The management of locally advanced rectal cancer has evolved significantly with the advent of Total Neoadjuvant Therapy. By incorporating systemic chemotherapy earlier in the treatment sequence, two major randomized trials—the PRODIGE 23 trial and the RAPIDO trial, have altered therapeutic paradigms.
The PRODIGE 23 trial adopted an induction chemotherapy approach, where patients received FOLFIRINOX before standard long-course chemoradiotherapy, followed by surgery and adjuvant chemotherapy. This technique sought to address micro metastatic disease early while retaining optimal local control.
In contrast, the RAPIDO trial used a short-course radiation as first approach, delivering 25Gy in 5 fractions followed by consolidation chemotherapy with either CAPOX or FOLFOX before surgery, omitting routine adjuvant chemotherapy.
A major difference between the two studies is how patients were stratified. The RAPIDO trial included patients with high-risk locally advanced rectal cancer (EMVI+, MRF+, cN2, cT4a or cT4b disease), whereas the PRODIGE 23 trial included a broader locally adInvanced rectal cancer population (cT3-T4).
The PRODIGE 23 trial demonstrated improved disease-free survival, higher pathological complete response rates, and better metastasis-free survival, whereas the RAPIDO trial showed a significant reduction in disease-related treatment failure, along with improved pathological complete response and a lower incidence of distant metastases.
Updated RAPIDO data showed that the initial reductions in disease-related treatment failure and distant metastases were maintained, but a higher rate of locoregional recurrence was observed with longer follow-up. Potential contributing factors may include differences in radiotherapy strategy, chemotherapy sequencing, timing of surgery, and the inclusion of an MRI-defined high-risk population. In comparison, PRODIGE 23 demonstrated sustained improvements in disease-free survival, metastasis-free survival, and overall survival with extended follow-up. Together, these trials show that different TNT strategies may offer different balances between systemic control, local control, toxicity, and feasibility.
Although PRODIGE-23 improves overall and disease-free survival, its intense nature can be difficult to implement in routine clinical practice- especially in India. Modifications such as dose adjustments are often needed to reduce toxicity, particularly neutropenia and improve tolerability.
Conclution
To conclude the PRODIGE 23 trial and RAPIDO trial collectively establish TNT as a cornerstone in rectal cancer management, but their application differs. The choice between them should be individualized, taking into consideration patient fitness, tumour characteristics, and risk profile, while also considering institutional expertise.
Written by Dr Balu Vijayan.