Late effects of Hodgkin lymphoma treatment
Authors:   , de Vries Simone 
Published: August 2023

Hodgkin lymphoma (HL) is one of the most commonly diagnosed malignancies among adolescents and young adults and has become a prototype of a curable malignancy because of improvements in combined modality treatment over the past decades. Currently, cure rates are exceeding 90% for patients with early-stage disease and approaching the same level in patients with advanced disease. However, both radiotherapy and chemotherapy for the treatment of HL are associated with late adverse effects, of which second malignant neoplasms (SMN) and cardiovascular disease (CVD) are the most serious. The general aim of this thesis was to evaluate late effects associated with treatment for HL.

In chapter 2 we examined the combined burden from SMN and CVD after treatment for HL. After a median follow-up of 22 years, we identified 888 SMNs and 1,153 CVDs in 1,247 patients. At 40 years after treatment for HL, the cumulative incidence for developing either SMN or CVD was 68% and the cumulative incidence for developing both SMN and CVD was 17%. We observed that radiotherapy was the strongest risk factor for developing both SMN and CVD in multivariable Cox regression models. Treating physicians should be aware of the increased risk of developing both SMNs and CVD in patients treated for HL until 2000.

In chapter 3, we assessed breast cancer risk in male 5-year HL survivors. After a median follow-up of 20 years, we observed eight cases of male breast cancer. Male HL survivors experienced a 23-fold increased breast cancer risk compared to general population rates, representing 1.6 excess breast cancers per 10,000 person-years. The overall cumulative breast cancer incidences at 20 and 40 years after HL treatment were 0.1%, and 0.7%, respectively. To ensure early diagnosis and treatment, clinicians should be alert to symptoms of breast cancer in male survivors of HL.

In chapter 4 we compared causes of death derived from medical records (CODMR) with causes of death derived from death certificates (CODDC), as processed by Statistics Netherlands, of patients primarily treated for HL or breast cancer. Overall, we observed high levels of agreement between CODMR and CODDC for common causes of death in HL (81%) and breast cancer patients (97%). Observed discrepancies between CODMR and CODDC frequently occurred in the presence of potential late effects of treatment for HL.

In chapter 5 we examined long-term cause-specific excess mortality after HL treatment. Whereas HL mortality statistically significantly decreased over calendar period of treatment, solid tumor mortality did not change in the most recent treatment era (1989-2000). We also observed that infectious disease mortality was not only increased after splenectomy but also after spleen irradiation. Compared with the general population, HL survivors have a substantially reduced life expectancy. Therefore, optimal selection of patients for primary chemotherapy is crucial, weighing risks of HL relapse against long-term toxicity.

In chapter 6 we aimed to develop prediction models for risk of coronary heart disease and heart failure for HL survivors treated in adolescence and (early) adulthood. We were able to predict coronary heart disease and heart failure risk at 20 and 30 years after treatment with moderate to good overall calibration and moderate discrimination (areas under the curve: 0.68-0.74), which was confirmed by external validation for the coronary heart disease model (areas under the curve: 0.73-0.74). On the basis of our model including prescribed mediastinal radiation dose, 30-year risks ranged from 4% to 78% for coronary heart disease and 3% to 46% for heart failure, depending on risk factors. These models can be used to identify HL survivors who might benefit from targeted screening for CVD and early treatment for CVD risk factors in survivorship care.