Abstract 3445: Long term effect of radiotherapy on risk of second primary lung cancer and overall mortality among lung cancer patients

Abstract Introduction: Radiotherapy has long been examined in association with second malignancies, but the impact of radiotherapy for initial primary lung cancer (IPLC) on the risk of second primary lung cancer (SPLC) remains controversial. We evaluated associations between IPLC radiotherapy and the risks of SPLC and overall mortality among lung cancer survivors. Methods: We identified 689,785 patients diagnosed with IPLC in 1988-2013 from SEER. We applied cause-specific Cox (CSC) regression to evaluate association between IPLC radiotherapy and SPLC risk, adjusting for age at IPLC diagnosis, IPLC stage and histology, and prior history of cancer. To allow a latency period of exposure to IPLC radiotherapy on SPLC risk, we performed subgroup analyses restricted to patients who survived ≥5 and ≥10 years after IPLC diagnosis. Using Cox regression, we evaluated association between IPLC radiotherapy and overall mortality, adjusting for the same covariates used in the CSC analysis. Mediation analysis quantified the indirect effect of IPLC radiotherapy on overall mortality mediated through radiotherapy-driven SPLC diagnosis. Validation utilized data from 7,758 IPLC patients (496 SPLCs) at Mayo Clinic. Results: Of 689,785 IPLC patients, 18,818 (2.7%) developed SPLC in SEER. IPLC patients treated with radiotherapy had a reduced SPLC risk versus non-irradiated patients when evaluated at the time of initial diagnosis (cause-specific hazard ratio [csHR]=0.90, P<1x10-6). However, the association between IPLC radiotherapy and SPLC risk was reversed when analyses were restricted to those who survived at least 5 years (csHR=1.08, P=0.01) and 10 years (csHR=1.16, P=0.009), thus long-term survivors treated with IPLC radiotherapy having a significantly increased risk of SPLC. Mayo Clinic data showed consistent results, with the effect of IPLC radiotherapy increasing from csHR of 2.41 (P<1x10-6) to 3.38 (P=0.001) among 5-year and 10-year survivors, respectively. Similarly, compared to non-irradiated patients, those treated with IPLC radiotherapy showed a significantly increased risk of overall mortality among 10-year survivors (hazard ratio [HR]=1.46, P<1x10-6 in SEER and HR=1.54, P=5.1X10-5 in Mayo Clinic). Mediation analysis showed that a substantial proportion of the total effect of IPLC radiotherapy on overall mortality—ranging from 32% to 59%—was due to radiotherapy-driven SPLC among 10-year survivors in SEER and Mayo Clinic. Conclusions: IPLC radiotherapy is associated with increased risks of SPLC and overall mortality, with its effects more pronounced among long-term survivors. Citation Format: Eunji Choi, Vicky T. Lam, Jacqueline A. Aredo, Ashok V. Kumar, Jason Wampfler, Julie T. Wu, David C. Christiani, Iona Cheng, Christopher I. Amos, Rayjean J. Hung, Leah M. Backhus, Joel W. Neal, Heather A. Wakelee, Ping Yang, Summer S. Han. Long term effect of radiotherapy on risk of second primary lung cancer and overall mortality among lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3445.