Secondary Malignancy Risk in Cervical Cancer Survivors After 40 Years of Follow-Up Stratified by Treatment Modality and Radiation Technique.

PURPOSE/OBJECTIVE(S) Survivors of cervical cancer who received chemotherapy and/or radiation therapy (RT) are at an increased lifetime risk of secondary malignancy (SM). We sought to characterize the risk of SM, stratified by treatment modality, radiation technique, age and time since diagnosis. MATERIALS/METHODS Utilizing the National Cancer Institute's Surveillance, Epidemiology and End Results Program database, we identified 42,359 patients representing 496,590 patient years with cervical cancer as first diagnosis between 1975 and 2016. Follow-up data was available up to 2016. Standardized incidence ratios (SIR; defined as observed-to-expected [O/E], which account for patient years at risk) and absolute excess risk of SM were assessed and quantified. Non-melanoma skin malignancies were excluded from analysis. RESULTS With a mean follow-up of 135 months, 4,519 (11%) of the 42,359 patients developed SM (O/E 1.25 compared to endemic rate, P < 0.01). Stratified by treatment modality, 19,331 patients received surgery only, 12,811 received radiation therapy (RT), 788 received chemotherapy (CT), and 8,288 received trimodality therapy (TMT). Relative to surgery only, higher risks of SM were seen with TMT (O/E 1.76, 95% CI 1.61-1.92) and RT (O/E 1.45, 95% CI 1.38-1.52), while receipt of CT did not show increased risk. Site-specific increased SM risks with RT included colon, rectum/rectosigmoid, lung/mediastinum, vulva and bladder, while TMT was associated with SM of the pancreas, lung/mediastinum, vagina, bladder, thyroid and leukemia (all P < 0.05). Stratified by radiation technique, 20,119 patients received no radiation, 8,046 received external beam (EBRT) only, 806 received brachytherapy (BT) only, and 12,247 received EBRT+BT. Relative to no radiation, higher risks of SM were seen with EBRT (O/E 1.55, 95% CI 1.43-1.68), BT (O/E 1.84, 1.44-2.31) and EBRT+BT (O/E 1.48, 95% CI 1.41-1.56). Site specific increased SM risks included bladder for all radiation techniques, pancreas, lung/mediastinum, and vulva for EBRT, rectum and kidney/renal pelvis for BT, and colon and bone/joint with EBRT+BT (all P < 0.05). Stratified by time since diagnosis showed that breast and thyroid malignancies were at highest risk of occurring within 10 years, while lung/mediastinal SMs were at highest risk more than 10 years from initial diagnosis. CONCLUSION This report represents the largest population-base cohort study analyzing secondary malignancy risk in cervical cancer survivors stratified by treatment modality and radiation technique to date. Cervical cancer survivors receiving adjuvant treatment have a higher risk of SM regardless of treatment modality. SM risk increased with receipt of any RT, including EBRT, BT, or EBRT+BT, but not with CT. Importantly, EBRT + BT did not increase rate of SM compared to EBRT. This highlights the importance of long post-RT follow-up in this population. AUTHOR DISCLOSURE C. Weil: None. M.W. Parsons: None. J. Chipman: None. R.D. Kraus: None. G. Suneja: Research Grant; National Institutes of Health. Honoraria; National Comprehensive Cancer Network. Travel Expenses; National Comprehensive Cancer Network, Radiation Oncology Institute, American Board of Radiology; Radiation Oncology Institute, National Comprehensive Cancer Network, ASTRO.L.M. Burt: ARRO executive committee. R. Dood: None. D.K. Gaffney: Research Grant; NCI. Consultant; NCI. run meetings; NCI.