162 Background: TNT, consisting of preoperative chemoradiation (CRT +5-FU) followed by 3 cycles FOLFOX chemotherapy (cCTX) and total mesorectal excison (TME), was performed in rectal cancer patients (stages UICC ≥ II) according to the TransValid-B-phase-I/II-protocol (WHO-UTN-U1111-1132-0235) at a single site. The aim was to evaluate safety, feasibility, and long-term survival. Furthermore, the impact of postsurgical surrogate-parameters was determined. Methods: 62 patients (15 f, 47 m; median age: 62 years) with resectable LARC of the lower (43.5%; < 6 cm from the anal verge) or mid rectal third (56.5%, ≥ 6 - 12 cm) were included. Staging procedures revealed a positive circumferential resection margin (CRM < 2 mm) in 85.5% and clinical stages II to IV in 3.2%, 88.7% and 8.1%, respectively. TNT was performed by radiation (28x 1.8 Gy; total 50.4 Gy), civ infusion of FU (250 mg/m2/d; d1 - d14 and d22 - d35) and OX (50 mg/m2 on d1, d8, d22 and d29). Four weeks later, 3 FOLFOX cycles were applied with OX (80-100 mg/m2), followed by FA (400 mg/m2) and 5-FU (civ, 2400 mg/m2 over 46h, on d1, d15 and d30). Five to six weeks after cCTx, TME was performed with peri-/postoperative control of the specimen (MERCURY-criteria, 7th TNM/UICC-classification). Acute toxicities were recorded according to NCI-CTC-AE criteria (v4.03). Progression-free (PFS), overall (OS) and cancer-specific survival (CSS) were calculated using Kaplan-Meier estimators, logrank tests and multiparametric Cox proportional-hazards models. Results: During CRT (n = 62) and cCTx (n = 60), CTC-AE grades ≥ 3 occurred in 25.8% and 8.5%, respectively. Complete irradiation, concomitant CTx and consolidation FOLFOX-CTx were administered in 98.4%, 95.2% and 83.3%, respectively. After TNT, preoperative re-assessment showed a shift from stages ≥ III to ≤ II in 65% and from positive to negative CRM in 48,3%. 58 patients (93.5%) underwent TME-surgery with R0, negative CRM and optimal quality of the specimen in 94.8%, 91.4%, and 89.7%, respectively. Postoperatively, stages 0 to IV and complete remission (pCR; T0 N0) were diagnosed in 15.5%, 19%, 31%, 24.1%, 10.3% and 17.2%, respectively. Nearly complete remission (nCR; T1-T2 N0 and TRG 2 or TRG 3) occurred in 17.2%. Median follow-up time was 63 months (mo; quartiles: 48-103 months). Mean PFS and CSS were significantly higher for ypUICC stage ≤ II compared to stage ≥ III (111 ± 7.2 mo vs. 67 ± 12.2 mo; p = 0.006 and 130 ± 3.5 mo vs. 94 ± 10.2 mo; p = 0.004). Mean OS was 117 ± 6.4 mo for stages ≤ II vs. 91 ± 10.1 mo for stages ≥ III (p = 0.087). OS and PFS for patients with good (pCR and nCR) vs. poor response were 125 ± 7.0 mo vs. 101.5 ± 7.8 mo (p = 0.043) and 114 ± 9.6 mo vs. 87.9 ± 9.2 mo (p = 0.083). Conclusions: TNT is a safe, highly feasible and well-tolerated regimen with a good response of the primary rectal cancer and locoregional lymph nodes. Good response (pCR, nCR) or stage ≤ II results in higher rates for PFS, OS, and CSS. Clinical trial information: 2011-004228-37 .
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