Colorectal-Specific Radiation Dose and Chemotherapy Risk for Subsequent Colorectal Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study (CCSS) Report.
Level 3 - non-randomized controlled study
Retrospective cohort study with longitudinal follow-up
PubMed 41032739 · doi:10.1200/JCO-25-00531
What was done
In the Childhood Cancer Survivor Study (CCSS), researchers evaluated 25,723 five-year survivors of childhood cancer diagnosed between 1970 and 1999 across a median follow-up of 28.5 years (range: 5.0–48.9 years). They examined associations between subsequent colorectal malignant neoplasms (SMNs) and colorectum-specific radiation metrics (mean colorectal dose [MCD] and percentage of colorectal volume receiving >=5 to 40 Gy) as well as cumulative chemotherapy doses (procarbazine, platinum agents, cyclophosphamide-equivalent, and doxorubicin-equivalent doses) using piecewise-exponential and excess rate ratio (ERR) models.
What was found
Across follow-up, 104 colorectal SMNs occurred. Colorectal cancer incidence increased with MCD: incidence rate ratios (IRRs) were 3.6 (95% CI, 1.9 to 6.9) for 10 to <20 Gy and 8.3 (95% CI, 3.9 to 17.8) for >=20 Gy, with an excess rate ratio of 20.8% per 1 Gy (95% CI, 9.0% to 32.5%). When >=20% of the colorectal volume received >=20 Gy (V20 Gy), risk rose with volume: IRR 3.8 (95% CI, 1.9 to 7.6) for 20% to <40%, 4.9 (95% CI, 2.0 to 12.0) for 40% to <80%, and 8.7 (95% CI, 3.5 to 21.6) for >=80%. For chemotherapy, elevated risks were observed for doxorubicin-equivalent dose >=250 mg/m2 (IRR 1.8; 95% CI, 1.0 to 3.0), cyclophosphamide-equivalent dose >=6,000 mg/m2 (IRR 3.7; 95% CI, 2.2 to 6.4), platinum dose >=450 mg/m2 (IRR 4.5; 95% CI, 2.0 to 10.1), and procarbazine >=7,036 mg/m2 (IRR 9.0; 95% CI, 4.3 to 18.9; ERR 73.0% per 1,000 mg/m2). In survivors without radiation, risk remained increased for platinum exposure (IRR 3.8; 95% CI, 1.1 to 12.7), alkylators (IRR 4.8; 95% CI, 1.6 to 14.4), and procarbazine (IRR 16.9; 95% CI, 5.9 to 48.8).
Why it matters
These organ-specific radiation volume metrics and chemotherapy dose-response curves provide precise parameters to refine pediatric radiation treatment planning and guide targeted colorectal cancer surveillance protocols for high-risk childhood cancer survivors.
Limits
The total number of colorectal cancer events was modest (104 cases out of 25,723 survivors), leading to wide confidence intervals for high-dose subgroups and non-radiation chemotherapy analyses. Treatment eras (1970–1999) reflect historical radiation techniques and chemotherapy regimens that may not fully reflect modern targeted therapy protocols.