Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial

Julia Kitz; Emmanouil Fokas; Tim Beissbarth; Philipp Ströbel; Christian Wittekind; Arndt Hartmann; Josef Rüschoff; Thomas Papadopoulos; Elisabeth Rösler; Peter Ortloff-Kittredge; Ulrich Kania; Hans Schlitt; Karl-Heinrich Link; Wolf Bechstein; Hans-Rudolf Raab; Ludger Staib; Christoph-Thomas Germer; Torsten Liersch; Rolf Sauer; Claus Rödel; Michael Ghadimi; Werner Hohenberger

doi:10.1001/jamasurg.2018.1607

. 2018 Jun 6;153(8):e181607. doi: 10.1001/jamasurg.2018.1607

Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer

Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial

Julia Kitz ¹, Emmanouil Fokas ^2,^✉, Tim Beissbarth ³, Philipp Ströbel ¹, Christian Wittekind ⁴, Arndt Hartmann ⁵, Josef Rüschoff ⁶, Thomas Papadopoulos ⁷, Elisabeth Rösler ⁸, Peter Ortloff-Kittredge ⁸, Ulrich Kania ⁹, Hans Schlitt ¹⁰, Karl-Heinrich Link ¹¹, Wolf Bechstein ¹², Hans-Rudolf Raab ¹³, Ludger Staib ¹⁴, Christoph-Thomas Germer ¹⁵, Torsten Liersch ¹⁶, Rolf Sauer ¹⁷, Claus Rödel ², Michael Ghadimi ¹⁶, Werner Hohenberger ¹⁸, for the German Rectal Cancer Study Group

¹Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany

²Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany

³Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany

⁴Institute of Pathology, University Medical Center Leipzig, Leipzig, Germany

⁵Institute of Pathology, University Medical Center Erlangen, Erlangen, Germany

⁶Institute of Pathology Nordhessen, Kassel, Germany

⁷Institute of Pathology, Klinikum Nürnberg Nord, Nuremberg, Germany

⁸Institute of Pathology, Mönchengladbach, Germany

⁹Department of General and Visceral Surgery, Krankenhaus Maria Hilf, Mönchengladbach, Germany

¹⁰Department of Visceral Surgery, University Medical Center Regensburg, Regensburg, Germany

¹¹Department of Visceral Surgery, Asklepios Paulinen Klinik Wiesbaden, Wiesbaden, Germany

¹²Department of General and Visceral Surgery, University Medical Center Frankfurt, Frankfurt, Germany

¹³Department of General and Visceral Surgery, University Medical Center Oldenburg, Oldenburg, Germany

¹⁴Department of General and Visceral Surgery, Klinikum Esslingen, Esslingen, Germany

¹⁵Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany

¹⁶Department of General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Germany

¹⁷Department of Radiation Therapy, University of Erlangen, Erlangen, Germany

¹⁸Department of General and Visceral Surgery, University of Erlangen, Erlangen, Germany

Group Information: The German Rectal Cancer Study Group members are listed at the end of this article.

Accepted for Publication: March 4, 2018.

^✉

Corresponding Author: Emmanouil Fokas, MD, DPhil, Department of Radiotherapy and Oncology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany (emmanouil.fokas@kgu.de).

Published Online: June 6, 2018. doi:10.1001/jamasurg.2018.1607

Author Contributions: Drs Fokas and Roedel had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kitz and Fokas contributed equally.

Concept and design: Fokas, Beissbarth, Stroebel, Rueschoff, Schlitt, Raab, Staib, Liersch, Roedel, Ghadimi, Hohenberger.

Acquisition, analysis, or interpretation of data: Kitz, Fokas, Beissbarth, Wittekind, Hartmann, Rueschoff, Papadopoulos, Roesler, Ortloff-Kittredge, Kania, Schlitt, Link, Bechstein, Staib, Germer, Liersch, Sauer, Roedel, Ghadimi, Hohenberger.

Drafting of the manuscript: Fokas, Beissbarth, Stroebel, Ortloff-Kittredge, Liersch, Roedel, Ghadimi.

Critical revision of the manuscript for important intellectual content: Kitz, Fokas, Beissbarth, Stroebel, Wittekind, Hartmann, Rueschoff, Papadopoulos, Roesler, Kania, Schlitt, Link, Bechstein, Raab, Staib, Germer, Liersch, Sauer, Roedel, Ghadimi, Hohenberger.

Statistical analysis: Fokas, Beissbarth, Liersch.

Obtained funding: Roedel.

Administrative, technical, or material support: Kitz, Fokas, Wittekind, Hartmann, Papadopoulos, Kania, Schlitt, Bechstein, Raab, Liersch, Sauer, Roedel.

Study supervision: Fokas, Stroebel, Wittekind, Rueschoff, Kania, Schlitt, Raab, Germer, Liersch, Sauer, Roedel, Ghadimi.

Other: Roesler, Ortloff-Kittredge.

Other–surgery and study participation, providing data, treatment coordination, and documentation of the patients within the bowel cancer center: Link.

Conflict of Interest Disclosures: None reported.

German Rectal Cancer Study Group: Julia Kitz, MD, University Medical Center Göttingen, Emmanouil Fokas, MD, University of Frankfurt, Tim Beissbarth, PhD, University Medical Center Göttingen, Philipp Ströbel, University Medical Center Göttingen, Christian Wittekind, University Medical Center Leipzig, Arndt Hartmann, MD, University Medical Center Erlangen, Josef Rüschoff, MD, Institute of Pathology Nordhessen, Thomas Papadopoulos, MD, Institute of Pathology, Klinikum Nürnberg Nord, Elisabeth Rösler, MD, Institute of Pathology Mönchengladbach, Peter Orloff-Kittredge, Institute of Pathology Mönchengladbach, Ulrich Kania, MD, Krankenhaus Maria Hilf, Hans Schlitt, MD, University Medical Center Regensburg, Karl-Heinrich Link, MD, Asklepio Paulinen Klinik Wiesbaden, Wolf Bechstein, MD, University Medical Center Frankfurt, Hans-Rudolph Raab, MD, University Medical Center Oldenburg, Ludger Staib, MD, Klinikum Esslingen, Christoph-Thomas Germer, MD, University Hospital Würzburg, Torsten Liersch, MD, University Medical Center Göttingen, Rolf Sauer, MD, University of Erlangen, Claus Rödel, MD, University of Frankfurt, Michael Ghadimi, MD, University Medical Center Göttingen, Werner Hohenberger, University of Erlangen, Ralf-Dieter Hofheinz, MD, University of Heidelberg, Dirk Arnold, MD, Asklepios Clinic Altona, Gerhard Grabenbauer, MD, DiaCura & Klinikum Coburg, Gunnar Folprecht, MD, University Hospital Carl Gustav Carus, Ullrich Graeven, MD, Kliniken Maria Hilf GmbH Mönchengladbach, Torsten Hothorn, PhD, University of Zurich, and Jürgen Weitz, MD, University Hospital Carl Gustav Carus.

Funding/Support: The study was funded by a grant from the German Cancer Aid (Deutsche Krebshilfe e.V.).

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

Additional Contributions: We thank the WiSP Research Institute (Langenfeld, Germany) for providing on-site monitoring, source data verification, and management for the clinical trial database. We thank the patients, investigators, and institutions involved in this trial. A portion of the study’s funding was used to compensate staff members of WiSP Research Institute.

^✉

Corresponding author.

PMCID: PMC6142959 PMID: 29874375

Key Points

Question

Does the quality of total mesorectal excision plane affect clinical outcomes in patients with rectal cancer that was treated with preoperative chemoradiotherapy and adjuvant treatment?

Findings

In this secondary end point analysis of a phase 3 randomized clinical trial, the quality of the total mesorectal excision plane was an independent prognostic factor for the local recurrence in rectal cancer.

Meaning

These data add high-level clinical evidence on the importance of pathology work-up and surgical skills in rectal cancer.

Abstract

Importance

Previous retrospective studies have shown that surgical quality affects local control in rectal cancer..

Objective

In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial.

Design, Setting, and Participants

The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010.

Interventions

Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy.

Main Outcomes and Measures

The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model.

Results

Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002).

Conclusions and Relevance

This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer.

Trial Registration

ClinicalTrials.gov Identifier: NCT00349076.

This secondary analysis of a randomized clinical trial investigates the prognostic role of the total mesorectal excision plane quality in patients with rectal cancer who were treated within the CAO/ARO/AIO-04 phase 3 randomized clinical trial.

Introduction

Randomized clinical trials have shown that preoperative chemoradiotherapy (CRT) or short-course radiotherapy (RT) before surgery improve local control in locally advanced rectal cancer.^1,2,3 Total mesorectal excision (TME) constitutes the current surgical treatment of choice for rectal cancer.⁴ The pathology studies by Quirke and colleagues^5,6,7 have demonstrated variability in the completeness of resected TME specimens. Three grades of TME quality have been defined, including the mesorectal plane (good-quality, complete, and smooth), intramesorectal plane (moderate-quality, nearly complete, and moderately irregular), and muscularis propria plane (poor-quality, incomplete, and severely irregular).⁶ Several studies have revealed that the quality of TME greatly determines long-term local control, but most studies consisted of retrospective series, whereas, to our knowledge, phase 3 trial evidence was only provided in the CR07 study.^{8,9,10,11,12,13}

The clinical relevance of the circumferential resection margin (CRM) after TME in rectal cancer has been described in several series.^{8,14,15,16,17} In a meta-analysis of more than 17 500 patients, Nagtegaal and Quirke¹⁸ showed that a tumor involvement of CRM (≤1 mm) was a predictor for both local and distant recurrence and overall survival (OS).¹⁸ The Magnetic Resonance Imaging and Rectal Cancer European Equivalence (MERCURY) study showed that high-resolution magnetic resonance imaging (MRI) enabled accurate staging, including the detection of CRM involvement that strongly correlated with worse disease-free survival (DFS) and local control rates.¹⁹

However, most previous reports were characterized by a relatively small sample size and retrospective nature, and phase 3 trial confirmation of the long-term effect of TME quality on local control, as initially reported in the CR07 trial, is lacking. In this study, we aimed to investigate the association of TME quality with clinical and pathologic parameters and its association with the clinical outcome as part of the large CAO/ARO/AIO-04 phase 3 trial. This randomized clinical trial assessed the clinical effect following the addition of oxaliplatin to 5-fluorouracil–based preoperative CRT and adjuvant chemotherapy.^20,21 The quality of TME was recorded prospectively in both arms of the trial using the system by Quirke and colleagues.^5,6,7

Methods

Study Design and Participants

The CAO/ARO/AIO-04 trial was a multicenter, 2-arm randomized phase 3 study. Its design and details have been previously reported.^20,21 The trial had approval by the local ethics committee of the University of Erlangen, Germany. Participants provided written informed consent. A description is shown in the eMethods in Supplement 1 and the eFigure 1 in Supplement 1 illustrates the treatment plan. The full trial protocol is provided in Supplement 2.

Pathologic Examination of Resected Specimen

A standardized pathology protocol for resected specimens was developed by the committee of reference pathologists (C.W., A.H., and P.S.).²⁰ Preparation, processing and analysis of the resected specimens has been reported in detail before.^22,23 The quality of TME plane (mesorectal, intramesorectal, and muscularis propria plane) was scored according to Quirke et al.⁸ Examples of TME planes are shown in eFigure 2 in Supplement 1. In addition to the pathologist-based evaluation, the quality of TME plane was also prospectively scored by the operating surgeon. A central pathology review of resected specimen was not performed. The follow-up process has been described in detail in eMethods in Supplement 1.

Statistical Analysis

Disease-free survival was defined as the time between patient randomization and either the formation of a macroscopically visible tumor following surgery (R2 resection), locoregional recurrence after an R0/1 resection, distant metastases or progression, or death from any cause, whichever occurred first. The cumulative incidence of locoregional and distant recurrences were defined as the time between patient randomization and the occurrence of any locoregional or distal recurrence, irrespective of whether this was a first event. The time from patient randomization to death from any cause was used to calculate OS.

The correlation of TME plane with clinicopathologic factors was assessed using the χ² test. This test was used to test the association of pathologist-based evaluation with surgeon-based evaluation of TME plane. A univariable analysis using the log-rank test was performed to investigate the prognostic value of TME, the treatment arm, pretreatment clinicopathologic factors, and postsurgical pathologic factors. The hazard ratios (HRs) and corresponding P values of the TME intergroup comparisons of intramesorectal vs mesorectal TME and muscularis propria vs mesorectal TME were calculated using a Cox regression model.

A multivariable analysis for OS, DFS, locoregional, and distant recurrence was conducted using Cox regression models. Patients with missing values in 1 or more of the variables (TME, treatment arm, local resection status, or pathologic stage) were excluded. A P value of less than .05 was considered significant. Statistical analyses were performed with SPSS, version 20 (SPSS Inc) and R, version 3.4 (R Foundation).

Results

Patient Characteristics and Association of TME With Clinicopathologic Factors

In total, 1265 patients were recruited for trial between July 25, 2006, and February 26, 2010. The Consolidated Standards of Reporting Trials diagram is shown in Figure 1. Total mesorectal excision quality as assessed by the pathologist was available for 1152 patients (eTable 1 in Supplement 1). The plane of surgery was comparable in the 2 treatment arms (mesorectal vs intramesorectal vs muscularis propria: 5-fluorouracil [FU], 80.8% vs 14.3% vs 4.9%, respectively; 5-FU + oxaliplatin, 80.7% vs 15.1% vs 4.3%, respectively; P = .82). Total mesorectal excision quality was significantly worse in patients with a more advanced cT category (mesorectal vs intramesorectal vs muscularis propria: cT2, 78.7% vs 21.3% vs 0%, respectively; cT3, 81.9% vs 14.1% vs 4.0%, respectively; cT4, 69.2% vs 16.7% vs 14.1%, respectively; missing, 40.0% vs 16.1% vs 4.8%, respectively; P < .001), lymph node involvement (mesorectal vs intramesorectal vs muscularis propria: cN0, 85.8% vs 0.4% vs 3.8%, respectively; cN1, 79.1% vs 16.1% vs 4.8%, respectively; P = .04), and tumors in the lower third of the rectum (mesorectal vs intramesorectal vs muscularis propria: distance from the anal verge of 0-5 cm, 72.6% vs 19.9% vs 7.4%, respectively; P < .001). There was no correlation between TME plane and any of the other factors (eTable 1 in Supplement 1).

Figure 1. — FU indicates fluorouracil; OX, oxaliplatin.

We next examined the correlation between pathologist-based evaluation and surgeon-based evaluation of TME plane quality (eTable 2 in Supplement 1). Compared with the pathologist-based mesorectal plane TME, surgeon-based evaluation showed agreement in 827 cases (86.4%). In contrast, a significant discrepancy was observed for intermesorectal plane, as only 68 surgeon-based evaluations (56.2%) of TME plane were in agreement with the pathologist assessment. For muscularis propria, agreement in TME plane quality evaluation occurred in 15 cases (75%).

Low anterior resection was associated with a significantly better plane of surgery compared with intersphincteric or abdominoperineal resection (mesorectal vs intramesorectal vs muscularis propria: anterior resection, 86.0% vs 11.3% vs 2.7%, respectively; abdominoperineal extirpation, 67.0% vs 23.0% vs 10.0%, respectively; intersphincter resection, 86.7% vs 13.3% vs 0%, respectively; other, 64.0% vs 24.0% vs 12.0%, respectively; P < .001). Similarly, the plane of surgery was significantly worse in patients with advanced ypT category (mesorectal vs intramesorectal vs muscularis propria: ypT0, 83.6 vs 12.2% vs 4.2%, respectively; ypT1/Tis, 90.5% vs 8.3% vs 1.2%, respectively; ypT3, 78.4% vs 16.1% vs 5.6%, respectively; ypT4, 50.0% vs 30.6% vs 19.4%, respectively; P < .001) and advanced ypN category (mesorectal vs intramesorectal vs muscularis propria: ypN, 82.2% vs 13.3% vs 4.5%, respectively; ypN1, 80.2% vs 16.3% vs 3.5%, respectively; ypN2, 69.8% vs 21.9% vs 8.3%, respectively; missing, 100.0% vs 0% vs 0%, respectively; P = .04) (Table 1).

Table 1. Association of the Pathologist-Based Quality of Total Mesorectal Excision (TME) With Posttreatment Patient and Tumor Factors in Patients Who Underwent an Operation and Received Preoperative 5-Fluorouracil–Based Chemoradiotherapy With or Without Oxaliplatin.

Characteristic	No. (%)				P Value
Characteristic	Total	Mesorectal	Intramesorectal	Muscularis Propria	P Value
Surgery method
Anterior resection	776 (67.4)	667 (86.0)	88 (11.3)	21 (2.7)	<.001^a
Abdominoperineal extirpation	291 (25.3)	195 (67.0)	67 (23.0)	29 (10.0)
Intersphincter resection	60 (5.2)	52 (86.7)	8 (13.3)	0 (0.0)
Other	25 (2.2)	16 (64.0)	6 (24.0)	3 (12.0)
Local resection status
R0	1102 (95.7)	898 (81.5)	158 (14.3)	46 (4.2)	.18
R1	21 (1.8)	16 (76.2)	5 (23.8)	0 (0.0)
R2	13 (1.1)	9 (69.2)	2 (15.4)	2 (15.4)
Missing	16 (1.4)	7 (43.8)	4 (25.0)	5 (31.2)
CRM^b
≤1 mm	62 (5.4)	39 (62.9)	13 (21.0)	10 (16.1)	<.001^a
>1 mm	803 (69.7)	655 (81.6)	117 (14.6)	31 (3.9)
pCR	178 (15.5)	148 (83.1)	22 (12.4)	8 (4.5)
Missing	109 (9.5)	88 (80.7)	17 (15.6)	4 (3.7)
Pathologic stage
0	185 (16.1)	151 (81.6)	26 (14.1)	8 (4.3)	.11
I	296 (25.7)	257 (86.8)	30 (10.1)	9 (3.0)
II	291 (25.3)	224 (77.0)	48 (16.5)	19 (6.5)
III	311 (27.0)	244 (78.5)	53 (17.0)	14 (4.5)
IV	53 (4.6)	40 (75.5)	10 (18.9)	3 (5.7)
Missing	16 (1.4)	14 (87.5)	2 (12.5)	0 (0.0)
ypT category
ypT0	189 (16.4)	158 (83.6)	23 (12.2)	8 (4.2)	<.001^a
ypT1/Tis	84 (7.3)	76 (90.5)	7 (8.3)	1 (1.2)
ypT2	321 (27.9)	269 (83.8)	44 (13.7)	8 (2.5)
ypT3	522 (45.3)	409 (78.4)	84 (16.1)	29 (5.6)
ypT4	36 (3.1)	18 (50.0)	11 (30.6)	7 (19.4)
ypN category
ypN0	798 (69.3)	656 (82.2)	106 (13.3)	36 (4.5)	.04^a
ypN1	257 (22.3)	206 (80.2)	42 (16.3)	9 (3.5)
ypN2	96 (8.3)	67 (69.8)	21 (21.9)	8 (8.3)
Missing	1 (0.1)	1 (100.0)	0 (0.0)	0 (0.0)

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Abbreviations: 5-FU, 5-fluorouracil; CRM, circumferential resection margin; pCR, pathological complete response; TME, total mesorectal excision.

^{^a}

Statistically significant.

^{^b}

TME quality was unknown in 5 patients with CRM involvement.

Involvement of CRM (≤1 mm) was found in 35 patients (6.2%) who were treated in the standard arm and in 32 patients (6.1%) in the experimental arm. An involved CRM occurred in 39 of 930 patients (3.7%) after mesorectal TME surgery, in 13 of 169 (7.6%) after intramesorectal, and in 10 of 53 patients (18.9%) after muscularis propria, respectively (P < .001) (Table 2). Circumferential resection margin involvement occurred in 31 of 729 patients (4.3%) who received low anterior resection, 26 of 276 patients (9.4%) after undergoing abdominoperineal resection, 3 of 52 patients (5.8%) after undergoing intersphincteric resection, and in 7 of the 29 patients (24%) who underwent an operation conducted with another surgical method (P < .001).

Table 2. Association of Posttreatment Clinical and Pathologic Factors With 3-Year Outcomes After Preoperative 5-Fluorouracil Chemoradiotherapy With or Without Oxaliplatin and Surgery.

Characteristic	No.	3-Y DFS		3-Y Cumulative Incidence of Distant Metastases		3-Y Cumulative Incidence of Local Recurrences After Local R0/R1 Resection		3-Y OS
Characteristic	No.	% (95% CI)	P Value	% (95% CI)	P Value	% (95% CI)	P Value	% (95% CI)	P Value
Pathologist-based TME
Mesorectal	930	75.9 (73.1-78.8)	.01^a	19.7 (17.0-22.4)	.03^a	3.3 (2.0-4.5)	<.001^a	90.3 (88.3-92.3)	.02^a
Intramesorectal	169	68.4 (61.6-76.0)		25.5 (18.3-32.0)		4.8 (1.2-8.1)		85.1 (79.7-91.0)
Muscularis propria	53	67.2 (55.6-81.3)		27.6 (14.2-39.0)		12.0 (2.5-20.5)		89.7 (81.6-98.7)
Surgeon-based TME
Mesorectal	957	75.3 (72.6-78.2)	.18	19.7 (17.0-22.3)	.23	3.5 (2.3-4.7)	.10	89.2 (87.2-91.3)	.31
Intramesorectal	121	69.9 (62.0-78.8)		24.0 (15.6-31.5)		7.3 (2.3-12.1)		89.5 (84.0-95.3)
Muscularis propria	20	68.8 (50.9-93.0)		31.2 (7.0-49.1)		5.3 (0.0-14.8)		94.7 (85.2-100)
Type of surgery
Anterior resection	814	77.4 (74.5-80.4)	<.001^a	18.0 (15.2-20.7)	.002^a	3.0 (1.8-4.3)	.01^a	90.7 (88.6-92.8)	<.001^a
Abdominoperineal resection	303	66.5 (61.2-72.2)		28.6 (23.1-33.8)		5.7 (2.8-8.5)		87.0 (83.1-91.1)
Intersphincteric	61	80.8 (71.2-91.7)		16.0 (5.8-25.1)		5.4 (0.0-11.2)		90.9 (83.6-98.8)
Other	33	56.5 (40.9-78.1)		26.5 (8.5-41.0)		12.3 (0.0-24.5)		69.7 (53.9-90.1)
Local resection status
R0	1151	76.4 (73.9-79.0)	<.001^a	19.5 (17.1-21.9)	<.001^a	3.2 (2.1-4.3)	<.001^a	90.9 (89.1-92.6)	<.001^a
R1	24	47.0 (30.0-73.4)		40.1 (15.3-57.6)		13.4 (0.0-29.8)		54.9 (37.5-80.4)
R2	15	NA		62.7 (25.1-81.4)		30.4 (0.4-51.3)		50.6 (30.1-84.8)
CRM
≤1 mm	67	41.4 (30.8-55.6)	<.001^a	45.9 (31.8-57.1)	<.001^a	22.8 (10.2-33.6)	<.001^a	68.9 (58.1-81.7)	<.001^a
>1 mm	834	72.0 (68.9-75.2)		23.3 (20.3-26.3)		3.2 (1.9-4.5)		88.9 (86.7-91.2)
pCR	185	94.2 (90.7-97.8)		2.9 (0.4-5.4)		0.0 (0.0-0.0)		96.5 (93.7-99.3)
ypT category
ypT0	197	92.9 (89.3-96.7)	<.001^a	3.9 (1.0-6.6)	<.001^a	0.0 (0.0-0.0)	<.001^a	96.2 (93.4-99.0)	<.001^a
ypT1/Tis	86	86.5 (79.4-94.3)		10.1 (3.2-16.5)		1.3 (0.0-3.8)		95.0 (90.2-99.9)
ypT2	343	83.1 (79.0-87.3)		12.7 (9.0-16.4)		1.9 (0.4-3.4)		93.6 (91.0-96.4)
ypT3	538	62.6 (58.5-67.0)		32.0 (27.7-36.0)		6.0 (3.8-8.1)		85.1 (81.9-88.3)
ypT4	43	42.8 (30.1-60.9)		44.1 (26.2-57.6)		22.8 (7.5-35.6)		62.7 (49.3-79.7)
ypN category
ypN0	839	82.7 (80.1-85.4)	<.001^a	12.5 (10.2-14.8)	<.001^a	2.2 (1.2-3.3)	<.001^a	92.6 (90.8-94.5)	<.001^a
ypN1	264	63.8 (57.9-70.2)		32.1 (25.9-37.9)		4.0 (1.4-6.5)		88.8 (84.9-93.0)
ypN2	102	32.8 (24.8-43.6)		58.8 (47.6-67.7)		20.3 (11.1-28.6)		64.1 (55.1-74.6)
Pathologic stage
0	193	94.4 (91.1-97.8)	<.001^a	2.8 (0.3-5.2)	<.001^a	0.0 (0.0-0.0)	<.001^a	96.6 (94.0-99.3)	<.001^a
I	316	89.0 (85.5-92.6)		7.9 (4.7-10.9)		0.7 (0.0-1.6)		95.6 (93.2-98.0)
II	302	72.8 (67.7-78.2)		20.4 (15.4-25.1)		3.7 (1.4-6.0)		89.5 (85.9-93.2)
III	323	63.3 (58.0-69.0)		30.6 (25.1-35.8)		7.8 (4.6-10.8)		86.0 (82.1-90.1)
IV	54	NA		NA		11.0 (1.4-19.7)		50.5 (38.1-67.0)

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Abbreviations: 5-FU, 5-fluorouracil; CRM, circumferential resection margin; DFS, disease-free survival; NA, not applicable; OS, overall survival; pCR, pathological complete response; TME, total mesorectal excision.

^{^a}

Statistically significant.

Prognostic Value of TME for Clinical Outcomes

The median follow-up was 50 (interquartile range, 38-61) months. Treatment in the experimental arm was a predictor for a superior 3-year DFS (5-FU CRT vs 5-FU/oxaliplatin CRT, 71.2% vs 75.9%, respectively; P = .03), the cumulative incidence of distant metastases (23.1% vs 19.2%; P = .04), and the cumulative incidence of local recurrences after R0/R1 resection (4.9% vs 3.2%; P = .01). A significantly better 3-year DFS and cumulative incidence of distant metastases correlated significantly with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (ECOG 0 vs ECOG 1 +2, 76.8% vs 63.4%, respectively, and 19.0% vs 29.15, respectively; P < .001 for both), early cT category (cT2 vs cT3 vs cT4, 77.7% vs 74.8% vs 56.7%, respectively, and 12.9% vs 20.4% vs 34.85, respectively; P < .001 for both) and low tumor grading (G1 vs G2 vs G3, 68.2% vs 75.7% vs 56.8%, respectively, and 21.8% vs 19.4% vs 35.9%, respectively; P < .001 and P = .001, respectively), whereas tumors located 0 to 5 cm from the anus were associated with a higher metastatic propensity (0-5 cm vs 5-10 cm vs >10 cm, 25.3% vs 19.2% vs 18.8%, respectively; P = .04). Age that was younger or equal to the median (age <63.6 years vs >63.6 years, 86.1% vs 90.5%, respectively; P = .01), an ECOG performance status of 0 (ECOG 0 vs ECOG 1 + 2, 90.8% vs 79.3%, respectively; P < .001), early cT category (cT2 vs cT3 vs CT4, 87.7% vs 89.1% vs 80.3%, respectively; P = .01), and low tumor grading (G1 vs G2 vs G3, 93.1% vs 89.9% vs 71.7%, respectively; P < .001) were associated with significantly better 3-year OS. A higher incidence of local recurrence was observed in patients with worse ECOG status (ECOG 0 vs ECOG 1+ 2, 3.4% vs 7.2%, respectively; P = .01) (eTable 3 in Supplement 1).

We next examined the prognostic role of post-CRT patient and tumor factors for all 4 clinical end points in a univariable analysis (Table 3). The quality of TME plane was significantly associated with 3-year DFS (mesorectal vs intramesorectal vs muscularis propria, 75.9% vs 68.4% vs 67.2%, respectively; P = .01, Figure 2A) the 3-year cumulative incidence of distant metastases (mesorectal vs intramesorectal vs muscularis propria, 19.7% vs 25.5% vs 27.6%, respectively; P = .03; Figure 2B), local recurrence after undergoing an R1/R0 resection (mesorectal vs intramesorectal vs muscularis propria, 3.2% vs 4.8% vs 12.0%, respectively; P < .001, Figure 2C) and OS (mesorectal vs intramesorectal vs muscularis propria, 90.3% vs 85.1% vs 89.7%, respectively; P = .02, Figure 2D). Notably, mesorectal vs muscularis propria TME was associated with significantly lower local recurrence rates (HR = 4.19; P < .001), whereas local recurrence after mesorectal TME was not significantly different compared with intramesorectal quality (HR = 1.47; P = .30). In total, 185 patients (16.0%) presented with pathological complete response but the univariate analysis failed to demonstrate a significant association of TME quality with either DFS (mesorectal vs intramesorectal vs muscularis propria TME, 93.2 % vs 86.4% vs 87.5%, respectively; P = .75), the cumulative incidence of distant metastases (mesorectal vs intramesorectal vs muscularis propria TME, 3.4% vs 9.1% vs 12.5%, respectively; P = .41), local recurrence (mesorectal vs intramesorectal vs muscularis propria TME, 4.1% vs 4.5% vs 12.5%, respectively; P = .12) or OS (mesorectal vs intramesorectal vs muscularis propria TME, 95.9% vs 100% vs 87.5%, respectively; P = .28) in this subgroup.

Table 3. Multivariate Analysis of Different Covariables on 3-Year Outcomes After Preoperative 5-Fluorouracil Chemoradiotherapy With or Without Oxaliplatin and Surgery^a.

Characteristic	DFS		Cumulative Incidence of Distant Metastases		Cumulative Incidence of Local Recurrences After Local R0/R1 Resection		OS
Characteristic	HR (95% CI)	P Value	HR (95% CI)	P Value	HR (95% CI)	P Value	HR (95% CI)	P Value
Pathologist-based TME
Mesorectal vs Intramesorectal	1.15 (0.86-1.56)	.35	1.18 (0.84-1.65)	.34	1.06 (0.48- 2.32)	.89	1.39 (0.94-2.06)	.10
Mesorectal vs Muscularis propria	1.55 (0.98-2.48)	.06	1.41 (0.83-2.41)	.20	3.72 (1.59- 8.71)	.002	1.37 (0.72-2.58)	.34
ypN category
ypN+ vs ypN0	2.28 (1.81-2.88)	<.001	2.87 (2.20-3.74)	<.001	2.54 (1.40- 4.63)	.002	1.99 (1.45-2.75)	<.001
ypT category
ypT3 vs ypT0-2	2.07 (1.61-2.66)	<.001	2.34 (1.74-3.15)	<.001	1.89 (0.95- 3.75)	.07	2.14 (1.50-3.05)	<.001
ypT4 vs ypT0-2	3.75 (2.19-6.42)	<.001	3.69 (1.95-6.98)	<.001	8.14 (2.99-22.14)	<.001	4.23 (2.11-8.50)	<.001
Treatment arm
5-FU/Ox-CRT vs 5-FU CRT	0.76 (0.61-0.95)	.016	0.80 (0.62-1.03)	.08	0.43 (0.23- 0.80)	.01	0.93 (0.68-1.26)	.64
Resection status
R1-2 vs R0	4.21 (2.73-6.51)	<.001	2.13 (1.23-3.69)	.01	4.75 (1.90-11.89)	<.001	3.26 (1.85-5.75)	<.001

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Abbreviations: CRT, chemoradiotherapy; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; Ox, oxaliplatin; TME, total mesorectal excision; 5-FU, 5-fluorouracil.

^{^a}

Patients with R2-resection were also included in the multivariate analysis for cumulative incidence of distant metastases and overall survival.

Figure 2. — A, Disease-free survival (intramesorectal vs mesorectal TME: hazard ratio [HR], 1.35; 95% CI, 1.01-1.80; P = .04; muscularis propria vs mesorectal TME: HR, 1.73; 95% CI, 1.13-2.66; P = .01; global P = .01). B, Cumulative incidence of distant metastases (intramesorectal vs mesorectal TME: HR, 1.34; 95% CI, 0.97-1.86; P = .08; muscularis propria vs mesorectal TME: HR, 1.69; 95% CI, 1.04-2.75; P = .03; global P = .03). C, Cumulative incidence of local recurrence (intramesorectal vs mesorectal TME: HR, 1.47; 95% CI, 0.71-3.06; P = .3; muscularis propria vs mesorectal TME: HR, 4.19; 95% CI, 1.94-9.05; P = .0003; global P < .001). D, Overall survival according to the TME plane (intramesorectal vs mesorectal TME: HR, 1.52; 95% CI, 1.04-2.21; P = .03; muscularis propria vs mesorectal TME: HR, 1.77; 95% CI, 1.00-3.14; P = .05; global P = .02). A univariable analysis was performed using the log-rank test. The HRs and corresponding P values of the TME intergroup comparisons (intramesorectal vs mesorectal TME, indicated by the blue lines; muscularis propria vs mesorectal TME, indicated by the red lines) were calculated using a Cox regression model.

Furthermore, abdominoperineal resection was associated with significantly worse 3-year DFS (anterior resection vs abdominoperineal resection vs intersphincteric vs other, 77.4% vs 66.5% vs 80.8% vs 56.5%, respectively; P < .001), cumulative incidence of distant (presenter resection vs abdominoperineal resection vs intersphincteric vs other, 18.0% vs 28.6% vs 16.0% vs 26.5%, respectively; P = .002) and local recurrence (anterior resection vs abdominoperineal resection vs intersphincteric vs other, 3.0% vs 5.7% vs 5.4% vs 12.3%, respectively; P = .01), and OS (anterior resection vs abdominoperineal resection vs intersphincteric vs other, 90.7% vs 87.0% vs 90.9% vs 69.7%, respectively; P < .001) compared with low anterior resection or intersphincteric resection. Local resection status (R0 vs R1 vs R2: DFS, 76.4% vs 47.0%; distant metastases, 19.5% vs 40.1% vs 62.7%; local recurrences, 3.2% vs 13.4% vs 30.4%; overall survival, 90.9% vs 54.9% vs 50.6%), CRM (<1 mm vs >1 mm vs pCR: DFS, 41.4% vs 72.0% vs 94.2%; distant metastases, 45.9% vs 23.3% vs 2.9%; local recurrences, 22.8% vs 3.2% vs 0.0%; overall survival, 68.9% vs 88.9% vs 96.5%), ypT (ypT0 vs ypT1/ypT2 vs ypT3 vs ypT4: DFS, 92.9% vs 86.5% vs 62.6% vs 42.8%; distant metastases, 3.9% vs 10.1% vs 12.7% vs 32.0% vs 44.1%; local recurrences, 0% vs 1.3% vs 1.9% vs 6.0% vs 22.8%; overall survival, 96.2% vs 95.0% vs 93.6% vs 85.1% vs 62.7%), ypN (ypN0 vs ypN1 vs ypN2: DFS, 82.7% vs 63.8% vs 32.8%; distant metastases, 12.5% vs 32.1% vs 58.8%; local recurrences, 2.2% vs 4.0% vs 20.3%; overall survival, 92.6% vs 88.8% vs 64.1%), and pathologic stage 0 vs 1 vs 2 vs 3 vs 4: DFS, 94.4% vs 89.0% vs 72.8% vs 63.3%; distant metastases, 2.8% vs 7.9% vs 20.4% vs 30.6%; local recurrences, 0% vs 0.7% vs 3.7% vs 7.8% vs 11.0%; overall survival, 96.6% vs 95.6% vs 89.5% vs 86.0% vs 50.5%) comprised the prognostic factors for all 4 clinical end points (P < .001 in each case) (Table 2).

In the multivariable analysis (Table 3), the plane of surgery (mesorectal vs muscularis propria TME) was an independent factor for the cumulative incidence of local recurrence (mesorectal vs muscularis propria: HR, 3.72; 95% CI, 1.59-8.71; P = .002). Notably, we excluded CRM, as several cases were either missing or unknown. Advanced ypT category (ypT3 vs ypT0-2 and ypT4 vs ypT0-2) was an adverse prognostic factor for 3-year DFS (HR, 2.07; 95% CI, 1.61-2.66 and HR, 3.75; 95% CI, 2.19-6.42, respectively; P < .001 for both), the cumulative incidence of distant metastases (HR, 2.34; 95% CI, 1.74-3.15 and HR, 3.69; 95% CI, 1.95-6.98, respectively; P < .001 for both), the cumulative incidence of local recurrence (HR, 1.89; 95% CI, 0.95-3.75 and HR, 8.14; 95% CI, 2.99-22.14, respectively; P = .07 and P < .001, respectively), and OS (HR, 2.14; 95% CI, 1.50-3.05 and HR, 4.23; 95% CI, 2.11-8.50, respectively; P < .001, respectively). Advanced ypN category (ypN+ vs ypN0) was associated with a less favorable outcome for all 4 clinical end points (HR, 2.28; 95% CI, 1.81-2.88; HR, 2.87; 95% CI, 2.20-3.74; HR, 1.99; 95% CI, 1.45-2.75; and HR, 2.54; 95% CI, 1.40-4.63, respectively; P < .001 in all except cumulative incidence of local recurrence, which was P = .002). Adding oxaliplatin to 5-FU–based treatment correlated with better DFS (HR, 0.76; 95% CI, 0.61-0.95; P = .02) and a lower incidence of local recurrences after R0/R1 resection (HR, 0.43; 95% CI, 0.23-0.80; P = .01). Complete resection status was associated with significantly superior outcomes for all 4 clinical end points. We failed to detect any further significance in multivariable analyses (Table 3).

As CRM has been reported to majorly affect local control,¹⁸ we performed an additional multivariable analysis that also included CRM on exclusion of all missing CRM cases to avoid statistical bias (eTable 4 in Supplement 1). Importantly, TME plane quality remained an independent prognostic factor for local recurrence (mesorectal vs muscularis propria: HR, 2.62; 95% CI, 1.11-6.18; P = .03), whereas CRM involvement (>1 mm vs ≤1 mm) was a predictor for worse DFS (HR, 1.58; 95% CI, 1.08-2.31; P = .02) and local recurrence (HR, 3.60; 95% CI, 1.66-7.79;P = .001).

Discussion

Total mesorectal excision represents the surgical technique of choice for treating rectal cancer.^4,24 Here, we investigated the prognostic role of the TME plane quality in patients with rectal cancer who were treated within the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Of the 1152 patients with known quality of TME plane, 930 (80.7%) had pathologist-confirmed mesorectal (good) quality of surgery. This aligns with data from modern clinical trials comparing open vs laparoscopic surgery that showed mesorectal TME in approximately 80% to 90% of patients^25,26 and exceeds the 52% and 56% reported in the MRC CR07⁸ and the Dutch Colorectal Cancer Group⁹ phase 3 studies. Leonard et al¹⁰ reported a mesorectal TME plane in 875 of 1382 resections (63%) based on the Belgian PROCARE database. Data similar to the PROCARE analysis were also reported by Leite et al¹³ and Maslekar et al.¹² The difference could in part be attributed to the different chronological periods of study conductance, as surgical training has evolved significantly during the last decade.

The roles of surgery and pathologists are key, as they both influence treatment decisions and clinical outcomes in rectal cancer.²⁷ In accordance with previous studies, TME was an independent prognostic factor for local recurrence. Although several reports have previously demonstrated the importance of an optimal TME plane for clinical outcomes, to our knowledge, only the CR07 trial by Quirke and colleagues⁸ has reported the prognostic effect of TME plane within a phase 3 study. Short-course radiotherapy resulted in a reduced local recurrence rate by more than 50% for all 3 TME planes, whereas the reduction in local recurrence rate postradiotherapy was most pronounced in the mesorectal TME plane group (HR = 4.5), indicating that patients benefit mostly when the best surgical procedure is combined with preoperative radiotherapy.⁸

In the comparison of pathologist-based vs surgeon-based evaluation of TME quality, we found a relatively high agreement (86.4%) in the mesorectal TME group but a significant discrepancy for intermesorectal plane (56.2%), emphasizing the importance of pathologist training for accurate prognostication of surgical outcomes.^27,28,29 To our knowledge, such a direct prospective comparison of pathologist-based vs surgeon-based evaluation of TME quality has not been reported before.

An advanced pathologic stage and abdominoperineal resection correlated with a worse quality of surgery in this trial. Some studies, including the MRC trial, have reported a lack of correlation between the pathologic stage and/or surgical technique with the plane of surgery, indicating that surgical skills greatly determine the pathologic outcome,⁸ whereas other series have found strong association.³⁰ The variability observed could be attributed to the different cohorts and the training of individual surgeons.^4,31,32 Also, there is an ongoing discussion as to whether more extensive surgical procedures, such as posterior pelvic exenterations, should be considered for bulky tumors of the lower third of rectum.^11,16,30

We failed to observe a significant association between TME plane quality and OS in a multivariable analysis. Nagtegaal et al⁹ have revealed OS rates of 86% and 76% for mesorectal and muscularis propria plane, respectively (P < .05) in univariable analysis, whereas this association was not assessed in the multivariable analysis. A study by Maslekar et al¹² did not find a significant association between surgical quality and OS.

Circumferential resection margin involvement strongly correlated with worse clinical outcomes in our cohort, in line with the meta-analysis data found for more than 17 000 patients by Quirke and Nagtegall.¹⁸ In that report, involved CRM was found to be more common in patients with advanced stage, ulcerative growth patterns, poor differentiation, vascular invasion, poor TME quality, abdominoperineal resection for tumors of lower third of rectum, and female sex.¹⁸ It has been hypothesized that CRM positivity possibly reflects more aggressive tumors that fail to respond to preoperative CRT. In the MERCURY study, Taylor et al¹⁹ used MRI for precise disease staging and demonstrated an adverse clinical association with positive CRM. Notably, in our series, the quality of TME plane remained an independent prognostic factor for local recurrence in the separate multivariable analysis that also included CRM.

Limitations

We acknowledge the limitations of our study. First, there was no central pathology review. The PROCARE study compared the quality of TME specimens as assessed by a central review panel and local pathologists for more than 250 patients with rectal cancer³³ and found no major discrepancies, whereas the prediction of clinical outcomes was comparable. Hence, under the prerequisite of adequate pathologist training, a central review may not have led to a significant correction of individual pathology reports.^28,33 Second, baseline MRI results were not compulsory in this trial and the relevance of MRI-defined staging in the context of TME quality could not be explored. Third, the trial was conducted during a period when open surgery was still standard in Germany, whereas laparoscopic or robotic surgery were only scarcely performed; hence, comparison of the outcome after open vs laparoscopic (or robotic) surgery cannot be conducted in our series.

Conclusions

Good-quality TME was associated with significantly better local control independently of other clinicopathologic factors, including CRM. This phase 3 randomized clinical trial confirms the long-term clinical association of TME plane quality with local recurrence as initially reported in the MRC CR07 study.⁸ Our secondary end point analysis adds high-level clinical evidence and highlights the roles of surgeons and pathologists in managing rectal cancer. Continuous training should be encouraged to further enhance surgical skills.

Supplement 1.

eMethods.

eFigure 1. Treatment schedule of the CAO/ARO/AIO-04 randomized phase 3 trial.

eFigure 2. Total mesorectal excision (TME) quality in surgical specimens. Examples of (a) mesorectal plane (TME quality: “good”) with complete and smooth surface and without coning; (b) intramesorectal plane (TME quality “moderate”) with moderately irregular surface; (c) muscularis propria plane (TME quality “poor”) with severely irregular surface.

eTable 1. Association of the pathologist-based quality of TME with pretreatment patient and tumor factors in operated patients receiving preoperative 5-FU based chemoradiotherapy with or without oxaliplatin

eTable 2. Correlation of pathologist-based with surgeon-based TME quality

eTable 3. Impact of pre-treatment clinical and pathologic factors on 3-year outcomes after preoperative 5-FU chemoradiotherapy +/- Oxaliplatin and surgery

eTable 4. Multivariate analysis of different covariables on 3-year outcomes after preoperative 5-FU chemoradiotherapy +/- oxaliplatin and surgery

Click here for additional data file.^{(184.7KB, pdf)}

Supplement 2.

Trial Protocol

Click here for additional data file.^{(383.8KB, pdf)}

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32.Foster JD, Gash KJ, Carter FJ, et al. Development and evaluation of a cadaveric training curriculum for low rectal cancer surgery in the English LOREC National Development Programme. Colorectal Dis. 2014;16(9):O308-O319. [DOI] [PubMed] [Google Scholar]
33.Demetter P, Jouret-Mourin A, Silversmit G, et al. ; PROCARE . Review of the quality of total mesorectal excision does not improve the prediction of outcome. Colorectal Dis. 2016;18(9):883-888. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods.

eFigure 1. Treatment schedule of the CAO/ARO/AIO-04 randomized phase 3 trial.

eTable 2. Correlation of pathologist-based with surgeon-based TME quality

eTable 3. Impact of pre-treatment clinical and pathologic factors on 3-year outcomes after preoperative 5-FU chemoradiotherapy +/- Oxaliplatin and surgery

eTable 4. Multivariate analysis of different covariables on 3-year outcomes after preoperative 5-FU chemoradiotherapy +/- oxaliplatin and surgery

Click here for additional data file.^{(184.7KB, pdf)}

Supplement 2.

Trial Protocol

Click here for additional data file.^{(383.8KB, pdf)}

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PERMALINK

Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer

Julia Kitz, MD

Emmanouil Fokas, MD, DPhil

Tim Beissbarth, PhD

Philipp Ströbel, MD

Christian Wittekind, MD

Arndt Hartmann, MD

Josef Rüschoff, MD

Thomas Papadopoulos, MD

Elisabeth Rösler, MD

Peter Ortloff-Kittredge, MD

Ulrich Kania, MD

Hans Schlitt, MD

Karl-Heinrich Link, MD

Wolf Bechstein, MD

Hans-Rudolf Raab, MD

Ludger Staib, MD

Christoph-Thomas Germer, MD

Torsten Liersch, MD

Rolf Sauer, MD

Claus Rödel, MD

Michael Ghadimi, MD

Werner Hohenberger, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Participants

Pathologic Examination of Resected Specimen

Statistical Analysis

Results

Patient Characteristics and Association of TME With Clinicopathologic Factors

Figure 1. Consolidated Standards of Reporting Trials Diagram of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial.

Table 1. Association of the Pathologist-Based Quality of Total Mesorectal Excision (TME) With Posttreatment Patient and Tumor Factors in Patients Who Underwent an Operation and Received Preoperative 5-Fluorouracil–Based Chemoradiotherapy With or Without Oxaliplatin.

Table 2. Association of Posttreatment Clinical and Pathologic Factors With 3-Year Outcomes After Preoperative 5-Fluorouracil Chemoradiotherapy With or Without Oxaliplatin and Surgery.

Prognostic Value of TME for Clinical Outcomes

Table 3. Multivariate Analysis of Different Covariables on 3-Year Outcomes After Preoperative 5-Fluorouracil Chemoradiotherapy With or Without Oxaliplatin and Surgerya.

Figure 2. Prognostic Significance of the Quality of Total Mesorectal Excision (TME) Plane in Rectal Cancer.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 3. Multivariate Analysis of Different Covariables on 3-Year Outcomes After Preoperative 5-Fluorouracil Chemoradiotherapy With or Without Oxaliplatin and Surgery^a.