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Figure.
Study Flow Diagrama
Study Flow Diagrama

CRM indicates circumferential resection margin; MRI, magnetic resonance imaging.

aThe initial number of patients assessed and excluded were not recorded; the Limitations section offers an explanation.

Table 1.  
Magnetic Resonance Imaging (MRI) Results Among 82 Patients
Magnetic Resonance Imaging (MRI) Results Among 82 Patients
Table 2.  
Pathology Results Among 82 Patients
Pathology Results Among 82 Patients
1.
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Wong  RK, Berry  S, Spithoff  K,  et al; Gastrointestinal Cancer Disease Site Group.  Preoperative or postoperative therapy for stage II or III rectal cancer: an updated practice guideline.  Clin Oncol (R Coll Radiol). 2010;22(4):265-271. doi:10.1016/j.clon.2010.03.002PubMedGoogle ScholarCrossref
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Sauer  R, Becker  H, Hohenberger  W,  et al; German Rectal Cancer Study Group.  Preoperative versus postoperative chemoradiotherapy for rectal cancer.  N Engl J Med. 2004;351(17):1731-1740. doi:10.1056/NEJMoa040694PubMedGoogle ScholarCrossref
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Kapiteijn  E, Marijnen  CA, Nagtegaal  ID,  et al; Dutch Colorectal Cancer Group.  Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.  N Engl J Med. 2001;345(9):638-646. doi:10.1056/NEJMoa010580PubMedGoogle ScholarCrossref
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Sebag-Montefiore  D, Stephens  RJ, Steele  R,  et al.  Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial.  Lancet. 2009;373(9666):811-820. doi:10.1016/S0140-6736(09)60484-0PubMedGoogle ScholarCrossref
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Bujko  K, Nowacki  MP, Nasierowska-Guttmejer  A, Michalski  W, Bebenek  M, Kryj  M.  Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.  Br J Surg. 2006;93(10):1215-1223. doi:10.1002/bjs.5506PubMedGoogle ScholarCrossref
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Marijnen  CA, van de Velde  CJ, Putter  H,  et al.  Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.  J Clin Oncol. 2005;23(9):1847-1858. doi:10.1200/JCO.2005.05.256PubMedGoogle ScholarCrossref
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Peeters  KC, van de Velde  CJ, Leer  JW,  et al.  Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients: a Dutch Colorectal Cancer Group study.  J Clin Oncol. 2005;23(25):6199-6206. doi:10.1200/JCO.2005.14.779PubMedGoogle ScholarCrossref
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Birgisson  H, Påhlman  L, Gunnarsson  U, Glimelius  B.  Occurrence of second cancers in patients treated with radiotherapy for rectal cancer.  J Clin Oncol. 2005;23(25):6126-6131. doi:10.1200/JCO.2005.02.543PubMedGoogle ScholarCrossref
10.
Stephens  RJ, Thompson  LC, Quirke  P,  et al.  Impact of short-course preoperative radiotherapy for rectal cancer on patients’ quality of life: data from the Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 randomized clinical trial.  J Clin Oncol. 2010;28(27):4233-4239. doi:10.1200/JCO.2009.26.5264PubMedGoogle ScholarCrossref
11.
Baxter  NN, Habermann  EB, Tepper  JE, Durham  SB, Virnig  BA.  Risk of pelvic fractures in older women following pelvic irradiation.  JAMA. 2005;294(20):2587-2593. doi:10.1001/jama.294.20.2587PubMedGoogle ScholarCrossref
12.
Taylor  FG, Quirke  P, Heald  RJ,  et al; MERCURY Study Group.  Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study.  Ann Surg. 2011;253(4):711-719. doi:10.1097/SLA.0b013e31820b8d52PubMedGoogle ScholarCrossref
13.
Strassburg  J, Ruppert  R, Ptok  H,  et al.  MRI-based indications for neoadjuvant radiochemotherapy in rectal carcinoma: interim results of a prospective multicenter observational study.  Ann Surg Oncol. 2011;18(10):2790-2799. doi:10.1245/s10434-011-1704-5PubMedGoogle ScholarCrossref
14.
Kreis  ME, Ruppert  R, Ptok  H,  et al; OCUM Study Group.  Use of preoperative magnetic resonance imaging to select patients with rectal cancer for neoadjuvant chemoradiation: interim analysis of the German OCUM trial (NCT01325649).  J Gastrointest Surg. 2016;20(1):25-32. doi:10.1007/s11605-015-3011-0PubMedGoogle ScholarCrossref
15.
Ruppert  R, Junginger  T, Ptok  H,  et al; OCUM Group.  Oncological outcome after MRI-based selection for neoadjuvant chemoradiotherapy in the OCUM rectal cancer trial.  Br J Surg. 2018;105(11):1519-1529. doi:10.1002/bjs.10879PubMedGoogle ScholarCrossref
16.
Rectal Cancer Alliance of Canada (RCAC); Rectal Cancer Alliance of Canada RCAC.  QuickSilver: a phase II study using magnetic resonance imaging criteria to identify “good prognosis” rectal cancer patients eligible for primary surgery.  JMIR Res Protoc. 2015;4(2):e41. doi:10.2196/resprot.4151PubMedGoogle ScholarCrossref
17.
Rickles  AS, Dietz  DW, Chang  GJ,  et al; Consortium for Optimizing the Treatment of Rectal Cancer (OSTRiCh).  Consortium for Optimizing the Treatment of Rectal Cancer (OSTRiCh). High rate of positive circumferential resection margins following rectal cancer surgery: a call to action.  Ann Surg. 2015;262(6):891-898. doi:10.1097/SLA.0000000000001391PubMedGoogle ScholarCrossref
18.
Al-Sukhni  E, Milot  L, Fruitman  M,  et al. User’s guide for the synoptic MRI report for pre-operative staging of rectal cancer: 2015. https://www.cancercareontario.ca/sites/ccocancercare/files/assets/CCOMRIRectalStagingUserGuide.pdf. Accessed February 23, 2019.
19.
Quirke  P, Steele  R, Monson  J,  et al; MRC CR07/NCIC-CTG C016 Trial Investigators; NCRI Colorectal Cancer Study Group.  Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG C016 randomised clinical trial.  Lancet. 2009;373(9666):821-828. doi:10.1016/S0140-6736(09)60485-2PubMedGoogle ScholarCrossref
20.
College of American Pathologists. Cancer protocol templates: colon and rectum. https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates. Accessed February 23, 2019.
21.
Kusters  M, Marijnen  CA, van de Velde  CJ,  et al.  Patterns of local recurrence in rectal cancer: a study of the Dutch TME trial.  Eur J Surg Oncol. 2010;36(5):470-476. doi:10.1016/j.ejso.2009.11.011PubMedGoogle ScholarCrossref
22.
Rosner  B. Fundamentals of Biostatistics. 4th ed. North Scituate, MA: Duxbury Press; 1995.
23.
ClinicalTrials.gov. PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery. https://clinicaltrials.gov/ct2/show/study/NCT01515787#moreinfo. Accessed June 2018.
24.
Kennedy  ED, Schmocker  S, Victor  C,  et al.  Do patients consider preoperative chemoradiation for primary rectal cancer worthwhile?  Cancer. 2011;117(13):2853-2862. doi:10.1002/cncr.25842PubMedGoogle ScholarCrossref
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Couture  J, Chan  R, Bouharaoui  F.  Patient’s preferences for adjuvant postoperative chemoradiation therapy in rectal cancer.  Dis Colon Rectum. 2005;48(11):2055-2060. doi:10.1007/s10350-005-0174-xPubMedGoogle ScholarCrossref
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Harrison  JD, Solomon  MJ, Young  JM,  et al.  Patient and physician preferences for surgical and adjuvant treatment options for rectal cancer.  Arch Surg. 2008;143(4):389-394. doi:10.1001/archsurg.143.4.389PubMedGoogle ScholarCrossref
27.
Solomon  MJ, Pager  CK, Keshava  A,  et al.  What do patients want? patient preferences and surrogate decision making in the treatment of colorectal cancer.  Dis Colon Rectum. 2003;46(10):1351-1357. doi:10.1007/s10350-004-6749-0PubMedGoogle ScholarCrossref
28.
Kennedy  ED, Borowiec  AM, Schmocker  S,  et al.  Patient and physician preferences for nonoperative management for low rectal cancer: is it a reasonable treatment option?  Dis Colon Rectum. 2018;61(11):1281-1289. doi:10.1097/DCR.0000000000001166PubMedGoogle ScholarCrossref
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Mühlbacher  AC, Juhnke  C.  Patient preferences versus physicians’ judgement: does it make a difference in healthcare decision making?  Appl Health Econ Health Policy. 2013;11(3):163-180. doi:10.1007/s40258-013-0023-3PubMedGoogle ScholarCrossref
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Original Investigation
April 11, 2019

Safety and Feasibility of Using Magnetic Resonance Imaging Criteria to Identify Patients With “Good Prognosis” Rectal Cancer Eligible for Primary Surgery: The Phase 2 Nonrandomized QuickSilver Clinical Trial

Author Affiliations
  • 1Division of General Surgery, Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada
  • 2Department of Surgery, University of Toronto, Toronto, Ontario, Canada
  • 3Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
  • 4Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
  • 5Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Toronto, Ontario, Canada
  • 6Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada
  • 7Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
  • 8Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 9Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
  • 10Department of Surgery, Centre Hospitalier Universitaire (CHU) de Quebec, Laval University, Quebec City, Quebec, Canada
  • 11Department of Surgery, St Paul’s Hospital, Providence Health Care, Vancouver, British Columbia, Canada
  • 12Department of Radiology, St Paul’s Hospital, Providence Health Care, Vancouver, British Columbia, Canada
  • 13Department of Pathology & Laboratory Medicine, St Paul’s Hospital, Vancouver, British Columbia, Canada
  • 14Department of Surgery, Foothills Medical Centre, University of Calgary, Calgary, Alberta, Canada
  • 15Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
  • 16Department of Surgery, North York General Hospital, Toronto, Ontario, Canada
  • 17Department of Pathology and Laboratory Medicine, North York General Hospital, Toronto, Ontario, Canada
  • 18Department of Medical Imaging, North York General Hospital, Toronto, Ontario, Canada
  • 19Department of Surgery, University Health Network, Toronto, Ontario, Canada
  • 20Department of Radiation Oncology, Southlake Regional Health Centre, Newmarket, Ontario, Canada
  • 21Department of Pathology and Laboratory Medicine, St Michael’s Hospital, Toronto, Ontario, Canada
  • 22Department of Radiation Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario, Canada
  • 23Department of Surgery, McGill University Health Centre (MUHC)–Montreal General Hospital, Montreal, Quebec, Canada
  • 24Department of Diagnostic Radiology, MUHC–Montreal General Hospital, Montreal, Quebec, Canada
  • 25Department of Radiation Oncology, MUHC–Montreal General Hospital, Montreal, Quebec, Canada
  • 26Department of Pathology and Laboratory Medicine, MUHC–Montreal General Hospital, Montreal, Quebec, Canada
  • 27Department of Surgery, CHU de Quebec, Laval University, Quebec City, Quebec, Canada
  • 28Department of Radiation Oncology, CHU de Quebec, Laval University, Quebec City, Quebec, Canada
  • 29Department of Medical Imaging, CHU de Quebec, Laval University, Quebec City, Quebec, Canada
  • 30Department of Pathology and Laboratory Medicine, CHU de Quebec, Laval University, Quebec City, Quebec, Canada
  • 31Department of Surgery, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
  • 32Department of Diagnostic Radiology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
  • 33Department of Radiation Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
  • 34Department of Pathology & Laboratory Medicine, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
  • 35Department of Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada
  • 36Department of Radiology, The Royal Marsden Hospital National Health Service (NHS) Foundation Trust, Surrey, England, United Kingdom
  • 37Department of Surgery, Eastern Health Authority, Memorial University, St John’s, Newfoundland, Canada
  • 38Division of General Surgery, Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Canada
  • 39Institute for Clinical Evaluative Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
JAMA Oncol. 2019;5(7):961-966. doi:10.1001/jamaoncol.2019.0186
Key Points

Question  Can magnetic resonance imaging (MRI) be used to select patients with “good prognosis” rectal tumors for primary surgery and safely avoid preoperative chemoradiotherapy?

Findings  In this nonrandomized phase 2 study, 82 patients with MRI-predicted good prognosis rectal cancer were included from 12 hospitals across Canada and underwent primary surgery. The positive circumferential resection margin rate was 4.9% (4 of 82).

Meaning  The use of MRI criteria to select good prognosis patients with rectal cancer for primary surgery results in a low rate of positive circumferential resection margin and suggests that chemoradiotherapy may not be necessary for all patients with stage II and III rectal cancer.

Abstract

Importance  Chemoradiotherapy (CRT), followed by surgery, is the recommended approach for stage II and III rectal cancer. While CRT decreases the risk of local recurrence, it does not improve survival and leads to poorer functional outcomes than surgery alone. Therefore, new approaches to better select patients for CRT are important.

Objective  To conduct a phase 2 study to evaluate the safety and feasibility of using magnetic resonance imaging (MRI) criteria to select patients with “good prognosis” rectal tumors for primary surgery.

Design, Setting, and Participants  Prospective nonrandomized phase 2 study at 12 high-volume colorectal surgery centers across Canada. From September 30, 2014, to October 21, 2016, a total of 82 patients were recruited for the study. Participants were patients newly diagnosed as having rectal cancer with MRI-predicted good prognosis rectal cancer. The MRI criteria for good prognosis tumors included distance to the mesorectal fascia greater than 1 mm; definite T2, T2/early T3, or definite T3 with less than 5 mm of extramural depth of invasion; and absent or equivocal extramural venous invasion.

Interventions  Patients with rectal cancer with MRI-predicted good prognosis tumors underwent primary surgery.

Main Outcomes and Measures  The primary outcome was the proportion of patients with a positive circumferential resection margin (CRM) rate. Assuming a 10% baseline probability of a positive CRM, a sample size of 75 was estimated to yield a 95% CI of ±6.7%.

Results  Eighty-two patients (74% male) participated in the study. The median age at the time of surgery was 66 years (range, 37-89 years). Based on MRI, most tumors were midrectal (65% [n = 53]), T2/early T3 (60% [n = 49]), with no suspicious lymph nodes (63% [n = 52]). On final pathology, 91% (n = 75) of tumors were T2 or greater, 29% (n = 24) were node positive, and 59% (n = 48) were stage II or III. The positive CRM rate was 4 of 82 (4.9%; 95% CI, 0.2%-9.6%).

Conclusions and Relevance  The use of MRI criteria to select patients with good prognosis rectal cancer for primary surgery results in a low rate of positive CRM and suggests that CRT may not be necessary for all patients with stage II and III rectal cancer.

Trial Registration  ISRCTN.com identifier: ISRCTN05107772

Introduction

It is well established that the main goal of rectal cancer treatment is to achieve a negative circumferential resection margin (CRM), which is the strongest predictor of local recurrence (LR). Currently, North American guidelines for the treatment of stage II and III rectal cancer recommend preoperative chemoradiotherapy (CRT), followed by surgery, because this approach has been shown to decrease the rate of LR in several well-designed randomized clinical trials (RCTs).1-6 However, with improvements in the quality of rectal cancer surgery, rates of positive CRM and LR have decreased. Therefore, while CRT still decreases the risk of LR by approximately 50%, the number of patients needed to treat to avoid one LR has increased markedly. Although in the era of modern rectal cancer surgery fewer patients benefit from CRT, the long-term adverse outcomes of treatment, including bowel and sexual dysfunction, have not changed.7-11 Therefore, a more selective approach to the use of CRT may allow for better functional outcomes, while maintaining oncologic outcomes. Both the MERCURY and OCUM study groups have tested more selective approaches to CRT to avoid radiotherapy in patients with stage I to III tumors at low risk of LR.12-15 The indications for CRT in these studies are largely based on the predicted status of the CRM (ie, distance to the mesorectal fascia) as determined by magnetic resonance imaging (MRI). In these studies, patients with a predicted CRM greater than 1 mm underwent primary surgery, and CRT was avoided. Both the MERCURY and OCUM have reported excellent oncologic results, with rates of positive CRM and LR less than 5% in patients undergoing primary surgery. Despite the promising findings, these studies included fewer than 600 patients. Therefore, additional investigations evaluating more selective approaches to the use of CRT are needed. The objective of the present phase 2 study was to prospectively evaluate the use of MRI criteria to identify patients with “good prognosis” rectal tumors for primary surgery in Canada.

Methods
Study Overview

This was a prospective nonrandomized phase 2 study conducted at 12 high-volume colorectal surgery centers across Canada (Figure). Each participating center designated a site lead for surgery, radiology, radiation oncology, and pathology. A QuickSilver study investigators’ meeting with all site leads was conducted to obtain consensus on the final trial protocol (Supplement 1).16 Research ethics and data sharing agreements were obtained from each participating center before the start of the study. Surgeons involved in the study identified consecutive patients with primary rectal cancer who met the study inclusion criteria. Rectal cancer was defined as adenocarcinoma 0 to 15 cm from the anal verge on endoscopy and proximal extent of the tumor at or below the sacral promontory on MRI.

Patient Sample

Patients were eligible for study enrollment if they were 18 years or older, expected to undergo radical resection (ie, not a local excision), had a good prognosis tumor based on MRI criteria, and were able to provide written informed consent. The MRI criteria for good prognosis tumors included (1) distance to the mesorectal fascia (ie, predicted CRM) greater than 1 mm from the primary tumor, discontinuous tumor nodule, or likely positive (ie, suspicious) lymph node; (2) T category of definite T2, T2/early T3, or definite T3 with less than 5 mm of extramural depth of invasion (EMD); and (3) absent or equivocal extramural venous invasion (EMVI). The status of the mesorectal lymph nodes was not considered a criterion for good prognosis tumors, and patients with N0-N2 disease were eligible for inclusion provided all other criteria were met. Among patients undergoing radical resection for rectal cancer, numerous studies1,2,17 have demonstrated that risks of a positive CRM or local tumor recurrence are higher when the procedure is an abdominoperineal vs low anterior resection. Therefore, to be cautious in this first prospective national-level study to date of new criteria for CRT, we excluded patients with a planned intersphincteric dissection, coloanal handsewn anastomosis, and/or abdominoperineal resection. Other exclusion criteria included suspicious extramesorectal lymph nodes or other metastatic disease, previous pelvic radiotherapy, more than one primary tumor, or history of other major malignant cancer within the last 5 years.

Radiology, Surgery, and Pathology Protocols and Assessments

Before the start of the study, webinars were conducted with participating radiologists, surgeons, and pathologists to ensure standardization of the MRI, surgical, and pathologic protocols and reports. The treating surgeon completed the preoperative assessment, including (1) digital rectal examination and endoscopic examination of the primary tumor; (2) computed tomography of the chest, abdomen, and pelvis; (3) pelvic MRI; and (4) presentation at a multidisciplinary cancer conference (MCC). Primary surgery was performed as soon as possible after obtaining written informed consent from the patient to participate in the study. The surgical procedure was left to the discretion of the treating surgeon and involved a partial (ie, 5 cm of mesorectum removed distal to the leading edge of the tumor) or total mesorectal excision (TME). Participating surgeons were fellowship trained in colorectal surgery or surgical oncology and were encouraged to use a synoptic operative report template designed specifically for the study.

A standard MRI protocol based on the results from the MERCURY study group was used and required high-resolution axial oblique T2-weighted sequences, and it was recommended that participating radiologists use a synoptic MRI report endorsed by Cancer Care Ontario and the Radiologic Society of North America.12,18 Preoperative MRI reports provided tumor location, N category, T category, and distance to the mesorectal fascia. Radiologists were not required to distinguish between T2 and T3 tumors with minimal extension beyond the bowel wall; therefore, designations were definite T2, T2/early T3, and definite T3 with less than 5 mm of EMD.

Macroscopic examination and processing of surgical specimens were performed according to the method by Quirke et al19 and included macroscopic evaluation of TME quality. Photographs of the intact specimens and cross-sectional sections were obtained. All mandatory data elements of the College of American Pathologists colorectal cancer protocol20 were evaluated and included in pathology reports. All final pathology reports were reviewed by the pathology site lead, who completed a standardized pathologic summary report that was submitted to the central study office located at Mount Sinai Hospital, Toronto, Ontario, Canada, with the corresponding pathology report. Participating pathologists were encouraged to use the College of American Pathologists checklist.20

Follow-up

The recommended adjuvant treatment of patients included in the study was (1) no further treatment for negative CRM and negative lymph nodes; (2) adjuvant chemotherapy for negative CRM and positive lymph nodes; and (3) postoperative CRT for positive CRM regardless of nodal status, followed by adjuvant chemotherapy, at the discretion of the treating center. Surveillance of all patients was recommended for a period of 5 years as per institutional protocol.

Data Collection

Participating surgeons were required to submit the MRI report, operative report, and pathology report to the central study office. Data from these reports were abstracted into the study database by a dedicated research coordinator.

Primary Outcome and Data Analysis

The primary outcome for the study was the proportion of patients with a positive CRM. A positive CRM was defined as any tumor, discontinuous tumor nodule, or positive lymph node located less than 1 mm from the CRM on final pathologic assessment. Descriptive and univariate analyses were used for patient, imaging, and tumor specimen characteristics. For the study, a baseline probability of a 10% positive CRM was selected and was considered the highest acceptable risk of positive CRM. This was based on the results of previous rectal cancer RCTs, in particular the MRC CR07 trial, which reported an overall positive CRM rate of 11.1% (134 of 1208).5,21

Based on 30 high-volume rectal cancer surgeons treating a minimum of 10 new patients with rectal cancer over a 2-year period, the target sample size for the study was 75 patients, assuming 30% (90 of 300) would meet the inclusion criteria and an 80% participation rate. Assuming a 10% probability of a positive CRM, this sample size was estimated to yield a 95% CI of ±6.7%.22 A data safety monitoring committee consisting of a statistician, surgeon, radiation oncologist, and pathologist (who were not participating in the study) reviewed interim assessments that occurred after every 25 patients accrued. The stopping rule for the study was a positive CRM of greater than 10% reported at any interim assessment.

Results

From September 30, 2014, to October 21, 2016, a total of 82 patients from 12 hospitals across Canada were recruited for the study. All eligible patients invited to participate in the study agreed and underwent primary surgery. Surgery was performed by 32 fellowship-trained surgeons. All patients were presented at MCCs, and adequate image quality and the use of pathology methods by Quirke et al19 were confirmed in 87% (71 of 82) and 88% (72 of 82), respectively. The mean time from MRI to surgery was 4.9 weeks (range, 1 day to 14 weeks).

Participant Characteristics

Most of the patients were male (74% [61 of 82]), and the median age at the time of surgery was 66 years (range, 37-89 years). All patients underwent restorative surgery, and a diverting ileostomy was created in 72% (59 of 82). Sixty-six percent (54 of 82) of the cases were performed using a laparoscopic approach.

MRI Findings

The MRI results are listed in Table 1. The MRI data were reported by 30 gastrointestinal radiologists. Most of the tumors were midrectal (65% [n = 53]), T2/early T3 (60% [n = 49]), with no suspicious lymph nodes (63% [n = 52]). The mean distance of the tumor to the mesorectal fascia was reported as 10.4 mm (range, 1.9-24 mm).

Pathologic Findings

The results of the pathologic assessments are listed in Table 2. The pathologic assessments were performed by 47 gastrointestinal pathologists. The quality of the TME was graded as complete or near complete in 98% (80 of 82) of the specimens. The mean CRM distance was 12.8 mm (range, 0-70 mm), and the mean number of lymph nodes retrieved was 25 (range, 7-53). Thirty-three cases (40%) were T2, and 40 cases (49%) were T3. Twenty-nine percent (24 of 82) of cases had positive mesorectal lymph nodes, and EMVI was present in 16% (13 of 82). Percentage agreement for lymph nodes between MRI and pathology was 68.3%. Ten cases (12%) were understaged, and 16 cases (20%) were overstaged. The positive predictive value was 46.7%, and the negative predictive value was 80.7%.

On final pathology, 91% (n = 75) of tumors were T2 or greater, 29% (n = 24) were node positive, and 59% (48 of 82) had stage II or III disease. Four patients had a positive CRM, for a positive CRM rate of 4.9% (95% CI, 0.2%-9.6%). In addition, one patient had a positive distal margin.

Details of Positive CRMs

The clinical and pathologic details for the 4 positive CRMs are listed in eTable 1 in Supplement 2. The first positive CRM was due to a discontinuous tumor nodule. The MRI was rereviewed at the MCC, and the tumor deposit was not visualized on the preoperative MRI. The patient subsequently received postoperative CRT, followed by adjuvant chemotherapy. The second positive CRM was due to primary tumor at the level of the intersphincteric space requiring a handsewn anastomosis and represented a protocol variation. This patient subsequently received only adjuvant chemotherapy. The third positive margin was also due to primary tumor. The time between the MRI and surgery was 14 weeks due to patient comorbidity and represented a protocol variation. This patient subsequently received postoperative CRT, followed by adjuvant chemotherapy. The fourth positive margin was due to a positive lymph node. The MRI was rereviewed at the MCC, and the lymph node was not visualized on the preoperative MRI. The patient subsequently received only adjuvant chemotherapy.

Follow-up Treatment

In total, 30% (25 of 82) of patients received additional adjuvant treatment. Six patients received postoperative CRT and adjuvant chemotherapy (2 positive CRM, 2 negative CRM with positive lymph nodes, and 2 negative CRM with discontinuous tumor nodules). Nineteen patients received adjuvant chemotherapy (2 positive CRM, 12 negative CRM with positive lymph nodes, 1 negative CRM with discontinuous tumor nodules, and 4 with negative CRM and EMVI present). Among patients with stage II or III tumors, 88% (42 of 48) received no form of radiotherapy.

Discussion

These results of the QuickSilver study show that the use of MRI criteria to select good prognosis rectal tumors for primary surgery is safe and feasible. The findings resulted in a positive CRM rate of 4.9% (95% CI, 0.2%-9.6%).

This study performed in Canada adds to the reported international experience of the MERCURY and OCUM studies, which included 122 and 254 patients, respectively (eTable 2 in Supplement 2).12,15 All 3 of these studies used high-resolution T2-weighted axial oblique MRI sequences. The common MRI criterion used to predict good prognosis rectal tumors was a predicted negative CRM, defined as distance of the tumor to the mesorectal fascia greater than 1 mm on MRI. Furthermore, none of the studies included the status of the mesorectal lymph nodes as an MRI criterion to predict good prognosis tumors. All of the studies had a similar proportion of patients with stage II or III disease and low rectal cancers. The positive CRM rates were 5% (4 of 82) in QuickSilver, 3% (4 of 122) in MERCURY, and 2% (2 of 134) in OCUM, and 5-year LR rates in the latter 2 studies were 3.3% and 2.0%, respectively. Taken together, the findings of these studies suggest that, in contrast to CRT for all stage II and III rectal tumors, a more selective approach to CRT based on predicted CRM status may also result in excellent oncologic outcomes.

The criteria to identify good prognosis patients will likely continue to evolve. We used the MERCURY study MRI criteria, which included both EMD and EMVI; however, we excluded patients with very low rectal cancers in which the surgeon recognized the need for an intersphincteric anastomosis or abdominoperineal resection. The OCUM study investigators considered distance to the mesorectal fascia as the only MRI criterion for their study and did not include either EMD or EMVI. Furthermore, patients in OCUM with T3 low tumors within 6 cm of the anal verge and all T4 tumors received CRT. Given that the long-term results for MERCURY and OCUM are similar, it seems that the use of the OCUM criteria may be more reproducible and feasible to adapt into clinical practice.

There is great interest in developing more selective approaches to CRT for patients with stage II and III rectal cancer. The MRC CR07/NCIC-CTG C016 was a multicenter RCT that compared short-course preoperative radiotherapy vs primary surgery, followed by selective postoperative CRT for patients with a positive CRM.5,19 Although the rate of positive CRM was similar in both groups (10% vs 12%), the rate of LR at 5 years was significantly lower in the preoperative radiotherapy arm (5% vs 12%). However, only 52% of the surgical specimens were in the mesorectal plane; because the mesorectal plane was an independent predictor of LR, it is possible that preoperative therapy compensated for inadequate TME surgery. The PROSPECT (N1048) trial is randomizing patients with resectable stage II or III (T2N1, T3N0, and T3N1) rectal cancer with noninvolved mesorectal fascia to standard preoperative CRT and surgery vs preoperative full-dose FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) chemotherapy, selective CRT, and then surgery.23 In the experimental arm, preoperative CRT is reserved for tumors that have less than 20% reduction in tumor volume after full-dose chemotherapy. Most patients eligible for PROSPECT would meet the eligibility criteria for QuickSilver, MERCURY, and OCUM and thus avoid neoadjuvant full-dose chemotherapy or CRT. Response to full-dose chemotherapy, predicted CRM status, and/or clinical stage II or III disease are varying criteria that can inform recommendations for preoperative radiotherapy among patients with rectal cancer. Moving forward, it is likely that other criteria (eg, biomarkers for response to radiotherapy) will emerge and require testing to determine if such factors more effectively balance optimization of functional and oncologic patient outcomes vs current selection criteria for preoperative radiotherapy.

No patient declined to participate in the study even though the consent process provided a detailed outline of the risks and benefits of primary surgery vs standard treatment with CRT. This result is consistent with the existing literature indicating that patients value functional outcomes relative to oncologic outcomes.24-29 Kennedy et al24 previously reported that 54% of future patients would not choose CRT until it offered an absolute reduction in LR from 15% to 5% or less. These results suggest that a significant proportion of patients may be willing to accept a higher risk of LR to avoid CRT to optimize functional results. Therefore, offering patients with good prognosis rectal cancer a choice between CRT and primary surgery may be more consistent with patient values.

Limitations

There are several limitations to this study. First, involved clinicians were from high-volume centers with focused expertise. Therefore, our identification of good prognosis patients and quality of treatment may not be generalizable. Second, our study excluded patients with an expected intersphincteric anastomosis or need for an abdominoperineal resection because the risk of positive CRM and LR is higher in these patients compared with low anterior resection. Moving forward, our next national study is testing the indications for patients with CRT with low tumors but with modifications for CRT that may be similar to those in the OCUM study. Third, we did not collect data for patients seen at participating centers who may have been eligible for the study but were not included. While our patient population included a high proportion of stage I tumors and a low proportion of node-positive tumors, our patient population is not considerably different from the MERCURY or OCUM study populations. Fourth, only the positive CRM rate is reported because long-term oncologic outcomes have not yet matured. However, we anticipate a low LR rate comparable to rates achieved in the MERCURY and OCUM studies given our similar rates of positive CRM.

Conclusions

Results of this study suggest that in high-volume centers, the use of MRI criteria to identify patients with good prognosis rectal cancer for primary surgery results in a positive CRM of less than 5%. These findings suggest that CRT may not be necessary for all patients with stage II and III rectal cancer. Further data will be required before this approach can be widely adopted into clinical practice.

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Article Information

Accepted for Publication: January 10, 2019.

Corresponding Author: Erin D. Kennedy, MD, PhD, Department of Surgery, Mount Sinai Hospital, 600 University Ave, Ste 449, Toronto, ON M5G 1X5, Canada (erin.kennedy@sinaihealthsystem.ca).

Published Online: April 11, 2019. doi:10.1001/jamaoncol.2019.0186

Author Contributions: Dr Kennedy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kennedy, Simunovic, Kirsch, Brierley, C. Brown, Vos, MacLean, Stotland, Streutker, Wong, Schmocker, Liberman, Reinhold, Kopek, Morin, McLeod, G. Brown, Mathieson, Baxter.

Acquisition, analysis, or interpretation of data: Kennedy, Simunovic, Jhaveri, Drolet, C. Brown, Xiong, MacLean, Kanthan, Stotland, Raphael, Chow, O'Brien, Cho, Streutker, Wong, Schmocker, Liberman, Reinhold, Kopek, Marcus, Bouchard, Lavoie, Morin, Périgny, Wright, Neumann, Clarke, Patil, Arnason, Williams, Pooni, Baxter.

Drafting of the manuscript: Kennedy, Simunovic, Schmocker, Reinhold, Baxter.

Critical revision of the manuscript for important intellectual content: Kennedy, Simunovic, Jhaveri, Kirsch, Brierley, Drolet, C. Brown, Vos, Xiong, MacLean, Kanthan, Stotland, Raphael, Chow, O'Brien, Cho, Streutker, Wong, Liberman, Reinhold, Kopek, Marcus, Bouchard, Lavoie, Morin, Périgny, Wright, Neumann, Clarke, Patil, Arnason, Williams, McLeod, G. Brown, Mathieson, Pooni, Baxter.

Statistical analysis: Kennedy, Simunovic, Schmocker, Pooni.

Obtained funding: Kennedy.

Administrative, technical, or material support: Kennedy, Simunovic, Kirsch, C. Brown, Vos, MacLean, Kanthan, Stotland, Cho, Streutker, Schmocker, Liberman, Reinhold, Marcus, Wright, Clarke, Arnason, Williams, McLeod, G. Brown, Mathieson.

Supervision: Kennedy, Simunovic, Brierley, Drolet, Kanthan, Stotland, Liberman, Reinhold, Morin, Neumann, G. Brown, Baxter.

Conflict of Interest Disclosures: Ms Schmocker and Dr Pooni reported receiving grants from the Mount Sinai Hospital - University Health Network (MSH-UHN) Academic Medical Organization Innovation Fund. Dr Liberman reported receiving support from Merck and Servier. Dr Clarke reported receiving grants from GE Healthcare. No other disclosures were reported.

Funding/Support: This work was supported by a peer-reviewed grant from the MSH-UHN Academic Medical Organization Innovation Fund. None of the investigators received any salary support for participating in the project. Travel and accommodation were reimbursed for the QuickSilver investigators’ meeting.

Role of the Funder/Sponsor: The funding sources 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.

Data Sharing Statement: See Supplement 3.

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