Loprinzi, C.L., Kugler, J.W., Sloan, J.A., Mailliard, J.A., LaVasseur, B.I., Barton, D.L., … Christensen, B.J. (2000). Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet, 356, 2059–2063.

Assess more definitively than previous studies the efficacy and toxicity of various doses of venlafaxine for treatment of hot flashes in the breast cancer survivor

Participants were assigned to placebo (n = 56), or venlafaxine 37.5 mg daily (n = 56), 75 mg daily (n = 55), or 150 mg daily (n = 54).

Patients eligible for this trial were 221 women who had a history of breast cancer or who were concerned about taking estrogen therapy for fear of developing breast cancer.

• Inclusion criteria:
  • Troublesome hot flashes, occurring at least 14 times per week; hot flashes severe enough for the patient to desire therapeutic intervention, and present for at least one month prior to study entry, older than 18 years; life expectancy at least 6 months; and ECOG performance status of 0–1.
  • Anti-estrogens and aromatase inhibitors were allowed if they had been started four weeks prior to study entry and scheduled to continue for the next five weeks.
• Exclusion criteria:
  • Concomitant therapies not allowed: antineoplastic chemotherapy, androgens, estrogens, progestins, antidepressants, clonidine, and combined ergotamine, alkaloids of belladonna, and phenobarbital.   
  • Use of venlafaxine in the past, any antidepressant treatment within the preceding two years, pregnancy, breastfeeding, use of other medications to treat hot flashes within the past two weeks, uncontrolled hypertension.

Double-blind, placebo-controlled, randomized trial

• The primary endpoint:  bivariate construct of average daily hot flash activity: the number of hot flashes and a score combining the number and severity of hot flashes
• Hot flash diaries
• Participants stratified by age (younger than 50 versus older than 50), current tamoxifen use, duration of hot flashes (less than 9 versus more than 9 months) and frequency of hot flashes/day.

It was calculated that a sample size of 50 patients per group would provide 80% power to detect differences in average hot-flash activity of standard deviation (SD) 0–6 (1–2 hot flashes per day, a score of 3 units, or a 21% fall from baseline) with a type 1 error rate of 5%.

Of the 229 patients who joined the study, 191 had data evaluable over the whole study period (50 from the placebo group, 49 from the venlafaxine 37.5 mg group, 43 from the venlafaxine 75 mg group, and 49 from the venlafaxine 150 mg group). After week 4 of treatment, median hot flash scores were reduced from baseline by 27%, 37%, 61%, and 61%, respectively, in the four groups. Frequencies of some side effects (mouth dryness, decreased appetite, nausea, and constipation) were significantly higher in the venlafaxine 75 mg and 150 mg groups than in the placebo group.

The trial suggests that venlafaxine can alleviate hot flashes and that the most appropriate dose for this indication is 75 mg.

Missing data were handled in several ways as a sensitivity analysis of the robustness of the results in relation to the missing data. Less than 10% of possible data were missing, and the results were consistent across a series of analyses by various imputation methods.

The study makes mention that venlafaxine may also be effective against hot flashes in men who have undergone androgen deprivation therapy for prostate cancer.