Clinical trial NCT03413254: Second and Third Look Laparoscopy in pT4 Colon Cancer Patients for Early Detection of Peritoneal Metastases
Official title: Second and Third Look Laparoscopy in pT4 Colon Cancer Patients for Early Detection of Peritoneal Metastases; the COLOPEC-II Randomized Multicentre Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Colorectal Cancer
Peritoneal Metastases
Keywords: pT4 colon cancer
Peritoneal metastases
Early detection
Diagnostic laparoscopy
Second look surgery
Third look surgery
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
First posted: 2018-01-29
Enrollment: 389
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Proportion of peritoneal metastases detected after a negative second look DLS
timeFrame: 20 months
Secondary outcomes:
measure: Incidence of PM at second look DLS after curative treatment of primary tumour, depending on pathological pT4 stage, pathological nodal stage and histology
timeFrame: 6-10 months
measure: Incidence of PM during first 20 months after curative resection of primary tumour, depending on pathological pT4 stage, pathological nodal stage and histology
timeFrame: 20 months
measure: Incidence of PM in patients who did or did not undergo adjuvant chemotherapy
timeFrame: 20 months
measure: Sensitivity, specificy, NPV and PPV of CT imaging to detect PM compared to DLS
timeFrame: 20 months
measure: Proportion of detected PM eligible for curative intent CRS+HIPEC at different follow-up intervals
timeFrame: 20 months
measure: 30-day morbidity related to second/third look DLS
timeFrame: From the second or third look DLS till 30 days postoperative
measure: Extent of adhesiolysis required at second/third look DLS assessed with the Zühlke score
timeFrame: 20 months
measure: 5-year peritoneal recurrence free survival
timeFrame: 5 years
measure: 5-year disease-free survival
timeFrame: 5 years
measure: 5-year overall survival
timeFrame: 5 years
measure: Quality of life assessed with the CRC-29 questionnaire
timeFrame: 2 years
measure: Quality of life assessed with the EQ-5D-5L questionnaire
timeFrame: 2 years
Other outcomes:
Locations:
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VUmc
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek
city: Amsterdam
country: Netherlands
facility: OLVG
city: Eindhoven
country: Netherlands
facility: Catharina hospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Nieuwegein
country: Netherlands
facility: St. Antonius hospital
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
References: