Surgical resection remains the hallmark therapy for primary colon cancer. It allows the patients to become clinically disease free, provides proper staging, and determines who should receive adjuvant systemic chemotherapy. Treatment options for patients with unresectable metastatic disease have improved significantly in the past few years. A review of the published data in the treatment of patients with Stage IV colorectal cancer, outlining the surgical and medical therapeutic options demonstrates that medical management, with combinations of cytotoxic chemotherapy, and/or biological agents, has resulted in an unprecedented Median Survival > 20 months.[1]

Peritoneal involvement in colorectal cancer occurs in approximately 30% of patients. Approximately 8% of patients are diagnosed with synchronous peritoneal dissemination at the time of primary colorectal surgery and 25% of patients have recurrence confined to the peritoneal cavity.[2] The management of disease limited to the peritoneal cavity has been controversial. However, at the present time, there is no published data that outlines the impact of these new therapeutic regimens when given to patients with colorectal cancer with metastatic disease confined to the peritoneum. Therefore, systemic treatment alone is an unproven therapeutic strategy for this particular group of Stage IV patients with limited peritoneal dissemination from a primary or recurrent colon cancer.

The present document will focus on the available scientific evidence of the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of peritoneal surface malignancies of colorectal origin.

In the 1990s, Sugarbaker and colleagues proposed cytoreductive surgery and perioperative intraperitoneal chemotherapy as a definitive treatment for peritoneal dissemination from appendiceal neoplasms and diffuse malignant peritoneal mesothelioma.([3], [4], [5]) Better surgical techniques that include Peritonectomy Procedures, standardized methods to deliver intraoperative hyperthermic intraperitoneal chemotherapy and better patient selection criteria, along with the strong treatment rationale and superior results when compared to historical controls, have lead to the establishment of numerous treatment centers in the United States and Europe. Over the last 5 years, an increasing number of international treatment centers have published their prospective results using cytoreductive surgery and HIPEC in the management of peritoneal surface malignancies of colorectal origin.([6], [7], [8], [9], [10]) In 2003, the Dutch group conducted a randomized controlled trial comparing systemic chemotherapy with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and this trial clearly demonstrated the superiority in survival of the combined treatment group.[11] In 2004, a multi-institutional registry study from 28 international treatment centers showed that the median survival was 19 months and 3-year survival was 39% after cytoreductive surgery and HIPEC for 506 patients with colorectal peritoneal carcinomatosis.[12]

An analysis of evidence indicates improvement of survival and potential for cure in patients with low volume metastatic adenocarcinoma of colonic origin limited to the peritoneal cavity using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). However, as pointed out by Yan et al in a recent systematic review of the quality of evidence in 14 rigorously selected series, there were 2 randomized controlled trials, one randomized comparative study, and 11 observational studies without control groups, including one multi-institutional study.[13] In addition, the indications for, the technique of HIPEC, the drugs used and the degree of heat, vary among physicians using these methods of treatment.

A recent international conference on this subject was convened and a consensus statement on the appropriate use of cytoreductive surgery and HIPEC was developed and adopted by the Peritoneal Surface Malignancy Group (PSMG) in an attempt to standardize the indications and techniques for this treatment. We agreed that the main strategy would be to use the peritonectomy procedures necessary to achieve a complete cytoreduction. After all resections were done then the hyperthermic chemotherapeutic perfusion would be carried out. We agreed that most of us use Mitomycin C with some not significant variations regarding dosage, temperatures and methods of delivery. We also recognize that there is some exciting and provocative data with the use of intraperitoneal Oxaliplatin and with the systemic use of biological agents.[14]

Reviewing the published data helps us learn about the outcome of patients with colorectal cancer with peritoneal dissemination treated with cytoreductive surgery and HIPEC. There is no question that 2-year survival rates are around 60% and 5-year survival rates approach 40% in many series when a complete cytoreduction can be achieved. However, review of the data also teaches us about the biology of the tumor as we all continue to have incomplete cytoreductions with an expected median survival of about 6 months. At the present time, we lack a universally accepted and easily reproducible prospective staging/scoring system that addresses the quantity and location of the peritoneal dissemination and its impact on achieving a complete cytoreduction. We also do not have a universal agreement on inclusion/exclusion criteria. Some centers would consider patients with a few liver metastases candidates for this procedure while other centers would consider this situation an absolute contraindication.

In the absence of a large prospective randomized trial that addresses all the above mentioned issues, it is going to be difficult to demonstrate the true impact of cytoreductive surgery and HIPEC on the natural biologic behavior of colorectal cancer with peritoneal dissemination, especially in the era of newer systemic therapy, keeping cytoreductive surgery and HIPEC still as an unproven and frequently questioned therapeutic treatment modality.

Therefore, this consensus statement represents a continuing starting point and only with close collaboration between Medical and Surgical Oncologists will we be able to answer these questions and provide the best multidisciplinary therapy to this particular group of Stage IV patients.

Preoperative Evaluation

Proper patient selection remains a crucially important aspect in the treatment of patients with peritoneal dissemination from colorectal cancer. As previously mentioned, long-term survival can only be achieved with cytoreductive surgery and HIPEC when a complete cytoreduction is accomplished. Review of the data in multiple series shows that those patients that have an incomplete removal of their peritoneal dissemination have a median survival of about 6 months and therefore these patients do not benefit from a surgical procedure.11-12In addition, they represent a financial burden to the institution.

Once a patient has been diagnosed with colorectal cancer with peritoneal involvement, the work-up usually includes a complete colonoscopy as well as a CT scan of the chest, abdomen and pelvis with maximum oral and intravenous contrast to evaluate the extent of peritoneal dissemination. A PET scan can be considered if there is any question of extra-abdominal disease. Review of two published series trying to address the diagnostic accuracy of the CT scan as an imaging modality can be summarized by stating that the detection of peritoneal carcinomatosis by CT scan is only moderately useful and that it has severe limitations in detecting small peritoneal implants, especially in the small intestine. In addition, CT scan was considered of limited value in selecting colorectal patients with peritoneal carcinomatosis who will not benefit from cytoreductive surgery with HIPEC.([15], [16])

Role of abdominal laparoscopy in the pre-treatment evaluation of peritoneal carcinomatosis

Garofalo et al reported on 97 cases of peritoneal carcinomatosis submitted to video laparoscopy to stage the disease. They achieved full laparoscopic Peritoneal Cancer Index assessment in 96/97 cases, while only 2/96 cases were under staged. There was a good correlation between the open successive surgery data and the laparoscopic Peritoneal Cancer Index. There was no mortality and no neoplastic colonization at the trocar port site. Patients with massive involvement of their small bowel or mesentery by staging laparoscopy should be considered not amenable for peritonectomy. They considered laparoscopy a useful tool in peritoneal surface malignancies. It allows direct visualization even of small cancer nodules and provides a reliable assessment of the feasibility of peritonectomy.[17]

A group of French investigators also evaluated the role of explorative laparoscopy to evaluate candidates for complete resection of peritoneal carcinomatosis combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Eleven patients planned to undergo a cytoreductive surgery + HIPEC underwent an explorative laparoscopy. Laparoscopic evaluation was successful in all 11 patients. The median operating time was 38 min (range 23-75 min). The laparoscopic examinations were well tolerated in all cases. For 3 patients, the peritoneal carcinomatosis was as judge as unresectable. A complete resection of the peritoneal carcinomatosis combined with HIPEC was performed in seven out of the eight patients with peritoneal carcinomatosis considered resectable at laparoscopy. One patient was diagnosed with more extensive disease than that as assessed by the evaluative laparoscopy.[18] Of note, in 20% of the patients taken directly for a laparotomy, a complete cytoreduction was not possible. The conclusion was that laparoscopic scoring of peritoneal carcinomatosis is accurate to assess the complete resectability of peritoneal carcinomatosis in patients for which there is inadequate or contradictory information concerning disease extent.

Variables associated with increased chances of having a complete cytoreduction

The following represent clinical and/ or radiographic variables that are usually associated with an increase chance of achieving a complete removal of all tumors during cytoreductive surgery.

• 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

These data represent characteristics that most peritoneal surface malignancy centers agreed upon but it has not been submitted to a prospective analysis. With the establishment of this consensus and the participation of most of the international groups, we hope we can validate these clinical and/or radiographic variables.

Eligibility Criteria

Establishing clear eligibility criteria for any given treatment plan seems obvious in order to maximize benefits and minimize unnecessary treatments. The indications for cytoreductive surgery and HIPEC in the treatment of peritoneal surface malignancies of colorectal origin have not been clearly defined and at the present time range from being indicated because the patient is in good physical condition to withstand this particular treatment to the patients that have failed every other possible treatment and are looking for a last chance.

Up to date, there are no published indications for the role of cyotreductive surgery and HIPEC in the treatment of peritoneal surface malignancies of colorectal origin. The medical oncology community, labels these patients as Stage IV disease and extrapolate data from the efficacy of modern combinations of cytotoxic and biological agents as their rationale to treat patients with colon cancer metastatic to the peritoneum. Unfortunately, they fail to realize that the vast majority of the patients on the trials that generated these data, were patients with metastatic extra-abdominal disease and the second largest group were patients with liver metastases.

On the other hand, an analysis of the published data by the surgical oncology community shows that the indications are very vague and none specific like, having a good performance status and few comorbidities in order to survive the operation. We have tried to identify those patients in whom this particular treatment option is not indicated, like in patients with extra-abdominal disease, or patients with multiple sites of intestinal obstruction or patients with too much disease. Sugarbaker et al evaluated the prognostic value of the Peritoneal Cancer Index (PCI) in patients with colorectal cancer undergoing cytoreductive surgery plus HIPEC. A PCI < 10 was associated with a 5-year survival rate of 50% while it was 0% if the PCI > 20 (p-value < 0.0001). Based on these data, they concluded that cytoreductive surgery plus HIPEC were contraindicated in patients with a PCI > 20.[19] Verwaal et al using their seven regions system found not only that the survival benefit was low in patients with more than 5 regions involved but also that the morbidity was increased in these patients.[20]

There are a few points on this subject that deserve attention. The story of surgical treatment of colorectal liver metastases is being rewritten with a different title. It would be impossible to think that a medical oncologist would recommend systemic therapy for a patient with a single liver metastasis 18 months after resection of the primary tumor as well as it would be impossible to think that a surgical oncologist would favor surgical treatment in a patient with a primary tumor and more than 20 liver metastases. In this particular setting of metastatic disease, the indications appear to be well described.

When it comes to metastatic disease to the peritoneum, we face the problem that not only we do not have a universally agreed upon scoring system to follow the patients from time zero, but that it is very difficult to measure with the current image modalities the amount and location of the disease. Most of the patients that we treat, at least in the United States, have failed every possible combination of cytotoxic and biological agents and come to us with a debilitated body and a depleted bone marrow. However, we most address that these patients represent the numerator and we do not know the denominator, making it very difficult to have meaningful conclusions on the effect of systemic therapy in patients with colorectal cancer metastatic to the peritoneum. In addition, it is also difficult to measure the benefit of the procedure. We all have seen patients with intractable ascites that require weekly paracentesis and that after cytoreductive surgery and HIPEC, live only 6 months but never needed to be tapped again. Palliative cytoreduction with HIPEC, plays a tremendous role in improving quality of life in these patients.

In summary, we know that most of the patients with an incomplete tumor removal will not benefit from cytoreductive surgery and HIPEC and face a median survival of 6 months. We also know that long-term survival can only be achieved with a complete removal of the peritoneal disease. We hope that with this consensus meeting, we can define how to tell these two groups apart.