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Dr. Marcello Deraco
U.O. Melanoma e Sarcoma
Istituto Nazionale Tumori Milano
Via Venezian 1
20133 Milano, Italia
www.marcelloderaco.com
info@marcelloderaco.com
Tel/ Fax: +39.02.76008435

Peritoneal carcinomatosis (PC) is a clinical entity with a unfavorable prognosis which characterizes the evolution of neoplastic diseases from the abdominal and/or pelvic organs and could also be the terminal stage of extra-abdominal tumors.

The decision to submit a primary gastrointestinal tumor to a surgical treatment is strongly conditioned by the presence of PC. In the former time PC was not considered amenable to a curative surgical treatment due to several reasons. The peritoneum was not considered an organ but simply a stratum of tissue covering the abdominal cavity and the internal organs. In reality it has a particular histologic structure, a vascularization and a specific function. Like the liver and the lungs the peritoneum constitutes the target for metastasis from various primary tumors, particularly from the abdominal and/or pelvic organs. Like any other organ the peritoneum could also originate a primary tumor such as peritoneal mesothelioma. The structure of the peritoneum is complex with a surface of 7.600 cm2 which is evenly distributed inside the abdominal cavity so that it can be in contact with all the organs localized inside. This anatomical disposition renders complex the distribution of eventual neoplastic process that can affect the peritoneum, regardless of the fact that it is primary or metastatic. The evolution of the surgical techniques and the availability of innovative surgical and anaesthesiologic resources allowed the advent of surgical therapy of the PC. Traditionally the PC has been treated with systemic chemotherapy and debulking surgery with only palliative scope.

In 2000, a prospective multicentric study was published on peritoneal carcinomatosis (EVOCAPE 1). The study recruited 125 patients with peritoneal carcinomatosis. There was a statistically significant difference in terms of overall survival according to the primary tumour histotype: 3.1, 5.2, 2.1 months respectively for gastric, colon and pancreas cancers. If we consider the subgroup of 118 patients with peritoneal carcinomatosis from colon cancer, 60% of the cohort presented metastatic nodules <2cm; however if the treatment did not achieved the curative intent the survival was limited. These findings guided several researchers to test innovative therapies for PC. In this context, the advent and evolution of locoregional therapy in the last 2 decades has changed the paradigm that has supported the management of patients affected by PC.

Principles of the methodology
The locoregional approach to peritoneal surface malignancies

The locoregional therapy is defined as the combination of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The rationale of this combined therapy for PC is based on the natural history of this clinical entity. In ovarian cancer and in considerable percentage of colon cancer cases the disease remains in the peritoneal cavity for most of its natural history. This pattern of spread would seem to indicate the potential usefulness of selectively increas ing drug concentration in the tumour -bearing area by direct intraperitoneal chemotherapy instillation. The drug concentration attainable through a locoregional approach allows to overcome the intrinsic or acquired drug resistance and simultaneously minimizing the systemic toxicity. In the early seventies, Dedrick designed a model taking into account the anatomic and physiologic characteristics of the peritoneal cavity and the pharmacokinetics of some chemotherapies . According to this model the locoregional administration of drugs allows a significantly higher concentration of chemotherapies in contact with the intrabdominal tumour as compared to the systemic instillation.

The rationale for the Intraperitoneal hyperthermic perfusion

A large intergroup trial randomized 546 stage III patients with epithelial ovarian cancer with optimal residual disease (defined as largest nodule 2 cm or less after cytoreduction) to intraperitoneal cisplatin plus intravenous cyclophosphamide or intravenous cisplatin plus intravenous cyclophosphamide. Intraperitoneal therapy was associated with a significantly improved median survival (49 versus 41 months) and fewer toxic side effects. The results of this trial have however, not substantially altered clinical practice. In a subsequent Gynecologic Oncology Group trial, 523 patients were randomized to intravenous cisplatin/paclitaxel of high-dose carboplatin followed by intraperitoneal cisplatin plus intravenous paclitaxel. The preliminary results demonstrated a significant increase in recurrence-free interval (28 versus 22 months), without the same favorable impact on overall survival.

However, the intraperitoneal chemotherapy carries some problems such as limited drug absorption into the tumour tissue in normothermic conditions and incomplete drug distribution due to the abdominal postoperative adhesion.

In an attempt to overcome these drawbacks, intraperitoneal chemotherapy in hyperthermic conditions has become an area of growing interest supported by experimental observations. In fact, at 40-42 ° C, neoplastic cells become more chemosensitive due to an increase in the intracellular concentration of drugs and in their activation process, especially for alkylating agents, and to alterations in the DNA repair process. Moreover, it has been shown that these events have a greater intensity in cisplatin-resistant rather than cisplatin-sensitive ovarian cancer cell lines. Formation of platinum-DNA adducts after cisplatin exposure is enhanced and/or adduct removal is increased in heated cells, resulting in a relatively higher DNA damage. The IPHP treatment was initially conceived for the treatment of gastrointestinal cancers following surgical intervention, and a slight increase in morbidity in patients treated by this locoregional approach has been reported .

One technical issue worth discussing is the optimal IPHP drug regimen. The criteria for choosing the ideal combination should be based on the pharmacokinetic profile of drugs, tumour chemo sensibility and toxicity. Ideally the drug must be water-soluble and of high molecular weight in order to guarantee a low peritoneal clearance. This, combined with a high systemic clearance, will result in pharmacological advantage expressed by a higher exposure of tumour to the agent (high AUCpe/AUCpl ratio). For intraperitoneal therapy to be effective against intraperitoneal tumors, the drug must also diffuse inward from the periphery of the tumour mass. The penetration ability of drug in the tumour is a function of passive diffusion, removal from by the capillary blood flow and temperature modulation. Penetration by passive diffusion is related to the AUCpe/AUCpl ratio, although this may not hold true for all drugs. Moreover, the drug should be a cell cycle non specific chemotherapeutic agent, which makes it suitable for single shot anticancer treatments. Finally, the influence of temperature in the cytotoxicity should also be of concern, so that the higher the cell killing capacity of the drug due to the hyperthermia the better.