Emerging Data on Side Effects of Aromatase Inhibitors

SAN ANTONIO—Aromatase inhibitors (AIs) are gaining favor over tamoxifen for the treatment of postmenopausal hormone receptor-positive breast cancer. Originally AIs were thought to improve upon the side-effects profile of tamoxifen, and although they are free of some of the side effects, longer experience using AIs has brought to light different side effects. Several poster studies at the San Antonio Breast Cancer Symposium focused on side effects such as arthralgias and myalgias, sexual and gynecologic side effects, and potential retinal problems—some of which can lead to poor adherence to treatment. Adherence Even though there is a strong evidence base supporting the use of AIs in postmenopausal, estrogen receptor (ER)-positive breast cancer, a substantial proportion of women treated in academic clinical practices have discontinued this therapy because of toxicity, noted Susan Dent, MD, a medical oncologist and Head of Clinical Trials at Ottawa Hospital Regional Cancer Centre. “The discontinuation rates of AI therapy that we found in this study of women with early breast cancer are of great concern,” Dr. Dent said. “The results suggest that interventions are needed to enhance compliance in women taking an AI.” She suggested that doctors and nurses discuss potential side effects of AIs prior to treatment, and recommended nonsteroidal inflammatory drugs for musculoskeletal pains. The study was based on a retrospective chart review of 640 postmenopausal women with early-stage hormone-sensitive breast cancer who were treated with an AI at the Ottawa Hospital Regional Cancer Centre between January 1, 1999 and December 31, 2006.Figure: Susan Dent, MD: “The discontinuation rates of AI therapy that we found in this study of women with early breast cancer are of great concern. The results suggest that interventions are needed to enhance compliance in women taking an AI.”The women received an AI either as upfront therapy for five years (43%), as part of a switching strategy after two to three years of tamoxifen (36%), or as extended therapy after five years of tamoxifen (21%). The average age at diagnosis was 60.3. Stage I patients represented 32% of the study population; Stage IIa, 36%; Stage IIb, 19%; Stage IIIa, 7%; and Stage IIIb, 7%. Seventy-eight percent of patients were both ER and progesterone receptor (PR) positive; and 17% were ER-positive and PR-negative. Toxicity was reported by 42% of patients, and AI therapy was stopped due to toxicity in 19%. The toxicities reported were similar to those reported elsewhere, except that fewer hot flashes were reported. Osteoporosis was found in a higher proportion of patients on an aromatase inhibitor than has been reported in the literature, but 17% of patients had documented bone loss prior to therapy. Myalgias/arthralgias were the most commonly reported toxicities, occurring in 30% of patients (197 of 640), of whom about 21% (42) discontinued AI therapy. Self-reported fracture rates were low in this study (4%) and did not appear to increase with longer duration of therapy. Dr. Dent said that withdrawal rates due to toxicity were higher in this study than in the big studies reported in the literature: ATAC, 11.1%; IES, 4.5%; and 4.5% in MA-17. “In our experience, women were more likely to stop an AI within the first two years of therapy [32%],” she said. “In this study, no differences in toxicities were seen based on choice of AI,” she added. Also, receptor status, age, and HER-2 status did not influence discontinuation rates of AI therapy, but patients who had prior systemic chemotherapy were more likely to stay on AI therapy (16.3% discontinued) than those who did not receive prior chemotherapy (21.8% discontinued), although this difference was not statistically significant. Aches, Pains Musculoskeletal pains are problematic for about 5% to 10% of women on aromatase inhibitors, said Kathleen Pritchard, MD, Senior Scientist and Chair of the Breast Group at Sunnybrook Odette Cancer Center in Toronto. “These side effects definitely reduce compliance.” Although both tamoxifen and AIs are much more tolerable than chemotherapy, they are hormones and have hormonal effects. “All drugs, including hormonal agents, cut two ways—having both risks and benefits,” she said. Dr. Pritchard said that in her practice, when a woman who is taking an adjuvant AI finds the myalgias and arthralgias difficult to tolerate, Dr. Pritchard will switch to another AI. “However, my impression is that all AIs can cause muscle aches and pains,” she commented. “If no AI can be tolerated, I will definitely switch to tamoxifen if the patient has not already completed five years of it, or with the new ATLAS data [also reported at the San Antonio meeting, suggesting that tamoxifen has benefits that extend beyond five years], perhaps even then. In the adjuvant setting, I would rather have my patients taking some hormonal agent than nothing. And tamoxifen is still an effective drug.” Another problem related to adherence to AIs is that there is no “feedback loop” to show patients that the drugs are effective. With statins or antihypertensive agents, cholesterol levels and blood pressure lowering effects can be measured, giving patients the reassurance that these drugs are working. “However, with drugs for cancer prevention, you are treating in a vacuum. “Adherence would be improved if measurements could reflect the benefits of the drugs,” Dr. Pritchard continued. She said that oncologists and nurses should reinforce the benefits of hormonal therapy, explaining to patients that these drugs cut the risk of recurrence by 50% from 2% a year for node-negative patients and 4% a year for node-positive patients. “If they know they are cutting the risk in half, they will probably feel the drugs are worth taking even with the side effects,” she said.Figure: Kathleen Pritchard, MD, noted that there is no “feedback loop” to show patients on aromatase inhibitors that the drugs are effective. For example, with statins or antihypertensive agents, cholesterol levels and blood pressure lowering effects can be measured.Long-Term Effects Despite the therapeutic benefit of exemestane observed in the original Intergroup Exemestane Study, a cohort of 582 women randomized to exemestane and tamoxifen had persistent sexual and gynecologic effects at seven years of follow-up—mainly, dyspareunia and loss of libido, according to data presented by Lesley J. Fallowfield, MD, Director of the CRUK Sussex Psychosocial Oncology Group at Brighton & Sussex Medical School. All women included in the study were treated with tamoxifen for two to three years and then randomized to continue on tamoxifen or to switch to exemestane for another two to three years; they all completed five years of hormonal therapy and then were followed for an additional two years. “Overall quality of life did not differ between the two groups at any time point,” Dr. Fallowfield said. “The efficacy of exemestane was not at the expense of quality of life in general. However, individual symptoms are troublesome and persistent—for example, vaginal bleeding and discharge on tamoxifen and vaginal dryness, dyspareunia, and loss of libido on exemestane. Libido never recovered when off treatment.” Severe loss of libido was reported in about one third of each group seven years after starting on tamoxifen. Loss of libido is a side effect of all hormonal therapy, Dr. Fallowfield noted. “But you can ameliorate this problem by giving women who start on this type of therapy education about what to expect and practical advice about the need for lubrication.” Overlooked Problem Dr. Pritchard added that the problem of sexual side effects is often overlooked but it is a big issue for some women. She said that devices like the Estring, which provides slow, continuous, local delivery of estrogen, or intra-vaginal estrogen cream used sparingly can be helpful for vaginal dryness, but this remains controversial for breast cancer survivors. In the MA-17 trial, she said, intra-vaginal estrogen cream was allowed for symptoms of vaginal dryness. “We are now reviewing the use, and hope, if numbers allow, to analyze whether any effect on efficacy was seen.” Retinal Hemorrhages A small percentage of women taking anastrozole for early breast cancer experience small retinal hemorrhages, according to a retrospective study reported by Alvin Eisner, PhD, Senior Scientist at the Neurological Sciences Institute and Research Associate Professor at the Casey Eye Institute, both of Oregon Health & Science University. Although the clinical significance of these hemorrhages is not known, Dr. Eisner recommended that women taking hormonal therapy for breast cancer who experience visual changes should undergo optical coherence tomography (OCT), “a powerful, new, non-invasive technology that is readily available,” and have their vision monitored at periodic intervals.Figure: Regarding the retinal hemorrhages that occurred in some of the women in the small study reported by Alvin Eisner, PhD, he said that although the clinical significance remains unknown, he recommends that patients who experience visual changes undergo optical coherence tomography and have their vision monitored.The study included 35 anastrozole users, 38 amenorrheic tamoxifen users, and 53 amenorrheic controls who were not using hormone replacement. Conventional retinal fundus photography of both eyes of each subject taking hormonal therapy and of controls were evaluated for the presence of retinal hemorrhages by an ophthalmologist without knowledge of the subjects' information. Photographs from an additional 36 women taking tamoxifen who were recruited for a previous study were also assessed for hemorrhages. OCT was used to measure retinal thickness and to detect posterior vitreous detachments (PVD). At the time of the San Antonio meeting, OCT was analyzed for one eye in each subject in: 17 non-PVD anastrozole users, 18 non-PVD tamoxifen users, and 23 non-PVD controls. Retinal hemorrhages were found in four users of anastrozole, one user of tamoxifen, and none of the control patients. Dr. Eisner said that the OCT scans suggest that anastrozole users often are subject to a pronounced degree of vitreo-retinal traction that results from estrogen depletion and may sometimes lead to retinal hemorrhages. Other factors, such as the use of aspirin and bisphosphonates for controlling common anastrozole-induced side effects, may also contribute to the development of retinal hemorrhages, he suggested. Further study of the ocular and visual effects of AIs is warranted, he said. ASCO's Choices for Top Cancer Advances of 2007 On the American Society of Clinical Oncology's annual list of the most significant advances in cancer treatment, prevention, and screening for last year, as chosen by a 21-member oncologist editorial board, were the following (listed in no particular order, a news release notes): ▪ The first systemic treatment for primary liver cancer. ▪ Treatments for advanced kidney cancer continue to expand. ▪ MRI better for screening women at high risk for breast cancer. ▪ HPV linked to head and neck cancers; possible new role for HPV vaccine. ▪ Drop in breast cancer linked to declining use of hormone-replacement therapy. ▪ Preventive radiation therapy can stop the spread of advanced lung cancer. FigureAnother 18 advances in prevention, screening, treatment, and survivorship were highlighted along with recommendations for the renewal of government funding for cancer research and the removal of barriers to clinical trial participation. The report is available online at ASCO's People Living with Cancer Web site: www.plwc.org.

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