KEY POINTS
- The review synthesizes current evidence for total neoadjuvant therapy, defined as delivery of the full systemic treatment course before surgery together with either 5 × 5 Gy short-course radiotherapy or long-course chemoradiotherapy. The authors consider TNT increasingly preferred for MRI-defined high-risk rectal cancer.
- In RAPIDO, short-course radiotherapy plus chemotherapy increased pathological complete response from 14.3% to 28.4% (p<0.001) and reduced 3-year disease-related treatment failure from 30.4% to 23.7% (HR 0.75; p=0.019) and distant metastases from 26.8% to 20.0% (HR 0.69; p=0.005).
- RAPIDO also illustrates an unresolved trade-off: grade ≥3 acute toxicity was 48% with TNT versus 25% with conventional chemoradiotherapy, and updated 5-year locoregional recurrence was 10.2% versus 6.1% (p=0.027), despite better systemic control.
- PRODIGE 23 demonstrated a different TNT strategy using induction FOLFIRINOX before chemoradiotherapy. Pathological complete response increased from 12% to 28%, while 3-year disease-free survival improved from 68.5% to 75.7% (HR 0.69; p=0.03); at seven years, disease-free survival remained 67.6% versus 62.5% (HR 0.80; p=0.048).
- Treatment sequence appears particularly important when organ preservation is the goal. CAO/ARO/AIO-12 produced pathological complete response in 25% with consolidation versus 17% with induction chemotherapy, while OPRA showed 3-year TME-free survival of 59% versus 43% (p=0.007) favoring chemoradiotherapy followed by consolidation chemotherapy.
- Longer OPRA follow-up maintained the organ-preservation advantage, with TME-free survival 54% versus 39% (p=0.012), without a corresponding disease-free-survival penalty. Local regrowth remains clinically important but salvage surgery was possible for most affected patients.
- Immunotherapy for mismatch-repair-proficient disease remains experimental. In the randomized phase II component of STELLAR II, adding sintilimab increased complete response from 25.0% to 45.5% (p=0.003) but also increased grade 3–4 toxicity from 19.4% to 34.5%; mature disease-free-survival data are pending.
CLINICAL TAKEAWAY
For MRI-defined high-risk locally advanced rectal cancer, TNT is now supported by multiple randomized trials and is increasingly embedded in guidelines. When organ preservation is a major objective, long-course chemoradiotherapy followed by consolidation chemotherapy currently has the strongest sequencing signal; the optimal radiation regimen, chemotherapy duration and role of immunotherapy remain unsettled.