Estrogen plus progestin and colorectal cancer incidence and mortality

Abstract

Purpose: During the intervention phase in the Women's Health Initiative (WHI) clinical trial, use of estrogen plus progestin reduced the colorectal cancer diagnosis rate, but the cancers were found at a substantially higher stage. To assess the clinical relevance of the findings, analyses of the influence of combined hormone therapy on colorectal cancer incidence and colorectal cancer mortality were conducted after extended follow-up.

Patients and methods: The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 16,608 postmenopausal women with an intact uterus who were randomly assigned to daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or matching placebo (n = 8,102). Colorectal cancer diagnosis rates and colorectal cancer mortality were assessed.

Results: After a mean of 5.6 years (standard deviation [SD], 1.03 years) of intervention and 11.6 years (SD, 3.1 years) of total follow-up, fewer colorectal cancers were diagnosed in the combined hormone therapy group compared with the placebo group (diagnoses/year, 0.12% v 0.16%; hazard ratio [HR], 0.72; 95% CI, 0.56 to 0.94; P = .014). Bowel screening examinations were comparable between groups throughout. Cancers in the combined hormone therapy group more commonly had positive lymph nodes (50.5% v 28.6%; P < .001) and were at higher stage (regional or distant, 68.8% v 51.4%; P = .003). Although not statistically significant, there was a higher number of colorectal cancer deaths in the combined hormone therapy group (37 v 27 deaths; 0.04% v 0.03%; HR, 1.29; 95% CI, 0.78 to 2.11; P = .320).

Conclusion: The findings, suggestive of diagnostic delay, do not support a clinically meaningful benefit for combined hormone therapy on colorectal cancer.

Fig 1.

CONSORT diagram. CEE, conjugated equine estrogen; MPA, medroxyprogesterone acetate.

Fig 2.

Colorectal cancer incidence by random allocation group. HR, hazard ratio.

Fig 3.

(A) Risk of death from invasive colorectal cancer and (B) risk of death after invasive colorectal cancer from date of random allocation by randomly assigned group. HR, hazard ratio.

Fig 4.

Overall survival after colorectal cancer diagnosis by random allocation group. HR, hazard ratio.

Fig A1.

Bowel examinations by treatment arm and year. flex. sig, flexible sigmoidoscopy

Fig A2.

Cumulative annualized incidence rates for invasive colorectal cancer by subgroups. Data are plotted as hazard ratios (HRs) with error bars showing 95% CIs. HRT, hormone replacement therapy; N/A, not applicable; NSAID, nonsteroidal anti-inflammatory drug.