Transanal vs Laparoscopic Total Mesorectal Excision and 3-Year Disease-Free Survival in Rectal Cancer: The TaLaR Randomized Clinical Trial

Ziwei Zeng; Shuangling Luo; Hong Zhang; Miao Wu; Dan Ma; Quan Wang; Ming Xie; Qing Xu; Jun Ouyang; Yi Xiao; Yongchun Song; Bo Feng; Qingwen Xu; Yanan Wang; Yi Zhang; Lishuo Shi; Li Ling; Xingwei Zhang; Liang Huang; Zuli Yang; Junsheng Peng; Xiaojian Wu; Donglin Ren; Meijin Huang; Ping Lan; Jianping Wang; Weidong Tong; Mingyang Ren; Huashan Liu; Liang Kang

doi:10.1001/jama.2024.24276

. 2025 Jan 23;333(9):774–783. doi: 10.1001/jama.2024.24276

Transanal vs Laparoscopic Total Mesorectal Excision and 3-Year Disease-Free Survival in Rectal Cancer

The TaLaR Randomized Clinical Trial

Ziwei Zeng ¹, Shuangling Luo ¹, Hong Zhang ², Miao Wu ³, Dan Ma ⁶, Quan Wang ⁷, Ming Xie ⁸, Qing Xu ⁹, Jun Ouyang ¹⁰, Yi Xiao ¹¹, Yongchun Song ¹², Bo Feng ¹³, Qingwen Xu ¹⁴, Yanan Wang ¹⁵, Yi Zhang ¹⁶, Lishuo Shi ¹⁷, Li Ling ¹⁸, Xingwei Zhang ¹, Liang Huang ¹, Zuli Yang ¹, Junsheng Peng ¹, Xiaojian Wu ¹, Donglin Ren ¹, Meijin Huang ¹, Ping Lan ¹, Jianping Wang ¹, Weidong Tong ⁵, Mingyang Ren ⁴, Huashan Liu ¹, Liang Kang ^1,^✉, for the Chinese Transanal Endoscopic Surgery Collaborative (CTESC) Group

¹Department of General Surgery (Colorectal Surgery), Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

²Department of Colorectal Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

³Department of Gastrointestinal Surgery, The Second People’s Hospital of Yibin, Yibin, Sichuan, China

⁴Department of Gastrointestinal Surgery, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong, Sichuan, China

⁵Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China

⁶Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China

⁷Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin, China

⁸Department of Gastrointestinal Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China

⁹Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

¹⁰Department of Gastrointestinal Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China

¹¹Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

¹²Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xian, Shanxi, China

¹³Department of Gastrointestinal Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

¹⁴Department of Gastrointestinal Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China

¹⁵Department of Gastrointestinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

¹⁶Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China

¹⁷Clinical Research Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

¹⁸Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, China

Group Information: The Chinese Transanal Endoscopic Surgery Collaborative (CTESC) Group members are listed in Supplement 4.

Accepted for Publication: October 16, 2024.

Published Online: January 23, 2025. doi:10.1001/jama.2024.24276

^✉

Corresponding Author: Liang Kang, MD, PhD, Department of General Surgery (Colorectal Surgery), Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Erheng Rd, Guangzhou, Guangdong 510655, China (kangl@mail.sysu.edu.cn).

Author Contributions: Drs Kang, Liu, M. Ren, Tong, and J. Wang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Zeng, Luo, Zhang, and M. Wu are joint first authors. Drs J. Wang, Tong, M. Ren, Liu, and Kang contributed equally and are co–senior authors.

Concept and design: Zeng, Luo, H. Zhang, M. Wu, Tong, Liu, Kang.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Zeng, Luo, H. Zhang, Liu, Kang.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Shi, Ling.

Obtained funding: Kang.

Administrative, technical, or material support: Zeng, Luo, H. Zhang, M. Wu, Ma, Q. Wang, Xie, Qing Xu, Ouyang, Xiao, Song, Feng, Qingwen Xu, Y. Wang, Y. Zhang, X. Zhang, L. Huang, Yang, Peng, X. Wu, D. Ren, M. Huang, Lan, J. Wang, Tong, M. Ren, Liu, Kang.

Supervision: Tong, M. Ren, Liu, Kang.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants from the Sun Yat-sen University Clinical Research 5010 Program (2016005), National Natural Science Foundation of China (82473451, 82472930, and 82200569), Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Innovative Clinical Technique of Guangzhou, and National Key Clinical Discipline.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Chinese Transanal Endoscopic Surgery Collaborative (CTESC) Group nonauthor collaborators appear in Supplement 4.

Meeting Presentation: The preliminary results of the TaLaR trial were presented at the 2024 American Society of Clinical Oncology Annual Meeting; June 3, 2024; Chicago, IL (abstract ID: 3516).

Data Sharing Statement: See Supplement 5.

Additional Contributions: We thank the patients who participated in this study and their families, as well as the nursing and research staff at the study centers. We also extend our gratitude to Y.X. Luo, MD (Sun Yat-sen University, Sixth Affiliated Hospital) and Q.M. Yin, PhD (Ruprecht Karl University of Heidelberg), for their generous assistance during the revision process of this article. Drs Luo and Yin did not receive compensation.

^✉

Corresponding author.

PMCID: PMC11880948 PMID: 39847361

Key Points

Question

Is transanal total mesorectal excision (TME) noninferior to laparoscopic TME in 3-year disease-free survival in patients with rectal cancer?

Findings

The transanal TME group exhibited 3-year disease-free survival of 82.1%, compared with 79.4% in the laparoscopic TME group. The lower tail of a 2-tailed 97.5% CI for the group difference in 3-year disease-free survival was above the noninferiority margin of −10 percentage points.

Meaning

This study supports the use of transanal TME for patients preoperatively assessed with stage I to III rectal cancer in places where expertise in surgical robotic techniques is not available.

Abstract

Importance

Previous studies have demonstrated the advantages of short-term histopathological outcomes and complications associated with transanal total mesorectal excision (TME) compared with laparoscopic TME. However, the long-term oncological outcomes of transanal TME remain ambiguous. This study aims to compare 3-year disease-free survival of transanal TME with laparoscopic TME.

Objective

To evaluate 3-year disease-free survival between transanal TME and laparoscopic TME in patients with rectal cancer.

Design, Setting, and Participants

This randomized, open-label, noninferiority, phase 3 clinical trial was performed in 16 different centers in China. Between April 2016 and June 2021, a total of 1115 patients with clinical stage I to III mid-low rectal cancer were enrolled. The last date of participant follow-up was in June 2024.

Interventions

Participants were randomly assigned in a 1:1 ratio before their surgical procedure to undergo either transanal TME (n = 558) or laparoscopic TME (n = 557).

Main Outcomes and Measures

The primary end point was 3-year disease-free survival, with a noninferiority margin of −10% for the comparison between transanal TME and laparoscopic TME. Secondary outcomes included 3-year overall survival and 3-year local recurrence.

Results

In the primary analysis set, the median patient age was 60 years. A total of 692 male and 397 female patients were included in the analysis. Three-year disease-free survival was 82.1% (97.5% CI, 78.4%-85.8%) for the transanal TME group and 79.4% (97.5% CI, 75.6%-83.4%) for the laparoscopic TME group, with a difference of 2.7% (97.5% CI, −3.0% to 8.1%). The lower tail of a 2-tailed 97.5% CI for the group difference in 3-year disease-free survival was above the noninferiority margin of −10 percentage points. Furthermore, the 3-year local recurrence was 3.6% (95% CI, 2.0%-5.1%) for transanal TME and 4.4% (95% CI, 2.6%-6.1%) for laparoscopic TME. Three-year overall survival was 92.6% (95% CI, 90.4%-94.8%) for transanal TME and 90.7% (95% CI, 88.3%-93.2%) for laparoscopic TME.

Conclusions and Relevance

In patients with mid-low rectal cancer, 3-year disease-free survival for transanal TME was noninferior to that of laparoscopic TME.

Trial Registration

ClinicalTrials.gov Identifier: NCT02966483

This randomized, open-label, phase 3 clinical trial investigates whether transanal total mesorectal excision is noninferior to laparoscopic total mesorectal excision in 3-year disease-free survival in patients with mid-low rectal cancer.

Introduction

Colorectal cancer is a widespread disease, ranking as the third-most common type of cancer worldwide.¹ Specifically, rectal cancer accounts for more than one-third of all colorectal cancer cases.¹ The primary treatment for rectal cancer typically involves a multidisciplinary approach, with surgical intervention as the cornerstone. Among surgical techniques, total mesorectal excision (TME) is established as the standard for mid and low rectal cancer.^2,3 In recent years, laparoscopic TME has gained preference due to its advantages, such as enhanced postoperative recovery and reduced complication rates. Furthermore, laparoscopic TME has demonstrated comparable long-term oncological outcomes to open TME.^4,5,6 Nonetheless, managing obesity in male patients with a constricted pelvic space presents specific challenges. Laparoscopic TME may result in suboptimal resection specimens, an increased complication rate, and a higher conversion rate.⁷

Robotic surgical procedures have become increasingly popular in recent years.^8,9 The robotic system offers enhanced visualization of the surgical field and superior instrument maneuverability with optimal stability. This allows for ambidextrous movements, reduces tremor, and improves dexterity, thereby enabling more precise dissection, even in confined spaces. These advantages could override the daunting challenges of laparoscopic TME. Compared with robotic surgical procedures, transanal TME, which utilizes laparoscopic instruments, has also garnered significant interest due to its potential to enhance visualization and facilitate dissection in the distal portion of the TME procedure.^10,11 Currently, transanal TME is considered an alternative method to address the challenges of laparoscopic TME, particularly in regions lacking access to surgical robots. Several studies have reported favorable results with transanal TME, indicating it may yield higher-quality resected specimens and achieve similar or improved short-term outcomes compared with laparoscopic TME.^12,13,14 Moreover, the benefits of transanal TME for postoperative recovery, quality of TME, and sphincter preservation have contributed to its growing adoption by surgeons for the management of mid-low rectal cancers.^14,15 Nonetheless, 2019 data from the Norwegian Colorectal Cancer Group reported a local recurrence rate of 7.9% (12/152) among patients treated with transanal TME, with 6 patients experiencing multiple local recurrences and 8 patients encountering local recurrence within 1 year.¹⁶ In contrast, the local recurrence rate in cohorts from the Norwegian Colorectal Cancer Registry was 3.4%, leading to the suspension of transanal TME in Norway.¹⁶ Furthermore, a Dutch study reported a high incidence of local recurrences (10% [12/120]) in an implementation cohort, including a significant rate of multifocal recurrences.¹⁷ These findings have raised substantial concerns regarding the oncological safety of transanal TME.¹⁸

Although the Ta-LaTME study group reported undiminished short-term outcomes between transanal TME and laparoscopic TME,¹⁹ and the TaLaR trial demonstrated comparable surgical safety of transanal TME and laparoscopic TME with improved recovery time for patients with mid-low rectal cancer,²⁰ evidence is still lacking to establish the effectiveness of long-term oncological outcomes of transanal TME for rectal cancer from large-scale randomized clinical trials. At present, trials such as COLOR III and ETAP-GRECCAR 11 are in the enrollment phase.^21,22 Consequently, this study aims to report 3-year long-term survival and locoregional recurrence in patients randomly assigned to undergo either transanal TME or laparoscopic TME within the framework of the TaLaR trial, with a particular focus on 3-year disease-free survival.

Methods

Study Design and Participants

The TaLaR trial, a phase 3, multicenter, randomized, clinical noninferiority study, recruited from April 2016 to June 2021 to compare the long-term oncological outcomes of transanal TME with laparoscopic TME in patients with rectal cancer. The trial included 16 centers across 10 provinces in China. Institutional review board approval was obtained from each participating hospital, and written informed consent was obtained from all patients. Randomization of eligible patients in a 1:1 ratio between transanal TME and laparoscopic TME treatments was facilitated through a web-based system at the data center in Guangzhou, China. The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

The eligibility criteria for this trial included patients aged 18 to 75 years with an American Society of Anesthesiologists class I to III classification, a diagnosis of clinical stage I to III rectal adenocarcinoma located below the peritoneal reflection confirmed by preoperative imaging, and potential candidates for curative treatment using sphincter-sparing techniques following TME principles. Exclusion criteria comprised patients with T1 cancers amenable to local resection, confirmed involvement of the circumferential resection margin by preoperative imaging, those who underwent an abdominoperineal resection, tumors involving the internal sphincter or levator ani, and patients with contraindications for surgical procedures. Patients underwent preoperative pelvic magnetic resonance imaging for rectal cancer and computed tomography for thoracic and abdominal conditions to exclude distant metastases. The detailed study protocol and comprehensive statistical analysis plan were approved and accessible in Supplement 1 and Supplement 2, respectively.

Randomization and Masking

Eligible patients were randomized preoperatively in a 1:1 ratio to undergo either transanal TME or laparoscopic TME through a web-based randomization system utilizing central allocation and stratification by center. Participating centers submitted patient information to the data center at the Sixth Affiliated Hospital of Sun Yat-sen University in Guangzhou, China, where central randomization was conducted. Information regarding treatment assignments was subsequently communicated to each participating center. After completing randomization, neither surgeons nor patients were masked to the treatment assignment. Detailed randomization information is available in Supplement 1.

Surgical Quality Control and Procedure

Surgeons were selected from the membership of the Chinese Transanal Endoscopic Surgery Collaborative (CTESC) Group, with eligibility criteria defined as follows: (1) completion of at least 100 laparoscopic TME and 50 transanal TME procedures by each surgical team; (2) an anticipated annual caseload of at least 50 laparoscopic TME and 30 transanal TME procedures; and (3) confirmation of qualification by the CTESC Research Committee, which required the evaluation of unedited videos from 2 laparoscopic TME and 2 transanal TME procedures performed on obese male patients (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared] ≥28) with rectal cancer below the peritoneal reflection.

Surgical quality control was ensured through the review of unedited videos by the CTESC Research Committee, which provided regular feedback to the investigators. Both transanal TME and laparoscopic TME procedures were performed in accordance with TME principles. The key distinction was that transanal TME was performed from a transanal bottom-up approach. The methods of anastomosis were not uniform, allowing for either handsewn or stapled anastomosis. Detailed information on the procedure is available in Supplement 1.

Follow-Up

The follow-up process was rigorously managed by specialized teams at each participating research center, which were responsible for scheduling and conducting regular assessments at predetermined intervals. In the first year after the surgical procedure, follow-up evaluations were conducted every 3 months, followed by every 6 months in the second year, and annually thereafter. Tumor marker examinations were performed at each designated time point. Colonoscopies, chest and abdominal computed tomographic scans, and pelvic magnetic resonance imaging were scheduled at 3, 12, 24, 36, 48, and 60 months postprocedure. Additional imaging examinations were recommended if symptoms or examination results indicated potential local recurrence or metastasis. Patients who refused follow-up according to the protocol were recorded as lost to follow-up and analyzed with the cases meeting the study criteria at the end of the study. The detailed follow-up outline is presented in Supplement 1.

Outcomes

In this analysis, the primary outcome measure focused specifically on 3-year disease-free survival, while secondary outcomes included 3-year overall survival and 3-year local recurrence. As of June 2024, this trial had a minimum follow-up period of 36 months postprocedure. Disease-free survival was defined as the time from intervention to disease or death from any cause, censored at the last day the patient was alive without evidence of disease. If there were no follow-up data on death or tumor recurrence, the final date of no relapse was confirmed as the termination point. A detailed definition of the outcomes is presented in Supplement 1.

Statistical Analysis

The sample size was calculated using PASS software. The estimated sample size for this trial was 1114 participants. The assumptions underlying the sample size calculation were based on 3-year disease-free survival or 5-year overall survival among patients with clinical stage I to III rectal cancer treated with laparoscopic TME. Based on trials comparing laparoscopic and open surgical procedures, which have used a noninferiority margin ranging from 5% to 15% for 3-year oncological outcomes,^5,23,24 a noninferiority margin of 10% for 3-year disease-free survival was selected for the current study. The anticipated 3-year disease-free survival and 5-year overall survival were set at 74.6% and 77.4%, respectively. An α error rate of 2.5% was allocated to each of the disease-free survival and overall survival end points, based on a Bonferroni correction, and a 2-tailed 97.5% CI was calculated to evaluate each of the 2 end points. If the lower 1.25% tail of the CI of difference in 3-year disease-free survival between the 2 groups was larger than the noninferiority margin of −10% difference, then transanal TME would be demonstrated to be noninferior to laparoscopic TME. The sample size was based on a designed power of 80% for both 3-year disease-free survival and 5-year overall survival. This relatively wide noninferiority margin was considered acceptable to clinicians and patients, given the expectation that transanal TME might be superior to laparoscopic TME in terms of less surgical trauma, quicker recovery, and higher rates of sphincter preservation.^14,20

By June 2024, this trial had a minimum follow-up of 36 months for patients after the surgical procedure, which would achieve sufficient power to test a noninferiority margin of −10% for the comparison of the 2 groups in 3-year disease-free survival. Consequently, the primary outcome reported in this study centered on 3-year disease-free survival. The evaluation of 3-year disease-free survival was conducted in the primary analysis set, excluding patients who were later discovered not to have met the inclusion criteria at baseline. In the transanal TME group, no patients underwent laparoscopic TME and no patients in the laparoscopic TME group underwent transanal TME. For this analysis, the primary analysis set and per-protocol populations were identical. Noninferiority of transanal TME to laparoscopic TME would be accepted if the lower tail of the estimated difference in 3-year disease-free survival, represented by the 97.5% CI, was above −10%.

The primary analysis was performed using a Cox proportional hazards model to calculate hazard ratios (HRs) with 97.5% CIs for 3-year disease-free survival and 95% CIs for 3-year overall survival and local recurrence, applying the log-rank test to calculate the P value. Three-year disease-free survival, overall survival, and local recurrence were estimated by Kaplan-Meier survival curves, along with corresponding 97.5% CIs for 3-year disease-free survival and 95% CIs for overall survival and local recurrence. Prior to analysis, the proportional hazards assumption was evaluated using the Schoenfeld residuals test. Univariate and multivariable Cox regression analyses were performed to estimate mean and secondary survival outcomes for 3-year disease-free survival and overall survival, with 95% CIs and P values between groups according to the HR accompanied by their 95% CI. Participants who refused follow-up according to the protocol after treatment were considered missing, and all values collected during the follow-up period were censored to assess the potential effect of any missing data. All statistical tests were 2-sided and, while specific P values are presented, those less than .05 were considered statistically significant. All statistical analyses were performed using SAS version 9.3 (SAS Institute). This trial utilized a data monitoring committee and is registered with ClinicalTrials.gov (NCT02966483).

Results

Patient Characteristics

The detailed short-term results were previously reported.²⁰ From April 2016 to June 2021, a total of 1115 patients were enrolled from 16 medical centers in China. As shown in Figure 1, the primary analysis set included 544 in the transanal TME group and 545 in the laparoscopic TME group. Baseline characteristics and pathological outcomes are shown in Table 1 (eTable 1 in Supplement 3), and the overall missing rate was 1.3% (14/1089). In this study, there were 359 and 333 male patients and 150 and 121 obese patients in the transanal TME and laparoscopic TME groups, respectively.

Figure 1. — TME indicates total mesorectal excision.

^aSurgeons decided to perform the abdominoperineal resection (Miles operation) procedure, according to the specific intraoperative circumstances. The Miles operation is used for the treatment of rectal cancers, involving the removal of the distal colon, rectum, and anal sphincter complex, resulting in a permanent colostomy.

^bTwo patients randomized to undergo transanal TME did not provide proper consent; hence, their data could not be used in any analysis.

^cPatients were found to have peritoneal metastasis (n = 1) or liver metastasis (n = 1) intraoperatively.

^dAfter the procedure, the patient refused to participate and have their data used in any analysis.

^eThe primary analysis set excluded patients who were later discovered not to have met the inclusion criteria at baseline.

Table 1. Patient Clinical and Histopathological Characteristics.

Characteristic	Transanal total mesorectal excision, No. (%) (n = 544)	Laparoscopic total mesorectal excision, No. (%) (n = 545)
Sex
Male	359 (66.0)	333 (61.1)
Female	185 (34.0)	212 (38.9)
Age, median (IQR), y	58 (50-67)	60 (52-67)
BMI, median (IQR)	22.9 (20.7-24.9)	22.8 (20.9-24.8)
ASA classification^a
I (Normal)	228 (41.9)	219 (40.2)
II	279 (51.3)	270 (49.5)
III	37 (6.8)	56 (10.3)
Tumor distance from anal verge, median (IQR), cm	5.0 (3.9-6.0)	5.5 (4.4-6.6)
Preoperative clinical stage^b
I (Less advanced)	105 (19.3)	89 (16.3)
II	220 (40.4)	243 (44.6)
III (More advanced)	219 (40.3)	213 (39.1)
Preoperative therapy	211 (38.8)	179 (32.8)
Chemotherapy plus radiation	93 (17.1)	59 (10.8)
Chemotherapy alone	116 (21.3)	120 (22.0)
Radiation alone	2 (0.4)	0
Pathological stage^c
I (Less advanced)	174 (32.0)	165 (30.3)
II	179 (32.9)	183 (33.6)
III (More advanced)	164 (30.1)	173 (31.7)
Pathologic complete response	27 (5.0)	24 (4.4)
Macroscopic completeness of resection
Complete	487 (89.5)	469 (86.1)
Nearly complete	57 (10.5)	76 (13.9)
Circumferential resection margin^d
Positive (≤1 mm)	5 (0.9)	5 (0.9)
Distal resection margin^e
Positive (≤1 mm)	2 (0.4)	4 (0.7)
No. of harvested lymph nodes, median (IQR)	14 (10-19)	15 (11-20)
Tumor differentiation
Well	45 (8.3)	34 (6.2)
Moderate	430 (79.0)	443 (81.3)
Poor	42 (7.7)	44 (8.1)
Lymphovascular invasion	71 (13.1)	84 (15.4)
Nerve invasion	63 (11.6)	56 (10.3)
Adjuvant chemotherapy	297 (54.6)	301 (55.2)

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Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).

^{^a}

ASA categorizes patients into 5 levels: I, normal, healthy; II, mild systemic disease; III, severe systemic disease; IV, severe systemic disease that is a constant threat to life; V, moribund undergoing surgical procedures or not, with little chance for survival.

^{^b}

According to 7th edition of American Joint Committee on Cancer Staging System, clinical stage I includes T1 or T2 with N0M0; II, T3 or T4 with N0M0; III, any T with N1M0 or N2M0; IV, any T or N with M1. Clinical stage evaluated by preoperative imaging.

^{^c}

Pathological stage I includes T1 or T2 with N0M0; II, T3 or T4 with N0M0; III, any T with N1M0 or N2M0; IV, any T or N with M1. Pathologic complete response defined as absence of malignant cells on specimen of rectal resection in patients previously treated with preoperative therapy. Pathological stage evaluated by rectal resection specimen.

^{^d}

Involvement of the circumferential resection margin considered if distance ≤1 mm from tumor to mesorectal fascia.

^{^e}

Positive distal resection margin defined if distance between closest tumor to cut edge of tissue ≤1 mm.

Primary Outcome

The incidence of recurrence within 3 years postprocedure was reported in 86 patients in the transanal TME group and 96 patients in the laparoscopic TME group (Table 2). Overall 3-year disease-free survival was 80.7% (97.5% CI, 78.1%-83.5%), with 82.1% (97.5% CI, 78.4%-85.8%) in the transanal TME group and 79.4% (97.5% CI, 75.6%-83.4%) in the laparoscopic TME group (Figure 2) (eTable 2 in Supplement 3). The difference in 3-year disease-free survival between the 2 groups was 2.7% (97.5% CI, −3.0% to 8.1%), with an HR of 0.86 (97.5% CI, 0.63-1.18). The lower tail of a 2-tailed 97.5% CI for the group difference in 3-year disease-free survival was above the noninferiority margin of −10 percentage points (Figure 3) (eTable 2 in Supplement 3). A similar HR was observed after adjusting for age, sex, pathological stage, neoadjuvant treatment, tumor differentiation, lymphovascular invasion, and nerve invasion (HR, 0.83 [95% CI, 0.63-1.10]) (eTable 3 in Supplement 3).

Table 2. Frequency of Causes of First Recurrence and Death Within 3 Years After Surgical Procedure in Patients Who Underwent Transanal Total Mesorectal Excision (TME) or Laparoscopic TME.

Event	No. of events		Difference (95% CI), %^a	Hazard ratio (95% CI)^b	P value^c
Event	Transanal TME (n = 544)	Laparoscopic TME (n = 545)	Difference (95% CI), %^a	Hazard ratio (95% CI)^b	P value^c
Recurrence^d	86	96	−1.8 (−6.4 to 2.8)	0.88 (0.66 to 1.18)	.41
Local^e	14	18	−0.7 (−2.9 to 1.5)	0.77 (0.38 to 1.54)	.46
Liver	9	11	−0.4 (−2.1 to 1.4)	0.81 (0.34 to 1.95)	.64
Lung	17	25	−1.5 (−3.9 to 1.0)	0.67 (0.36 to 1.24)	.20
Multiple sites^f	28	27	0.2 (−2.6 to 3.0)	1.02 (0.60 to 1.74)	.93
Other or uncertain sites^g	18	15	0.6 (−1.7 to 2.8)	1.18 (0.60 to 2.35)	.63
Death^h	40	50	−1.8 (−5.3 to 1.6)	0.79 (0.52 to 1.20)	.27
Rectal cancer	29	37	−1.5 (−5.3 to 1.6)	0.78 (0.48 to 1.26)	.31
Other causeⁱ	11	13	−0.4 (−2.3 to 1.6)	0.83 (0.37 to 1.86)	.66

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^{^a}

For outcomes other than all-cause death, the risk difference was calculated by subtracting the cumulative incidence over the first 3 years in the transanal TME group from that of the laparoscopic TME group, considering competing events. For all-cause death, the risk difference was determined by subtracting the 3-year overall survival rate of the transanal TME group from that of the laparoscopic TME group.

^{^b}

For outcomes other than all-cause death, competing risks survival regression was used to derive the hazard ratio, 95% CI, and P value. For total recurrence, all-cause death was treated as a competing event. For specific types of recurrence, other types of recurrence and death were treated as competing events. For deaths due to rectal cancer, other causes of death were treated as competing events and vice versa. Mixed-effects Cox regression was used for all-cause death.

^{^c}

P values correspond to the hazard ratios.

^{^d}

Refers solely to first-time recurrence, even though patients may have experienced multiple recurrences.

^{^e}

Includes patients with local recurrence.

^{^f}

Includes patients with simultaneous recurrences at 2 or more sites, such as local, peritoneum, liver, lung, bone, brain, distant lymph node, or other hematogenous metastatic site.

^{^g}

Encompasses hematogenous recurrences at sites other than local recurrence, liver, and lung, such as recurrences at distant lymph nodes, brain, bone, peritoneum, and unspecified sites.

^{^h}

Post hoc exploratory outcomes.

^ⁱ

Encompasses deaths from other cancers, noncancer diseases, unintentional injuries, and unknown causes.

Figure 3. — ^aDifference between transanal TME and laparoscopic TME was 2.7% (97.5% CI, −3.0% to 8.1%).

^bTransanal TME − laparoscopic TME.

As shown in Figure 2 and eTable 4 in Supplement 3, there were no significant differences between the transanal TME and laparoscopic TME groups across different pathological stages (stage I: HR, 1.29 [95% CI, 0.61-2.73]; stage II: HR, 0.68 [95% CI, 0.41-1.11]; stage III: HR, 0.97 [95% CI, 0.67-1.40]).

Secondary Outcomes

A total of 19 patients in the transanal TME group and 23 patients in the laparoscopic TME group experienced a local recurrence within 3 years postprocedure. No patients experienced multifocal local recurrence. Three-year local recurrence for all patients was 4.0% (95% CI, 2.8%-5.2%), with the transanal TME group at 3.6% (95% CI, 2.0%-5.1%) and the laparoscopic TME group at 4.4% (95% CI, 2.6%-6.1%), demonstrating similar rates (HR, 0.81 [95% CI, 0.44-1.49]) (eFigure 1 in Supplement 3). eFigure 1 and eTable 4 in Supplement 3 indicate no significant difference in 3-year local recurrence between the 2 groups across different pathological stages (stage I: HR, 0.96 [95% CI, 0.24-3.84]; stage II: HR, 0.49 [95% CI, 0.17-1.45]; stage III: HR, 1.28 [95% CI, 0.50-3.24]).

At 3 years postprocedure, 90 patients had died (Table 2), yielding a 3-year overall survival of 92.6% (95% CI, 90.4%-94.8%) in the transanal TME group and 90.7% (95% CI, 88.3%-93.2%) in the laparoscopic TME group (HR, 0.78 [95% CI, 0.52-1.19]) (eFigure 2 in Supplement 3). The cumulative incidence of cause-specific death did not significantly differ between the 2 groups (Table 2). As shown in eFigure 2 and eTable 4 in Supplement 3, when analyzed by pathological stage, 3-year overall survival was comparable between groups in patients with stages I and II rectal cancer (stage I: HR, 3.40 [95% CI, 0.71-16.36]; stage II: HR, 1.36 [95% CI, 0.63-2.97]), but in stage III patients, the transanal TME group had better overall survival compared with the laparoscopic TME group (stage III: HR, 0.51 [95% CI, 0.29-0.89]). A similar HR was observed after adjusting for age, sex, neoadjuvant treatment, pathological stage, tumor differentiation, lymphovascular invasion, and nerve invasion (HR, 0.77 [95% CI, 0.50-1.17]) (eTable 3 in Supplement 3).

Subgroup Analysis

Three-Year Disease-Free Survival

Three-year disease-free survival for male patients was 81.4% in the transanal TME group and 76.2% in the laparoscopic TME group (HR, 0.75 [95% CI, 0.54-1.05]) (eFigure 3 in Supplement 3). For patients with a BMI of greater than 25, the rates were 84.4% and 78.7% in the transanal TME and laparoscopic TME groups, respectively (HR, 0.74 [95% CI, 0.42-1.31]). Among patients who received preoperative therapy, the rates were 76.2% in the transanal TME group and 77.6% in the laparoscopic TME group (HR, 1.08 [95% CI, 0.71-1.63]). For tumors larger than 3 cm, the rates were 78.7% for transanal TME and 76.4% for laparoscopic TME (HR, 0.89 [95% CI, 0.60-1.32]).

Three-Year Overall Survival

In subgroup analysis (eFigure 4 in Supplement 3), 3-year overall survival for male patients was 93.0% in the transanal TME group compared with 89.3% in the laparoscopic TME group (HR, 0.64 [95% CI, 0.38-1.06]). For patients with a BMI of greater than 25, the rates were 92.5% in the transanal TME group and 89.8% in the laparoscopic TME group (HR, 0.72 [95% CI, 0.49-1.64]). Among patients with tumors larger than 3 cm, the rates were 91.9% for transanal TME and 86.6% for laparoscopic TME (HR, 0.58 [95% CI, 0.32-1.05]).

Discussion

This study previously demonstrated that circumferential resection margin positivity, macroscopic quality of the TME specimen, the number of harvested lymph nodes, and perioperative morbidity were comparable between the transanal TME and laparoscopic TME groups. Additionally, patients who underwent transanal TME exhibited faster postoperative recovery.²⁰ This study aimed to report 3-year disease-free survival in patients with rectal cancer treated with either transanal TME or laparoscopic TME. The findings indicate that 3-year disease-free survival for transanal TME is noninferior to that of laparoscopic TME. Furthermore, this trial demonstrated that 3-year overall survival and 3-year local recurrence in patients with rectal cancer who underwent transanal TME were comparable to those who underwent laparoscopic TME.

Although transanal TME was introduced more than a decade ago, several retrospective studies have found that the oncological outcomes of transanal TME are comparable to those of laparoscopic TME; the lack of high-quality randomized clinical trials to report these outcomes highlights an urgent need for rigorous research to provide robust evidence. For instance, Hol et al reported a 2.0% local recurrence with a minimum follow-up of 36 months in 159 patients, with 3-year disease-free survival and overall survival of 83.6% and 92.0%, respectively.²⁵ Roodbeen et al reported a 3.3% local recurrence with a median follow-up of 25.5 months in 767 patients with rectal cancer, with 3-year disease-free survival and overall survival of 77.6% and 93.4%, respectively.²⁶ As the first and largest randomized clinical trial to date comparing the long-term oncologic outcomes of transanal TME and laparoscopic TME, this study confirms that disease-free survival of the transanal TME group was noninferior to that of the laparoscopic TME group (82.1% vs 79.4%; difference, 2.7% [97.5% CI, −3.0% to 8.1%]; HR, 0.86 [97.5% CI, 0.63-1.18]). Furthermore, overall survival was similar between the 2 groups (92.6% vs 90.7%). Similar rates of disease-free survival were observed in patients diagnosed at the same pathological stage. It is worth noting that the transanal TME group exhibited better overall survival compared with the laparoscopic TME group in patients with stage III cancer (HR, 0.51 [95% CI, 0.29-0.89]). These results suggest that transanal TME is a viable option for patients with mid-low rectal cancer, potentially offering advantages over laparoscopic TME in 3-year survival outcomes. However, further studies are necessary to validate these findings.

In patients with a relatively narrow pelvic surgical space, transanal TME is considered to enhance surgical quality and may improve patient outcomes.¹⁰ It is generally accepted that males and obese patients have a relatively narrow surgical space. In this study, according to criteria for obesity in Asian populations, individuals with a BMI greater than 25 were classified as obese. Subgroup analysis indicated a trend toward improved 3-year disease-free survival and overall survival with transanal TME compared with laparoscopic TME in male patients (disease-free survival: HR, 0.75; overall survival: HR, 0.64) and patients with a BMI greater than 25 (disease-free survival: HR, 0.74; overall survival: HR, 0.72) (eFigures 3 and 4 in Supplement 3). Considering the characteristics of rectal cancer in European and US populations, where obese or male patients are more prevalent, this procedure may have significant clinical application value.¹ Notably, these trends not achieving statistical significance may be due to limited sample sizes in the subgroup analyses. Further studies with larger sample sizes are needed to validate these findings.

Concerns regarding the long-term oncological outcomes of transanal TME for rectal cancer are reminiscent of those associated with the initial adoption of laparoscopic TME. Studies by Larsen et al and Oostendorp et al reported local recurrence of 7.9% and 10%, respectively, in patients who underwent transanal TME.^16,17 Inadequate purse-string closure of the rectum and intraoperative rectal injury may contribute to multifocal local recurrences.¹⁸ Given the learning curve associated with new surgical techniques, transanal TME follows a trajectory like that of laparoscopic TME for rectal cancer.^14,27 Studies have indicated that the effective learning curve for laparoscopic rectal surgical procedures ranges from 40 to 80 cases.^4,28,29 The investigators’ previous study identified that the primary surgeon surpassed the learning curve after 42 cases.¹⁴ Therefore, to ensure that participating surgeons have surpassed the learning curve, the unedited videos of 2 laparoscopic TME and 2 transanal TME procedures needed to be reviewed by the CTESC group, specifically in obese male patients with rectal cancer below the peritoneal reflection. Additionally, the frequency of transanal TME and laparoscopic TME procedures performed by the participating surgeons was also an important consideration for the study. In this study, the local recurrence was 3.6% in the transanal TME group and 4.4% in the laparoscopic TME group (HR, 0.81 [95% CI, 0.44-1.49]), indicating comparability and acceptability. The major site of local recurrence was the anastomotic area, with no multifocal local recurrence reported. Thus, transanal TME can provide comparable 3-year oncological outcomes to laparoscopic TME when performed by experienced surgeons.

The safety and feasibility of robotic procedures for rectal cancer have been well established.^8,9 Peirce et al reported that robotic procedures offer improved urinary and erectile function in male patients compared with conventional laparoscopic procedures for rectal cancer.³⁰ Larson et al demonstrated that robotic rectal cancer procedures are associated with better short-term outcomes, including lower complication rates and reduced conversion to an open surgical procedure.³¹ Feng et al found that robotic procedures result in higher oncological quality of resection, reduced surgical trauma, and improved postoperative recovery compared with conventional laparoscopic techniques.³² Compared with surgical robots, transanal TME also offers distinct advantages in accessing the distal rectum and operating within the narrow confines of the pelvis, making it a valuable approach in the management of rectal cancer in areas where expertise in surgical robotic techniques is not available. However, addressing the learning curve associated with transanal TME is crucial and it is imperative to explore strategies to assist surgeons in overcoming this challenge. Based on experience, adverse outcomes associated with the learning curve can be mitigated through animal models, comprehensive gross experiments, standardized training programs, and the initial selection of patients with earlier-stage disease who have not undergone neoadjuvant chemoradiotherapy for transanal TME. Presently, the application of single-port surgical robots exhibits notable flexibility in confined spaces and high compatibility with the natural anatomy of the anus. This could potentially expedite the implementation of robotic transanal TME and facilitate its mastery; however, further research and validation are required.^33,34 Furthermore, the application of artificial intelligence in transanal TME procedures can assist in recognizing surgical dimensions during operations and guide surgeons in real-time resections. This technology may also aid surgeons in swiftly and accurately identifying relevant anatomical structures, thereby enhancing their mastery of transanal TME.^35,36 Consequently, transanal TME is likely to continue being promoted as an alternative treatment for rectal cancer in areas where expertise in surgical robotic techniques is not available.

Limitations

This study has limitations. First, the participating surgeons in this trial were all experienced in transanal TME, which limits the generalizability of results to surgeons without technical expertise in this technique. Second, all study patients included in this trial underwent sphincter-sparing surgical procedures, preventing adequate assessment of the effects of transanal TME on sphincter preservation. Third, it is important to note that all participating centers in this trial were in China. Given the unique demographic characteristics of the Asian population, caution is advised when applying the findings to patients from other racial and ethnic backgrounds. Fourth, despite the large sample size of this study, it had limited power to detect small effect sizes that may nevertheless be clinically important. Specifically, the lower tail of the estimate for 3-year disease-free survival difference was −3%, corresponding to an upper limit of an HR of 1.18, indicating that the hazard rate of adverse events could be up to 18% higher for patients who underwent transanal TME. Fifth, given the limited availability of surgical robots in China at the time this study was conducted, it did not include a robotic surgical procedure group in the design. In future research, the investigators plan to include robotic surgical procedures as an experimental group.

Conclusions

The TaLaR trial indicates that transanal TME is as safe and effective as laparoscopic TME for patients with mid-low rectal cancers, measured by 3-year disease-free survival.

Supplement 1.

Study Protocol

jama-e2424276-s001.pdf^{(1.1MB, pdf)}

Supplement 2.

Statistical Analysis Plan

jama-e2424276-s002.pdf^{(410KB, pdf)}

Supplement 3.

eTable 1. Clinical and Histopathological Characteristics of Followed and Missing Patients

eTable 2. Survival Analysis for transanal TME and laparoscopic TME

eTable 3. Adjusted Hazard Ratio for 3-year disease-free survival and overall survival among Primary Analysis Set Patients with transanal TME or laparoscopic TME

eTable 4. Survival Analysis for transanal TME and laparoscopic TME According to Pathological Stage

eFigure 1. Kaplan-Meier Curves showing Accumulative Local Recurrence for transanal total mesorectal excision vs laparoscopic total mesorectal excision within 3 years after Surgery

eFigure 2. Kaplan-Meier Curves showing Overall Survival for transanal total mesorectal excision vs laparoscopic total mesorectal excision within 3 years after Surgery

eFigure 3. Subgroup Analysis for 3-year disease-free survival based on sex, BMI, tumor size or preoperative therapy

eFigure 4. Subgroup Analysis for 3-year overall survival based on sex, BMI, tumor size or preoperative therapy

jama-e2424276-s003.pdf^{(717.1KB, pdf)}

Supplement 4.

Nonauthor Collaborators

jama-e2424276-s004.pdf^{(132.7KB, pdf)}

Supplement 5.

Data Sharing Statement

jama-e2424276-s005.pdf^{(16.6KB, pdf)}

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Supplementary Materials