Second primary cancer risks in seminoma patients treated with current and previous radiotherapy protocols: a systematic literature review

Background and purpose: Postoperative radiotherapy (RT) with para-aortal (PAO) +/- para-iliac (dog-leg) fields in seminoma patients is an effective treatment, associated with a lifetime risk of developing infra-diaphragmatic radiation-induced second primary cancers (SPC). We performed a systematic review to investigate dose to organs at risk (OAR), associated SPC risks, and landmark changes in RT-protocols, with a special interest in proton therapy. Methods: A systematic literature search (1990-2024) was conducted using PRISMA guidelines. Results: We identified eleven cohort studies reporting consistently excess SPC risks for pancreas, kidney, stomach, and (for dog-leg field) bladder, and colorectum after RT. Important RT-landmarks during the past 60 years were: abandoning mediastinal and inguinal RT, PAO only in stage I, prescription-dose reductions from 30-40 Gy to 20-26 Gy, largely abandoning elective PAO for stage I seminoma in favour of active surveillance, and introduction of proton therapy. RT remains an option in stage II (dog-leg with boosting) and high-risk stage I seminoma. Two studies estimated the dose-response-relationship for pancreas and stomach. Five planning studies showed consistent OAR dose reductions with proton versus photon therapy. Similar or higher OAR doses were observed with intensity-modulated versus conventional RT, due to larger low-dose baths. Conclusions: Established SPC risks have changed clinical practice in seminoma patients, and remain relevant for current RT practice. Proton therapy has the potential to reduce dose in relevant OARs at risk for SPCs. Further research on dose-response relationships for SPCs with fractionated RT and protons is needed to improve SPC risk assessment.