Advancing Evidence Based Survivorship Care after Hodgkin Lymphoma Treatment

The aim of this thesis was to generate real-world evidence to support evaluation of the survivorship care program for ≥5-year Hodgkin lymphoma (HL) survivors in the Netherlands (BETER care). The first BETER clinics were established in 2013–2016, following the development of national screening guidelines. The BETER guidelines offer screening and treatment recommendations for a broad range of potential late adverse events, tailored to survivors’ risk profiles . In this thesis, we focused on cardiovascular diseases (CVDs), breast cancer (BC), hypothyroidism, and severe infections. The BETER guidelines are based on a large body of epidemiological studies describing the increased risks of late adverse events in HL survivors. However, screening recommendations were often based on evidence in other high-risk populations (e.g. BRCA-mutation carriers for BC screening) or expert opinion, due to the absence of data specific to HL survivors. To date, evidence on health gains and financial benefits from survivorship care in lymphoma and childhood cancer survivors is limited to simulation studies that largely rely on assumptions. In Chapter 2, we evaluated screening yield in 186 survivors eligible for BETER cardiovascular screening who first visited the clinic in 2013–2016 (median follow-up: 2.2 years, median 3 visits). Screening identified ≥1 cardiovascular risk factor (active smoking, body mass index ≥25 kg/m², newly diagnosed or uncontrolled dyslipidemia, hypertension, or Diabetes) in 55.4% of survivors. Additionally, 31.1% were newly diagnosed with CVD. In Chapter 3, we assessed the diagnostic value of the combination of magnetic resonance imaging (MRI) and mammography, and each modality alone, for BC detection in 134 female HL survivors ≥8 years after treatment with chest radiotherapy (RT). Sensitivity was highest for MRI and mammography combined (though not significantly different), while specificity was significantly better for mammography alone (false positive results were mostly driven by MRI). All screen-detected tumors (n=18) were DCIS or stage T1. Chapter 4 describes the INSIGHT study protocol (results are described in Chapters 5-7). In Chapter 5, we described that average survivorship clinic attendance among 516 survivors invited to eight BETER clinics was 70%. Male sex was associated with higher odds of non-attendance (Odds Ratio (OR) 1.61 (95% Confidence Interval (CI) 1.01–2.56)), while history of subsequent malignancy lowered odds of non-attendance (OR 0.41 (95% CI 0.19–0.89)). History of CVD showed a similar but non-significant trend. In Chapter 6, we compared health-related quality of life (HRQoL), knowledge, and distress levels between HL survivors who attended BETER from 2013-2016 onwards (n=251, median follow-up 6.5 years, median 6 visits) and those eligible during the same period, but not invited until 2019–2024 (n=119). All outcomes were similar in both groups. Survivors’ knowledge of late effects was suboptimal. Eighty percent of survivors perceived the BETER visits as beneficial, while 12% found them burdensome. In Chapter 7, we compared HL survivors invited for BETER care in 2013–2016 (n=491) to matched survivors not invited until 2019–2024 (n=373). Both groups had a median age of ~46 years and were 15–18 years post-diagnosis at study start. Over 8.5 years of follow-up, ~1/3 of survivors in both groups developed disease burden attributable to one or more events of interest (CVD, BC, hypothyroidism, severe infections), without significant differences between the groups. Increased CVD incidence was observed among screened survivors in the first three years of follow-up, but not thereafter. Results suggested suboptimal management of survivor’s cardiovascular risk and vaccinations by BETER clinicians and general practitioners (GPs). Our findings do not imply that BETER care is not beneficial for individual survivors. Greater involvement of survivors, amendment of cardiovascular risk management guidelines, and better collaboration between GPs and hospital clinicians are needed to provide evidence-based and future-proof survivorship care for (Hodgkin) lymphoma survivors.