Purpose: Hodgkin lymphoma (HL) survivors have an increased colorectal cancer (CRC) risk, which may be related to subdiaphragmatic radiation and/or alkylating chemotherapy. While radiation dose-response relationships for breast, lung, stomach, pancreas and esophagus cancer after HL have been demonstrated, no previous studies have investigated this for CRC after HL. This study aimed to quantify CRC rate according to radiation dose to the large bowel and procarbazine dose.
Methods: We conducted a nested case-control study among 2996 five-year HL survivors treated in 1965-2000 at ages 15-50 years, who were followed for a median duration of 26.1 years. Treatment information was collected for 78 CRC cases and 238 controls, individually matched on sex, age at HL diagnosis and date of HL diagnosis. Mean radiation doses to the large bowel were estimated by reconstructing individual radiotherapy treatments on representative computed tomography datasets. Rate ratios (RRs) were estimated using conditional logistic regression. Excess rate ratios (ERRs) were modelled to evaluate the excess rate associated with each gray increase in radiation dose and effect modification by procarbazine was explored.
Results: The median age at HL diagnosis was 33.0 years and the median interval between HL and CRC was 25.7 years. Increased CRC rates were seen for patients who received subdiaphragmatic radiation (RR 2.4; 95% confidence interval (CI) 1.4-4.1) and those who received >8.4 g/m2 procarbazine (RR 2.5; 95% CI 1.3-5.0). Overall, CRC rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The effect of radiation dose on CRC rate was modified by cumulative procarbazine dose: the ERR/gray to the whole large bowel was 3.5% (95% CI 0.4-12.6%) for patients who did not receive procarbazine, and increased 1.19-fold (95% CI 1.06-1.33) for each g/m2 increase in procarbazine dose, with an ERR/gray of 15.0% for patients who received 8.4 g/m2 procarbazine.
Conclusion and relevance: This is the first study to demonstrate a dose-response relationship between radiation and CRC risk, and modification of this effect by procarbazine. Results enable individualized CRC risk estimations, identification of high-risk survivors and optimization of treatment strategies for future patients.
Yvonne M.G. Geurts, Rebecca Shakir, Georgios Ntentas, Sander Roberti, Marianne Aznar, Katinka John, Johanna Ramroth, Cécile P.M. Janus, Augustinus Krol, Judith Roesink, Richard W.M. van der Maazen, Josée M. Zijlstra, Sarah Darby, Berthe M. P. Aleman, Flora E. van Leeuwen, David Cutter, Michael Schaapveld