Diffuse Peritoneal Mesothelioma (DPM) is an uncommon tumour arising from the serosa of the abdominal cavity. Malignant mesothelioma is known to have a direct causal relation with asbestos exposure and millions of people have been professionally or accidentally exposed to asbestos during the last decades. More recent investigations have implicated Simian Virus (SV40) in the etiology of this tumour [1].

Incidence of malignant mesothelioma has been rising worldwide since 1970 and is not expected to peak for another 10 to 20 years [2]. In the United States, where the incidence peak has likely already been reached, about 2500 new cases of are registered each year [3]. DPM accounts for 10 to 20% of all forms of malignant mesothelioma [3].

To date, there have been no universally accepted treatment for DPM. In the past the disease was treated at most cancer centres with systemic or intra-peritoneal chemotherapy, alone or in combination with palliative surgery and, in a few patients, total abdominal radiation. Clinical results of conventional treatment modalities have been far from satisfactory either in terms of cure or palliation. Recent publications from Bethesda MD, New York, Milan (Italy), Lyon (France) and Washington DC reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with hyperthermic intra-peritoneal chemotherapy (HIPEC).

The present paper focuses on the available scientific evidences concerning DPM management, in an attempt to build a consensus on the therapeutic indications and controversial issues of  CRS and HIPEC .

New standard of care for diffuse, malignant peritoneal mesothelioma ?

There are objective difficulties in planning  phase III clinical trials in this setting, due to the rarity of the disease. Furthermore, a randomized study would compare a potentially curative treatment with a palliative one. Accordingly, all the available clinical information have been obtained by retrospective historical case series or by single centre phase I/II prospective trials. An extensive literature search of all the published data on both traditional and innovative treatments  of DPM has been recently conducted [4]. Median survival after palliative surgery and systemic and/or intra-peritoneal chemotherapy is about one year, ranging from 9 to 15 months ([5], [6], [7], [8], [9], [10], [11]). Conversely, the median survival after aggressive surgery combined with HIPEC has approached 5 years and seems to improve with subsequent reports ([4], [12], [13], [14], [15], [16], [17], [18]). Taken together, the aforementioned data strongly suggest that extensive cytoreductive surgery and HIPEC should be regarded as the new standard of care for DPM. Taken together these data suggest that treatment of PMP by means of CRS and HIPEC is supported by "(Type 3)", as evidence is available from non-randomised studies, with external controls allowing comparisons.

Preoperative evaluation of patients affected by DPM

Early recognition of DPM can be problematic, due to its rarity and unspecific presentation. The disease is commonly diagnosed at advanced stage and in women often confused with ovarian cancer. This frequently results in initial mistreatment before the patient is admitted to referral centres ([19], [20]).

The goals of a rationale diagnostic pathway are to start an adequate and timely treatment and to optimize the clinical results. Since DPM has a great propensity to implant at needle tracts, laparoscopic port sites or surgical incisions, preventing disease dissemination as a consequence of inappropriate invasive procedures is an additional primary objective [15]. Imaging studies play a relevant role in the management of candidates to multimodality treatment but pathological confirmation is always required for definitive diagnosis [20].

CT-scan is the imaging test of choice for DPM. The CT-scan findings associated to the disease have been recently reviewed. Diffuse disease distribution throughout the peritoneal cavity with large tumour volume in the mid-abdomen and in the pelvis are the radiological features which may increase the level of clinical suspicion. Additional findings that could be of help in the differential diagnosis from other gastrointestinal or gynaecologic malignancies are the lack of a primary site and the absence of lymph node or distant metastases [21]. The role of other imaging studies, such as magnetic resonance or positron emission tomography is presently unclear.

Laboratory tests are not useful in the diagnosis of DPM since only unspecific alterations, such as thrombocytosis, hypo-albuminemia or elevated erythrocyte sedimentation rate, may be occasionally observed (1-2). In a recent study  CA125 was preoperatively elevated in the majority of patients with DPM, while CEA and CA19.9 were normal in all of them. These data indicate that CA125 elevation is not a valid criterion to exclude DPM from diagnosis, although the tumour is less common than ovarian cancer [22].

In spite of the quality of modern immunocytochemical and ultra-structural methods, cytological analyses of ascitic fluid are often inconclusive (15, 19-20). Laparoscopy is a recommended minimally invasive tool to obtain samples of tumour tissue for histo-pathological studies. Allowing direct inspection of peritoneal surfaces, laparoscopy may facilitate disease staging and the selection of surgical candidates. Exploratory laparotomy should to be avoided in patients with suspected DPM or peritoneal dissemination of unknown origin. If DPM is discovered in asymptomatic individuals undergoing abdominal exploration for other causes, the surgeon should perform only multiple tumour biopsies, in an effort to preserve as much as possible the integrity of the peritoneal barrier, thus not hindering a future surgical cytoreduction. 

The differentiation from benign mesothelial proliferations or from other peritoneal malignancies is a common diagnostic problem and requires appropriate immunohistochemical studies. DPM is characterized by positive staining for calretinin, epithelial membrane antigen (EMA), Wilms tumour 1 antigen (WT1), cytokeratin 5/6, human mesothelial cell 1 (HBME-1), mesothelin and negative staining for CEA, B72.3, MOC-31, TTF-1 and Ber-EP4. In most cases positive calretinin and EMA with negative CEA is highly suggestive of DPM [23]. When immunohistochemistry results are equivocal, electron microscopy may be of help. Confirmation of the diagnosis in highly qualified referral centres  is recommended ([1], [2]).

Diagnosis of DPM should include the definition of the histological sub-variant, which is prognostically and therapeutically relevant. Diffuse malignant mesothelioma is the most common mesothelial tumour. Localized forms usually show a benign clinical behaviour. According to the WHO classification, DPM can be broadly divided as displayed in table n.1 ([24], [25]).

Table n.1 Pathological classification of diffuse malignant mesothelioma (DMP)

Selecting the appropriate candidates to cytoreductive surgery and HIPEC

Due to its complexity, the combination cytoreductive surgery and HIPEC is expensive in terms of financial resources, operative time and major morbidity [26]. Patient selection is important to maximize the results of treatment, excluding patients who will not benefit from a potentially life threatening procedure.

Candidates have to be medically fit in order to undergo safely to CRS with HIPEC. Patients affected by peritoneal carcinomatosis with performance score of 2 to 3 according to the Eastern Cooperative Oncology Group (ECOG) have shown significantly poorer overall survival after CRS and HIPEC, compared to those with ECOG score of 1 [27]. Data from Milan demonstrate that ECOG score is independently related to progression-free survival in patients with diffuse malignant peritoneal mesothelioma (DMPM) [18].

Hepatic or extra-abdominal metastases and peritoneal disease not amenable of macroscopically complete cytoreduction are exclusion criteria for CRS and HIPEC. An accurate radiological evaluation can avoid unnecessary laparotomy if such features are detected. Preoperative CT-scan can reliably assess size and distribution of tumour deposits within the abdominal cavity and assists the physicians not only in planning the surgical cytoreduction but also in the identification of patients most likely to benefit from a comprehensive treatment plan. Tumour mass >5 cm in the epigastric region and loss of normal architecture of the small bowel and its mesentery (segmental obstruction and nodular thickening) are related to failure in adequately removing all the macroscopic tumour. In a composite analysis, none of the patients with both these radiological features had an adequate cytoreduction. Patients lacking these two preoperative CT-scan findings had a 94% probability of adequate cytoreduction [28].

Tumour biology is one of the most relevant prognostic determinant for either pleural or peritoneal mesothelioma ([1], [2]). Patients affected by border-line malignant potential variants (well-differentiated papillary and multicystic) are generally good candidates for CRS and HIPEC. By contrast, biphasic and sarcomatoid histology is associate to poor prognosis; these patients are rarely amenable to integrated treatment and  the decision to undertake such approach should be carefully evaluated [2]. Epithelial variants with intermediate prognosis represents the great majority of DPM. In this setting additional selection factors would be needed to identify patients who will benefit from the procedure and to design an individualized multimodality treatment plan.

To date, only few centres have clinically investigated the potential prognostic factors for patients with DPM treated by cytoreductive surgery and HIPEC as summarized in table n. 2 along with the statistical methods used. There is a substantial agreement among the different experiences about the variables related to reduced overall survival: male sex, incomplete surgical cytoreduction and aggressive tumour histology. Besides biphasic/sarcomatoid morphologic features and high mitotic count, also other variables which were significantly correlated to reduced overall survival by univariate statistical analysis, such as tumour invasion of deep tissues, no history of prior surgical debulking and non incidental diagnosis can be considered markers of aggressive biological behaviour. Finally, Cerruto have recently demonstrated by multivariate analysis that the size of the nucleus of the DPM cells is independently associated with survival [29].

Correlation to progression-free survival was analyzed in only two studies. No prior debulking, deep tissue invasion, ECOG performance status >0 and mitotic count >5/50 HPF  were recognized by multivariate analysis as independent predictor of adverse prognosis ([14], [18]).

Table n.2. prognostic factors for peritoneal mesothelioma after cytoreductive surgery and HIPEC

Since no reliable staging system for DPM is currently available, we propose a rationale operative prognostic classification for patients with DPM candidate to CRS and HIPEC. Based on the aforementioned clinical data,  the classification involves the following parameters: 1) presence of extra-abdominal  and/or hepatic metastases; 2) disease potentially suitable for complete surgical cytoreduction at preoperative imaging studies; 3) prognostic factors (histology, nuclear grade, mitotic count). Prospective studies would be needed to validate such classification (see table n.3/4).

Table n3 Proposal for preoperative Proposal for DMPeM Preoperative Staging 

Table n 4 Proposal for Proposal TSP Postoperative Staging for DMPeM

Accurate exploration of the abdominal cavity and lyses of adherences are needed to assess peritoneal disease extent. The surgical cytoreduction is aimed at removing all the macroscopic tumour. Formal peritonectomy of the pelvis and the upper quadrants, complete greater and lesser omentectomy are required also in case of non apparent involvement, due to the high probability of microscopic disease spread. Splenectomy and hysterectomy with bilateral salpingo-oophorectomy are necessary in most patients. Small volume tumour implants on bowel serosa and mesentery can be electro-fulgurated. Conversely, the opportunity to perform multivisceral organ resections in case of massive involvement should be carefully evaluated in light of the deriving functional consequences and the individual prognosis.

Technique of HIPEC (open vs. closed), type and dose of antiblastic drugs, duration of treatment and degree of hyperthermia vary from one series to other, as summarized in table n.5. Cisplatin has a favourable pharmacological profile for intra-peritoneal administration and is likely the most active drug against either pleural or peritoneal mesothelioma [30]. Accordingly, Cis-platin-based schedules have been adopted by all centres but one. Mitomycin-C and doxorubicin have been mostly used in association with cis-platin. Theoretically, the latter has some advantage for intra-peritoneal administration, since pharmacokinetic studies have demonstrated a better area under the curve ratio of peritoneal fluid to plasma [27]. Moreover, doxorubicin has shown a great activity in primary tissue cultures obtained from surgical specimens of DPM (unpublished data). A major technical variation is represented by EPIC but the contribution of such therapeutic tool in addition to CRS and HIPEC is presently unknown. A comprehensive treatment plan including induction intra-peritoneal CT, second-look surgery, HEPIC and total abdomen radiation have been tested in a phase I/II trial [16]. To date there are no data in the literature to compare the validity of the treatment protocols proposed by the different centres.

Clinical follow-up after CRS and HIPEC can be carried out on out-patient base. In asymptomatic patients thoracic/abdominal/pelvic CT-scan should be performed every 3-4 month during the first two years and every 6 month afterward. A recent study suggests the utility of circulating CA125 to assess postoperative disease progression in patients with elevated baseline levels (22).

Table n.5 Technical features of cytoreductive surgery and HIPEC

The role of systemic chemotherapy (CT) in DPM management is still challenging. Cisplatin has shown the better activity rates as a single agent and particularly in combination with gemcitabine [30]. A phase III clinical trial testing a new antifolates drug (pemetrexed) in combination with cisplatin versus cisplatin alone showed increased response rate and overall survival. Such combination is currently considered by many oncologists the regimen of choice for pleural mesothelioma [31]. There are little information on the effectiveness of this combination for DPMP. The preliminary results of a non randomized trial started in June 2002 account for an overall objective response rate of 26% among 73 patients with DPM [32].

These data suggest that systemic CT may be integrated with the combined loco-regional treatment strategy  for DMPM. On the bases of the existing literature, the role of systemic CT as adjuvant or neo-adjuvant treatment in patients undergoing CRS and HIPEC still has to be established. Nevertheless, patients at high risk for postoperative failure may be potential candidate for adjuvant systemic CT. Furthermore, patients not suitable for immediate cytoreduction and HIPEC may theoretically benefit of induction systemic CT to reduce disease extent and undergo a second comprehensive surgical evaluation.

Future perspectives

Advances in diagnosis of DPM may come form new imaging or laboratory tests. Positron emission tomography combined with CT-scan is a new imaging technique which may be able to preserve the high resolution of CT-scan and to provide at the same time more functional information then CT-scan. This technique has been suggested to reliably detect extra-abdominal disease and to accurately assess response to chemotherapy in patients with mesothelioma [2].

Serum mesothelin-related proteins are a soluble form of mesothelin which is elevated in 84% of patients with pleural mesothelioma and in only 2% with other pulmonary diseases [33]. Serum osteopontin levels were shown to be significantly higher in patients with pleural mesothelioma than in those with asbestos exposure [34]. No data are presently available about the clinical utility of these antigens in DPM management.    

Microarray techniques can assess simultaneously the expression of thousands of gene in a single tumour sample. Mesothelioma and normal pleural samples have been compared in a recent analysis providing information about gene expression differences between the paired normal and neoplastic tissues [35]. A microarray study yielded a 99% accuracy in the difficult pathological distinction between pleural malignant mesothelioma and lung carcinoma. Such result was obtained by measuring the expression levels of 3 pair of genes encoding for calretinin and TTF-1, which are widely used for the immunohistochemical characterization of mesothelioma [36]. Microarrays are now being used to systematically investigate the molecular changes that may predict the individual response to specific drugs and correlate to clinical outcome [2].

Due to the limited activity of traditional drugs, new therapeutic agents are presently matter of both clinical and experimental investigations. The platelet-derived growth factor (P-DGF) and the epidermal growth factror (EGF) signalling pathway have been demonstrated to be active in malignant mesothelioma. Imatinib and gefitinib, respectively, block these pathway. However, early studies with these compounds have not yielded convincing results in the treatment of mesothelioma [37].

Data from extensive studies in mouse models have showed that mesothelioma is apparently sensitive to immunotherapy. These findings have been supported by studies in human beings with interferon-alpha, interleukin-2 and macrophage stimulating factors, although standard use in clinical practice is not yet warranted [38]. Recent studies in animals suggest the potential efficacy of the combination of immunotherapy with apoptotic-inducing agents, such as gemcitabine [39].     

Two separate gene therapy approaches to mesothelioma have been tested, involving respectively “suicide gene” and immunomodulatory gene therapy. Encouraging response in small groups of men has been observed [40]. Preliminary results indicate that the presence of multiple telomere maintenance mechanisms and the over-expression of survivin, an inhibitors of apoptosis protein, could be involved, respectively, in the dysregulation of the apoptotic pathways and in the immortalization of mesothelioma cells (unpublished data). This could open new opportunities for the design of novel therapeutic strategies.

Other novel agents are involved  in clinical trials: bevacizumab, thalidomide and PTK/ZK 787 are new antiangiogenetic drugs targeting in part the vascular endothelial growth factor (VGEF) pathway; histone deacetylase and proteosome inhibitors are other drugs blocking specific mesothelioma pathway ([1], [2]).