Background: Standard therapy (neoadjuvant chemoradiotherapy - CRT, surgery, adjuvant chemotherapy- ChT) of locally advanced rectal cancer (LARC) achieves excellent local control, but survival is still poor due to distant metastases, which remain the leading cause of death for these patients. In recent years the concept of total neoadjuvant therapy (TNT) has been developed, where systemic ChT that mainly affects micrometastasis is placed with CRT prior to surgery.
Patients and methods: In a retrospective study, we compared patients with LARC with high risk factors for failure who were treated with standard therapy or TNT. High risk factors for failure were defined as presence of one of the factors: T4, N2, positive mesorectal fascia, presence of extramural vascular invasion, presence of lateral lymph node. TNT consists of 12 weeks of induction ChT with CAPOX or FOLFOX, CRT with capecitabine and six to eight weeks of consolidation ChT with CAPOX or FOLFOX prior to surgery. Primary endpoint was pathological complete response (pCR).
Results: 72 patients treated with standard therapy and 89 patients with TNT were included in analysis. Groups matched by gender, clinical disease stage, performance status and tumor location from anal verge. Groups differed significantly in age and in proportion of high risk factors for failure, but these characteristics alone did not have significant effect on pCR. Compared to standard therapy showed TNT higher proportion of pCR (23% vs. 7%; p 0.01), lower NAR prognostic score (median 8.43 vs. 14.98; p < 0.05), higher T- and N-downstaging (70% and 94% vs. 51% and 86%), equivalent R0 resection rate (95% vs. 93%), shorter time to stoma closure (average 20 vs. 33 weeks; p < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs. 76%; p < 0.05), lower proportion of acute toxicity grade ⡥ 3 during ChT (3% vs. 14%, p < 0.05), equivalent acute toxicitiy and compliance during CRT and in postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with IMRT/VMAT than with 3D conformal radiotherapy (32% vs. 9%; p < 0.05).
Conclusion: Compared to standard therapy the outcome of patients with LARC with high risk factors for failure is better in TNT in terms of pCR and prognostic NAR score. It is necessary to continue evaluation of the long-term effects of TNT. Higher rate of pCR with IMRT/VMAT is attributed to shorter irradiation times, accuracy of more advanced irradiation technique and hypofractionation that was made possible by the more advanced irradiation technique.