RCT: Menopause Symptoms Mistaken for Tamoxifen Side Effects

Roxanne Nelson, BSN, RN

July 06, 2017

Symptoms that are assumed to be side effects of tamoxifen may be naturally occurring, according to new findings.

In a large, randomized trial that included nearly 4000 women, researchers found that symptoms were somewhat similar between individuals using tamoxifen as breast cancer prophylaxis and those receiving placebo.

However, although about two thirds of the overall cohort adhered to either their tamoxifen regimen or placebo for at least 4.5 years, significantly fewer women were adherent to their tamoxifen regimen (65.2% vs 74%; P < .001).

Dropout rates were highest after the first 12 months of follow-up, the researchers note. This coincides with the time frame in which women are most susceptible to experiencing drug-related side effects.

The findings were published online June 29 in the Journal of Clinical Oncology.

The International Breast Intervention Study (IBIS-1), which has been ongoing for 25 years, is a randomized controlled trial that has been investigating the effectiveness of tamoxifen in reducing the risk for breast cancer among women deemed at high risk.

The current analysis included 3823 women from the United Kingdom. The women were randomly assigned to receive placebo (n = 1933) or tamoxifen 20 mg/day (n = 1890).

The mean time patients remained on treatment was 4.3 years, which was higher among those receiving placebo than among those receiving tamoxifen (4.4 years vs 4.1 years; P < .001).

Adherence Poorer With Tamoxifen

"Overall, women on placebo were more adherent than those on tamoxifen, which is partly due to placebo being better tolerated," said coauthor Ivana Sestek, PhD, lecturer in medical statistics at Queen Mary University of London, United Kingdom. "We only looked at symptoms reported at 6 months of follow-up, and therefore it is possible that part of the explanation could be due to onset of later symptoms.

"It's also possible that our measures were not sensitive enough to pick up different levels of severity," she noted, "And it's also possible that other symptoms could be affecting adherence that were not assessed in this study, such as night sweats."

Dr Sestek and her colleagues note that there were significant differences in the proportion of women who adhered to the regimen after 12 months (P < .003); differences appeared greatest at 54 months. The rates of discontinuance of treatment were highest within the first 12 to 18 months of follow-up; the rate was greater among the tamoxifen group (7.4% placebo vs 12.2% tamoxifen) but then declined after this period.

"In several clinical trials with tamoxifen ― including the current IBIS-I trial ― we observed that side effects occur early, some of them induced by tamoxifen, which is an indication that the drug works, and hence, some women experience side effects early," Dr Sestek told Medscape Medical News. "Tamoxifen increases some symptoms in some women, but overall, only a proportion of these are actually attributed to the drug."

In the multivariate analysis, women taking tamoxifen (odds ratio [OR] = 0.67; P < .001) and those who reported menopausal symptoms at baseline (OR = 0.73; P < .001) were less likely to adhere to the treatment.

Other factors associated with lower odds of adherence included smoking (OR = 0.57; P < .001), being an exsmokers (OR = 0.82; P = .016), undergoing hormone replacement therapy (HRT) at baseline (OR = 0.81; P = .028), and having previously undergone HRT (OR = 0.67; P < .001).

Conversely, factors associated with higher odds of adherence included increasing age (OR = 1.03 per year; P < .001), being premenopausal (OR = 1.29; P = .009), and having a higher Tyrer-Cuzick risk score (OR = 1.03 per 1% increase; P = .046).

Adherence Symptom Specific

Adherence varied according to specific symptom experienced.

Women who experienced nausea/vomiting were less likely adhere to placebo (OR = 0.58; P = .023) or tamoxifen (OR = 0.57; P = .007). Headaches only had a bearing on adherence in the placebo group (OR = 0.62; P = .016).

Gynecologic symptoms were significant for women in the tamoxifen arm (OR = 0.77; P = .024). Hot flushes did not affect adherence for either group.

Nausea and vomiting are not the common symptoms associated with the menopause, Dr Sestek explained, although prevalence is increased among perimenopausal and postmenopausal women.

"Furthermore, these symptoms were also reported as side effects among women who take tamoxifen in the treatment setting, and therefore we decided to include them here," she said. "It is fairly common among people taking medication to experience symptoms of nausea, even if that medication does not cause the symptom. When symptoms occur, people will occasionally attribute them to the drug, if they can."

Dr Sestek also pointed that some symptoms, such as vaginal dryness, may be related to menopause but are exacerbated by tamoxifen.

"Hot flushes and other gynecological symptoms are naturally occurring menopausal symptoms but also are increased with tamoxifen," she said, "but the association between hot flushes or gynecological symptoms and adherence was largely similar between the tamoxifen and placebo arms."

Thus, women may be attributing age-related symptoms to their assigned medication, Dr Sestek added. "This is suggestive of the 'nocebo' response, whereby seemingly inert substances cause adverse symptoms and side effects."

Tamoxifen Underused

It it not known whether symptoms subsided when the women stopped taking tamoxifen. There was no follow-up specifically of women who stopped with the allocated treatment because of side effects. The women were only followed for the primary endpoint of breast cancer development and secondary endpoints that included other cancer types and mortality.

"We did not ask specific questions about side effects," said Dr Sestek. "Although some women might see improvements with symptoms attributed to treatment, others will still experience them as they are naturally occurring."

The authors point out that in general, tamoxifen is underutilized as a chemopreventive agent. Only about 16% of women deemed to be at a higher risk of developing breast cancer take tamoxifen, as previously reported by Medscape Medical News.

Data suggest that there is at least a 30% reduction in the risk for breast cancer among women using selective estrogen receptor modulators, but these agents are associated with a higher risk for thromboembolic events and endometrial cancer, particularly tamoxifen. Concern about these side effects is cited as a major deterrent to initiating these therapies.

"It is true that uterine cancer and thromboembolic events are associated with tamoxifen, but these events are rare," said Dr Sestek. "The long-term follow-up results of the IBIS-I study showed that the benefit-to-harm ratio for the use of tamoxifen to prevent breast cancer in high-risk women was substantially improved.

"However, this is definitely an individual decision and one that a woman should make after detailed discussion with her physician," she emphasized. "For many of these women, preventive therapy is their only option for prevention, and they want to avoid experiencing a breast cancer, as they have experience of seeing its effects in their immediate family."

Dr Sestek has disclosed no relevant financial relationships. Coauthor Prof Jack Cuzick has received institutional research funding from AstraZeneca, and he receives a share in royalties from Myriad Genetics to Queen Mary University of London for the development of a cell-cycle progression score (Prolaris).

J Clin Oncol. Published online June 29, 2017. Full text

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