Hormone replacement therapy (HRT) using oestrogen and progestin increases the risk of death from lung cancer, research published online in The Lancet concludes.
It reports on a new analysis of data from the Women’s Health Initiative (WHI) trial, which looked at the use of combined HRT in post-menopausal women. The trial was stopped early in 2002 after five and a half years because it found women on HRT had a higher risk of blood clots, heart disease, stroke and breast cancer.
This new report looked at data gathered during the WHI study and for another two years after it ended. It found that although women taking combined HRT did not have a significantly increased risk of lung cancer, they did have a greater risk of dying from it, with 73 deaths among those receiving HRT compared to 40 deaths in those taking a placebo.
This trial tested one type of combined HRT. Other preparations, particularly oestrogen-only therapy, may have different risks. The absolute numbers of women diagnosed with lung cancer were small; 16 per 1,000 women taking HRT for about eight years compared to 13 per 1,000 of those on the placebo. The small numbers of cases may affect the reliability of the risk estimates, especially as the original study did not plan to look at lung cancer and this may have increased the probability that a significant finding occured by chance.
Smokers already have a substantially higher risk of getting lung cancer, and a similar proportion of women smoked in the HRT group and the placebo group at the start of the study. Smoking rates were not assessed again.
The researchers suggest that the risk of lung cancer should be included in risk-benefit discussions with women considering combined HRT, particularly those with current risk factors for lung cancer, for example smokers or former long-term smokers. Other specialists have recommended that women at high risk of lung cancer, and especially those with a smoking history, should probably avoid this therapy completely.
Where did the story come from?
This research was carried out by Rowan Chlebowski and other members of the US Women’s Health Initiative investigators group. Funding was received from the National Heart, Lung and Blood Institute, National Institutes of Health. It was published online in the peer reviewed medical journal The Lancet.
What kind of scientific study was this?
This research was a retrospective (post-hoc) analysis of the Women’s Health Initiative (WHI) randomised controlled trial, which investigated the effects of combined HRT (oestrogen plus progestin) in post-menopausal women. The WHI trial was stopped early in July 2002 as the health risks were found to exceed the benefits of treatment. Results after an average five and a half years of treatment found that women on combined HRT were found to have increased risk of cardiovascular disease, coronary heart disease, stroke, venous thromboembolism, and breast cancer, although they had lower risks of fractures and colorectal cancers. The increased risk of death among the treated women at this stage appeared to be partly due to an increased risk of lung cancer in the HRT group compared to the placebo group (33 deaths compared to 15 deaths).
To assess whether there was a true association between HRT and lung cancer, the researchers carried out a further analysis of the lung cancers diagnosed in the trial and over an extended follow-up period to March 2005.
The WHI was conducted in 40 centres across the US between 1993 and 1998. A total of 16,608 women aged between 50 and 79 years who had gone through a natural menopause were randomised to receive either a daily HRT tablet (8,506 women) or matching placebo (8,102 women). The HRT tablet contained 0.625mg conjugated equine oestrogen combined with 2.5 mg medroxyprogesterone acetate. The largest age group (45%) were in the 60 to 69 age bracket, and 84% of the total sample were white. Three-quarters of the women had never used hormone therapy before, although almost half had previously used oral contraceptives. Half were never smokers and half were former or current smokers.
Study drugs were discontinued if the women developed breast cancer, any disease of the uterus lining, venous thromboembolism (for example, DVT), malignant melanoma, significant increase in triglyceride levels, or if they used any other non-study hormone preparations. Self-reported adverse disease outcomes were collected at six-monthly intervals by phone call, in addition to annual assessments at the clinic. Initial self-reports of outcomes (including cancers) were confirmed by physicians at the local clinic.
In their post-hoc analysis (meaning that the outcome analysed was not a predefined outcome at the beginning of the study) the researchers assessed incidence and mortality rates for all lung cancer, and specifically for small-cell lung cancer (the most aggressive type), and non-small-cell lung cancer (three different types, of which adenocarcinoma is the most common).
What were the results of the study?
An average of 2.4 years after the trial finished, 109 women in the combined HRT group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16% compared with 0.13%) although this difference was not significant (risk ratio 1.23, 95%, confidence interval 0.92 to1.63). Rates of non-small-cell lung cancer were slightly, although again not significantly, greater among treated women (96 compared with 72; incidence per year 0.14% compared with 0.11%).
However, significantly more women actually died from lung cancer in the combined HRT group than the placebo group (73 deaths compared with 40; yearly incidence 0.11% compared with 0.06%), with a 71% increased risk of death among treated women (risk ratio 1.71, 95% confidence interval 1.16 to 2.52). This was due to the significantly greater number of deaths among women with non-small-cell lung cancer in the combined HRT group compared to the placebo group (62 deaths versus 31 deaths). Both groups had similar numbers of small-cell lung cancers detected and deaths from this cancer. There was also a greater proportion of metastatic tumours among treated women.
What interpretations did the researchers draw from these results?
The researchers conclude that, although lung cancer rates did not increase as a result of treatment with combined HRT, the number of deaths from lung cancer did increase among treated women. This was due to the higher rate of death from non-small-cell lung cancer.
What does the NHS Knowledge Service make of this study?
The study found that although women taking combined HRT did not have a significantly increased risk of lung cancer, they did have a greater risk of dying from it. In particular, this was attributed to an increase in risk of non-small cell lung cancer. The researchers say that previous research indicates the presence of oestrogen receptors in the lungs, which could potentially explain the proliferation of cancers under the influence of oestrogen. The researchers also suggest that oestrogen stimulates the growth of blood vessels, and an increased vascular supply to the lungs may aid the spread of the cancer to other sites of the body.
However, some limitations should be noted:
- This trial assessed only one form of combined HRT. Although results may be similar for other preparations containing conjugated oestrogen at a higher or lower dose or with a different progestogen, it cannot be assumed that this is the case.
- There is no data available from the study report on how cancer diagnosis was made, how it was treated, or how it responded to treatment.
- Overall, the absolute numbers of those diagnosed with lung cancer were very small: 1.3% in the treatment group compared with 1.0% in the placebo group. Women taking HRT for short periods for severe menopausal symptoms should remember that the absolute lung cancer risk from HRT remains small. The small numbers of cases may affect the reliability of the risk estimates, especially with a post-hoc analysis such as this, which has an increased probability that a significant finding occurs by chance.
The researchers advise that further studies of HRT should be carried out which clearly specify the type of HRT used (combined oestrogen plus progestin or oestrogen alone), how long it is used for, and examine rates of lung cancer as an outcome, specifically non-small-cell lung cancer rates.
The risk of combined HRT was not attenuated by smoking. As smokers already have a substantially higher risk of getting lung cancer compared to non-smokers, the increased risk because of taking HRT can be added to the increase in risk due to smoking.
The Women’s Health Initiative group suggest that, as a result of their trial, the issue of lung cancer risk may need to be incorporated into risk–benefit discussions with women considering combined HRT, particularly those women with risk factors for lung cancer, such as current or ex-smokers.
Chlebowski RT, Schwartz AG, Wakelee H, et al., Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised controlled trial, Lancet September 20, 2009.
Farquhar C, Marjoribanks J, Lethaby A, Suckling JA, Lamberts Q. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews 2009, Issue 2