Peritoneal carcinomatosis is detected in approximately 10% of patients at the time of primary cancer resection.¹ The prognostic study of Chu et al.,¹ in 1989, reported 45 patients with a median survival of 6months after treatment with 5-fluorouracil and leucovorin. A French multicentre prospective study² reported 118 patients studied from 1995 to 1997, with a median survival of 5.2months. In a recent retrospective analysis of 3019 colorectal cancer patients, 13% of patients presented with carcinomatosis and had a median survival of 7months.³ Despite the development of new more effective chemotherapeutic agents and combinations, the results of systemic chemotherapy treatment remain disappointing, with a limited impact on survival.^4–6 Interesting survival results were obtained with the use of irinotecan or oxaliplatin on metastatic colorectal patients, but a great majority of patients had liver metastasis without peritoneal carcinomatosis.⁷⁸#

Novel therapeutic approaches to peritoneal carcinomatosis have emerged, combining cytoreductive surgery and peritonectomy procedures⁹ with perioperative intraperitoneal chemotherapy, including early postoperative intraperitoneal chemotherapy (EPIC) and/or intraperitoneal chemohyperthermia (IPCH).^10–12#

Several phase II studies reported the use of this combined therapeutic strategy for patients with colorectal carcinomatosis with interesting survival results (Table 1). Many investigators demonstrate the importance of residual tumour volume following cytoreductive surgery. With a median follow-up of more than 4years, Elias et al.,¹² who treated 56 patients with complete cytoreductive surgery followed by early postoperative intraperitoneal chemotherapy or IPCH, reported 2-year and 5-year survival rates of 60% and 27%, respectively. All phase II studies reported median survival of more than 2years and 5-year survival more than 20% for patients treated with complete macroscopic cytoreductive surgery or with residual tumour nodules less than 5mm following cytoreduction.#

Moreover, the Netherlands Centre Institute reported a phase III study comparing standard treatment with palliative surgery followed by systemic 5-fluorouracil and leucovorin as first-line chemotherapy with maximal cytoreductive surgery with IPCH followed by the same regimen, in patients with known colorectal carcinomatosis.¹³ It strongly demonstrated the benefit of the combined procedure and was stopped for ethical reasons.#

Despite many phases II and a phase III study suggesting benefit, the oncologic community remains sceptical regarding this combined therapeutic approach. To provide further data a collaborative effort of 28 institutions involved in the treatment of peritoneal surface malignancies provided information on a large number of patients with colorectal carcinomatosis, in order to evaluate the efficiency of this treatment, to answer questions regarding patient selection, and to identify principal prognostic indicators.#

In the last decade, results of loco-regional treatment giving a hope of cure in selected carcinomatosis patients emerged. This treatment combined cytoreductive surgery with perioperative intraperitoneal chemotherapy. Cytoreductive surgery attempts to remove all macroscopic visible tumour with comprehensive visceral resections and peritonectomy procedures, stripping involved portions of the peritoneum.⁹ Perioperative intraperitoneal chemotherapy is used at the end of the operation to destroy residual microscopic disease thereby preventing malignant cell implantation and cancer recurrence.¹⁸ Institutions involved in the treatment of peritoneal surface malignancies developed two concepts of intraperitoneal chemotherapy which can be delivered alone or in association: the IPCH¹⁰¹⁹ and the EPIC.¹²²⁰ The international registration including a large population of 506 patients,¹⁴ confirmed the interesting survival results observed in many single institution's studies using the combination of cytoreductive surgery and perioperative intraperitoneal chemotherapy for the treatment of colorectal carcinomatosis (Table 1). With an overall median survival of 19.2months, the 3-year and 5-year survival rates were 39% and 19%, respectively. Thirty-eight 5-year survivors were observed whereas no patient survived beyond 5years in the studies dedicated to the natural history of colorectal carcinomatosis.#

The combination of two aggressive loco-regional therapeutic approaches can lead to increased morbidity and mortality rates. This international registration reported morbidity and mortality rates of 22.9% and 3.7%, respectively, with 8.3% of digestive fistula. These results are comparable to those previously reported by the two most important trials dedicated to the analysis of the complications following cytoreductive surgery and perioperative intraperitoneal chemotherapy and which concluded that morbidity was correlated to the magnitude of surgery.²¹²² No evaluation of the magnitude of surgery was recorded in the registration, but it was observed that extended carcinomatosis which required extensive cytoreductive surgery had a significant negative influence on the rate of complications. Elias et al.,¹² who treated patients with the combined procedures only when complete cytoreductive surgery was possible, previously reported that morbidity rates were correlated with carcinomatosis extent. Surgeons must use their judgment to achieve a balance between the postoperative risk of extensive surgery and potential benefit in survival and quality of life. Extended carcinomatosis is also a negative prognostic indicator. Its association with other negative prognostic indicators such as lymph node involvement, poor differentiation, liver metastasis may lead to contraindicate patients for aggressive surgery combined with perioperative intraperitoneal chemotherapy with a curative intent. The high but acceptable complications emphasize the necessity for patient selection. As age over 65years appeared to be a significant negative prognostic indicator of survival, this aggressive combined procedures should be reserved to younger patient, without cardio-respiratory or renal failure, especially when carcinomatosis is extended and requires an extensive cytoreductive surgery to expect survival benefit.#

As it was previously reported by single institution studies,^10121920 the completeness of cytoreduction was reported in the registration as the principal independent prognostic indicator. For patients treated by complete cytoreduction, the median survival reached 32.4months and the 5-year survival was 31%. These results should shake the scepticism of the oncologic community. In 1988, a multi-institutional study of 859 patients who had undergone liver resections for colorectal liver metastasis was reported.²³ The 5-year actuarial survival rate was 33% whereas postoperative deaths were censored. Since that time, to our knowledge, no randomized trial has demonstrated the benefit of surgery for the treatment of resectable colorectal liver metastasis. However, is there any oncologist who will not refer one of his patients with resectable liver metastasis from colorectal cancer to the surgeon? Even if the study of peritoneal carcinomatosis is more difficult in that diagnostic tests to precisely assess the extent and the possibility of complete resection are missing, each patient with colorectal carcinomatosis should be referred to centres involved in the management of peritoneal malignancies for evaluation. Peritoneum should be considered as an organ and peritoneal carcinomatosis should be treated as well as other metastases (liver, lung). Moreover, a procedure combining cytoreductive surgery and perioperative intraperitoneal chemotherapy does not contraindicate a second procedure for patients who presented with recurrence. Indeed, the few patients who underwent a second combined procedure reached a median survival of 57.6months. This aggressive therapeutic strategy may lead to long-term survival for selected patients. As loco-regional recurrences occurred in 41.9% of patients treated with CCR-0 or CCR-1 resection and as their median disease-free survival was 13months, a second-look procedure may be indicated at 1year for patients who presented without any evidence of recurrence on morphologic examination. Recurrences with limited carcinomatosis, often undetectable on the standard morphologic examination, could be treated with greater efficiency with a second combined procedure.#

Independent negative prognostic indicators included lymph node involvement and synchronous resection of liver metastasis. As they seemed to profoundly influence the prognosis, they must be carefully assessed: preoperative CT scan and/or intraoperative ultrasonography for the detection of liver metastasis and multiple intraoperative biopsies for the assessment of lymph node involvement. They usually indicate systemic dissemination of the disease. An exclusive loco-regional therapeutic approach for a disease that is not confined to the peritoneum cannot be sufficient. Additional systemic chemotherapy should be indicated in these cases. Many of the patients included in the registration underwent systemic chemotherapy before and after the procedures. In this retrospective review the variability between administration and drugs used was too great to allow us a firm conclusion as to whether chemotherapy improved prognosis. It is beyond the capability of this analysis to confirm or deny the value of adjuvant or preoperative systemic chemotherapy. However, adjuvant systemic chemotherapy significantly improved survival in the group of patients treated with incomplete cytoreduction. Because of the recent development and the interesting results in metastatic colorectal patients of new anticancer drugs such as oxaliplatin and irinotécan,⁷⁸ systemic chemotherapy using these two drugs should be proposed to patients with carcinomatosis which cannot be completely resected or associated with liver metastasis and lymph node involvement and may be evaluated by randomized studies. The use of preoperative systemic chemotherapy had a significantly negative influence on survival. This could be explained by the fact that this chemotherapy delayed the combined procedure and the surgery and might have compromised the possibility of complete cytoreduction. But patients given preoperative chemotherapy may also have had more disease burden, which would explain their course.#

The type of perioperative intraperitoneal chemotherapy remains controversial but most of the centres involved in the treatment of peritoneal surface malignancies are currently using IPCH, which was part of treatment for 75.7% of patients in the registration. Unfortunately, as with EPIC, the procedure is not standardized, with many variations in exposure techniques, drugs, drug doses, duration, temperature, and flow rates.^24–26 There are some technical differences between EPIC and IPCH that may be exploited in different patient populations. EPIC has the advantage that it can be performed anywhere and at any time because it does not necessitate any special apparatus. This is most relevant and useful when the carcinomatosis is a fortuitous discovery during laparotomy. Pestiau and Sugarbaker²⁰ reported the better prognosis of patients with colorectal carcinomatosis treated with concomitant management of primary tumour. The registration felt to demonstrate that synchronous treatment of carcinomatosis with the resection of primary tumour improved overall survival. The theoretical deficiencies of EPIC include a failure to uniformly treat all the peritoneal surfaces, failure to provide the additive effect of hyperthermia,²⁷²⁸ a requirement for 5days of added patient discomfort, and the maintenance of high concentration of chemotherapy surrounding intestinal anastomoses, which increased the risk of complications, as was observed in the present study. No significant differences in survival were observed between patients treated by IPCH alone, EPIC alone, or both, but survival results were better with the association. Regarding the design and the bias of the registration and the great heterogeneity of the techniques and drugs used, no conclusions on the more efficient perioperative intraperitoneal chemotherapy can be established.#

The novel therapeutic approach combining cytoreductive surgery and perioperative intraperitoneal chemotherapy may be the most promising new treatment for colorectal cancer for the next decade. It offers hope for cure to patients who had in the past no escape from a terminal illness. The international registration, despite its bias due to its design, identified several useful prognostic indicators for patient selection. The use of perioperative intraperitoneal chemotherapy and its modalities still need to be validated by randomized studies. We probably have to use new anti-cancer drugs such as oxaliplatin or irinotecan, which had already been tested with IPCH and which seemed to give preliminary interesting survival results despite a high haematological toxicity,²⁹³⁰ A trial comparing IPCH with the most modern systemic polychemotherapy, after maximal cytoreductive surgery, is warranted. Although this trial would have a strong scientific and ethical rationale, the team undertaking it will probably face numerous recruitment difficulties due to the patients' refusal to be randomized into the control group.³¹#