Tamoxifen related side effects and their impact on breast cancer incidence: A retrospective analysis of the randomised IBIS-I trial.

BACKGROUND: Studies in the adjuvant setting have shown that endocrine therapy related side effects predict breast cancer recurrence risk. Here, we assess the relationship between early reported side effects and incidence of breast cancer in women randomised to tamoxifen for cancer prevention in the International Breast Intervention Study (IBIS)-I trial. METHODS: Women randomised to tamoxifen in the IBIS-I trial and for whom side effect status was known at the 6-month follow-up visit were included in this analysis. Side effects included in this analysis were hot flushes, vaginal discharge, and vaginal dryness. The primary endpoint was all breast cancer and secondary endpoint was oestrogen receptor (ER) positive breast cancer. Cox proportional hazard models were used to investigate breast cancer incidence in the tamoxifen group with and without side effects reported within 6 months of randomisation. RESULTS: Women randomised to tamoxifen and reporting hot flushes at the 6-month follow-up visit had a non-statistically significant increase in breast cancer compared to those without hot flushes (HR = 1.26 (0.98-1.62), P = 0.08). A significant higher breast cancer risk was observed for postmenopausal women who reported hot flushes at the 6-month follow-up visit compared to those without hot flushes (HR = 1.59 (1.12-2.26), P = 0.01). A higher risk was observed for ER-positive breast cancer in postmenopausal women (HR = 1.81 (1.19-2.74), P = 0.01). No significant associations between gynaecological side effects and breast cancer occurrence was observed. CONCLUSIONS: Overall, no association between side effects reported at 6 months and subsequent breast cancer occurrence was observed. Some side effects might be useful markers for breast cancer occurrence in postmenopausal women.

Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial.

OBJECTIVES: To compare efficacy, satisfaction and tolerability of oral dydrogesterone and micronized vaginal progesterone gel used for luteal supplementation. STUDY DESIGN: Randomized controlled trial. A total of 853 infertile women undergoing IVF/ICSI treatment in University Hospital Center "Sisters of Mercy", Zagreb, Croatia. Luteal support was provided as Crinone 8%(®) vaginal progesterone gel (90mg) administered daily, or oral dydrogesterone Duphaston(®) (2× 10mg) administered two times daily. Progesterone was administered from the day of oocyte retrieval (day 0) till pregnancy test or in a case of pregnancy, until week 10. RESULTS: The on-going pregnancy rates were comparable between Crinone 8%(®) vaginal progesterone gel and oral dydrogesterone - Duphaston(®) (28.1% versus 30.3%; OR 1.11 (0.82-1.49 with 95% CI)). Overall satisfaction and tolerability were significantly higher in the dydrogesterone group than in the Crinone group. Vaginal bleeding, interference with coitus and local adverse side effects such as vaginal irritation and discharge occurred significantly more in Crinone group than in dydrogesterone group. CONCLUSIONS: Oral dydrogesterone is effective drug, well tolerated and accepted among patients and can be considered for routine luteal support. CLINICAL TRIAL REGISTRATION NUMBER: NCT01178931; www.clinicaltrials.gov.

Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomisation.

BACKGROUND: The Intergroup Exemestane Study (IES) (ISRCTN11883920) demonstrated improved survival for postmenopausal women with ER-positive/unknown primary breast cancer who switched to exemestane after 2-3 years tamoxifen, compared with those continuing on tamoxifen to complete 5 years therapy. This was achieved without detriment to on-treatment quality-of-life (QoL). We report on- and post-treatment QoL impact in IES. METHODS: A total of 582 patients from 8 countries participated in the QoL substudy. Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine symptom subscale (ES) were completed at baseline, 3, 6, 9, 12, 18, 24, 30, 36, 48 and 60 months. The primary endpoint was FACT-B Trial Outcome Index (TOI); secondary endpoints included severity of individual endocrine symptoms. RESULTS: Both the groups showed gradual improvement in overall QoL and lessening of total endocrine symptoms post treatment compared with baseline (P<0.002). There was no evidence of any between-group differences in TOI. Vasomotor complaints remained high on treatment. Vaginal discharge was more frequent (P<0.01) with tamoxifen up to 24 months from baseline. In both the groups, post-treatment libido did not recover to baseline levels. CONCLUSION: Clinical benefits of switching to exemestane are accompanied by good overall QoL. Although some symptoms persist, the majority of endocrine symptoms improve after treatment completion.

Safety, tolerability and pharmacokinetics of intravaginal pentamycin.

BACKGROUND/AIMS: Intravaginal pentamycin is a polyene macrolide with a broad spectrum of antimicrobial activity and is effective in various forms of infectious vaginitis. We evaluated the safety, tolerability and pharmacokinetics of escalating doses of this product. METHODS: Nineteen healthy volunteers were randomized to receive double blind one of five doses of intravaginal pentamycin (3, 10, 30, 60 or 100 mg) or the corresponding dose of pentamycin vehicle daily for 6 days. Patients with symptomatic vaginitis received a single dose of 60 (n = 6) or 100 mg (n = 6) of intravaginal pentamycin. Safety and tolerability parameters were monitored throughout the study. Plasma concentrations of pentamycin were measured daily in the healthy volunteers and on the day of drug application in the patients. RESULTS: The most frequently reported adverse events were mild or moderate vaginal discharge and mild symptoms of vaginal irritation (mainly pruritus or burning sensation), which also occurred in women who applied the vehicle. No patient with symptomatic vaginitis reported treatment-related adverse events. The plasma levels of pentamycin were below the quantification limit in all samples. CONCLUSION: Intravaginal pentamycin does not cause adverse reactions compared with vehicle and is not absorbed through the intact or the inflamed vagina.

Ultrasonographic uterine changes and vaginal discharges following intrauterine infusion of liquid paraffin in cows.

This study was conducted to examine uterine changes and uterocervical discharges following intrauterine infusion with liquid paraffin (LP) during the luteal phase by ultrasonic and vaginoscopic examinations in cows. Multiparous dairy cows (n=10) were infused with 50 ml physiological saline (PS group; n=5) or liquid paraffin (LP group; n=5) on day 10 or 11 after ovulation (day 0: ovulation). Vaginoscopic, rectal and ultrasonogaphic examinations were carried out at 0.25, 1, 2, 3, 4, 6, 8, 12 and 24 h after the LP and PS infusion and then at daily intervals until subsequent ovulation after the infusions. The mean volumes of recovered discharges from the vagina within 6 h after infusion were significantly greater (P<0.05) in the LP group than in the PS group (33.0 +/- 9.9 vs.14.0 +/- 13.9 ml). Yellowish-white discharge was first observed at 3.2 +/- 0.5 and 3.6 +/- 0.6 h after infusion and lasted for 12.2 +/- 2.9 and 2.1 +/- 1.5 days for the LP and PS groups, respectively, showing a significant difference (P<0.05) in duration. Subsequently, transparent discharge appeared again 2-3 days before the subsequent ovulation after the treatments in both groups and disappeared on the day prior to or the day of ovulation. During the immediate examination after the infusion, the cavity of the uterine horn appeared anechoic and dilated in the images of both groups. The anechoic images changed to echoic images at 2.2 +/- 0.8 and 2.6 +/- 0.9 h after the infusion in the LP and PS groups, respectively, and the echoic images lasted for 12.2 +/- 2.9 and 2.1 +/- 1.5 days in the LP and PS groups, respectively. These results suggest that the appearance and disappearance of intrauterine anechoic and echoic images reflect the appearance and disappearance of the characteristics of the recovered LP/PS-like liquid and yellowish-white and transparent discharges from the vagina.

Current status of aromatase inhibitors in the management of breast cancer and critique of the NCIC MA-17 trial.

BACKGROUND: The third-generation aromatase inhibitors reduce circulating estrogen levels in postmenopausal women and are well tolerated orally for breast cancer. Their role in the management of advanced breast cancer has already been recognized. This article reviews the evidence for their role in the adjuvant treatment of early-stage disease. METHODS: Three large multicenter trials are reviewed. The ATAC trial compared anastrozole and tamoxifen or a combination of the two, for 5 years from the point of diagnosis. The NCIC trial published the results of letrozole compared with placebo after the completion of 5 years of tamoxifen. Most recently, the Intergroup Exemestane Study reported a comparison of 5 years of tamoxifen vs 2 years of tamoxifen followed by 3 years of exemestane. RESULTS: The aromatase inhibitor arm in each of these studies was associated with improved disease-free survival and good tolerability. Because of the three different settings, cross-trial comparisons of the different aromatase inhibitors are impossible, but in each case the novel therapy appears promising. CONCLUSIONS: This review is critical of the early stopping of the NCIC study and recommends more mature follow-up in each case until distant disease-free or overall survival rates can be measured and then correlated with adverse events. The late onset of osteoporotic fractures is a concern that must be addressed before tamoxifen can be abandoned in favor of the aromatase inhibitor in each of the three clinical points: at diagnosis, at midway through a course of tamoxifen, and as an extension to the conventional 5-year period of endocrine therapy.

Vaginal wetness: an underestimated problem experienced by progestogen injectable contraceptive users in South Africa.

This paper reports on the common experience of vaginal wetness amongst South African users of progestogen-only injectable contraceptives. The observations emerged in the course of a community-based cross-sectional household survey undertaken in a rural district of KwaZulu-Natal in South Africa. The purpose of the survey was to elicit self-reporting on side effects of injectable contraceptive methods. Eight hundred and forty-eight women aged 15-49 were interviewed and 22.1% reported current use of an injectable contraceptive method, either depot medroxyprogesterone acetate (Depo-Provera) or norethisterone oenanthate (Nur-Isterate). Other modern methods used were oral hormonal contraceptives (4.5%), male condoms (1.3%), the intrauterine device (0.1%), and tubal ligation (0.1%). Vaginal wetness was reported by 18.4% of users and was one of the most common side effects, second only to amenorrhoea (62.5%). It was also what 17.5% of the women liked least about using this method. According to almost half the respondents, men regard women who use the injectable contraceptive as "wet", "cold" and/or "tasteless". These survey findings were supported by participants of 14 focus group interviews held in the sub-district. Since some South African men may prefer dry sex the perception that the injectable contraceptive increases vaginal wetness may be problematic for women who use it. Whilst vaginal wetness can only be classified as a subjective side effect at this stage, further investigations are needed as many South African women opt to use this method.

Raloxifene is associated with less side effects than tamoxifen in women with early breast cancer: a questionnaire study from one physician's practice.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) are being used increasingly for the prevention and treatment of breast cancer. The currently available SERMs, tamoxifen and raloxifene, are both associated with antiestrogenic side effects that can be bothersome. However, no data exist on how they compare in this regard. We conducted a retrospective, questionnaire-based study to answer this question. METHODS: Women with early breast cancer in one physician's practice who had received either or both of these drugs were surveyed using a self-administered questionnaire. Respondents graded the frequency and severity of side effects related to estrogen deprivation, such as vaginal dryness, mood changes, hot flashes, weight gain, and changes in libido, as well as other side effects, such as vaginal discharge. They were separated into three groups for analysis (group 1, tamoxifen only; group 2, raloxifene only; group 3, both drugs). Side effects graded 4 or 5 (or weight gain >10 pounds) were considered severe. RESULTS: Two hundred sixty-four questionnaires were available for analysis. Women on raloxifene had a shorter average duration of therapy. In comparing the tamoxifen and raloxifene groups, vaginal discharge, severe hot flashes, and weight gain of >10 pounds were significantly more frequent with tamoxifen. However, weight gain was also related to the duration of therapy with either drug. CONCLUSIONS: In this observational study, antiestrogenic side effects were common with either tamoxifen or raloxifene. Raloxifene is associated with significantly less vaginal discharge and severe hot flashes than tamoxifen in women with early breast cancer. Although weight gain of >10 pounds may also occur less frequently on this drug, this may be confounded by the shorter average duration of raloxifene therapy.

Vaginal discharge: a perceived side effect and minor reason for discontinuation in hormonal injectable users in South Africa.

Poor compliance and high discontinuation rates have been observed in users of injectable hormonal contraception in South Africa. The objective of this study was to assess the side effects and reasons for discontinuation in new users of both depot-medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN). One hundred and eighty nine women were recruited into a two-year follow-up study. At each visit for a repeat injection, users were asked about bleeding patterns and side effects. Vaginal discharge, often described as watery in consistency, was perceived to be a problem amongst women and their partners. In total, one fifth (20%) of women reported an increase in discharge during use of the method and three women cited this discharge to be the primary reason for discontinuation of the method. This side effect was mainly noted in the first few months of use. Health care providers believed that this was a side effect of both DMPA and NET-EN, and women who presented with this complaint were rarely investigated for presence of sexually transmitted diseases.

Effect of selective estrogen receptor modulators on reproductive tissues other than endometrium.

The objective of this paper is to review the published and unpublished knowledge of the effect of selective estrogen receptor modulators on reproductive tissues other than endometrium. Pharmaceutical companies developing or marketing selective estrogen receptor modulators (SERMs) were identified. The investigators at each company responsible for the conduct of investigational trials were contacted and queried about reports of adverse events in any ongoing or completed trials involving SERMs produced by their company. Levormeloxifene and idoxifene trials noted a higher proportion of surgery for pelvic organ prolapse in treated versus untreated women. The development of these pharmaceutical agents was discontinued, primarily for endometrial concerns. However, pelvic organ prolapse was reported to the FDA as an adverse event associated with both drugs. Study weaknesses preclude a definitive association between the agents and pelvic organ prolapse. The treated groups were not necessarily similar for confounding factors such as age, parity, obesity, cigarette smoking, and other risk factors for pelvic organ prolapse. Tamoxifen and raloxifene increase hot flash intensity and frequency. Ovarian cyst formation and uterine fibroid growth have also been reported with some SERMs. The identification and assessment of the impact of current and future SERMs on the pelvic floor and other genital tissues will be important to understanding their potential long-term application in disease treatment and prevention.

Safety evaluation of nonoxynol-9 gel in women at low risk of HIV infection.

OBJECTIVE: To determine the safety of a vaginal microbicide, COL-1492, containing 52.5 mg nonoxynol-9, applied once daily for 14 days among healthy volunteers. METHODS: A randomized, double-blind controlled trial with three arms, COL-1492 gel versus placebo gel versus no-treatment controls, was conducted. Outcomes of interest were reported genital symptoms, incidence of gynaecological signs, and incidence of genital lesions revealed by colposcopy. Participants were enrolled in four centres (Belgium, The Netherlands, and two in Thailand). RESULTS: A total of 534 women participated in the study: 179 used COL-1492, 178 used placebo, and 177 were no-treatment controls. Study visits were scheduled 1 week prior to enrollment (day -7), day 0 (enrollment), day 8 and day 14. The most frequently reported genital symptom was vaginal discharge in both the COL-1492 and placebo groups. This appeared to be related to leakage of the product out of the vagina. The incidence of lesions associated with epithelial disruption (ulcers and abrasions) was very low (< 2%) and there was no statistically significant difference between the three groups. Of the lesions observed by colposcopy that did not involve epithelial disruption, petechial haemorrhage was the most frequently detected, with an incidence of 20.1, 9.0 and 7.3% in the COL-1492, placebo and control groups, respectively. COL-1492 users had a higher incidence of erythema (8.4 versus 2% in the other groups). CONCLUSION: COL-1492 showed minimal toxicity when applied once daily. A Phase III trial to assess the product's effectiveness in HIV prevention is currently ongoing.

A study of the effects of tamoxifen in the frail elderly: difficulties encountered in nursing home research.

OBJECTIVE: This study was conducted in order to determine whether the effects of tamoxifen in elderly, frail nursing home residents are similar to those that have been previously reported for younger postmenopausal women. DESIGN: A chart review study. SETTING: The Jewish Home and Hospital for Aged (JHHA), a subacute long-term care facility. PARTICIPANTS: One hundred fifty-eight women who had been at the JHHA at any time since 1986. One hundred ten had a history of breast cancer; 43 of these had been treated with tamoxifen while at the JHHA (Group I), and 66 had not (Group II). The remaining 49 women had no history of breast cancer (Group III). MEASUREMENTS: Data were collected from the time of admission to the JHHA through August, 1994 on: chemistry profiles, bone fractures apparently not a consequence of metastasis, gynecological parameters, and thromboemboli. RESULTS: The lack of pre-admission clinical information presented problems regarding research design and the interpretation of our findings. Nevertheless, compared to women who had not been treated with tamoxifen, treated women had a significantly elevated incidence of vaginal discharge (P = 0.01) and a lower prevalence of elevated total cholesterol (P = 0.04). Although not statistically significant, they also had decreased levels of low density lipoprotein cholesterol and an increased incidence of thromboemboli and bone fractures. CONCLUSIONS: While some of the effects of tamoxifen in elderly, frail women are similar to those observed in younger, postmenopausal women, others may be different. Our results suggest a need for further innovative studies that focus on the consequences of tamoxifen treatment in the elderly, frail population.