated with bicalutamide alone reported breast pain compared with two of 30 receiving both bicalutamide and tamoxifen.
The breast pain was usually manifested as soreness around the nipple. The difference between the groups achieved statistical significance at the p<.005 level, he reported in his poster presentation.
In addition, 16 of the 30 patients on monotherapy had increases in breast size, compared with six of the 30 receiving both agents.
“Tamoxifen 20 mg given once weekly significantly reduces the incidence of gynecomastia and mastalgia associated with bicalutamide therapy,” Dr. Eaton said. “There was no evidence of reduced tumor control when tamoxifen was co-administered with bicalutamide, as indicated by prostate-specific antigen concentrations.”
Need Longer-Term Data
“This is a very interesting study,” commented Durado Brooks, MD, Director of Prostate and Colorectal Programs for the American Cancer Society, “and we do need something to treat these side effects of bicalutamide therapy. However, this is a one-year study, and bicalutamide is often taken for long periods of time. I would like to see some long-term results with this study—especially to see if there are no adverse long-term effects of the use of tamoxifen.”
Dr. Brooks said he was particularly concerned about the long-term impact on blood clotting—a risk of tamoxifen therapy as well as a risk factor associated with cancer itself.
Dr. Eaton noted that bicalutamide is commonly prescribed in prostate cancer in neoadjuvant and adjuvant settings as well as a monotherapy. However, as many as 70% of patients on the therapy complain about breast soreness and breast enlargement.
The changes are likely due to the unopposed action of estrogen in the body that is upset by hormonal manipulation caused by bicalutamide, he suggested.
“We theorized that tamoxifen, as a potent anti-estrogen, would prevent these painful conditions.”
23% of patients (7 of 30) treated with bicalutamide alone had breast pain vs only 7% (2 of 30) of those who had both bicalutamide and tamoxifen. Similarly for increases in breast size: 53% (16 of 30) vs 20% (6 of 30), respectively.
However, use of tamoxifen on a once-daily basis as often prescribed to women might increase testosterone levels, which could adversely affect outcomes in prostate cancer.
Because tamoxifen has a long half-life, the researchers decided to try a weekly dose of tamoxifen in an effort to relieve possible breast pains and swelling.
Tamoxifen has a half life of six days, Dr. Eaton noted. “There were no apparent safety concerns with the tamoxifen and bicalutamide combination.”
The incidences of nausea, diarrhea, impotence, and flushing were similar in both groups of patients in the open-label, randomized study. The impact on quality of life was deemed to be greater in the monotherapy group.
Eleven people taking bicalutamide said there was a moderate impact on their quality of life due to the drugs, but no one getting tamoxifen said there was a moderate impact.
The study included 60 men starting primary hormonal manipulation therapy for prostate cancer. They were all taking bicalutamide at 150 mg once daily and were randomly selected to two equal groups:
- ▪ One group was given tamoxifen at 20 mg once weekly simultaneously with bicalutamide.
- ▪ The second group received only bicalutamide.
Patients in both groups were monitored at monthly intervals for twelve months. Baseline PSA and liver-function tests were assessed and repeated monthly together with breast disc measurement.
Testosterone levels were measured at six and 12 months. All the men taking the combination completed the year-long study; three men in the bicalutamide monotherapy group dropped out.
In looking at the PSA levels, the researchers reported that bicalutamide therapy sharply reduced PSA in both groups. At the start of the trial, those receiving combination therapy had PSA levels of about 15.9 ng/mL compared with about 14.4 ng/mL for those receiving bicalutamide alone.
At the three-month assessment, PSA levels for both groups were less than 2 ng/mL; at six months the levels for both groups declined even further, although the difference was slight.
After a year, PSA levels in the combination group had fallen 14.8 ng/ml, to an average of 1.1 ng/ml, while the patients with monotherapy bicalutamide had achieved a decrease in PSA of 13.1 ng/mL to an average of 1.3 ng/mL.
Testosterone levels in both groups actually fell during the year, while remaining within the normal range of between 7.4 and 25.7 nmol/L.
Among those on bicalutamide monotherapy, the mean testosterone level was 24.2 nmol/L at six months and 20.7 nmol/L after 12 months; for those on combination therapy, the mean at six months was 22.5 nmol/L at six months and 21.8 nmol/L at 12 months.