Iatrogenic menopause following gynecological malignancy: time for action!

With increasingly successful treatments for malignancy, gynecological and otherwise, many women are being given the gift of life but are losing the ability to live it to its full. The decision to use hormone therapy following non-hormone-dependent malignancy is relatively easy. It becomes rather more problematic when treatment has been for potentially estrogen-sensitive tumors. It is imperative that time is found to discuss survivorship issues which include the effect of treatment on ovarian reserve and the benefits and risks of hormone therapy. Whilst much attention has been given to general survivorship issues, there has been little attention paid to the impact of menopause on quality of life, physically, psychologically and psychosexually. If menopause is anticipated, referral to a menopause service should be built into the care pathway, ideally before iatrogenic intervention has commenced, but otherwise in a timely manner post-treatment. It is important that the oncologist, surgeon and menopause specialist have a consistent view on how the patient should be managed to maintain confidence and avoid confusion. At Imperial College London, we have introduced a Young Woman’s Breast Cancer Pathway which facilitates the efficient multidisciplinary management of all aspects of young women’s health following diagnosis of breast cancer.

In the discussion between the menopause health-care professional and the patient, the following should be taken into account when deciding on use of hormone therapy. Clearly, the patient’s view is of paramount importance – some women prioritize quality of life whereas others view the risk of recurrence of their malignancy as the most important factor. The age of the patient will determine how much of her life will be spent in a menopausal state, assuming she survives the malignancy long term. This will then dictate the impact of long-term conditions such as osteoporosis, cardiovascular disease and dementia1. There is evidence that iatrogenic menopause due to malignancy leads to a greater risk of bone loss compared to iatrogenic menopause for benign reasons, even after controlling for hormone therapy usage2. The reason for this may be that a significant proportion of women receiving chemotherapy for malignancy are treated with concomitant corticosteroids which accelerate bone breakdown.

Symptom severity and duration will determine the degree of impact on personal, social and professional quality of life. The type and stage of tumor and hormone receptor expression should also be taken into account, although management is often decided on first principles rather than evidence. Treatment can be started immediately or delayed if there are concerns about risk of recurrence and hormone sensitivity of the tumor. Holidays from hormone therapy may be built in when some recovery of ovarian function is expected. BRCA1- and BRCA2-positive women who undergo bilateral oophorectomy may not need to be excluded from hormone therapy, particularly if they have had prophylactic bilateral mastectomy3.

The data for risk of recurrence following gynecological malignancy are mainly observational or case–control. In endometrial cancer, the data come from one randomized, controlled trial4 and a mixture of case–control and observational studies. The total risk of recurrence is low in the few studies conducted thus far and from clinical experience. This may be partly due to selection of cancer cases for hormone treatment which are lower grade and earlier stage. There is uncertainty whether the addition of progestogen confers a protective effect for endometrial cancer recurrence and this has to be counterbalanced to the potential increased risk for breast cancer with combined therapy. In ovarian cancer, a recent meta-analysis of two randomized, controlled trials and four case–control studies found that there was a non-significant risk of recurrence for hormone therapy use after surgery and/or medical treatment5. There was no significant effect for stage of epithelial ovarian cancer or hormone therapy subtype. More information is required as to the relevance of estrogen and progesterone receptor status, but this should be taken into account in deciding whether to prescribe. There are few meaningful data regarding the rare subtypes of endometrial and ovarian cancer. As far as breast cancer is concerned, it is disappointing that the two Swedish trials (HABITS and Stockholm)6^,7 and the UK trial at the Royal Marsden came to a premature ending as a result of the WHI study findings. There was a significant increased risk of recurrence in 'HABITS' which was not seen in 'Stockholm', probably because the majority of women were on tamoxifen in the latter trial. Cervical, vaginal and vulval cancer do not appear to respond adversely to the use of hormone therapy.

In conclusion, an unfortunate by-product of surgical and medical treatment of gynecological cancers is the loss of ovarian function which usually follows. This often has an impact on quality of life and long-term health. The focus of research and medical expenditure thus far has been to optimize survival rates in cancer sufferers. These endeavors should, of course, continue, but equal attention should now be given to funding research into the impact of medical interventions such as hormone therapy and alternatives to optimize effectiveness and confirm safety. After all, longevity means very little without quality of life.