Lateral Nodal Recurrence in Rectal Cancer (LaNoReC)

Local recurrence rates in rectal cancer have reduced dramatically since the introduction of the total mesorectal excision (TME) technique and neoadjuvant (chemo)radiotherapy (C))RT) to overall rates of 5-year local recurrence to 5-10%.

However, distal rectal cancers have a tendency to spread to lateral lymph nodes and it was recently shown that patients with enlarged lateral lymph nodes of ≥7mm short-axis size have a considerable chance of a local recurrence: 15-20%. This is regardless of CRT with TME in two retrospective cohorts (Lateral Node Consortium and Snapshot Rectal Cancer 2016 study). According to the Lateral Node Consortium study, this rate was significantly reduced to <6% when performing a lateral lymph node dissection (LLND) after (C)RT + TME.

A major drawback of these recent multi-center studies is their retrospective nature. Therefore, in the Netherlands, radiologists, radiation oncologists, surgeons and pathologists have recently been educated and trained to enhance knowledge and awareness of LLNs and to implement nerve-sparing minimally invasive LLND.

The LaNoReC trial is a prospective registration study aimed at evaluating oncological outcomes after multi-disciplinary training. The main question of this study is whether, after dedicated training and the performance of LLNDs, the lateral local recurrence rate in rectal cancers with enlarged nodes (≥7mm) can be reduced to below 6%.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer

Detailed Description

Local recurrence rates in rectal cancer have reduced dramatically since the introduction of the total mesorectal excision (TME) technique. These rates have been lowered further with the use of neoadjuvant (chemo)radiotherapy ((C)RT) regimens in appropriate cases, decreasing overall rates of 5-year local recurrence to 5-10%. However, in patients with enlarged lateral lymph nodes (LLNs, ≥7mm short-axis size), recurrence rates have remained high, up to 20%. Most likely, this is caused by lymphatic spread of low rectal cancer to the lateral compartments. Western surgeons have always relied on (C)RT to sterilize the lateral compartments, containing the internal iliac and obturator lymph nodes, alleviating fears of operative morbidity and nerve function disorders associated with a lateral lymph node dissection (LLND), mainly performed in the East. Furthermore, most Western clinicians consider lateral nodal disease to represent metastatic disease, not amendable to cure.

The Lateral Node Consortium undertook a multi-centre study with 12 centres from seven countries, collecting data over a 5-year period, including all consecutive patients operated for a cT3 or T4 rectal cancer. In all patients, every series of MRIs was re-reviewed by a standardized protocol, examining lateral pelvic nodes, defining these according to size and the presence of malignant features and relating these to the development of locally recurrent disease. In the first publication of the consortium with a total of 1216 patients, it was shown that pre-treatment lateral lymph node (LLN) size of ≥7 mm, results in an unacceptably high incidence of lateral local recurrence of 20%, despite (C)RT with TME. Within the consortium, several centres performed LLND's after (C)RT, which resulted in a significantly lower rate of lateral local recurrence of 6% in nodes ≥7 mm (p = 0.042). Furthermore, LLN enlargement did not influence distant metastases rate, suggesting it is a local issue which requires to be addressed through targeted treatment in the pelvis, rather simply representing a marker of poor prognosis and distant disease.

Additionally, a second study, the Snapshot Rectal Cancer 2016 was conducted in 2020. This national retrospective cohort study included 3057 patients operated for rectal cancer in 2016 with a 4-year follow-up period. Radiologists were trained for LLN classification and measurements and re-reviewed MRIs of 882 patients with low (≤8cm from the anorectal junction), cT3/4 rectal cancer who received neoadjuvant (chemo)radiotherapy with the help of two atlases. This study found a 4-year LLR risk of 15% in presence of enlarged LLNs.

The major drawback of these multi-center studies are their retrospective nature. Radiological reporting of LLNs was low for primary MRIs, which may have influenced treatment decisions. Consequently, LLNs may have not been separately included in irradiation field. Moreover, neither study was able to investigate the effect of LLND in a trained setting. In the Netherlands, radiologists, radiation oncologists, surgeons and pathologists have recently been educated and trained to enhance knowledge and awareness of LLNs and to implement nerve-sparing minimally invasive LLND. The LaNoReC describes a prospective evaluation of oncological outcomes after multi-disciplinary training, thereby aiming for a 50% reduction in LLR rates.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Miranda Kusters, MD, PhD; Phone Number: 0031204444444; Email: m.kusters@amsterdamumc.nl
• Study Contact Backup: Name: Eline van Geffen, MD; Phone Number: 0031204444444; Email: lanorec@amsterdamumc.nl

Study Locations

• Netherlands
  • North-Holland
    • Amsterdam, North-Holland, Netherlands, 1081 HV
      • Recruiting
      • Amsterdam University Medical Centers
      • Contact: Miranda Kusters, MD, PhD; Phone Number: 003120-4444444; Email: m.kusters@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with rectal cancer with one or more lateral nodes with a short-axis of ≥7mm or ≥5mm with one or more malignant features (i.e. round shape, irregular margins, heterogeneity, loss of fatty hilum).

Description

Inclusion Criteria:

• All patients with rectal cancer with one or more lateral nodes with a short-axis of ≥7mm or ≥5mm with one or more malignant features (i.e. round shape, irregular margins, heterogeneity, loss of fatty hilum).

Exclusion Criteria:

• Younger than 18 years old
• Pelvic irradiation in the medical history
• Previous lateral lymph node dissection related to pelvic malignancy
• Synchronous distant metastases
• Familiar adenomatous polyposis
• Synchronous colon cancer with a higher stage than rectal cancer
• Absolute contraindication for general anaesthesia
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lateral local recurrence	Lateral local recurrence diagnosed during the follow up	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free survival	The measure of time after treatment during which no sign of cancer is found.	3 years
Overall patient survival	The percentage of people who are alive 3 years after the surgery.	3 years
Morbidity and functional outcomes assessed by LARS questions	Use of questionnaire LARS	3 years
Quality of life as assessed by the EORTC QLQ-CR29	Quality of life as assessed by the EORTC QLQ-CR29	3 years
Quality of life as assessed by the EQ-5D	Quality of life as assessed by the EQ-5D	3 years
Quality of life as assessed by the QLQ-C30	Quality of life as assessed by the QLQ-C30	3 years

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Miranda Kusters, MD, PhD, VUMedicalCentre

Publications and helpful links

General Publications

• Ogura A, Konishi T, Cunningham C, Garcia-Aguilar J, Iversen H, Toda S, Lee IK, Lee HX, Uehara K, Lee P, Putter H, van de Velde CJH, Beets GL, Rutten HJT, Kusters M; Lateral Node Study Consortium. Neoadjuvant (Chemo)radiotherapy With Total Mesorectal Excision Only Is Not Sufficient to Prevent Lateral Local Recurrence in Enlarged Nodes: Results of the Multicenter Lateral Node Study of Patients With Low cT3/4 Rectal Cancer. J Clin Oncol. 2019 Jan 1;37(1):33-43. doi: 10.1200/JCO.18.00032. Epub 2018 Nov 7.
• Ogura A, Konishi T, Beets GL, Cunningham C, Garcia-Aguilar J, Iversen H, Toda S, Lee IK, Lee HX, Uehara K, Lee P, Putter H, van de Velde CJH, Rutten HJT, Tuynman JB, Kusters M; Lateral Node Study Consortium. Lateral Nodal Features on Restaging Magnetic Resonance Imaging Associated With Lateral Local Recurrence in Low Rectal Cancer After Neoadjuvant Chemoradiotherapy or Radiotherapy. JAMA Surg. 2019 Sep 1;154(9):e192172. doi: 10.1001/jamasurg.2019.2172. Epub 2019 Sep 18.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2020
• Primary Completion (Anticipated): October 1, 2026
• Study Completion (Anticipated): October 1, 2026

Study Registration Dates

• First Submitted: June 30, 2020
• First Submitted That Met QC Criteria: July 22, 2020
• First Posted (Actual): July 24, 2020

Study Record Updates

• Last Update Posted (Estimate): January 19, 2023
• Last Update Submitted That Met QC Criteria: January 16, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Recurrence; Rectal Neoplasms
• Other Study ID Numbers: A2021.0524.0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD data that underlie results in a publication can be made available upon reasonable request
• IPD Sharing Time Frame: Starting after initial publication of data
• IPD Sharing Access Criteria: Requests will be assessed by the study team

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No