ReviewTreatment of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: State of the art and future developments
Introduction
Peritoneal carcinomatosis (PC) is a clinical entity with unfavourable prognosis that commonly characterises the terminal evolution of abdominopelvic neoplastic diseases [1]. Traditionally, this condition has been regarded as a lethal disease, as most patients with carcinomatosis die within 6 months [2], [3]. Being particularly difficult to treat, cancers with widespread peritoneal dissemination often cause their great morbidity and mortality through progressive involvement of the peritoneal surfaces. Even in patients resected for intra-abdominal carcinomas, PC is the most common cause of death [4], [5], [6]
During the last decade, there has been renewed interest in peritoneal-surface malignancy. The improved understanding of the biology of tumors with intraperitoneal dissemination without evidence of systemic metastases has prompted the search for new aggressive therapeutic approaches. Intraperitoneal chemohyperthermia in the first place, since 1980 [7], and successively combined with peritonectomy procedures, since 1995 [8], has been used for the treatment of PC deriving from gynecological and nongynecological malignancies. Since then, various cancer treatment centers all over the world have become interested in this treatment modality and have reported their experience with HIPEC using different devices with encouraging preliminary results [2]. Globally, as most synchronous PC is confined to the peritoneal cavity and is a localised disease [1], there is an evolving paradigm shift in the management of PC to achieve locoregional control, similar to hepatectomy for patients with isolated liver metastasis deriving from colorectal carcinoma.
This innovative and aggressive treatment regimen directed at the whole abdomen and pelvis is able, despite high post-operative morbidity rates, to eradicate carcinomatosis and improve long-term survival rates for selected patients [8], [9]. The rationale for HIPEC is based on direct cytotoxicity of hyperthermia against malignant cells, enhancement of the cytotoxicity of anticancer drugs, and the pharmacokinetic advantages of the intraperitoneal route for chemotherapy [4], [6].
The biological basis of PC and the most recent knowledge on this new treatment modality are here comprhensively reviewed. Future directions are conclusively discussed.
Section snippets
Epidemiology
Primary peritoneal malignant disorders (such as peritoneal mesothelioma) are rare, while PC is a common manifestation of digestive-tract and gynecological cancers, usually appendiceal tumours, ovarian cancer, colorectal cancer, or gastric cancer [2].
The peritoneal dissemination may be present at the time of diagnosis of the primary tumor, but it arises more frequently as a tumor recurrence after radical surgical treatment [4]. In gastric cancer, 10–20% of patients deputed for potentially
Pathophysiology of peritoneal carcinomatosis
The mechanisms governing carcinomatosis are multifactorial. Basically, they include the peritoneal dissemination of free cancer cells, exfoliating as a consequence of direct invasion by the primary tumor [23]. Subsequently, they implant to the peritoneal surface right through the presence of adhesion molecules [4], [5]. Another mechanism considered responsible of peritoneal dissemination is the passage of malignant cells through lymphatic fluid or venous blood, which are retained within the
History
Beginning from studies on ovarian cancer, in the 1930s Meigs was the first to advocate CRS followed by adjuvant radiotherapy [25] and, successively, the concept of ultraradical cytoreduction of PC was optimized in the late 1960s and 1970s, when Munnell and Griffiths independently demonstrated improved survival rates achieved by more extensive surgery with the size of residual disease being the most important prognostic factor [26], [27].
In 1969 Long et al. [28] reported long survival times in
Rationale
As shown by pharmacokinetic studies [4], [5], [6], when an antitumor drug was administered intraperitoneally in large volumes, a significantly greater concentration was obtained in the abdominal cavity compared with the circulating blood. Because the peritoneal permeability is considerably less than the plasma clearance, this ‘peritoneal plasma barrier’ mechanism provides locally dose-intensive therapy, so that higher concentrations of anticancer drugs can act in direct contact with tumor cells
Technique
A number of different techniques for the administration of intraperitoneal chemotherapy in hyperthermia associated with CRS have been described. Mainly variations in perfusate temperature, chemotherapeutic drug and dosage, total volume of instillate, duration of intraperitoneal chemotherapy, temperature of dynamic flow, and whether the abdomen remain open or not during the perfusion have been reported [2].
Indications
The common conditions of peritoneal diseases to be treated with this procedure are those limited to the abdomen that is completely or significantly resectable. These usually originated from gastric cancer, colorectal cancer, appendiceal cancer, and ovarian cancer. Also primary peritoneal malignancies are candidate.
However, qualitative and quantitative indicators are needed to assess patient’s eligibility for such an invasive form of treatment. Patients must be able to medically and safely
Prognostic indicators
Quantitative prognostic indicators are generally useful to guide selection of patients who are most likely to respond to the treatment and to exclude those who have little or no chance of benefiting from this high-risk management protocols. Unfortunately, to date, firmly codified indicators for the selection of patients for cytoreduction plus HIPEC are not available.
Preoperative imaging, essentially TC and MRI, that theoretically could assist not only in planning cytoreduction but also in
Morbidity and mortality
Such procedures are generally long and technically challenging, and it is not surprising that considerable rates of morbidity and mortality may result, particularly when HIPEC is combined with extensive cytoreduction [16], [35], [36], [39].
Despite having been in existence for about 20 years, there still exists a lack of acceptance of this treatment, essentially due to the high morbidity and mortality that for long has been regarded as the main cause of criticism against the safety of this
Survival
Systemic chemotherapy demonstrates little impact on the treatment of peritoneal malignancy. Despite showing encouraging tumor response rates, it does not definitively improve survival rates [2].
To date, no prospective randomized study has been conducted to evaluate the efficacy of cytoreduction plus HIPEC for the treatment of PC regardless of primary-tumor type; whereas, a single randomized controlled study specifically designed for the treatment of PC of colorectal cancer origin [82] is
State of the art and future prospects
The operative procedures, CRS, and the HIPEC systems are expensive and complex in design and application for the particular aggressive treatment modality needed for carcinomatosis. They require not only highly specialized human resources, but also complex technological facilities, for which a learning curve exists too. Over the years numerous groups of surgeons have become involved, but at present only few centers have gained experience exceeding 100 cases and HIPEC procedure has not been
Conclusion
Cytoreductive surgery and HIPEC are an aggressive multidisciplinary approach to a difficult oncologic situation which demonstrates a positive emerging trend towards the expected survival rates in patients with PC.
On the basis of published evidence, HIPEC impacts on the survival rate after complete CRS, thus a potential cure of PC is at present a realistic option that can no longer be ignored. Nevertheless, it is clear that CRS plus HIPEC is not indicated for all patients with PC, but has an
Conflict of interest statement
All the authors disclose any potential or actual personal, political or financial interest in the material, information or techniques described in the paper.
Authorship Statement
Guarantor of the integrity of the study: Enrico Pinto
Study concepts:Franco Roviello
Study design: Stefano Caruso, Alfonso De Stefano
Definition of intellectual content: Daniele Marrelli
Literature research: Alessandro Neri, Corrado Pedrazzani
Clinical studies:Bin Wu, Xuefeng Liu, Guiyang Cai
Acknowledgements
All authors disclose any potential or actual personal, political or financial conflict of interest in the material, information or techniques described in the paper.
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