We need to educate young lung cancer patients about menopause risk

Abstract

Background Approximately 220,000 Americans are diagnosed with lung cancer each year, leading to 150,000 deaths annually [1]. While the incidence of lung cancer has been decreasing in men, among women the rate has plateaued after increasing for years [1]. A recent study revealed that the incidence of lung cancer in young women has surpassed that of young men between 30 and 54 years of age [2]. These recent trends underscore the importance of understanding the effect of lung cancer treatments on fertility and menopause in young women. Chemotherapy-associated infertility and premature menopause are known to be frequent concerns among young women diagnosed with other cancers, sometimes impacting cancer-directed therapy decisions and quality of life [3,4]. Amenorrhea (particularly when it is long lasting) is a surrogate for gonadotoxicity in women. Anticancer drugs may diminish fertility and lead to menopause via ovarian atrophy, stromal fibrosis and vascular toxicity [5]. Various types of chemotherapy have been shown to destroy rapidly growing mature ovarian follicles and to induce apoptosis in primordial ovarian follicles [5]. Chemotherapy-induced infertility is most burdensome for younger patients (who have more frequently not completed their desired child-bearing). Female patients treated for cancer during childhood go on to have half as many live births as their sisters who did not get chemotherapy [6]. Alkylating agents such as cyclophosphamide are known to be more gonadotoxic than many other classes of chemotherapeutics and higher doses of cyclophosphamide are most problematic [7]. An analysis of patients with breast cancer enrolled in the International Breast Cancer Study Group Trials V and VI revealed that time to menopause after receiving cyclophosphamide, methotrexate and 5-fluorouracil is dose-dependent; in women younger than 35 who received one or no cycles of cyclophosphamide, methotrexate and 5-fluorouracil, 37% were menopausal in 5 years, significantly less than the 65% of women under 35 who received six or seven cycles [8]. Risk of ovarian toxicity increases with age; amenorrhea occurs at least temporarily in more than 80% of premenopausal women treated with the more modern combination of anthracycline, taxane and cyclophosphamide for early stage breast cancer, but nearly half of women less than 40 eventually resume menses while less than 5% of those over age 50 do [9]. Similarly, in lymphoma patients, treatment regimens that contain high doses of alkylating agents are associated with the highest risk of menopause and risks are age dependent [10]. While the gonadotoxic effects of many standard treatment regimens for breast cancer and lymphoma are well studied, the risk of menopause and infertility in premenopausal women with lung cancer remains uncertain. In small cell lung cancer, cisplatin plus etoposide is the standard first-line chemotherapy treatment for both limited and extensive stage disease. Platinum-based chemotherapy regimens are frequently first-line choices for non-small-cell lung cancer in both the nonmetastatic and metastatic setting [11]. A patient with metastatic disease often instead receives tyrosine kinase inhibitors (TKIs) as first-line treatment if the tumor has a targetable mutation. Immunotherapy plus chemotherapy is recommended for tumors with low PDL-1 expression, whereas immunotherapy alone is used in patients with high PDL-1 expression [11]. The gonadotoxicity of these drugs is understudied; while cisplatin is