Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma

Abstract

ImportanceHodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear.ObjectiveTo quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors.Design, Setting, and ParticipantsA nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022.ExposuresMean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets.Main Outcomes and MeasuresExcess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored.ResultsThe study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose.Conclusions and RelevanceThis nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.

Reappraisal of the role of radiation therapy in lymphoma treatment

“…Hence, avoiding RT, even at great costs, seems to have gained wide popularity. However, if this comes at a cost from more intensive systemic treatments or a higher risk of relapse, then trying to avoid radiotherapy may backfire 20–24 . Serious long‐term side effects are also caused by systemic treatments, for example, second malignancies and cardiac toxicities.…”

“…However, if this comes at a cost from more intensive systemic treatments or a higher risk of relapse, then trying to avoid radiotherapy may backfire. [20][21][22][23][24] Serious long-term side effects are also caused by systemic treatments, for example, second malignancies and cardiac toxicities. What we need are tools to find the optimal combination of systemic treatments and modern RT, taking lymphoma subtype, anatomic location and extent of disease, patient age, sex, comorbidities, and preferences into account.…”