1 Cancer Treatment Reviews 38 (2012) Contents lists available at SciVerse ScienceDirect Cancer Treatment Reviews journal homepage: Anti-Tumour Treatment Diffuse malignant peritoneal mesothelioma An update on treatment Peyman Mirarabshahii b,c, Krishna Pillai b,c, Terence C. Chua a,b,c, Mohammad H. Pourgholami b,c, David L. Morris a,b,c, a Hepatobiliary and Surgical Oncology Unit, University of New South Wales, Department of Surgery, Sydney, Australia b Cancer Research Laboratories, Department of Surgery, St. George Hospital, Sydney, Australia c St. George Clinical School, University of New South Wales, Kogarah, Sydney, NSW 2217, Australia article info abstract Article history: Received 17 May 2011 Received in revised form 24 October 2011 Accepted 25 October 2011 Keywords: Malignant peritoneal mesothelioma Cytoreductive surgery Hyperthermic intraperitoneal chemotherapy Doxorubicin Pemetrexed Cisplatin Mesotheliomas are aggressive and lethal neoplasms arising from mesothelial cells lining the pleura, peritoneum, tunica vaginalis testis and pericardium. Malignant peritoneal mesothelioma accounts for about 30% of all mesotheliomas. Asbestos is the main known cause of the disease. Presenting symptoms in these patients include: ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting. Electron microscopy, immunohistochemistry, computed tomography scan, echotomography, magnetic resonance imaging, positron emission tomography and laparoscopy are used in diagnosis and follow-up. Chemotherapy alone is considered as a palliative treatment for these patients who are not eligible for radical surgery. The most promising non-surgical approach today in the management of peritoneal mesothelioma is the use of the combination chemotherapy regime of an antifolate (pemetrexed and raltitrexed) and a platinum based (cisplatin) agent with a median survival of about months. Due to peritoneal confinement of malignant mesothelioma and low occurrence of metastasis, a locoregional approach consisting of cytoreductive surgery and perioperative intraperitoneal chemotherapy has been introduced as a curative treatment option over the last decade with an overall 5-year survival rate of 29 63%. In this locoregional approach, surgery can separate the adhesions and remove the bulky tumor, leaving microscopic residual tumors much more susceptible to the killing effect of chemotherapeutic drugs. Here in St. George hospital, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (using cisplatin and doxorubicin) resulted in significant survival advantage. This article describes how the prognosis of the disease has changed over the last decade. Ó 2011 Elsevier Ltd. All rights reserved. Introduction Corresponding author at: Level 3 Pitney Building, Gray Street, UNSW Department of Surgery, St. George Hospital, Kogarah, Sydney, NSW 2217, Australia. Tel.: ; fax: address: (D.L. Morris). Peritoneal mesothelioma was first described by Miller and Wynn in Mesothelioma is an aggressive lethal neoplasm arising from mesothelial cells lining the pleura, peritoneum, tunica vaginalis testis and pericardium. 2 Primary diffuse malignant peritoneal mesothelioma (DMPM) is a rare clinical entity, accounting for about 30% of all mesothelioma, 2 4 in which variable history of pleural plaques and asbestos exposure may be present. 4 The lifetime probability of peritoneal mesothelioma has been reported as 1 per 10,000 women and between 1 and 1.5 per 10,000 in men. 5 In developed countries, malignant mesothelioma is the most frequent malignant neoplasm of the peritoneum. 6 Age-standardized incidence rates range from 0.5 to about 3 cases per million among men and from 0.2 to about 2 cases per million for women. 6 The overall annual incidence of mesothelioma encompassing pleural, peritoneal, and retroperitoneal variants in Australia is 15.8 per million. 7 Annual incidence of DMPM in USA is cases. 8 Women with DMPM have had better survival which may be related to the favourable clinical and histopathological features associated with the tumors in women. 8 Associated tumors with DMPM are colorectal cancer, cheek basocellular carcinoma, papillary thyroid carcinoma, tongue carcinoma, bladder carcinoma, testicular seminoma, lung non-small-cell carcinoma and ileus neuroendocrine carcinoma. 9 Both localized and DMPM form solid masses, but cystic and mucoid regions within the tumor may occur and create a heterogeneous consistency on the cut surface of the tumor. 10 Recurrence rates continue to be very high with significant morbidity. 4 The life expectancy of untreated patients and patients treated with conventional means is 4 12 months. 11,12 However, with the introduction of radical debulking surgery combined with heated intraperitoneal chemotherapy, as described by Sugarbaker group, patients survival has improved. 11 Methods A search was performed on the PubMed database from 1980 to March 2011 using the key words: mesothelioma, peritoneal /$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi: /j.ctrv
2 606 P. Mirarabshahii et al. / Cancer Treatment Reviews 38 (2012) mesothelioma, malignant peritoneal mesothelioma, malignant peritoneal mesothelioma treatment, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy with a focus on epidemiology, pathophysiology and diagnosis of malignant peritoneal mesothelioma. The most important eligibility for selected publications was providing information about treatment options, methods and outcomes, especially, most recent improvements in these areas. Only articles or abstracts published in English were eligible. Pathophysiology Asbestos is the main known cause of the disease, although association between asbestos and DMPM seems to be less strong than in the case of pleural mesothelioma. 6 Only 33% of patients with DMPM report a history of asbestos exposure, 13 and only 23% of women who develop DMPM have been exposed to asbestos. 10 Over 20 million people in the US are at the risk of developing malignant mesothelioma due to asbestos exposure. 14 Three mechanisms have been proposed for carcinogenesis of asbestos: first, genesis of free radicals, by asbestos itself, responsible for coding DNA lesions in different genes implicated in the initiation and proliferation of cancers; second, asbestos mediated local chronic inflammatory release of free radicals and hyper secretion of cytokines and cellular growth factor by effector cells; third, co-carcinogenic effect of asbestos fibres by acting as vectors for carcinogens of chemical origin on target cells. 15 The latent period between asbestos exposure and disease onset averages about years. 16 One hypothesis regarding the origin of DMPM is that ingested asbestos fibres migrate through the bowel wall and then cause local carcinogenesis. 2 In DMPM, the casual link to asbestos exposure is much stronger for men than for women. 17 Ionizing radiation, radiation therapy, mica exposure, recurrent peritonitis, administration of thorium dioxide, simian virus 40 (SV40) and chronic pancreatitis may have some roles in the induction of DMPM. 6,18 Diagnosis The diagnosis of peritoneal mesothelioma is often delayed and peaks at years from the time of initial exposure to asbestos. 3 Presenting symptoms in DMPM patients include: ascites (77%), abdominal pain (69%), asthenia (43%), weight loss (32%), anorexia (30%), abdominal mass (30%), fever (22%), diarrhea (17%) and vomiting (15%), inguinal or umbilical hernia (5 10%) which could be incarcerated, and rarely skin or subcutaneous nodules. 9,19 22 Manzini et al. described a classification of DMPM based survival and its associated clinical presentation consisting of three clinical types: the classical type characterized by abdominal swelling due to ascites and/or an abdominal mass often associated with abdominal pain and weight loss; the surgical type, characterized by a surgical emergency; and the medical case, characterized by fever, diarrhea, weight loss, and acute phase changes, in a clinical picture resembling that of intestinal inflammatory bowel disease. 23 DMPM is categorized into three pathologic subtypes: epithelial (56%), sarcomatous (32%), and mixed (13%). 2 Further, immunohistochemistry has taken over the role of electron microscopy in the diagnosis of DMPM, although the later technique is still considered to be the gold standard for diagnosis. 17 Malignant mesothelioma is characterised by the presence of staining for calrentinin, cytokeratin5/6, EMA, WT1, anti-mesothelial cell antibody-1 and mesothelin with absence of staining of markers for malignancies of the gastrointestinal tract including carcinoembryonic antigen and MOC-31 (or B72.3, Ber-EP4, or BG-8). 13,16,24 Laboratory tests measuring tumor markers such as CA 125, CA 15-3, serum mesothelin-related protein(smrp) and osteopontin are useful in diagnosis and may be suitable in assessing response to treatment and disease progression. 16,25 C-ERC/mesothelin and N-ERC/mesothelin may be very promising tumor markers for mesothelioma. 26,27 However, there are no established reliable immunohistochemical or molecular markers that can differentiate between benign or reactive mesothelial proliferations and diffuse malignant mesothelioma. 28,29 The main differential diagnosis of epithelioid DMPM, the most common histologic type, is with metastatic adenocarcinoma of ovarian, breast, or lung origin, and reactive mesothelium. 17 Measurement of mesothelin concentrations in the pleural and/or peritoneal effusion of patients may aid in the differential diagnosis of mesothelioma in patients presenting with effusions. 30,31 These pathological diagnosis criteria has achieved consensus opinion at the International Mesothelioma Interest Group meeting. 32 A separate distinct entity of mesothelioma is the multicystic subtype. This pathologic subtype of mesothelioma is regarded as a borderline malignant tumor for which was studied in a collaborative institutional registry by the Peritoneal Surface Oncology Group International. 33 Radiological assessment is usually carried out using computed tomography (CT) scan, but more recently magnetic resonance imaging (MRI), positron emission tomography (PET) have also been utilized. 9 Radiographically, DMPM may have multiple manifestations on CT, which include thickening of the peritoneum, mesentery and pleura, nodules of varying sizes and shapes, mesenteric or omental infiltrations, omental caking, ascites, bone destruction and lymphadenopathy. 4,16,34 The most common sites of positive lymph node are the external, internal and common iliac lymph nodes and ileo-colic lymph nodes. 35 CT findings of recurrent malignant peritoneal mesothelioma may vary with different patterns of peritoneal involvement. Although, ascites is the most common finding and in the majority of patients, recurrence is confined to peritoneal cavity, it may be accompanied by solid peritoneal involvement. 4 There are three types of CT appearance of DMPM: dry painful type is the most common, in which CT shows a large mass or multiple small peritoneal masses in an abdominal quadrant, with no sign of ascites; the wet type is associated with intestinal distension and ascites, widespread small nodules and plaques, and no solid masses; and finally, mixed type. 1 Oesophagoduodenoscopy and colonoscopy are commonly performed to exclude an intraluminal lesion in the stomach (gastric cancer) and bowel (colon cancer). 16 Laparoscopy may be used to assess and stage patients with peritoneal surface malignancies. Today, the minimally invasive technique of laparoscopy is considered the diagnostic tool of choice, 9,16,36 where tumor biopsy may be obtained to provide a definitive diagnosis through pathological and immunohistochemical examination. 2 In nearly all cases, malignant mesothelioma demonstrate clonal cytogenetic aberrations indicative of malignancy, of which the more common aberrations include deletions of 1p, 3p,6q, 9p, 22q, and trisomy 7, which can be detected by fluorescence using a combination of appropriate probes. 28 The peritoneal cancer index (PCI) is an assessment combining lesion size (lesion size 0 3) with tumor distribution (abdominopelvic region 0 12), to quantify the extent of disease as a numerical score (PCI 0 39). 37 It is, the summation of lesion-size score (LS-0 Table 1 Tumor-node-metastasis (TNM) staging system for diffuse malignant peritoneal mesothelioma. Stage Tumor Node Metastasis I T1 N0 M0 II T2-3 N0 M0 III T4 N0-1 M0-1 T1-4 N1 M0-1 T1-4 N0-1 M1
3 P. Mirarabshahii et al. / Cancer Treatment Reviews 38 (2012) no visible tumor, LS-1 tumor nodules <0.5 cm, LS-2 tumor nodules between 0.5 cm and 5 cm and LS-3 tumor nodules>5 cm) in each of 13 abdominopelvic regions with a maximal score of A recently published staging system for DMPM includes the peritoneal cancer index, lymph node involvement and extra-abdominal metastasis. This staging system evaluated in a multi-institutional registry has been shown to stratify survival by stage with stage I, II and III disease having a 5-year survival of 87%, 53% and 29% respectively. This staging system should now be universally applied in patients with DMPM (Table 1). 39 Treatment Curative locoregional therapy In the past, DMPM was treated at most cancer centres with a combination of systemic chemotherapy, palliative surgery and in a few patients total abdominal radiation which may achieve a median survival of 12 months. 18 Due to peritoneal confinement of DMPM and low occurrence of distant metastasis, a locoregional approach consisting of cytoreductive surgery (CRS) plus perioperative intraperitoneal chemotherapy has been introduced as a curative treatment strategy over the last decade. 18,40 43 Based on the anatomic location of the tumor distribution, cytoreductive surgery removes as much visible tumor as possible, may require up to six peritonectomy procedures consisting of: greater omentectomysplenectomy, left upper quadrant peritonectomy, right upper quadrant peritonectomy, lesser omentectomy-cholecystectomy with stripping of omental bursa, pelvic peritonectomy with sleeve resection of the sigmoid colon and antrectomy, to resect or strip cancer from all intraabdominal surfaces. 44,45 It has been shown in the experience of the National Cancer Institute of Milan that pathologically negative lymph nodes as compared to patients who had a positive lymph node and those who did not have lymph node examination was associated independently with survival in DMPM. 46 Completeness of cytoreduction score (CCR score) is used to record the volume of residual disease following CRS (Table 2). 37 As the completeness of cytoreduction is the single most dominant factor influencing survival after treatment, the ability to achieve this preoperatively may best be predicted by a diagnostic laparoscopy to select appropriate patients for surgery. 47 Intraperitoneal chemotherapy The new concept in chemotherapy in this field is that, not only multiple agents are required but also multiple routes of administration are needed in the treatment of peritoneal surface malignancy. 48 From a theoretical perspective multi-agent chemotherapy used by multiple routes of administration and targeted to the peritoneal surface by hyperthermia may result in an optimal combination of cancer therapy and hyperthermia in patients with peritoneal carcinomatosis. 48 Thermal enhancement of many chemotherapeutic agents was maximized at temperatures between 40.5 C and 43 C and referred to as moderate hyperthermia. 48 Hyperthermic intraperitoneal chemotherapy (HIPEC) is performed intraoperatively. This has been referred to using several different nomenclatures including heated intraoperative intraperitoneal chemotherapy Table 2 completeness of cytoreduction (CCR) score. CCR score Residual tumor nodule diameter 0 No visible tumor 1 <2.5 (mm) 2 Between 2.5 (mm) and 2.5 (cm) 3 >2.5 cm or a confluence of tumor nodules remaining at any site (HIIC), intraperitoneal hyperthermic chemoperfusion (IPHC). 49 In this review HIPEC is used. At present, HIPEC consists of instillation of heated chemotherapy directly to peritoneal cavity during operation (at the end of cytoreductive surgery) with or without early postoperative intraperitoneal chemotherapy (EPIC). Two methods (closed and open) have been used in HIPEC. Begossi et al. has suggested that the open technique is superior to the closed technique in allowing adequate and uniform exposure of all the abdominal and pelvic surfaces to intraperitoneal chemotherapy, as demonstrated by the dye studies. 50 In a study, after finding wide variation of temperatures in closed methodology of HIPEC, Elias et al. recommended the use of an open abdomen technique with manual distribution of heat and chemotherapy solution. 51 The confinement of disease within the peritoneal cavity allows the use of intensified locoregional chemotherapy that avoids the toxicity observed in systemic administration. 52 Nevertheless, eventual drug clearance still occurs through systemic routes after absorption through the peritoneal plasma membrane, hence, the safe dose of most drugs instilled into the peritoneal cavity is identical to the intravenous doses. The exceptions are drugs with hepatic metabolism, such as 5-fluorouracil and gemcitabine. 38 The advantages of CRS and HIPEC are: first, surgery can separate the adhesions and remove the bulky tumor, leaving microscopic residual tumors much more susceptible to the killing effect of chemotherapeutic drugs; second, intraperitoneal chemotherapy in comparison with systemic chemotherapy provide a much higher concentration of intraperitoneal drug at tumor bearing sites and lower systemic side effects. this preferential high intraperitoneal concentration of drug can occur with gemcitabine, doxorubicin, melphalan, mitomycin c, cisplatin, mitoxantrone, oxaliplatin, etoposide, irinotecan, paclitaxel, docetaxel, 5-flurouracil, floxuridine and carboplatin; third, heat increases the cytotoxic effect of chemotherapy agents and penetration of chemotherapy into cancerous tissue. 48,53 Contraindications As the combined treatment involves extensive surgical resections followed by a course of chemoperfusion with hyperthermia, it is considered an intense treatment that will exert an enormous stress on the body. 54 Hence, patients should be carefully evaluated for co-morbid illnesses that would make them an unacceptable operative risk, and subsequently, CT scan and possible laparoscopy should be performed to assess resectability with the appreciation that patients with suboptimal resection do very poorly. Based on the experience of Gomez-Portilla et al., the authors observed that the poor outcomes and aggressive tumor behaviour by biphasic and sarcomatous that these two subtypes should be excluded. 55 Table 3 lists the contraindications of CRS plus HIPEC. 53 Different protocols for combination therapy Begossi et al. divided CRS and intraperitoneal chemotherapy into four major steps: electrosurgery for tumor resection and Table 3 Contraindication of CRS plus HIPEC. Medically unfit patients Extra abdominal disease Parenchymal hepatic metastases Bulk retroperitoneal disease Incomplete resection of peritoneal tumor or inability to reduce tumor effectively Age over 70
4 608 P. Mirarabshahii et al. / Cancer Treatment Reviews 38 (2012) peritonectomy; hyperthermic intraperitoneal chemotherapy; reconstruction; and early postoperative intraperitoneal chemotherapy. These authors believed that heat necrosis and further locoregional chemotherapy could reduce the likelihood of cancer dissemination and local recurrence. According to their protocol, approximately 24 h after surgery, early postoperative intraperitoneal chemotherapy is initiated by clamping of the surgical drains for 23 h and unclamping to drain over an hour with repeating of this sequence for the next five consecutive days. 50 Esquivel et al. have opened a protocol in which patients with peritoneal surface malignancies and no gross evidence of carcinomatosis on their CT scans will undergo a diagnostic laparoscopy, if indeed they have low-volume carcinomatosis, as defined by peritoneal cancer index equal or less than 10, then the procedure will continue laparoscopically. The HIPEC regime used in this study was cisplatinum and adriamycin for 90 min at 43 C. 56 For heated intraoperative intra peritoneal chemotherapy, mitomycin C (between 10 and 30 mg/ m 2 ) is the most frequently used chemotherapy agent, and a second regimen that has been extensively used clinically is a combination of cisplatin 50 mg/m 2 and doxorubicin 15 mg/m One major problem in treatment of patients with DMPM has been the recurrence of tumor in surgery incision sites. It is believed that the addition of HIPEC and EPIC (as part of intraperitoneal chemotherapy) will reduce the risk of this occurrence. 51 A generic schematic representation of potential treatment approaches of the combination therapy is shown in Fig. 1. Intraperitoneal doxorubicin has shown a prolonged retention in the peritoneal cavity and its concentration in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min.the pharmaco-dynamic profile of doxorubicin showed an unexpected sequestration of the drug in the tumor nodules. 57 Also, it has been reported that the extremely high area under curve (AUC) ratio of intraperitoneal chemotherapy concentration to plasma concentration seen with paclitaxel recommends it for early postoperative intraperitoneal chemotherapy. 18 In 2002, Sugarbaker et al. suggested cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel as a combination therapy for DMPM. 58 According to Mohamed et al., in physically fit patients who are responding well to therapy, a second-look surgery is often recommended. 59 They proposed cytoreductive surgery, HIPEC with cisplatin 50 mg/m 2 and doxorubicin 15 mg/m 2 and early postoperative intraperitoneal chemotherapy with paclitaxel 20 mg/m 2 and long-term intraperitoneal chemotherapy with paclitaxel starting from 6 8 weeks after discharge from hospital and recommended to continue aggressive locoregional treatment strategy. Their goal of treatment was to use surgery and regional chemotherapy maximally in every patient to the limit of patient tolerance. Indeed they reported a more systematic approach to peritoneal mesothelioma with debulking surgery and systemic chemotherapy, including paclitaxel, cisplatin, or doxorubicin. 59 Yan et al. proposed after CRS, HIPEC with doxorubicin (15 mg/m 2 ) and cisplatin (50 mg/m 2 ) is administered at approximately 42 C in 1.5% dextrose peritoneal dialysis solution for 90 min. 49 They also suggested EPIC with paclitaxel as being used as the standard treatment for patients with DMPM. 49 At the National Cancer Institute of Milan, Deraco et al. enrolled DMPM patients to undergo CRS and HIPEC with cisplatin(25 mg/m 2 ) and mitomycin C(3.3 mg/m2) or cisplatin (43 mg/m 2 ) and doxorubicin(15.25 mg/l). 60 This group also further treatment patients with small bowel disease and histologically aggressive tumors (nuclear size 3 or 4) with systemic pemetrexed and cisplatin preoperatively prior to the combined treatment. 61 Our experience The various intraperitoneal chemotherapy regimens used in our centre for HIPEC consist of mitomycin c, cisplatin, doxorubicin/cisplatin, or mitomycin c/cisplatin and 5-FU for EPIC. 11 The suitability to undergo treatment is based on the patients performance status, inter-current co-morbidities, extent of disease on computed tomography (CT) scan and feasibility of maximal cytoreduction. 12 Prior to treatment, all patients undergo a physical examination, blood tests, including full blood count, serum electrolytes and creatinine, liver function tests and tumor markers (CA 125, CA19.9, CEA and afp). Imaging tests include oral and intravenous contrast CT scan of the chest, abdomen and pelvis. The cytoreductive procedure is performed according to Sugarbaker s techniques. 45 For DMPM, we use an open technique for HIPEC with cisplatin (50 mg/m 2 ) and doxorubicin (15 mg/m 2 ) in 3L of 1.5% dextrose peritoneal analysis solution at 42 C for 90 min with stirring performed every 15 min to improve drug distribution. 12 Prognosis Fig. 1. Schematic treatment pathway for diffuse malignant peritoneal mesothelioma combining cytoreductive surgery and intraperitoneal chemotherapy. Cerruto et al. identified histomorphological parameters in DMPM to have an important role in predicting survival of this rare entity if a uniform management plan is used. 62 According to their study, type and nuclear/nucleolar size are the most important variables that determine survival. 62 Validated clinicopathologic prognostic factors of poor survival for DMPM are non-epithelioid tumor type, poor performance status, male gender, high white blood cell count, and low haemoglobin levels. 17 Based on a proposed TNM staging system for peritoneal mesothelioma median survival for stage 1, 2, 3 and 4 respectively is: 52, 32.5, 15.5 and 13.5 months. 63 Before locoregional approach survival in DMPM ranged from 7 to 13.5 months. 59 The overall 5-year survival year rate following complete cytoreductive surgery with intraperitoneal chemotherapy reaches 29 63%. 64 Table 4 shows the survival rates in key publications reporting outcomes of CRS and HIPEC for DMPM patients. In a study by Sebbag et al., positive predictive factors of survival which were identified by univariate analysis included female sex, good health status, minimal previous surgery, low peritoneal cancer index, complete cytoreduction and undergoing second-look surgery correlated with improved survival. 65 From
5 P. Mirarabshahii et al. / Cancer Treatment Reviews 38 (2012) Table 4 Results of locoregional surgery for DMPM (NR refers to not reported). Treatment centre the same institution, multivariate analysis demonstrated that lymph node metastasis not detected; female gender; epithelial type; and adequate cytoreduction were independently associated with an improved survival. 35 A recent systematic review of cytoreductive surgery and perioperative intraperitoneal chemotherapy for malignant peritoneal mesothelioma from seven observational studies reported a median survival time ranging from 34 to 92 months. 66 Morbidity and mortality Two significant predictive factors for major morbidity in this treatment are the number of surgical anastomoses and extent of cytoreduction. 67 Common post-operative complication include prolonged intestinal ileus and infections secondary to intraabdominal collection. Other complications include intestinal perforation, fistula, bile leakage, pancreatitis, urinary tract infection, pneumonia, deep vein thrombosis/pulmonary emboli and bleeding. 53 The main chemotherapy related side effects are bone marrow suppression and renal insufficiency mostly with use of cisplatin. 53 Fluid resuscitation is of paramount importance in these patients because of the fluid losses from ongoing surgery, blood loss, and hyperthermia, and often patients require more than L of fluid resuscitation. 67 Additionally, systemic hyperthermia from the hyperthermic peritoneal chemoperfusion can cause adverse effects such as a hyperdynamic state, cardiovascular compromise, and organ injury resulting from cellular and enzymatic dysfunction, so interventions to keep the core body temperature in the normal range during hyperthermic peritoneal perfusion are critical to avoiding these disturbances. 67 The morbidity rate of 25 40% and mortality of 0 8% may be acceptable in light of current standards for management of advanced gastrointestinal cancer, but can be reduced with improved patient selection, technical skills, intraoperatively and postoperative care. 18 A low colorectal anastomosis, more than four peritonectomy procedures in an operation, operative duration greater than seven hours are associated with major complications. 68 From our experience, majority of morbidity results from intra-abdominal collections. Systemic chemotherapy Patients (n) Median survival (months) Wakeforest University Baptist Medical Centre 89 National Cancer Institute Milan Basingstoke and North Hampshire NR Foundation Trust 90 Institut Gustave-Roussy Washington Hospital Center Centre Hospitalier Universitaire de Strasbourg 93 National Institute of Health Bethesda St George Hospital Sydney NR 5-Year survival (%) Chemotherapy alone is considered a palliative treatment for DMPM patients who are not eligible for radical surgery. The most promising non-surgical approach today in the management is the use of the combination chemotherapy comprising of pemetrexed and cisplatin or gemcitabine. This combination regime has been shown to result in a median survival of about months. 12,69,70 In the single randomized phase III trial examining the role of pemetrexed in combination with cisplatin, the median survival of 12.1 months in the combination arm compared to 9.3 months in the cisplatin alone arm (p = 0.02). 71 This trial led to the recognition of the role of pemetrexed in the treatment of mesothelioma. However, the rarity of this disease has limited replication of this trial and the use of this drug is now approved by the United States Food and Drug Administration and Eli Lilly Company for use under an Expanded access program, allowing its use in patients with mesothelioma where there is no other treatment or satisfactory alternative therapy before formal approval. This initiative has become an international program and is also widely adopted in major European cancer treatment centres. In a large study of this expanded access program in the United States, Janne et al. reported outcome data of 1056 patients with malignant mesothelioma who received at least one dose of treatment and demonstrated a disease control rate defined by complete response, partial response and stable disease achieved in 71.2% of patients with a median survival of 13.1 months. 72 Specific to DMPM, 109 patients received pemetrexed and the outcomes were reported by Carteni et al. 73 demonstrating an overall response rate of 18.7%, overall disease control rate of 68.1%, and an overall 1-year survival rate of 47.4%. The estimated median survival in this cohort is likely to be about 12 months which is similar to a previously reported study in the United States using the Expanded Access Program for pleural mesothelioma. 72 More recently, Simon et al. 74 reported a small phase II multicentre trial of pemetrexed in combination with gemcitabine. This regimen results in a high incidence of neutropenia that led to one treatment related mortality (5%) but achieved substantial survival gains with a median time to progressive of 10.4 months and an overall survival (OS) of 26.8 months. This result by far represents the best documented result of survival from systemic chemotherapy treatment of mesothelioma. In elderly and unfit patients, it is suggested that single-agent pemetrexed (500 mg/m 2 i.v. every 3 weeks) may be considered. 13 In a study of 81 patients with DMPM from 14 institutions in Italy, most common regimes comprised of pemetrexed and cis/carboplatin or gemcitabine and cis/carboplatin. 9 On an experimental note, Kusama et al. described a case of recurrent sarcomatoid MPM which recurred 22 days after surgery, and treatment with an aggressive combination of chemotherapy of cyclophosphamids, vincristine, adriamycin and dacarbazin (CYVADIC) showing a remarkable reduction of tumor burden after two cycles, but yet unfortunately recurred again. 75 Very recently, it has been shown that premetrexed plus cisplatin accomplish a particularly high clinical benefit rate on chemo-naïve patients. 76 It must be noted that the effect of third space fluid (ascites or pleural effusion) on pemetrexed is unknown and dose reduction may be exercised at the commencement of treatment to avoid toxicity. Intraperitoneal (i.p.) administration of cytotoxic agents could, theoretically, improve their therapeutic activity. 77 For example, the i.p. administration of cisplatin yielded an i.p. concentration that was folds higher than the plasma concentration. 77 Epinephrine was thought to improve the depth of platinum compound diffusion, both by limiting the drainage of the drug through the peritoneal and tumor vasculature (the draining off hypothesis), and by decreasing the high interstitial pressure in solid tumors. One-five (mg/l) of epinephrine could be infused into the peritoneal cavity of patients with peritoneal carcinomatosis, which are probably sufficient for maintaining a constant vasoconstriction of the peritoneal and tumoral microvasculature bed, and this may enhance the penetration of cisplatin into peritoneal tumor nodules. 77 Laparoscopic intraperitoneal chemotherapy (with cisplatin and doxorubicin) may be a good therapeutic option to palliate malignant ascites in patients not eligible for a radical cytoreductive
6 610 P. Mirarabshahii et al. / Cancer Treatment Reviews 38 (2012) treatment, preliminary data indicate that it may potentially result in dramatic reduction of ascites and provide symptomatic relief in patients with debilitating malignant ascites. 78,79 These results remain preliminary and require further investigation. With a molecular weight of and a 24-fold increase exposure of peritoneal surfaces with intraperitoneal administration compared with intravenous administration of pemetrexed may make it suitable for intraperitoneal delivery. 80 In one study, combination use of pemetrexed and cisplatin showed a partial response in four of seven patients (57%) with mesothelioma. 80 In summary, agents commonly used in systemic chemotherapy regimens include combination of cisplatin, irinotecan, cyclophosphamide, doxorubicin, dacarbazine, gemcitabine and pemetrexed. 16 Although not commonly used, the combination of radiotherapy and intraperitoneal chemotherapy may be a suitable option in the palliative setting primarily aimed at prolonging survival. 81 Targeted therapy It has been suggested that piroxicam sensitizes mesothelioma cells to cisplatin by modulating the expression of several target genes. 82 Therapeutic value of targeting different receptor tyrosine receptors, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and mesenchymal-epithelial transition factor (MET) may prove to be beneficial in combination with chemotherapy. 17 Bortezomib, a proteasome inhibitor, was reported to induce cell cycle arrest and apoptosis in mesothelioma cell lines in vitro, which was also observed in vivo, probably via blocking of the nuclear factor-kappab (NF-jB) transcription factor. 17 ZD1839, an inhibitor of epidermal growth factor receptor, imatinib mesylate, an inhibitor of tyrosine kinases associated with platelet derived growth factor receptor, and drugs targeting vascular endothelial growth factor like SU5416, thalidomide and bevacizumab are also proposed for mesothelioma treatment. 83 Zaffaroni et al. reported that surviving as well as other inhibitors of apoptosis proteins, are largely expressed in clinical DMPM and suggests that strategies aimed at down-regulating surviving may provide a novel approach for the treatment of the malignancy. 84 Also, Xia et al. reported that frequent surviving expression was found in mesothelioma cell lines and solid tumors, and blocking of surviving by antisense oligonucleotides induced apoptosis in the MS-1 and H28 MM cell lines. 85 Considering that mesothelin is highly expressed in epithelial malignant mesothelioma, Hassan et al. described three mesothelin targeted agents: SS1P a recombinant immunotoxin targeting mesothelin, MORAb-009 a chimeric anti-mesothelin monoclonal antibody and CRS-207 a live-attenuated listeria monocytogenes vector encoding human mesothelin. 86 Continuous infusion of anti-mesothelin recombinant immunotoxin SS1P (25 lg/kg/d x10) in a patient with peritoneal mesothelioma who had severe ascites before SS1P requiring frequent paracentesis and profound hypoalbuminemia led to resolution of ascites and for which the response lasted for several months. 87 A recent study has demonstrated that CA125 binds mesothelin, thus playing a likely role in cancer dissemination within the peritoneal cavity and being a potential target for antibody-based treatment. 88 Conclusion Diffuse malignant peritoneal mesothelioma is a progressive and ultimately fatal disease. In recent years, our better understanding of the tumor biology and clinical behaviour of this disease has led to improved treatment strategies aimed at controlling the disease. The biggest accomplishment in this disease to improve survival by far may be attributed to combined cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy. Institutional data from a number of major treatment centres indicate that in well selected patients, this treatment may achieve a 5-year survival of 47% as indicated in the multi-institutional registry study. Conflict of interest No potential conflicts of interest relevant to this article were reported. Acknowledgement Peyman Mirarabshahi is supported by an Australian Postgraduate Scholarship Award. References 1. Bridda A, Padoan I, Mencarelli R, Frego M. Peritoneal mesothelioma: a review. Med Gen Med 2007;9(2): Tanida S, Kataoka H, Kubota E, Mori Y, Sasaki M, Ogasawara N. 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