Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy
M Ali K Motamedi
Nicole T Mak
Carl J Brown
Manoj J Raval
Ahmer A Karimuddin
Dean Giustini
Paul Terry Phang
Corresponding author.
Collection date 2023.
Abstract
Background
Total mesorectal excision is the standard of care for stage I rectal cancer. Despite major advances and increasing enthusiasm for modern endoscopic local excision (LE), uncertainty remains regarding its oncologic equivalence and safety relative to radical resection (RR).
Objectives
To assess the oncologic, operative, and functional outcomes of modern endoscopic LE compared to RR surgery in adults with stage I rectal cancer.
Search methods
We searched CENTRAL, Ovid MEDLINE, Ovid Embase, Web of Science ‐ Science Citation Index Expanded (1900 to present), four trial registers (ClinicalTrials.gov, ISRCTN registry, the WHO International Clinical Trials Registry Platform, and the National Cancer Institute Clinical Trials database), two thesis and proceedings databases, and relevant scientific societies' publications in February 2022. We performed handsearching and reference checking and contacted study authors of ongoing trials to identify additional studies.
Selection criteria
We searched for randomized controlled trials (RCTs) in people with stage I rectal cancer comparing any modern LE techniques to any RR techniques with or without the use of neo/adjuvant chemoradiotherapy (CRT).
Data collection and analysis
We used standard Cochrane methodological procedures. We calculated hazard ratios (HR) and standard errors for time‐to‐event data and risk ratios for dichotomous outcomes, using generic inverse variance and random‐effects methods. We regrouped surgical complications from the included studies into major and minor according to the standard Clavien‐Dindo classification. We assessed the certainty of evidence using the GRADE framework.
Main results
Four RCTs were included in data synthesis with a combined total of 266 participants with stage I rectal cancer (T1‐2N0M0), if not stated otherwise. Surgery was performed in university hospital settings. The mean age of participants was above 60, and median follow‐up ranged from 17.5 months to 9.6 years. Regarding the use of co‐interventions, one study used neoadjuvant CRT in all participants (T2 cancers); one study used short‐course radiotherapy in the LE group (T1‐T2 cancers); one study used adjuvant CRT selectively in high‐risk patients undergoing RR (T1‐T2 cancers); and the fourth study did not use any CRT (T1 cancers).
We assessed the overall risk of bias as high for oncologic and morbidity outcomes across studies. All studies had at least one key domain with a high risk of bias. None of the studies reported separate outcomes for T1 versus T2 or for high‐risk features.
Low‐certainty evidence suggests that RR may result in an improvement in disease‐free survival compared to LE (3 trials, 212 participants; HR 1.96, 95% confidence interval (CI) 0.91 to 4.24). This would translate into a three‐year disease‐recurrence risk of 27% (95% CI 14 to 50%) versus 15% after LE and RR, respectively.
Regarding sphincter function, only one study provided objective results and reported short‐term deterioration in stool frequency, flatulence, incontinence, abdominal pain, and embarrassment about bowel function in the RR group. At three years, the LE group had superiority in overall stool frequency, embarrassment about bowel function, and diarrhea.
Local excision may have little to no effect on cancer‐related survival compared to RR (3 trials, 207 participants; HR 1.42, 95% CI 0.60 to 3.33; very low‐certainty evidence). We did not pool studies for local recurrence, but the included studies individually reported comparable local recurrence rates for LE and RR (low‐certainty evidence).
It is unclear if the risk of major postoperative complications may be lower with LE compared with RR (risk ratio 0.53, 95% CI 0.22 to 1.28; low‐certainty evidence; corresponding to 5.8% (95% CI 2.4% to 14.1%) risk for LE versus 11% for RR). Moderate‐certainty evidence shows that the risk of minor postoperative complications is probably lower after LE (risk ratio 0.48, 95% CI 0.27 to 0.85); corresponding to an absolute risk of 14% (95% CI 8% to 26%) for LE compared to 30.1% for RR. One study reported an 11% rate of temporary stoma after LE versus 82% in the RR group. Another study reported a 46% rate of temporary or permanent stomas after RR and none after LE.
The evidence is uncertain about the effect of LE compared with RR on quality of life. Only one study reported standard quality of life function, in favor of LE, with a 90% or greater probability of superiority in overall quality of life, role, social, and emotional functions, body image, and health anxiety. Other studies reported a significantly shorter postoperative period to oral intake, bowel movement, and off‐bed activities in the LE group.
Authors' conclusions
Based on low‐certainty evidence, LE may decrease disease‐free survival in early rectal cancer. Very low‐certainty evidence suggests that LE may have little to no effect on cancer‐related survival compared to RR for the treatment of stage I rectal cancer. Based on low‐certainty evidence, it is unclear if LE may have a lower major complication rate, but probably causes a large reduction in minor complication rate. Limited data based on one study suggest better sphincter function, quality of life, or genitourinary function after LE. Limitations exist with respect to the applicability of these findings. We identified only four eligible studies with a low number of total participants, subjecting the results to imprecision. Risk of bias had a serious impact on the quality of evidence. More RCTs are needed to answer our review question with greater certainty and to compare local and distant metastasis rates. Data on important patient outcomes such as sphincter function and quality of life are very limited. Results of currently ongoing trials will likely impact the results of this review. Future trials should accurately report and compare outcomes according to the stage and high‐risk features of rectal tumors, and evaluate quality of life, sphincter, and genitourinary outcomes. The role of neoadjuvant or adjuvant therapy as an emerging co‐intervention for improving oncologic outcomes after LE needs to be further defined.
Keywords: Adult; Humans; Infant; Abdominal Pain; Combined Modality Therapy; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Recurrence, Local/epidemiology; Rectal Neoplasms; Rectal Neoplasms/surgery
Plain language summary
Is local or major surgery better for treating early rectal cancer with or without additional treatments before or after surgery?
Key messages
We are uncertain if local excision (LE) (removal through the anus of an early rectal cancer that has not grown beyond the muscle layer of the rectum, or stage I) may shorten the period of being cancer‐free after surgery compared to radical resection (RR) (removing the entire rectum and its surrounding tissues through a major surgery). It is also unclear if LE affects cancer‐related survival related compared with RR.
There is probably a large reduction in minor complications after surgery (only necessitating medications or supportive measures) with LE compared with RR for the treatment of early rectal cancer. It is unclear if LE lowers the rate of major complications.
Based on only one study, LE results in better quality of life and anal sphincter function.
What is early rectal cancer?
Rectal cancer presents at an early stage in one‐third of patients and does not invade beyond the muscle layer of bowel wall; this is classified as stage I, or early rectal cancer. People with early rectal cancer may experience bleeding or pain, or only get diagnosed on screening colonoscopy. We undertook this review to compare standard surgery for rectal cancer to a new, smaller surgery that has been increasingly adopted in recent decades.
How is early rectal cancer treated?
The currently recommended treatment for stage I rectal cancer is a major surgery for removal of the rectum with all its surrounding supporting tissues, known as radical resection (RR). This extensive surgery carries significant risks of surgical and functional complications. Recently, an alternative treatment using advanced instruments through the anus has been popularized. This has enabled precise removal, or local excision (LE), of only the tumor safely through the anus with fewer complications and faster recovery. Sometimes additional therapies such as chemotherapy or radiotherapy may be used in conjunction before or after the surgery.
What did we want to find out?
We compared RR to LE to find out whether LE is as effective as or better than RR with regard to:
1. disease recurrence and survival;
2. functional and quality of life outcomes;
3. side effects and complications after undergoing surgery.
What did we do?
We looked for studies that compared RR with LE in people with early rectal cancer with or without the use of any additional treatments. We compared, summarized, and combined the results across studies and rated our confidence in the evidence.
What did we find?
We found four studies that involved 266 participants with early rectal cancer with a median age of 60 years undergoing RR or LE. Participants were studied from 17.5 months in the shortest study to up to 9.6 years in the longest study. Three studies were carried out in European countries and one in China. One study did not use any additional therapy; two studies used chemotherapy or radiotherapy before the surgery; and one study used chemotherapy after the surgery for select patients. Three of the four studies were funded by government agencies.
Main results
Results suggest that RR may decrease the chance of disease coming back locally or in other organs of the body. This means for every 100 patients undergoing LE, up to 27 may develop recurrence at 3 years compared with 15 patients per 100 after RR.
Only one study looked at anal sphincter function, including the ability to control stool or flatulence, number of leakage episodes, and the need to use diapers. RR was associated with short‐term deterioration in stool frequency, flatulence, incontinence, abdominal pain, and embarrassment about bowel leakage. At 36 months after surgery, participants in the LE group had better overall stool frequency, stool frequency at night, and less embarrassment about leakage and diarrhea.
It is unclear if LE affects cancer‐related survival. Additionally, studies did not present the results in a way that could help us answer if LE affects the chance of disease coming back in the pelvis.
We are uncertain if LE results in a lower rate of major complications after surgery, but we found that LE probably causes a large reduction in minor complications.
The only study that evaluated quality of life or urinary and sexual function after surgery reported a 90% or greater probability that LE results in a better overall quality of life, various role/social/emotional functions, body image, health anxiety, and urinary incontinence. The same study reported similar sexual function after both surgeries.
What are the limitations of the evidence?
We have low confidence in the evidence mainly because it was based only on a few studies, and due to the way the studies were conducted. In addition, it is possible that the results of the studies could have been affected by the fact that participants and investigators were aware of which treatment participants had received.
How up‐to‐date is this evidence?
This review is current to February 2022.
Summary of findings
Summary of findings 1. Local excision compared to radical resection for stage I rectal cancer in adults, with or without neoadjuvant or adjuvant therapy.
| Local excision compared to radical resection for stage I rectal cancer in adults, with or without neoadjuvant or adjuvant therapy | ||||||
| Patient or population: stage I rectal cancer in adults Setting: academic hospital Intervention: local excision Comparison: radical resection | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with radical resection | Risk with local excision | |||||
| Disease‐free survival (D‐FS) | 15 per 100 | 27 per 100 (14 to 50) | HR 1.96 (0.91 to 4.24) | 212 (3 RCTs) | ⊕⊕⊝⊝ Lowa,b | The HR signifies increased risk of disease recurrence after local excision compared to radical resection. The estimated risks at 3 years (based on Bach 2020) are 27% (14% to 50%) after local excision and 15% after radical resection. |
| Sphincter function | Bach 2020 reported short‐term deterioration in stool frequency, flatulence, incontinence, abdominal pain, and embarrassment about bowel function in radical resection participants. At 3 years, local excision participants had superiority in overall stool frequency, embarrassment about bowel function, and diarrhea. Chen 2013 reported anal incontinence in 3 participants in the local excision group and none in the radical resection group, and "rectal pain" in 30/30 local excision participants vs 20/30 radical resection participants. Winde 1997 reported transient incontinence to stools in 2 local excision participants vs 1 participant after radical resection. | ‐ | 165 (3 RCTs) | ⊕⊕⊝⊝ Lowa,c | ||
| Cancer‐related survival (C‐RS) | 7 per 100 | 10 per 100 (4 to 21) | HR 1.42 (0.60 to 3.33) | 207 (3 RCTs) | ⊕⊝⊝⊝ Very lowd,e,f | The HR is very uncertain about the risk of death due to cancer after local excision compared to radical resection, corresponding to a risk at 3 years of 10% (4% to 21%) after local excision and 7% after radical resection (based on Bach 2020). |
| Local recurrence‐free survival (LR‐FS) | Bach 2020 reported a local recurrence probability of 91% (95% CI 79 to 100) after local excision at 3 years, with no cases after radical resection. Lezoche 2012 reported local recurrence in 4/50 participants after local excision and 3/50 participants after radical resection after 10 years. Chen 2013 reported local recurrence in 2/28 participants after local excision vs none after radical resection at 1 year. Winde 1997 reported local recurrence in 1/25 participants after local excision vs 0/25 participants after radical resection. | ‐ | 265 (4 RCTs) | ⊕⊕⊝⊝ Lowa,b | We were unable to pool results due to lack of survival data in the studies. | |
| Major postoperative complications | 11 per 100 | 6 per 100 (2 to 14) | RR 0.53 (0.22 to 1.28) | 266 (4 RCTs) | ⊕⊕⊝⊝ Lowa,b | |
| Minor postoperative complications | 30 per 100 | 14 per 100 (8 to 26) | RR 0.48 (0.27 to 0.85) | 266 (4 RCTs) | ⊕⊕⊕⊝ Moderatea | |
| Quality of life | Bach 2020 reported 90% or greater probability of local excision being superior in overall quality of life; role, social, and emotional functions; body image; and health anxiety. | ‐ | 55 (1 RCT) | ⊕⊕⊝⊝ Lowa,c | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and therelative effect of the intervention (and its 95% CI). CI: confidence interval;HR: hazard ratio;RCT: randomized controlled trial;RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See an interactive version of this table: gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_422684233061566160. | ||||||
aWe downgraded the certainty of evidence by one level for risk of bias. The method of randomization was not adequately described in one study; blinding of participants, personnel, and outcome assessors were not undertaken or described in any of the studies; and selective reporting was at unclear risk of bias in one study, leading to a judgment of high risk of bias. bWe downgraded the certainty of evidence by one level for imprecision considering the wide 95% CI around effect estimates that includes the line of no effect. Additionally, the optimal information size criterion was not met, and the conventional or Trial Sequential Analysis‐calculated monitoring boundaries were not crossed. cOnly one study reported objective sphincter and quality of life results, and other studies only reported symptoms related to these outcomes, thus we downgraded this outcome for indirectness. dWe downgraded the certainty of evidence by one level for high risk of bias. The method of randomization was not adequately described in one study; blinding of participants, personnel, and outcome assessors was not undertaken or described in any of the studies; and selective reporting was at unclear risk of bias in one study. eWe downgraded the certainty of evidence by one level given that overall survival data from the studies was used as proxy for cancer‐related survival. fWe also downgraded for imprecision, since the optimal information size criterion was not met, and considering the wide 95% CIs around effect estimates, which include both significant harm and significant benefit.
Background
Description of the condition
Colorectal cancer is a public health concern worldwide. It is the third most frequent cancer overall, with more than 1.8 million new cases globally each year (Vogel 2017;GLOBOCAN 2018). It is the second leading cause of cancer deaths, and caused 880,792 deaths in 2018 (GLOBOCAN 2018). The overall incidence of and mortality rate for colorectal cancer have declined in recent decades. However, for people under 55, the incidence is increasing at an annual rate of 2.4%, and the mortality rate at 1% (American Cancer Society 2018). Rectal cancer accounts for 35% of colorectal cancer cases, and is expected to increase in both genders (Glynne‐Jones 2017).
These concerning figures have prompted major advances in screening programs and diagnostics. As a result, approximately one‐third of rectal cancer patients present with early and localized stage I cancer, that is a tumor (T) confined to superficial layers (submucosa (T1) or muscularis propria (T2)) of the rectal wall without any evidence of local lymph node spread (N0) or distant metastasis (M0) (American Joint Committee on Cancer 2017). Stage I rectal cancer thus makes up a significant percentage of rectal cancers, and has a five‐year survival rate of about 90% (American Cancer Society 2014;National Cancer Institute 2017).
However, this favorable survival statistic is derived from populations undergoing standard 'radical resection' of rectal cancer, in which the tumor and regional lymph nodes are removed. Since stage I rectal cancer is generally characterized by the absence of any local spread, this radical approach may be an overtreatment for this subset of patients. However,Mou 2013 andSaraste 2013 report that even clinical T1‐2N0M0 rectal cancers can have undetected lymph node involvement rates of 6% to as high as 65%, and 11% to 78%, for T1 and T2 tumors respectively, depending on the presence of high‐risk pathologic features in the tumor. Radical resection removes rectal lymph nodes and minimizes the risk of leaving any residual cancer (Chen 2006).
Description of the intervention
Radical resection of the rectum is performed according to principles of total mesorectal excision (TME), by which the tumor and all lymph nodes around the rectum are precisely removed as a whole within a mesorectal fascial envelope (Heald 1982). Principles of TME are strictly followed in all radical surgery methods including Hartmann’s resection, low anterior resection, or abdominoperineal resection, which may be performed through the abdomen using open, laparoscopic, hand‐assisted laparoscopic, or robotic techniques. More recently, TME has also been performed by a two‐phase transabdominal‐transanal approach, transanal TME (TaTME) (Sylla 2010;Ma 2016;de Lacy 2018).
Radical surgery has emerged as the standard of care since it significantly reduces local recurrence and improves the oncologic results for rectal cancer patients (Heald 1982). However, it is associated with considerable morbidity, not only from the operation itself, but also from the resulting functional impairment. Transabdominal rectal surgery involves incising through the abdominal wall necessitating hospital admission for pain control, intravenous fluids, and recovery. It also requires an anastomosis that is challenging to perform trans‐abdominally, especially for low‐lying rectal tumors, and carries a risk of leakage and sepsis. Furthermore, resection of the rectum and consequent loss of rectal reservoir function may result in abnormal bowel habits (low anterior resection syndrome) and fecal incontinence. Lastly, injury to autonomic nerves during pelvic surgery may cause urinary incontinence and sexual dysfunction in a significant number of patients (Hendren 2005;Andersson 2014). While utilization of radical surgery is justified in patients with invasive rectal cancer with a high probability of local spread, its use in T1 or T2 rectal cancers that may not require an extensive lymph node removal is questionable due to the high associated postoperative morbidity.
In contrast to radical surgery, local excision avoids an abdominal incision, risk of an anastomotic leak, and functional problems of a pelvic resection, by precisely targeting and removing only the tumor through the anus. This less‐invasive approach is thus associated with fewer postoperative complications compared to radical surgery: 5.6% versus 14.6%, respectively (You 2007). However, traditional 'open' transanal excision was associated with an unacceptably high local recurrence rate of up to 30% (Parks 1968), compared to a low recurrence rate of 2% to 4% with radical surgery (Garcia‐Aguilar 2000;Mellgren 2000;Madbouly 2005;Ptok 2007). Improved visualization could be achieved using trans‐sphincteric and trans‐sacral approaches, but these were associated with high rates of fistula formation (Harvey 2004). Technological advances have offered improved visualization for transanal local excision through insufflating the rectum and magnifying the lesion. The first technical advance was the introduction of transanal endoscopic microsurgery (TEM). Using instruments manufactured by Wolf, Professor Buess in Germany pioneered endoscopic transanal removal of rectal lesions (Buess 1983). This advance incorporates a rigid proctoscope with optics enabling clear visualization and magnification of the lesion with three‐dimensional depth perception. At present, several other platforms also provide equipment for transanal excision using the same concept, including transanal endoscopic operation (TEO), transanal minimally invasive surgery (TAMIS), and transanal single‐port microsurgery (TSPM). TEM and TEO use rigid proctoscopes, while TAMIS and TSPM use flexible anal ports with laparoscopic instruments (Atallah 2010;Khoo 2010;Lorenz 2010). While these transanal procedures cannot achieve total mesorectal excision from a technical standpoint, their improved visualization and higher accuracy decrease positive resection margins, and hence local recurrence rates, approaching radical total mesorectal excision surgery results (Serra‐Aracil 2008;Bach 2009;Hompes 2011).
How the intervention might work
Since local excision does not treat potential metastases to regional lymph nodes, a chance of local spread remains. Neoadjuvant or adjuvant chemoradiotherapy may be used to treat regional spread and improve local control and survival after local excisions (Winde 1996;Lezoche 2008;Nair 2008;Doornebosch 2009;Morino 2011;Sasaki 2017). Chemoradiotherapy may be rationally applied for T1 and T2 cancers with higher‐risk pathological features including poor differentiation, lymphovascular invasion, and tumor budding (Nash 2009).
Why it is important to do this review
While several studies and reviews have sporadically evaluated some surgical techniques for T1 and T2 rectal cancer (e.g.Shaikh 2015), we aimed to systematically summarize the evidence on the safety and efficacy of the radical versus local approach. Given that local excision is increasingly being adopted worldwide, it should be evaluated accurately and regularly using the high‐quality Cochrane methodology to ensure it is at least of equal oncological effectiveness to radical resection, in addition to its major advantage of being less invasive. With the addition of neoadjuvant or adjuvant chemoradiotherapy to treatment protocols, it is also important to determine whether chemoradiotherapy enables the use of local excision techniques for higher‐grade tumors (T2) or those with high‐risk features. Equal efficacy of local excision and radical resection would potentially translate into safer surgery, fewer sphincter and genitourinary complications, and better quality of life, all important outcomes from the patient's perspective (Wrenn 2018). Given the rapid advances in technology and surgical techniques, it is necessary and timely to assess and summarize the short‐ and long‐term outcomes from recent trials to support the continued use of local excision as an equivalent or superior option to radical surgery for people with stage I rectal cancer.
Objectives
To assess the oncologic, operative, and functional outcomes of modern endoscopic local excision compared to radical resection surgery in adults with stage I rectal cancer.
Methods
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs) that compared local excision (LE) and radical resection (RR) for stage I rectal cancer. Published and unpublished studies, including non‐English language studies, were eligible for inclusion.
We excluded cluster‐RCTs, which are an unsuitable and unlikely design for this type of intervention, and studies that did not report separate data for benign and malignant lesions. We considered for inclusion studies that included only a subset of relevant participants based on the availability of separate data for those participants in the article or upon request from the authors.
Types of participants
Participants aged 18 years or older who had RR or LE for rectal cancer, defined as a tumor with distal extension to ≤ 15 cm from the anal verge (measured by sigmoidoscopy) with the following stage criteria:
stage I (T1‐2N0M0, Tumor, Node, Metastasis (TNM) staging system) (American Joint Committee on Cancer 2017); or
stage A (Dukes staging system) (Astler 1954).
We excluded participants with stage 0 (TisN0M0) rectal cancer, as well as participants with locally advanced cancer (stage II or higher), synchronous lesions, recurrent cancer, or tumor types other than adenocarcinoma.
Types of interventions
Intervention arm: local excision (LE)
Local excision implies full‐thickness excision of the lesion with free margins and with curative intent using any of the aforementioned local excision techniques: TEM, TEO, TAMIS, or TSPM.
Descriptions of local excision techniques
TEM (transanal endoscopic microsurgery): surgical removal of the tumor through a 4‐centimeter rigid rectoscope by establishing pneumorectum and using an oblique‐angled stereoscopic endoscope with modified surgical instruments (Buess 1983).
TEO (transanal endoscopic operation): surgical removal of the tumor using a similar platform to TEM but with regular laparoscopic instruments (insufflator, graspers, thermal energy devices, and needle drivers) through the rigid rectoscope.
TAMIS (transanal minimally invasive surgery) and TSPM (transanal single port microsurgery): removal of the tumor through a single‐incision laparoscopic surgery port (SILS port, or GelPOINT path transanal access platform) to establish pneumorectum, by using ordinary laparoscopic instruments, including graspers, thermal energy devices, and needle drivers (Atallah 2010; Khoo 2010; Lorenz 2010).
Control arm: radical resection (RR)
Radical resection techniques serve as the standard control interventions. Procedures such as Hartmann’s resection, low anterior resection, and abdominoperineal resection are included. These procedures accomplish complete resection of the rectum with regional lymph nodes within the mesorectal fascia (i.e. TME) using the open, laparoscopic, robotic, or TaTME approach.
Descriptions of radical operations to achieve TME
Hartmann's resection (proctosigmoidectomy): surgical resection of the rectosigmoid colon with closure of the anorectal stump and formation of an end‐colostomy, temporarily or permanently.
Low anterior resection: surgical removal of the rectum harboring the tumor and subsequent anastomosis of the colon to the remaining rectum.
Abdominoperineal resection: surgical removal of a low‐lying rectal tumor involving the anal sphincter with creation of a permanent colostomy.
TaTME (transanal total mesorectal excision): surgical removal of a rectal tumor through a combined transabdominal‐transanal minimally invasive approach, where the proximal dissection is performed through the abdomen laparoscopically and distal dissection through a transanal approach.
As outlined in the protocol, we aimed to undertake three sub‐comparisons in this study: 1) LE versus RR; 2) chemoradiotherapy (CRT) + LE versus RR; and 3) CRT + LE versus CRT + RR, keeping in mind the variety of approaches in practice for stage I rectal cancer. However, these sub‐comparisons were not performed given the low number of studies.
Types of outcome measures
We sought the following outcomes of interest.
Primary outcomes
1. Primary outcomes
Disease‐free survival (D‐FS), defined as the chance that a participant is without local recurrence or metastasis at a given time point.
Sphincter function, as measured by standardized scales such as the Wexner scale,Jorge 1993, and low anterior resection syndrome (LARS) score,Emmertsen 2012.
Secondary outcomes
2. Oncologic outcomes
Cancer‐related survival (C‐RS), defined as the chance that a participant has not died of reasons related to cancer at a given time point.
Local recurrence‐free survival (LR‐FS), defined as the chance that a participant is without local recurrence of cancer at a given time point.
Metastasis‐free survival (M‐FS), defined as the chance that a participant is without metastasis of cancer at a given time point.
3. Surgical outcomes
30‐day postoperative mortality.
Major and minor surgical complications (using the Clavien‐Dindo classification, Dindo 2004, grades I and II as minor, and grades III or higher as major).
Length of hospital stay (LoS, days).
Incomplete resection/conversion rate.
4. Functional outcomes
Quality of life, as measured by standardized scales such as the 36‐item Short Form Health Survey (SF‐36, Ware 1992) and EQ‐5D (The EuroQol Group 1990).
Genitourinary function, as measured by standardized scales such as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire ‐ Colorectal Cancer Module (EORTC QLQ‐CR29) (Gujral 2007).
Search methods for identification of studies
Electronic searches
We searched the following bibliographic databases on 1 February 2022 for primary studies from 1983 onward (date of introduction of TEM and newer procedures), without any language restrictions:
the Cochrane Library ‐ Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2022) (searched 1 February 2022) (Appendix 1);
Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) (1946 to 1 February 2022) (Appendix 2);
Ovid Embase (1974 to 1 February 2022) (Appendix 3);
Web of Science Core Collection (1 February 2022) (Appendix 4).
Searching other resources
Grey literature
We searched for grey literature in ProQuest Dissertations & Theses Global (www.proquest.com/pqdtglobal) and the Conference Proceedings Citation Index ‐ Science (1990 to 1 February 2022). A list of the most relevant conferences to include in the grey literature search was compiled and used based on consulting the expert opinion of a group of colorectal surgeons. The following peer‐reviewed conferences were selected based on their impact within the rectal cancer literature (from 1983 to present): European Colorectal Congress; American Society of Colon and Rectal Surgeons Annual Meeting; International Society of Laparoscopic Colorectal Surgeons Congress; and Congress of Asia Pacific Federation of Coloproctology. We also looked for relevant documents in key organizations such as the American Society of Clinical Oncology (ASCO), the American Society of Colon and Rectal Surgeons (ASCRS), the European Society of Coloproctology (ESCP), and the European Society for Medical Oncology (ESMO) from 1983 onwards.
Handsearching
We handsearched reference lists of all retrieved and relevant publications identified through the above strategies. We identified reviews, meta‐analyses, and guidelines on the topic of our review and looked for any relevant studies.
Unpublished and ongoing studies
We searched the trial registries listed below on 1 February 2022 for unpublished and ongoing studies. If relevant, we contacted the authors to ask for their respective data (strategies for ongoing trials are presented in Appendix 5).
US National Library of Medicine ClinicalTrials.gov (www.clinicaltrials.gov)
ISRCTN registry (www.isrctn.com)
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (trialsearch.who.int/)
National Cancer Institute (NCI) Clinical Trials Registry (www.cancer.gov/about-cancer/treatment/clinical-trials)
We updated the search results no later than three months prior to submission of the review, with any new relevant articles evaluated to be added to the review or flagged as awaiting classification.
Data collection and analysis
Selection of studies
Two review authors (MAKM and NM) independently screened the titles and abstracts of studies identified from the electronic, grey literature, and handsearches, and determined whether a study was eligible for inclusion (see Criteria for considering studies for this review). We have presented a PRISMA flow diagram that documents the study selection process (Moher 2009). We retrieved the full texts of potentially eligible references for definitive assessment of eligibility. At this stage, we only excluded those studies classified by both review authors as ‘exclude.’ Any disagreements were resolved through discussion with a third review author (PTP). We attempted to obtain further information about any trial published only as an abstract. If a full report was not available, or there was insufficient information to determine the eligibility of a study, we labeled the study as 'awaiting classification' and contacted the study authors. We listed all studies excluded after full‐text assessment with the main reasons for their exclusion in a table. We conducted the review process, including screening, study selection, risk of bias assessment, and data extraction, using Covidence software (Covidence).
Data extraction and management
Two review authors (MAKM and NM) independently extracted data from the included trials using a piloted data extraction form based on the CONSORT statement for non‐pharmacological interventions for RCTs (Boutron 2008). For each included study, we attempted to obtain the protocol of the study to extract the following variables in full for presentation in a 'Characteristics of included studies' table.
Study title, authors, accrual dates, year of publication, journal citation
Funding sources and conflicts of interest
Study setting, design, single center/multicenter (and number of centres)
Inclusion and exclusion criteria
Number of participants randomized/assessed for each outcome
Number of exclusions/withdrawals/missing data
Follow‐up duration
Age, sex, and relevant baseline characteristics of participants (e.g. comorbid conditions)
Stage of rectal cancer and tumor characteristics in intervention groups
Intervention and control
Co‐interventions (e.g. neoadjuvant/adjuvant CRT)
Outcome measures reported
Treatment protocol and quality of intervention (Herbert 2005)
Risk of bias domains
We reported the data according to the intention‐to‐treat principle. The review authors compared the results and resolved any disagreements by discussion until a consensus was reached. One review author (MAKM) populated the data onto the review file in Review Manager Web using Covidence software (RevMan Web 2022), and a second review author (NM) checked the data entry.
For surgical complications in studies before 2004 or those not using the Clavien‐Dindo classification, if recategorization and pooling such data with Clavien‐Dindo grades was reasonable, we attempted to do so. Otherwise, we reported these data separately.
If relevant data were not directly reported (e.g. hazard ratio and its 95% confidence interval for time‐to‐event data, or standard deviation for continuous data), we extracted the data required for their estimation using Parmar’s methods (Parmar 1998; Tierney 2007; Higgins 2011). For any studies not in English, Spanish, or French (in which at least one of the review authors was fluent), we planned official translation by a professional translation service.
Dealing with duplicate publications
When multiple reports of a particular study were identified, the study was the unit of interest. Duplicate publications or multiple reports of a study were linked and included in the 'Characteristics of included studies' tables. We gave priority to the report with the most complete data and longest follow‐up. The primary source for each study is indicated in the study references.
Assessment of risk of bias in included studies
Two review authors (MAKM and NM) independently assessed risk of bias across the following domains based on criteria used in the Cochrane risk of bias tool, as described in Section 8.5.d of theCochrane Handbook for Systematic Reviews of Interventions (Appendix 6) (Higgins 2017). We assessed each domain as having low, high, or unclear risk of bias. Any disagreements were resolved by discussion to reach consensus or by involved a third review author (PTP) if necessary.
We considered the domains of random sequence generation, allocation concealment, incomplete outcome data, and selective reporting as 'key domains' when assessing the risk of bias in each study. For individual outcomes, we also used other domains for assessing the risk of bias (Appendix 7). We summarized and presented the overall risk of bias for each outcome considering the assessments for its key domains in two different manners (Appendix 8) (Higgins 2017), as follows.
Within each study across domains: each outcome was defined as having a ‘low risk of bias’ only if it met all the key domains; as ‘high risk of bias’ if it demonstrated high risk of bias for one or more domains; or ‘unclear risk of bias’ if it demonstrated unclear risk of bias for at least one key domain without any ‘high risk of bias’ for other domains.
Across studies: each outcome was rated as having ‘low risk of bias’ if most information was from studies at low risk of bias; as ‘high risk of bias’ if the proportion of information from studies at high risk of bias was sufficient to affect the interpretation of the results; or ‘unclear risk of bias’ if most information was from studies at low or unclear risk of bias.
We acknowledge that certain outcomes are subjective and thus affected by lack of masking in a study (self‐reported or investigator‐reported outcomes, e.g. outcome 1.2 sphincter function). Subjective outcomes that were inconsistently reported were described and tabulated but excluded from statistical analysis. On the other hand, objective outcomes were less affected by lack of blinding, and all data relating to these outcomes were extracted. However, studies not providing quantitative and validated measures of objective outcomes were flagged for high risk of bias.
Measures of treatment effect
The measure of treatment effect depended on the types of data presented in individual studies:
for time‐to‐event data (e.g. D‐FS), we used hazard ratio (HR) and its 95% confidence interval (CI);
for dichotomous data (e.g. major postoperative complications), we extracted the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed, in order to estimate the risk ratio (RR) and its 95% CI;
for continuous data (e.g. LoS), we calculated the mean difference (MD) with standard deviation (SD). If measures were reported using different scales (e.g. quality of life), we would use the standardized mean difference (SMD); however, this was not necessary. When medians and interquartile range were the only data provided, we used the median as a proxy measure of the mean and the difference between the first and third interquantile as equivalent to 1.35 times SD.
We reported study results with their associated 95% CIs.
Unit of analysis issues
The unit of analysis was the individual participant. We did not include cluster‐randomized trials or other forms of trial designs that can introduce unit of analysis issues. We aimed to consider any multi‐arm randomized trials, given that participants in a given arm met the inclusion criteria and had separate data available.
Dealing with missing data
In the case of missing data, we attempted to contact the study authors to obtain the data and documented our attempts and their replies in the 'Characteristics of included studies' table. Where we were unsuccessful, we analyzed the data as reported and attempted to address the potential impact of the missing outcomes on the results of the review by performing a sensitivity analysis (best‐case/worst‐case analysis). However, this was limited by the scarcity of evidence. We also documented the number of participants randomized and analyzed to clarify the possibility of attrition bias.
In the surgical treatment of participants with stage I rectal cancer, exclusion of participants after randomization is sometimes justifiable. For example, some participants admitted to the trial may have been found intraoperatively to have metastatic disease, resulting in their becoming ineligible for the trial (Fergusson 2002;Higgins 2017). We considered this type of postrandomization exclusion as appropriate.
Assessment of heterogeneity
Where we considered studies to be sufficiently similar based on evaluation of participants and interventions to allow pooling of data using meta‐analysis, we assessed the degree of heterogeneity by examining the Chi2 test for heterogeneity. We reported our reasons for deciding that studies were similar enough to pool statistically. We quantified heterogeneity using the I2 statistic, with an I2 value of 50% or more considered to represent substantial heterogeneity; however, we interpreted this value in light of the size and direction of effects and the strength of the evidence for heterogeneity based on the P value from the Chi2 test (Deeks 2017). Where heterogeneity was present in pooled effect estimates, we explored possible reasons for variability by conducting subgroup analyses to examine if the population, interventions, and outcomes (or how they were measured) differed substantially. Given that we included few trials in the meta‐analysis, the Chi2 test had little power to detect heterogeneity, therefore we did not necessarily interpret a non‐significant result as evidence of no heterogeneity, but instead interpreted the findings with care.
Where we detected substantial clinical, methodological, or statistical heterogeneity across included studies, we did not report pooled results from meta‐analysis but instead used a narrative approach to data synthesis. We also attempted to explore possible clinical or methodological reasons for this variation by grouping studies that were similar in terms of surgical methods, co‐interventions, or other possible factors to explore differences in intervention effects.
Assessment of reporting biases
We attempted to minimize reporting bias by undertaking a comprehensive searching, including both published and unpublished trials, and critically appraising studies to ensure that they met the standard for a Cochrane Review. We could not assess potential publication bias using funnel plots as recommended in Chapter 10 of theCochrane Handbook for Systematic Reviews of Interventions because we included fewer than 10 studies (Page 2020). Nevertheless, we interpreted the findings cautiously.
Data synthesis
We performed the analyses using Review Manager Web, and applying Chapter 9 of theCochrane Handbook as a guide (Deeks 2017). We combined the outcome measures from individual trials in a meta‐analysis to calculate a pooled effect estimate for each outcome only if the study participants, interventions, and outcomes were clinically and methodologically comparable to provide a meaningful summary. We used a random‐effects model for analysis. For time‐to‐event data, we used generic inverse variance to employ effect estimates from the studies (Mantel 1959; Deeks 2017). We used the Peto odds ratio (Peto OR) method where the event rate was less than 10% (Deeks 2017). When we were unable to pool data and perform meta‐analysis for a given outcome, we reported the data qualitatively for the outcome across studies. We presented a narrative summary of the outcome in tables. We acknowledged and took into account the heterogeneity of the studies in our interpretation of results.
Subgroup analysis and investigation of heterogeneity
We aimed to undertake the following subgroup analyses:
participants with T1 versus T2 tumors (Monson 2013);
receiving neoadjuvant versus adjuvant CRT (Akgun 2017).
We attempted to conduct a subgroup analysis based on specific type of CRT followed by formal statistical testing, if applicable.
Sensitivity analysis
We aimed to undertake sensitivity analyses for risk of bias by excluding studies deemed at high risk of bias for the key domains; by changing from random‐effects to fixed‐effect models for meta‐analysis (Mantel 1959); by excluding small or large studies from the analysis; and by excluding studies with a high rate of missing data.
Trial Sequential Analysis
We performed a Trial Sequential Analysis (TSA) using TSA software to calculate the required information size and to determine whether the cumulative Z‐curve of the TSA boundaries for benefit, harm, or futility were crossed for the main outcomes in the summary of findings table (Thorlund 2011).
Summary of findings and assessment of the certainty of the evidence
We applied the GRADE approach developed by the GRADE Working Group for grading the certainty of evidence (GRADE Working Group 2004). The GRADE approach specifies four levels of certainty (high, moderate, low, and very low), which can be downgraded by one (serious concern) or two levels (very serious concern) for the following reasons: study limitations (risk of bias), inconsistency (unexplained heterogeneity, inconsistency of results), indirectness (indirect population, intervention, control, outcomes), and imprecision (wide CIs) or potential publication bias (Schünemann 2011).
We used GRADEpro GDT software to construct our summary of findings table and grade the certainty of the evidence (GRADEpro GDT). Results were confirmed by involving the second and adjudicating review authors and automatically imported into the review file on Review Manager Web.
We predetermined the following outcomes for our main summary of findings table (Table 1): D‐FS, sphincter function, C‐RS, LR‐FS, major postoperative complications, minor postoperative complications, and quality of life, according to our protocol. A summary of findings table with all outcomes is separately reported (Table 2).
1. Local excision compared to radical resection for stage I rectal cancer with or without neoadjuvant or adjuvant therapy—all study outcomes.
| Local excision compared to radical resection for stage I rectal cancer with or without neoadjuvant or adjuvant therapy | ||||||
| Patient or population: early rectal cancer with or without neoadjuvant or adjuvant therapy Setting: tertiary care hospitals Intervention: local excision Comparison: radical resection | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with radical resection | Risk with local excision | |||||
| Disease‐free survival | 15 per 100 | 27 per 100 (14% to 50%) | HR 1.96 (0.91 to 4.24) | 212 (3 RCTs) | ⨁⨁◯◯ Lowa,b | The HR signifies an increased risk of disease recurrence after local excision compared to radical resection. The estimated risks at 3 years (based on Bach 2020) are 27% (14% to 50%) after local excision and 15% after radical resection. |
| Sphincter function | Bach 2020 reported short‐term deterioration in stool frequency, flatulence, incontinence, abdominal pain, and embarrassment about bowel function in radical resection participants. At 3 years, local excision participants had superiority in overall stool frequency, embarrassment about bowel function, and diarrhea. Chen 2013 reported anal incontinence in 3 participants in the local excision group and none in the radical resection group, and "rectal pain" in 30/30 local excision participants vs 20/30 radical resection participants. Winde 1997 reported transient incontinence to stools in 2 local excision participants vs 1 after radical resection. | 165 (3 RCTs) | ⨁⨁◯◯ Lowa,c | |||
| Cancer‐related survival | 7 per 100 | 10 per 100 (4% to 21%) | HR 1.42 (0.60 to 3.33) | 207 (3 RCTs) | ⨁◯◯◯ Very lowd,e,f | The HR is very uncertain about the risk of death due to cancer after local excision compared to radical resection, corresponding to a risk at 3 years of 10% (4% to 21%) after local excision and 7% after radical resection (based on Bach 2020). |
| Local recurrence‐free survival | Bach 2020 reported a local recurrence probability of 91% (95% CI 79 to 100) after local excision at 3 years, with no cases after radical resection. Lezoche 2012 reported local recurrence in 4/50 local excision participants and 3/50 radical resection participants after 10 years. Chen 2013 reported local recurrence in 2/28 participants after local excision vs none after radical resection at 1 year. Winde 1997 reported local recurrence in 1/25 participants after local excision vs 0/25 participants after radical resection. | 265 (4 RCTs) | ⨁⨁◯◯ Lowa,b | We were unable to pool results due to lack of survival data in the studies. | ||
| Metastasis‐free survival | Bach 2020 reported 3 vs 2 metastases after local excision and radical resection, respectively, during the 3‐year follow‐up, but HR could not be calculated due to unavailability of censoring data. Chen 2013 did not report any metastasis during follow‐up. Lezoche 2012 reported 2 events in each group during the first 4 years of follow‐up. Winde 1997 reported 1 metastasis after radical resection only. | 265 (4 RCTs) | ⨁⨁◯◯ Lowa,b | We were unable to pool results due to lack of survival data in the studies. | ||
| 30‐day postoperative mortality | 0 per 100 | 0 per 100 | Not estimable | 268 (4 RCTs) | ⨁⨁⨁⨁ High | There were 0 cases of 30‐day mortality in the included studies. |
| Major postoperative complications | 11 per 100 | 6 per 100 (2 to 14) | RR 0.53 (0.22 to 1.28) | 266 (4 RCTs) | ⨁⨁◯◯ Lowa,b | |
| Minor postoperative complications | 30 per 100 | 14 per 100 (8 to 26) | RR 0.48 (0.27 to 0.85) | 266 (4 RCTs) | ⨁⨁⨁◯ Moderatea | |
| Length of stay (LoS) | MD 6.8 days shorter (95% CI 2.5 to 11.1). Chen 2013 reported an LoS of 9.9 (SD = 2) vs 17.8 (SD = 2.3) days; Lezoche 2012 reported an LoS of 3 (SD = 0.74) vs 6 (SD = 1.48) days; and Winde 1997 reported an LoS of 5.7 (SD = 4) vs 15.4 (SD = 2) days. | ⨁⨁◯◯ Lowa,g | ||||
| Incomplete resection/conversion rate | 5 per 100 | 5 per 100 (2 to 15) | RR 1.02 (0.34 to 3.03) | 268 (4 RCTs) | ⨁◯◯◯ Very lowa,b,h | |
| Genitourinary function | Bach 2020 reported 90% or greater probability of local excision being superior for urinary incontinence. There were no significant differences in impotence or dyspareunia. Winde 1997 reported "disturbed micturition" in 2 participants in each surgery group. | ⨁⨁◯◯ Lowa,c | ||||
| Quality of life | Bach 2020 reported 90% or greater probability of local excision being superior in overall quality of life; role, social, and emotional functions; body image; and health anxiety. | ⨁⨁◯◯ Lowa,c | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and therelative effect of the intervention (and its 95% CI). CI: confidence interval;HR: hazard ratio;MD: mean difference;N/A: not applicable;RCT: randomized controlled trial;RR: risk ratio;SD: standard deviation | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aWe downgraded the certainty of evidence by one level due to risk of bias. The method of randomization was not adequately described in one study; blinding of participants, personnel, and outcome assessors were not undertaken or described in any of the studies; and selective reporting was at unclear risk of bias in one study, leading to a judgment of high risk of bias. bWe downgraded the certainty of evidence by one level for imprecision considering the wide 95% CI around effect estimates that includes the line of no effect. Additionally, the optimal information size criterion was not met, and the conventional or Trial Sequential Analysis‐calculated monitoring boundaries were not crossed. cThe certainty of evidence is limited by the lack of available data and imprecision. dWe downgraded the certainty of evidence by one level due to high risk of bias. The method of randomization was not adequately described in one study; blinding of participants, personnel, and outcome assessors was not undertaken or described in any of the studies; and selective reporting was at unclear risk of bias in one study. eWe downgraded the certainty of evidence by one level given that overall survival data from the studies were used as proxy for cancer‐related survival. fWe also downgraded for imprecision, since the optimal information size criterion was not met, and considering the wide 95% CIs around effect estimates, which includes both significant harm and significant benefit. gWe downgraded for indirectness, given that one of the studies used an open surgical approach, and in two studies it was not clear if enhanced‐recovery protocols after surgery were used, which can directly affect LoS and may not reflect the current surgical practice. hHeterogeneity was substantial (I2 = 72%) between the studies. Overlap of CIs was minimal. This was to some degree anticipated due to different factors between studies in terms of patients, severity of disease, surgeries performed, and use of chemoradiotherapy. We judged that the impact of this inconsistency was not serious on the certainty of evidence.
Results
Description of studies
Results of the search
The literature searches found 14,312 titles, including 12,715 titles from bibliographic databases, 1421 from trial registries, and 176 titles from other sources. After removal of 8115 duplicates, 6197 reports were screened, of which 6156 did not meet the eligibility criteria. There was almost perfect agreement between review authors in the screening stage (agreement = 99.8%, Cohen’s kappa = 0.90). Seventeen studies (41 records) proceeded to full‐text review, of which 9 studies (16 records) were ineligible and excluded, with reasons provided inCharacteristics of excluded studies. There was also almost perfect agreement at the full‐text screening stage (agreement = 91.4%, Cohen’s kappa = 0.82). Four of the remaining eight studies (9 records) did not have any data available either because they were ongoing,Rombouts 2017;NCT03431428;Serra Aracil 2018, or had a mixed group of patients with no separate data available for eligible participants, and was therefore assessed as awaiting classification,Rullier 2020. Consequently, we included four studies (16 reports) that reported outcomes on LE versus RR for stage I rectal cancer (Winde 1997;Lezoche 2012;Chen 2013;Bach 2020). A PRISMA flow diagram is shown inFigure 1.
1.
PRISMA flow diagram.
Studies awaiting classification and ongoing studies
One study had a subgroup of potentially eligible participants, but no data had become available by the time of this review, and it was therefore assessed as awaiting classification (Characteristics of studies awaiting classification) (Rullier 2020, GRECCAR‐2). The following three studies are ongoing and have potentially eligible participants or subgroups of participants (Characteristics of ongoing studies): the three‐arm STAR‐TREC study,Rombouts 2017, compares TME to LE and CRT or LE and short‐course CRT in participants with mrT1‐3bN0M0 rectal adenocarcinoma;Serra Aracil 2018 compares CRT plus TEM to radical surgery (TME) in participants with T2‐3N0M0 rectal cancer; andNCT03431428 compares LE to Miles procedure (abdominoperineal resection (APR) and TME) after preoperative CRT in participants with rectal cancer stage lower than cT3cN1M0.
Included studies
The results of this review are based on four studies published between 1997 and 2020 (Winde 1997; Lezoche 2012; Chen 2013; Bach 2020). The studies collectively reported on 266 participants with T1‐T2N0M0 rectal cancer undergoing local excision by TEM versus TME by open/laparoscopic low anterior resection (LAR) or APR. The duration of follow‐up ranged from a mean of 17.5 months, Chen 2013, to a median of 9.6 years, Lezoche 2012.
The Winde 1997 study was a parallel‐design, single‐center RCT of 53 participants with uT1N0M0 rectal cancer randomized to TEM or open anterior resection; no CRT was used. The Lezoche 2012 study was a single‐center RCT of 100 cT2N0M0 rectal cancer patients randomized to TEM versus laparoscopic TME. All participants received neoadjuvant long‐course CRT and were followed for a median of 9.6 years. The Chen 2013 study was a parallel‐design, single‐center RCT of 58 participants with T1‐2N0M0 rectal cancer randomized to TEM or laparoscopic LAR. Lastly, the Bach 2020 study was a multicenter, parallel‐design feasibility study across 21 centers in the UK, randomizing 55 participants with T2N0 or lower rectal tumors to either TME or short‐course radiotherapy followed by TEM; it evaluated patient quality of life and sphincter/genitourinary functions. For further details, see Characteristics of included studies.
The included studies differed in several factors including inclusion criteria for participants, interventions, use of neoadjuvant or adjuvant CRT, follow‐up investigations, and duration of follow‐up.
Criteria used for inclusion of rectal cancer patients
All studies used the TNM staging system to identify stage I rectal cancer patients and excluded patients with locally advanced and poorly differentiated rectal tumors (American Joint Committee on Cancer 2017). Preoperative work‐up was stated as proctoscopy with biopsies, total colonoscopy, abdominal and endoluminal ultrasound scanning in Winde 1997, without any mention of abdominal or pelvic magnetic resonance imaging (MRI) or computed tomography (CT) scan. Lezoche 2012 used endorectal ultrasonography, rigid sigmoidoscopy with biopsies, total colonoscopy, helical whole‐body CT, and pelvic MRI to stage the tumors. Chen 2013 used pelvic MRI or CT to evaluate the tumor alongside proctoscopy and endoluminal ultrasound. Bach 2020 used colonoscopy, biopsy, high‐resolution pelvic MRI, endorectal ultrasound (optional) and CT scan of the thorax, abdomen, and pelvis. Winde 1997 included participants with ultrasonographic T1; Lezoche 2012 included participants with T2 tumors following neoadjuvant CRT with exclusion of those with tumor progression post‐CRT; Chen 2013 included clinical T1‐T2 tumors; and Bach 2020 included rectal adenocarcinomas staged T2N0 or lower.
Surgery
The technique used for LE was TEM in all studies. The technique for TME was open LAR in Winde 1997, laparoscopic LAR or APR in Lezoche 2012, laparoscopic LAR in Chen 2013, and minimally invasive, open, or hybrid LAR or APR in Bach 2020.
Use of chemoradiotherapy
No CRT was used in Winde 1997, while all participants in Lezoche 2012 received neoadjuvant CRT as long‐course three‐dimensional four‐field pelvic chemoradiotherapy with daily 5‐fluorouracil before randomization. Chen 2013 used adjuvant chemotherapy (FOLFOX‐4) in eight (of 30) participants who had high‐risk tumors postoperatively. Bach 2020 used neoadjuvant short‐course radiotherapy in participants in the LE arm.
Follow‐up protocol
There were slight differences between follow‐up protocols to detect local or distant recurrence: Winde 1997 followed up participants by tumor markers, chest radiography, abdominal and endoluminal ultrasonography, and proctoscopy every 3 months for the first 2 years and then every 6 months for up to 5 years and annually thereafter; Lezoche 2012 followed up with tumor markers and sigmoidoscopy every 3 months for the first 3 years and every 6 months thereafter, and whole‐body CT and pelvic MRI every 6 months for the first 5 years; Chen 2013 followed up with tumor markers, chest radiography, ultrasonography, colonoscopy every 6 months, and abdominal/pelvic CT or MRI annually for the first 5 years; and Bach 2020 used carcinoembryonic antigen at 12, 24, and 36 months, and CT scan of the thorax, abdomen, and pelvis at 12 and 24 months. Additionally, LE patients had white‐light endoscopy and MRI scans every 3 months for 2 years, then every 6 months for up to 3 years.
Excluded studies
We excluded nine studies (comprising 16 records, seeCharacteristics of excluded studies). We excluded one study that was a single‐arm trial (Ahmad 1998); two trials that compared traditional open LE to TME,Dewey 1985, or TaTME to laparoscopic TME (Pontallier 2016); three studies that did not have an LE arm (Luo 2005;ISRCTN27293422;NCT02022553); one study that included T3‐T4 rectal cancer patients (Bosset 2006); and two ongoing studies that randomized participants after LE to completion TME versus observation,NCT03548844, or to completion TME versus adjuvant CRT,Borstlap 2016, due to ineligible design.
Risk of bias in included studies
The risk of bias for each outcome across domains in each included study and overall is presented in Table 3; judgments for each risk of bias domain in each included study are shown in Characteristics of included studies and Figure 2. Across studies, all outcomes had an overall high risk of bias mainly due to lack of blinding and allocation concealment. Only 30‐day postoperative mortality was not likely to be influenced by the knowledge of intervention received and was thus judged as having a low risk of bias. Lezoche 2012 and Bach 2020 had low risk of bias.
2. Risk of bias for each outcome across domains in each included study.
| Outcome | Bach 2020 | Chen 2013 | Lezoche 2012 | Winde 1997 | Across studies |
| Disease‐free survival | High | High | High | N/A | High |
| Sphincter function | High | N/A | N/A | N/A | High |
| Cancer‐related survival | High | N/A | High | High | High |
| Local recurrence‐free survival | High | High | N/A | N/A | High |
| Metastasis‐free survival | N/A | N/A | N/A | N/A | N/A |
| 30‐day mortality | Low | Low | Low | Low | Low |
| Major postoperative complications | High | High | High | High | High |
| Minor postoperative complications | High | High | High | High | High |
| Length of stay | N/A | High | High | High | High |
| Incomplete resection/conversion rate | High | High | High | High | High |
| Quality of life | High | N/A | N/A | N/A | N/A |
| Genitounrinary function | High | N/A | N/A | N/A | N/A |
N/A, not available.
2.
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
Allocation
Three of the four included studies described details of random sequence generation and were therefore assessed as at low risk of selection bias (Winde 1997;Lezoche 2012;Bach 2020).Chen 2013 did not describe the details of randomization and was judged as at unclear risk of bias. Two studies described allocation concealment in adequate detail and were assessed as at low risk of bias (Lezoche 2012;Bach 2020), whereas the other two studies did not describe any method of concealment and were judged as having unclear risk of bias (Winde 1997;Chen 2013).
Blinding
As anticipated in the protocol and due to the nature of interventions, no blinding of participants or personnel was undertaken in any of the trials, hence all four studies were judged as at high risk of bias for blinding. Similarly, there was no mention of blinding of outcome assessors in any of the studies, which were therefore assessed as at high risk of detection bias.
Incomplete outcome data
We assessed one study as at unclear risk of attrition bias because the authors excluded from the analysis two TEM patients who had perforation during the procedure (Chen 2013). We did not detect any attrition bias in the other three studies and rated them as at low risk of bias.
Selective reporting
A study protocol was available for only two studies (Lezoche 2012;Bach 2020), which showed satisfactory reporting of the outcomes, hence we judged these studies as at low risk of reporting bias. No protocols were available for the other two studies, which we judged to be at unclear risk of bias.
Other potential sources of bias
There was a lack of information regarding the funding agency in Winde 1997, but there was no indication that this might have affected the design, undertaking, or results of the study, thus it was assessed as at low risk of other bias. We detected no other sources of bias in Lezoche 2012 and Bach 2020. Selective use of adjuvant CRT in eight RR participants postoperatively rendered Chen 2013 at high risk of bias for unequal use of co‐interventions without a full intention‐to‐treat analysis.
Effects of interventions
See:Table 1
See: Table 1; Table 2; Table 4
3. Reported data for oncologic outcomes analyzed using generic inverse variance method.
| Outcome | Study | Local excision | Radical resection | Relative effect estimate and test for difference | ||||
| Events | Total | Reported estimate | Events | Total | Reported estimate | |||
| Disease‐free survival | Winde 1997 | 1 | 25 | Not reported | 1 | 28 | Not reported | Not reported |
| Lezoche 2012 | 6 | 50 | Disease‐free survival probability: 88% (95% CI 75 to 94) | 5 | 50 | Disease‐free survival probability: 90% (95% CI 78 to 96) | Log rank test P = 0.686 | |
| Chen 2013 | 2 | 28 | Not reported | 0 | 30 | Not reported | Not reported | |
| Bach 2020 | 9 | 26 | Disease‐free survival of 76% (95% CI 60 to 95) | 5 | 28 | Disease‐free survival 85% (95% CI 73 to 100) | Hazard ratio 2.32 (95% CI 0.77 to 6.95); P = 0.12 | |
| Cancer‐related survival (or overall survival) | Winde 1997 | 1 | 25 | Survival probability at 5 years: 96% (SD = 4.08) | 1 | 28 | 5‐year survival: 96% (SD = 3.2) | Hazard ratio 1.02 (increased risk with local excision) log‐rank test Chi2 = 0.0002, P = 0.98 |
| Lezoche 2012 | 4 | 50 | Survival probability at median 9.6 years: 89% (95% CI 70 to 96) | 3 | 50 | Survival probability at median 9.6 years: 94% (95% CI 82 to 98) | Log‐rank test P = 0.687 | |
| Chen 2013 | 0 | 28 | 100% | 0 | 30 | 100% | P = 1.00 | |
| Bach 2020 | 4 | 26 | Overall survival estimate at 3 years: 88% (95% CI 77 to 100) | 3 | 28 | Overall survival estimate at 3 years: 93% (95% CI 83 to 100) | Hazard ratio 1.95 (95% CI 0.47 to 8.16) P = 0.35 | |
| Local recurrence‐free survival | Winde 1997 | 1 | 25 | Local recurrence rate: 4% | 0 | 28 | Not reported | Not reported |
| Lezoche 2012 | 4 | 50 | Local recurrence rate: 8% | 3 | 50 | Local recurrence rate: 6% | Not reported | |
| Chen 2013 | 2 | 28 | Local recurrence rate: 7.1% | 0 | 30 | Local recurrence rate: 0% | P = 0.229 | |
| Bach 2020 | 3 | 26 | 3‐year probability of 91% (95% CI 79 to 100) | 0 | 28 | Not reported | Not reported | |
| Metastasis‐free survival | Winde 1997 | 0 | 25 | Not reported | 1 | 28 | Not reported | Not reported |
| Lezoche 2012 | 2 | 50 | Distant metastasis rate: 4% | 2 | 50 | Distant metastasis rate: 4% | Not reported | |
| Chen 2013 | 0 | 28 | Distant metastasis rate: 0% | 0 | 30 | Distant metastasis rate: 0% | P = 1.00 | |
| Bach 2020 | 3 | 26 | Not reported | 2 | 28 | Not reported | Not reported | |
CI, confidence interval;SD, standard deviation.
The source of data was all available reports of the four studies. Some time‐to‐event data estimates were not readily available in the reports. We contacted the authors of the included studies for separate data and clarification, but no primary or complementary data could be obtained. If not directly reported, data were extracted from Kaplan‐Meier curves published in the studies in conjunction with data from text, using the data extraction sheet according to Tierney methods (Tierney 2007). We made the following assumptions with regard to the data used to calculate the outcomes.
In Winde 1997, the timing of censored data for the calculation of hazard risks was estimated from the Kaplan‐Meier curve in the paper, without the numbers of patients at risk given. Moreover, survival probability data was taken as a proxy for the calculation of C‐RS, being in agreement with the text stating that two participants experienced disease recurrence and died. This study was left out of the analysis for D‐FS, LR‐FS, and M‐FS, considering the low number of events and lack of censoring data.
Lezoche 2012 did not provide information on the timing of local versus distant recurrences, hence it could not be used in the calculations of LR‐FS and M‐FS.
Chen 2013 did not provide a Kaplan‐Meier curve or survival analyses. Follow‐up was complete for a period of 12 months; an assumption was made that there was similarly no censoring until 16 months to be able to calculate the D‐FS outcome.
In the Bach 2020 study, overall survival was used as a proxy for C‐RS. This study was used to estimate the baseline risk for D‐FS and C‐RS at three years.
Postoperative complications were individually examined and categorized into major (grade III or IV) or minor (grade I or II) according to the Clavien‐Dindo classification to permit pooling in data synthesis (Dindo 2004). Only Bach 2020 reported functional outcomes (outcomes 1.2, 4.1, and 4.2), hence we reported the results for these outcomes narratively.
Comparisons
Due to the availability of only four studies, we were not able to perform the three intended comparisons with regard to the use of CRT. We compared the two interventions irrespective of the use of co‐interventions, but considered this as a source of heterogeneity when interpreting the results and grading the certainty of evidence. Sensitivity analysis for CRT was not possible for the same reason.
Primary outcomes
1.1 Disease‐free survival
See: Table 1; Table 2; Table 4
The proportion of disease recurrence was 13.9% (18/129) in the LE group and 8.0% (11/136) in the RR group during the follow‐up period. Low‐certainty evidence suggests that RR may result in a large improvement in disease‐free survival (Analysis 1.1; 3 studies, 212 participants; hazard ratio (HR) 1.96, 95% confidence interval (CI) 0.91 to 4.24; I2 = 0%; Figure 3). In absolute terms using the control group in Bach 2020, this HR would translate into absolute disease recurrence risks of 27% (95% CI 14 to 50%) versus 15% after LE and RR, respectively, at three years.
1.1. Analysis.
Comparison 1: Local excision versus radical resection irrespective of chemoradiotherapy, Outcome 1: Disease‐free survival
3.
Forest plot of comparison: 1 Local excision versus radical resection, outcome: 1.1 Disease‐free survival.
We downgraded the certainty of evidence by one level for risk of bias. The method of randomization was not adequately described in one study; blinding of participants, personnel, and outcome assessors was not possible or undertaken in any of the studies; and selective reporting was at unclear risk of bias in one study, leading to an assessment of high risk of bias. We also downgraded for imprecision considering the wide 95% CI around effect estimates that includes the line of no effect. Additionally, the optimal information size criterion was not met, and the conventional or TSA‐calculated monitoring boundaries were not crossed (see 'Trial Sequential Analysis' below).
1.2 Sphincter function
We assessed the evidence for this outcome as of low certainty. Only Bach 2020 objectively evaluated sphincter function. As such, there were insufficient data to provide a pooled analysis of sphincter function. Bach 2020 reported deterioration in RR participants of stool frequency, flatulence, incontinence, abdominal pain, and embarrassment about bowel function at six months. At 36 months, differences in favor of LE were observed in overall stool frequency (difference of 16.3 points, of 100), stool frequency at night (difference of 25.4 points, of 100), and embarrassment about bowel function (difference of 31.7 points, of 100). A moderate increase from baseline diarrhea scores for RR participants (an increase of 13.4 points, of 100) in comparison with LE (a decrease of 6.8 points, of 100) was reported. Fecal incontinence scores were comparable (both with mild symptoms). Using a Bayesian model, at 36 months there was a 90% or greater probability of superiority for LE in diarrhea, stool frequency, and embarrassment about bowel function; this probability was 81% for constipation, 78% for blood/mucous in stools, and 51% for fecal incontinence and flatulence.
Chen 2013 reported anal incontinence in three participants in the LE group and none in the RR group and "rectal pain" in 30 of 30 participants in the LE group versus 20 of 30 participants in the RR group. Winde 1997 reported transient incontinence to stools in two LE participants compared to one participant after RR.
The quality of evidence was limited by the high risk of performance and detection bias, as well as imprecision due to lack of data, not meeting the optimal information size.
Secondary outcomes
See: Table 1; Table 2; Table 4
2. Oncologic outcomes
2.1 Cancer‐related survival
Three of the four included studies reported overall or cancer‐related survival rates. Bach 2020 reported overall survival and censoring could not be determined based on the data provided; overall survival was considered as a proxy for C‐RS based on the judgment that the reason for most deaths was cancer‐related (provided in supplementary material). Chen 2013 did not report any deaths after the surgery. The proportion of deaths due to cancer, in the three included studies with at least three years of follow‐up, was 8.9% (9/101) in the LE group and 6.6% (7/106) in the RR group. Very low‐certainty evidence suggests that LE may have little to no effect on cancer‐related survival compared to RR (Analysis 1.2: 3 studies, 207 participants; HR 1.42, 95% CI 0.60 to 3.33; I2 = 0%; Figure 4). This would translate into an absolute cancer‐related mortality risk of 10% (95% CI 4 to 21%) after LE at three years, compared to 7% after RR, based on data from Bach 2020.
1.2. Analysis.
Comparison 1: Local excision versus radical resection irrespective of chemoradiotherapy, Outcome 2: Cancer‐related survival
4.
Forest plot of comparison: 1 Local excision versus radical resection, outcome: 1.2 Cancer‐related survival.
Similar to the primary outcome, we downgraded the certainty of evidence by one level due to high risk of bias in the included studies related to lack of blinding of participants, personnel, and outcome assessors. We also downgraded for imprecision, since the optimal information size criterion was not met (see 'Trial Sequential Analysis' below) and considering the wide 95% CIs around effect estimates, which include both significant harm and benefit.
2.2 Local recurrence‐free survival
All studies reported local recurrence after surgery. However, only two studies had survival data required for analysis, and studies were not pooled (Chen 2013; Bach 2020). The crude proportion of local recurrence was 7.8% (10/129) in the LE group and 2.2% (3/136) in the RR group. Bach 2020 reported a three‐year LR‐FS probability of 91% (95% CI 79 to 100) and no recurrences in the RR group. Chen 2013 reported two cases of local recurrence in the LE group compared to none in the RR group, which was not statistically different. Lezoche 2012 reported four local recurrences in the LE group versus three in the RR group during the follow‐up in the cohort of patients with T2 after CRT. Winde 1997 reported one local recurrence only in the LE group.
We assessed the certainty of the evidence as low due to high risk of bias related to lack of adequate blinding that would likely have affected outcome assessment, as well as imprecision due to lack of data and the wide 95% CIs around effect estimates of the two available studies, not meeting the optimal information size criterion (see 'Trial Sequential Analysis' below).
2.3 Metastasis‐free survival
Three of the four studies reported metastasis occurrences. None of the studies had survival data or provided sufficient detail to calculate M‐FS, thus HR was not estimable. The overall crude proportion of participants with distant metastasis among studies was 3.9% (5/129) in the LE group and 3.7% (5/136) in the RR group. Bach 2020 reported three versus two metastases after LE and RR, respectively, during the three‐year follow‐up, but HR could not be calculated due to the unavailability of censoring data. Chen 2013 did not report any metastasis during the follow‐up. Lezoche 2012 reported two events in each group during the first four years of follow‐up. Winde 1997 reported one metastasis in the RR group only.
We downgraded the certainty of evidence for risk of bias and imprecision, similar to previous oncologic outcomes and for similar reasons.
3. Surgical outcomes
3.1 30‐day postoperative mortality
There was no 30‐day postoperative mortality in any of the trials (Analysis 1.3).
1.3. Analysis.
Comparison 1: Local excision versus radical resection irrespective of chemoradiotherapy, Outcome 3: 30‐day postoperative mortality
3.2 Postoperative complications
All studies reported postoperative complications. None of the trials reported postoperative complications according to the Clavien‐Dindo classification (Dindo 2004). Bach 2020 reported serious adverse events, defined as those that caused death, threat to life, prolonged hospital stay, readmission to hospital, or persistent disability. Lezoche 2012 defined major complications as complications requiring surgical treatment. No definitions were given in the Chen 2013 and Winde 1997 studies. Using details presented in all reports of the studies, we reviewed and categorized complications into major (grade III to IV) or minor (I to II). A categorization of each complication in each study is presented in Table 5.
4. Reclassification of postoperative complications into major or minor.
| Study | Minor (I to II) | Major (III to IV) | ||
| LE | RR | LE | RR | |
| Bach 2020 | Diarrhea (1) Rectal pain (1) Total = 2 | Acute kidney injury (2) Diarrhea (1) Deep vein thrombosis (1) Pancreatitis (1) Ileus (1) Pneumonia (2) Total = 8 | Anastomotic leak (1) Rectal bleed (2) Total = 3 | Anastomotic leak (2) Anastomotic stricture (1) Cardiac arrest (1) Rectal bleed (1) Total = 5 |
| Chen 2013 | Rectal bleeding (2) Pneumonia (1) Anal incontinence (3) Total = 6 | Rectal bleeding (3) Rectal perforation/anastomotic leakage (2) Pneumonia (1) Total = 6 | 0 | 0 |
| Lezoche 2012 | Suture‐line leakage (6) Total = 6 | Bleeding requiring transfusion (12) Suture‐line leakage (5) Total = 17 | Perianal phlegmon (1) Total = 1 | Anastomotic leakage (3) Total = 3 |
| Winde 1997 | Disturbed micturition (2) Transient incontinence for stools (2) Total = 4 | Diarrhea/constipation (5) Disturbed micturition (2) Transient incontinence for stools (1) Abdominal wall hernia (1) Rectal bleeding (1) Total = 10 | Rectal bleeding (1) Leakage or suture dehiscence healed by secondary intention (1)* Peritoneal perforation and abscess (1) Ischemic compartment syndrome (1) Total = 4 | Abdominal healing by secondary intention (4) Leakage or suture dehiscence (1) Anastomotic stricture (1) Small bowel obstruction (1) Total = 7 |
LE, local excision;RR, radical resection.
*This complication was not presented in the table of complications but was mentioned in the text of an earlier report of the same set of participants (Winde 1996).
Bach 2020 reported 5 (18%) serious adverse events (as defined in the study) in the LE group compared to 15 (53%) in the RR group (P = 0.04). There was only one case of anastomotic leak in the LE group, in a participant whose primary surgery was low anterior resection, which was a switch from their assigned LE group to RR, but analyzed per intention‐to‐treat principle. Additionally, there were two cases of rectal bleeding. In the RR group, major complications included anastomotic leak in two participants, and stricture, cardiac arrest, and rectal bleed in one participant each.
Chen 2013 reported no major complications after surgery in either study group. The rate of other complications such as rectal bleeding, rectal perforation/anastomotic leakage, pneumonia, and transient (< 5 days) anal incontinence was similar between groups. Rectal pain was reported in all participants in the LE group versus 20/30 of participants in the RR group.
Lezoche 2012 reported no statistically significant differences between groups in terms of minor or major postoperative complications. Six participants in the LE group had anastomotic leakage that resolved with conservative measures, and one participant developed a perianal phlegmon that required ileostomy. In the RR group, 10 participants required intraoperative blood transfusion due to bleeding; five participants had minor anastomotic leakage; two participants had postoperative hemorrhage requiring blood transfusions; and three participants had major anastomotic leakage requiring ileostomy.
Winde 1997 reported Douglas pouch abscess, rectal bleeding, suture dehiscence healed by secondary intention, and ischemic compartment syndrome as single events in different participants in the LE group, as well as two participants with disturbed micturition and two participants with transient incontinence to stools. In the RR group, seven major complications were reported including abdominal healing by secondary intention in four participants, and leakage/suture dehiscence, anastomotic stricture, and small bowel obstruction in one participant each. Minor complications included diarrhea/constipation in five participants, disturbed micturition in two participants, and transient incontinence to stools, abdominal wall hernia, and rectal bleeding in one participant each.
3.2.1 Major postoperative complications
There was no case of major complications in Chen 2013. The overall proportion of participants experiencing major postoperative complications was 6.2% (8/130) in the LE group and 11% (15/136) in the RR group. It is unclear if LE may result in lower major complication rates compared to RR (Analysis 1.4; 4 studies, 266 participants; risk ratio 0.53, 95% CI 0.22 to 1.28; I2 = 0%; Figure 5; low‐certainty evidence). Based on the pooled estimate from the included studies, this translates to 6% (95% CI 2 to 14%) major complications after LE versus 11% after RR.
1.4. Analysis.
Comparison 1: Local excision versus radical resection irrespective of chemoradiotherapy, Outcome 4: Major postoperative complications
5.
Forest plot of comparison: 1 Local excision versus radical resection irrespective of chemoradiotherapy, outcome: 1.7 Major postoperative complications.
We downgraded the certainty of the evidence by two levels for risk of bias and imprecision. The method of randomization was not adequately described in one study; allocation concealment was at as unclear risk of bias in two studies; blinding of participants, personnel, and outcome assessors was not undertaken in any of the studies; and incomplete or selective reporting was at unclear risk of bias in two studies. We also downgraded for imprecision by one level considering the wide 95% CIs around effect estimates that include the line of no effect. Additionally, optimal information size criterion was not met (see 'Trial Sequential Analysis' below).
Of note, and not counted as a complication, Lezoche 2012 reported 11 (22%) temporary and 12 (24%) definitive stomas in the RR group versus nil in the LE group; Bach 2020 reported 3 (11%) temporary stomas in the LE group compared to 23 (82%) in the RR group.
3.2.2 Minor postoperative complications
The overall proportion of participants experiencing minor postoperative complications was 13.8% (18/130) in the LE group and 30.1% (41/136) in the RR group. Moderate‐certainty evidence shows that LE probably results in a lower minor complication rate (Analysis 1.5; 4 studies, 266 participants; risk ratio 0.48, 95% CI 0.27 to 0.85; I2 = 18%; Figure 6). This would translate into a 14% (95% CI 8% to 26%) minor complication rate after LE compared to 30% after RR.
1.5. Analysis.
Comparison 1: Local excision versus radical resection irrespective of chemoradiotherapy, Outcome 5: Minor postoperative complications
6.
Forest plot of comparison: 1 Local excision versus radical resection irrespective of chemoradiotherapy, outcome: 1.8 Minor postoperative complications.
Similar to major complications and for the same reasons, we downgraded the certainty of the evidence by one level for risk of bias. We did not downgrade for imprecision considering the 95% CI around effect estimates, and crossing the monitoring boundaries in TSA analysis (see 'Trial Sequential Analysis' below).
3.3 Length of stay
We assessed the evidence for this outcome as of low certainty. Three trials reported length of stay. Pooling of data revealed a mean difference (MD) of 6.8 days (95% CI 2.5 to 11.1) in favor of LE. For LE versus RR, respectively, Chen 2013 reported an LoS of 9.9 (SD = 2) versus 17.8 (SD = 2.3) days; Lezoche 2012 reported an LoS of 3 (SD = 0.74) versus 6 (SD = 1.48) days; and Winde 1997 reported an LoS of 5.7 (SD = 4) versus 15.4 (SD = 2) days. Statistical heterogeneity was very high (I2 = 98%), with no substantial overlap in 95% CIs between the studies. This heterogeneity could be explained for the most part by the clinical diversity such as significant improvements in postoperative care protocols (such as enhanced recovery after surgery) as well as differences in study populations, open versus laparoscopic interventions, and other co‐interventions used (Analysis 1.6). Lack of evidence precluded a further investigation of heterogeneity by sensitivity or subgroup analyses, but after consideration of clinical heterogeneity, the same direction of estimates, and the use of random‐effects model still resulting in significant benefit, we did not consider the impact of this heterogeneity as severe on the quality of evidence. Switching to a fixed‐effect analysis would result in an MD of 4 days (95% CI 3.6 to 4.4).
1.6. Analysis.
Comparison 1: Local excision versus radical resection irrespective of chemoradiotherapy, Outcome 6: Length of stay
We thus downgraded the certainty of the evidence for risk of bias due to lack of blinding, as well as for indirectness, given that one study used an open surgical approach and in two studies it was not clear if enhanced‐recovery protocols after surgery were used, which can directly affect LoS and may not reflect the current surgical practice.
3.4 Incomplete resection/conversion rate
Three of the four studies reported conversion rates. Winde 1997 did not report any participants requiring conversion. The proportion of participants requiring conversion to open was 5.3% (7/132) in the LE group and 5.1% (7/136) in the RR group. In LE participants, this corresponded to conversion to a radical approach, and in the RR group, this entailed conversion from laparoscopic to open surgery. Very low‐certainty evidence suggests that LE is not associated with increased conversion rate (Analysis 1.7; 4 studies, 268 participants; risk ratio 1.02, 95% CI 0.34 to 3.03; I2 = 77%). Translated to absolute terms, this corresponds to 5.3% with LE compared to 5.1% after RR, although the true effect for LE could be anywhere between 1.8% to 15.6%.
1.7. Analysis.
Comparison 1: Local excision versus radical resection irrespective of chemoradiotherapy, Outcome 7: Incomplete resection/conversion rate
Only Bach 2020 reported participants with positive margins. Out of 27 participants randomized to organ preservation, one participant underwent salvage for positive margins after LE and three for high‐risk features.
We downgraded the certainty of the evidence by one level for risk of bias, as previously described for oncologic outcomes. Additionally, heterogeneity was substantial (I2 = 77%) between studies, and overlap of CIs was minimal. While this was partly anticipated due to different factors between the studies in terms of patients, severity of disease, surgeries performed, and use of CRT, we judged that the impact of this inconsistency was serious on the certainty of evidence since it could not be fully explained and studies had conflicting findings. We also downgraded by one level for imprecision considering the wide 95% CIs around effect estimates that included the line of no effect. Additionally, the number of events was very low, and the optimal information size was not met.
4. Functional outcomes
4.1 Quality of life
We assessed the evidence for this outcome as of low certainty. Only one study, Bach 2020, evaluated objective quality of life in participants. The authors reported no baseline differences in scores for symptom items. At three months, there were moderate differences between groups favoring LE for overall quality of life, health anxiety, and physical, social, and role function. There were persistent moderate or large deteriorations in overall quality of life, health anxiety, role and social function, and body image scores compared to baseline in the RR group, while there was no significant deterioration in the LE group. At 36 months, body image score difference was 25.7 points in favor of LE. Using a Bayesian model, the study authors reported that there was 90% or more probability that LE patients do better at three years with regard to global health status as well as role, emotional, social, and cognitive functioning, body image, and health anxiety scores. Other studies reported sporadic functional outcomes. Chen 2013 reported a significantly shorter postoperative period to oral intake, bowel movement, and off‐bed activities in LE participants. Winde 1997 reported higher doses of analgesia required for RR participants. Lezoche 2012 reported faster oral intake on the first postoperative day for LE participants compared to on day one or two for RR participants.
4.2 Genitourinary function
We assessed the evidence for this outcome as of low certainty. Bach 2020 reported scores for genitourinary function, using EORTC QLQ‐C29 and ‐C30 surveys. The authors reported slightly better short‐term male and female libido scores for LE, which reversed toward the 36 months of follow‐up. Dyspareunia and impotence scores remained somewhat comparable. LE participants scored better for urinary incontinence and frequency, but scores for dysuria were similar between groups. Formal statistical testing showed a 96% probability of LE participants having better function for urinary incontinence at three years, but not for male libido (female libido not analyzed), dyspareunia, impotence, urinary frequency, or dysuria. Winde 1997 reported "disturbed micturition" in two participants in each surgery group.
Subgroup analysis
D‐FS according to T1 versus T2 rectal cancer
The ability to perform subgroup analysis was limited in this review by the fact that only four studies with a low number of events were included, and no separate data were available for T1 versus T2. Bach 2020 and Chen 2013 had a mixed group of T1‐T2 participants. When comparing Winde 1997, which included T1 patients, to Lezoche 2012, which included T2 patients, for the primary outcome of D‐FS, T1 patients had an HR of 1.00 (95% CI 0.07 to 14.10) compared to T2 patients, who had an HR of 1.26 (95% CI 0.39 to 4.08) after LE. Despite the overlap in 95% CIs of estimates in all studies, formal subgroup analysis could not be carried out to determine the impact of tumor stage.
D‐FS according to neoadjuvant versus adjuvant chemoradiotherapy
Similarly, due to the low number of studies, we were not able to undertake a subgroup analysis for the use of CRT or its type. Only Lezoche 2012 used neoadjuvant CRT in all participants. Bach 2020 used neoadjuvant short‐course radiotherapy in LE participants, and Chen 2013 used adjuvant chemotherapy selectively in eight high‐risk patients after RR.
Sensitivity analysis
Trial Sequential Analysis
We performed TSA for the main outcomes in the summary of findings table to determine if monitoring boundaries for benefit/harm or futility were crossed and the optimal information size. The results are summarized in Table 6.
5. Trial Sequential Analysis results.
| Outcome | Optimal information size for RCT and estimated by TSA* | Optimal information size met? | Study estimate | TSA‐adjusted HR and CI | Conventional or TSA boundaries of benefit, harm, or futility crossed? | Interpretation |
| Disease‐free survival (D‐FS) | RCT: 686 participants TSA: 880 participants (to detect 5% difference in D‐FS [85% vs 90%]) | No | HR 1.96 (0.91 to 4.24) | 1.85 (0.35 to 9.36) | None | More information is required to conclude possible harm. |
| Cancer‐related survival (C‐RS) | RCT: 488 participants TSA: 977 participants (to detect 5% difference in C‐RS [89% vs 94%] based onLezoche 2012) | No | HR 1.42 (0.60 to 3.33) | 1.3 (0.01 to 310.74) | None | More information is required to conclude possible harm. |
| Local recurrence‐free survival (LR‐FS) | RCT: 141 participants TSA: 283 participants (to detect 10% difference in LR‐FS [85% vs 95%]) | No | N/A | 2.51 (0.71 to 8.82) | Futility boundary crossed. | It is unlikely that more information will show a significant difference between LE and RR. |
| Major complications | RCT: 488 participants TSA: 977 participants (to detect 5% difference in rate [6% vs 11%]) | No | Risk ratio 0.53 (0.22 to 1.28) | 0.59 (0.09 to 4.02) | None | More information is required to conclude possible advantage of LE. |
| Minor complications | RCT: 101 participants TSA: 249 participants (to detect 15% difference in rate [13.8% vs 30.1%]) | Yes | Risk ratio 0.48 (0.27 to 0.85) | 0.48 (0.25 to 0.92) | TSA boundary of benefit crossed, but crosses back below the line. Cumulative Z appears above the monitoring boundary of benefit after theBach 2020 study. | More information required to confirm superiority of LE.** |
CI, confidence interval;HR, hazard ratio;LE, local excision;N/A, not available;RCT, randomized controlled trial;RR, radical resection;TSA, Trial Sequential Analysis.
*Sample size for RCT calculated based on an alpha error of 0.05 and power of 0.80. **Removing theWinde 1997 study, which used an open RR approach, rendered the result insignificant: risk ratio 0.49, 95% CI 0.15 to 1.64; I2 = 44%.
Excluding studies at high risk of bias for key domains
All of the included studies had at least one domain with unclear or high risk of bias for the primary outcome. As a result of this and due to the scarcity of evidence, the impact of studies at high risk of bias could not be sufficiently investigated. However, excluding the study at high risk of bias did not impact the estimates or their direction significantly for the primary or other oncologic outcomes. For minor surgical complications, removing two studies at high risk of bias, Chen 2013 and Winde 1997, did not affect the significance or direction of the estimate. However, removing the Winde 1997 study, which was at high risk of bias for key domains, and only used an open RR approach, rendered the estimate not significant (risk ratio 0.49, 95% CI 0.21 to 1.12; I2 = 45%). Removing this study from the TSA had a similar effect (risk ratio 0.49, 95% CI 0.15 to 1.64, I2 = 44%). Results for other surgical outcomes did not change upon exclusion of studies at high risk of bias.
Changing the statistical model from random‐effects to fixed‐effect
Changing from a random‐effects statistical model to fixed‐effect model did not significantly affect the estimates, direction, or magnitude of effect for the primary outcome and oncologic outcomes, as well as for surgical outcomes. Due to the low number of included studies, we could not vigorously evaluate the effect of study size, degree of missing data, or unpublished studies and those at high risk of bias.
Discussion
We have presented the current evidence on oncologic efficacy and safety of modern endoscopic local excision techniques in comparison to RR with standard TME surgery for stage I rectal cancer. We identified four published RCTs alongside four ongoing or potentially eligible studies that can contribute data to answer this clinical question. Considering the scarcity and low certainty of evidence presented in this review, an update of this study is needed that will include new information as it becomes available.
Summary of main results
Overall, in terms of oncologic outcomes, low‐certainty evidence suggests that LE may have inferior D‐FS compared to RR, but it is unclear if LE affects C‐RS. There was limited evidence with regard to LR‐FS and M‐FS, but individual studies did not reveal a major difference in these metrics. In terms of surgical morbidity, low‐certainty evidence suggests that LE may result in lower major complications, and probably has a better minor complication rate. There was a major lack of evidence with regard to the proposed advantages of local excision techniques, that is sphincter, genitourinary function, and quality of life. Individual outcomes were generally in favor of LE, including from one high‐quality RCT.
Overall completeness and applicability of evidence
As modern endoscopic local excision techniques continue to gain popularity and expand their application, high‐quality research is essential to compare their oncologic and operative advantages and pitfalls. This review found limited evidence of generally low certainty questioning their role in the treatment of stage I rectal cancer that is confined to the rectal wall not invading beyond the muscular layer, but highlighting their advantages in terms of morbidity and quality of life. There are some considerations regarding the applicability of these conclusions.
Firstly, there is generally a consensus,NCCN 2018, that low‐risk favorable T1 tumors (well‐ or moderately differentiated, submucosal invasion grade 1,Kikuchi 1995, with no venous or lymphatic invasion or other adverse features,Beaton 2013, could be sufficiently treated with a high‐accuracy local excision technique such as TEM due to high success rates (Junginger 2016). The role of LE for higher‐grade T1 or T2 tumors remains to be defined. However, TEM has been used in investigational settings in patients with higher‐grade tumors who are otherwise unfit for radical surgery and has shown merit, especially when used in conjunction with chemoradiotherapy or adjuvant therapy in compassionate care (Sasaki 2017;Jones 2019). Insufficient evidence precluded a subgroup analysis for T1 versus T2 tumors or the use of chemoradiotherapy, but the results from theLezoche 2012 study have suggested a role for LE both oncologically and surgically. It should be noted that accuracy of staging is essential, and the challenge of this is reflected in the studies included in this review. Stage migration continues to be an issue in the treatment and study of rectal cancer. Mandatory MRI and endorectal ultrasound (ERUS) must be judiciously applied.
Secondly, the role of chemoradiotherapy remains to be defined in relation to local excision, as we found only two randomized trials with low risk of bias that used neoadjuvant radiotherapy or CRT in T2 or lower patients. These studies reported comparable disease‐free survivals of 76% for LE and 85% for RR at three years (Bach 2020), and 88% for LE and 90% for RR during a follow‐up of 9.6 years (Lezoche 2012). Multiple studies from proponents of organ preservation also support this approach when good follow‐up surveillance is feasible in high‐risk T1, T2, and even T3N0 tumors, with reported recurrence rates below 10% and disease‐free survival rates around 90% (Lezoche 2002;Wawok 2018;Parikh 2019). A meta‐analysis of neoadjuvant CRT + TEM suggested similar oncologic outcomes to TME in T2N0M0 patients (Xu 2017); however, high‐quality evidence is very limited. This approach has its limitations, including the possibility of overtreatment and exposing patients to CRT toxicity or multiple procedures (Garcia‐Aguilar 2015;Verseveld 2015). In addition, there may be differences in down‐staging and survival between neoadjuvant radiotherapy and chemoradiotherapy. This approach may thus not be advisable in good surgical candidates, at least until we have stronger proof of oncologic efficacy and proven functional superiority of LE. Currently and under research protocols, such an approach may be limited to good responders after neoadjuvant CRT, with completion/salvage TME in poor responders. Several ongoing RCTs are designed to investigate the role of TEM after neoadjuvant CRT (Rombouts 2017;NCT03431428;Serra Aracil 2018). The use of neoadjuvant radiotherapy, as in theBach 2020 study, however, may prove to be an effective alternative to CRT. We were not able to perform a subgroup analysis based on neo/adjuvant radiotherapy or CRT to better investigate their safety and effectiveness.
Lastly, the use of adjuvant CRT or radiotherapy after LE in high‐risk tumors may be another organ‐preserving alternative. An analysis of 3786 patients from the Surveillance, Epidemiology, and End Results (SEER) registry database suggested similar five‐year cancer‐specific and overall survival rates for LE + adjuvant radiotherapy versus TME in people with T2 rectal cancer (Wang 2018). A similar analysis byOlsheski 2013 found similar oncologic outcomes in stage I rectal cancer patients undergoing LE + radiotherapy versus APR. Individual experiences have also been reported for this approach, with a three‐year local recurrence of 6.9% for high‐risk T1 tumors offered adjuvant radiotherapy (Jones 2019), and five‐year D‐FS of 89.8% for high‐risk T1 and T2 patients offered adjuvant chemoradiotherapy (Jeong 2016). Further trials are needed to clarify the role of adjuvant therapy.
Regarding morbidity, we found low‐certainty evidence suggesting similar major morbidity for LE compared to RR.Winde 1997 mostly contributed to the major postoperative complication rate, which could reflect the initial technical challenges of TEM and the open approach for RR used in the study.Lezoche 2012, the highest‐quality RCT available, as well asBach 2020, reported only a few major complications after LE and RR. However, RR but not LE incurred an ostomy in a significant proportion of participants in both studies.
There were fewer minor complications after LE. While individual included studies reported comparable complication rates after the two approaches, they generally supported better and faster recovery after LE. In line with the results of this review, current evidence supports lower morbidity rates for LE (You 2007;Sgourakis 2011), while more robust and recent data are pending.
Better sphincter function, quality of life, and genitourinary function are assumed advantages of LE; yet evidence to support this claim is scarce.Doornebosch 2007 reported similar quality of life after TEM versus TME, while sphincter function for TEM patients was superior. Similarly,D’Ambrosio 2016 reported better quality of life at six months after endoluminal excision of T2‐T3 cancer compared with TME, whereas at one year, an advantage for LE only remained regarding sphincter function. TheBach 2020 study is the latest evidence of high quality that suggests many quality of life, sphincter, and genitourinary advantages for LE over RR at three years of follow‐up.
Quality of the evidence
We assessed the certainty of the evidence using the GRADE approach, which takes into account the risk of bias in included studies, inconsistency, indirectness, imprecision, publication bias, observing a large effect, plausible confounding, and dose‐response gradient.
Regarding risk of bias, one trial was at unclear risk of selection bias, and two trials were at unclear risk of bias for allocation concealment. Blinding of participants, personnel, and outcome assessors was not undertaken or reported in any of the included trials. As for the other risk of bias domains, we assessed one study as having unclear risk of attrition bias, and two studies as having unclear risk of selective reporting. Risk of bias was overall judged to negatively affect the oncologic and surgical outcomes given the lack of blinding of outcome assessors.
Regarding inconsistency, given that the statistical methods have major limitations to detect heterogeneity when the number of studies is less than 10, we looked at the degree of overlap of 95% CIs for each outcome to detect a serious impact on the certainty of the evidence. Oncological outcomes, D‐FS, and C‐RS had good concordance among the included studies and were consistent. For minor complications, heterogeneity was minimal (I2 = 18%) and could be explained by differences in patient populations of different risks and disease severity, surgeries performed, as well as co‐interventions. We did not downgrade for inconsistency. Inconsistency was also judged to affect incomplete resection/conversion rate, since studies had conflicting findings that could not be explained by clinical variations. However, we judged LoS to be consistent among studies, since it was generally in favor of LE, and the observed heterogeneity could mostly be explained.
Regarding indirectness, we judged the applicability to be limited for C‐RS given that overall survival was used as a proxy for calculating this outcome, as well as for the LoS outcome given the recent evolution of enhanced recovery protocols and improved perioperative care.
Similarly, we downgraded the certainty of the evidence for most outcomes for imprecision considering the wide 95% CIs around effect estimates, except for minor complication rate and LoS. Only four studies with few events were used in data synthesis, and optimal information size criterion was not met and TSA boundaries of confidence were not crossed for any of the outcomes, except for minor complications.
We did not downgrade for publication bias, observing a large effect, and other confounding given that the certainty of the evidence for all outcomes was downgraded for other reasons discussed previously.
Potential biases in the review process
We tried to minimize bias by implementing a comprehensive search strategy for the electronic databases. We further searched the trial registries for ongoing trials, theses and proceedings databases, and publications of the most relevant surgical and oncological associations. We contacted the authors of eligible studies for clarification and data on the missing items. The review process involved two review authors working independently at all stages of screening and study selection, quality appraisal, and data extraction. Data entry and analyses were rechecked by an adjudicating review author (NM) as well as by a biostatistician.
The major limitation of this review is the small number of included studies with low event rates, not meeting the optimal information size criterion and subjecting outcomes to imprecision. We could not evaluate publication bias using the funnel plots since only a few studies were identified. Our review methods did not allow for detection of serious or rare adverse events. In addition, despite contacting the authors of studies, some issues remained obscure and required assumptions to be made as outlined in theResults section. Moreover, we were not able to obtain separate data for eligible participants in theRullier 2020 study (GRECCAR‐2, which included T3 stage cancers), as well as any of the ongoing unpublished studies (Rombouts 2017;NCT03431428;Serra Aracil 2018). Last but not least, an inherent bias could be introduced when using the indirect methods to estimate hazard ratio limits and standard errors, since they were not reported and had to be calculated.
Agreements and disagreements with other studies or reviews
Several reviews have compared LE to RR (Sgourakis 2011;Sajid 2014;Kidane 2015;Lu 2015;Shaikh 2015;Xu 2017). These reviews differed from the current review with regard to their inclusion and exclusion criteria, the type of studies included, the methodology of review and search strategy, and the focus of the review. All of these reviews included both RCTs and observational studies. In contrast, our review focuses on evidence from RCTs, and a formal quality assessment of each study was performed. With the included RCTs generally well‐reported, with the exception of the aforementioned heterogeneity, this review gives the clinician a greater certainty of the point estimates of effect for the reported outcomes.
Authors' conclusions
Implications for practice.
We found low‐certainty evidence from four randomized studies that local excision (LE) by modern endoscopic techniques may result in lower disease‐free survival in the treatment of stage I rectal cancer. Importantly, data were lacking on other oncologic metrics such as local recurrence‐free survival and metastasis‐free survival to permit stronger conclusions. Our results in this context may emphasize the adjunctive role of chemoradiotherapy (CRT) with LE to improve local and distant control. Based on the current evidence, however, it is uncertain whether cancer‐related survival may be compromised after LE. It is important to note that since subgroup analysis was not performed in this review, we could not investigate whether the observed results are consistent across low‐risk versus high‐risk cancers.
For surgical outcomes, no early mortality was reported by any of the studies after either approach, reflecting the overall safety of surgical treatment of stage I rectal cancer including that of radical resection (RR). Due to a lack of unified outcomes reporting for surgical complications, we categorized them according to Clavien‐Dindo classification (Dindo 2004). This process exposed the heterogeneity between the studies in terms of study populations, interventions and co‐interventions, and postoperative recovery protocols, among others. The major complication rate, based on low‐certainty evidence, may be lower after LE, with evidence showing an advantage for LE in terms of minor morbidity, alongside higher stoma rates after RR. Furthermore, we were unable to draw any firm conclusions about multiple suggested advantages of LE such as sphincter function preservation, quality of life after surgery, and genitourinary function beyond what was shown by Bach 2020.
When discussing surgical options with patients with early rectal cancer, the possible lower disease‐free survival and uncertainty about cancer‐related survival should be discussed along with lower stoma rates and minor morbidity rates as well as improved quality of life. Considering the morbidities of RR, organ‐ and function‐preserving strategies are becoming of particular interest, especially in the management of the young rectal cancer patient. However, no recommendations can be made at this time based on the available evidence.
Implications for research.
There are multiple implications of the results of this review for future research, as follows.
Patient selection
There are two distinct circumstances under which LE would be utilized as an organ‐sparing approach for rectal cancer management. Firstly, as similar to the focus of this review, in a patient diagnosed with stage I rectal cancer without nodal or distant spread, there is an option to undergo LE rather than RR. However, this review cautions that the LE may result in lower disease‐free survival and thus cannot safely recommend LE as an oncologically equivalent approach compared to RR, especially when data regarding cancer‐related survival are uncertain. More data from new and ongoing trials are needed to estimate local and distant recurrence rates. Secondly, in a patient with more advanced stages of cancer such as T3aN0‐1, it may be possible to use neoadjuvant CRT to downstage the lesion to become suitable for LE. As suggested by Shaikh 2015, this approach may be an alternative to radical surgery. Future research should ideally enroll same‐risk and same‐stage patients to compare these two approaches and report separate data according to accurate disease stage and high‐risk features.
Comparisons and co‐interventions
Rectal tumors must be accurately assessed for high‐risk features (e.g. SM3, lymphovascular invasion, poor differentiation, and tumor budding) since the higher risk of lymph node involvement associated with these features would necessitate treatments in addition to LE. Application of neoadjuvant radiotherapy or CRT could potentially expand the indications of LE by downstaging the tumor and treating the possible spread of tumor to surrounding tissues. As demonstrated by Lezoche 2012, a patient with a clinically node‐negative T2 tumor undergoing LE after CRT would have the same disease‐free survival as a similar patient undergoing RR up to 10 years of follow‐up. A multicenter STAR‐TREC trial (Rombouts 2017), the larger study containing data from the TREC study (Bach 2020), has suggested a maximal organ‐preserving strategy and aims to evaluate patients with T1‐T3bN0M0 rectal cancer following randomization to three possible arms: total mesorectal excision (TME) surgery, neoadjuvant CRT and LE in good responders (but incomplete clinical response), short‐course radiotherapy and LE in good responders (but incomplete clinical response); TME would be offered to any poor responders. The strategy of neoadjuvant radiation to downstage cancer followed by transanal endoscopic microsurgery (TEM) is also being investigated by Serra Aracil 2018, who aims to compare neoadjuvant CRT followed by LE to TME in patients with T2‐3N0M0 rectal cancer. These studies would provide more insight into the extent to which we can expand the application of LE for the treatment of rectal cancer. Future research would ideally also clarify the role of adjuvant therapy in patients with stage I rectal cancer, as there is evidence that adjuvant radiotherapy would result in similar cancer‐specific and overall survival even in T2 rectal cancers (Wang 2018).
Outcomes
Only one of the studies included in this review evaluated sphincter function, quality of life, and genitourinary function. Other patient‐centered outcomes such as permanent ostomy rate should be considered in the future. Given that there was also an incomplete reporting of survival analyses in these studies, with suspicion of selective reporting, and that there was no subgroup analysis of final pathological stage, future research should focus on precise and complete reporting of time‐to‐event survival outcomes and ideally make their data available for meta‐analyses. Special attention should also be paid to standardized reporting of all outcomes, including postoperative complications, as none of the studies used a validated scale for this purpose.
History
Protocol first published: Issue 3, 2000
| Date | Event | Description |
|---|---|---|
| 4 December 2020 | Feedback has been incorporated | Changes made in response to editorial comments. |
| 29 October 2018 | Amended | Review authors' comments incorporated. |
| 22 May 2018 | Amended | Protocol revised. |
| 2 May 2018 | Amended | Protocol revised. |
| 21 February 2018 | Amended | Protocol updated. |
Notes
This review continues the work from two previously published protocols (Ramirez 2000;Borao 2011). Before undertaking the review, we updated the protocol to include only the modern endoscopic local excision techniques and ensured that it aspires to the latest Cochrane methodology.
Acknowledgements
We would like to thank the current and previous editors of the Cochrane Colorectal Cancer Group for their relentless support and guidance, as well as Mr Lovedeep Gondara of Surgical Oncology Network, BC Cancer Agency (BCCA), Vancouver, BC and Ms Hong Qian of Centre for Health Evaluation and Outcome Sciences (CHEOS), Providence Health Care Research Institute, Vancouver, BC for helping with the statistical aspect of the review.
Editorial and peer‐reviewer contributions
Cochrane Colorectal supported the authors in the development of this intervention review.
The following people conducted the editorial process for this article.
Sign‐off Editors (final editorial decision): Nicole Skoetz, University of Cologne and University Hospital Cologne, Germany, Co‐ordinating Editor of the Cochrane Haematology Group; and Emmanuel Effa, Department of Internal Medicine, College of Medical Sciences, University of Calabar, Nigeria
Managing Editor (selected peer reviewers, collated peer‐reviewer comments, provided editorial guidance to authors, edited the article): Samuel Hinsley and Colleen Ovelman, Central Editorial Service
Editorial Assistant (conducted editorial policy checks and supported the editorial team): Leticia Rodrigues, Central Editorial Service
Copy Editor (copy editing and production): Lisa Winer, Cochrane Copy Edit Support
Peer reviewers (provided comments and recommended an editorial decision): Rachel Richardson, Associate Editor, Evidence Production and Methods Directorate (Methods), Maria‐Inti Metzendorf (Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich‐Heine University, Duesseldorf, Germany) (Search), Rutger Stijns, Department of Surgery, Radboudumc Nijmegen, the Netherlands (Clinical), Avanish Saklani, Mufaddal Kazi, Tata Memorial Hospital (Clinical), MG Varma, MD, Department of Surgery, University of California, San Francisco (Clinical), and Doaa Wael Elgendy, Ain Shams University, Faculty of Medicine (Consumer)
Appendices
Appendix 1. Cochrane Central Register of Controlled Trials (CENTRAL)
#1 exp Rectal Neoplasms/
#2 ((rect* or anal* or anus*) near/3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumor* or tumour* or sarcom* or polyp* or adenom*)):ti,ab,kw
#3 (#1 or #2)
#4 Colorectal Surgery/
#5 (protectom* or Mason or Kraske or TEM or TEMS or Miles or Hartmann):ti,ab,kw
#6 ((open or radical or local) near/3 (surgery or resection or treatment or management or excision or intervention)):ti,ab,kw
#7 ((rect* or anal* or anus* or endoscopic or micro or anterior or abdominal perineal or transanal) near/3 (resection or surgery or microsurgery)):ti,ab,kw
#8 (#4 or #5 or #6 or #7)
#9 (#3 and #8)
Appendix 2. MEDLINE search strategy
1. exp Rectal Neoplasms/
2. ((rect* or anal* or anus*) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumor* or tumour* or sarcom* or polyp* or adenom*)).mp.
3. 1 or 2
4. exp Colorectal Surgery/
5. (protectom* or Mason or Kraske or TEM or TEMS or Miles or Hartmann).mp.
6. ((open or radical or local) adj (surgery or resection or treatment or management or excision or intervention)).mp.
7. ((rect* or anal* or anus* or endoscopic or micro or anterior or abdominal perineal or transanal) adj (resection or surgery or microsurgery)).mp.
8. 4 or 5 or 6 or 7
9. 3 and 8
10. randomized controlled trial.pt.
11. controlled clinical trial.pt.
12. randomi*ed.ab.
13. placebo.ab.
14. clinical trials as topic.sh.
15. randomly.ab.
16. trial.ti.
17. 10 or 11 or 12 or 13 or 14 or 15 or 16
18. exp animals/ not humans.sh.
19. 17 not 18
20. 9 and 19
Appendix 3. Embase search strategy
1. rectum tumor/
2. ((rect* or anal* or anus*) adj (carcinom* or neoplas* or adenocarcinom* or cancer* or tumor* or tumour* or sarcom* or polyp* or adenom*)).mp.
3. 1 or 2
4. rectum surgery/
5. (protectom* or Mason or Kraske or TEM or TEMS or Miles or Hartmann).mp.
6. ((open or radical or local) adj (surgery or resection or treatment or management or excision or intervention)).mp.
7. 4 or 5 or 6
8. 3 and 7
9. CROSSOVER PROCEDURE.sh.
10. DOUBLE‐BLIND PROCEDURE.sh.
11. SINGLE‐BLIND PROCEDURE.sh.
12. (crossover* or cross over*).ti,ab.
13. placebo*.ti,ab.
14. (doubl* adj blind*).ti,ab.
15. allocat*.ti,ab.
16. trial.ti.
17. RANDOMIZED CONTROLLED TRIAL.sh.
18. random*.ti,ab.
19. 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20. (exp animal/ or exp invertebrate/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans or man or men or wom?n).ti.)
21. 19 not 20
22. 8 and 21
Appendix 4. Science Citation Index search strategy
Topic=((“colorectal neoplasm”) or (“colorectal tumour”) or (“colorectal adenocarcinoma”) or (“colorectal cancer”) or (“colorectal carcinoma”) or (“rectal tumour”) or (“rectal tumour”) or (“rectal cancer”) or (“rectal carcinoma”) or (“rectal neoplasm”) or (“rectal adenocarcinoma”) or (“rectal malignancy”) or (“colorectal malignancy”)) AND Topic=(early) AND Topic=((“local treatment“) or (“local management“) or (“local surgery“) or (“transanal surgery“) or (“local excision“) or (TEM) or (TEMS) or (“transanal endoscopic microsurgery“) or (“endoscopic surgery“) or (“microsurgery“) or (“abdominoperineal resection“) or (“anterior resection“) or ("Hartmann") or ("transanal total mesorectal excision") or (TaTME) or ("transanal minimally invasive surgery") or (TAMIS) or (“transanal endoscopic operation“) or (TEO) or (“transanal single port microsurgery“) or (TSPM))
Refined by: Document Type=(ARTICLE OR PROCEEDINGS PAPER)
Databases=SCI‐EXPANDED
Appendix 5. Search strategies for ongoing studies
ClinicalTrials.gov by United States National Library of Medicine (http://www.clinicaltrials.gov)
Strategy: Condition: rectal cancer. Intervention: (radical OR total OR mesorectal) AND (local OR endoscopic OR transanal OR natural orifice) AND (surgery OR resection OR excision OR microsurgery). Limits: Study type: interventional studies.
International Standard Randomised Controlled Trial Number Registry (http://www.ISRCTN.com)
Strategy: Radical OR local OR transanal OR excision OR TEM OR TAMIS OR TEO OR TSPM
The International Clinical Trials Registry Platform by World Health Organization (http://apps.who.int/trialsearch)
Strategy: Radical OR local OR transanal OR excision OR TEM OR TAMIS OR TEO OR TSPM.
National Cancer Institute (NCI) Clinical Trials Registry (www.cancer.gov/clinicaltrials)
Strategy: Cancer Type/Condition: Rectal cancer. Stage/Subtype: stage I rectal cancer. Trial Type: Treatment. Trial Status: Active.
Appendix 6. Criteria for judging risk of bias in the risk of bias assessment tool
| RANDOM SEQUENCE GENERATION Selection bias (biased allocation to interventions) due to inadequate generation of a randomized sequence | |
| Criteria for a judgement of ‘Low risk’ of bias | The investigators describe a random component in the sequence generation process such as: · referring to a random number table; · using a computer random number generator; · coin tossing; · shuffling cards or envelopes; · throwing dice; · drawing of lots; · minimization.* *Minimization may be implemented without a random element, and this is considered equivalent to being random. |
| Criteria for a judgement of ‘High risk’ of bias | The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: · sequence generated by odd or even date of birth; · sequence generated by some rule based on date (or day) of admission; · sequence generated by some rule based on hospital or clinic record number. Other non‐random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of non‐random categorization of participants, for example: · allocation by judgement of the clinician; · allocation by preference of the participant; · allocation based on the results of a laboratory test or a series of tests; · allocation by availability of the intervention. |
| Criteria for a judgement of ‘Unclear risk’ of bias | Insufficient information about the sequence generation process to permit a judgement of ‘Low risk’ or ‘High risk’ |
| ALLOCATION CONCEALMENT Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment | |
| Criteria for a judgement of ‘Low risk’ of bias | Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation. · Central allocation (including telephone, web‐based, and pharmacy‐controlled randomization) · Sequentially numbered drug containers of identical appearance · Sequentially numbered, opaque, sealed envelopes |
| Criteria for a judgement of ‘High risk’ of bias | Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: · using an open random allocation schedule (e.g. a list of random numbers); · using assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); · alternation or rotation; · date of birth; · case record number; · any other explicitly unconcealed procedure. |
| Criteria for a judgement of ‘Unclear risk’ of bias | Insufficient information to permit a judgement of ‘Low risk’ or ‘High risk.’ This is usually the case if the method of concealment is not described, or not described in sufficient detail to allow a definitive judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque, and sealed. |
| BLINDING OF PARTICIPANTS AND PERSONNEL Performance bias due to knowledge of the allocated interventions by participants and personnel during the study | |
| Criteria for a judgement of ‘Low risk’ of bias | Any one of the following. · No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding · Blinding of participants and key study personnel ensured, and it is unlikely that the blinding could have been broken |
| Criteria for a judgement of ‘High risk’ of bias | Any one of the following. · No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding · Blinding of key study participants and personnel attempted, but it is likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding |
| Criteria for a judgement of ‘Unclear risk’ of bias | Any one of the following. · Insufficient information to permit a judgement of ‘Low risk’ or ‘High risk’ · The study did not address this outcome |
| BLINDING OF OUTCOME ASSESSMENT Detection bias due to knowledge of the allocated interventions by outcome assessors | |
| Criteria for a judgement of ‘Low risk’ of bias | Any one of the following. · No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding · Blinding of outcome assessment ensured, and it is unlikely that the blinding could have been broken |
| Criteria for a judgement of ‘High risk’ of bias | Any one of the following. · No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding · Blinding of outcome assessment, but it is likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding |
| Criteria for a judgement of ‘Unclear risk’ of bias | Any one of the following. · Insufficient information to permit a judgement of ‘Low risk’ or ‘High risk’ · The study did not address this outcome |
| INCOMPLETE OUTCOME DATA Attrition bias due to the amount, nature, or handling of incomplete outcome data | |
| Criteria for a judgement of ‘Low risk’ of bias | Any one of the following. · No missing outcome data · Reasons for missing outcome data are unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias) · Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups · For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is not enough to have a clinically relevant impact on the intervention effect estimate · For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes is not enough to have a clinically relevant impact on observed effect size · Missing data have been imputed using appropriate methods |
| Criteria for a judgement of ‘High risk’ of bias | Any one of the following. · Reason for missing outcome data likely to be related to true outcome, with either an imbalance in numbers or reasons for missing data across intervention groups · For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is enough to induce clinically relevant bias in intervention effect estimate · For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes is enough to induce clinically relevant bias in observed effect size · ‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomization · Potentially inappropriate application of simple imputation |
| Criteria for a judgement of ‘Unclear risk’ of bias | Any one of the following. · Insufficient reporting of attrition/exclusions to permit a judgement of ‘Low risk’ or ‘High risk’ (e.g. number randomized not stated, no reasons for missing data provided) · The study did not address this outcome |
| SELECTIVE REPORTING Reporting bias due to selective outcome reporting | |
| Criteria for a judgement of ‘Low risk’ of bias | Any of the following. · The study protocol is available, and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way · The study protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon) |
| Criteria for a judgement of ‘High risk’ of bias | Any one of the following. · Not all of the study’s prespecified primary outcomes have been reported · One or more primary outcomes is reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified · One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect) · One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis · The study report fails to include results for a key outcome that would be expected to have been reported for such a study |
| Criteria for a judgement of ‘Unclear risk’ of bias | Insufficient information to permit a judgement of ‘Low risk’ or ‘High risk.’ It is likely that the majority of studies will fall into this category. |
| OTHER BIAS Bias due to problems not covered elsewhere in the table | |
| Criteria for a judgement of ‘Low risk’ of bias | The study appears to be free of other sources of bias. |
| Criteria for a judgement of ‘High risk’ of bias | There is at least one important risk of bias. For example, the study: · had a potential source of bias related to the specific study design used; · has been claimed to have been fraudulent; or · had some other problem. |
| Criteria for a judgement of ‘Unclear risk’ of bias | There may be a risk of bias, but there is either: · insufficient information to assess whether an important risk of bias exists; or · insufficient rationale or evidence that an identified problem will introduce bias. |
Appendix 7. Key domains for assessing risk of bias for individual outcomes
| Outcome | Risk of bias domain | |||||
| 1. Random sequence generation | 2. Allocation concealment | 3. Blinding of participants/ personnel (a)/outcome assessors (b) | 4. Incomplete outcome data | 5. Selective reporting | 6. Other problems in protocol execution or design that may affect individual outcomes | |
| 1.1 Disease‐free survival | • | • | b | • | • | • |
| 1.2 Sphincter function | • | • | a,b | • | • | • |
| 2.1 to 2.3 Oncologic outcomes | • | • | b | • | • | • |
| 3.1 30‐day postoperative mortality | • | • | • | • | • | • |
| 3.2 Major and minor postoperative complications | • | • | a,b | • | • | • |
| 3.3 Length of stay | • | • | a,b | • | • | • |
| 3.4 Incomplete resection/conversion rate | • | • | b | • | • | • |
| 4.1, 4.2 Functional outcomes | • | • | a,b | • | • | • |
Appendix 8. Summary assessment of the risk of bias for each outcome
| Risk of bias | Interpretation | Within a study | Across studies |
| Low risk of bias | Plausible bias unlikely to seriously alter the results | Low risk of bias for all key domains | Most information is from studies at low risk of bias. |
| Unclear risk of bias | Plausible bias that raises some doubt about the results | Unclear risk of bias for 1 or more key domains | Most information is from studies at low or unclear risk of bias. |
| High risk of bias | Plausible bias that seriously weakens confidence in the results | High risk of bias for 1 or more key domains | The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results. |
Appendix 9. Sensitivity analysis
| Sensitivity analysis for: | Original analysis (effect estimate (95% CI) | Sensitivity analysis (effect estimate (95% CI) |
| Changing statistical model from random‐effects to fixed‐effect (outcome: minor postoperative complications) | Risk ratio 0.48 (0.27 to 0.85) | Risk ratio 0.46 (0.28 to 0.76) |
CI: confidence interval
Data and analyses
Comparison 1. Local excision versus radical resection irrespective of chemoradiotherapy.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Disease‐free survival | 3 | 212 | Hazard Ratio (IV, Random, 95% CI) | 1.96 [0.91, 4.24] |
| 1.2 Cancer‐related survival | 3 | Hazard Ratio (IV, Random, 95% CI) | 1.42 [0.60, 3.33] | |
| 1.3 30‐day postoperative mortality | 4 | 0 | Risk Ratio (IV, Random, 95% CI) | Not estimable |
| 1.4 Major postoperative complications | 4 | 266 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.53 [0.22, 1.28] |
| 1.5 Minor postoperative complications | 4 | 266 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.27, 0.85] |
| 1.6 Length of stay | 3 | 211 | Mean Difference (IV, Random, 95% CI) | ‐6.81 [‐11.12, ‐2.50] |
| 1.7 Incomplete resection/conversion rate | 4 | 268 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.02 [0.34, 3.03] |
Characteristics of studies
Characteristics of included studies [ordered by year]
Winde 1997.
| Study characteristics | ||
| Methods |
| |
| Participants |
| |
| Interventions |
‐‐‐‐‐‐ CRT: none | |
| Outcomes |
| |
| Notes | Conflict of interest: none declared We contacted the authors in February 2020, but no data from the 1997 study were available separately. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were selected at random (number table) randomly distributed to the treatment arms" |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgment of low or high risk |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding |
| Blinding of outcome assessment (detection bias) | High risk | No blinding of outcome assessment, and assessment of outcome is likely to be influenced by knowledge of intervention received |
| Incomplete outcome data (attrition bias) | Low risk | Reasons for missing outcome data unlikely to be related to true outcome. |
| Selective reporting (reporting bias) | Unclear risk | Insufficient information to permit judgment of low or high risk |
| Other bias | Low risk | No other sources of bias |
Lezoche 2012.
| Study characteristics | ||
| Methods |
| |
| Participants |
| |
| Interventions |
‐‐‐‐‐‐ CRT: All participants underwent long‐course 3‐dimensional 4‐field chemoradiotherapy in the prone position, with bladder preparation and use of intravenous contrast. The total dose given was 50.4 Gy in 28 fractions over 5 weeks. The irradiated areas were: anus, rectum, mesorectum, and regional and iliac lymph nodes. The superior limit was L5–S1 and the inferior limit around 3 to 5 cm under the ischiopubic ramus. A continuous infusion of 5‐fluorouracil 200 mg/m2 per day was administered during radiotherapy treatment. | |
| Outcomes |
| |
| Notes | Conflict of interest: the authors declared no conflict of interests. We contacted the authors in February 2020, but received no response. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Using a computer random number generator" to randomize participants |
| Allocation concealment (selection bias) | Low risk | "Sequentially numbered, opaque, sealed envelopes" were used |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding |
| Blinding of outcome assessment (detection bias) | High risk | No blinding of outcome assessment, and assessment of outcome is likely to be influenced by knowledge of intervention received |
| Incomplete outcome data (attrition bias) | Low risk | No missing outcome data |
| Selective reporting (reporting bias) | Low risk | The study protocol was available, and all of study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way. |
| Other bias | Low risk | No other sources of bias detected. |
Chen 2013.
| Study characteristics | ||
| Methods |
| |
| Participants |
| |
| Interventions |
‐‐‐ CRT: High‐risk LAR patients (8 of 30 participants) received adjuvant FOLFOX‐4 chemotherapy because of having lymphovascular invasion (n = 7) or poorly differentiated tumor (n = 1). | |
| Outcomes |
| |
| Notes | Conflict of interest: none declared We contacted the authors in February 2020, but received no response. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information about the sequence generation process to permit judgment of low or high risk: "Patients were assigned to TEM or LAR in a random and equal way" |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgment of low or high risk |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding |
| Blinding of outcome assessment (detection bias) | High risk | No blinding of outcome assessment, and assessment of outcome is likely to be influenced by knowledge of intervention received |
| Incomplete outcome data (attrition bias) | Unclear risk | ‘As‐treated’ analysis was undertaken, as compared to intention‐to‐treat analysis. Study protocol is not available. |
| Selective reporting (reporting bias) | Unclear risk | Insufficient information to permit judgment of low or high risk |
| Other bias | High risk | Adjuvant therapy only in "high risk" LAR participants. No TEM participants received CRT. |
Bach 2020.
| Study characteristics | ||
| Methods |
| |
| Participants |
| |
| Interventions |
‐‐‐ CRT: Only for participants in the local excision group, 3‐dimensional pelvic conformal short‐course radiotherapy with 25 Gy in 5 fractions over a period of 5 to 7 days with photon energies of at least 6 MV and a 3‐ or 4‐field technique. The clinical radiotherapy target volume included the tumor, mesorectum, and internal iliac, obturator, and presacral nodes, up to the level of S2/3 junction. | |
| Outcomes |
Quality of life:
Function scores:
aIn a participant who deviated from group allocation and underwent LAR instead of LE. bAll 3 participants had previously declined planned conversion to total mesorectal excision despite having high‐risk TEM features: ypT3 in 2 participants and R1 in 1 participant. *P = 0.04, Chi2 test | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Treatment allocation was done with a computer‐based randomization service accessed by telephone or web link" |
| Allocation concealment (selection bias) | Low risk | "Treatment allocation was done with a computer‐based randomization service accessed by telephone or web link" |
| Blinding (performance bias and detection bias) All outcomes | High risk | No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding |
| Blinding of outcome assessment (detection bias) | High risk | No blinding of outcome assessment, and assessment of outcome is likely to be influenced by knowledge of intervention received |
| Incomplete outcome data (attrition bias) | Low risk | No missing outcome data. Intention‐to‐treat analysis used. |
| Selective reporting (reporting bias) | Low risk | The study protocol is available, and all the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way. |
| Other bias | Low risk | No other sources of bias detected. |
APR: abdominal perineal resection; CI: confidence interval; CRT: chemoradiotherapy; ELRR: endoluminal locoregional resection; HR: hazard ratio; IQR: interquartile range; LAR: low anterior resection; LE: local excision; QOL: quality of life; RR: radical resection; SD: standard deviation; TEM: transanal endoscopic microsurgery; TME: total mesorectal excision; TNM: tumor‐node‐metastasis
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Ahmad 1998 | Ineligible study design: a single‐arm trial of local excision |
| Borstlap 2016 | Ineligible study design: randomization after LE to completion total mesorectal excision or adjuvant chemoradiotherapy |
| Bosset 2006 | Ineligible patient population: T3‐T4 rectal cancer patients |
| Dewey 1985 | Ineligible interventions: open transanal resection technique vs abdominal perineal resection |
| ISRCTN27293422 | Ineligible interventions: radical resection of stage II to III rectal adenocarcinoma without a local excision arm |
| Luo 2005 | Ineligible interventions: no local excision arm in the study |
| NCT02022553 | Ineligible interventions: selective endoarterial oil chemoembolization of rectal arteries |
| NCT03548844 | Ineligible study design: randomization after LE to completion TME or observation |
| Pontallier 2016 | Ineligible interventions: transanal total mesorectale excision vs laparoscopic total mesorectal excision |
Characteristics of studies awaiting classification [ordered by study ID]
Rullier 2020.
| Methods |
|
| Participants |
|
| Interventions |
‐‐‐ CRT: 3‐dimensional conformal pelvic radiotherapy delivering 50 Gy with high‐energy (18 MV) photons in fractions of 2 Gy, 5 days a week over 5 weeks. Capecitabine 1600 mg/m2 per day, 5 days per week, and oxaliplatin 50 mg/m2 per week were administered during radiotherapy. |
| Outcomes | 5‐year oncological outcomes of local recurrence, metastatic disease, disease‐free survival, overall survival, and cancer‐specific mortality |
| Notes | This study has a subgroup of eligible participants. We contacted the authors regarding separate data, and the process of data acquisition was initiated by a bilateral contract between the authors' institutions to transfer anonymous data. Separate data for T2 patients were not available for inclusion in the review at the time of submission. |
CRT: chemoradiotherapy; LE: local excision; RR: radical resection; TEM: transanal endoscopic microsurgery; TME: total mesorectal excision; TNM: tumor‐node‐metastasis
Characteristics of ongoing studies [ordered by study ID]
NCT03431428.
| Study name | Comparison of short‐term efficacy and long‐term prognosis for reduction surgery and radical resection in almost‐cCR rectal cancer patients |
| Methods | Multicenter, parallel‐design randomized trial |
| Participants | Patients with clinical stage rectal tumor lower than cT3cN1M0 |
| Interventions |
|
| Outcomes | Primary outcomes:
Secondary outcomes:
|
| Starting date | 13 February 2018 |
| Contact information | Rui Zhang, doctor
8613898872185
Email: zzzrrr1234@sina.com Xin Liu, master 8618900918981 Email: liuxin5626855@sina.com |
| Notes | We contacted the authors for possible data and data of publication, but have received no response. |
Rombouts 2017.
| Study name | STAR‐TREC study (STAR‐TREC: can we save the rectum by watchful waiting or TransAnal microsurgery following [chemo‐] radiotherapy vs total mesorectal excision for early rectal cancer?) |
| Methods | 3‐arm (1:1:1) randomization of mrT1‐3bN0M0 patients to TME, CRT and LE, or short‐course radiotherapy and LE (in good responders) |
| Participants | Patients with mrT1‐3bN0M0 adenocarcinoma of the rectum |
| Interventions | (1:1:1) to:
|
| Outcomes | Safety outcomes:
Efficacy outcomes:
|
| Starting date | 26 October 2016 |
| Contact information | Mr Simon Bach The University of Birmingham Academic Department of Surgery 4th Floor QE Hospital Edgbaston Birmingham B15 2TH United Kingdom +44 121 371 5889 Email: simon.bach@uhb.nhs.uk |
| Notes | We contacted the author regarding data availability and publication date; the probable publication date is summer 2020. |
Serra Aracil 2018.
| Study name | TAU‐TEM study (Non‐inferiority multicenter prospective randomized controlled study of rectal cancer T2‐T3 [superficial] N0, M0 undergoing neoadjuvant treatment and local excision [TEM] vs total mesorectal excision [TME]) |
| Methods | Prospective, multicenter, randomized controlled non‐inferiority trial |
| Participants | Patients with rectal adenocarcinoma less than 10 cm from the anal verge and up to 4 cm in size, staged as T2 or T3‐superficial N0‐M0 |
| Interventions |
|
| Outcomes | Primary:
Secondary:
|
| Starting date | 4 March 2011 |
| Contact information | Xavier Serra‐Aracil +34937231010 ext 20009 |
| Notes | We contacted the author regarding data availability and publication date, but the attempt was unsuccessful. |
CRT: chemoradiotherapy; LE: local excision; TEM: transanal endoscopic microsurgery; TME: total mesorectal excision
Differences between protocol and review
We did not undertake formal subgroup or sensitivity analyses given that only four studies were included in the review. The evaluation of funnel plots for publication bias was also precluded by the low number of studies. Furthermore, the low number of studies prevented us from undertaking all of the intended comparisons between the two surgery groups outlined in the protocol.
Contributions of authors
Conception and design of the review: all authors Co‐ordination of the review: MAKM Search and selection of studies: DG, MAKM, NM, PTP Collection of data for the review: MAKM, NM Assessment of risk of bias in the included studies: MAKM, NM, PTP Analysis of data: MAKM GRADE assessment: MAKM, PTP Interpretation of data: all authors Writing/critical revision of the review: all authors
All authors approve the final version of the review and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Sources of support
Internal sources
Cochrane Colorectal Cancer Group, Denmark
Continues editorial support and guidance
External sources
BC Cancer Agency, Canada
Statistical support
Declarations of interest
MAKM has no conflicts of interest to disclose.
NM has no conflicts of interest to disclose.
CB has no conflicts of interest to disclose.
MR has no conflicts of interest to disclose.
AK has no conflicts of interest to disclose.
DG has no conflicts of interest to disclose.
PTP has no conflicts of interest to disclose.
New
References
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