Clinical trial NCT04486131: Lateral Nodal Recurrence in Rectal Cancer
Official title: Lateral Nodal Recurrence in Rectal Cancer
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Rectal Cancer
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2020-07-24
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
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).

Brief summary: 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%.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Lateral local recurrence
timeFrame: 3 years
Secondary outcomes:
measure: Disease-free survival
timeFrame: 3 years
measure: Overall patient survival
timeFrame: 3 years
measure: Morbidity and functional outcomes assessed by LARS questions
timeFrame: 3 years
measure: Quality of life as assessed by the EORTC QLQ-CR29
timeFrame: 3 years
measure: Quality of life as assessed by the EQ-5D
timeFrame: 3 years
measure: Quality of life as assessed by the QLQ-C30
timeFrame: 3 years
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centers
state: North-Holland
Study officials:
affiliation: VUMedicalCentre
name: Miranda Kusters, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.