Late adverse effects of treatment in female survivors of Hodgkin lymphoma

Introduction: Female Hodgkin lymphoma (HL) survivors are known to be at increased risk of cardiovascular disease, primary ovarian insufficiency and breast cancer due to their history of treatment with radiotherapy and/or chemotherapy. Previous studies have reported on the separate risks of these late adverse effects, but it is unknown whether and how these outcomes affect each other’s pathogenesis. In addition, the late effects themselves may lead to subsequent health problems, since primary ovarian insufficiency has been associated with reduced bone mineral density and neurocognitive dysfunction in the general population. In order to reduce morbidity and improve quality of life among female HL survivors, more knowledge on late effects is needed to improve early detection and treatment of late adverse effects along with prevention strategies. In this thesis, we examined the risks of breast cancer, cardiovascular disease, and primary ovarian insufficiency in female HL survivors and their possible subsequent health problems. We hereby focused on the influence of endogenous and exogenous gonadal hormones. Since little is known about the risk of breast cancer in male HL survivors, we also took a sidestep and investigated their HL treatment-specific breast cancer risk compared with the general population. Methods: We used an existing cohort of 3,905 5-year HL survivors who were treated in Dutch hospitals between 1965 and 2000. Data on treatments for HL and breast cancer, reproductive factors, hormone use, and late effects have been collected from medical records, and obtained through linkages with hospital registries, the Dutch Cancer Registry, and the Central Bureau for Genealogy. In addition, questionnaires were sent out to patients, general practitioners and cardiologists. Results and conclusions: Our results show that female HL survivors treated between 1965 and 2000 experience increased risks of morbidity and mortality from cardiovascular disease, breast cancer and primary ovarian insufficiency for many decades after their HL treatment. Many HL survivors develop two or more of these late adverse effects at a young age, making it important to raise awareness about the high risks among HL survivors, and their physicians. This will stimulate caretakers to screen for late adverse effects, and to adjust breast cancer treatment in female HL survivors who already have cardiovascular disease at breast cancer diagnosis, or were treated with cardiotoxic HL treatment. Risk factors for breast cancer observed in the general population, such as duration of ovarian function and menopausal hormone therapy use also influence breast cancer risk in female HL survivors. However, menopausal hormone therapy use did not appear to increase breast cancer risk in female HL survivors with an early menopause. It may therefore be safe for these women to use menopausal hormone therapy to alleviate menopausal symptoms and prevent osteoporosis, but our findings need to be confirmed in future studies. Moreover, breast cancer risk increased linearly with radiation dose and this radiation dose-response relationship was not affected by endogenous and exogenous hormone exposure. Besides female HL survivors, male HL survivors also have an increased breast cancer risk compared to the general population. Although male breast cancer after HL treatment is an uncommon event, clinicians should be aware of this strongly increased risk, particularly in patients treated with chest radiotherapy and a young age at HL treatment. A reassuring finding was that, in contrast to the general population, female HL survivors with a therapy-induced primary ovarian insufficiency did not have an increased cardiovascular disease risk. The knowledge obtained in this thesis can be used to improve survivorship care in order to improve the health and quality of life of HL survivors. It can also be used in risk prediction modelling and guide treatment of current patients.