Clinical advancements in total neoadjuvant therapy for locally advanced rectal cancer: a narrative review
Review Article

Clinical advancements in total neoadjuvant therapy for locally advanced rectal cancer: a narrative review

Angelo Pirozzi1,2,3, Celine Hoyek3, Naohiro Okano3,4, Leticia Assad Maia Sandoval5, Binbin Zheng-Lin3, Oluseyi Abidoye3, Cody Eslinger3, Mohamad Bassam Sonbol3, Mitesh J. Borad3, Tanios S. Bekaii-Saab3

1Department of Biomedical Sciences, Humanitas University, Milan, Italy; 2Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy; 3Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Phoenix, AZ, USA; 4Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan; 5Department of Internal Medicine, Mayo Clinic School of Graduate Medical Education, Scottsdale, AZ, USA

Contributions: (I) Conception and design: A Pirozzi, C Hoyek, TS Bekaii-Saab; (II) Administrative support: O Abidoye, LAM Sandoval; (III) Provision of study materials or patients: B Zheng-Lin, C Eslinger; (IV) Collection and assembly of data: N Okano, O Abidoye; (V) Data analysis and interpretation: MB Sonbol, MJ Borad; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Angelo Pirozzi, MD. Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy; Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Phoenix, AZ, USA. Email: pirozzi.angelo@mayo.edu.

Background and Objective: Total neoadjuvant therapy (TNT), which integrates systemic chemotherapy and chemoradiotherapy before surgery, has been shown to improve pathological complete response (pCR) rates and treatment compliance compared to traditional postoperative strategies in locally advanced rectal cancer (LARC). Landmark phase II and III trials have explored various TNT approaches, differing in chemotherapy regimens, radiotherapy (RT) schedules, and surgical timing. However, due to substantial heterogeneity across these studies, it remains challenging to define a single, optimal TNT strategy suitable for all patients. Our aim is to analyze the current evidence to tailor TNT strategies.

Methods: We conducted a comprehensive literature review using the PubMed database, applying the advanced search tool with filters set for studies published between 2015 and 2025. The search strategy included a combination of free-text terms and MeSH keywords related to “rectal cancer”, “locally advanced”, and “total neoadjuvant therapy”.

Key Content and Findings: This review summarizes the clinical evidence supporting TNT in LARC, highlights key trials shaping current practice, and discusses emerging strategies such as organ preservation, immunotherapy, and biomarker-driven approaches. We analyzed both phase II and III trials validating the role of TNT, exploring the advantages and limitations of each strategy. We also evaluated the feasibility of treatment de-escalation, particularly for low-risk patients and those with microsatellite instability (MSI) or deficient mismatch repair (dMMR). Moreover, we emphasized the predictive value of pCR in identifying candidates for organ preservation strategies aimed at reducing the long-term toxicities associated with surgery and RT. Finally, based on the available evidence, we proposed a clinical algorithm to guide treatment decision-making in clinical practice.

Conclusions: Further refinement of TNT strategies is necessary, especially in tailoring treatment intensity, identifying candidates for RT omission, and selecting patients suitable for non-operative management (NOM). Circulating tumor DNA (ctDNA) is emerging as a promising biomarker for real-time assessment of minimal residual disease (MRD), potentially enabling personalized treatment adjustments. However, its routine clinical application requires validation in prospective trials.

Keywords: Locally advanced rectal cancer (LARC); induction chemotherapy (INCT); consolidation chemotherapy (CNCT); chemoradiotherapy; immunotherapy

Received: 03 April 2025; Accepted: 14 July 2025; Published online: 26 September 2025.

doi: 10.21037/actr-25-58

Introduction

Background

Colorectal cancer (CRC) is the most frequent gastrointestinal malignancy by incidence, and it is the second leading cause of cancer-related death globally (1,2). In the last few decades, successful progress from screening programs, diagnosis, and approvals of new systemic options have significantly improved the survival of patients, especially in the advanced setting (3,4). However, remarkable steps have also been made in earlier stages, especially for the management of locally advanced rectal cancer (LARC), with the implementation of new strategies combining and/or sequencing locoregional treatments [surgery, radiotherapy (RT)] and systemic therapy (chemotherapy, immunotherapy) (5,6) (Figure 1). Notably, the local relapse (LR) rate has been reduced to 10% from 30–35% in the last decade (7,8). The management of LARC has consistently aimed to achieve a delicate balance between quality-of-life preservation and overall survival (OS) improvement.

Figure 1 Timeline of main events and trials in locally cancer treatment. DFS, disease-free survival; LCRT, long-course chemoradiotherapy; MSI, microsatellite instability; N, node; NOM, non-operative management; SCRT, short-course radiotherapy; T, tumor; TME, total mesorectal excision; TNT, total neoadjuvant therapy.

Rationale and knowledge gap

Currently, international guidelines (9,10) recommend total neoadjuvant therapy (TNT) as a new standard of care for stage II and III LARC, which increased the rate of pathological complete response (pCR) from 12% to 25% while maintaining a safe toxicity profile (9). This recommendation comes from the last follow-up updates of landmark phase II (OPRA, CARO/ARO/AIO-12) and phase III trials (PRODIGE-23, RAPIDO, STELLAR) assessing the efficacy and safety of TNT. However, these trials significantly differed in design, chemotherapy regimens, RT dose and schedule, and surgery time after conclusion of TNT. This heterogeneity highlights the ongoing debate regarding the optimal TNT approach and its appropriate patient selection, reinforcing the notion that “one size does not fit all” for a complex disease such LARC. In addition, for a small subgroup of patients (10–15%) with deficient mismatch repair/microsatellite instability (dMMR/MSI), immunotherapy alone in the neoadjuvant setting has been established as a powerful tool allowing the possibility to achieve high pCR rate (90–100%) (9,11,12). Based on these new findings, multiple efforts are ongoing to define reliable patient characteristics to select those who would most benefit from a watchful waiting strategy, potentially avoiding surgery.

Objective

With this review, we aim to summarize and integrate the evidence supporting TNT, highlight key clinical trials along with their most recent follow-up data, explore organ preservation strategies, discuss the latest studies on promising biomarkers, and outline future perspectives based on major clinical trials. We report the latest updates from the main phase II and III clinical trials that have shaped current treatment paradigms. We present this article in accordance with the Narrative Review reporting checklist (available at https://actr.amegroups.com/article/view/10.21037/actr-25-58/rc).

Methods

Literature published in PubMed from 2015 to 2025 was searched to obtain a comprehensive review. The three main topics, “rectal cancer”, “locally advanced”, and “total neoadjuvant therapy”, were developed by integrating free-text keywords with MeSH terms for literature retrieval by the advanced search tool. The “rectal cancer” term was encoded with the following string: “Rectal Neoplasms”[Mesh] OR “rectal cancer”. The “locally advanced” term was encoded as follows: “Locally advanced” OR “unresectable”. The “total neoadjuvant therapy” term was encoded as follows: “Total neoadjuvant therapy” OR “TNT” OR “preoperative therapy” OR “neoadjuvant therapy”. The detailed search strategy is presented in Table 1.

Table 1

The search strategy summary

Items Specification
Date of search 12/02/2025
Database searched PubMed
Search terms used “Locally advanced” OR “unresectable” AND “Rectal Neoplasms”[Mesh] OR “rectal cancer” AND “Total neoadjuvant therapy” OR “TNT” OR “preoperative therapy” OR “neoadjuvant therapy”
Timeframe 2015–2025
Inclusion and exclusion criteria Inclusion criteria: clinical trials, retrospective study, case reports. Exclusion criteria: literature published in languages other than English was excluded
Selection process It was conducted independently by A.P., C.H., N.O.; data selection is the intersection of the search of three authors

TNT principle and first clinical evidence

The use of concomitant chemoradiation therapy (CRT) in the preoperative setting followed by total mesolectal excision (TME) with or without adjuvant chemotherapy (ACT) with fluoropyrimidine-containing regimens has been the standard of care for LARC for more than 20 years (13,14). However, the effectiveness of this strategy was limited by low patient compliance, with only 40–73% of patients able to complete ACT in the main clinical trials (EORTC, CHRONICLE, DCCG) (15-17). The reasons for poor adherence were postoperative complications, drug toxicity, disease progression, and patient refusal (18). In addition to staging, pathological features and tumor location play a significant role in determining the risk of relapse in rectal cancer. Anatomical landmarks allow for differentiation between the colon, rectum, and anal canal, as tumors vary considerably in behavior depending on their location (12). On magnetic resonance imaging (MRI), the rectum is typically defined as the segment below an imaginary line from the sacral promontory to the upper limit of the symphysis pubis (approximately 15 cm from the anal verge) (13). Classically, it is divided into three parts: superior, middle, and inferior, corresponding respectively to tumors located within >10–15 cm, 5–10 cm, and <5 cm from the anal verge (19,20). Tumor location within these segments has prognostic implications, with low rectal tumors (<5 cm from the anal verge) being associated with worse outcomes, as recognized in both National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines (21,22). This was further validated by a large, population-based study from the Swedish ColoRectal Cancer Registry, which analyzed recurrence patterns in 9,428 patients who underwent curative resection between 2011 and 2018, with a median follow-up of 72 months. Eighteen percent had distal recurrence and 3% had locoregional recurrence at 5 years. In the same study, key predictors of distant recurrence included also advanced pathological stage (pT4a, pN2b), tumor deposits (TD), and lateral pelvic lymph node involvement (19). Based on this and other supporting evidence (23-25), features such as low tumor location, high tumor-node-metastasis (TNM) stage (cT4, cN2), mesorectal fascia (MRF+) involvement, extramural vascular invasion (EMVI+), and lateral lymph node metastases (LN+) have been consistently associated with an increased risk of relapse, particularly distant metastases (26). These observations helped define the population most in need of TNT strategies, as evaluated in phase II trials such as ARO-12 and OPRA, which introduced the concept of preoperative chemotherapy administered either before or after neoadjuvant chemoradiation (NCRT).

CAO/ARO/AIO-12

The CARO/ARO/AIO-12 trial enrolled 306 patients with stage II/III LARC randomized into two arms. Both arms received NCRT therapy with a continuous infusion of fluorouracil (250 mg/m2) on days 1–14 and 22–35, oxaliplatin (50 mg/m2) on days 1, 8, 22, and 29 of RT and concurrent RT with intensity-modulated radiation therapy (IMRT) 50.4 Gy/28 fractions (F). The experimental arm [NCRT-consolidation chemotherapy (CNCT)] was treated with CNCT after CRT based on oxaliplatin 100 mg/m2, leucovorin 400 mg/m2, continuous infusion of fluorouracil 2,400 mg/m2 over 46 hours (h) repeated on day 5 for three cycles (FOLFOX). The other arm [induction chemotherapy (INCT)-CRT] received the same chemotherapy scheme before CRT. After completing the sequence of CRT and chemotherapy, the two groups underwent TME. The primary endpoint was pCR, with a higher rate reported in the CRT-CNCT arm (5% vs. 17%). However, more patients completed the treatment in the INCT-CRT arm (92% vs. 85%). CRT-related grade 3–4 toxicity was lower (37% vs. 27%) in the NCRT-CNCT group and was associated with better compliance (27).

OPRA

Another trial confirming the feasibility of a TNT approach in LARC was the OPRA trial. This phase II trial enrolled 324 patients randomized into two arms. The primary endpoint was disease-free survival (DFS). One arm received INCT with FOLFOX ×8 cycles biweekly or CAPOX ×5 cycles every three weeks followed by CRT with capecitabine (825 mg/m2) twice daily orally or fluorouracil 225 mg/m2/day continuous infusion during RT per medical oncologist preference and concurrent RT (5,000–5,600 cGy) IMRT/3D-conformal RT. The other arm received a similar chemotherapy regimen as a CNCT following CRT. After the two TNT approaches were completed, both groups underwent either TME or watchful waiting, based on the achievement of a clinical complete response (cCR). At the median follow-up of 3 years, three-year DFS was 76% [95% confidence interval (CI): 69–84%] for the INCT-CRT group and 76% (95% CI: 69–83%) for the CRT-CNCT group. Three-year TME-free survival was 41% (95% CI: 33–50%) in the INCT-CRT group and 53% (95% CI: 45–62%) in the CRT-CNCT group. No differences were found in other efficacy outcomes, including OS (27,28). Importantly, patients treated with TME after regrowth had similar DFS rates to those who received TME after restaging.

Phase III clinical trials assessing TNT vs. standard of care

A major reason for treatment failure in LARC has been the high rate of distant metastases (29–39%) in first clinical trials (16,29-34) focusing on preoperative long CRT. The necessity to control distant micrometastasis has led to the design of clinical trials with short-radiotherapy (SCRT) regimens, allowing patients to receive CNCT sooner. The main phase 3 trials evaluating this strategy were the RAPIDO, STELLAR and PRODIGE-23 trials. Differences in terms of patient characteristics, outcomes of efficacy and safety of the trials analyzed are reported in Tables 2,3.

Table 2

Design, efficacy and safety of the main clinical trials assessing total neoadjuvant strategies

Patient features CARO/ARO/AIO-12 (27,35) (INCT-CRT sequence vs. CRT-CNCT sequence) OPRA (28,36) (INCT-CRT sequence vs. CRT-CNCT sequence) PRODIGE-23 (37,38) (experimental vs. control arm) RAPIDO (39) (experimental vs. control arm) STELLAR (40) (experimental vs. control arm)
Number of patients 156 vs. 150 158 vs. 166 231 vs. 230 462 vs. 450 298 vs. 293
Median age, years 62 vs. 61 59 vs. 56 61 vs. 62 62 vs. 62 55 vs. 56
Sex
   Male 68% vs. 67% 65% vs. 61% 65% vs. 68% 65% vs. 68% 72% vs. 70%
   Female 32% vs. 33% 35% vs. 39% 35% vs. 32% 35% vs. 32% 28% vs. 30%
Clinical T stage
   T2 4% vs. 3% 7% vs. 13% 1% vs. 1% 3% vs. 3% 2% vs. 3%
   T3 84% vs. 78% 78% vs. 76% 81% vs. 84% 65% vs. 66% 82% vs. 84%
   T4 12% vs. 18% 15% vs. 11% 18 vs. 16% 32% vs. 30% 16% vs. 13%
Clinical N stage
   cN-negative 10% vs. 9% 30% vs. 28% 10% vs. 10% 9% vs. 8% 14% vs. 16%
   cN-positive 86% vs. 90% 70% vs. 72% 90% vs. 90% 86% vs. 93% 86% vs. 84%
Distance from anal verge (cm)
   Median (IQR) NA 4.3 (3.0–6.3) vs. 4.5 (3.0–6.5) NA NA NA
   0–5 41% vs. 41% NA 38% vs. 36% 22% vs. 26% 49% vs. 50%
   >5–10 43% vs. 49% NA 49% vs. 51% 39% vs. 34% 50% vs. 50%
   >10 6% vs. 3% NA 13% vs. 13% 32% vs. 34% 1% vs. 0%
High risk features
   EMVI (+) NA NA NA 32% vs. 28% 53% vs. 42%
   MRF+ 31% vs. 22% NA 26% vs. 27% 62% vs. 60% 56% vs. 56%
   Lateral N+ NA NA NA 14% vs. 15% NA

CNCT, concomitant chemotherapy; CRT, chemoradiation therapy; EMVI, extramural vascular invasion; INCT, induction chemotherapy; IQR, interquartile range; MRF, mesorectal fascia; N, node; NA, not available; T, tumor.

Table 3

Design, efficacy and safety of the main clinical trials assessing total neoadjuvant strategies

Variable CARO/ARO/AIO-12 (27,35) OPRA (28,36) PRODIGE-23 (37,38) RAPIDO (39) STELLAR (40)
Phase II II III III III
Experimental arm 3× FOLFOX → LCRT → S 8× FOLFOX/5× CAPOX → LCRT → S 6× FOLFIRINOX → LCRT → S → 6× FOLFOX/4× capecitabine SCRT → 6× CAPOX or 9× FOLFOX → S SCRT → 4× CAPOX → S → 2× CAPOX
Control arm LCRT → 3× FOLFOX → S LCRT → 8× FOLFOX/5× CAPOX → S LCRT → S → 12× FOLFOX/8× capecitabine LCRT → S → optional 8× CAPOX/12× FOLFOX LCRT → S → 12× FOLFOX/8× capecitabine
Primary endpoint pCR DFS DFS DrTF DFS
Surgery performed 91% vs. 95% 47% vs. 36% 92% vs. 95% 91% vs. 88% 78% vs. 77%
pCR 17% vs. 25% NA (NOM) 28% vs. 12% 28% vs. 14% 22% vs. 12%
Local relapse rate
   3-year 9 (6%) vs. 7 (5%)* 95% vs. 94% 4% vs. 6% 8% vs. 6% 8% vs. 11%
   5-year NA 94% vs. 90% NA 10% vs. 6% NA
   7-year NA NA 5% vs. 8% NA NA
DFS
   3-year 73% vs. 73% 76% vs. 76% 76% vs. 69% 24% vs. 30% 64% vs. 62%
   5-year NA 72% vs. 71% 73% vs. 65% 28% vs. 34% NA
   7-year NA NA 68% vs. 62% NA NA
DMFS
   3-year 18% vs. 16% 84% vs. 82% 79% vs. 72% 20% vs. 27% 75
   5-year NA 82% vs. 79% 82% vs. 73% 23% vs. 30% NA
   7-year NA NA 79% vs. 72% NA NA
OS
   3-year 92% vs. 92% NA 91% vs. 88% 89% vs. 89% 86% vs. 75%
   5-year NA 88% vs. 88% 87% vs. 80% 82% vs. 80% NA
   7-year NA NA 82% vs. 76% NA NA
TRAEs G3–G4 17.4% vs. 11.8% 44% vs. 46% 47% vs. NA 48% vs. NA 27% vs. NA
Median follow-up 43 months 3 years 46.5 months 5.6 years 35 months

*, 3-year locoregional cumulative incidence. DFS, disease-free survival; DMFS, distant metastasis free survival; DrTF, disease-related treatment failure; LCRT, long-course chemoradiotherapy; NA, not available; NOM, non-operative management; OS, overall survival; pCR, pathologic complete response; SCRT, short-course radiotherapy; TRAE, treatment-related adverse event.

RAPIDO

The RAPIDO trial was a randomized, open-label trial assessing the role of SCRT followed by CNCT before TME. This trial aimed to decrease the risk of distant metastasis and maintain local disease control (41). Patients enrolled had ≥1 high-risk feature defined on pelvic MRI as clinical tumor stage cT4a or cT4b, extramural vascular invasion, clinical nodal stage cN2, involved MRF, or enlarged lateral lymph nodes. The experimental arm included 462 patients treated with 5 F × 5 Gy followed by CNCT with CAPOX ×6 cycles or FOLFOX4 ×9 cycles within 11–18 days after the last RT, and TME. The control arm included 450 patients. Patients received NCRT with capecitabine 825 mg/m2 BD orally along with RT (50.4 Gy/28 F or 50 Gy/25 F) followed by surgery 6–10 weeks after the last RT fraction and subsequent ACT with CAPOX for eight cycles or FOLFOX4 for 12 cycles within 6–8 weeks. The primary endpoint was the 3-year disease-related treatment failure (DRTF), defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumor, or treatment-related death. threat three years from the trial start, DRTF was 23.7% (95% CI: 19.8–27.6%) in the experimental group vs. 30.4% (95% CI: 26.1–34.6%) in the control group [hazard ratio (HR) 0.75, 95% CI: 0.60–0.95; P=0.02]. The most common grade ≥3 adverse events (AEs) during preoperative therapy was diarrhea both in the experimental group (18%) and in the standard of care group (9%). Serious AEs occurred in 38% of patients in the experimental group and, in the standard of care group, in 34% of patients without ACT and 34% receiving ACT (39). These results led to considering the experimental arm of the RAPIDO trial as a new standard of care. However, a later updated follow-up of 8 years showed overall LR rates were 11% (46/430) after TNT and 6% (24/419) after CRT (HR 1.91, 95% CI: 1.17–3.13, P=0.01), respectively. Prata et al. analyzed factors influencing locoregional recurrence rates and identified that LR occurred mostly in patients treated with sphincter-preserving surgery. Following sphincter-preserving surgery, 12% (TNT) and 5% (CRT) of patients developed a LR, compared to 8% vs. 7%, respectively, after abdominopelvic resection [Pinteraction=0.13] (42).

STELLAR

The STELLAR study had a similar design to the RAPIDO trial, with the addition of ACT after TME. The experimental arm received a SCRT of 5 F × 5 Gy followed by CNCT with four cycles of CAPOX after CRT, 7–14 days after completion of RT, surgery 6–8 weeks after preoperative treatment, and ACT with CAPOX ×2 cycles. The standard group received long NCRT with capecitabine (825 mg/m2 BD + RT 50 Gy/25 F over 5 weeks), surgery 6–10 weeks after the last RT administration, and ACT CAPOX ×6 cycles. At a median follow-up of 68.7 months, 5-year DFS was 62.0% and 58.7% in the TNT and CRT groups (HR, 0.849; 90% CI: 0.689 to 1.046; P<0.001 for non-inferiority) The previously reported OS benefit favoring TNT over CRT was sustained at 5 years, with OS rates of 78.1% vs. 69.7% (HR 0.739; 95% CI: 0.550–0.993; P=0.044). No significant difference was observed in the incidences of distant metastasis (HR 0.826; P=0.22) or locoregional recurrence (HR =0.814; P=0.42) at 5 years (43). However, TNT group demonstrated a significant OS benefit in patients aged ≤55 years (HR 0.644; P=0.047), with MRF-positive status (HR 0.676, P=0.04) or with EMVI-positive status (HR 0.659, P=0.03). No significant differences in quality of life (QoL) or anorectal function were observed between treatment groups.

PRODIGE-23

The PRODIGE-23 was an open-label multicenter, randomized trial assessing the use of FOLFIRINOX regimen as Induction-chemotherapy (IC-CT). Patients enrolled had stage cT3/cT4 M0 and were randomly assigned (1:1) to two arms. The experimental arm included 231 patients treated with IV FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, fluorouracil 2,400 mg/m2 biweekly for 6 cycles), followed by neoadjuvant CRT with capecitabine 800 mg/m2 BD orally 5 days/week plus concurrent RT 50 Gy for 5 weeks and TME with ACT with mFOLFOX6 biweekly/capecitabine 1,250 mg/m2 BD orally on days 1–14 every 3 weeks for 3 months. The control arm included 230 patients with the same sequence except for the omission of neoadjuvant FOLFIRINOX and longer adjuvant therapy (6 months). At a median follow-up of 46.5 months, 3-year DFS rates were 76% (95% CI: 69–81%) in the neoadjuvant chemotherapy group and 69% (95% CI: 62–74%) in the standard-of-care group (HR 0.69, 95% CI: 0.49–0.97; P=0.03). Neoadjuvant chemotherapy was associated with grade 3–4 AEs such as neutropenia (17%) and diarrhea (11%). During CRT, the most common grade 3–4 AEs was lymphopenia both in the neoadjuvant chemotherapy group (28%) vs. and in the standard-of-care group (30%). During ACT, the most common grade 3–4 AEs were lymphopenia (11% in the neoadjuvant chemotherapy group vs. 27% in the standard-of-care group), neutropenia (6% vs. 18%), and peripheral sensory neuropathy (12% vs. 21%). Serious AEs occurred in 27% of cases in the neoadjuvant chemotherapy group and 22% in the control group (P=0.17) (38). The PRODIGE-23 showed perioperative mFOLFIRINOX improved efficacy outcomes compared to 6 months of adjuvant therapy with FOLFOX.

No RT approach

The concern regarding overtreatment in some patients without high-risk features has driven the development of strategies that omit RT to spare debilitating toxicity that might compromise the quality of life in the long term, such as sexual dysfunction and urinary and fecal incontinence (38). This idea was supported by results from prospective studies evaluating the use of MRI to distinguish patients with low/high risk of local and/or distant relapse. The MERCURY and OCUM trials identified patients with good prognoses based on MRI features. The MERCURY trial found that patients with tumor >1 mm from the MRF and T2/T3a/T3b stage (<5-mm extension beyond muscularis propria) that were treated without preoperative or postoperative RT, had a 5-year DFS of 85% and LR rate of only 3% (38,44). In the prospective OCUM study, 257 patients with tumors ≤1 mm from MRF (low-risk group) underwent upfront TME without RT, whereas 271 patients with MRF involvement of >1 mm and/or cT4 and cT3 tumors in the lower third of the rectum (high-risk group) received preoperative CRT followed by TME surgery. The 5-year LR rate was 3.8% (95% CI: 1.4–6.2%) vs. 5.9% (95% CI: 3.0–8.8%) in the low-risk vs. high-risk groups, respectively (44). Based on this promising evidence, the PROSPECT study was the first positive phase III, multicenter, unblinded, non-inferiority trial evaluating neoadjuvant FOLFOX (with NCRT given only if the primary lesion downsized by <20% or if FOLFOX was discontinued due to toxicity) vs. CRT. 1,194 patients enrolled were enrolled. Patients evaluated had clinical stage T2N+, T3N0, or T3N+ and were candidates for sphincter-sparing surgery. The primary endpoint was DFS. At a median follow-up of 58 months, FOLFOX was non-inferior to CRT for DFS (HR 0.92; 90.2% CI: 0.74–1.14; P=0.005 for non-inferiority). Five-year DFS was 80.8% (95% CI: 77.9–83.7%) in the FOLFOX group and 78.6% (95% CI: 75.4–81.8%) in the CRT group. OS was similar between the two groups (HR 1.04; 95% CI: 0.74–1.44) as well as LR rate (HR 1.18; 95% CI: 0.44–3.16). In the FOLFOX group, 53 patients (9.1%) received CRT, and 8 (1.4%) received postoperative CRT. These results established that patients with T3N0–1 middle/upper LARC, a tumor depth of extramural invasion of >5 mm without a threatened MRF, may be offered neoadjuvant chemotherapy omitting RT.

Discussion and future perspectives

Non-operative management (NOM)

The growing proportion of patients reaching a cCR has pushed research to define patients eligible for NOM. Currently, the OPRA trial response criteria are widely spread used to define a cCR, near cCR, and incomplete clinical response (iCR) based on digital rectal examination, endoscopy, and MRI assessment (Table 4). The first strong evidence of the feasibility of an NOM strategy came from Habr-Gama et al., who described clinical outcomes from 265 patients with distal rectal cancer eligible for surgery receiving NCRT with 5-FU. Pretreatment mean tumor size was 3.7 cm (1–7 cm), and initial mean distance from anal verge was 3.6 cm (0–7 cm). According to pretreatment clinical and radiologic staging, 14 patients had a T2 lesion (19.7%), 49 patients had T3 lesions (69%), and 8 had T4 lesions (11.3%). Sixteen patients had radiologic evidence of N lesions (22.5%). Interestingly, 22 patients who achieved an iCR treated by surgery with no pathologic sign of disease were compared to 71 patients with cCR treated by NOM. Patients with a cCR were monitored using monthly clinical and endoscopic exams, and pelvic computed tomography (CT) scans every 6 months for the first year. The follow-up interval was increased to 2 and 6 months during the second and third year, respectively (45,46). Five-year OS and DFS rates were 88% and 83% in the resection group and 100% and 92% in the observation group, respectively. Other real-world experiences and retrospective studies confirmed these results. Interestingly, van der Valk et al. built and analyzed an International Watch and Wait Database (IWWD), including 1,009 patients in whom TME was omitted for patients with cCR. At baseline, the clinical T stage was cT1 in 14 patients (1.6%), cT2 in 226 (25.7%), cT3 in 451 (51.3%), cT4 in 30 (3.4%), and unknown in 159 patients (18.1%). The clinical N stage was cN0 in 309 patients (35.1%), cN1 in 271 (30.8%), cN2 in 167 (19.0%), and unknown in 133 patients (15.1%). At a median follow-up time of 3 years, the 2-year local regrowth rate was 25.2%, with almost the totality of cases (97%) detected in the first 2 years and 8% of patients developing distant metastases. The 5-year OS was 85% (95% CI: 80.9–87.7%) and 5-year disease-specific survival was 94% (95% CI: 91–96%) (47). Similarly, the “OnCoRe project” was a propensity-score matched cohort analysis made in the United Kingdom that offered management with the watch-and-wait strategy to 129 patients who achieved cCR and surgical resection to 228 who did not have a cCR. Among patients with a cCR, undergoing a watch-and-wait strategy, the pretreatment tumor stage was cT2 in 31 patients (24%), cT3 in 90 patients (70%), and cT4 in 8 patients (6%). Pretreatment nodal (N) status was N0 in 45 patients (35%) and N1–N2 in 84 patients (65%). At a median follow-up of 33 months, 44 patients (34%) had local regrowth, and 36/41 (88%) with no distant recurrence were salvaged. The 3-year DFS [88% (95% CI: 75–94%) with watch and wait (WW) vs. 78% (95% CI: 63–87%) with surgical resection; P=0.043] and 3-year OS [96% (95% CI: 88–98%) vs. 87% (95% CI: 77–93%); P=0.02] were similar between the two groups. However, there was an absolute difference of 26% (95% CI: 13–39%) in patients who avoided permanent colostomy in favor of the WW group (48). A retrospective case series from United States showed optimal outcomes in rectal preservation and pelvic tumor control in patients undergoing WW. One hundred thirteen patients with a cCR after completing different neoadjuvant therapy strategies (27% NCRT alone, 42% Induction chemotherapy-neoadjuvant chemoradiation therapy (IC-NCRT), 29% Neoadjuvant chemoradiation therapy-consolidation chemotherapy, 2% only chemotherapy) agreed to a WW strategy and were compared to 136 patients who underwent TME and had a pCR. Among patients undergoing WW strategy, the clinical T stage was cT2 in 23 patients (20%) and cT3 in 90 patients (80%). The nodal status was cN0 in 39 patients (35%) and cN1–N2 in 74 patients (66%). The WW group had 22 (19%) local regrowths, all treated by salvage surgery. No local recurrences occurred in the pCR group. At a median follow-up of 43 months, 5-year OS was 73% (95% CI: 60–89%) in the WW group and 94% (95% CI: 90–99%) in the pCR group; 5 year-DFS was 75% (95% CI: 62–90%) in the WW group and 92% (95% CI: 87–98%) in the pCR group. Distant metastases were more commonly found in the WW group with LR vs. those who did not have local regrowth (36% vs. 1%, P<0.001) (49). The phase III OPERA trial demonstrated that adding a contact X-ray brachytherapy (CXB, 50 kV) boost to standard NCRT significantly improves organ preservation in patients with early low- to mid-rectal adenocarcinoma (cT2–cT3b, <5 cm). Among 141 eligible patients, the 5-year organ preservation rate was 79% with CXB vs. 56% with external beam radiotherapy (EBRT) boost alone (P=0.004). The benefit was especially pronounced in tumors <3 cm (93% vs. 54%). Clinical complete/near-complete response rates were higher with CXB (92% vs. 64%), and local regrowth was lower (17% vs. 39%), although the difference was not statistically significant at 5 years (P=0.10). CXB did not worsen bowel function, and mild rectal bleeding resolved in most cases after 3 years (50). A recent single-arm phase II trial (NO-CUT) evaluating the use of INCT with CAPOX followed by CRT and WW in case of cCR and operative management in those with incomplete response, confirmed data of the INCT arm of the OPRA trial (51). Despite this evidence, further confirmatory studies are needed to identify the most effective and safest strategy for organ preservation. Interestingly, the WW approach is shifting towards earlier stages (cT1–3N0), sparing upfront surgery for these patients (51). Several trials have assessed TNT strategies such as CRT, chemotherapy alone, or RT intensification with EBRT with an organ preservation rate of approximately 50 % in this population at preliminary data (52-55).

Table 4

OPRA trial response assessment criteria

Exams Clinical complete response Near complete clinical response Incomplete clinical response
DRE Normal Smooth induration Palpable tumor
Endoscopy Flat, white scar Superficial ulceration Visible tumor
Telangiectasias Small nodules
No ulceration Irregular mucosa
No nodularity Mild erythema of the scar
MRI Only dark T2 signal Mostly dark T2 signal with 1–2 foci of intermediate T2 signal with 1–2 foci of intermediate T2 signal More intermediate than dark T2 signal
Invisible or very few lymph nodes <5 mm in short axis diameter Partially regressed lymph nodes (≥5 mm in short axis diameter) Persistently enlarged lymph nodes
Absent restricted diffusion Significantly regression of restricted diffusion Persistent restricted diffusion

DRE, digital rectal examination; MRI, magnetic resonance imaging.

Personalization of RT dose

An area of ongoing interest is the feasibility of personalizing RT dosing to reduce treatment-related toxicity and minimize the risk of over/undertreatment. The current paradigm assumes that all patients derive equal benefit from a uniform RT dose. The standard preoperative neoadjuvant RT dose for patients with stage II/III rectal cancer is 45 Gy to the pelvic area worldwide. However, a phase II study explored the feasibility of dose escalation in combination with capecitabine. Specifically, increasing the dose to the primary tumor from 50 to 55 Gy in 25 F, while maintaining 45 Gy to the pelvic area, led to a pCR rate of 37.5% (56). Additionally, a systematic review and meta-analysis by Burbach et al. suggested that escalating the radiation dose to ≥60 Gy in this setting further improved pCR rates (57). These findings were corroborated by a systematic review and meta-analysis by Hearn et al., which evaluated the efficacy of a total RT dose >54 Gy. Pooled estimates for pCR, toxicity, and R0 resection across 37 eligible publications (n=1,817 patients) were 24.1% (95% CI: 21.2–27.4%), 11.2% (95% CI: 7.2–17.0%), and 90.7% (95% CI: 87.9–93.8%), respectively. Nonetheless, a definitive dose-response relationship was not identified in the regression analysis, and additional evidence is warranted due to the predominance of heterogeneous, single-arm studies to date (58). These findings underscore the importance of tailoring the radiation dose to each individual patient to optimize therapeutic outcomes. One innovative approach to personalization is the genome-based model for radiation dose adjustment (GARD), which was developed to predict response to neoadjuvant RT based on gene expression profiles from fresh-frozen tumor samples in a cohort of 64 patients. This population included 1.5% with T2, 46.3% with T3, and 52.2% with T4 stage disease. A pCR was observed in 15.6% (n=10) of patients, while the remaining 84.4% (n=54) did not respond. The personalized radiotherapy dose (pGRT dose) was calculated using the formula nd = GARD/(α + βd). Notably, only 17% of patients received a pGRT dose within the guideline-recommended range of 45–50 Gy, indicating considerable variability in optimal dosing requirements—even among patients with similar clinical profiles (59). This highlights the potential utility of genome-informed approaches to guide individualized RT dosing and treatment planning. However, prospective studies and implementation in clinical trials are needed to validate their use in clinical practice.

MSI subtype

Approximately 10–15% of patients with CRC have dMMR, which consists in the loss of function of at least one of four proteins (MLH1, MSH2, MSH6, PMS2) involved in DNA damage repair. Of note, the germline loss of the same proteins leads to the development of Lynch syndrome characterized by an increased risk of developing CRC as well as other types of neoplasia (i.e., endometrial cancer, gastric cancer) (60). These patients, overall identified as MSI-high, have an increased rate of mutations which favors the development of abnormal proteins (neo-antigens) that, ultimately, trigger the immune system activation against cancer cells (61,62). This mechanism led to the development of clinical trials assessing the use of immunotherapy, particularly anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1). Cercek et al. enrolled 47 dMMR patients with LARC in a phase II study evaluating the use of anti-PD-1 drug, dostarlimab, for 6 months. Co-primary endpoints are response rate and sustained cCR rate. A sustained complete response was defined as a complete pathologic response at surgery or no evidence of tumor by MRI, endoscopy, and digital rectal exam for at least 12 months following completion of therapy. All patients enrolled achieved a complete clinical response (12). Other studies are assessing the efficacy and safety of the combination of immunotherapy and chemotherapy in the same population. A phase II trial tested the use of sintilimab monotherapy in MSI-H/dMMR LARC. After four cycles of immunotherapy, 17 patients were randomized to TME followed by four cycles of adjuvant sintilimab +/− CAPOX chemotherapy vs. 4 cycles of sintilimab followed by TME or WW for patients with a cCR. A complete response was reported for 12/16 patients (75%; 95% CI: 47–92%). All patients were alive at a median follow-up of 17.2 months; none had disease recurrence. Only one (6%) patient had one grade 3–4 AEs (grade 3 encephalitis) (63). A promising line of research is exploring the combination of immunotherapy with RT due to preclinical data suggesting that RT might increase tumor immunogenicity (64-67). Based on this hypothesis, a phase Ib study is assessing hypofractionated RT (5 Gy × 5 F) and three cycles of sintilimab (200 mg IV every 2 weeks) followed by radical surgery 6–8 weeks after RT. Similarly, the single-arm phase II trial EA2201 (NCT04751370) will evaluate the sequence of nivolumab and ipilimumab (nivo-ipi) for two cycles followed by SCRT (5 Gy × 5 F) and two additional cycles of nivo-ipi prior TME (68).

Role of circulating tumor DNA (ctDNA) in treatment allocation

Despite promising results from clinical trials assessing TNT regimens, there is still a lack of personalization to tailor treatment strategies to patients who may derive greater benefit from a specific strategy. The most common clinical parameter currently used as a surrogate to predict a better prognosis and decreased risk of relapse is cCR at 6–8 weeks from the end of CRT (69). cCR is achieved in 10–30% of patients (70,71) and guides us to consider NOM or surgery based on the current guidelines (9). In this context, liquid biopsy is a practice-changing tool for personalizing care. Liquid biopsy refers to the isolation of cancer-derived components, such but not limited to circulating tumor cells, ctDNA, microRNAs, and proteins from peripheral blood or other body fluids (i.e., ascites, urine, pleural effusion, and cerebrospinal fluid) (72-74). The main research focus in the last decade has been on ctDNA, which may be used as a prognostic and predictive biomarker at diagnosis, a tool to escalate/de-escalate neoadjuvant strategies, treatment selection after surgery, and minimal residual disease (MRD) assessment (4). In a retrospective study, six patients received SCRT (5 × 5 Gy) followed by surgery, six patients were treated according to RAPIDO protocol with SCRT followed by chemotherapy (FOLFOX4) and subsequent surgery, and five patients received conventional neoadjuvant CRT with 5-FU followed by surgery. Liquid biopsies were collected before and immediately after the conclusion of neoadjuvant RT. A decrease in ctDNA level was found in 8/12 patients and an increased/mixed response in 4/12 patients. However, no statistical correlation was found between clinical response and ctDNA analysis. Another study evaluating the use of ctDNA as a biomarker of response to TNT was the phase II trial GEMCAD 1402. This trial randomized 180 patients with LARC to mFOLFOX6 +/− aflibercept, followed by CRT and surgery. ctDNA from blood samples was taken at baseline and after TNT within 48 hours before surgery; 144 paired plasma samples from 72 patients were included. Pre-surgery ctDNA was significantly associated with systemic recurrence, shorter DFS (HR 4.0; P=0.03), and shorter OS (HR 23.0; P<0.0001) (75). This study positively showed the possibility of using ctDNA to identify patients at high risk of distant recurrence and less favorable prognosis. Intriguing results also came from a meta-analysis evaluating the meaning of ctDNA detection at different time points (baseline, post-NCRT, post-surgery). The authors found no correlation between baseline ctDNA with survival outcomes [recurrence free survival (RFS), OS] and pCR. However, ctDNA detection post-NCRT was associated with detrimental RFS (HR 9.16, 95% CI: 5.48–15.32), OS (HR 8.49, 95% CI: 2.20–32.72), and probability to achieve pCR [odds ratio (OR) 0.40, 95% CI: 0.18–0.89] (76). Similarly, patients with ctDNA detection post-surgery had worse RFS (HR 14.94; 95% CI: 7.48–29.83). In addition, ctDNA might serve as a predictor for developing metastases during the neoadjuvant treatment and post-surgery. Khakoo et al. analyzed 243 ctDNA plasma samples from 47 patients with LACR undergoing CRT. With a median follow-up of 26.4 months, metastasis-free survival was shorter in patients with detectable ctDNA after completing CRT (HR 7.1; 95% CI: 2.4–21.5; P<0.001) (77).

Practical barriers

Despite the promising results of new therapeutic strategies, such as immune checkpoint inhibitors for MSI-high patients and the use of ctDNA to guide multimodality therapy, significant practical barriers remain. In the U.S., treatment costs, including surgery, RT, and long-term follow-up with MRI, may exceed $180,000 on average, limiting access for underinsured populations (78). However, a cost-effectiveness analysis found that TNT is still associated with a more convenient cost of $40,708 per life-year gained, compared to $44,248 per life-year for conventional therapy (79). Another limitation is the fragmentation of care. Patients often receive different treatment modalities such as chemotherapy, radiation, and surgery at separate centers. An analysis of 63,299 patients from the U.S. National Cancer Database found that 66% of those with LARC received fragmented care. This was significantly associated with poorer survival especially among patients living ≥100 miles from the treatment hospital (HR 1.377, P=0.01). In contrast, unified care at academic centers was linked to improved OS compared to both fragmented care at academic centers and care at non-academic centers (P<0.001) (80). Immunotherapy economic burden on the healthcare system is also a factor to evaluate. In the metastatic setting, pembrolizumab is well-known to be highly cost-effective for the first-line treatment of unresectable or metastatic MSI-H/dMMR CRC in the US at a willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY). In addition, immunotherapy decreases costs associated with administering treatment, managing AEs, providing subsequent treatment and end-of-life care (81,82). It is reasonable to expect at least a similar benefit seen for the advanced setting but this needs to be confirmed with further studies in LARC.

Strengths and limitations of this review

This review provides a critical overview of the evidence that has reshaped the treatment algorithm for LARC over the past decade, with a particular focus on key phase III clinical trials. The literature search was independently verified by three authors to ensure objectivity and accuracy. In addition to summarizing pivotal studies, we highlight emerging strategies aimed at advancing the standard of care toward a more personalized and less invasive approach. Some of these innovations, such as the use of immunotherapy in patients with MSI-high tumors, have already begun to influence clinical practice. Others, including ctDNA and genomic-based approaches for tailoring RT, represent promising future directions. While this review does not adopt a systematic review or meta-analysis methodology, it is intended to serve as a solid foundation for further investigation into this increasingly complex field. The evolving management of LARC requires an integrated understanding of recent advancements across oncology, radiation therapy, surgery, and tumor biology. Expanding future literature searches to include databases beyond PubMed may also enhance the comprehensiveness of subsequent reviews.

Conclusions

TNT has been established as the new standard of care for LARC based on results from large phase 3 trials. Moreover, it provides a rationale for the potential omission of locoregional treatments (surgery, RT) and all their associated AEs (sexual dysfunction, incontinence, dysuria). Regarding microsatellite stability (MSS) patients, the absence of direct comparisons between the different strategies and the heterogeneity in study populations makes it challenging to identify the most effective approach. The OPRA trial, notably, showed that organ preservation is achievable in 50% of patients with LARC following TNT, without compromising efficacy outcomes considering historical controls. This trial, along with CAO/ARO/AIO-12, established the proof of principle of the feasibility and safety of a TNT approach with favorable clinical outcomes. Of note, the CAO/ARO/AIO-12 results highlighted that CNCT was associated with higher chances of pCR compared to INCT putting the base for its use as a standard of care in this setting. However, the main limitation of both trials was the lack of control arm, including patients receiving only NCRT followed by TME and ACT, which was the current standard of care at that time. Additionally, both trials used a long course chemoradiation strategy, raising uncertainty about the feasibility of SCRT strategies that could potentially increase patient compliance, and reduce the interval to surgery. For MSI patients, immunotherapy is considered the primary option: the findings of Cercek et al. highlight the possibility for these patients to avoid chemotherapy-related toxicity and radiation therapy with improved compliance and preserved quality of life. Through a cautious cross-trial comparison, a practical algorithm may be defined based on the risk of LACR (low, intermediate, high), which considers the presence and combination of five high-risk features at baseline pelvic MRI: T4, N2, TD, EMVI+, MRF+, enlarged lateral pelvic lymph nodes (Figure 2). Our recommendations are based on clinical-pathologic features in the absence of validated biomarkers for improved treatment personalization. ctDNA is a promising biomarker in this setting, however, itis not currently adopted in clinical practice due to the lack of large prospective studies and phase III clinical trials.

Figure 2 Treatment flowchart of locally advanced rectal cancer highlighting current TNT strategies. +, positive. cCR, clinical complete response; CT, chemotherapy; CRT, chemoradiation therapy; dMMR, deficient mismatch repair; EMVI, extramural vascular invasion; LARC, locally advanced rectal cancer; MRF, mesorectal fascia; MMR, mismatch repair; MSI, microsatellite instability; MSS, microsatellite stability; N, node; ncCR, near complete clinical response; NOM, non-operative management; pMMR, proficient mismatch repair; RT, radiotherapy; SRT, short-radiotherapy; T, tumor; TD, tumor deposits; TNT, total neoadjuvant therapy; WW, watch and wait.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://actr.amegroups.com/article/view/10.21037/actr-25-58/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-58/coif). N.O. reports receiving honoraria from Taiho Pharmaceutical, Eisai, Bayer Yakuhin, Chugai Pharma, Ono Pharmaceutical, Daiichi Sankyo, AstraZeneca, Nihon Servier, Incyte, and MSD. M.B.S. reports receiving honoraria from Novartis. M.J.B. reports receiving grant support from Relay Pharmaceuticals, Taiho, Basilea, Novartis, Incyte, and Kinnate. T.S.B.S. reports receiving research funding from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and BMS; royalties or licenses from UpToDate; consulting fees from Servier, Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA, Merck, Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, AstraZeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine, Sanofi, Glaxo SmithKline, and Xilio; participation on a Data Safety Monitoring Board or Advisory Board of the Valley Hospital, Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCan, and 1Globe; holding a leadership or fiduciary role in Imugene, Immuneering, Xilis, Replimune, Artiva, and Sun Biopharma; and patents licensed to Imugene and Recursion Pharmaceuticals. The other authors have no conflicts of interest to declare.

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doi: 10.21037/actr-25-58
Cite this article as: Pirozzi A, Hoyek C, Okano N, Sandoval LAM, Zheng-Lin B, Abidoye O, Eslinger C, Sonbol MB, Borad MJ, Bekaii-Saab TS. Clinical advancements in total neoadjuvant therapy for locally advanced rectal cancer: a narrative review. AME Clin Trials Rev 2026;4:3.

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