Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: survival outcomes and patient selection

Abstract

Background: Chemotherapy hyperthermic intraperitoneal chemotherapy (HIPEC) is playing an ever increasing role in the management of colorectal cancer (CRC) with peritoneal metastases (PM) as results approach those of surgical resection of liver metastases. Selection criteria for treatment type, sequence and timing of currently available therapies remain ill-defined.

Methods: We review the current published literature analyzing outcomes by treatments with surgery, systemic chemotherapy, cytoreductive surgery (CRS) and HIPEC, and ongoing clinical trials. A clinical pathway that incorporates all currently available therapies, determining the timing and sequence of such therapies was constructed.

Results: Most of the literature on outcome data comes from studies reporting the results of CRS and HIPEC with large series showing a median survival of 32-47 months. Meanwhile, the vast majority of patients, over 90% in the United States, are being treated with palliative systemic therapies following the NCCN guidelines.

Conclusions: Cooperation between medical and surgical oncologists represents an unmet need in oncology when it comes to patients with CRC with PM. The presented clinical pathway constitutes a feasible and much needed first step to start this cooperation.

Keywords: Cytoreductive surgery (CRS); colorectal cancer (CRC); hyperthermic intraperitoneal chemotherapy (HIPEC); peritoneal carcinomatosis.

Figure 1

Clinical pathway for the management of peritoneal surface malignancies of colorectal origin. ^a, this should include a recent colonoscopy. A CT scan of the chest, abdomen and pelvis with maximum oral and intravenous contrast. A PET scan should be done in those patients in whom there is evidence or suggestion of hematogenous dissemination on the CT scan. K-ras status should be determined in all patients. ^b, patients with peritoneal metastases and LLM should be referred to a medical oncologist for systemic therapy. Patients with 3 or fewer small, liver metastases (20) can be considered for cytoreductive surgery and HIPEC if they had a good response to the first 3 months of systemic therapy. ^c, best systemic therapy includes a combination of cytotoxic chemotherapy and biological agents. Cetuximab or panitumumab should be considered in those patients that could potentially become surgical candidates and are K-ras wild type. ^d, the Peritoneal Surface Disease Severity Score (PSDSS) (Table 2) was introduced in an attempt to stratify patients with colorectal cancer with peritoneal metastases according to four tiers of estimated disease severity based on a 3-point scale that includes: (I) symptoms; (II) extent of peritoneal dissemination; and (III) primary tumor histology. ^e, variables associated with increased chances of having a complete cytoreduction: complete cytoreduction means that no macroscopic residual disease was left after the operative procedure. The following are clinical and radiographic variables that are usually associated with increase chances of achieving a complete removal of all tumor greater than 2.5 mm; ECOG performance status 2 or less; no evidence of extra-abdominal disease; up to 3 small, resectable parenchymal hepatic metastases; no evidence of biliary obstruction; no evidence of ureteral obstruction; no evidence of intestinal obstruction at more than one site; small bowel involvement: no evidence of gross disease in the mesentery with several segmental sites of partial obstruction; small volume disease in the gastro-hepatic ligament. ^f, PSDSS II patients that have a low CT-PCI (PCI <10) and are good candidates for a complete cytoreduction can go directly to surgery and have systemic therapy after. ^g, PSDSS III have a very low chance of having an upfront complete cytoreduction and therefore should have best systemic therapy first. Re-staging and re-evaluation should be done after 2 or 3 months of systemic therapy. ^h, PSDSS IV patients do not have a good long term outcome even when achieving a complete cytoreduction. These patients should have best systemic therapy first and should have cytoreductive surgery and HIPEC under a clinical protocol. ⁱ, best systemic therapy includes a combination of cytotoxic chemotherapy and biological agents. Consider cetuximab or panitumumab in those patients that are K-ras wild type. If using bevacizumab, it appears to be prudent to hold the bevacizumab after cycle #5 and use only the cytotoxoc agents for cycle #6. ^j, the three parameters evaluated to judge the response to the “neo-adjuvant” systemic therapy include: (I) performance status; (II) CEA; and (III) imaging studies. Improvement of at least one of these parameters with the other two remaining unchanged should be the minimum requirement to consider a response as good. Patients with PSDSS II and III, who had a good response, should be evaluated for cytoreductive surgery and HIPEC. ^k, worsening of any of these three parameters while receiving systemic therapy should be considered as not having a good response. In this situation, systemic therapy should be continued and changing the cytotoxic and/or biological regimen should be considered. ^l, American Society of Peritoneal Surface Malignancices Standardized HIPEC delivery in patients with colorectal cancer with peritoneal dissemination. (I) HIPEC method: closed; (II) drug: mitomycin C; (III) dosage: 40 mg; (IV) timing of drug delivery: 30 mg at time zero; 10 mg at 60 minutes; (V) volume of perfusate: three liters; (VI) inflow temperature: 42 degrees celsius; (VII) duration of perfusion: 90 minutes. ^m, patients with a PSDSS I that had cytoreductive surgery and HIPEC should receive standard best systemic therapy. Patients with a PSDSS of II or III that had a poor response to their first 3 months of systemic therapy and then have a good response after changing systemic agents should be considered for cytoreductive surgery and HIPEC. HIPEC, hyperthermic intraperitoneal chemotherapy.