Optimizing total neoadjuvant therapy in locally advanced rectal cancer: risk stratification should not be overlooked

ABSTRACT

Chemoradiotherapy plus total mesorectal excision has been established as the standard treatment for locally advanced rectal cancer (LARC) and can achieve satisfactory local control. However, systemic control of LARC, especially in patients with risk factors for poor prognosis, is still of concern. As application of total neoadjuvant therapy (TNT) has been proposed as a potential solution, a clearer risk stratification of LARC to guide individual treatment is needed. Combination therapy such as targeted therapy or immunotherapy can be used to increase treatment intensity for high-risk LARC. In this review, we evaluate recent trials of several treatment modalities, specifically focusing on intensified TNT regimens for high-risk LARC with the goal of summarizing optimal clinical strategies and future study designs.

Graphical abstract

An overview of treatment strategies for high-risk LARC. (LARC - locally advanced rectal cancer; CRT - chemoradiotherapy; TME – total mesorectal excision; EMVI - extramural venous invasion; MRF - mesorectal fascia; SCRT – short-course radiotherapy; TNT – total neoadjuvant therapy; pCR – pathological complete response).

1. Introduction

Colorectal cancer (CRC) is the third most diagnosed cancer and is ranked second in cancer‐related deaths around the world with a steadily increasing incidence [1]. All too often, however, rectal cancer is first diagnosed in advanced stages, resulting in a heavy economic and health burden to both patients and society.

Locally advanced rectal cancer (LARC) is usually defined as stage III-IV clinical tumor (cT) and/or regional lymph node (cN) positive disease, without distant metastases, based on rectal magnetic resonance imaging (MRI). In the past two decades, neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been established as the standard treatment and has been reported to achieve satisfactory locoregional control with local recurrence rates approximately between 5% and 9% [2–4]. However, distant recurrence rates remain high, at about 30%, and constitute the leading cause of treatment failure and patient death.

With the constantly evolving development of imaging technology, risk factors associated with poor prognosis, such as extramural venous invasion (EMVI), mesorectal fascia (MRF) involvement, mucin content, and lateral lymph node involvement can be comprehensively evaluated to guide staging, treatment, and prognosis [5]. LARC can be further stratified into various subgroups according to the risk of local recurrence and distant metastasis, leading to the concept of risk-adapted, personalized treatment. Numerous clinical studies have attempted to control distant metastasis and improve long-term survival for high-risk LARC patients by combining induction chemotherapy (INCT), consolidation chemotherapy (CNCT), targeted therapy, and even immunotherapy [6–8]. While these studies have yielded remarkable results that might be helpful for clinical use, unanswered questions that deserve further exploration remain.

This review mainly focuses on clinical trials investigating the treatment of high-risk LARC. We discuss the stratification of LARC to propose a clearer definition of high-risk LARC and evaluate the clinical value and underlying limitations of each of the published trials to optimize future study designs and clinical strategies.

2. Risk stratification of locally advanced rectal cancer

In 2008, Smith and Brown classified rectal cancer into three groups, known as the “good-bad-ugly” rectal cancers, depending on the existence of prognostic factors for both local recurrence and distant metastasis [9]. This classification was applied in the EXPERT and the EXPERT-C trials [10,11], which focused on the “bad” and the “ugly” groups, which are akin to LARC. Blomqvist et al [12]. slightly modified the classification to emphasize the local failure risk, therefore omitting EMVI, considered as an important sign of systemic disease. Thanks to the accuracy of EMVI detected by high-resolution MRI [13], Taylor et al [14]. reported that MRI-predicted low-risk cT stage (cT1–2 and cT3a/b) tumors can be safely managed by surgery, paving to road toward subdivision of the cT stage in risk classification by later guidelines: ESMO divided cT3a/b into the “intermediate” subgroup in its 2017 version, leaving cT3c/d in the “bad” subgroup with intensified therapeutic options [15]. However, all the aforementioned classifications have never been validated in large cohorts. Bogveradze et al [16]. conducted a multi-center retrospective analysis of 712 patients in the Netherlands to explore the evolution in rectal cancer MRI staging and risk stratification. By applying the novel criteria (high risk being cT3c/d-4, cN+, MRF+, EMVI+ vs. low risk for the others), the risk classification changed from high to low risk in 18.0% of cases and from low to high risk in 1.7% (total 19.7%). All in all, risk stratification for LARC leads to more detailed and precise divisions between low-risk and high-risk subgroups so that divergent strategies can be applied to guide individual treatment. Thus, regimens for low-risk LARC tend to become less intensified to reduce possible adverse effects and achieve organ preservation. For example, the goal of the PROSPECT trial was to prove the non-inferiority of neoadjuvant chemotherapy compared to conventional CRT for low-risk patients (cT2N+ or cT3Nany) [17]. Conversely, other researchers recommended intensified treatment modalities because of the unsatisfactory distant recurrence control in high-risk LARC (Table 1). The RAPIDO and the TNTCRT trials both chose LARC patients with at least one high-risk factor as suitable candidates for TNT [18,19]. This trend was validated by the 2017 amendment of ESMO guidelines [15]. However, most clinical trials had overly wide-ranging inclusion criteria from low-risk to high-risk patients, probably because of the lack of consensus in the definition and LARC risk stratification. Herein, we propose a comprehensive assessment standard for high-risk LARC: patients with at least one of the following risk factors evaluated on rectal MRI can be considered as high-risk LARC: cT3c/d or cT4, cN2, EMVI+, MRF+, lateral lymph node involvement. Nevertheless, a prospective cohort is needed to confirm its validity.

Table 1.

Recommended therapeutic options for high-risk LARC with clear risk factor stratification in previous studies and guidelines.

	Year	Risk stratification	Description	Recommended therapeutic options
Smith et al. [9]	2008	Bad	cT3c/d, cN2, EMVI+, MRF-	4 cycles of CAPOX+CRT+TME
		Ugly	Potential MRF+ disease
Blomqvist et al. [12]	2008	Bad	Mid/upper rectum cT3c/d, low rectum also includes cT3b, cT4 with peritoneal or vaginal involvement only, cN+, MRF-	Neoadjuvant CRT/SCRT with immediate surgery
		Ugly	T4 with overgrowth to prostate, seminal vesicles, base of urinary bladder, pelvic side walls or floor, sacrum positive lateral lymph nodes, MRF+	Neoadjuvant CRT/SCRT with delayed surgery
ESMO guidelines [15]	2017	Bad	cT3c/d or very low localization levators threatened, MRF-; cT3c/d mid-rectum, cN+, EMVI+, limited cT4aN0	CRT/SCRT+TME, depending on need for regression
		Ugly	cT3 with any MRF+, any cT4a/b, lateral lymph node positive	CRT+surgery (TME and more extended surgery if needed due to tumor overgrowth), or SCRT+FOLFOX with delayed surgery
RAPIDO trial [18]	2021	High-risk	cT4a/b, cN2, EMVI+, MRF+, lateral lymph node positive	SCRT +6 cycles of CAPOX/9 cycles of FOLFOX+TME
The Netherlands cohort [16]	2022	High-risk	cT3c/d-4, cN+, MRF+, EMVI+	/
TNTCRT trial [19]	2024	High-risk	cT4a/b, cT3c/d with EMVI+, cN2, MRF+, lateral lymph node positive	1 cycle of induction CAPOX+concurrent CRT with CAPOX + 3 cycles of consolidation CAPOX
ASCO guideline [20]	2024	High-risk	cT4, EMVI+, and/or tumor deposits, MRF+, or threatened intersphincteric plane	TNT

Abbreviations: EMVI = extramural venous invasion; MRF = mesorectal fascia; CRT = chemoradiotherapy; SCRT = short-course radiotherapy; TME = total mesorectal excision; FOLFOX consists of oxaliplatin, leucovorin, 5-fluorouracil; CAPOX consists of capecitabine, oxaliplatin.

3. Total neoadjuvant therapy

Adjuvant chemotherapy after CRT plus TME remains controversial because of lack of proof of improved overall survival [21–23]. Therefore, TNT was created to transfer adjuvant chemotherapy to preoperative chemotherapy to increase therapeutic efficacy. The rationale for TNT is multifaceted, including (1) tumor down-staging to enhance radical surgery and control locoregional relapse, (2) early eradication of occult distant micrometastases to decrease systemic recurrence, (3) better physical state and tolerance to toxicity, (4) prolongation of the interval between radiotherapy and TME to achieve greater tumor regression so that organ preservation could become possible through sphincter-sparing surgery or “Watch&Wait” (W&W) strategy [23], (5) a significantly increased OS rate, with a 5-year 7% survival benefit in favor of TNT [20]. As a result, TNT has been incorporated into several guidelines as a preferred regimen and is gaining prominence in LARC treatment [15,20,24].

3.1. TNT with conventional chemotherapy

Several phase II trials have tested the safety and efficacy of TNT regimens [25–27]. In the Spanish GCR-3 trial, TNT including INCT was compared with CRT followed by TME and adjuvant chemotherapy. Complete resection and pCR rates were similar, but patients had better compliance (94% vs. 49%; p = 0.0001) and lower grades III-IV adverse events (19% vs. 54%; p = 0.0004) with TNT compared to adjuvant chemotherapy [28]. Long-term follow-up yielded similar outcomes in survival and recurrence [27]. This provided the rationale for further phase III trials to show that TNT can provide satisfactory survival outcomes with better patient compliance and less toxicity than conventional methods.

The UNICANCER-PRODIGE 23 trial is one of the most pivotal phase III randomized controlled trials (RCTs) that explored the efficacy of TNT. This trial randomized 461 patients with cT3–4 rectal cancer [29]. The TNT group had a higher pCR rate (28% vs. 12%; P＜0.0001). A statistically significantly improved 3-year DFS was observed in the TNT group (76% vs. 69%, p = 0.034), probably because of the lower 3-year metastasis-free survival (MFS) (79% vs. 72%, p = 0.017). In the recent update of 7-year results, all survival endpoints had an absolute increase in the TNT group compared to the CRT group [30]. The results of the PRODIGE 23 trial provide evidence of better control of distant metastasis for LARC patients who receive an intensified TNT approach. The inclusion criteria of the PRODIGE-23 trial were quite wide-ranged (cT3/4): 50% of patients recruited in the TNT group were cT3c-4 and 26% were cN2; 10% of patients had enlarged lateral lymph nodes and 21% were MRF+. Nevertheless, we cannot calculate the accurate proportion of high-risk LARC patients in this trial; a post-hoc analysis of this subgroup might provide more convincing results.

The phase III TNTCRT randomized trial specifically compared TNT and conventional CRT in a high-risk LARC population [19]. A total of 458 LARC patients with at least one high-risk factor (cT4a-b, cT3c-d with EMVI+, cN2, MRF+, or enlarged lateral lymph nodes) were recruited. The TNT group received CAPOX during the TNT (1 cycle of INCT, 2 cycles of concurrent chemotherapy, and 3 cycles of CNCT). The TNT group achieved a statistically significantly higher a) pCR rate (27.5% vs. 9.9%, p = 0.0001), b) number of patients with cCR (13 vs. 2), c) 3-year DFS rate (77.0% vs. 67.9%, [HR] 0.623; 95% CI 0.435–0.892, p = 0.009), and d) 3-year MFS rate (83.0% vs. 74.2%; [HR] 0.595, 95% CI 0.392–0.903, p = 0.013); conversely the difference in 3-year OS (90.3% vs. 87.9%; [HR] 0.747, 95% CI 0.441–1.266), was not statistically significant (p = 0.276). Nonetheless, the TNTCRT trial provided persuasive evidence that intensified TNT clearly improved the CR rate and survival outcomes in high-risk LARC.

TNT, including SCRT, is another option for high-risk LARC patients. The Polish II study enrolled 541 patients with primary or locally recurrent cT4 or fixed cT3 and assigned them to receive either SCRT with CNCT (3 cycles of FOLFOX4) or CRT. Tumor resection was mandatory in both groups. The primary endpoint, R0 resection, and pCR rates were similar in both groups, but preoperative treatment-related acute toxicity was statistically significantly lower in the TNT group (p = 0.006). Likewise, 3-year OS was statistically significantly higher in the TNT group (73% vs. 65%, p = 0.046), although no statistically significant differences were observed in 3-year DFS or cumulative incidence of recurrences [31]. Long-term results indicated that the statistically significant difference in OS disappeared at 8 years ([HR] 0.90; 95% CI 0.70–1.15; p = 0.38), while other survival and oncological outcomes remained similar [32]. Therefore, the authors concluded that the superiority of preoperative SCRT over CRT was not demonstrated. Of note, the study methodology expected to detect at least a 10% improvement of the R0 resection rate, which it did not meet (p = 0.07). Considering the ease of applicability and lower toxicity of SCRT, a non-inferiority design might have been more appropriate.

The RAPIDO trial also investigated SCRT versus CRT in TNT, including 920 high-risk LARC (cT4a/b, EMVI (+), cN2, MRF (+), and enlarged lateral lymph nodes) patients [7,33]. The TNT group had a statistically significantly higher pCR rate (28% vs. 14%, P＜0.0001). The primary endpoint was disease-related treatment failure (DrTF), defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumor, or treatment-related death. The 3-year DrTF was statistically significantly higher in the CRT group (30.4% vs. 23.7%, [HR] 0.75, 95% CI 0.60–0.95; p = 0.019). At a median follow-up of 5.6 years, the difference in DrTF decreased to 6% (27.8% vs. 34.0%, p = 0.048), which was just over the statistical significance level (0.0424) according to the protocol. This is probably attributed to the statistically significant worse locoregional control (10% vs. 6%, p = 0.027) in the TNT group [6]. In addition, the TNT group had a statistically significant lower cumulative probability of distant metastases (23.0% vs. 30.4%, p = 0.011). No statistically significant differences were observed in OS (81.7% vs. 80.2%, p = 0.50) [18]. Although the results of the RAPIDO trial demonstrated that the SCRT-based TNT method might favor systemic control, the risk of local recurrence deserves attention and further investigation. The main limitation of the RAPIDO trial is that adjuvant chemotherapy in the CRT group was not mandatory. If adjuvant chemotherapy were beneficial, this could have biased the statistical estimates in favor of the experimental group.

The STELLAR phase III trial in China was also designed as an SCRT-based TNT regimen to explore its noninferiority to standard CRT. Patients with distal or middle-third, cT3–4, and/or N+ rectal cancer were randomly assigned to TNT with CNCT or CRT. The total rate of pCR and sustained cCR in the TNT group was statistically significantly higher than in the CRT group (21.8% vs. 12.3%, p = 0.002). However, the TNT group had statistically significantly higher acute grade III-V toxicities during preoperative treatment (26.5% vs. 12.6%, P＜0.001). TNT was non-inferior with respect to 3-year DFS (64.5% vs. 62.3%; P＜0.001 for noninferiority). There was no statistically significant difference in locoregional or distant recurrence between the two groups, but for an unknown reason the TNT group had better 3-year OS (86.5% vs. 75.1%; p = 0.033). However, the noninferiority design limited the interpretation of these results.

In general, most clinical trials comparing TNT with conventional CRT yielded a statistically significantly increased pCR rate in favor of TNT. This indicates that TNT can provide a better tumor response before surgery, which benefits patients who have a heavy tumor burden or have a strong desire for organ preservation. Specifically, CRT followed by CNCT will allow a longer interval from the last fraction of radiotherapy to surgery, leaving sufficient time for tumor regression. Although these studies share homogeneity in phase III RCT design, sample size, and primary endpoint, their outcomes are difficult to compare directly due to the divergent inclusion criteria and different regimens. The RAPIDO and TNTCRT trials focused on high-risk LARC patients, and pCR rates in the TNT group were similar (28% vs 27.5%) [18,19]. It is noteworthy that the RAPIDO trial had an increased local recurrence rate compared to other studies, probably due to the appliance of 3D-CRT instead of intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) in high-risk LARC [6]. The STELLAR trial, however, achieved a favorable locoregional control by applying IMRT to all patients [34]. RAPIDO and PRODIGE-23 trials differed in study designs and enrolled populations, representing two opposite strategies. The PRODIGE-23 tended to include a wide range of LARC patients to receive TNT, while the RAPIDO trial restricted an intensified TNT regimen in high-risk patients. Although the priority of TNT was demonstrated in both studies, the differences in study design led to inherent limitations of inter-trial comparison. Therefore, more clinical trials are warranted to determine the optimal TNT regimen for routine practice (Table 2). The conclusion of the ASCO meta-analysis might act as a surrogate reference [20]: TNT improves OS compared with conventional CRT ([HR] 0.78; 95% CI 0.62–0.97), but the improvement in DFS by TNT was not statistically significant ([HR] 0.86; 95% CI 0.71–1.04). Although more cohorts and longer follow-ups are warranted, the potential improvement in survival together with the satisfactory pCR rate indicates that TNT is optimal for high-risk LARC patients.

Table 2.

Clinical trials of TNT for LARC.

Study	Year	Phase	Sample size	Eligible criteria	Study design	Primary endpoint	pCR (%)	3y-DFS (%)	3y-OS (%)	Other results (%)
PRODIGE-23 [29]	2021	Phase 3	461	cT3–4	FOLFIRINOX × 6→CRT→Surgery→mFOLFOX6 × 6/CAPE × 4 CRT→Surgery→mFOLFOX6 × 12/CAPE × 8	3-year DFS	28 12	76 69	91 88	/
TNTCRT [19]	2024	Phase 3	458	cT4a/b, cT3c/d with EMVI+, cN2, MRF+, or enlarged lateral lymph nodes	CAPOX × 1→CRT(CAPOX × 2)→CAPOX × 3→Surgery CRT→ Surgery→Adjuvant CAPOX	DFS	27.5 9.9	77.0 67.9	90.3 87.9	3-year MFS: 83.0% vs. 74.2% cCR: 13 vs. 2
Polish II [31]	2016	Phase 3	541	cT3–4	SCRT→FOLFOX4 × 3→Surgery CRT→Surgery	R0 resection	16 12	53 52	73 65	/
RAPIDO [18]	2021	Phase 3	920	cT4a/b, cN2, EMVI+, MRF+, enlarged lateral lymph nodes	SCRT→CAPOX × 6/FOLFOX4 × 9→Surgery CRT→Surgery→± CAPOX × 8/FOLFOX4 × 12	3-year DrTF	28 14	76* 70*	89 89	3-year DrTF: 23.7% vs. 30·4%
STELLAR [34]	2022	Phase 3	599	cT3–4, cN+, low/mid rectum	SCRT→CAPOX × 4→Surgery→CAPOX × 2 CRT→Surgery→CAPOX × 6	3-year DFS	17 12	65 62	87 75	/
CAO/AIO/ARO-12 [35]	2019	Phase 2	311	cT3 in low rectum, cT3b and above in mid rectum, cT4, or cN+	FOLFOX × 3→CRT→Surgery CRT→FOLFOX × 3→Surgery	pCR	17 25	73 73	92 92	/
OPRA [36]	2022	Phase 2	324	clinical stages II/III	FOLFOX × 8/CAPOX × 5→CRT→Surgery CRT→FOLFOX × 8/CAPOX × 5→Surgery	3-year DFS	/	76 76	Similar	3-year TME-free survival: 41% vs. 53%

Abbreviations: LARC = locally advanced rectal cancer; TNT = total neoadjuvant therapy; EMVI = extramural venous invasion; MRF = mesorectal fascia; CRT = chemoradiotherapy; SCRT = short-course radiotherapy; FOLFIRINOX consists of oxaliplatin, irinotecan, calcium folinate, 5-fluorouracil; FOLFOX consists of oxaliplatin, leucovorin, 5-fluorouracil; CAPOX/XELOX consists of capecitabine, oxaliplatin; *estimated from DrTF; DrTF = disease-related treatment failure; MFS = metastasis-free survival; DFS = disease-free survival; pCR = pathological complete response; OS = overall survival.

3.2. TNT with targeted therapy or immunotherapy

Targeted agents such as bevacizumab or cetuximab are widely used in the treatment of metastatic rectal cancer and have been found to profoundly improve patient OS [37,38]. However, little benefit was borne out in the perioperative treatment of stage II/III colorectal cancer [39]. Therefore, researchers explored the possibility of incorporating targeted therapy into neoadjuvant treatment for high-risk LARC patients. Several phase II studies designed targeted agents-based TNT and compared their efficacy with standard CRT [40–43] (Table 3).

Table 3.

Clinical trials combining targeted agents or ICBs into TNT.

	Study	Time	Phase	Sample size	Eligible criteria	Study design	pCR (%)	3y-DFS (%)	3y-OS (%)	Other results (%)
Targeted Therapy	Yu et al. [42]	2018	Phase 2	45	clinical stages II/III	XELOX+BV × 1→CRT+BV→Surgery→XELOX × 3+CAPE × 2	39.5	/	95.3	3y-PFS: 88.6
	TRUST [43]	2019	Phase 2	49	high-risk cT3, cT4, cN+	FOLFOXIRI+BV × 6→CRT+BV→Surgery	36.4	/	/	2y-DFS: 80.45
	INOVA [40]	2019	Phase 2	91	high-risk LARC, low/mid rectum	FOLFOX4+BV × 4→ CRT+BV→Surgery CRT+BV→Surgery	23.8 11.4	84.6 75.1	95.5 88.4	/
	Felice et al. [41]	2021	Phase 2	28	cT3–4, cN0–2	Ras-wild: FOLFOXIRI+panitumumab/cetuximab × 4→CRT→Surgery Ras-mutant: FOLFOXIRI+BV × 4→CRT→Surgery	21.4	/	/	cCR: 10.7
Immunotherapy	VOLTAGE-A [44]	2022	Phase 2	39	cT3–4, cN0–2	CRT→Nivolumab × 5→Surgery	30	/	/	/
	Lin et al. [45]	2021	Phase 2	30	cT3-4N0/cT1-4N+	SCRT→CAPOX × 2+camrelizumab→Surgery	46.2	/	/	/
	PKUCH-04 [46]	2022	Phase 2	25	LARC	CAPOX × 3+Camrelizumab→CRT→CAPOX × 2→Surgery	33.3	/	/	cCR or near cCR: 16
	TORCH [47]	2024	Phase 2	121	cT3–4 and/or cN1	SCRT→CAPOX × 6+Toripalimab CAPOX × 2+Toripalimab→SCRT→CAPOX × 4+Toripalimab	50 50	/	/	CR rate: 56.5% vs. 54.2%
	UNION [48]	2024	Phase 3	231	cT3–4/cN+	SCRT→CAPOX × 2+ Camrelizumab CRT→CAPOX × 2	39.8 15.3	/	/	CR rate: 41.6% vs. 18.6%

Abbreviations: ICB = immune checkpoint blockade; TNT = total neoadjuvant therapy; LARC = locally advanced rectal cancer; CRT = chemoradiotherapy; SCRT = short-course radiotherapy; FOLFOXIRI consists of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan; FOLFOX consists of oxaliplatin, leucovorin, 5-fluorouracil; CAPOX/XELOX consists of capecitabine, oxaliplatin; CAPE = capecitabine; BV = bevacizumab; PFS = progression-free survival; DFS = disease-free survival; pCR = pathological complete response; OS = overall survival.

A phase II study in China recruited patients with clinical stages II-III rectal cancer who were treated with bevacizumab-based INCT and CRT [42]. The pCR rate reached 39.5%: of note, 25% of patients experienced postoperative anastomotic leakage. The overall 3-year PFS and 3-year OS rates were 88.6% and 95.3%, respectively. The TRUST trial enrolled patients with cN+ or cT4 or high-risk cT3 LARC [43]: 16 out of 44 patients reached pCR (36.4%). However, 18% of enrolled patients presented an anastomotic leakage. 2-year DFS was 80.45% (95% CI 78.79–82.10) which met the primary endpoint. The two-arm INOVA trial applied bevacizumab-based CRT in patients with mid/low high-risk LARC. The pCR rate was 23.8%. During follow-up, 19.6% of patients in arm A and 22.2% in arm B developed anastomotic leakage. 5-year DFS and 5-year OS were both superior in arm A. The INOVA trial was the only trial of this category to report 3-year follow-up. A phase II trial conducted by Felice et al [41]. enrolled 28 patients with cT3–4 rectal adenocarcinoma and positive lymph nodes. Patients further received bevacizumab or panitumumab/cetuximab-based TNT, according to Ras-BRAF status. Postoperative complications occurred in 5 of 22 patients (22.7%), while 11 patients (39.3%) presented a complete (32.1%) or nearly complete pathological response (7.2%).

Overall, adding targeted agents to TNT regimens increases the pCR rate by 2–3 times, but the adverse effects of the drugs should not be ignored. Toxicities during CRT and early postoperative complications such as anastomotic leakage are common bevacizumab-related peri-operative complications. The optimal interval between bevacizumab therapy and surgery lacks a clear definition, but a longer interval before surgery and a protective prophylactic ostomy might help reduce complications. The common limitation of these phase II trials is that the number of patients is small. Besides, long follow-up and survival outcomes are not regularly reported. Last but not least, the inclusion criteria are excessively extensive and molecular classifications have not been applied in most trials.

There is no doubt that immunotherapy of immune checkpoint blockades (ICBs) has become the primary regimen for dMMR/MSI patients with rectal cancer. However, part of pMMR/MSS patients also show a response to ICBs. Considering that radiotherapy can sensitize refractory tumors to ICIs through increased tumor immunogenicity and activated immune response [49], multiple phase II trials have added ICIs after radiotherapy as CNCT. Although the sample sizes are small and the follow-up is ongoing, the pronounced increase in pCR rate observed until now is encouraging [44,45,50,51] (Table 3).

The VOLTAGE-A trial enrolled MSS patients with T3-4N0-2M0 rectal cancer and used nivolumab as CNCT after CRT. A 30% pCR rate was achieved [44]. Lin et al [48]. combined SCRT and camrelizumab-based CNCT as TNT for patients with T3-4N0M0 or T1-4N+M0 rectal cancer. Among patients who underwent surgery, 48.1% had a pCR, including 46.2% for pMMR tumors. The PKUCH 04 trial designed a camrelizumab-based TNT in pMMR/MSS LARC and 33.3% of patients had a pCR [46]. However, some trials incorporated dMMR/MSI-H LARC into eligible participants, leading to overtreatment.

The TORCH trial is a multicenter, randomized phase II trial that enrolled 130 pMMR/MSS LARC patients [47]. Six cycles of neoadjuvant immunochemotherapy (CAPOX+ toripalimab) were given in different sequences (group A: CNCT, group B: INCT+CNCT). The CR rate was 56.5% in group A and 54.2% in group B. The TORCH trial had a remarkably higher CR rate than the SCRT-based TNT approaches. One possible explanation is that the TORCH trial had a lower proportion of high-risk patients (fewer cT4 [17% vs. 31%] and cN2 [48% vs. 65%]) than the RAPIDO trial.

The UNION trial, a multicenter randomized phase III trial, compared the efficacy and safety of SCRT followed by CAPOX and camrelizumab (n = 113) to CRT followed by CAPOX alone (n = 118) [48]. The pCR rate was statistically significantly higher in the experimental arm (39.8% vs. 15.3%, p < 0.001). This trial applied a risk stratification during analysis, defining high-risk patients to have at least one of the following factors: cT4, cN2, EMVI+, CRM+. The proportion of high-risk patients included was 77.9% and 77.1%. The limitation of this study was the absence of long-term benefits in survival outcomes.

Taken together, despite the dominant role ICBs play in treating dMMR/MSI-H patients, pMMR/MSS patients were also proven to benefit from the addition of ICBs in neoadjuvant regimens. Besides, some studies have identified predictive biomarkers that assist in selecting good responders to their regimens, such as PD-L1 expression, CD8/effector Treg ratio, tumor mutation burden, FGFR1–3 deletion or LRP1B mutation [44,45,52,53]. Nevertheless, further studies are still needed to validate the predictive value of these biomarkers. Moreover, novel combination strategies such as dual immunotherapy or immunotherapy plus targeted therapy can be proposed to explore their feasibility in high-risk LARC population, which requires more intensified strategies [54–56].

4. Radiotherapy modalities in TNT

Radiotherapy also aims to control local recurrence [57]. SCRT (25 Gy in 5 fractions) and CRT (45–50.4 Gy in 25–28 fractions concurrently with 5-FU or capecitabine) are the two most widely used regimens. Several guidelines have established conventional CRT as the reference treatment for LARC highlighting its advantages: better tumor regression and local control compared to radiotherapy alone. While SCRT statistically significantly reduced the duration of radiotherapy, providing a less expensive and more convenient treatment schedule for both patients and radiotherapy centers, higher doses per fraction of SCRT might result in increasing rates of irradiation-related toxicity and cause surgical complications [58]. SCRT and CRT have been compared in three RCTs [59–61]. The Polish I trial compared CRT with delayed surgery and SCRT with immediate surgery; no statistically significant difference was found in OS or DFS outcomes [60]. The Trans-Tasman trial had a similar study design, and no statistically significant difference in OS was observed [61]. The Lithuanian trial compared CRT with SCRT alone and observed a statistically significantly higher 3-year DFS rate (59% vs. 75.1%, p = 0.022) with similar OS [59]. However, these trials were underpowered because of poor quality and insufficient follow-up. Besides, the primary endpoint of the Polish I trial was the sphincter preservation rate, while that in the Trans-Tasman was local recurrence, which focused on locoregional control instead of systemic control. The Stockholm III trial compared SCRT with immediate surgery, SCRT with delayed surgery, and CRT with delayed surgery [62]. The primary endpoint was time to local recurrence: no statistically significant difference was observed between SCRT with immediate surgery and CRT with delayed surgery. At interim analysis SCRT with delayed surgery group achieved a higher pCR rate (11.8% vs. 1.7%; p = 0.001), but the median time from the date of randomization to local recurrence was statistically significantly shorter than in the other two groups [63]. Comparable survival outcomes were observed during long-term follow-up [62]. Taken together, no sufficient evidence has been collected to demonstrate the superiority of CRT or SCRT over the other.

Several clinical trials mentioned above chose SCRT as preoperative radiotherapy in their TNT regimen, such as Polish II, RAPIDO, and STELLAR. One possible explanation is that SCRT can shorten the duration of the TNT treatment. Indeed, SCRT can usually be terminated within 1 week, so it can be administered between two cycles of drug administration without disturbing the systemic treatment schedule. Hence, SCRT-based TNT management can be a new cost-effective and convenient option for LARC patients. Until now, there are no studies exploring the therapeutic difference between SCRT-based TNT and CRT-based TNT regimens.

Considering the short-term and long-term toxic effects of radiotherapy [64], research is ongoing to investigate whether neoadjuvant chemotherapy can be a substitute for CRT without increasing the risk of recurrence. Three clinical trials compared neoadjuvant chemotherapy versus neoadjuvant CRT [17,65,66]. The PROSPECT trial recruited 1194 cT2N+, cT3Nany patients who were candidates for sphincter-sparing surgery to receive either neoadjuvant mFOLFOX6 or CRT [17,67]. Patients with cT4, cN2, and tumor visible within 3 mm of the radial margin were excluded. In the FOLFOX group, 9.1% of patients received extra CRT because of tumor regression＜20% (6.5%) or discontinued FOLFOX treatment. DFS-survival was not inferior in the FOLFOX group ([HR] 0.92, 90.2% CI 0.74–1.14; p = 0.005 for noninferiority). Similar pCR, OS, and local recurrence rates were observed in both groups. The CONVERT trial enrolled 663 cT2N+ or cT3-4aNany, MRF- patients assigned either to CAPOX or CRT [66]. Similar pCR rates were observed in both groups (11.0% vs 13.8%, p = 0.33), but the survival outcomes are still maturing. The FOWARC phase III trial included 495 stage II/III patients: no statistically significant difference was found in DFS, local recurrence, distant metastasis, or OS between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy. Of note, the FOWARC trial contained some high-risk patients (33% MRF+), who exhibited a higher local recurrence rate than the PROSPECT trial. The outcomes achieved by these studies indicate that omitting radiotherapy as a de-escalation strategy is the current trend in low-risk LARC treatment.

5. Future prospectives

There is little doubt that TNT has become the most prominent treatment modality in LARC, but controversies exist. Firstly, as TNT covers a wide range of treatment modalities, a more precise population selection is required to avoid undertreatment or overtreatment. What must be prioritized is the large-scale validation of risk stratification for LARC, and therefore establishing globally recognized criteria to better guide population selection and clinical intervention. Secondly, for high-risk LARC patients, an intensified TNT regimen is strongly recommended to achieve better tumor response before surgery. Moreover, several subgroups suitable for different regimens can be defined. For patients who have a heavy tumor burden or are eager for organ preservation, TNT with CNCT procures an adequate interval before surgery to allow tumor regression. The W&W strategy enables patients who achieve cCR to avoid surgery and have a better quality of life. For patients who have risk factors for distant metastasis (cN2, EMVI+, enlarged lateral lymph nodes), TNT with INCT is recommended. The distinction between SCRT and CRT is still under discussion, and more head-to-head RCTs are needed to provide credible evidence. Thirdly, more and more studies have started to consider targeted agents and ICBs as combination therapy to increase the intensity of TNT. More phase III studies with persuasive survival outcomes are in demand. Lastly, for low-risk patients, it is of great importance to explore the feasibility of de-escalation strategies. Omission of radiotherapy has been explored by several clinical trials and achieved encouraging outcomes. Besides, some researchers also considered omitting neoadjuvant treatment in low-risk LARC (the TaLaR-02 trial, NCT05984485). Since the study is still ongoing, convincing results are warranted.

6. Conclusion

With the development of preoperative imaging evaluation and the predictive ability of risk factors for patient prognosis, the treatment for LARC might be individualized depending on risk stratification. As for high-risk LARC, intensified TNT regimens consisting of INCT, CNCT, radiotherapy, targeted therapy, and immunotherapy might not only increase organ preservation through tumor regression but also reduce distant metastasis to improve long-term survival. However, clinical trials specifically concentrating on high-risk LARC are limited but should be encouraged.

Funding Statement

The work was supported by the Science and Technology Commission of Shanghai Municipality [24010702200] and Shanghai Jiaotong University scientific and technological innovation [YG2023QNB07].

Article highlights

Risk Stratification of LARC

• With the development of imaging technology, risk factors associated with poor prognosis can be evaluated to stratify LARC for risk-adapted treatment.

• High-risk LARC refers to LARC with several risk factors such as lower tumor location, advanced clinical T and N stage, lateral lymph node invasion, EMVI+, and MRF+ which has poor prognosis and impaired survival.

Total Neoadjuvant Therapy in LARC

• Benefits of TNT in LARC include better tumor downstaging, early eradication of micrometastases, and improved patient tolerance.

• The improvement in survival and the satisfactory pCR rates are in favor of TNT as the optimal therapeutic choice for high-risk LARC patients.

• Phase II trials incorporating targeted agents and ICIs into TNT demonstrated increased pCR; however, long-term follow-up of survival outcomes is warranted.

Radiotherapy Modalities in TNT

• CRT provides better tumor regression, while SCRT is shorter, cost-effective, and easier to integrate into systemic treatment.

• The PROSPECT, CONVERT, and FOWARC trials support de-escalation strategies omitting radiotherapy for low-risk patients.

Future Perspectives

• Large-scale validation of LARC risk stratification is needed to standardize treatment guidelines.

• High-risk LARC patients benefit from intensified TNT, while low-risk patients may undergo de-escalated therapy.

• The role of targeted therapy and immunotherapy in TNT is promising but requires further study

Author contributions statement

Jingyi Liu: Investigation, Writing-Original Draft; Writing-review & editing;

Ximo Xu: Investigation

Hao Zhong: Investigation

Mengqin Yu: Investigation

Naijipu Abuduaini: Investigation

Abe Fingerhut: Supervision; Writing-review & editing;

Zhenghao Cai: Conceptualization; Writing-review & editing;

Bo Feng: Supervision;

Statement: All figures and tables have been originally created for the purpose of this manuscript and has not been published previously.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.