Advances in the management of peritoneal mesothelioma

Abstract

Malignant peritoneal mesothelioma (PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be suggested by occupational exposure history, but ultimately relies heavily on imaging and diagnostic biopsy. Early treatment options including palliative operative debulking, intraperitoneal chemotherapy, and systemic chemotherapy have marginally improved the natural course of the disease with median survival being approximately one year. The advent of cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has dramatically improved survival outcomes with wide median survival estimates between 2.5 to 9 years; these studies however remain largely heterogeneous, with differing study populations, tumor biology, and specific treatment regimens. More recent investigations have explored extent of cytoreduction, repeated operative intervention, and choice of chemotherapy but have been unable to offer definitive conclusions. CRS and HIPEC remain morbid procedures with complication rates ranging between 30% to 46% in larger series. Accordingly, an increasing interest in identifying molecular targets and developing targeted therapies is emerging. Among such novel targets is sphingosine kinase 1 (SphK1) which regulates the production of sphingosine-1-phosphate, a biologically active lipid implicated in various cancers including malignant mesothelioma. The known action of specific SphK inhibitors may warrant further exploration in peritoneal disease.

Key Words: Peritoneal mesothelioma; Mesothelioma; Hyperthermic intraperitoneal chemotherapy; Cytoreduction; Sphingosine kinase; Sphingosine-1-phosphate; FTY720

Core tip: Peritoneal mesothelioma (PM) historically has been associated with a very poor prognosis. Cytoreduction with hyperthermic intraperitoneal chemotherapy improved survival outcomes but carries significant morbidity. Increasingly, research has focused on identifying molecular targets and only a handful have been described; even fewer directed therapies have been evaluated. We review the role of sphingosine kinase 1 and sphingosine-1-phosphate (S1P) signaling in PM and discuss the possibility of targeting it with FTY720, a functional antagonist of S1P Receptor 1. Further investigation is warranted in this new avenue of interest.

INTRODUCTION

Epidemiology of peritoneal mesothelioma

Peritoneal mesothelioma (PM) represents the second most common site of malignant mesothelioma and accounts for 10% to 20% of reported cases[1,2]. Of the 10589 patients with mesothelioma identified in the SEER database between 1973 and 2005, 1112 or 10.5% had disease which was abdominal in origin. Modest differences in incidence rates have been reported among Western countries ranging between 0.5 to 3 cases per million[3]. In the United States, the overall incidence has remained unchanged but age adjusted rates have demonstrated a stepwise increase per decade with 15000 cases projected to occur by 2050[3-5]. Males constitute 56% of cases; compared to those with thoracic disease, patients with PM are more likely to be female[6] and younger[7]. No racial predilection has been recognized[2,4].

Asbestos exposure is the strongest known risk factor for the development of malignant mesothelioma[5]. The association with peritoneal disease, while observed in various epidemiological reports, however, is weaker and not conclusive[3,8]. Factors abating this relationship have included long latency periods of 20 to 50 years from exposure to disease and lack of pathogenesis directly implicating asbestos fibers[8,9]. There is some evidence, however, to suggest that cumulative exposure has been associated with increased prevalence. Berry et al[10] studied the exposure of crocidolite among miners over several decades. More than 67% of identified cases of peritoneal mesothelioma occurred with an exposure of greater than 50 fibers per mL years; this was in contrast to only 16% subjects who developed disease with less than 10 fibers per mL years of exposure. Likewise, no cases of PM were observed within 20 years of exposure. Various other environmental factors have been implicated and include thorotrast, erionite - volcanic ash, therapeutic radiation, and chronic peritonitis[3,11]. In the absence of environmental exposures, familial Mediterranean fever, mesothelioma genetic susceptibility syndrome with BRCA germline mutations, and simian vacuolating virus have been postulated to contribute to PM[2,12].

Presentation and diagnostic workup

Symptoms and signs are non-specific with most relating increasing abdominal girth, ascites, or pain[12,13]. Other reported findings have included weight loss, fevers, night sweats, early satiety, anorexia, emesis, constipation, and presence of umbilical hernia; an abdominal mass was appreciated in 10%-30%[13,14]. Computed tomography (CT) imaging is the most common initial imaging modality and can reveal moderate to extensive ascites with peritoneal, visceral, or omental involvement. Yan et al[15] reported that CT radiographic findings of large tumor burden with significant bowel distortion or the presence of a small bowel obstruction to be predictive of incomplete resectability. MRI imaging may more accurately quantify the extent of disease, however, its routine use is not supported yet[16]. The role of PET scan is not well defined and may be have some limited use in the detection of recurrent disease[17]. Biopsy is required to establish a diagnosis and can be performed radiographically or surgically. Paracentesis with fluid cytology has a variable sensitivity of 32% to 76% with the major limitation being difficulty in distinguishing benign from malignant lesions[2,18]. Various serum tumor markers have also been explored. CA-125 and CA15.3 were noted to be elevated at baseline in 53.3% and 48.5% of patients; their role, however, may be more important in monitoring disease recurrence or progression than at initial diagnosis[19,20].

TREATMENT

Outcomes of conventional treatment

Traditional treatments for peritoneal mesothelioma have historically yielded modest survival ranging between 6 and 16 mo with median survival being approximately one year[21,22]. Operative therapies have largely centered around palliative cytoreduction. Rogoff et al[23] reported one of the earliest series with 6 of 12 patients undergoing debulking with a median survival being no greater than 13 mo for the entire cohort. More recent series have reported similar median survival periods of one year[13,24,25]; compared with operative biopsy alone, however, debulking offered a modest survival improvement of 7 mo[24]. The use of conventional systemic chemotherapy likewise has not greatly impacted the natural course of PM with response rates between 11% and 28%[26-28]. More recent novel cytotoxic agents like premetrexed have improved response rates to as high as 37% with median survival ranging between 7.6 and 12.1 mo with dual agent regimens; Simon et al[29] reported an improved survival period of 26.8 mo with gemcitabine combination therapy in 20 patients but regimen was accompanied with a 60% incidence of grade 3 or 4 neutropenia[27-29]. Monotherapy with intraperitoneal chemoinfusion has likewise not offered any significant benefit with reported outcomes of 9 to 12 mo[30,31].

Cytoreduction with hyperthermic intraperitoneal chemotherapy

Cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been more widely adopted over the last 15 years and has been campaigned as the standard of care for patients with operable disease[1]. Ma et al[32] was the first to report its technical efficacy in ten patients in 1997; he reported no treatment related mortality and symptomatic ascites palliation in 7 patients. Two years later, Park et al[33] reported on 18 patients undergoing CRS + HIPEC with a two year survival rates of 80% and progression free survival of 26 mo. In studies reporting at least 2 year outcome data, median survival has varied greatly ranging between 29.5 and 100 mo and five year overall survival between 30%-90% when reported (Table 1). The wide range of these findings reflects the heavily heterogeneous nature of differing study populations, eras of treatment, institutional follow-up protocols, chemotherapy regimens, operative techniques, and tumor biology. The most numerous reports have been coordinated or originated mainly from two principal centers: the National Cancer Institute of Milan (Milan, Italy) and the Washington Cancer Center (Washington, DC, United States). Larger series, however, have relied on appropriate collaborative approaches[20,34-45]. Yan et al[42] published the largest longitudinal series with 405 patients in a multi-institutional review between 1989 and 2009. Here, 92% of patients received HIPEC most commonly with cisplatin and doxorubicin and an additional 23% subsequently received early post-operative chemotherapy between postoperative day 1 and 5, most commonly with paclitaxel. Overall median survival was 53 mo and five year survival was 47%. Such multi-institutional registries have gone onto be utilized in assessing large-population based prognostic factors[43,46,47].

Table 1 Selected studies examining overall survival with cytoreduction and hyperthermic intraperitoneal chemotherapy.

Ref.	Year	Era	Sample No.	Age	Gender (female)	HIPEC Agents	Histological Subtype or Grade	Follow-up	Median survival	1 yr	2 yr	3 yr	5 yr	7 yr	10 yr
Park et al[33]	1999	1993-1998	18	47	28%	CDDP	9 E, 3 mixed 1 MMF 1 cystic 4 Unk	19	NR		80
Loggie et al[112]	2001		12	511	8%	MMC	Not stated	45.2	34.2	60	60	50	33	33
Feldman et al[48]	2003	1993-2002	49	47	43%	CDDP	26 E, 4 S 16 TP 1 adenomatoid	28.3	92	86	77	59	59
Costamagna et al[61]	2003	1995-2003	24			CDDP + DOXO, single agent MMC or DOXO			40	78	70	70	52
Brigand et al[6]	2006	1989-2004	15	53.6	29%	CDDP + MMC	12 E, 2 B 1 MC	46.7	35.6	69.3	57.7	43.3	28.9
Elias et al[60]	2007	1996-2005	26	461	46%	oxaliplatin + irinotecan, single agent oxaliplatin or DOXO	13 E, 1 B 11 TP, 1 MC	55	100	88	83	68	63
Gómez Portilla et al[113]	2007	1998-2005	7	501	43%	CDDP + DOXO, single agent MMC or oxaliplatin	5 E, 2 B	11	NR	43	43	43	43
Hesdorffer et al[55]	2008	1997-2000	27	531	26%	CDDP + MMC	23 E, 4 S		70			67%
Passot et al[114]	2008	1989-2006	22			CDDP + MMC	16 E, 3 B 3 MC	47	36.9	69	62	52	31
Chua et al[115]	2009	1997-2008	20	55.71	30%	CDDP + DOXO	16 E, 1 B, 2 S 1 MC	18.1	29.5	78.2		46.3
Blackham et al[49]	2010	1993-2008	34	54.91	32%	CDDP or MMC	29 E, 4 B 1 Unk	72	40.8	61		56	17
Kluger et al[54]	2010	1997-2004	47	491	36%	CDDP + MMC	43 E, 4 B	54	54.9	80.9		61.7	48.9
Cao et al[46]	2012	1989-2009	294	50	46%	CDDP + DOXO2	259 E, 27 B/S 8 Unk	25	67	83	62	52
Alexander et al[47]	2013	1992-2010	211	52	60%	CDDP or MMC	113 High, 54 Low 44 Unk		38.4				41		26
Schaub et al[59]	2013	1994-2010	104	50.9	39%	CDDP	90 E, 14B/S	49.4	52			58	46
Wong et al[52]	2013	2004-2012	26	64	38%	CDDP	15 E, 3 B 1 MMF 3 WD, 1 cystic 3 Unk		41.2
NMDeraco et al[37]	2003	1995-2002	19	491	53%	CDDP + MMC or DOXO	13 E, 1 S, 1 mixed 2WD, 2MC	27	NR			69
NMDeraco et al[39]	2003		28		61%								70
NMDeraco et al[38]	2003		61	511	49%	CDDP + MMC or DOXO		20					54
NMDeraco et al[40]	2006	1995-2005	49	521		CDDP + DOXO or MMC	43 E, 6 B	20.31					57
NMDeraco et al[50]	2013	1995-2011	116	54.41	48%	CDDP + DOXO or MMC	105 E, 11 B/S	32.91					49
NMBaratti et al[20]	2007	1997-2005	60	53.5	60%		43 E, 6 B 5 MC, 6 P	23					53.7
NMBaratti et al[36]	2007	1995-2006	12	38	100%	CDDP + DOXO	4 MC, 8 WD	27	NR				90
NMBaratti et al[35]	2010	1996-2008	83	54	55%	CDDP + MMC or DOXO	72 E, 10 B, 1 S	52	44				49.5		45.5
NMBaratti et al[34]	2013	1996-2012	108	56.5	46%	CDDP + DOXO or MMC	93 E, 14 B, 1 S	48.8	63.2				52.4		44.6
WCYan et al[45]	2006		100	501	40%	CDDP + DOXO	86 E, 7 B/S 7 Unk	48	52	78		55	46	39
WCYan et al[44]	2007	1989-2005	70	471	43%	CDDP + DOXO	65 E, 5 B	35	59	82	67	57	49
WCYan et al[41]	2007	1989-2005	62	471	45%	CDDP + DOXO	57 E, 5 B	37	79	84		58	50
WCYan et al[42]	2009	1989-2009	401	501	44%	CDDP + DOXO2 or MMC, single agent CDDP or MMC	318 E, 48 B/S 35 Unk	33	53	81		60	47
WCYan et al[43]	2011	1989-2009	294	501	46%	CDDP + DOXO2	259 E, 27 B/S 8 Unk	24	67	83	62	52

¹Mean values are indicated with an asterisk. Follow-up and survival are reported in months;

²Most common chemotherapy agent reported. The principal centers including the National Cancer Institute of Milan and the Washington Cancer Center are noted with superscripts NM and WC, respectively. NR: Not reached; CDDP: Cisplatin; MMC: Mitomycin or Mitomycin C; DOXO: Doxorubicin; E: Epithelial or epithelioid subtype; B: Biphasic; S: Sarcomatoid or sarcomatous; B/S: Biphasic or sarcomatoid; MMF: Malignant or epithelial with mucinous features; MC: Benign multicystic; TP: Tubillopapillary; P: Papillary or mixed papillary; WD: Well-differentiated; Unk: Unknown or not specified.

Reports describing long term survival at 10 years are slowly emerging. Two studies listed survival estimates as secondary outcomes and ranged between 26% and 44.6%[35,47]. Baratti et al[34] reported on 10 year prognosis in 108 patients undergoing complete cytoreduction and HIPEC at two centers. Chemotherapy regimens included cisplatin and doxorubicin in the vast majority of patients and cisplatin or mytomycin-C in six. At five and ten years, overall estimates were 52.4% and 44.6%, respectively, and median survival was 63.2 mo.

The most optimistic, large series survival estimates were reported by Feldman et al[48] in 49 patients. More than half of patients had previously undergone debulking surgery, and thereafter, all subjects underwent HIPEC with cisplatin. Thirty five patients or 72% additionally received a single postoperative intraperitoneal (IP) dose of fluorouracil and paclitaxel. Median overall survival was 92 mo and 1, 3, and 5 year survival was 86%, 59%, and 59%, respectively. Worse survival was associated with deep tumor invasion, age greater than 60 years, absence of prior debulking, and residual disease greater than 1 cm. Of note, 36% of patients had lower grade histology which impacted survival on univariate analyses. Baratti et al[36], likewise, reported an exceptional 5 year survival estimate of 90% with median survival not being reached; however, this study sought to describe borderline malignant sub-types of PM in 12 patients.

Chemotherapy agents used for HIPEC

No randomized clinical trials exist that assess which HIPEC chemotherapy regimen is superior. The majority of retrospective reports have described cisplatin mono- or dual therapy (Table 1). Blackham et al[49] investigated 19 patients receiving monoagent mitomycin and 15 receiving cisplatin in a retrospective review; he found patients administered cisplatin were more likely to be alive at 1, 2, and 3 years with a nearly 30 mo median survival advantage. Similarly, Alexander et al[47] identified the use of cisplatin over mitomycin-C to be associated with favorable survival; this however was noted only in optimally cytoreduced patients. The choice of agents seems largely driven by an institution’s experience more so than empiric evidence.

The role of peri-operative systemic chemotherapy in addition to HIPEC with CRS was examined retrospectively by Deraco et al[50] in 90 patients. Sixty of these patients received preoperative chemotherapy most commonly with a platinum-based agent and premetrexed or gemcitabine; 12 patients underwent triple agent therapy and two received more than three drugs. An additional 30 patients naïve to systemic therapy received post-operative treatment with platinum with premetrexed or gemcitabine. These cohorts were compared to 26 patients who underwent a logoregional approach only. No significant difference was observed in overall survival among groups with the survival estimate being 49% at 5 years for the entire series. A trend towards improved progression free survival, however, was observed in those receiving preoperative treatment, and overall 3 year survival favored those treated with preoperative pemetrexed and platinum chemotherapy (63% vs 42%-48%, non-significant). No differences in prognostic factors were identified among groups and the epithelioid histological was most common subtype. Yan et al[42] similarly reported on 22 patients receiving pemetrexed dual agent therapy after cytoreductive surgery and demonstrated no significant influence on survival. To date, combination regional and systemic therapies for PM remain largely unexplored.

Role of aggressive cytoreduction regimens

The extent of cytoreduction has repeatedly shown to impact survival[40,51,52]; a handful of studies have gone onto better define the role of aggressive cytoreduction. The underlying principle of cytoreduction is to remove all the macroscopic disease and use HIPEC to address any remaining microscopic disease[1]. Baratti et al[53] attempted to address the benefit of patients undergoing resection of peritoneum free of gross disease in addition to macroscopic disease. In a case-control study, 30 patients undergoing selective resection of macroscopic disease were compared to a cohort of 30 individuals undergoing “complete” parietal peritonectomy, which included abdominal regions uninvolved by disease. The five year overall survival was significantly greater at 63.9% vs 40% in the “complete” resection group. The median overall survival was not reached in the “complete” group despite a follow-up of 50.3 mo and was 29.6 mo in the selective resection group. Progression free survival was likewise significant being 54.3% vs 24.9% in favor of more aggressive peritonectomy. Interestingly, “complete” resection carried no significant increase in operative risk and was associated with a shorter length of stay by 8 d. A subsequent pathologic review revealed peritoneal disease involvement in 54% of samples deemed grossly negative at exploration which may warrant more aggressive cytoreduction approach.

More recently, previously abandoned and multi-stage modalities have been re-explored with the use of CRS and HIPEC. Wong et al[52] addressed the outcomes of repeated CRS with HIPEC. Twenty six of 29 patients underwent debulking with cisplatin-based HIPEC. Eight or 31% then went on to have one or more repeated HIPEC procedures. The median overall survival for the re-operation group was far superior at 80 mo compared to 27.2 mo in the single treatment cohort. The median time to the second operation was 15.6 mo and most (77%) received early postoperative chemotherapy with Taxol and 5-fluorouracil. Both groups otherwise had similar completeness of cytoreduction scores, demographics, and similar overall number of complications. Kluger et al[54] reported on two-stage operative cytoreduction with intraperitoneal chemotherapy in 47 patients. Subjects initially underwent partial cytoreduction with peri-operative intraperitoneal therapy with single or dual regimens of cisplatin, gemcitabine, doxorubicin, or gamma interferon. A second laparotomy with CRS and HIPEC was performed in 35 using cisplatin and mitomycin C; median survival was 54.9 mo with 1, 3, and 5 year overall survival being 81%, 62% and 49%, respectively. Hesdorffer et al[55] reported on multi-modality treatment in 27 patients who underwent operative debulking with post-operative IP therapy followed by HIPEC with mitomycin and cisplatin and then followed by whole abdominal radiation between 3000 and 3080 cGy. Overall median survival was 70 mo and three year survival was 67%. The retrospective nature of these reviews limits drawing any firm conclusions, but a multi-modality approach may offer the most aggressive treatment for patients with PM.

Role of laparoscopy

Diagnostic laparoscopy with biopsy has been previously described as a safe alternative in obtaining a histological diagnosis[13,56]. Its role in assessing resectability before CRS with HIPEC in PM was explored in 33 patients. Patients with potentially resectable disease on pre-operative imaging underwent exploration. Ninety one percent of patients were deemed likely to obtain complete cytoreduction; of these, only one patient was not on subsequent laparotomy, yielding an overall specificity of 75% and accuracy of 97%[57].

Prognostic factors in CRS with HIPEC

More than half of the studies reporting on prognostic factors have reported completeness of cytoreduction to be associated with improved survival on multivariate analyses[35,38,40,42,43,45,50-53]. Nodal status, histological subtype, nuclear grade, and mitotic count have also been cited[34,35,40,42,43,45,47,51-54] (Table 2). Concordant findings were reported in the large multi-institutional series by Yan et al[42]. Interestingly, 29 patients did not receive HIPEC; a subsequent multivariate sub-analysis demonstrated that HIPEC correlated with improved survival. Baratti et al[53] similarly identified another surgical factor, “complete” peritonectomy, as positive influencing survival.

Table 2 Prognostic factors in cytoreduction and hyperthermic intraperitoneal chemotherapy procedures.

Ref.	Year	Sample No.	Prognostic factors overall survival (multivariate only)
Deraco et al[38]	2003	61	Completeness of cytoreduction
Feldman et al[48]	2003	49	1No prior debulking, deep invasion, age > 60, residual disease > 1 cm
Nonaka et al[51]	2005	35	Completeness of cytoreduction, low mitotic count, lower nuclear grade
Deraco et al[40]	2006	49	Completeness of cytoreduction, low mitotic count/50 HPF
Yan et al[45]	2006	100	No lymph node metastasis, female gender, epithelial type, adequate cytoreduction
Baratti et al[20]	2007	60	1High-grade histology, WHO performance status > 0, Inadequate cytoreduction
Yan et al[41]	2007	62	Mesothelioma nuclear size
Yan et al[42]	2009	401	Epithelial subtype, absence of lymph node metastasis, completeness of cytoreduction 0/1, HIPEC
Baratti et al[35]	2010	83	Pathologically negative lymph nodes, epithelial subtype, mitotic count ≤ 5/50 HPF, Completeness of cytoreduction
Kluger et al[54]	2010	47	1Biphasic histological subtype
Yan et al[43]	2011	294	1Biphasic/sarcomatoid subtype, completeness of cytoreduction score of 2/3, proposed TNM Stage II or III
Cao et al[46]	2012	294	Female gender, TNM staging
Baratti et al[53]	2012	60	Complete parietal peritonectomy, complete cytoreduction, negative lymph nodes, Epithelial histology, low MIB-1 index
Alexander et al[47]	2013	211	Age < 60 yr, R0-1 vs R2-3, low histologic grade, use of cisplatin vs mitomycin-C
Baratti et al[34]	2013	108	Epithelial histology, histologically negative lymph nodes, Ki-67 < 10%
Deraco et al[50]	2013	116	Histological subtype, completeness of cytoreduction, absence of morbidity 3-5 grade
Schaub et al[59]	2013	104	Histological subtype, pre-CRS PCI, preoperative serum CA-125
Wong et al[52]	2013	29	Lower peritoneal carcinoma index, completeness of cytoreduction
Pillai et al[58]	2013	33	Presence of nuclear estrogen receptor beta

¹Variables that have negatively impacted overall survival.

Female gender was shown by Cao et al[46] to be among patient factors to positively influence survival; the female cohort accounted for 46% in the study population and was more likely to have lower peritoneal cancer indices and earlier stage compared to males[41,46]. Interestingly, the presence of the nuclear estrogen receptor beta was shown to be an independent predictor of survival in peritoneal disease[58]. Schaub et al[59] found pre-operative CA-125 to influence survival; a prognostic nomogram was proposed by incorporating this marker along with peritoneal cancer index and histological subtype as clinical assessment tool for 3 and 5 year survival; positive predictive values have been reported as 73.1% and 73.9% respectively.

Morbidity and peri-operative mortality

Overall morbidity rates have varied widely between 14% and 71% (Table 3). Larger series with at least 50 subjects have reported 28%-41% incidence of grade 3 or greater complications[35,42,44,45,50,53]. When reported, peri-operative mortality has ranged between 1% and 11% and re-operation rates up to 20% with the most common indication being hemorrhage[6,34,37,42,44,46,47,52,60-62]. Complications related to fistula formation, perforation, dehiscence, abscess formation are significant and in large series have been reported in up to 18% of cases[42]. Cardiopulmonary complications are the second most frequently encountered followed by those related to infection. It remains difficult to distinguish those complications stemming from operative intervention and those related to chemotherapy regimens. In terms of long-term survival, Deraco demonstrated worse survival with patients with grade 3 to 5 complications[50]. Length of stay has been investigated in a handful of reports and has ranged from 9 to 41.5 d; Wong et al[52] reported on a median stay of only 8 d for patients undergoing repeat HIPEC. Surprisingly, morbidity rates only have a weak association with the duration of inpatient admission; other factors such as administration of early post-operative chemotherapy may be involved but are not reported.

Table 3 Morbidity, peri-operative mortality, and length of stay associated cytoreduction with hyperthermic intraperitoneal chemotherapy.

Ref.	Year	Sample No.	Complication rate	Peri-operative mortality	Re-operation	Abdominal	Cardiac/pulmonary	Sepsis	Wound Infection	Other infection	Renal	Vascular	Hematologic	Other	LOS
Park et al[33]	1999	18	24%		1	1	1	1	2	1				1
Feldman et al[48]	2003	49	25%	0	2	4	5	2	3	1	1			2
Costamagna et al[61]	2003	24	26%	11
Brigand et al[6]	2006	15	40%	0	0					0	0			0	16.3
Elias et al[60]	2007	26	54%	4	4	1	1			4	1	3	2	2	281
Gomez et al[113]	2007	7	71%												41.51
Hesdorffer et al[55]	2008	27	30%	0		2	1			1		1		3
Passot et al[114]	2008	22	47%	0
Chua et al[115]	2009	20	65%	1		2	5	2			1		1	3	16.51
Yano et al[62]	2009	17	41%	5.8			2			2		1		3
Kluger et al[54]	2010	47	34%	2	1	3	9	2	2	9	2	1		1	161
Cao et al[46]	2012	294	33%	2		50	38				26		15		231
Alexander et al[47]	2013	211	30%	2.3	20	20	25		9			6	8	11	11
Wong et al[52]	2013	29	65%	4	1	4	1		6		2		10	4	9
Deraco et al[37]	2003	19	25%	0		3				1	1			3	321
Deraco et al[39]	2003	28	14%	0
Deraco et al[38]	2003	61	23%	0		7
Deraco et al[40]	2006	49	15%G3			9	2	4		5	4		3	5	241
Deraco et al[50]	2013	116	41%G3	2.6											25
Baratti et al[36]	2007	12	8%G3	0	1	1
Baratti et al[116]	2008	5	20%G3	0	1	1
Baratti et al[35]	2010	83	28%G3	2.4
Baratti et al[117]	2010	12	8%G3	0											18
Baratti et al[53]	2012	60	28%G3	0	7	8	4	3	1		7	2	5	1
Baratti et al[34]	2013	108	39%	1.9		14	10	6			10		7
Yan et al[45]	2006	100	36%G3	5		6	8	7		11		5	8	10	221
Yan [44]	2007	70	41%G3	3	4	3	4	3		2		4	5	3	231
Yan et al[42]	2009	401	46%G3	2		74	57				39		25		221

¹Mean values. Cells with the superscript G3 represent grade 3 or above complications. Abdominal complications include perforation, abscess formation, dehiscence, and fistula. "Other" complications include neurological and musculoskeletal complaints, emesis, and dehydration. Numerical values represent cases or patient number unless otherwise stated.

FUTURE DIRECTIONS; MOLECULAR TARGETED THERAPY

Investigated molecular targets and therapeutic agents

A variety of molecular targets have been identified in PM and of these, a handful of respective therapeutic agents have been investigated. Foster et al[63] discovered mutations in the epidermal growth factor receptor (EGFR) in a subset of 29 patients, which were associated with a higher rate of optimal cytoreduction and a trend towards improved 3 year overall and progression free survival. Erlotinib, an EGFR inhibitor, was then investigated using COS-7 cell lines transfected with mutant EGFR at different drug concentrations along with EGF; based on subsequently decreased EGFR phosphorylation, it was postulated that erlotinib may warrant further exploration. Kalra et al[64], however, questioned any wide spread role of EGFR targeted therapies because none of 33 peritoneal mesothelioma tumors he interrogated expressed EGFR sensitizing mutations.

Varghese et al[65] identified up-regulation in genes related to the phosphatidylinositol-3 kinase (PI3K) and the mammalian target of rapamycin (mTOR) signaling pathways to be associated with poorer survival among 41 patients undergoing CRS and HIPEC. Under-expression was associated with an 80% 3 year survival with a median period of 69.5 mo compared with 47.4 mo for the entire cohort and 24 mo for over-expressers. Using an in vitro model, cells were treated with a dual PI3K and mTOR inhibitor, NVP-BEZ235, demonstrated significant suppression of cell proliferation[65].

Mesothelin, glycosylphosphatidylinositol-anchored glycoprotein, has also been recognized to be highly expressed in malignant mesothelioma along with pancreatic, ovarian, and some lung cancers. Three agents targeting mesothelin have been tested to date; 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[66]. Of these, SS1P has undergone phase I testing in 24 patients including five with peritoneal mesothelioma and has shown short term resolution of ascites in one patient[67,68]. The second trial demonstrated a partial response with SS1P in two of 12 patients with PM[67,68]. Hassan et al[69] reported on a regimen of SS1P, pentostatin, and cyclophosphamide in eleven patients with mesothelioma; two patients with peritoneal disease had a significant tumor reduction up to 8 and 14 mo, respectively. More recent studies have reported on newer mesothelin-targeted agents including the immunocytokine IL12, which has shown comparable anti-tumor activity to SS1P in a murine model of PM[70].

Molecular targets on the horizon include MUC1, a glycoprotein associated with various cancers including breast, colon, and pancreatic adenocarcinoma; recently, Pillai demonstrated that MUC1 was expressed in 90% of patients with PM and may have some prognostic value in predicting poorer survival[71]. Bromelain, a complex of proteolytic enzymes, has been postulated to target glycoproteins including MUC1, and initial experiments have demonstrated that chemo-resistant peritoneal mesothelioma cells lines have increased chemotherapy sensitivity with bromelain combination therapy[72]. Some skepticism exists as no studies have directly examined the effect of this agent on MUC1 in peritoneal disease.

Sphingosine kinase 1 as a novel target for mesothelioma

Sphingosine kinase 1 (SphK1) is the lipid kinases that phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a lipid mediator. S1P is an important bioactive lipid that has been implicated in multiple physiologic and pathologic processes such as, inflammation, atherosclerosis, asthma, osteoporosis, diabetes, obesity, and particularly cancer, due to its role in cell survival, proliferation, migration, angiogenesis, and lymphocyte trafficking[73,74].

The molecular functions of S1P can be divided into its intracellular action and extracellular signaling, which is coined “inside-out” signaling[73,74]. Intracellular S1P can directly regulate its target proteins, which are histone deacetylases (HDACs) and the E3 ubiquitin ligase tumor-necrosis factor (TNF) receptor-associated factor 2 (TRAF2)[75,76]. Through the regulation on these proteins, S1P involves epigenetic regulation of gene expression of NF-κB signaling, which play key roles in cancer biology. As for the inside-out signaling of S1P, transporters such as ABC transporters and Spns2 have been identified[77,78]. These transporters allow S1P to be exported outside the cell and act as a ligand on membranous five S1P specific G-protein coupled receptors (S1PR1-5), which activate multiple downstream signaling pathways regulating cell differentiation, migration, and survival in an autocrine, paracrine, and/or endocrine manner[79].

Owing to the role of S1P in cancer cells, studies investigating SphK1 as an oncogene have steadily increased[80]. It has been known that S1P possesses a strong angiogenic property[81]. Considering a critical role of lymphangiogenesis in cancer progression[82], our group reported on a new aspect of the SphK1/S1P axis by its involvement in breast cancer-induced lymphangiogenesis which precedes breast cancer metastasis[83,84]. Recently, we have also further demonstrated the indispensable role of the SphK1/S1P axis in colitis and colitis-associated cancer[85-87] .

The role of the SphK1/S1P axis in mesothelioma has not been reported only until recently. Kalari et al[88] demonstrated elevations in SphK1 expression in both the epithelial and sarcomatoid subtypes of human pleural mesothelioma compared with non-tumor specimens. They further delineated the function of SphK1 in vitro and in vivo. Examining mesothelioma cell lines, SphK1 mRNA and protein expression were higher in malignant cells, and this over-expression correlated with cellular proliferation. The possible mechanism was S1P regulation on expression of cell cycle-related genes via histone acetylation. The SphK2 isotype was not implicated in tumorigenesis.

Using the SphK1 inhibitor, SphK-I₂, or gene silencing, S1P production and cell proliferation were likewise reduced. The authors additionally conducted an alternative in vivo model in which they exposed the peritoneal lining of mice to mesothelioma inducing agents, specifically long multiwalled carbon nanotubes (MWNT). Exposure to MWNTs have been reported to cause development of granulomas in p53-knockout mice[89]. Compared to wild type mice, the Sphk1 knockout mice demonstrated significantly less MWNT-induced granulomatous inflammation. This result suggested the in vivo role of SphK1 as promoting mesothelioma development.

Recently, studies investigating agents targeting S1P signaling have been tested in various settings[90]. Among these, FTY720 has shown some promise; FTY720 (Fingolimod; trade name Gilenya, Novartis) is a FDA-approved drug for treating relapsing forms of multiple sclerosis[91]. It has been shown FTY720 acts as a pro-drug which is mainly phosphorylated in vivo by SphK2[92-94]. The phospho-FTY720 mimics S1P action by binding to S1PR1 which is then internalized and degraded[95,96]. S1PR1 signaling, itself, is important for lymphocyte egress from thymus and secondary lymphoid organs to the periphery[97,98]. The down-regulation of S1PR1, therefore, through the known action of FTY720, is considered as immunomodulatory by inducing lymphopenia without generalized immunosuppression[96,99]. In addition to the immunosuppressant property, several reports about FTY720 as an anti-cancer drug in various malignancies have rapidly accumulated[100,101]. We recently reported, in a murine colitis-associated colon cancer model, the administration of FTY720 dramatically reduced tumor size, multiplicity, and tumor load via the reduction of SphK1 and S1PR1 expression[85,86]. Others have gone onto also characterize FTY720 as a SphK1 inhibitor in multiple cancer cell lines[102-104]. In hematopoietic malignancies or lung cancer, FTY720 acts as an activator of tumor suppressor protein phosphatase 2A (PP2A) and shows promising preclinical activity[105-108]. In hepatocellular carcinoma, FTY720 was found to decrease recurrence after liver transplantation via down-regulation of S1PR1[109]. FTY720 was additionally suggested in combinational therapy with sunitinib for breast cancer, with milatuzumab for lymphoma, and radiotherapy for prostate cancer[103,110,111]. Taken together, targeting S1P signaling by FTY720 might be a potential strategy for pharmoco-therapeutics for peritoneal mesothelioma (Figure 1).

Figure 1 Role of sphingosine 1-phosphate in peritoneal mesothelioma. Inflammation is critical to the development of peritoneal and sphingosine 1-phosphate (S1P) plays an essential role linking it to cancer. Targeting S1P, therefore, with agents like the pro-drug FTY-720 may suppress this process.

CONCLUSION

Peritoneal mesothelioma remains a rare, infrequent disease which historically has been associated with a poor prognosis. Demonstrable improvements in survival have been made with the wider employment of cytoreduction and HIPEC and a generally more aggressively-focused treatment regimen. Yet despite these advances, significant morbidity still persists and a few options exist for those not amenable to operative intervention. Novel molecular targets such as SphK1 have only recently been associated with PM and represent a potentially promising venue for drug therapy in the future.