September 29, 2009 — Hormone replacement therapy (HRT) using estrogen and progestin is associated with an increased risk for death from lung cancer, according to the results of an analysis of data from the Women's Health Initiative (WHI) trial reported in the September 20 Online First issue of The Lancet. These results were initially presented at the American Society of Clinical Oncology 45th Annual Meeting as reported by Medscape Oncology.
"In the post-intervention period of the...WHI trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo," write Rowan T. Chlebowski, from Los Angeles Biomedical Research Institute at Harbour-University of California, Los Angeles, Medical Center, Torrance, California, and colleagues from the WHI Investigators. "Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period."
The WHI study, which was a randomized, double-blind, placebo-controlled trial performed at 40 US centers, was stopped early when health risks of HRT were found to exceed benefits. With use of a computerized, stratified, permuted block algorithm, 16,608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive a once-daily tablet of 0.625-mg conjugated equine estrogen plus 2.5-mg medroxyprogesterone acetate (n = 8506) or matching placebo (n = 8102). Data from treatment and postintervention follow-up periods allowed determination of incidence and mortality rates for all lung cancer, small-cell lung cancer, and non–small-cell lung cancer, with analysis by intent-to-treat. Mean treatment duration was 5.6 ± 1.3 years, and mean additional follow-up duration was 2.4 ± 0·4 years.
Lung cancer was diagnosed in 109 women in the combined hormone therapy group vs 85 in the placebo group (incidence per year, 0.16% vs 0.13%; hazard ratio [HR], 1.23; 95% CI, 0.92 - 1.63; P = .16). Non–small-cell lung cancer was diagnosed in 96 women in the HRT group vs 72 in the placebo group (0.14% vs 0.11%; HR, 1.28; 95% CI, 0.94 - 1.73; P = .12).
Mortality rate from lung cancer was greater in the combined hormone therapy group vs the placebo group (73 vs 40 deaths; 0.11% vs 0.06%; HR, 1.71; 95% CI, 1.16 - 2.52; P = .01). This excess mortality rate in the HRT group was primarily attributed to more deaths from non–small-cell lung cancer (62 vs 31 deaths; 0.09% vs 0.05%; HR, 1.87; 95% CI, 1.22 - 2.88; P = .004). Both groups had similar incidence and mortality rates of small-cell lung cancer.
"Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer," the study authors write. "These findings should be incorporated into risk–benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer."
Limitations of this study include post hoc analysis, small number of lung cancers and small-cell lung cancers, and absence of information on treatment after diagnosis. In addition, the results cannot be extrapolated to other oral or topical hormone treatments or other treatment durations.
"There were significantly more poorly differentiated cancers and cancers with metastatic spread in the combined hormone therapy group than in the placebo group," the study authors conclude. "These findings, together with the substantial increase in mortality after a diagnosis of non-small-cell lung cancer, suggest that the main effect of combined hormone therapy might be on stimulating growth of already established non-small-cell lung cancers."
In an accompanying comment, Apar Kishor Ganti, MD, from the University of Nebraska Medical Center in Omaha, discusses the clinical implications of these findings for women considering use of HRT for perimenopausal symptoms.
"Because the optimum safe duration of hormone-replacement therapy in terms of lung-cancer survival is unclear, such therapy should probably be avoided in women at a high risk of developing lung cancer, especially those with a history of smoking," Dr. Ganti writes. "These results, along with the findings showing no protection against coronary heart disease, seriously question whether hormone-replacement therapy has any role in medicine today. It is difficult to presume that the benefits of routine use of such therapy for menopausal symptoms outweigh the increased risks of mortality, especially in the absence of improvement in the quality of life."
The National Heart, Lung and Blood Institute, National Institutes of Health, funded this study. Some of the study authors have disclosed various financial relationships with AstraZeneca, Novartis, Lilly, Amgen, Pfizer, the National Institutes of Health, the National Cancer Institute of Canada, and/or Wyeth. Dr. Ganti has disclosed no relevant financial relationships.
Lancet. Published online September 20, 2009. Abstract
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