台灣癌症醫誌 (J. Cancer Res. Pract.) 2(1), 83-92, 2015 DOI: 10.6323/JCRP.2015.2.1.11

journal homepage:www.cos.org.tw/web/index.asp Case Report

Malignant Peritoneal Mesothelioma

Zhong-Yi Lin1,2, Cheng-Hsin Chu1,2,3, Horng-Yuan Wang1,2,3, Shou-Chuan Shih1,2,3, Ming-Jen Chen1,2,3*

1Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan 2Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan 3Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

Abstract. Malignant peritoneal mesothelioma (MPM) is rare. It is difficult to diagnose early and re- sponds poorly to treatment. There is no optimal and effective treating consensus so far. We re- port three patients of MPM treated at Mackay Memorial Hospital in recent 3 years. They were two men and one woman without asbestos exposure related to their occupations. Due to failure in early diagnosis of MPM, none of them survived for more than 5 months. We make a brief re- view from the previous literature. These three cases were compared with the reviewing data in many aspects including the risk factor, clinical presentation, diagnostic options, and manage- ment. Besides, some latest clinical trials are introduced in this report.

Keywords : malignant peritoneal mesothelioma, peritoneal tumor, abdominal carcinomatosis

病例報告

腹膜惡性間皮細胞瘤

林仲一 1,2 朱正心1,2,3 王鴻源1,2,3 施壽全1,2,3 陳銘仁1,2,3*

1 馬偕紀念醫院 肝膽腸胃內科 2 馬偕醫護管理專科學校 3 馬偕醫學院 醫學系

中文摘要 腹膜惡性間皮細胞瘤相當罕見。它很難早期被診斷，並且對於治療的反應也不好。 至今仍然未見有效的治療共識。我們收集到馬偕醫院這三年發現的三個病例，包含不同 職業的兩位男性與一位女性患者。由於無法早期診斷，他們存活都沒有超過五個月。我 們回顧從前發表之相關文章，在危險因子、臨床症狀、診斷策略、與相關治療這幾方面 來與我們發表的病例相比較。此外，有關最新的治療研究也在這篇文章中介紹。

關鍵字: 腹膜惡性間皮細胞瘤、腹膜腫瘤、腹膜內癌轉移擴散

INTRODUCTION mesothelioma is the most common type followed by Malignant mesothelioma is a malignancy arising peritoneal type [1]. There is a strong relationship be- from the serosal membranes of the pleura, peritoneum, tween asbestos exposure and the development of mes- pericardium, and tunica vaginalis testes. The pleural othelioma at any location [2]. One study pointed out

Open access under CC BY-NC-ND license. 84 Z. Y. Lin et al./JCRP 2(2015) 83-92 that the link between exposure to asbestos and perito- He visited the emergency department of Mackay neal mesothelioma is less strong than it is for pleural Memorial Hospital because of abdominal pain and mesothelioma, particularly among women [3]. But no distention for two weeks. The chief complaints were reason has been found to explain this difference. As- poor appetite, abdominal distention and dyspnea on bestos exposure-induced MPM generally required a exertion for about one month. Leukocytosis (15400/ higher cumulative dose than malignant pleural uL) and anemia (Hemoglobin: 8.5g/dl) were noted. mesohtelioma [3]. In the United States, the overall Physical examination detected peritoneal signs (dif- prevalence is 1-2 cases per million, with an estimated fuse rebounding pain without specific location). Then incidence of 200-400 new cases annually [4]. In Tai- computed tomography of the whole abdomen revealed wan Lee et al. reported a total of 423 cases of malig- a large right liver tumor (more than 10 cm in diameter) nant mesothelioma which were registered from 1979 and carcinomatosis (Figure 1A). Moderate amount of to 2005 [5]. Up to 91% of these patients in their study ascites was also seen. Under the impression of liver were diagnosed as peritoneal or pleural mesothelioma. tumor rupture with peritonitis, he was transferred to The median survival of malignant mesothelioma was the intensive care unit. A series of examinations in- 7.6 and 13.5 months for males and females, respec- cluding of abdominal echo, cytological analysis of tively. The male to female ratio is 1.5:1. MPM is a ascites, esophagogastroduodenalscopy (EGD) and fatal disease without specific initial clinical presenta- serum tumor marker were performed in turn in order tions. No serum marker or typical image criteria have to discover the nature of the abdominal tumors. The been established to diagnose this disease early [6, 7]. positive findings were elevated serum, CA-125 One study for proposal of the TMN staging system for (297u/mL), and β2-microglobulin (9360μg/mL). Di- peritoneal mesothelioma enrolled 294 patients, of agnostic laparoscopy for taking an omental specimen whom 242 patients (82.3%) were classified as stage II was performed. Under microscopic investigation, or III. The TMN staging for peritoneal mesothelioma high-grade, poorly differentiated carcinoma cells were has three stages with 5-year-survial rate as 87, 53, and found (Figure 1B). The tumor cells were positive for 29%, respectively. Therefore most cases were diag- some immunohistochemical staining including CK7, nosed at the advanced stage at the time of diagnosis vimentin, calretinin, D2-40, thrombomodulin (Figure [8]. We share three cases of MPM in the present 2A-2D), and negative for CEA, RCC, CK20, HepPar, communication. and mucicarmine. Hepatocellular carcinoma and met- astatic adenocarcinoma were therefore excluded. The CASE REPORTS pathological diagnosis was epithelioid type, pleo- morphic subtype of MPM. This patient died of pro- Case 1 found septic shock leading to multiple organ failure A 57-year-old man, a retired taxi driver, had a his- after admission for 15 days. Due to rapid progression, tory of hepatitis B, diabetes mellitus, and hypertension. no active treatment such as chemotherapy or radio- therapy could be arranged for this patient.

*Corresponding author: Ming-Jen Chen M.D. Case 2 *通訊作者：陳銘仁醫師 A 71-year-old woman, a housewife, had a history Tel: +886-2-25433535 ext.3993 of diabetes mellitus. She suffered from abdominal Fax: +886-2-25433642 pain and body weight loss of up to 5 kg within one E-mail: [email protected] month, and looked for medical advice at the hemato- Z. Y. Lin et al./JCRP 2(2015) 83-92 85

Figure 1. (A) Contrast computed tomography of abdomen presents with large liver tumor (red arrows) in Segments 7, 6, and 1. Carcinomatosis, celiac trunk lymphadenopathy, and much ascites are also noted (white arrows). (B) Under microscopy hematoxylin and eosin stain, the omental tissue is effaced by clusters of high-grade epithelioid neoplastic cells with increased mitotic figures, including abnormal form

logical outpatient service. Two liver tumors were Case 3 found in segment 6 and 7 on abdominal sonography. A 73-year-old man, a retired labor, had a past his- Abdominal computed tomography demonstrated mas- tory of coronary artery disease post-bypass graft and sive ascites and carcinomatosis (Figure 3). Differential right renal stone post-extracorporeal shock wave lith- diagnosis included hepatocellular carcinoma, meta- otripsy (ESWL). Investigation was started at the static tumor from the alimentary tract or urogential Mackay Memorial Hospital urological outpatient tract. The serum CA-125 level was elevated (530.2 clinic because of right flank pain and hemospermia. u/ml). However, no tumor formation was found by One 1.2 cm right renal stone was found. A second ses- gynecological echo. The ascites cytology revealed sion of ESWL was suggested. Three months later, he atypical reactive mesothelial cells with prominent nu- was still afflicted with intermittent right flank pain. cleoli. Due to the failure of finding out the origin of Double colon series, pan-endoscopy, and small bowel peritoneal tumors by noninvasive examinations, diag- series showed negative findings. Abdominal echo re- nostic laparoscopy was performed. The final diagnosis vealed a hypo-echoic mass, suspecting a large sub- from biopsy specimen was epithelioid type, solid sub- capsular hematoma in the right liver with blood clot in type MPM. After receiving two cycles of pemetrexed Morrison’s pouch. The hematoma was regarded as the with cisplatin, she developed of intra-abdominal in- side effect of ESWL at that time. Abdominal comput- fection with septic shock, which progressed to death. ed tomography was arranged on account of unresolved We had no time to perform further image studies to symptoms including hematuria. The report confirmed evaluate the response to treatment. Refractory ascites, a hematoma covering the right liver and one right re- however, implied that the disease was under progres- nal stone (Figure 4A). Two months later, he was sion. We are in lined to think that she died of progres- transferred to the emergency department with the sive MPM and the complication of septic shock. The complaint of severe abdominal pain and body weight survival period after diagnosis was only 4 months. loss of up to 8 kg. Abdominal computed tomography subsequently discovered the peritoneal carcinomatosis 86 Z. Y. Lin et al./JCRP 2(2015) 83-92

Figure 2. The tumor cells under special immunohistological stain are positive for CK7, vimentin, calretinin, and D2-40

(Figure 4C,4D). A series of non-invasive examinations the treatment. The patient suffered from persistent including serum tumor markers could not help in fever and leukocytosis after the first cycle of chemo- finding out the tumor origin. By way of diagnostic therapy. Finally, septic shock led the patient to his laparoscopy an omental specimen was obtained for death. We are of the opinion that he died of progres- pathological study. The diagnosis was epithelioid-type, sive MPM and the complication of septic shock. The tubulopapillary-subtype MPM. The gallium-67 whole survival period after the diagnosis of the tumors found body scan performed before the first cycle of systemic by abdominal echo was 5 months, or only two months chemotherapy revealed rapid progression of the tumor after final diagnosis. into pelvic cavity compared with last abdominal computed tomography one month before. No further DISCUSSION image examination was performed after chemotherapy. According to epidemiologic data, exposure to as- Therefore it was difficult to evaluate the efficacy of bestos is an established risk factor for developing Z. Y. Lin et al./JCRP 2(2015) 83-92 87

Figure 3. Contrast computed tomography of abdomen presents with prominent carcinomatosis (arrows)

MPM [2]. The relation of relative risk to the exposure patients were afflicted with refractory ascites. dose for MPM is not linear; while that for pleural There are some diagnostic strategies including la- mesothelioma is nearly linear [3]. It is presumably boratory findings and image examinations. However, related to the dynamics controlling the distribution of those examinations except the histological study are asbestos fibers around the body which partially lodge short of high specificity and sensitivity [6,7]. Elevated into the peritoneal membrane. It is more complex than serum levels of hyaluronan, CA-125, alpha fetoprotein, the absorbing mechanism of direct inhalation in pleu- CEA, and mesothelin were found in some patients, but ral mesothelioma [3]. Besides asbestos, other risk these levels are poorly correlated to the disease pro- factors including radiation and mineral fibers have gression [6,7]. Elevated CA-125 was found in case 1 also been reported [9,10]. With respect to the patients and case 2 in our report. None of them had elevated mentioned in our report, one was a taxi driver, another serum CEA or alpha fetoprotein. Radiological exami- a labor, and the last a housewife. To the best of our nation such as computed tomography or magnetic acknowledge, none of them had a history of any ex- resonance cannot offer adequate accuracy for differen- posure to asbestos. According to the occupation risk tial diagnosis [7]. Combined image guiding biopsy factors in Sweden for MPM, bricklayers and plumbers and immunohistochemical staining can help in diag- had the highest risk. Farmers and self-employees had nosing MPM precisely [11]. Cytologic analysis of a relatively low risk [2]. ascites has its limitations in differential diagnosis of There are no specific clinical presentations for di- malignant or benign reactive peritoneal mesothelioma agnosis of MPM [4]. Most cases were asymptomatic because it lacks the evidence of stromal invasion to until the tumors occupied most of the abdominal cav- peritoneum [11,12]. In the beginning, the contrast ity [4]. The most frequent complaint is abdominal pain computed tomography failed to detect a peritoneal (35%), and the second, abdominal swelling (30%) [4]. lesion in case 3 until the disease progressed to perito- According to the initial clinical presentations of the neal carcinomatosis. patients in our report, their pain were often diffuse and It is difficult to distinguish MPM from some peri- nonspecific. This kind of unspecific pain often leads toneal tumors which mimic MPM in the clinical and to a delay in diagnosis and till the time when these image patterns by the histological appearance. Those 88 Z. Y. Lin et al./JCRP 2(2015) 83-92

Figure 4. (A,B) Pictures of first contrast abdominal computer tomography. In Figure 4A, the hypodense area (ar- row) covering right liver surface is thought to be a hematoma. However, omental thickening (arrow) is also noted in the right lower abdominal quadrant in Figure 4B. (C,D) These are pictures of subsequent liver dynamic computed tomography (arterial phase) 2 months afterward. Obvious abdominal carcino- matosis is found (arrow)

tumors are: sarcoma, melanoma, primary papillary adenocarcinoma markers, including carcinoembryonic serous carcinoma of the peritoneum, serous ovarian antigen (CEA), thyroid transcription factor-1, LeuM1, carcinomas, colorectal adenocarcinoma diffusely in- Ber-Ep4, B72.3, Bg8, and MOC-31. volving the peritoneum, and borderline serous tumors Mesotheliomas have three basic histologic forms: [4]. A panel with immunohistochemical markers has epithelioid (the most frequent), sarcomatoid (least been suggested for diagnostic aid [13]. Most mesothe- frequent), and mixed (biphasic). In most cases, all liomas stain positively for antimesothelial cell anti- three type features will be encountered in a single tu- body-1, D2-40, calretinin, cytokeratins5/6, Wilms tu- mor [13]. The morphological category is based on the mor-1, thrombomodulin, and mesothelin which are 2004 World Health Organization (WHO) criteria (less absent in those serous carcinoma mentioned above. than 10% sarcomatoid component defined as epitheli- Cytokeratin statins are absent in sarcoma and mela- oid type; otherwise defined as biphasic type) [14]. The noma. Mesotheliomas usually stain negative for other pure sarcomatoid type peritoneal mesothelioma is very Z. Y. Lin et al./JCRP 2(2015) 83-92 89 rare. In general, the epithelioid type has the best in the past [9]. The median survival period was uni- prognosis, followed by the biphasic type [14]. Ac- formly less than one year, and long-term survival was cording to the 2004 WHO classification, the malignant uncommon [15]. The median survival for untreated epithelioid mesothelioma have five histological sub- patients was approximately 6 months [15]. Over the types, that is, trabecular, tubulopapillary, micropapil- past 5 years, experiences in cytoreductive surgery lary, solid, and pleomorphic [14]. There is no pub- (CRS) and hyperthemic intraperitoneal chemotherapy lished paper in the literature discussing the prognostic (HIPC) were accumulated gradually. Markedly im- difference of each epithelioid subtype in malignant proved outcomes including the survival rate have been peritoneal mesothelioma. One research, however, re- reported. Some papers reported their phase II and ob- ported this difference with malignant pleural mesothe- servation experiences with CRS and HIPC in the US lioma [14]. In that study, the trabecular and tubulopa- and Europe reaching the satisfied outcome with an pillary subtypes had a longer overall survival time overall fiver-year survival rates ranging from 29% to than the micropapillary and pleomorphic subtypes. 57%, and median survival time of up to 70 months [16, The pleomorphic subtype, in particularly, was an in- 17]. The advantages of CRS combined with HIPC dependent predictor for worse overall survival in the over the conventional systemic chemotherapy are that multivariate analysis setting. The pleomorphic subtype they remove macroscopic tumors, decreasing tumor showed no significant difference in overall survival burden [16,17]. Heated and direct-contact chemother- compared with biphasic (p=0.96) and sarcomatoid type apy drugs provide higher concentration and penetra- (p=0.15). The authors defined the solid and micro- tion into mesentery nodules [17, 18]. However not all papillary as high-grade subtype in epithelioid mesothe- patients are candidates for CRS and HIPC; patients lioma. With regard to the pleomorphic subtype which with poor performance and extra-peritoneal metastasis had aggressive clinical and biologic behavior such as are not suitable for such treatment [17]. Moreover the prominent lymphatic, vascular invasion, and rapid re- skill of the surgeon plays an important role in com- currence, the authors proposed that it was best regard- pleteness of cytoreduction surgery [19]. Based on the ed as a sarcomatoid pattern rather than an epithelioid best knowledge and a report in the literature, a re- one. There were some histological features belonging search by Pubmed et al, there is no published report to epithelioid mesothelioma, namely, microcystic, clear from Taiwan on the application of HIPC and cy- cell, deciduoid, and small cell types. That study did not toredutive surgery in MPM. In our report, these three demonstrate any association of those histological fea- patients did not undergo cytoreductive surgery and tures with prognosis. Multicytic peritoneal mesotheli- HIPC. This was due either to advanced disease with oma and well-differentiatedpapillary mesothelioma are liver metastasis and our lacking of experience. This two rare subgroups which are nearly always encoun- approach may be adopted in the future with gathering tered in peritoneal mesothelioma of females. They are more evidence and increased experience in cytoreduc- variants of epithelioid mesothelioma and have excel- tion surgery. lent prognosis [13]. In 2004, pemetrexed was approved worldwide to Due to rarity and lack of prospective large scale be used in combination with cisplatin for the treatment clinical trials, there is still no consensus for optimal of malignant pleural mesothelioma in patients whose treatment so far. Localized MPM can be resected by disease was not resectable [20]. However, up to now surgical intervention. However, the diffuse-type of no chemotherapeutic agent, either alone or in combi- invasive mesothelioma was managed with chemo- nation, has demonstrated a consistent survival ad- therapy and even radiotherapy after palliative surgery vantage in peritoneal mesothelioma. Currently, there is 90 Z. Y. Lin et al./JCRP 2(2015) 83-92 no approved treatment for peritoneal mesothelioma REFERENCES [20]. Many researches on evaluating the efficacy pro- 1. Boffetta P. Epidemiology of peritoneal mesothe- file when peritoneal mesothelioma patients were lioma: a review. Ann Oncol 18: 985-990, 2007. treated with pemetrexed with or without a platinum 2. Hemminki K, Li X. Time trends and occupational agent demonstrate that pemetrexed or cisplatin alone risk factors for peritoneal mesothelioma in Swe- is inferior to pemetrexed combined with cisplatin or den. J Occup Environ Med 45: 451-455, 2003. carboplatin in the response rate [20]. One study re- 3. Hodgson JT, Darnton A. The quantitative risks of ported this difference among these regimens in the mesothelioma and lung cancer in relation to as- response rate [20] (pemetrexed, pemetrexed with cis- bestos exposure. Ann Occup Hyg 44: 565-601, platin, and pemetrexed with carboplatin): 12.5%, 2000. 20.0%, and 24.1%, respectively. Pemetrexed com- 4. Borrida A, Padoan I, Mencarelli R, et al. Perito- bined with cisplatin is still thought to be more effi- neal mesothelioma: a review. MedGenMed 9: cient in treating MPM. 32-35, 2007. Recently molecularly targeted therapy agents have 5. Lee LJ, Chang YY, Wang JD. Impact of malig- been introduced to treat advanced malignant mesothe- nant mesothelioma in Taiwan: a 27-year review of lioma (including pleural type). Tremelimumab in a population-based cancer registry data. Lung Can- small single arm, phase II study reported positive cer 68: 16-19, 2010. treating outcome [21]. Tremelimumab is a monoclonal 6. Baratti D, Kusamura S, Martinetti A, et al. Circu- antibody of cytotoxic T-lymphocyte antigen 4 lating CA125 in patients with peritoneal mesothe- (CTLA4), which is a powerful negative regulator of T lioma treated with cytoreductive surgery and in- cell activation. By means of blockage of CTLA4, the traperitoneal hyperthermic perfusion. Ann Surg activated cytotoxic T lymphocyte can eliminate the Oncol 14: 500-508, 2007. tumor cells more efficiently. This study enrolled only 7. Kebapci M, Vardareli E, Adapinar B, et al. CT 29 participants. Though none-attained a complete re- findings and serum ca 125 levels in malignant sponse, two patients (7%) had a durable partial re- peritoneal mesothelioma: report of 11 new cases sponse (one lasting 6 months and the other lasting 18 and review of the literature. Eur Radiol 13: months). However nine patients (31%) had a median 2620-2026, 2003. progression-free survival of only 6.2 months. The au- 8. Yan TD, Deraco M, Elias D, et al. A novel tumor- thor recognized that tremelimumab seemed to have node-metastasis (TNM) staging system of diffuse encouraging clinical activity in previously treated pa- malignant peritoneal mesothelioma using outcome tients with advanced malignant mesothelioma. Other analysis of a multi-institutional database. Cancer experimental approaches with immunotherapeutic 117: 1855-1863, 2011. agents including bevacizumab, thalidomide, sorafenib, 9. Yan TD, Edwards G, Alderman R, et al. Morbidity sunitinib, imatinib, vatalanib, cediranib, and vorinostat and mortality assessment of cytoreductive surgery [22-29] have been reported, but no established role and perioperative intraperitoneal chemotherapy has yet been found in the treatment of mesothelioma. for diffuse malignant peritoneal mesothelioma--a In conclusion, MPM is a rare, highly lethal, and prospective study of 70 consecutive cases. Ann rapidly progressive malignancy. There is no consensus Surg Oncol 14: 515-525, 2007. for established treatment so far. Further researches for 10. Chua TC, Yan TD, Morris DL. Outcomes of cy- MPM are ongoing and we hope that they will offer us toreductive surgery and hyperthermic intraperito- a better, feasible treatment in the future. neal chemotherapy for peritoneal mesothelioma: Z. Y. Lin et al./JCRP 2(2015) 83-92 91

the Australian experience. J Surg Oncol 99: 109- Funded Peritonectomy Center. Ann Surg Oncol 113, 2009. 14: 2270-2280, 2007. 11. Sugarbaker PH, Welch LS, Mohamed F, et al. A 20. Cartenia G, Manegold C, Garcia GM, et al. Ma- review of peritoneal mesothelioma at the Wash- lignant peritoneal mesothelioma: Results from the ington Cancer Institute. Surg Oncol Clin N Am International Expanded Access Program using 12: 605-621, 2003. pemetrexed alone or in combination with a plati- 12. Manzini Vde P, Recchia L, Cafferata M, et al. num agent. Lung Cancer 64: 211-218, 2009. Malignant peritoneal mesothelioma: a multicenter 21. Calabrò L, Morra A, Fonsatti E, et al. Treme- study on 81 cases. Ann Oncol 21: 348-353, 2010. limumab for patients with chemotherapy-resistant 13. Husain AN, Colby T, Ordonez N, et al. Guidelines advanced malignant mesothelioma: an open-label, for pathologic diagnosis of malignant mesotheli- single-arm, phase 2 trial. Lancet Oncol 14: 1104- oma: 2012 update of the consensus statement 1111, 2013. from the International Mesothelioma Interest 22. Buikhuisen WA, Burgers JA, Vincent AD, et al. Group. Arch Pathol Lab Med 137: 647-667, Thalidomide versus active supportive care for 2013. maintenance in patients with malignant mesothe- 14. Kadota K, Suzuki K, Sima CS, et al. Pleomorphic lioma after first-line chemotherapy (NVALT 5): epithelioid diffuse malignant pleural mesothelio- an open-label, multicentre, randomised phase 3 ma: a clinicopathological review and conceptual study. Lancet Oncol 14: 543-551, 2013. proposal to reclassify as biphasic or sarcomatoid 23. Nowak AK, Millward MJ, Francis J, et al. Phase mesothelioma. J Thorac Oncol 6: 896-904, 2011. II study of sunitinib as second-line therapy in ma- 15. Eltabbakh GH, Piver MS, Hempling RE, et al. lignant pleural mesothelioma (MPM). J Clin Clinical picture, response to therapy, and survival Oncol 26: 15s: 8063-8070, 2008. of women with diffuse malignant peritoneal mes- 24. Mathy A, Baas P, Dalesio O, et al. Limited effi- othelioma. J Surg Oncol 70: 6-12, 1999. cacy of imatinib mesylate in malignant mesothe- 16. Hesdorffer ME, Chabot JA, Keohan ML, et al. lioma: a phase II trial. Lung Cancer 50: 83-86, Combined resection, intraperitoneal chemotherapy, 2005. and whole abdominal radiation for the treatment 25. Porta C, Mutti L, Tassi G. Negative results of an of malignant peritoneal mesothelioma. Am J Clin Italian Group for Mesothelioma (G.I.Me.) pilot Oncol 31: 49-54, 2008. study of single-agent imatinib mesylate in malig- 17. Yan TD, Brun EA, Cerruto CA, et al. Prognostic nant pleural mesothelioma. Cancer Chemother indicators for patients undergoing cytoreductive Pharmacol 59: 149-150, 2007. surgery and perioperative intraperitoneal chemo- 26. Millward M, Parnis F, Byrne M, et al. Phase II therapy for diffuse malignant peritoneal mesothe- trial of imatinib mesylate in patients with ad- lioma. Ann Surg Oncol 14: 41-49, 2007. vanced pleural mesothelioma. Proc Am Soc Clin 18. Ceelen WP, Påhlman L, Mahteme H. Pharmaco- Oncol 22: 912-920, 2003. dynamic aspects of intraperitoneal cytotoxic 27. Jahan PA, Wang XF, Krug ML, et al. Sorafenib in therapy. Cancer Treat Res 134: 195-214, 2007. malignant mesothelioma (MM): A phase II trial of 19. Yan TD, Links M, Fransi S, et al. Learning curve the Cancer and Leukemia Group B. J Clin Oncol for cytoreductive surgery and perioperative intra- 25: 18s: 7007-7015, 2007. peritoneal chemotherapy for peritoneal surface 28. Van Schil PE, Baas P, Gaafar R, et al. Phase II malignancy--a journey to becoming a Nationally feasibility trial of induction chemotherapy fol- 92 Z. Y. Lin et al./JCRP 2(2015) 83-92

lowed by extrapleural pneumonectomy and post- study of an oral histone deacetylase inhibitor, su- operative radiotherapy for cT3N1M0 or less ma- beroylanilide hydroxamic acid, in patients with lignant pleural mesothelioma. J Clin Oncol 27: advanced cancer. J Clin Oncol 23: 3923-3931, 15s: 7509-7517, 2009. 2005. 29. Kelly WK, O'Connor OA, Krug LM, et al. Phase I