Optimal Sequence for Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: An Evidence-Based Review

Abstract

Introduction: Historically, multimodal therapeutic strategies involving preoperative chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (CT) have been employed to treat locally advanced rectal cancer (LARC). Total Neoadjuvant Therapy (TNT) is showing promise in improving outcomes. Despite its benefits, the optimal sequencing within TNT-whether induction chemotherapy should precede or follow chemoradiotherapy-remains a critical question. This study endeavors to explore the effects of different TNT sequencing strategies on patient outcomes, including tumor downstaging, pathological response, organ preservation, and the balance between efficacy and tolerability.

Methods: Our methodology entailed a comprehensive literature review conducted on Medline, focusing on recent research, including retrospective studies, systematic reviews, and clinical trials. The review emphasized the comparison of induction chemotherapy versus consolidation chemotherapy within TNT regimens, assessing outcomes such as pathological response, organ preservation rates, and adverse effects. To ensure the selection of appropriate and high-quality studies, specific inclusion and exclusion criteria were applied.

Results: The analysis revealed that induction chemotherapy might lead to decreased adherence to subsequent chemoradiotherapy while offering an early intervention against micrometastasis and potentially improving overall chemotherapy compliance. Conversely, consolidation chemotherapy has been associated with higher pathological complete response (pCR) rates and improved tolerability, indicating its potential for patients requiring local symptom relief or those eligible for a nonoperative management approach. Comparative studies like CAO/ARO/AIO-12 and the OPRA trials have significantly contributed to our understanding, suggesting that while both strategies have distinct advantages, the choice between induction and consolidation chemotherapy should be tailored based on individual patient profiles and tumor characteristics.

Conclusion: This narrative review underscores the importance of a nuanced approach to TNT sequencing in locally advanced rectal cancer, highlighting the need for further research to refine treatment strategies.

Keywords: adenocarcinoma; chemotherapy; radiotherapy; rectal cancer; total neoadjuvant therapy.

FIGURE 1

Design of studies evaluating induction chemotherapy as a TNT approach. This figure provides an overview of six different studies, including clinical trials and retrospective studies, that evaluated the use of induction chemotherapy before neoadjuvant chemoradiotherapy as part of the TNT approach in locally advanced rectal cancer treatment. Each column outlines a different study's treatment regimen, including the chemotherapy protocols, radiation therapy, and timing of surgery. CAPOX, Capecitabine, 1000 mg oral BD Days 1–14 + oxaliplatin 130 mg/m2 Day 1, Q3 weeks; CT, chemotherapy; EBRT, external beam radiation therapy; FOLFOX, Oxaliplatin 85 mg/m2 + 5‐FU CIV infusion 2400 mg/m2 days 1–3 ± 5‐FU 400 mg/m2 IV bolus + Leucovorin 400 mg/m2 Q2 weeks; mFOLFOX6, Oxaliplatin 85 mg/m² 2h IV + Leucovorin 400 mg/m² 2h IV + Fluorouracil 400 mg/m² IV then 2400 mg/m² CIV over 46 h Q2 weeks.nCRT, neoadjuvant chemoradiotherapy; NOM, nonoperative management; RT, radiation therapy; TME, total mesorectal excision.

FIGURE 2

Design of studies evaluating consolidation chemotherapy as a TNT approach. This figure illustrates the design of eight studies evaluating the use of consolidation chemotherapy within a total neoadjuvant therapy approach for locally advanced rectal cancer. It compares various regimens, including neoadjuvant chemoradiotherapy, short‐course or long‐course radiotherapy followed by consolidation chemotherapy, and the timing of surgery. Each study represents a different approach to integrating consolidation chemotherapy into the TNT framework to improve treatment outcomes. CAPOX, Capecitabine, 1000 mg oral BD Days 1–14 + oxaliplatin 130 mg/m2 Day 1, Q3 weeks; CCT, consolidation chemotherapy; CT, chemotherapy; FOLFOX4, Oxaliplatin 85 mg/m² IV day 1 + Leucovorin 200 mg/m² IV days 1,2 + FU 400 mg/m² IV + FU 600 mg/m² IV for 22 h days 1,2.IMRT, intensity‐modulated radiation therapy; mFOLFOX6, Oxaliplatin 85 mg/m² 2h IV + Leucovorin 400 mg/m² 2h IV + Fluorouracil 400 mg/m² IV then 2400 mg/m² CIV over 46 h Q2 weeks; nCRT, neoadjuvant chemoradiotherapy; NOM, nonoperative management; RT, radiation therapy; TME, total mesorectal excision.

FIGURE 3

Design of studies comparing CCT‐TNT and ICT‐TNT approach. This figure summarizes studies comparing the consolidation chemotherapy versus the induction chemotherapy as part of the TNT approach in locally advanced rectal cancer treatment. The studies include the CAO/ARO/AIO‐12 trial (Phase II, multicenter, randomized), the OPRA trial (Phase II, randomized, nonblinded), and a retrospective study by Moyer et al. Each study is depicted with two arms, detailing the sequence of induction chemotherapy, neoadjuvant chemoradiotherapy, consolidation chemotherapy, and the timing for total mesorectal excision or nonoperative management. CAPEOX, Capecitabine, 1000 mg oral BD Days 1–14 + oxaliplatin 130 mg/m2 Day 1, Q3 weeks.CT, chemotherapy; FOLFOX, Oxaliplatin 85 mg/m2 + 5‐FU CIV infusion 2400 mg/m2 Days 1–3 ± 5‐FU 400 mg/m2 IV bolus + Leucovorin 400 mg/m2 Q2 weeks; nCRT, neoadjuvant chemoradiotherapy; NOM, nonoperative management; RT, radiation therapy; TME, total mesorectal excision.