Risk of secondary malignancies in non-Hodgkin lymphoma survivors: 40 years of follow-up assessed by treatment modality.
Authors: Parsons Matthew , Chipman Jonathan , Rock Calvin , Stephens Deborah Marie , Shah Harsh , Hu Boyu , Tao Randa , Tward Jonathan David , Gaffney David K. 
Published: June 2021

e19525

Background: Survivors of non-Hodgkin lymphoma (NHL) are at increased risk of secondary malignancies (SM). We quantified this risk in survivors with over 40 years of follow-up, and evaluated differences in risk by treatment modality. Methods: Standardized incidence ratios (SIR, observed-to-expected [O/E] ratio), which accounts for patient years at risk, and absolute excess risk of SM were assessed in 142,837 patients diagnosed with NHL as a first malignancy between 1975 and 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Follow up was available through 2016. Non-melanoma skin cancers were not counted as SM. SIRs were also evaluated for patients stratified by age at and latency from diagnosis. Results: In all, 14,101 patients received radiotherapy alone (RT), 68,424 received chemotherapy alone (CT), and 18,339 received chemotherapy and radiation (CRT). In total, 15,979 patients (11%) developed SM, more than the endemic rate (O/E 1.29; P < .01). Overall, patients treated with any RT (RT+CRT) had a similar risk of SM as those who did not receive RT (O/E 1.29 for both compared to endemic rate). Patients treated with RT had more risk of female breast cancer and less risk of leukemia than unirradiated patients (P < .05). Patients treated with any CT (CT+CRT) had increased SM rates compared with those who did not receive CT [O/E 1.33 (95% CI 1.30-1.35) vs 1.24 (95% CI 1.21-1.26), respectively], which included increased risks of leukemia, Kaposi sarcoma, kidney, pancreas, rectal, head and neck, and colon cancers and decreased risk of prostate cancer (P < 0.05). When stratified by four treatment groups (no CT or RT, RT alone, CT alone, CRT), there were no differences in SM rates between the no therapy and RT alone groups (O/E 1.24 95% CI 1.21-1.27 and O/E 1.23 95% CI 1.18-1.28 respectively). CT alone and CRT were associated with increased risk of secondary malignancy compared to the no therapy group (O/E 1.32 95% CI 1.29-1.35 and O/E 1.35 95% CI 1.29-1.40 respectively). CT alone was also associated with increased risk of leukemia, Kaposi sarcoma, kidney, head and neck and thyroid cancers, and a decreased risk of prostate cancer (P < .05). CRT was associated with increased risk of head and neck and female breast cancers (P < .05). There was no difference in the overall risk of SM between the CT alone and CRT groups and female breast cancer was the only site at which CRT was associated with higher risk than CT alone. Of note, female breast cancer risk was highest in those diagnosed under 25 years of age and at latencies of greater than 10 years. Conclusions: This is the largest study to examine secondary malignancy risk in patients with NHL and has the longest follow-up. Patients treated with RT alone did not have an increased SM risk compared to those who received no RT or CT. The risk of SMs was increased overall for NHL survivors and varied with treatment modality.