Colorectal cancer is one of the leading causes of cancer death in developed countries. Surgery is the primary treatment and recurrence following surgery is a major problem and is often the ultimate cause of death. In colon cancer endoperitoneal recurrence account for 10% of all recurrences and generally occurs within 3 years of resection. Specific features of the primary tumor like size and depth of bowel wall invasion (pT3-pT4), which determine a specific clinical evolution ( exfoliation of cancer cells) are responsible for endoperitoneal recurrence. Cytoreductive Surgery (CRS) defined as removal of macroscopic abdominal and peritoneal disease combined with Hyperthermic Perioperative Chemotherapy (HIPEC) is the treatment considered standard of care for selected patients with moderate to small volume peritoneal metastases secondary to colorectal cancer. Nevertheless treatment of locoregional recurrence and peritoneal metastases in colon cancer are disappointing first because only 30% of patients can be surgically treated and second because of this 30% only 15- 30% survive 5 years, leaving only 10% of patients with a chance of being cured. In surgical series, the majority (around 70%), of patients with a diagnosis of colonic cancer operated with curative intent, have a pT3-4 tumor, which is the high-risk class of patients for local recurrence and peritoneal metastases. In this scenario the most effective strategy to combat endoperitoneal recurrence seems prevention. In studies performed in our Institution, we showed how a proactive management of peritoneal metastases in colon cancer patients considered at high-risk for peritoneal recurrence according specific features (pT3, pT4 any N, M0) influence outcome. These results should be validated by larger controlled studies, and this is the aim of the PROMENADE protocol, to verify if surgery combined with HIPEC could represent a mean of tertiary prevention of endoperitoneal recurrence in high-risk colon cancer.
Proactive protocols aim to prevent, in advanced (but without metastases) colonic cancer that underwent primary surgical treatment, metachronous peritoneal recurrence rate. Three issues justify conducting trials on proactive management of endoperitoneal spread disclosing the possibility of an improvement of the present knowledge: the incidence of endoperitoneal spread, its prognosis, and the cost-effectiveness ratio of treatment. The literature on the incidence provides little help partly because many studies consider colon and rectal cancer together and some refer to locoregional recurrence whereas others use the term peritoneal metastases. Sometimes, surprisingly, peritoneal seeding and ovarian metastases from colon cancer are considered distant metastases, a statement that may seem correct according to TNM staging system, but according to the true incidence of locoregional recurrence seems misleading (Jung-A Yun et al. 2016 Ann Surg). Data suggesting that we maybe have some problems in a real evaluation of the rate of locoregional recurrence come from a collective review of more than 27000 patients with colon cancer resected for cure; a wide difference from 5 to 12 % were referred (Manfredi S et al. 2006 Br J Surg; Park JH et al. 2015 Dis Colon Rectum; Buunen M et al. 2009 Lancet Oncol; Green BL et al. 2013 Br J Surg; Sjovall A et al. 2007 Ann Surg Oncol; Elferink MA et al. 2012 Ann Surg Oncol; Cortet M et al. 2013 Colorectal Dis; Kornmann M et al. 2013 Clin Colorectal Cancer; Krarup PM et al. 2014 Ann Surg; Watanabe T et al. 2015 J Clin Oncol). In other series analyzing peritoneal metastases, metachronous spread after primary colonic resection varies from 3 to 5% but increases to 7% if we analyze the data for patients with pT3 and pT4 tumors (Van Gestel YR et al. 2014 Eur J Surg Oncol; Kerscher AG et al. 2013 Br J Cancer; Segelman J et al. 2012 Br J Surg). Possibly more reliable data come from a Dutch study that with a median 34 month follow-up and analyzing the outcome in 446 patients with colon cancer stage I to III resected for cure, 17% had recurrent disease and half of these patients had local or peritoneal disease (Duineveld LA et al. 2016 Ann Fam Med). Regarding prognosis, a paper published by Franko et al. (2016 Lancet Oncol), shows that in patients with metastatic spread from colorectal cancer, peritoneal involvement, either as the only metastatic site or associated with other sites, worsens prognosis. Surgical series describing treatment of so-called locoregional recurrence from colon cancer give disappointing results. Elferink MA et al. (2012 Ann Surg Oncol) showed that out of 2,282 patients resected for colon cancer, 127 had within 5 years a locoregional recurrence and only 39 (30%) could be surgically treated and the overall survival was 8%. But when literature data refers specifically to peritoneal metastases, in a series from Gustave Roussy (Goerè D et al. 2013 Ann Surg) of 107 selected patients with peritoneal metastases from colorectal cancer that underwent cytoreductive surgery (CRS) plus HIPEC, the rate of survival approach data previous cited, with 16% of patients considered cured. With the rising drug costs in the United States the cost-effectiveness (CE) treatment strategies for metastatic colorectal cancer are becoming important (Goldstein DA et al.2016 Clin Colorectal Cancer). Recent analysis revealed that the thereshold for the definition for a CE health care intervention in these patients is 130,000 US dollars for quality-adjusted life year (Lee CP et al. 2009 Value in Health). If we want to calculate the cost-benefit ratio for patients who undergo cytoreductive surgery plus HIPEC, the treatment that more than others in selected patients guarantees a cure, the incremental cost-effective ratio per life-year saved, ranges from 44,000 AU$ and 58,000 euro (Vanounou T et al. 2016 Ann Surg Oncol). We propose a more basic count based on the series by Gustave Roussy. Bonastre et al. (2008 Value in Health), calculated a mean 81,000 euro spent per patient treated with CRS plus HIPEC in Gustave Roussy, which if multiplied by the 107 published by Goere et al., provides a figure of more than 8 million euro; this amount divided by the 17 patients considered cured yielding half a million euro for each live saved. These figures make a strategy for prevention indispensable. Finally the incidence the poor prognosis and the high treatment related cost of endoperitoneal recurrence in colorectal cancer support the efforts on developing proactive protocols.