Simone de Vries1, Michael Schaapveld1,2, Pieternella J. Lugtenburg3, Laurien A. Daniëls4, Eefke J. Petersen5, Josée M. Zijlstra7, Gustaaf W. van Imhoff7, Richard W. M. van der Maazen8, Max Beijert9, Anna M. van Eggermond1, Leontien C. M. Kremer10, Marieke W. J. Louwman2, Marnix Lybeert11, Jan Paul de Boer12, Berthe M. P. Aleman13, Flora E. van Leeuwen1
1Department of Epidemiology, Netherlands Cancer Institute, Amsterdam,2Netherlands Comprehensive Cancer Organization (IKNL), Utrecht,3Department of Hematology, Erasmus MC Cancer Institute, Rotterdam,4Department of Radiation Oncology, Leiden University Medical Center, Leiden,5Department of Hematology, University Medical Center Utrecht, Utrecht,6Department of Hematology, VU University Medical Center Amsterdam, Amsterdam,7Department of Hematology, University Medical Center Groningen, Groningen,8Department of Radiation Oncology, Radboud University Medical Center, Nijmegen,9Department of Radiation Oncology, University Medical Center Groningen, Groningen,10Late Effects Research Group, Princess Máxima Center for Pediatric Oncology, Utrecht,11Department of Radiotherapy, Catharina Hospital, Eindhoven,12Department of Hematology, The Netherlands Cancer Institute, Amsterdam,13Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Background: Hodgkin lymphoma (HL) treatment has been associated with long-term increased risk of adverse events, including second malignancies, cardiovascular disease (CVD), and infections. We assessed cause-specific mortality by treatment period and follow-up interval, and by stage and primary treatment modality.
Methods: Our multicenter cohort included 4,663 HL patients, diagnosed before age 51, and treated between 1965–2000. Cumulative cause-specific mortality by treatment period and follow-up interval, and by stage and primary treatment (irrespective of relapse treatment) was estimated with other causes of death as competing risk.
Results: After a median follow-up of 18.6 years since HL treatment, 1,848 patients had died (36.0% from HL, 24.5% from solid tumors, 16.8% from CVD). Mortality risk for causes of death other than HL remained increased throughout follow-up: after 35 years risk was 4.7-fold increased compared to the general population. At 30 years, cumulative all-cause mortality amounted to 47.8%, with 14.8% 30-year mortality from HL (Table 1). Both all-cause and HL mortality were lower in patients treated 1989–2000 compared with 1965–1976: 20-year all-cause mortality 44.3% vs. 19.9%, and 20-year HL mortality 29.2% vs. 5.5%, respectively. No decrease in cumulative mortality in more recent treatment periods was observed yet for solid tumors and CVD.
For stage I-II, 35-year cumulative HL mortality according to primary treatment modalities was 7.2% for radiotherapy (RT) alone, 11.3% for chemotherapy (CT) alone, and 11.4% for RT+CT. By contrast, 35-year cumulative mortality from all other causes varied considerably between treatments, 48.4% for RT, 17.9% for CT, and 40.0% for RT+CT. For stage III-IV, 35-year HL mortality was higher: 31.9% for RT, 25.8% for CT, and 23.9% for RT+CT, while 35-year mortality from other causes was 46.0%, 26.8%, and 44.0% for the different primary treatments, respectively.
Conclusion: Long-term HL survivors experience elevated risks from causes of death other than HL for at least 35 years after treatment. Whereas HL mortality substantially decreased in more recent treatment periods, solid tumor and CVD mortality did not. Overall, we observed lower risks for HL and other cause mortality in patients primarily treated with CT only. However, this study was not based on data from randomized trials, implying that conclusions with respect to harms and benefits of primary treatment modalities warrant cautious interpretation.