CADTH Health Technology Review

Transanal Total Mesorectal Excision for Adults With Rectal Cancer

Rapid Review

Authors: Angela M. Barbara, Anusree Subramonian, Jennifer Horton

Key Messages

• Transanal total mesorectal excision may result in lower rates of conversion to open procedure and a better circumferential resection margin compared with laparoscopic total mesorectal excision in adults with rectal cancer.

• Transanal total mesorectal excision may be comparable to laparoscopic total mesorectal excision for cancer recurrence, survival, death, and short-term safety outcomes in adults with rectal cancer.

• Total mesorectal excision may be more cost-effective than laparoscopic and open total mesorectal excision in adults with rectal cancer, but this is uncertain.

Context and Policy Issues

Colorectal cancer is projected to be the fourth most-diagnosed cancer in 2022 in Canada.¹ It is also the second-leading cause of cancer death, accounting for 11% of all cancer deaths.¹ Rectal cancer is a subset of colorectal cancer, with symptoms that include changes in bowel habits, rectal bleeding, and weight loss.² The 5-year survival of patients with advanced rectal cancer is 58%.³ The treatment of rectal cancer can be challenging because what works for 1 patient may not work for another.³ Surgery is 1 of the main therapies for rectal cancer, with the primary goal of complete removal of the tumour.⁴ The stage, size, and location of the tumour, and the patient’s characteristics (e.g., sex, body mass index, skeletal morphology) can affect the choice of surgical approach for rectal cancer.⁴

Total mesorectal excision (TME), which involves the complete removal of the rectum and surrounding lymphatic tissue,⁵ is the standard of care for tumours in the distal to middle rectum.⁶ TME can be performed with open or laparoscopic techniques.² Conventional open surgery is a procedure in which the surgeon makes a large incision to access the surgery site.^7,8 In contrast, laparoscopic surgery is a less-invasive and more advanced procedure in which a laparoscope is used to make a much smaller incision.^7-9 Laparoscopic TME (LaTME) can be complicated by certain factors, such as a narrow pelvis, obesity, or large tumours, which can reduce the surgeon’s ability to access the distal part of the rectum.^5,10 In such cases, a laparoscopic procedure would need to be converted to the more invasive open TME procedure, which may result in worse short-term post-surgical outcomes.²

Transanal endoscopic surgery is a technique that offers access to rectal cancers through the anus.¹¹ Transanal total mesorectal excision (TaTME) is a surgical procedure that combines the transanal endoscopic surgery approach with the LaTME procedure. The TaTME approach is a minimally invasive surgery for rectal cancer which may facilitate access to tumours that are not amenable to the laparoscopic approach (e.g., patients who are obese, patients who have a narrow pelvis).⁴ For distal and middle rectal cancers, the TaTME surgical treatment facilitates reaching tumours in the distal part of the rectum through the transanal approach and tumours in the middle rectum laparoscopically.⁴

A previous CADTH report on this topic¹² found strong evidence based on 5 moderate- to high-quality systematic reviews (SRs) and 6 low- to moderate-quality non-randomized studies that suggested that TaTME was clinically effective and safe for patients with rectal cancer based on the assessment of short-term outcomes compared with LaTME. However, the report had insufficient evidence about the comparative clinical effectiveness of TaTME versus LaTME over the long term or TaTME versus open TME, and it had no cost-effectiveness evidence for either of the comparisons.¹²

The purpose of the current report is to review and critically appraise recent evidence pertaining to the clinical effectiveness and the cost-effectiveness of TaTME for adults with rectal cancer compared with conventional open TME or LaTME

Research Questions

1. What is the clinical effectiveness of transanal total mesorectal excision for adults with rectal cancer?

2. What is the cost-effectiveness of transanal total mesorectal excision for adults with rectal cancer?

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources, including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were TaTME and rectal cancer. No filters were applied to limit the retrieval by study type. If possible, retrieval was limited to the human population. The search was completed on September 16, 2022, and was limited to English-language documents published since January 1, 2020.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were published before 2020. SRs in which all relevant studies were captured in other more recent or more comprehensive SRs were excluded; the references of these SRs are provided in Appendix 6. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SRs. Non-randomized studies were excluded.

Table 1: Selection Criteria

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)¹³ for SRs, the Downs and Black checklist¹⁴ for randomized studies, and the Drummond checklist¹⁵ for economic evaluations. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 454 citations were identified in the literature search. Following screening of titles and abstracts, 407 citations were excluded and 47 potentially relevant reports from the electronic search were retrieved for full-text review. A grey literature search found no potentially relevant publications for full-text review. Of these potentially relevant articles, 37 publications were excluded for various reasons, and 10 publications met the inclusion criteria and were included in this report. These comprised 8 SRs, 1 randomized controlled trial (RCT), and 1 economic evaluation. The PRISMA¹⁶ flow chart of the study selection is presented in Appendix 1.

Additional references of potential interest are provided in Appendix 6.

Summary of Study Characteristics

Eight SRs,^17-24 1 RCT,²⁵ and 1 economic evaluation²⁶ were included in this report.

Two SRs^18,24 also assessed other surgical interventions (e.g., robotic TME). For those 2 SRs,^18,24 only the subset of primary studies meeting our inclusion criteria were presented here.

The prospective cohort study by Wasmuth et al. (2020)²⁷ was of special interest to potential users of this review. However, it did not meet our inclusion criteria because it was a non-randomized study. However, the study²⁷ was included in 1 SR²⁴ that has been included in this report.

Additional details regarding the characteristics of included publications are provided in Appendix 2.

Study Design

This report includes 8 SRs with meta-analyses^17-24 that were published between 2021 and 2022. The relevant primary studies in the SRs ranged between 7 and 26. These primary studies were either parallel RCTs or comparative non-randomized studies (prospective or retrospective cohort studies and matched case-control studies). The latest literature search dates were between January 2019 and November 2021.

There was some overlap in the primary studies included in the SRs; the degree of overlap is summarized in Appendix 5.

The RCT²⁵ was an open-label, noninferiority trial performed at 16 hospitals in 10 provinces in China from April 2016 to June 2021.

One economic evaluation²⁶ by the National Institute for Health and Care Excellence National Guideline Alliance was included in this report. It was a cost-effectiveness analysis, using the public perspective (i.e., National Health Service [NHS] and personal and social services, both in the UK) with a lifetime horizon. A partitioned survival analysis approach was used for the analysis. The model considered 3 health states: alive without progressed disease, alive with progressed disease, and death. The clinical data were sourced from an evidence review conducted by the National Institute for Health and Care Excellence National Guideline Alliance, which was presented in the same publication.²⁶ Cost data, including treatment costs and procedure costs, were obtained from the NHS. Equipment costs and quality-of-life estimates were obtained from the published literature. Several assumptions were used in the model. Estimate of occurrence of complication (e.g., surgical site infection) after TaTME procedure was assumed to be equivalent to that of the laparoscopic surgery. It was assumed that the complications have only short-term impact on quality of life. Patients were assumed to be treated with 6 cycles of systemic chemotherapy. For TaTME, the systemic chemotherapy and palliative costs were set to zero. The costs were based on 2016–2017 values (£), with a discount rate of 3.5%, and a willingness-to-pay (WTP) threshold of £20,000 per quality-adjusted life-year (QALY).²⁶

Country of Origin

The first authors of the SRs were from Australia,²⁰ China,^17,22 Italy,¹⁸ Morocco,²³ Russia,¹⁹ and South Korea.^21,24 The primary studies in 7 SRs^17,19-24 relevant to this report were conducted in Belgium, China, Denmark, France, Hong Kong, Italy, Poland, Russia, South Korea, Spain, Taiwan, the Netherlands, and the US. One SR¹⁸ did not report where the included studies were conducted.

The authors of the RCT²⁵ were from China, where the trial was conducted.

The cost-effectiveness analysis was conducted in the UK.²⁶

Patient Population

All 8 SRs^17-24 included adults with rectal cancer. The RCT²⁵ included adults with stages I to III rectal cancer.

The cost-effectiveness analysis²⁶ was based on a clinical evidence review involving adults with non-metastatic rectal cancer.

Interventions and Comparators

The intervention was TaTME, and the comparator was LaTME in all 8 SRs^17-24and the RCT.²⁵ One SR²⁴ also included 2 primary studies in which the comparator was LaTME or open TME.

The intervention of interest in the cost-effectiveness analysis²⁶ was the TaTME procedure. The relevant comparators considered in the model were open surgery and laparoscopic surgery.

Outcomes

All 8 SRs^17-24 and the RCT²⁵ reported on various intraoperative, oncological, pathological, and postoperative outcomes.

Three SRs^21-23 and the RCT²⁵ reported on conversion to open procedure. Conversion in LaTME was defined as when the procedure was completed with open surgery.^21,22 Conversion in TaTME was defined as a case in which the procedure was completed by open surgery or the TME was performed by the transanal approach, but the conversion occurred at the transabdominal phase.²¹

Intraoperative blood loss was investigated by 2 SRs^21,22 and the RCT.²⁵ Intraoperative complications were reported by 1 SR²² and the RCT,²⁵ which defined intraoperative complications as unexpected surgical adverse events occurring during surgery (e.g., iatrogenic injury of the blood vessels, bowel, or other organs; hemorrhage; subcutaneous emphysema; and CO₂ embolism). The length of hospital stay was reported by 3 SRs^21-23 and the RCT.²⁵ One SR²¹ reported readmission and reoperation.²¹ The RCT²⁵ also reported secondary surgery.

One SR¹⁸ assessed local recurrence. Two SRs^19,24 assessed both local and distant recurrence. Three SRs^18,19,24 reported overall and disease-free survival.

Positive circumferential resection margin (CRM) or CRM involvement was investigated by 5 SRs^{17,18,21,23,24} and the RCT.²⁵ Positive or clear CRM was defined as tumour-free at a distance of at least 1 mm from the mesorectal fascia.^18,25 CRM length was reported by 2 SRs.^21,22 Positive digital resection margin (DRM) was reported by 4 SRs^17,18,21,23 and the RCT.²⁵ DRM was defined as more than 1 mm between the closest tumour to the cut edge of the tissue.²⁵ DRM length was reported by 2 SRs.^21,22

Incompleteness of TME was assessed by 3 SRs^17,21,24 and the RCT.²⁵ Completeness or quality of TME was reported by 3 SRs^18,22,23 and the RCT.²⁵ The SR by Milone et al. (2022)¹⁸ assessed completeness of TME using the Quirke criteria.¹⁸ In the SR by Ziati et al. (2021)²³ and the RCT,²⁵ TME quality was considered complete or nearly complete. Harvested lymph nodes were reported by 4 SRs^17,21-23 and the RCT.²⁵

Two SRs^19,20 assessed health-related quality of life using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). This is a validated scale that measures the quality of life in cancer patients by through 30 questions about 5 functional aspects (physical, role, emotional, cognitive, and social), 8 symptoms (fatigue, nausea, pain, dyspnea, loss of appetite, insomnia, constipation and diarrhea, financial strain), and global health status.^18-20 Two SRs^18,19 reported health-related quality of life using the EQ Visual Analogue Scale, which records the patient’s self-rated health and can be used as a quantitative measure of health outcome that reflects the patient’s own judgment. The complementary EQ-5D 3 Levels descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. Each dimension has 3 levels: no problems, some problems, and extreme problems.¹⁹

Mortality was reported by 3 SRs^18,21,22 and the RCT.²⁵ Postoperative complications were reported by 4 SRs^18,20,22,23 and the RCT.²⁵ Two SRs^18,22 used the Clavien-Dindo classification to rank postoperative complications, in which grades I and II were categorized as minor and grades III to V were classified as major complications. In the RCT,²⁵ specific postoperative complications were diagnosed according to ether an image-based physical evaluation or obvious clinical evidence, and then were stratified by the Clavien-Dindo classification system.

The RCT²⁵ also assessed incision infection and abdominal and pelvic infection. Anastomotic leakage was reported by 2 SRs^18,23 and the RCT.²⁵ Anastomotic leakage was defined as clinical evidence of a defect of the integrity of the intestinal wall at the anastomotic site or presence of a pelvic abscess adjacent to the anastomosis.²⁵ Ureter or urethral injury was reported by 1 SR,²¹ and intestinal obstruction was reported by 1 SR²¹ and the RCT²⁵

The outcome of the included economic evaluation²⁶ was incremental cost-effectiveness ratio (ICER) reported as cost per QALY.

Summary of Critical Appraisal

Systematic Reviews

All included SRs^17-24 were generally well conducted, but with several limitations. In all SRs,^17-24 the review objective was clearly stated, a literature search was conducted using multiple databases, a list of the included primary studies was presented, the characteristics of the included studies were described, the risk of bias of included studies was assessed, and potential publication bias was investigated.

One SR¹⁸ had a published protocol and another SR²¹ registered its review in PROSPERO. No pre-published protocol was referenced in any of the other 6 SRs,^{17,19,20,22-24} and it is unclear if they had methods that were established a priori. Six SRs^{17,19-21,23,24} included clear statements regarding the use of Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement standards for the conduct of the SRs and meta-analyses.¹⁶ One SR¹⁹ used Cochrane SR methodology.²⁸

Study selection and data extraction was completed by 2 reviewers in 3 SRs.^18,19,24 Five SRs^17,20-23 did not report how study selection was performed but did report that data extraction was performed independently by 2 reviewers. Therefore, the potential for errors in study selection cannot be ruled out in these reviews. A list of excluded studies was not presented in any of the included SRs.^17-24 In the absence of justifications for excluding studies, it is unclear if the selection process captured all the relevant studies.

The SR by Li et al. (2022)¹⁷ reported on whether personnel, patients, and outcome assessors were blinded in the included RCTs. One of the 2 RCTs in the SR¹⁷ included blinded study personnel and participants; outcome assessors were not blinded in either trial.¹⁷ Unblinded studies are at an increased risk for bias.

Seven SRs^17,19-24 assessed the quality of included non-randomized studies using the Newcastle-Ottawa scale, and 1 SR¹⁸ used the ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions). Three SRs^17,20,22 assessed the quality of included RCTs with the Jadad scale, and 1 SR¹⁸ used the Cochrane RoB 2 tool. All SRs assessed between-study heterogeneity using I² measure of inconsistency. Clear criteria for the selection of a random- or fixed-effect model for the meta-analyses were provided in 4 SRs.^{17-19,21,22,24} Random-effect meta-analyses were performed in 2 SRs^20,23 with no clear rationale provided for the use of the random-effect model compared with the fixed-effect model.

Three SRs^17,19,20 did not report the study designs of non-randomized trials (e.g., prospective observational study). Reporting of study designs was possibly inaccurate in another SR.¹⁸ For example, an included primary study identified by the original authors as a matched case-control study was described by 2 SRs as a retrospective study¹⁷ or a retrospective cohort study,¹⁸ suggesting reporting errors.

Four SRs^19,21,23,24 were limited by including only non-randomized studies and no RCTs. In these SRs,^19,21,23,24 all non-randomized studies were pooled in meta-analyses, regardless of study design (e.g., cohort, case-control). The other 4 SRs^17,18,20,22 included a mix or RCTs and non-randomized studies. In these SRs,^17,18,20,22 RCTs and non-randomized studies were pooled in meta-analyses. The Cochrane Handbook for Systematic Reviews of Interventions²⁸ recommends that different observational study designs, or observational and randomized studies, should not be combined in a meta-analysis because this causes increased heterogeneity.²⁸

In 7 SRs,^17-22,24 the authors provided a statement on conflict of interest. In 1 SR,²³ the authors did not declare whether they had any conflicts of interest.

Randomized Controlled Trial

The included RCT²⁵ clearly reported the objective, interventions, and findings. The authors described the randomization method and reported baseline characteristics of all randomized participants, including those who dropped out. The participants were recruited at 16 centres, and the treatment sites were likely representative for receiving TME for rectal cancer. However, all participating centres were in China; therefore, their findings may not be generalizable to Canadian settings.

The primary outcomes were 3-year disease-free survival and 5-year overall survival.²⁵ Sample size calculation was conducted based on the primary outcomes, and the required sample size was achieved at the desired 80% power to detect differences in treatment effect between intervention groups. However, as of the time of publication,²⁵ data on disease-free survival or overall survival were expected at a future date and were not reported in the article.

The early analysis was pre-planned, and the reported outcomes were assessed with appropriate statistical tests. Blinding of patients, study personnel, and outcome assessors was not feasible due to the nature of the intervention. Interoperative and postoperative outcomes were assessed by the participating surgeons. Pathological outcomes were evaluated by 2 specialized pathologists in each participating centre in a blinded manner. All outcomes were reviewed by the Chinese Transanal Endoscopic Collaborative (group that launched the RCT).²⁵

Economic Evaluation

The research question and the objective of the cost-effectiveness analysis²⁶ were clearly described. The type of analysis, perspectives, and time horizon were described and were appropriate for the purpose. The interventions and comparators considered in the model were also appropriate, and the comparators were alternate approaches to the intervention of interest. A partitioned survival analysis model was used for the analysis. In a partitioned survival analysis model, patients belong in 1 of the mutually exhaustive health states, which is determined by overall survival curves. This decision modelling tool is commonly used for economic analyses of interventions for advanced cancers.²⁹ The rationale for this model was described well. The health states were distinct and covered all probable scenarios after the treatment. The sources of data used in the model were clear. The clinical estimates were based on results from an SR of clinical effectiveness with detailed methodology. The clinical effectiveness SR had well-defined eligibility criteria and a comprehensive literature search. Meta-analyses were conducted to quantitatively synthesize the evidence. Cost data, including procedure costs and equipment costs, were sourced from reputable source. Results of the base-case analysis were clearly reported. Deterministic sensitivity analyses were conducted to identify which factors influenced the cost-effectiveness. A cost-effectiveness acceptability curve was presented. The conclusions of the analysis were presented well with appropriate caveats.

However, the analysis was not without limitations. Although a detailed critique of the partitioned survival analysis model is beyond the scope of this report, a major limitation of the model is that mutually exhaustive health states were assumed when, in reality, this may not be true.²⁹ There was a lack of clinical data for TaTME for some outcomes (e.g., complications).²⁶ The authors used assumptions to fill in these gaps. For example, occurrence of surgical site infection for TaTME was assumed to be equivalent to the laparoscopic approach. Complications were assumed to have only short-term effects on quality of life. The costs of systemic chemotherapy and palliative care were set to zero for TaTME. The validity of these assumptions in real-life settings were unclear. For the outcome overall survival, the effect estimate from the clinical review was not statistically significant because the confidence interval passed the point of no effect. However, a point estimate of the hazard ratio was used in the analytic model, which showed increased survival and reduced recurrence with TaTME. It is likely that TaTME was associated with lower QALYs and increased costs than what was considered in the model, since there could be no change in overall survival with TaTME. This could affect result of the analysis in favour of the comparators. Additionally, the authors conducted a sensitivity analysis by using only statistically significant results, which found that TaTME was no longer the optimal approach. Considering the assumptions and these limitations, the validity of the results may be low, and should be interpreted with caution. When reporting results of the analysis, numerical ICERs for each treatment option were not reported, which made independent assessment of the results challenging. It was unclear whether the WTP threshold was appropriate for the settings. Finally, the study was conducted in the UK from the perspective of the NHS.²⁶ The generalizability of the findings to Canadian settings is unclear.

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Summary of Findings

There was some overlap in the primary studies that were included in the SRs.^17-24 Therefore, to minimize duplication of reporting, meta-analyses for a clinical effectiveness outcome in 1 SR were not reported if all included studies were captured in a more recent or more comprehensive meta-analysis in another SR. If study outcomes were included in 1 of the meta-analyses, they were reported only in the pooled estimates (and not the individual study level results). Appendix 4 presents the main study findings.

Clinical Effectiveness of Transanal Total Mesorectal Excision for Adults With Rectal Cancer

Conversion to Open Procedure

Evidence from 2 SRs^21,22 and the RCT²⁵ indicated that TaTME was associated with a statistically significant lower rate of conversion to open procedure compared with LaTME. Heterogeneity among the included studies was zero in 1 SR^21,22 and not important in the other SRs,^21,22 indicating that the results were consistent across studies in both SRs.^21,22

Intraoperative Blood Loss

Two SRs^21,22 reported no statistically significant difference in intraoperative blood loss between the TaTME and LaTME groups. There was moderate to substantial heterogeneity in the analyzed studies. The RCT²⁵ found that intraoperative estimated blood loss was comparable between TaTME and LaTME.

Interoperative Complications

One SR²² and the RCT²⁵ reported that intraoperative complication rates were not significantly different between the TaTME and LaTME groups. There was no heterogeneity among the studies in the SR.²²

Length of Hospital Stay

Two SRs^21,22 and the RCT²⁵ reported no significant differences in length of hospital stay between the TaTME and LaTME groups. Both SRs^21,22 found substantial heterogeneity in hospital stay between studies included in the meta-analysis.

Readmission

One SR²¹ reported no statistically significant difference in readmissions between the TaTME and LaTME groups, and moderate heterogeneity.

Reoperation

One SR²¹ reported no statistically significant difference in reoperations between the TaTME and LaTME groups. There was no heterogeneity between included studies. The RCT²⁵ reported that 4.4% of patients in the TaTME group and 3.5% of patients in the LaTME group required secondary surgery within 30 days after surgery because of anastomotic leakage, anastomotic bleeding, intestinal obstruction, abdominal or pelvic infection, or intraperitoneal bleeding.

Recurrence of Cancer

Two SRs^19,24 found no statistically significant difference in local recurrence of cancer between the TaTME group and the open TME or LaTME groups. One of these SRs²⁴ reported substantial heterogeneity in local recurrence. This heterogeneity was due to 1 prospective observational study (Wasmuth et al. [2020]). In contrast, another SR¹⁸ reported that local recurrence was statistically significantly lower in the TaTME group compared with the open TME or LaTME groups based on 1 included retrospective observational study.

Two SRs^19,24 reported no statistically significant differences in distant cancer recurrence between the TaTME group and the open TME or LaTME groups.

Disease-Free Survival

Two SRs^18,24 reported that disease-free survival was not statistically significantly different in the TaTME group compared with the open TME or LaTME groups.

Overall Survival

Two SRs^18,24 reported no statistically significant differences in overall survival between the TaTME group and the open TME or LaTME groups.

Circumferential Resection Margin

Two SRs^17,24 showed that the positive CRM was statistically significantly lower in the TaTME group compared with the LaTME group. A third SR¹⁸ reported that clear CRM was not statistically significantly different between the TaTME and LaTME groups. Li et al. (2022)¹⁷ performed a subgroup analysis by study design in their SR and found a statistically significant difference in positive CRM only when 2 included RCTs were pooled. In the subgroup analyses of the prospective observational studies and of the retrospective observational studies, there were no statistically significant differences in the positive CRM between the TaTME and LaTME groups. The RCT²⁵ reported no statistically significant difference in positive CRM between the TaTME and LaTME groups.

Two SRs^21,22 reported no statistically significantly difference in length of CRM between the TaTME group and the open TME or LaTME groups, but there was notable heterogeneity.

Distal Resection Margin

Three SRs^17,18,23 and the RCT²⁵ reported that positive DRM was not statistically significantly different between the TaTME and LaTME groups.

Two SRs^21,22 reported no statistically significant differences in length of DRM between TaTME and open TME or LaTME. One SR²¹ reported high heterogeneity among studies, and the other SR²² reported no heterogeneity.

Completeness or Quality of Mesorectal Excision

One SR¹⁷ reported the findings for mesorectum incompleteness in 3 different ways. Two different effect estimates were reported in the text and in a forest plot. Although both effect estimates indicated a significant difference in favour of TaTME compared with LaTME, the authors reported narratively that there was no significant difference in the mesorectum incompleteness rate observed between the TaTME and LaTME groups.¹⁷ Therefore, the results from this SR are unclear.¹⁷

Findings from the other SRs^18,21,24 found no statistically significant differences in completeness of mesorectum between the TaTME and LaTME groups. The RCT²⁵ reported no statistically significant difference in specimen quality of mesorectum excision between the TaTME and LaTME groups. The quality of the TME specimen was complete and nearly complete in all cases; none of the patients in the trial had an incomplete TME.²⁵

Harvested Lymph Nodes

One SR¹⁷ found no significant difference in the number of harvested lymph nodes observed between the TaTME and LaTME groups; however, the heterogeneity was substantial.¹⁷ One cohort study in another SR²¹ and the RCT²⁵ also reported no statistically significant differences in number of harvested lymph nodes between the TaTME and LaTME groups.

Health-Related Quality of Life

Three SRs^18-20 reported that overall or global measures of health-related quality of life were not statistically significantly different between the TaTME and LaTME groups.

Mortality

Perioperative mortality was assessed in 1 SR,²² and was found to be not statistically significantly different between the TaTME and LaTME groups. There was no heterogeneity in the analyzed studies.

The results from 2 SRs^18,21 and the RCT²⁵ indicated no statistically significant differences in 30-day post-operative mortality between the TaTME and LaTME groups. The RCT²⁵ reported that 1 patient in the TaTME group died of septic shock as a result of abdominal infection, and 1 patient in the LaTME group died of a cerebrovascular accident.²⁵ One SR²¹ reported that 1 patient in the TaTME group died and 3 patients in the LaTME group died (causes of death were not reported).

Postoperative Complications

One SR¹⁸ found no statistically significant difference in minor complications assessed 30 days post-surgery between the TaTME and LaTME groups. Two SRs^21,22 reported no statistically significant differences in major complications between the TaTME and LaTME groups, and another SR²³ also found no statistically significant differences between TaTME in LaTME in postoperative complications. There was no heterogeneity in studies analyzed in 3 SRs.^18,21,22 In the RCT,²⁵ there was no statistically significant difference in the overall postoperative complication rate between the TaTME and LaTME groups. Based on the Clavien-Dindo classification of surgical complications, the severity of surgical complications between the 2 groups did not differ.²⁵ Another SR²⁰ found no statistically significant difference in complications requiring surgery between the TaTME and LaTME groups.

Anastomotic Leak

Two SRs^18,21 and the RCT²⁵ found no statistically significant difference in the rate of anastomotic leakage between the TaTME and LaTME groups.

Infection

The RCT²⁵ reported no statistically significant differences in the rates of incisional infection and abdominal or pelvic infection between the TaTME and LaTME groups.

Urethral Injury

One SR²¹ found no statistically significant difference in ureter or urethral injury between the TaTME and LaTME groups.

Intestinal Obstruction

One SR²¹ reported no statistically significant difference in intestinal obstruction between the TaTME and LaTME groups. However, the RCT²⁵ reported a statistically significantly lower rate of intestinal obstruction in the TaTME group compared with the LaTME group.

Cost-Effectiveness of Transanal Total Mesorectal Excision for Adults With Rectal Cancer

The authors of the cost-effectiveness analysis²⁶ reported that, at a WTP threshold of £20,000 per QALY, TaTME was the most cost-effective (dominant) option compared with open surgery and laparoscopic surgery. TaTME was the least expensive option, with the highest QALY among all compared approaches in the base-case analysis. The numerical ICERs of each approach were not reported. The authors also noted that these results were based on the effect estimate for overall survival associated with TaTME, which was obtained from their clinical effectiveness review.²⁶ However, the estimates were not statistically significant. When a sensitivity analysis using only statistically significant estimates was conducted, laparoscopic surgery was found to be the most cost-effective approach. In most other scenarios, TaTME remained the most cost-effective option.

The cost-effectiveness acceptability curve of the base-case analysis showed that that TaTME was the most cost-effective option compared with open surgery and laparoscopic surgery at various WTP thresholds. At a WTP threshold of £20,000 per QALY, the probability of TaTME being the cost-effective option was 86% compared with 2% and 13% for open surgery and laparoscopic surgery, respectively.²⁶

Limitations

The majority of the clinical effectiveness evidence supporting the SRs was derived from retrospective observational studies with few participants (less than 100). Of a total of 46 primary studies in the 8 SRs,^17-24 3 were RCTs, whereas the rest were non-randomized studies. The limited number of RCTs included reduces the quality of evidence because observational studies have inherent biases due to potential confounding factors, such as sex, body mass index, American Society of Anesthesiologists classification, tumour stage, distance from anal verge, and neoadjuvant chemoradiotherapy.

Due to the nature of the intervention, blinding was generally not feasible in all primary studies. Lack of blinding particularly effects subjective outcomes, such as health-related quality of life.

Heterogeneity in pooled analyses was reported for several outcomes (interoperative blood loss, hospital stay, local recurrence, CRM length, DRM length, harvested lymph nodes). Heterogeneity may have resulted from the pooling of different study designs, different numbers of surgeons who performed the procedures, different experiences with the surgical procedures, and variable lengths of follow-up. Inconsistency causes uncertainty in the findings presented in the SRs. Also, the evidence in the SRs focused on short-term rather than long-term outcomes.

TaTME was developed as a surgical alternative for specific subgroups of patients (e.g., patients with obesity; male patients with bulky distal tumours; patients with a narrow pelvis).^4,30 However, evidence on using TaTME in these subgroups of patients was not available in the studies included in this report. Inconsistency between the results of 3 SRs^17,18,24 and the RCT²⁵ was observed for positive CRM. There was also inconsistency between the results of 1 SR²¹ and the RCT²⁵ for intestinal obstruction following surgery. These conflicting findings may present challenges to interpretation. However, none of the results were in direct opposition to each other (i.e., a statistically significant positive association compared with a statistically significant negative association).

The cost-effectiveness evidence was based on 1 economic evaluation²⁶ with several limitations as detailed in the Critical Appraisal section. There was uncertainty about the validity of increased survival with TaTME because the clinical data supporting the analysis were inconclusive, and assumptions regarding complications and costs of TaTME were unclear. Overall, the evidence from the cost-effectiveness analysis was uncertain.

None of the SRs, primary studies within the SRs,^17-24 RCT,²⁵ or economic evaluation²⁶ were conducted by authors in Canada. It is unclear if the clinical effectiveness and cost-effectiveness findings are generalizable to Canadian clinical practice.

Conclusions and Implications for Decision- or Policy-Making

This report was based on 8 SRs,^17-24 1 RCT,²⁵ and 1 economic evaluation²⁶ that explored the clinical effectiveness of TaTME compared with LaTME or open TME for adults with rectal cancer. The results of the SRs^17-24 were based on many moderate- to high-quality non-randomized studies and some moderate- to high-quality RCTs (as assessed by the review authors). The clinical effectiveness of TaTME was primarily compared with LaTME, which reflects the current shift from the conventional open approach to the minimally invasive laparoscopic technique.^{17,20,21,26,31}

Overall, the evidence regarding clinical effectiveness suggests that TaTME has lower rates of conversion^21,22 and positive CRM^17,21,22,24 compared with LaTME or open TME. For other assessed outcomes, the evidence indicates that TaTME was as clinically effective and safe compared with LaTME or open TME for patients with rectal cancer. Specifically, no statistically significant differences were found between TaTME and LaTME or open TME for intraoperative blood loss,^21,22 intraoperative complications,^22,25 hospital stay,^21,22,25 readmission,²¹ reoperation,^21,25 local and distant recurrence,^19,24 overall and disease-free survival,^18,19,24 CRM length,^21,22 DRM,^{17,18,22,23,25} DRM length,^21,22 completeness or quality of TME,^18,21-25 harvested lymph nodes,^17,21,25 global health-related quality of life,^18-20 mortality,^18,21,22,25 postoperative complications,^18,20-22,25 and anastomotic leakage.^21,22,24

TaTME may be cost-effective compared with open TME and LaTME. However, the only available evidence was from 1 economic evaluation²⁶ based in the UK, and the findings were uncertain.

Based on the available evidence, it may be reasonable to expect that TaTME may be an effective and safe alternative to LaTME and/or open TME for the treatment of patients with rectal cancer. However, the limitations of the included literature should be considered when interpreting the findings of this report. Large-scale clinical trials with longer follow-up periods are required to better determine the effect of TaTME on long-term outcomes. Future economic evaluations conducted from the Canadian perspective may be helpful to further inform clinical and policy decisions.

References

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31.Lo Bianco S, Lanzafame K, Piazza CD, Piazza VG, Provenzano D, Piazza D. Total mesorectal excision laparoscopic versus transanal approach for rectal cancer: A systematic review and meta-analysis. Ann Med Surg (Lond). 2022;74:103260. PubMed

Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Systematic Reviews

CENTRAL = Central Register of Controlled Trials; CRM = circumferential resection margin; DRM = distal resection margin; LaTME = laparoscopic total mesorectal excision; NR = not reported; NRS = non-randomized studies; TaTME = transanal total mesorectal excision; TME = total mesorectal excision.

Table 3: Characteristics of the Included Primary Clinical Study

ASA = American Society of Anesthesiologists; CRM = circumferential resection margin; DRM = distal resection margin; LaTME = laparoscopic total mesorectal excision; IQR = inter-quartile range; RCT = randomized controlled trial; TaTME = transanal total mesorectal excision; TME = total mesorectal excision.

^aAt the time of publication, data on 3-year and 5-year outcomes was not yet available. The publication reported on initial study findings.

Table 4: Characteristics of Included Economic Evaluation

NHS = National Health Service; NICE = National Institute of Health and Care Excellence; NG = NICE guidance; NR = not reported; QALY = quality-adjusted life-years; QoL = quality of life; RR = relative risk; TaTME = transanal total mesorectal excision; WTP = willingness to pay threshold.

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 5: Strengths and Limitations of Systematic Reviews Using AMSTAR 2¹³

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; CRM = circumferential resection margin; GIN = Guidelines International Network; NRS = non-randomized study; NOS = Newcastle-Ottawa Scale; NRS = non-randomized studies; PICO = population/participants, intervention, comparison, outcomes; ROB-2 = Risk of Bias tool for randomized trials, version 2; RCT = randomized controlled trial; ROBINS-I = Risk Of Bias In Non-randomized Studies - of Interventions.

Table 6: Strengths and Limitations of the Clinical Study Using the Downs and Black Checklist¹⁴

CTESC = Chinese Transanal Endoscopic Surgery Collaborative; IQR = inter-quartile range; TaTME = transanal total mesorectal excision.

Table 7: Strengths and Limitations of the Economic Evaluation Using the Drummond Checklist¹⁵

HR = hazard ratio; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-years; TaTME = transanal total mesorectal excision.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 8: Summary of Findings by Outcome — Intraoperative Outcomes

CI = confidence interval; IQR = inter-quartile range; LaTME = laparoscopic total mesorectal excision; MA = meta-analysis; MD = mean difference; NR = not reported; NRS = non-randomized study; NSS = not statistically significant; OR = odds ratio; RCT = randomized controlled trial; RR = risk ratio; SD = standard deviation; SR = systematic review; TaTME = transanal total mesorectal excision.

Table 9: Summary of Findings by Outcome — Oncological outcomes

CI = confidence interval; HR = hazard ratio; LaTME = laparoscopic total mesorectal excision; MA = meta-analysis; NR = not reported; NRS = non-randomized study; OR = odds ratio; RR = risk ratio; SR = systematic review; SS = statistically significant; TaTME = transanal total mesorectal excision.

Table 10: Summary of Findings by Outcome — Survival

CI = confidence interval; HR = hazard ratio; I² = LaTME = laparoscopic total mesorectal excision; NR = not reported; NRS = non-randomized study; NSS = not statistically significant; RR = risk ratio; SR = systematic review; TaTME = transanal total mesorectal excision.

Table 11: Summary of Findings by Outcome — Pathological Outcomes

CI = confidence interval; CRM = circumferential resection margin; DRM = digital resection margin; IQR = inter-quartile range; LaTME = laparoscopic total mesorectal excision; MA = meta-analysis; MCC = matched case-control; MD = mean difference; NR = not reported; NRS = non-randomized study; NSS = not statistically significant; OR = odds ratio; RCT = randomized controlled trial; RR = risk ratio; SR = systematic review; TaTME = transanal total mesorectal excision.

^aFindings reported in the narrative text of the document.

^bFindings reported in Figure 5 forest plot of mesorectum incompleteness risk ratios.

Table 12: Summary of Findings by Outcome — Health-Related Quality of Life

CI = confidence interval; EORTC QLQC30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-3L = EQ-5D 3 Levels; LaTME = laparoscopic total mesorectal excision; NR = not reported; NRS = non-randomized study; TaTME = transanal total mesorectal excision; QoL = quality of life; SR = systematic review; VAS = visual analogue scale.

^aVeltcamp et al. (2019a).

^b.Length of follow-up was reported in the SR by Milone et. (2022).

^cBjoern et al. (2019).

^dMora et al. (2018).

Table 13: Summary of Findings by Outcome — Mortality

CI = confidence interval; LaTME = laparoscopic total mesorectal excision; MA = meta-analysis; NR = not reported; NRS = non-randomized studies; OR = odds ratio; RCT = randomized controlled trial; RR = risk ratio; SR = systematic review; SS = statistically significant; TaTME = transanal total mesorectal excision.

Table 14: Summary of Findings by Outcome — Harms

CI = confidence interval; LaTME = laparoscopic total mesorectal excision; MA = meta-analysis; NR = not reported; NRS = non = randomized studies; NSS = not statistically significant; OR = odds ratio; RCT = randomized controlled trial; RR = risk ratio; SR = systematic review; TaTME = transanal total mesorectal excision.

Table 15: Summary of Findings of Included Economic Evaluation

CEAC = cost-effectiveness acceptability curve; CI = confidence interval; HR = hazard ratio; ICER = incremental cost-effectiveness ratio; NG = NICE guidance; NICE = National Institute for Health and Care Excellence; NR = not reported; OS = overall survival; QALY = quality-adjusted life-years; RR = relative risk; TaTME = transanal total mesorectal excision; WTP = willingness to pay.

Appendix 5: Overlap Between Included Systematic Reviews

Note that this appendix has not been copy-edited.

Table 16: Overlap in Relevant Primary Studies Between Included Systematic Reviews

ESCP = 2017 European Society of Coloproctology collaborating group

Appendix 6: References of Potential Interest

Previous CADTH Reports

Transanal Total Mesorectal Excision for Adult Patients with Rectal Cancer: A Review of Clinical Effectiveness and Cost-Effectiveness. Ottawa (ON): CADTH. 2020. https://www.cadth.ca/transanal-total-mesorectal-excision-adult-patients-rectal-cancer-review-clinical-effectiveness-and

Systematic Reviews

Full Overlap of Primary Studies With Included Systematic Reviews

Aubert M, Mege D, Panis Y. Total mesorectal excision for low and middle rectal cancer: laparoscopic versus transanal approach-a meta-analysis. Surg Endosc. 2020;34(9):3908-3919. PubMed

Hajibandeh S, Hajibandeh S, Eltair M, et al. Meta-analysis of transanal total mesorectal excision versus laparoscopic total mesorectal excision in management of rectal cancer. Int J Colorectal Dis. 2020;35(4):575-593. PubMed

Lo Bianco S, Lanzafame K, Piazza CD, Piazza VG, Provenzano D, Piazza D. Total mesorectal excision laparoscopic versus transanal approach for rectal cancer: A systematic review and meta-analysis. Ann Med Surg (Lond). 2022;74:103260. PubMed

van der Heijden JAG, Koeter T, Smits LJH, et al. Functional complaints and quality of life after transanal total mesorectal excision: a meta-analysis. Br J Surg. 2020;107(5):489-498. PubMed

Wang X, Zheng Z, Yu Q, et al. Impact of Surgical Approach on Surgical Resection Quality in Mid- and Low Rectal Cancer, A Bayesian Network Meta-Analysis. Front Oncol. 2021;11:699200. PubMed

No Comparator

Casey L, Larach JT, Waters PS, et al. Application of minimally invasive approaches to pelvic exenteration for locally advanced and locally recurrent pelvic malignancy - A narrative review of outcomes in an evolving field. Eur J Surg Oncol. 2022;17:17. PubMed

Lau SYC, Choy KT, Yang TWW, et al. Defining the learning curve of transanal total mesorectal excision: a systematic review and meta-analysis. ANZ J Surg. 2022;92(3):355-364. PubMed

Wasmuth HH, Gachabayov M, Bokey L, et al. Statistical, Clinical, Methodological Evaluation of Local Recurrence Following Transanal Total Mesorectal Excision for Rectal Cancer: A Systematic Review. Dis Colon Rectum. 2021;64(7):899-914. PubMed

Economic Evaluations

Comparative Cost-Analysis

Di Candido F, Carvello M, Keller DS, et al. A comparative cost analysis of transanal and laparoscopic total mesorectal excision for rectal cancer. Updates Surg. 2021;73(1):85-91. PubMed

Review Articles

Guo Z, Ji X, Wang S, et al. Clinical Status and Future Prospects of Transanal Total Mesorectal Excision. Front. 2021;11:752737.

Vannijvel M, Wolthuis AM. Limitations and Concerns with Transanal Total Mesorectal Excision for Rectal Cancer. Clin. 2022;35(2):141-145. PubMed