Early Menopause in 64% of Young Lung Cancer Patients

Rate Is Similar to Breast Cancer

Nick Mulcahy

September 04, 2018

Chemotherapy-induced menopause occurs in more than half of young women treated for lung cancer, according to the first-ever study on amenorrhea rates in women younger than 50 years.

"Chemotherapy for lung cancer patients appears to increase risk of early loss of menses in survivors," conclude the authors, led by Elizabeth Cathcart-Rake, MD, a medical oncology fellow at the Mayo Clinic in Rochester, Minnesota.

Treatment-related amenorrhea is a surrogate for infertility and early menopause, they explain.

The study was published online August 27 in Menopause.

Chemotherapy-induced amenorrhea has been widely studied in other survivors, especially breast cancer and lymphoma survivors, but there is little information about the phenomenon in lung cancer, the authors write. More than 5000 premenopausal women are diagnosed with lung cancer yearly in the United States.

As part of a program at the Mayo Clinic, from 1999 to 2016, a cohort of 182 premenopausal women with lung cancer were surveyed at diagnosis and annually thereafter about their menstrual status. The researchers recorded the chemotherapy agents administered and "self-reported menopause" (ie, ceasing of menstruation).

A total of 85 patients (median age at diagnosis, 44 years; range, 34 - 48 years) received chemotherapy, and 64% self-reported that they had become menopausal within a year of diagnosis.

The finding can be a discussion point with patients in practice, suggested Cathcart-Rake in comments to Medscape Medical News. "This study helps to inform the important conversations between physicians and patients about the likelihood of premature menopause, facilitating referrals to reproductive endocrinology for patients who desire fertility preservation," she said.

This high rate of self-reported amenorrhea is "only slightly lower" than the rates seen in breast cancer survivors of similar age who received chemotherapy regimens containing cyclophosphamide, observe Cathcart-Rake and colleagues.

Within 1 year of diagnosis, all of the 85 young women with lung cancer in the study had been treated with platinum agents (cisplatin, carboplatin), and a majority (54; 64%) of the group also received taxanes (paclitaxel, docetaxel). Additionally, some of the women (27; 32%) received antimetabolites (pemetrexed, gemcitabine), and nearly as many (25; 29%) were treated with topoisomerase inhibitors (etoposide, topotecan). Ten women (12%) were treated with other agents.

Notably, 94 women in the 182-person premenopausal cohort did not receive chemotherapy, and only 15% of that group self-reported menopause.

Also, three women received targeted therapy, such as an EGFR inhibitor alone. Two remained premenopausal at the final qualifying survey, completed a median of 3 years after diagnosis.

The authors state that, in general, women who remain amenorrheic 2 years after chemotherapy "do not frequently regain menstrual function."

In the study, the median time from diagnosis to first survey was 20.4 months (range, 12 - 202 months).

One of the keys in discussing the new data with patients is to emphasize potential risks — not certainties, suggested JoAnn Pinkerton, MD, executive director of the North American Menopause Society, who was not involved in the study and was asked for comment. "Periods stopping while taking chemotherapy does not mean the ovary will not recover. The ovaries of women under age 40 are more likely to recover than those of women over 40," she said in an email to Medscape Medical News.

The mean age of the patients in the study was 42.7 years.

Pinkerton, who is also a professor of obstetrics and gynecology at the University of Virginia in Charlotteville, emphasized that physicians should encourage young women "to seek fertility preserving options if desired."

The new data come from a mostly nonsmoking population. Of the women who reached menopause within 1 year of diagnosis, 71% were never-smokers, and of the women who remained premenopausal or perimenopausal at their final survey, 51% were never-smokers.

It's Not Just Alkylating Agents

The new data provide additional insight into the ovarian toxicity of the different types of chemotherapy.

Prior studies have suggested that alkylating agents, such as cyclophosphamide, are responsible — and "notorious" — for much of the ovarian toxicity experienced by young women with certain cancers, the authors observe. These drugs are believed to "destroy quiescent ovarian follicles by triggering follicle activation and apoptosis concurrently," they say.

However, the new findings, as well as others in the past, make it "clear" that nonalkylating agents, such as platinum salts, can also damage ovarian function, the authors state.

The stakes are high regarding adverse events from chemotherapy for these young women. "Permanent loss of ovarian function results in infertility, estrogen deprivation symptoms (eg, hot flashes and vaginal dryness), and bone loss," write the authors.

The prospect of early menopause can affect treatment decisions. The authors cite a study of 620 female breast cancer survivors younger than 40 years; more than half of the patients were concerned about infertility after treatment, and 26% reported that those concerns affected their treatment choices (Clin Obstet Gynecol. 2010;53:727-739).

Limitations and Thoughts on Immmunotherapies

The study has several limitations, the authors note. Of the 182 participants, 81 provided only one qualifying survey, which was obtained an average of 2.6 years after the diagnosis of lung cancer. Another limitation is the heterogeneity of cancer-directed therapies.

Further studies are needed to assess the gonadotoxic effects of each different chemotherapy agent and related regimens used to treat lung cancer, say the authors.

There is also the question of how immunotherapies, such as anti-PD1 agents, affect the ovaries.

Immunotherapy is being increasingly utilized in a variety of settings for lung cancer (either alone or in combination with chemotherapy), pointed out Cathcart-Rake. More research is needed to ascertain whether immunotherapy alone detrimentally affects ovarian function, she added.

In the meantime, "chemotherapy continues to be an important backbone for lung cancer therapy, especially for patients whose tumors do not express a known driver mutation and for those with low PDL1 expression," she emphasized. "Therefore, research on chemotherapy toxicities continues to be very relevant."

The study was funded by the Mayo Clinic and the National Institutes of Health. Dr Cathcart-Rake and Dr Pinkerton have disclosed no relevant financial relationships. Other study authors have reported financial ties to Gynesonics, Bayer, GlaxoSmithKline, Astellas, Welltwigs, AbbVie, Roche, and Biogen.

Menopause. Published online August 27, 2018. Abstract

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