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

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In a Dutch study reported in JAMA Oncology, Geurts et al found a dose-response relationship between radiotherapy and risk of colorectal cancer among survivors of Hodgkin lymphoma, with the risk being increased with increasing procarbazine dose.

Study Details

The nested case-control study included 5-year survivors of Hodgkin lymphoma from five centers in the Netherlands who were diagnosed between 1964 and 2000 at 15 to 50 years of age.  Survivors who developed colorectal cancer (cases) and those who did not (controls) were individually matched for sex, age at Hodgkin lymphoma diagnosis, and date of Hodgkin lymphoma diagnosis. Excess rate ratios (ERRs) were modeled to assess excess risk associated with each 1-Gy increase in radiotherapy dose, and potential interactions with procarbazine dose were analyzed.

Key Findings

The study population consisted of 316 survivors (mean age at diagnosis = 33 years) who were followed for a median of approximately 26 years. The population included 78 cases who developed colorectal cancer and 238 controls who did not. Treatment for Hodgkin lymphoma, including relapse, consisted of chemotherapy alone in 5% of cases and 14% of controls, radiotherapy alone in 26% and 37%, and both in 69% and 50%. Procarbazine was received by 63% and 53% of patients, respectively.

The median interval between Hodgkin lymphoma and colorectal cancer diagnoses was 25.7 years (interquartile range = 18.2–31.6 years). 

In patients receiving radiotherapy, the median mean radiation dose to the whole large bowel was 8.8 Gy in cases and 1.6 Gy in controls. In patients receiving procarbazine, the median cumulative dose was 8.4 g/m2 in cases and 8.0 g/m2 in controls.

Risk of colorectal cancer was significantly increased by receipt of subdiaphragmatic radiotherapy vs no subdiaphragmatic radiotherapy (rate ratio [RR] = 2.4, 95% confidence interval [CI] = 1.4–4.1) and by receipt of a procarbazine dose > 8.4 g/m2 vs no procarbazine (RR = 2.5, 95% CI = 1.3–5.0). Receipt of 10 to < 20 Gy (RR = 2.1, 95% CI = 1.0–4.5) and ≥ 20 Gy (RR = 3.0, 95% CI = 1.5–6.2) to the whole large bowel were associated with increased risk of colorectal cancer compared with receipt of 0 to < 1 Gy.

Overall, risk of colorectal cancer increased linearly with mean radiation dose to the whole large bowel (overall ERR/Gy = 9.2%, 95% CI = 2.5%–23.0%) and mean dose to the affected segment (overall ERR/Gy= 7.5%, 95% CI = 2.2%–17.8%).  

The association between radiotherapy dose and colorectal cancer risk was stronger with increasing procarbazine dose. The ERR/Gy to the whole bowel was 3.5% (95% CI = 0.4%–12.6%) among patients who did not receive procarbazine. For each 1 g/m2 increase in procarbazine dose, the ERR/Gy increased 1.19-fold (95% CI = 1.06–1.33-fold), with an ERR/Gy of 15.0% among patients who received 8.4 g/m2.

The investigators concluded, “This nested case-control study of 5-year Hodgkin lymphoma 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.”

Michael Schaapveld, PhD, of the Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the Dutch Cancer Society and Cancer Research UK. For full disclosures of the study authors, visit

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