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Second and Third Look Laparoscopy in pT4 Colon Cancer Patients for Early Detection of Peritoneal Metastases (COLOPEC-II)

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ClinicalTrials.gov Identifier: NCT03413254
Recruitment Status : Recruiting
First Posted : January 29, 2018
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information
First Submitted Date  ICMJE January 5, 2018
First Posted Date  ICMJE January 29, 2018
Last Update Posted Date July 16, 2019
Actual Study Start Date  ICMJE March 1, 2018
Estimated Primary Completion Date October 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 1, 2018)
Proportion of peritoneal metastases detected after a negative second look DLS [ Time Frame: 20 months ]
Peritoneal metastases that are detected using either routine follow-up or third look DLS according to randomization.
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
Proportion of peritoneal metastases detected after a negative second look DLS [ Time Frame: 20 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 1, 2018)
  • Incidence of PM at second look DLS after curative treatment of primary tumour, depending on pathological pT4 stage, pathological nodal stage and histology [ Time Frame: 6-10 months ]
    Occult peritoneal metastases not detected by routine CT scan 6-9 months after primary resection of pT4 colon cancer, that are detected at second look DLS performed at 6-10 months after the primary resection.
  • Incidence of PM during first 20 months after curative resection of primary tumour, depending on pathological pT4 stage, pathological nodal stage and histology [ Time Frame: 20 months ]
    This outcome measure tries to stratify pT4 colon cancer patients in clinically relevant subgroups based on their risk to develop PM.
  • Incidence of PM in patients who did or did not undergo adjuvant chemotherapy [ Time Frame: 20 months ]
    This outcome measure analysis a potential impact of adjuvant chemotherapy on the development of PM.
  • Sensitivity, specificy, NPV and PPV of CT imaging to detect PM compared to DLS [ Time Frame: 20 months ]
    Diagnostic accuracy of CT using DLS findings as gold standard.
  • Proportion of detected PM eligible for curative intent CRS+HIPEC at different follow-up intervals [ Time Frame: 20 months ]
    This outcome measures determines the clinical impact of PM detection, considering potentially curative intent treatment.
  • 30-day morbidity related to second/third look DLS [ Time Frame: From the second or third look DLS till 30 days postoperative ]
    This outcome measure is important to determine the harm/benefit ratio of DLS.
  • Extent of adhesiolysis required at second/third look DLS assessed with the Zühlke score [ Time Frame: 20 months ]
    The Zühlke score measures the severity of intraabdominal adhesions.
    1. Filmy adhesions.
    2. Stronger adhesions requiring some sharp dissection.
    3. Dense vascularized adhesions requiring sharp dissection.
    4. Extreme dense vascularized adhesions with high risk for organ damage during dissection.
    A higher score indicates a worse outcome.
  • 5-year peritoneal recurrence free survival [ Time Frame: 5 years ]
    This outcome measure determines whether third look DLS has any impact on the overall detection of PM.
  • 5-year disease-free survival [ Time Frame: 5 years ]
    Important long-term oncological endpoint to determine the potential oncological benefit of third look DLS.
  • 5-year overall survival [ Time Frame: 5 years ]
    Important long-term oncological endpoint to determine the potential oncological benefit of third look DLS.
  • Quality of life assessed with the CRC-29 questionnaire [ Time Frame: 2 years ]
    Assessing impact of invasive diagnostic procedures on QOL.
  • Quality of life assessed with the EQ-5D-5L questionnaire [ Time Frame: 2 years ]
    Assessing impact of invasive diagnostic procedures on QOL.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
  • Incidence of PM at second look DLS after curative treatment of primary tumour, depending on pathological pT4 stage, pathological nodal stage and histology [ Time Frame: 6-10 months ]
  • Proportion of PM at 20 months after curative resection of primary tumour that was detected with routine follow-up including CT-abdomen at 18 months [ Time Frame: 20 months ]
  • Proportion of PM at 20 months after curative resection of primary tumour that was found during the third look DLS in the experimental arm [ Time Frame: 20 months ]
  • Incidence of PM during first 20 months after curative resection of primary tumour, depending on pathological pT4 stage, pathological nodal stage and histology [ Time Frame: 20 months ]
  • Incidence of PM in patients who did or did not undergo adjuvant chemotherapy [ Time Frame: 20 months ]
  • Clinical manifestation of PM within 6 months of second look DLS [ Time Frame: 16 months ]
  • Sensitivity of CT imaging to detect PM compared to DLS [ Time Frame: 20 months ]
  • Proportion of detected PM eligible for curative intent CRS+HIPEC at different follow-up intervals [ Time Frame: 20 months ]
  • 30-day morbidity related to second/third look DLS [ Time Frame: From the second or third look DLS till 30 days postoperative ]
  • Extent of adhesiolysis required at second/third look DLS assessed with the Zühlke score [ Time Frame: 20 months ]
    The Zühlke score measures the severity of intraabdominal adhesions.
    1. Filmy adhesions.
    2. Stronger adhesions requiring some sharp dissection.
    3. Dense vascularized adhesions requiring sharp dissection.
    4. Extreme dense vascularized adhesions with high risk for organ damage during dissection.
    A higher score indicates a worse outcome.
  • 5-year peritoneal recurrence free survival [ Time Frame: 5 years ]
  • 5-year disease-free survival [ Time Frame: 5 years ]
  • 5-year overall survival [ Time Frame: 5 years ]
  • Quality of life assessed with the CRC-29 questionnaire [ Time Frame: 2 years ]
  • Quality of life assessed with the EQ-5D-5L questionnaire [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Second and Third Look Laparoscopy in pT4 Colon Cancer Patients for Early Detection of Peritoneal Metastases
Official Title  ICMJE Second and Third Look Laparoscopy in pT4 Colon Cancer Patients for Early Detection of Peritoneal Metastases; the COLOPEC-II Randomized Multicentre Trial
Brief Summary The COLOPEC II multicentre randomized trial will investigate the role of second and third look laparoscopy to detect metachronous peritoneal metastases at a clinically occult stage during the follow-up of pT4 colon cancer patients. It is expected that detection of PM at a clinically occult stage will translate into survival benefit, due to higher percentage of patients eligible for curative intent treatment with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
Detailed Description

Problem description Approximately 20-30% of patients with pT4 colon cancer develop peritoneal metastases (PM). The only proven curative option for macroscopic PM is cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC), but the efficacy and morbidity highly depend on the extent of peritoneal involvement. Unfortunately, due to restricted accuracy of imaging modalities and the absence of early symptoms, PM are often detected at a stage in which only about 20-25% of patients are eligible for CRS+HIPEC, and even these patients appear to have a relatively high peritoneal cancer index (PCI). New diagnostic strategies are urgently required to detect PM at an early stage, resulting in a higher percentage of patients eligible for CRS+HIPEC, which will translate into better survival because of the uniformly reported direct association between PCI and survival.

Proposed solution Preliminary findings of the COLOPEC trial (NCT02231086) revealed that PM were already detected at intentionally adjuvant HIPEC within 2 months after resection of the primary tumour in 10% of patients with pT4 colon cancer. Based on these findings and literature, second look diagnostic laparoscopy (DLS) to detect PM when the disease is still potentially curable by CRS+HIPEC may be considered as an essential component of early follow-up of pT4 colon cancer. This needs confirmation in a larger patient cohort before implementing this in practice. Furthermore, metachronous PM develop later on (>12 months) in an additional 15-20% of the patients. These patients will be missed by a second look DLS and might therefore benefit from a third look DLS later on, which will be investigated in the COLOPEC II trial.

Objective The primary aim of this study is to determine the added value of third look DLS after a negative second look DLS in pT4 colon cancer patients to detect PM at a clinically occult stage.

Study design This is a randomized multicentre trial in which eligible patients will have routine CT-abdomen at 6 months postoperative (+3 months for those still treated with adjuvant chemotherapy), followed by second look DLS within 1 month after CT if no PM or other metastases not amenable for local treatment are detected. Patients without PM found during second look DLS will subsequently be randomized between routine follow-up including CT-abdomen at 18 months in the control arm, or an experimental arm with a third look DLS provided that PM or incurable metastases are absent at the 18 months CT-abdomen. The primary endpoint of the study is the proportion of PM detected after negative second look DLS. The primary endpoint will be determined at 20 months.

Study population Patients aged 18-80 years who underwent intentionally curative resection of pT4a,bN0-2M0 colon cancer or rectosigmoid cancer above the peritoneal reflection, either with or without adjuvant systemic chemotherapy, who are fit enough and surgically accessible to undergo second look DLS between 6-10 months postoperatively and subsequent treatment of PM if detected.

Intervention DLS will be performed in patients not already diagnosed with PM and without other metastases that impede curative intent treatment. Access to the abdominal cavity is obtained under general anaesthesia by open introduction away from areas of expected adhesions, followed by adhesiolysis if necessary. Complete staging of the intra-abdominal cavity is performed, with biopsy of any lesion suspicious of PM, and determining the PCI for those patients with suspected PM.

Expected outcome It is hypothesized that in patients who had a negative second look DLS, PM become clinically apparent in 5% until 20 months postoperatively with routine follow-up. A third look DLS following a negative CT-abdomen at 18 months postoperative is expected to detect an additional 10% of PM. It is expected that detection of PM at a clinically occult stage will translate into survival benefit, based on the observation that survival rates after CRS+HIPEC are higher if the PCI is lower.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:
In order to prevent caretakers from being influenced by the assigned follow-up strategy, the randomization outcome will remain unknown to everyone involved in the patient's care until the 18 months CT-scan is reported by the radiologist.
Primary Purpose: Diagnostic
Condition  ICMJE
  • Colorectal Cancer
  • Peritoneal Metastases
Intervention  ICMJE
  • Other: Routine follow-up
    Patients visit the outpatient clinic twice a year during the first two to three years and annually thereafter, until five years postoperative. CEA-levels are determined at 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 48 and 60 months after primary resection. Detection of liver metastases with ultrasound or CT is performed at 12, 24, 36, 48 and 60 months postoperative. At 6 and 18 months postoperative, a CT-scan is part of the study protocol, but ultrasound of the liver is allowed for other time intervals during follow-up. Colonoscopy is performed at 12 and 48 months postoperative.
  • Procedure: Second look DLS
    Second look DLS is performed within one month from negative CT at 6-9 months (depending last date of adjuvant chemotherapy) and normal CEA. Laparoscopic access to the abdominal cavity is obtained under general anaesthesia, followed by adhesiolysis if necessary. Complete staging is performed, with biopsy of any lesion suspicious of PM, and determining the peritoneal cancer index (PCI) in case of PM. Conversion to laparotomy not allowed for better exposure, but only for intra-operative complications.
  • Procedure: Third look DLS
    Third look DLS is performed within one month from negative CT at 18 months and normal CEA. Laparoscopic access to the abdominal cavity is obtained under general anaesthesia, followed by adhesiolysis if necessary. Complete staging is performed, with biopsy of any lesion suspicious of PM, and determining the peritoneal cancer index (PCI) in case of PM. Conversion to laparotomy not allowed for better exposure, but only for intra-operative complications.
Study Arms  ICMJE
  • Active Comparator: 2nd look DLS + routine FU
    Follow-up after curatively resected pT4 colon cancer, consisting of second look DLS after negative CT abdomen at 6-9 months and normal CEA, with subsequent routine follow-up according to the Dutch colorectal cancer guideline until 5 years.
    Interventions:
    • Other: Routine follow-up
    • Procedure: Second look DLS
  • Experimental: 2nd and 3rd DLS + routine FU
    Follow-up after curatively resected pT4 colon cancer, consisting of second look DLS after negative CT abdomen at 6-9 months and normal CEA, with subsequent routine follow-up and third look DLS after negative CT abdomen at 18 months and normal CEA. Third look DLS is not performed in patients with evidence of disease that is not curable, or in those already diagnosed with PM in the preceding period.
    Interventions:
    • Other: Routine follow-up
    • Procedure: Second look DLS
    • Procedure: Third look DLS
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 14, 2019)
389
Original Estimated Enrollment  ICMJE
 (submitted: January 26, 2018)
398
Estimated Study Completion Date  ICMJE February 1, 2025
Estimated Primary Completion Date October 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Curative intent resection of pT4a,bN0-2M0 colon cancer or rectosigmoid cancer above the peritoneal reflection, with or without adjuvant systemic therapy;
  • Age between 18 and 80 years;
  • Written informed consent.

Exclusion Criteria:

  • Histological subtype other than (mucinous) adenocarcinoma or signet-ring cell carcinoma;
  • Clinical condition that does not allow for second look surgery or subsequent treatment of PM if detected;
  • Second look surgery thought not to be technically possible (i.e. because of extensive abdominal surgery / re-interventions).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Vivian P. Bastiaenen, M.D. +31205665199 V.P.Bastiaenen@amc.nl
Contact: Pieter J. Tanis, M.D. PhD P.J.Tanis@amc.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03413254
Other Study ID Numbers  ICMJE NL61507.018.17
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study Sponsor  ICMJE Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP