KEY POINTS
- The review revisits preoperative short-course radiotherapy at 25 Gy in 5 consecutive 5-Gy fractions versus long-course chemoradiotherapy delivering approximately 50–50.4 Gy in 25–28 fractions with concurrent chemotherapy.
- The clinical paradox is illustrated by RAPIDO: short-course radiotherapy-based total neoadjuvant therapy produced more pathologic complete responses (28% vs 14%) but also more 5-year locoregional recurrence than standard long-course chemoradiotherapy (10% vs 6%, p=0.027). The authors caution that RAPIDO was not a clean comparison of radiotherapy fractionation alone.
- Radiobiologically, 25 Gy in five fractions corresponds to an estimated EQD2 of 36 Gy using an α/β ratio of 5 Gy. Accounting for treatment acceleration and an assumed repopulation correction of 0.2–0.4 Gy/day increases the estimated time-corrected EQD2 to approximately 41–47 Gy, still raising the question of why short-course treatment performs so well clinically.
- The proposed explanation extends beyond direct DNA damage. Larger fractions may enhance cGAS–STING/type-I interferon signaling, antigen presentation and T-cell activation, while shorter treatment schedules may expose circulating lymphocytes, pelvic marrow and regional lymph nodes to less cumulative radiation.
- In the 231-patient phase III UNION trial, short-course radiotherapy followed by camrelizumab plus CAPOX produced a pathologic complete response rate of 39.8%, versus 15.3% with long-course chemoradiotherapy followed by CAPOX. However, this comparison changes both fractionation and immunotherapy exposure.
- More informative same-platform comparisons have also shown sizeable gains. In SPRING-01, adding sintilimab to short-course radiotherapy-based total neoadjuvant therapy increased pathologic complete response from 32.7% to 59.2%; in STELLAR II, the corresponding increase was 25.0% to 45.5%.
- Across the literature synthesized by the authors, pathologic complete response rates were approximately 25–28% with total neoadjuvant therapy, 22–38% with long-course chemoradiotherapy plus immunotherapy, and 40–61% with short-course radiotherapy plus immunotherapy. These figures largely arise from separate trials, and mature local-control, survival, toxicity and organ-preservation data remain essential before concluding that short-course radiotherapy is the superior immune partner.
CLINICAL TAKEAWAY
The emerging short-course radiotherapy–immunotherapy signal in locally advanced rectal cancer is difficult to ignore, particularly because randomized studies have shown substantial increases in complete response. But the biological hypothesis is ahead of the clinical evidence: long-term control, toxicity and organ-preservation outcomes are still needed before this becomes a new standard.