Total Neoadjuvant Therapy (TNT) versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and Meta‐Analysis

Abstract

Background

Total neoadjuvant therapy (TNT) is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant chemoradiotherapy prior to surgery. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). We conducted this meta‐analysis to assess such concerns.

Materials and Methods

Head‐to‐head phase II/III RCTs were searched in Embase, PubMed, Web of Science, and the Cochrane Library, as well as other sources. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were disease‐free survival (DFS), overall survival (OS), local recurrence‐free survival, distant metastasis‐free survival, and the R0 resection rate.

Results

Eight phase II/III RCTs involving 2,196 patients with LARC were assessed. The primary analysis demonstrated a statistically significant improvement in the pCR rate for TNT treatment (odds ratio, 1.77; 95% confidence interval [CI], 1.28–2.45; p = .0005). TNT treatment also showed improvements in DFS and OS outcomes compared with standard chemoradiotherapy (hazard ratio [HR], 0.83; 95% CI, 0.72–0.96; p = .03 and HR, 0.88; 95% CI, 0.74–1.05; p = .15). In addition, TNT treatment showed significant efficacy in reducing the risk of distant metastasis (HR, 0.81; 95% CI, 0.68–0.95; p = .012).

Conclusion

The overall pCR rate may be improved with TNT compared with standard treatment. The TNT strategy may also improve DFS and OS and reduce the risk of distant metastasis.

Implications for Practice

Locally advanced rectal cancer (LARC) is a relatively common disease, with a poor prognosis because of its high metastatic potential. The role of total neoadjuvant therapy (TNT) has always been controversial. This meta‐analysis found that TNT in LARC is associated with a significant improvement in overall pathologic complete response rate, disease‐free survival, overall survival, and distant metastasis‐free survival compared with standard treatment. TNT is a promising strategy for LARC, especially for patients who have little desire for surgery.

Short abstract

Total neoadjuvant therapy (TNT) is a novel therapeutic approach for locally advanced rectal cancer that delivers both systemic chemotherapy and neoadjuvant chemoradiotherapy before surgery; however, this approach remains controversial. This article reports the results of a meta‐analysis comparing TNT with standard chemotherapy.

Introduction

Colorectal cancer is the second cause of cancer‐related deaths worldwide and accounts for 10% of all cancer types [1]. For patients with locally advanced rectal cancer (LARC), multimodal treatment consisting of neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery and adjuvant chemotherapy has become the standard of care [2]. Although the standard treatment models have resulted in tumor downstaging, improved quality of life, and lowered rates of local disease recurrence [3], pathologic complete response (pCR) is only achieved in 10%–30% of patients with LARC using neoadjuvant CRT, with a high rate of distant metastasis (DM) also remaining in such patients, seriously threatening their life [4]. As for postoperative chemotherapy, the National Comprehensive Cancer Network guidelines recommend TME should be followed by adjuvant systemic chemotherapy; however, less than 50% of eligible patients receive their scheduled adjuvant chemotherapy due to delays, treatment compliance, and postoperative complications [5, 6].

To overcome such problems, a novel therapeutic approach, total neoadjuvant therapy (TNT), attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Accumulating evidence shows that TNT in patients with LARC is expected to improve survival and reduce DM via systematic chemotherapy to prevent the onset of micrometastases [7]. TNT has also been associated with better compliance, a decrease in toxicity, a reduced need for ileostomy and its duration, and increased complete clinical response, followed by the watch and wait strategy to improve anal sphincter preservation rates [3, 8, 9, 10, 11, 12]. TNT is a promising treatment for with LARC and has been explored in previous single‐arm trials, albeit with small sample sizes. These studies show that the pCR in patients who received TNT treatment was approximately 20%–40% [13, 14]. In a retrospective cohort study, patients with LARC treated with the TNT approach of induction chemotherapy followed by CRT before surgery received a greater percentage of the planned chemotherapy dose than those in the standard CRT group. The TNT group also had a higher pCR rate than the adjuvant chemotherapy group (36% vs. 21%) [15].

Recently, multiple randomized controlled trials (RCTs) evaluated different TNT strategies compared with standard CRT therapy, in terms of CRT sequencing and systematic chemotherapy, radiotherapy modality, and TNT intensity. Yet, the efficacy and safety of TNT remains controversial. This meta‐analysis aims to explore the pCR and survival value of TNT treatment compared with standard CRT. A previous meta‐analysis reported TNT increased the odds of pCR by 39% [8] compared with standard CRT and suggested TNT had better survival than standard CRT. Here, our study builds upon previous understandings by including newer and more reliable research data with larger sample sizes, better quality prospective RCTs, and more detailed subgroup analysis.

Materials and Methods

Study Eligibility and Identification

Embase, PubMed, Web of Science, the Cochrane Library, and other sources were comprehensively searched up to July 15, 2020. Search terms and their combinations included “neoadjuvant therapy,” “rectum tumor,” and “randomized controlled trial.” The detailed search strategy is listed in supplemental online Table 1. Book abstracts and conference proceedings were manually searched to ensure the latest oncological data were considered. After screening titles and abstracts, literature selection was conducted by two independent reviewers (S.L. and L.X.). We also reviewed the reference lists of relevant studies to confirm all eligible studies were included in this meta‐analysis. Our inclusion criteria were (a) prospective phase II or III trials involving rectal cancer patients; (b) patients who received induction (or consolidation) chemotherapy plus neoadjuvant chemoradiotherapy; and (c) at least one available outcome data regarding systemic therapy in patients with LARC. Studies that failed to meet the above criteria were excluded from this meta‐analysis. This systematic review is registered at PROSPERO (registration no. CRD42020187992).

Outcome Measures, Data Extraction, and Quality Assessment

Clinical outcomes were pCR, disease‐free survival (DFS), overall survival (OS), local recurrence‐free survival (LRFS), distant metastasis‐free survival (DMFS), and R0 resection rate. Two investigators (S.L. and T.J.) used a standardized form to independently extract the summaries, clinical outcomes, and study data (the study's authors, publication year, patient categories, age, gender, clinical stage, oncologic performance scale, study design, therapeutic regimens, sample size, and the distance between the tumor and the anal verge). The methodological quality of each study was assessed by two reviewers according to the Cochrane Handbook for Systematic Reviews of Interventions. Seven aspects were assessed: random sequence generation, allocation sequence concealment, blinding of participants and personnel, blinding of the outcome assessment, incomplete outcome data, selective reporting, and other biases. Each included study was assessed for a “high risk of bias,” “low risk of bias,” or “unclear risk of bias.” Any disagreements were resolved by consensus.

Statistical Analysis

The hazard ratios (HRs) for survival outcomes (DFS, OS, LRFS and DMFS), and the odds ratio (OR) for binary outcomes (pCR, R0 resection rate) as well as their 95% confidence intervals (CIs) were used to measure the efficacy and safety of the treatment strategies. For specific comparisons, an agent with HR for DFS, OS, LRFS, and DMFS <1 or OR for pCR and R0 resection rate >1 was deemed preferable to its contrast in efficacy. The statistical significance of the studies was evaluated by the Z test with significance set at a p < .05. Heterogeneity among the studies was quantified using Cochran's Q‐statistic and I² statistic. Substantial heterogeneity was considered to exist with a p < .1 or I² > 30%, and the random‐effects method was reported after exploring the causes of heterogeneity. Otherwise, the fixed‐effects method was reported.

For the primary outcomes, we performed subgroup analysis for treatment sequence, TNT intensity and type of radiotherapy. A sensitivity analysis was performed by removing each study in turn to establish the extent to which they contributed to the overall result. All statistical tests were performed by Review Manager version 5.3 and Stata version 12.0.

Results

Characteristics of the Selected Studies

According to the retrieval strategy and other sources, 4,874 related studies were initially identified. In total, 2,881 potential studies were included after removing 1,993 duplicates, 2,578 were excluded from title and abstract screening, 303 studies were considered eligible for full‐text assessment, 289 full‐text articles were excluded, 146 studies were excluded because they were not randomized control trials, 62 lacked relevant intervention or endpoints, 54 studies were excluded as they were reviews, and 12 studies were excluded because of no available results, and our efforts were unsuccessful in contacting the authors for further data. Eight RCTs met the inclusion criteria in this analysis [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. All eight studies (n = 2,196 patients) were included in this final analysis (n = 1,113 treated with TNT and n = 1,083 treated with standard CRT). This study's flowchart is presented in Figure 1.

Figure 1.

Preferred reporting items for systematic reviews and meta‐analysis flowchart. Abbreviation: RCT, randomized control trial.

Our analysis included four phase II trials and four phase III trials. In most of the included studies, induction or consolidation (neoadjuvant) chemotherapy was multiagent oxaliplatin‐based (n = 6) [17, 18, 20, 25, 26, 29]. One study [24] used 5‐fluorouracil plus folinic acid and another one used mFOLFIRINOX [30] (modify oxaliplatin, irinotecan, leucovorin, 5‐fluorouracil). Three studies [17, 18, 30] used an induction treatment paradigm, and five studies [20, 24, 25, 26, 29] explored the effects of consolidation treatment. In five studies [17, 18, 24, 26, 30], patients were treated with standard, long‐course CRT (~50.4 Gy) in the experimental arm. In three studies [20, 25, 29], short‐course radiotherapy (5 × 5 Gy) was the selected regimen (Table 1). For detailed patient characteristics of each trial, see Table 2.

Table 1.

Trial characteristics

Study	Author/PI, yr	Study ID Numbers	Primary endpoint	Secondary endpoints	Study design	Study period	No. of trial centers	TNT treatment strategy vs. standard treatment strategy
Marechal/2011	Marechal, 2011	EudraCT: 2006‐006646‐34	ypT0‐1N0 rate	1. pCR rate 2. toxic effects 3. sphincter preservation rate	Phase II RCT	n.i.	Multicenters	mFOLFOX6 × 2 ‐CRT [5FU + 50.4 Gy] ‐ TME vs. CRT [5FU + 50.4 Gy] ‐ TME
GCR‐3	Fernandez‐Martos, 2015	NA	pCR	1. Toxicity 2. treatment compliance, downstaging 3. R0 resection rates 4. 30‐d surgical complications 5. cumulative incidence of LR 6. DMs 7. DFS 8. OS	Phase II RCT	May 2006 to December 2007	14	Capeox × 4 ‐ CRT [Capeox+50.4 Gy] ‐ TME vs. CRT [Capeox+50.4 Gy] ‐ TME ‐ Capeox × 4
POLISH II	Bujko, 2016	NCT00833131, PGBRJG0109	The rate of patients with R0 resection [time frame: surrogate endpoint available immediately after surgery]	1. Overall long‐term survival 2. Progression‐free long‐term survival 3. the rate of local failures 4. the rate of distant metastases 5. the rate of early toxicity of neoadjuvant treatment according to the NCI CTCAE (version 3.0) 6. the rate of postoperative complications 7. the rate of late toxicity according to the RTOG/EORTC scale 8. the rate of complete pathological response	Phase III RCT	November 2008 to November 2012	39	5 × 5Gy ‐ FOLFOX4 × 3 ‐TME vs. CRT [50.4 Gy + 5 ‐ FU+ AF + OXA] ‐ TME
WAIT	Moore, 2017	ACTRN12611000339954	pCR rate	n.i.	Phase II RCT	April 2012 to June 2014	3	CRT [5FU + 50.4 Gy] ‐5FU + LV × 3 ‐TME vs. CRT [5FU + 50.4 Gy] ‐ TME
KCSG CO 14‐03	Kim, 2018	NCT01952951, KCSG CO14‐03	Downstaging rate [time frame: expected average of 15 wk after start of study treatment]	1. Pathologic response 2. radiologic response rate 3. toxicity profile 4. pattern of failure 5. local control rate 6. relapse‐free survival 7. disease‐free survival 8. overall survival 9. quality of life	Phase II RCT	June 2014 to September 2017	7	CRT [Cape/5FU + 50.4 Gy] ‐Capox × 2 ‐TME vs CRT [Cape/5FU + 50.4 Gy] ‐ TME
STELLAR	Jing, 2019	NCT02533271 XT2015‐03, CH‐GI‐090	disease‐free survival rate [time frame: 3 yr]	1. overall survival rate 2. incidence of surgical complications 3. incidence of acute toxicities during radiation or chemotherapy	Phase III RCT	August 2015 to August 2023	11	5 × 5Gy ‐ Capeox × 4 ‐ TME ± Capeox × 2 vs. CRT [25 × 2Gy + Cape] ‐ TME ± Capeox × 6
RAPIDO	Hospers G, 2020	NCT01558921, NL36315.042.11, 2010‐023957‐12 (EudraCT Number)	Disease‐related treatment failure [time frame: 3 yr follow‐up after surgery]	1. Overall survival 2. CRM negative rate 3. pCR rate 4. Short and long‐term toxicity 5. Surgical complications 6. Quality of life questionnaires	Phase III RCT	June 21, 2011, to March 8, 2020	56	5 × 5Gy ‐ Capeox × 6/FOLFOX4 × 9‐TME vs. CRT [28 × 1.8Gy/25 × 2Gy‐Cape] ‐ TME ‐ Capeox × 8/FOLFOX4 × 12
PRODIGE 23	T. Conroy, 2020	NCT01804790, PRODIGE 23 ‐ UCGI 23	disease‐free survival [time frame: 3 yr]	Overall survival [time frame: 7 yr]	Phase III RCT	January 2012 to September 2019	36	mFOLFIRINOX × 6 ‐ CRT [50.4Gy/25F + Cape] ‐ TME ‐ mFOLFOX6 × 6/Cape × 4 vs. CRT [50.4Gy/25F + Cape] – TME ‐ mFOLFOX6 × 12/Cape × 8

Abbreviations: 5FU, 5‐fluorouracil; Cape, capecitabin; Capox, capecitabine + oxaliplatin; CRM, circumferential resection; CRT, chemoradiotherapy; DFS, disease‐free survival; DM, distant metastasis; FOLFOX, oxaliplatin + calcium folinate +5‐fluorouracil; LR, local relapse; mFOLFIRINOX, modify oxaliplatin + irinotecan + calcium folinate +5‐fluorouracil; mFOLFOX, modify oxaliplatin + leucovorin +5‐fluorouracil; n.i., no information; NA, not applicable; OS, overall survival; pCR, pathologic complete response; PI, principal investigator; RCT, randomized clinical trial; TME, total mesorectal excision.

Table 2.

Patients’ characteristics

Study	Author/PI, yr	Sample size of ITT analysis		Gender, No.				Age, yr		Oncologic performance scale, No.		Clinical stage, No.		Distance between tumor and anal verge (cm)		Circumferential margin, No.
				TNT treatment		Standard treatment
		TNT treatment	Standard treatment	Female	Male	Female	Male	TNT treatment	Standard treatment	TNT treatment	Standard treatment	TNT treatment	Standard treatment	TNT treatment	Standard treatment	TNT treatment	Standard treatment
Marechal/2011	Marechal, 2011	28	29	7	21	13	16	62 (22–80)	62 (44–79)	ECOG‐0 (21), ECOG‐1 (7)	ECOG‐0 (25), ECOG‐1 (4)	cT2 (1), cT3 (25), cT4 (2), Any cTxN+ (26)	cT2 (3), cT3 (23), cT4 (3), Any cTxN+ (25)	Lower third (11), middle third (13), upper third (4)	Lower third (13), middle third (9), upper third (7)	>5 mm (18), ≤5 mm (7), not carried out (3)	>5 mm (15), ≤5 mm (9), not carried out (5)
GCR‐3	Fernandez‐Martos, 2015	56	52	17	19	18	34	60 (38–76)	62 (42–75)	ECOG‐0 (33), ECOG‐1 (22), ECOG‐2 (1), Unknown (‐)	ECOG‐0 (36), ECOG‐1 (15), ECOG‐2 (‐), Unknown (1)	T4 resectable (7), T3 low third (≤6 cm from pectineal line) (18), threatened or involved MRF (‐), any T3N+ (31), missing data (‐)	T4 resectable (3), T3 low third (≤6 cm from pectineal line) (12), threatened or involved MRF (5), any T3N+ (31), missing data (1)	n.i.	n.i.	n.i.	n.i.
POLISH II	Bujko, 2016	261	254	78	183	85	169	60 (54–66)	60 (55–65)	WHO‐0 (129), WHO‐1 (120), WHO‐2 (11), WHO‐3 (1)	WHO‐0 (126), WHO‐1 (115), WHO‐2 (5), WHO‐3 (0)	cT3 (88), cT4 (165), recurrent (8)	cT3 (83), cT4 (163), recurrent (8)	0–5 (148) >5–10 (106) >10–15 (7)	0–5 (138) >5–10 (99) >10–15 (16) no data (1)	n.i.	n.i.
WAIT	Moore, 2017	25	24	7	18	6	18	59.7 ± 9.9	60.5 ± 12.6	n.i.	n.i.	T2 (0), T3 (24), T4 (1), N0 (0), N1 (6), N2 (19)	T2 (1), T3 (18), T4 (5), N0 (2), N1 (7), N2 (15)	6.6 ± 2.6	6.0 ± 2.5	clear (10), threatened (8), involved (7)	clear (12), threatened (4), involved (8)
KCSG CO 14–03	Kim, 2018	53	55	17	36	9	46	56 ± 10	55 ± 8	ECOG‐0 (16), ECOG‐1 (37)	ECOG‐0 (16), ECOG‐1 (39)	T3 (44), T4 (9), N0 (3), N+ (49), unknown (1)	T3 (45), T4 (10), N0 (4), N+ (51), unknown (0)	n.i.	n.i.	Involved (14), not involved (37), unknown (2)	Involved (16), not involved (38), unknown (1)
STELLAR	Jing, 2019	104	105	n.i.	n.i.	n.i.	n.i.	n.i.	n.i.	n.i.	n.i.	n.i.	n.i.	n.i.	n.i.	MRF (+) (14)	MRF (+) (15)
RAPIDO	Hospers G, 2020	462	450	162	300	138	312	62 (31–83)	62 (23–84)	ECOG‐0 (369), ECOG‐1 (93)	ECOG‐0 (365), ECOG‐1 (85)	cT2‐3N0 (24), cT2‐3N+ (289), cT4N0 (23), cT4N+ (124)	cT2‐3N0 (19), cT2‐3N+ (278), cT4N0 (23), cT4N+ (121)	<5 cm (103), 5–10 cm (180), ≥10 cm (145), unknown (32)	<5 cm (114), 5–10 cm (148), ≥10 cm (148), unknown (21)	MRF+ (284)	MRF+ (263)
PRODIGE 23	T. Conroy, 2020	231	230	81	150	74	156	61 (34–77)	62 (26–75)	WHO‐0 (179), WHO‐1 (52)	WHO‐0 (185), WHO‐1 (45)	T2 (3), T3 (187), T4 (41), N+ (206)	T2 (2), T3 (192), T4 (36), N+ (207)	≤5 cm (87), 5.1–10 cm (114), 10.1–15 cm (30)	≤5 cm (83), 5.1–10 cm (118), 10.1–15 cm (29)	≤1 mm (60)	≤1 mm (64)

Abbreviations: CRM, circumferential resection margin; ECOG, Eastern Cooperative Oncology Group; ITT, intention to treat; MRF, mesorectal fascia; n.i., no information; NA, not applicable; pCR, pathologic complete response; RCT, randomized clinical trial; TNT, total neoadjuvant therapy; WHO, World Health Organization.

Risk of Bias

Risk of bias was performed by two investigators (S.L. and T.J.) using the Cochrane risk‐of‐bias tool. All eight trials (100%) described adequate random sequence generation and all eight (100%) had adequate treatment allocation concealment. Patients and care providers were blinded in seven trials (87.5%), and seven trials (87.5%) blinded the outcome assessment process. Detailed risk information is provided in supplemental online Figure 1.

Meta‐Analysis of pCR Rates

For the primary endpoint pCR percentage, eight trials were analyzed with a total of 2,196 patients. All trials reported a pCR rate which demonstrated a statistically significant benefit for TNT treatment (OR, 1.77; 95% CI, 1.28–2.45; p = .0005; Fig. 2A).

Figure 2.

Forest plots for pathologic complete response. (A): Pathologic complete response with total neoadjuvant therapy versus standard chemoradiation, (B) subgroup analysis induction chemotherapy followed by chemoradiotherapy (CRT) vs. CRT followed by consolidation chemotherapy, (C) subgroup analysis TNT‐like vs. TNT, (D) subgroup analysis. Long‐course radiotherapy vs. short‐course radiotherapy are shown. Abbreviations: CI, confidence interval; OR, odds ratio; TNT,

There were different results in the subgroup analysis with CRT followed by consolidation chemotherapy (CRT + CT) versus induction chemotherapy followed by CRT (CT + CRT). Patients treated with CRT + CT (OR, 1.76; 95% CI, 1.20–2.57; p = .004; Fig. 2B) had a higher pCR rate than those who received CT + CRT (OR, 1.59; 95% CI, 0.70–3.60; p = .26; Fig. 2B). We defined two groups according to the total time of neoadjuvant radiotherapy and chemotherapy: less than 12 weeks was considered a TNT‐like strategy, and more than 12 weeks was considered a TNT strategy. In the TNT‐like studies (OR, 1.31; 95% CI, 0.84–2.06; p = .24; Fig. 2C), there was no significant difference in the pCR rate between TNT and the standard treatment arms, although TNT studies (OR, 2.19; 95% CI, 1.59–3.03, p < .00001; Fig. 2C) had a higher pCR compared with standard treatment. The pCR comparisons were also different in the short‐course radiotherapy subgroup (OR, 1.91; 95% CI, 1.35–2.70; p = .0003; Fig. 2D) and the long‐course radiotherapy subgroup (OR, 1.48; 95% CI, 0.76–2.88; p = .25; Fig. 2D).

Meta‐Analysis of Survival Outcomes

For survival outcomes, TNT treatment showed improvements in DFS and DMFS compared with standard CRT (HR, 0.83; 95% CI, 0.72–0.96, p = .03 and HR, 0.81; 95% CI, 0.68–0.95; p = .012; Fig. 3A, D). As for OS and LRFS, no statistically significant differences were observed in the TNT treatment compared with standard treatment (HR, 0.88; 95% CI, 0.74–1.05; p = .15 and HR, 1.19; 95% CI, 0.94–1.51; p = .151; Fig. 3B, C).

Figure 3.

Forest plots for survival endpoints. Analysis for (A) disease‐free survival, (B) overall survival, (C) local recurrence‐free survival, and (D) distant metastasis‐free survival are shown. Abbreviations: CI, confidence interval; TNT, total neoadjuvant therapy.

Meta‐Analysis of the R0 Resection Rate

In comparative studies of the R0 resection rate, the intention‐to‐treat population was the one that could be resected; thus, only four studies were included [18, 24, 25, 31]. No statistically significant findings were observed between patients who received TNT and standard treatment (OR, 1.04; 95% CI, 0.71–1.53; p = .85; Fig. 4).

Figure 4.

Forest plot for the R0 resection rate. Abbreviations: CI, confidence interval; OR, odds ratio; TNT, total neoadjuvant therapy.

Surgery and safety

Grade 3–4 acute toxicities were more common in the TNT treatment group (9%–41%) than in the standard treatment group (2%–29%). Gastrointestinal (diarrhea, nausea), hematologic (neutropenia), and fatigue adverse events were the most common chemoradiotherapy‐related toxicities. Overall, the surgical methods used and the main postoperative complications of TNT regimens were comparable with standard CRT (Table 3).

Table 3.

Surgery and safety

Study	Author/PI, yr	Type of surgery, %		Grade 3–4 toxicities, %		Main grade 3–4 acute toxicities of CRT % (≥5%)		Main postoperative complications % (≥5%)
		TNT treatment	Standard treatment	TNT treatment	Standard treatment	TNT treatment	Standard treatment	TNT treatment	Standard treatment
Marechal/2011	Marechal, 2011	TME (86), APR (11)	TME (79), APR (17)	Grade 3–4 (26)	Grade 3–4 (7)	gastrointestinal (15), hematological (11)	gastrointestinal (4), hematological (‐)	global postoperative complications (25), pelvic/perineal infections (21)	global postoperative complications (31), pelvic/perineal infections (24)
GCR‐3	Fernandez‐Martos, 2015	None (4), low anterior (48), abdominoperineal (40), missing (4)	None (11), low anterior (56), abdominoperineal (33), missing (‐)	Grade 3–4 (23)	Grade 3–4 (29)	diarrhea (5)	diarrhea (16)	Infection and wound healing (27), reoperation (8)	Infection and wound healing (20), reoperation (7)
POLISH II	Bujko, 2016	Anterior resection (50), APR (37), Hartmann's procedure (10), resection of locally recurrent tumor (3)	Anterior resection (49), APR (41), Hartmann's procedure (9), resection of locally recurrent tumor (2)	3 (19), 4 (4), toxic deaths (1)	3 (16), 4 (5), toxic deaths (3)	n.i.	n.i.	Anastomotic dehiscence requiring reoperation (6). Other complications requiring reoperation (8). Treated conservatively (15)	Anastomotic dehiscence requiring reoperation (4). Other complications requiring reoperation (7). Treated conservatively (12)
WAIT	Moore, 2017	APR/Hartmann (28), Anterior resection (72)	APR/Hartmann (50), Anterior resection (50)	Clavien‐Dindo 3 (12.50), Clavien‐Dindo 4 (20)	Clavien‐Dindo 3 (4.17), Clavien‐Dindo 4 (4)	n.i.	n.i.	n.i.	n.i.
KCSG CO 14‐03	Kim, 2018	APR (6.8), LAR (77.3), other types of SSS (15.9)	APR (0), LAR (88.5), Other types of SSS (11.5)	Grade 3–4 (9)	Grade 3–4 (4)	NA	NA	NA	NA
STELLAR	Jing, 2019	Dixon (40.4), Mile's (53.8), Hartmann's procedure (5.8)	Dixon (44.8), Mile's (53.3), Hartmann's procedure (1.9)	Grade 3–4 (26)	Grade 3–4 (13)	NA	NA	Grade 3–4 (9)	Grade 3–4 (2)
RAPIDO	Hospers G, 2020	No resection (<1), Hartmann's procedure (5), abdominoperineal resection (34), (low) anterior resection (58), of which without stoma (10), other (2)	No resection (<1), Hartmann's procedure (3), abdominoperineal resection (39), (low) anterior resection (55), of which without stoma (12), other (3)	Grade 3 (41), grade 4 (7)	Grade 3 (23), grade 4 (2)	diarrhea (18), vascular disorders (8)	diarrhea (9), vascular disorders (4)	Pneumonia (5), other infection (7), intra‐abdominal infection (5), reoperations (10)	Pneumonia (3), other infection (5), intra‐abdominal infection (5), reoperations (8)
PRODIGE 23	T. Conroy, 2020	n.i.	n.i.	n.i.	n.i.	Neutropenia (16.9), G‐CSF use (27.0), diarrhea (11.1), fatigue (7.1), nausea (6.2)	n.i.	postoperative morbidity (29.3)	postoperative morbidity (31.2)

Abbreviations: APR, abdominoperineal resection; CRT, chemoradiotherapy; G‐CSF, granulocyte colony stimulating factor; LAR, low anterior resection; n.i., no information; NA, not applicable; SSS, sphincter‐saving surgery; TME, total mesorectal excision; TNT, total neoadjuvant therapy.

Publication bias

For the pCR meta‐analysis, the shape of the funnel plots did not show any evidence of asymmetry (supplemental online Fig. 2). There was no obvious evidence of publication bias.

Discussion

To our knowledge, this is the most comprehensive and complete meta‐analysis of RCTs comparing TNT and standard treatment in patients with LARC. Compared with a previously published systematic review, our study includes more up‐to‐date data from the PRODIGE 23 [30], RAPIDO [31], STELLAR, and POLISH II (8‐year survival) trials [27]. We found that the overall pCR rate may be improved with TNT compared with standard treatment (OR, 1.77; 95% CI, 1.28–2.45; p = .0005), which is consistent with Petrelli's study. TNT may also improve OS and DFS and reduce the risk of DM.

Taking a closer look at the treatment strategies reveals the importance of the interval between the completion of CRT and surgery on pCR. The subgroup analysis showed that TNT following CRT, chemotherapy, and then surgery had a higher pCR rate than the standard regimen (OR, 1.76; 95% CI, 1.20–2.57; p = .004). This is consistent with the findings of the subgroup analysis of the CAO/ARO/AIO‐12 [32] trial, which showed that different TNT treatment sequences followed by CRT, chemotherapy, and then surgery would have a higher pCR rate compared with TNT following the sequence of chemotherapy, CRT, and then surgery (25% vs. 17%). The authors of the CAO/ARO/AIO‐12 trial also speculated that the prolonged interval between the completion of CRT and surgery may have contributed to a higher pCR. In fact, Garcia‐Aguilar et al. made similar comparisons in the OPRA trial [33], where they reported that patients treated with CRT followed by systemic chemotherapy increased the chances of sphincter perseveration compared with patients who receive systemic chemotherapy followed by CRT. However, the induction chemotherapy subgroup exhibited no statistical advantage, which might be ascribed to the small sample size.

Another subgroup analysis also revealed the importance of intensity in preoperative chemotherapy conducive to an increased pCR rate. Based on the total time of neoadjuvant radiotherapy and chemotherapy, we divided studies into two groups: a TNT‐like subgroup and a TNT subgroup. The TNT subgroup showed a statistically higher pCR rate compared with standard treatment. The Timing trial also presented similar results in its assessment of whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of the pCR rate in a four‐arm design. The pCR rates were 18%, 25%, 30%, and 38% for the four groups, respectively [34, 35]. The pCR rate tended to increase with the number of added mFOLFOX6 cycles during the waiting period. Our results reaffirm the positive value of the TNT strategy when using a full dose of neoadjuvant radiotherapy and chemotherapy.

Relatedly, the radiotherapy dose fraction method also impacts the pCR rate. Over the last few decades, long‐course radiotherapy and short‐course radiotherapy have been developed in parallel, and both are used in neoadjuvant treatment of with LARC. However, which yields superior results is controversial and appears to differ based on certain localities. In general, short‐course radiotherapy is preferred in Northern Europe, whereas long‐course radiotherapy has more support in the U.S. and other European countries [36]. In our study, short‐course preoperative radiotherapy combined with chemotherapy showed a significantly improved pCR rate than the standard CRT regimen (OR, 1.91; 95% CI, 1.35–2.70; p = .0003). Interestingly, all three short‐course radiotherapy subgroup trials were TNT with a consolidation chemotherapy strategy, whereas most of the long‐course radiotherapy subgroup trials were TNT with an induction chemotherapy strategy. The higher pCR rate may be due to the fact that the short‐course radiotherapy subgroup trials had longer intervals between radiotherapy and surgery. Early European studies have reported a higher pCR rate with LARC patients treated with short‐course radiotherapy followed by consolidation chemotherapy, even in the presence of metastatic disease [37, 38], which was the rationale for the POLISH II and RAPIDO studies. One meta‐analysis showed that the pCR rate was higher when surgery was delayed than when it was when performed within 1 week after short‐term radiotherapy, and it was even higher when consolidation chemotherapy was integrated prior to surgery [39]. Short‐course radiotherapy followed by consolidation chemotherapy shows considerable promise, but there is no consensus on the optimal time interval between radiotherapy and chemotherapy, the duration of consolidation chemotherapy, or the ideal modes. Three short‐term radiotherapy TNT studies in our meta‐analysis used three different designs: three cycles of FOLFOX (6 weeks) after 1 week of radiotherapy in the POLISH II trial, four cycles of CAPOX (12 weeks) 11 to 18 days after radiotherapy in the RAPIDO trial, and six cycles of CAPOX (18 weeks) 1 week after radiotherapy in the STELLAR trial. Future studies need to determine the optimal chemotherapy start time after short‐course radiotherapy completion, as well as the ideal regimen and chemotherapy cycle before surgery.

The obvious finding to emerge from this systematic review is that DFS and DMFS may increase with TNT compared with standard CRT (HR, 0.83; 95% CI, 0.72–0.96; p = .03 and HR, 0.81; 95% CI, 0.68–0.95; p = .012). In the Timing study, the four groups showed statistically significant differences in DFS (50%, 81%, 86%, 76%, p = .004) [35]. This is an integral finding supporting the TNT strategy, because DFS and DMFS are long‐term endpoints and may bring about overall survival benefits for some with LARC. As for DFS and DMFS, subgroup analysis was not performed because of the limited availability. Further analysis are needed when the data is available.

One unanticipated finding was that LRFS decreased in the TNT group (HR, 1.19; 95% CI, 0.94–1.51, p = .151). This may be explained by the fact that two of the three included studies used short‐course radiotherapy followed by consolidated chemotherapy. Multiple trials and meta‐analysis appear to demonstrate that short‐course radiotherapy and long‐course radiotherapy are roughly equal in terms of local control [40, 41, 42, 43, 44, 45]. Yet, the interval time between surgery and radiotherapy is an important factor that should be taken into consideration for local recurrence‐free survival. The RCT Lyon R90‐01 indicated that an appropriately prolonged interval time may better tumor regression and improve the pCR rate and sphincter preservation rates. Since then, 6–8 weeks has been considered the most appropriate time for surgery after CRT [46]. Dr. Garcia‐Aguilar et al. found that pelvis fibrosis was more severe with an 11‐week interval time than with a 6‐week interval time after CRT [34]. The results of the GRECCAR‐6 RCT similarly showed that an 11‐week interval after CRT increased the risk of postoperative complications and local recurrence, compared with a 7‐week interval [47]. This may be due to pelvis fibrosis, edema, and accumulating local inflammation making it more difficult to ensure the surgical plane, thereby increasing the difficulty of TME surgery and consequently reducing the R0 resection rate [48, 49, 50, 51].

Grade 3–4 acute toxicities for TNT treatment were generally higher than those from standard CRT treatment. The highest grade 3 acute toxicity was 41% (RAPIDO), but there is no evidence that increased toxicity affects the survival of patients.

Another benefit of the TNT strategy is that it may facilitate greater organ preservation. However, sphincter‐preserving surgery data were too heterogeneous to be pooled in this meta‐analysis. Some studies did not aim to improve anal retention, which may have been one of the sources of heterogeneity. The OPRA study found that the TME‐free rate increased in both TNT treatment groups compared with standard treatment in patients with LARC. An ongoing phase II trial (NCT03840239) in China is evaluating whether two cycles of chemotherapy (CAPOX) before, during, and after long‐course radiotherapy will improve o sphincter preservation rates [52]. The results of this study are eagerly anticipated.

This meta‐analysis has several limitations. First, although eight high‐quality trials were included, only 2,196 patients were analyzed. Second, because of a lack of individual patient data, some analysis were not feasible, including subgroup analysis stratified by clinical stage and the distance between the tumor and the anal verge, and comparison of patients’ compliance to the treatment strategies.

Conclusion

Regardless of the above limitations, this meta‐analysis comprehensively determined the role of TNT. TNT may help improve the pCR rate, increase DFS and OS, and reduce the risk of DM, compared with standard neoadjuvant CRT among patients with LARC. TNT following the sequence of CRT, chemotherapy, and then surgery had a significantly higher pCR rate than the standard regimen. High‐intensity TNT may also be a good choice for patients who are apprehensive or who have little desire for surgery.

Author Contributions

Conception/design: Shuang Liu, GC and YHG, Weiwei Xiao

Provision of study material or patients: Shuang Liu, Lin Xiao

Collection and/or assembly of data: Shuang Liu, Ting Jiang, Shanfei Yang

Data analysis and interpretation: SL Shuang Liu Ting Jiang, Lin Xiao, Qing Liu

Manuscript writing: Shuang Liu, Ting Jiang, Lin Xiao

Final approval of manuscript: Shuang Liu, Ting Jiang, Lin Xiao, Shanfei Yang, Qing Liu, Yuanhong Gao, Gong Chen, Weiwei Xiao

Disclosures

The authors indicated no financial relationships.

Supporting information

See http://www.TheOncologist.com for supplemental material available online.

Appendix S1. Figures.

Supplemental Table 1 MEDLINE search strategy