Second and third look laparoscopy in pT4 colon cancer patients for early detection of peritoneal metastases; the COLOPEC 2 randomized multicentre trial.

In 2015, the incidence of colorectal cancer was 15.500 in the Netherlands. A
common place for recurrence is the peritoneum, which is the sole site of
metastasis in up to 25%. Peritoneal metastases (PM) were traditionally
associated with dismal prognosis. Modern systemic chemotherapy prolonged median
survival to a maximum of 24 months, but long-term survival remains limited. The
only curative option is cytoreductive surgery (CRS) followed by hyperthermic
intraperitoneal chemotherapy (HIPEC), but the efficacy highly depends on the
extent of peritoneal involvement. The availabilty of an effective therapy and
the fact that CRS+HIPEC yields better survival rates and lower postoperative
morbidity when the extent of peritoneal disease is more limited underline the
importance of detection and treatment of PM in its initial stages. Due to
absence of symptoms and restricted accuracy of imaging modalities, PM are often
detected at a stage in which only about 25% of patients can be treated with
CRS+HIPEC. The only way to diagnose minimal PM at an overt stage is by
re-exploration of the abdominal cavity during second look surgery. Since it is
an invasive and costly procedure, second look surgery should only be proposed
to selected patients at high-risk of developing PM. Peritoneal metastases (PM)
can develop in approximately 30% after curative resection of pT4 colon cancer.
Restricted sensitivity of imaging modalities in combination with a poor
prognosis if PM are detected at a clinically apparent stage underlines the need
for early detection and prevention strategies. The COLOPEC trial
(NL49960.018.14) randomized 205 patients with T4 colon cancer between adjuvant
HIPEC followed by routine systemic chemotherapy and systemic chemotherapy alone
between March 2015 and March 2017. Preliminary findings revealed that PM were
already detected at intentionally adjuvant hyperthermic intraperitoneal
chemotherapy (HIPEC) between 5-8 weeks 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 cytoreductive surgery (CRS) and HIPEC was considered to
be an essential component of follow-up of locally advanced colon cancer.
However, some metachronous PM develop later on. For this reason, there might be
benefit of a third look DLS after a negative second look DLS to detect occult
metachronous PM later on, which is the primary research question of the
proposed trial.

The primary aim of this study is to determine the added value of third look DLS
to detect PM at a clinically occult stage following a negative second look DLS.

This is a randomised 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 being eligible for curative intent
treatment are detected. Patients without PM found during second look DLS will
subsequently be randomised between routine follow-up including CT-abdomen at 18
months in the control arm, or an experimental arm with a third look DLS if no
PM or other metastases not being eligible for curative intent treatment are
detected at 18 months CT.

Third look DLS will be performed between 18 and 20 months after primary tumour
resection 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 peritoneal cancer index (PCI) for those
patients with suspected PM.

The burden for the patients is to undergo DLS in outpatient surgery setting.
DLS is associated with a risk of wound infection of the trocar sites, bleeding
from the abdominal wall or biopsy sites, and bowel injury related to
adhesiolysis. Intervention-related morbidity is assumed to be low. With an
expected number needed to diagnose clinically occult PM of 10, DLS related
morbidity will probably not outweigh the potential survival benefit related to
higher proportions of curative intent treatment compared to detection at a
clinically apparent stage.