Hillerdal G, Sorensen JB, Sundström S, Riska H, Vikström A, Hjerpe A.

Department of Lung Medicine and Allergology, Karolinska University Hospital, Solna, Stockholm, Sweden. gunnar.hillerdal@karolinska.se

Abstract

Background: Malignant pleural mesothelioma has a poor prognosis and there is limited effect of treatment. The Nordic Mesothelioma groups decided in the year 2000 to investigate a combination of liposomized doxorubicin, carboplatin, and gemcitabine for this disease in a phase II study.

Methods: From January 2001, to December 2003, 173 evaluable patients with biopsy-verified malignant mesothelioma were included. Two patients were lost to follow-up, but all the others were followed for at least 4 years or until death.

Results: Toxicity was fairly low. There were 56 responses (32.4%), of which 2 were complete; the median time to progression was 8.6 months, and the median overall survival was 13 months. Some patients had their responses 4 to 6 months after last treatment. For 116 patients with epitheloid subtype, median survival was 17 months. A subgroup of these patients with good performance status, early stage, and age 70 years or less, showed a median survival of 22 months.

Conclusion: The treatment yields good results with a high number of responses and long survival, and a low toxicity. The long survival of the epitheloid subgroup with good prognostic factors is as good as or even better than some studies on radical surgery or multimodal treatment, underlining the need of randomized studies to evaluate such treatment options.

Hesdorffer ME, Chabot J, DeRosa C, Taub R.

Mesothelioma Applied Research Foundation, Santa Barbara, CA, USA. mhesdorer@curemeso.org

Abstract

Opinion statement: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that rapidly spreads within the confines of the abdominal cavity to involve most accessible peritoneal and omental surfaces. Current treatment options are unsatisfactory, and new approaches are needed. Recent publications have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC). We have noted at our institution prolonged survival in selected patients after intensive multimodality treatment. Our most recently reported trial included initial laparatomy with omentectomy, resection of peritoneal implants, and placement of bilateral peritoneal Portacath; repeated courses of intraperitoneal chemotherapy with doxorubicin, cisplatin, and interferon gamma; second-look laparotomy; and intraoperative hyperthermic perfusion with mitomycin and cisplatin, followed by whole abdominal radiation. To date there have been no universally accepted treatments for MPM. Unless referred to a specialty center, patients are routinely treated with pemetrexed and cisplatin which has been shown to increase survival in pleural mesothelioma.

Patriti A, Cavazzoni E, Graziosi L, Pisciaroli A, Luzi D, Gullà N, Donini A.

Section of General and Emergency Surgery, Department of Surgery, University of Perugia, Perugia, Italy. albertopatriti@gmail.com

Abstract

A variety of options have been proposed to treat malignant ascites but most of them have failed to reach a significant impact in terms of palliation. Laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC) could represent a good therapeutic tool for patients in whom medical therapies have failed and peritoneovenous shunting is contraindicated. Here we present a case of a 49-year-old woman with malignant ascites secondary to peritoneal spreading of a right pleural mesothelioma. After failure of medical therapy, the patient underwent LHIPEC with Cisplatin 25 mg/m/L and Doxorubicin 7 mg/m/L. A dramatic reduction of ascites was documented in the postoperative period and the patient experienced complete abdominal symptom relief. Ascites did not recur during a follow-up period of 6 months. LHIPEC could be a good therapeutic option to palliate malignant ascites from mesothelioma in cases not eligible for a radical treatment. Further studies are needed to standardize dosage and perfusion parameters.

Van der Speeten K, Stuart OA, Mahteme H, Sugarbaker PH.

Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600, Genk, Belgium, kurt.vanderspeeten@zol.be.

Abstract

Purpose: A pharmacologic analysis of intracavitary doxorubicin in the treatment of patients with intracavitary cancer dissemination was performed to further evaluate the possible benefits of this treatment modality.

Methods: Twenty appendiceal malignancy patients with peritoneal carcinomatosis (PC), three appendiceal malignancy patients with direct extension into the pleural cavity, 20 patients with peritoneal mesothelioma and one patient with pleural mesothelioma were available for pharmacologic monitoring. After intraperitoneal or intrapleural administration of doxorubicin, plasma and peritoneal fluid samples were obtained at 15, 30, 45, 60 and 90 min in all patients. After intrapleural administration, plasma and pleural fluid samples were collected at similar intervals. Tumor and normal tissues were obtained when available. Doxorubicin concentrations were determined by high-performance liquid chromatography (HPLC).

Results: Intraperitoneal doxorubicin showed a prolonged retention in the peritoneal cavity. Doxorubicin concentrations in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min. For appendiceal malignancy, the concentrations of doxorubicin were significantly higher in minimally aggressive mucinous tumors. Pleural chemotherapy solutions retained doxorubicin to a greater extent than peritoneal fluid.

Conclusions: Doxorubicin shows characteristics favorable for intracavitary administration with sequestration of doxorubicin in cancer nodules.

Keywords: Intraperitoneal chemotherapy – Intrapleural chemotherapy – Doxorubicin – Pharmacokinetics – Pharmacodynamics – Appendiceal cancer – Peritoneal mesothelioma – Pleural mesothelioma

Harrison LE, Bryan M, Pliner L, Saunders T.

Division of Surgical Oncology, UMDNJ-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103, USA. L.Harrison@umdnj.edu

Abstract

Background: Cytoreduction coupled with hyperthermic intraperitoneal chemotherapy (HIPEC) is an attractive treatment option for a select group of patients with abdominal-only malignancy. The present phase I study examined the safety and pharmacokinetics of intraperitoneal pegylated liposomal doxorubicin (PLD) used in the context of HIPEC in patients with advanced abdominal-only malignancies.

Methods: Patients with advanced abdominal malignancies underwent maximal cytoreduction and HIPEC with escalating doses of PLD (15-100 mg/m(2)). Perfusate, serum, and tissue doxorubicin levels were measured in five patients undergoing HIPEC at the maximum tolerated dose.

Results: Twenty-one patients were enrolled in this trial. The maximum dose evaluated in this trial was 100 mg/m(2) and was well tolerated. The most common grade 3/4 complications were superficial wound infection and prolonged ileus. One patient developed an anastomotic leak in the postoperative period, requiring re-exploration. The median postoperative length of stay was 7 days (range, 4-29 days), three patients required readmissions within 30 days, and there were no operative mortalities The median follow-up time for was 13.7 months (range, 3-38 months). The median overall survival was 30.6 months with a median disease-free survival of 25 months.

Conclusions: We report that HIPEC with PLD following maximal cytoreduction in patients with advanced abdominal-only gastrointestinal or gynecologic malignancies is well tolerated. Encouraging survival after cytoreduction and HIPEC with PLD suggest that a phase II trial to verify activity is indicated.

Baratti D, Kusamura S, Sironi A, Cabras A, Fumagalli L, Laterza B, Deraco M.

Department of Surgery, National Cancer Institute, Milan, Italy.

Abstract

Background: Multicystic peritoneal mesothelioma (MPM) is an extremely uncommon lesion with uncertain malignant potential. Multiple recurrences after surgical interventions and transition to aggressive malignancies have been reported. Here, we review our experience with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of MPM.

Patients and Methods: Five women with MPM underwent 6 procedures of cytoreduction and close-abdomen HIPEC with cisplatin and doxorubicin. Three patients had recurrent disease after 1, 2 and 4 previous debulkings, respectively.

Results: Optimal cytoreduction (residual tumor nodules < or =2.5 mm) was performed in all the procedures. One grade 4 postoperative complication (NCI/CTCAE v.3.0) and no operative mortality occurred. Median follow-up was 31 months (range 3-102). MPM recurred in two patients: one is presently disease-free after a second cytoreduction with HIPEC and the other is alive with minimal stable disease.

Conclusion: Definitive eradication by means of cytoreduction and HIPEC seems a safe and effective therapeutic option for MPM.

Riganti C, Doublier S, Aldieri E, Orecchia S, Betta PG, Gazzano E, Ghigo D, Bosia A.

Biology and Biochemistry, University of Torino; and Research Center on Experimental Medicine (CeRMS), Via Santena 5/bis, 10126 Torino, Italy.

Abstract

Human malignant mesothelioma (HMM), which is strongly related to asbestos exposure, exhibits high resistance to many anticancer drugs. Asbestos fibers deposition in the lung may cause hypoxia and iron chelation at the fibers surface. Hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), which is upregulated by a decreased availability of oxygen and iron, controls the expression of membrane transporters, such as P-glycoprotein (Pgp), which actively extrude the anticancer drugs. This study has been aimed to assess whether asbestos may play a role in the induction of doxorubicin resistance in HMM cells through the activation of HIF-1{alpha} and an increased expression of Pgp.

After a 24 h incubation with crocidolite asbestos, or with the iron chelator dexrazoxane or under hypoxia, HMM cells were tested for HIF-1{alpha} activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect.

Crocidolite, dexrazoxane and hypoxia caused HIF-1{alpha} activation, Pgp overexpression and increased resistance to doxorubicin accumulation and toxicity. These effects were prevented by the coincubation with the cell-permeating iron salt ferric nitrilotriacetate (FeNTA), which caused an increase of intracellular iron bioavailability, checked as increased activity of the iron regulatory protein-1 (IRP-1). Crocidolite, dexrazoxane and hypoxia induce doxorubicin resistance in HMM cells by increasing HIF-1{alpha} activity, through an iron-sensitive mechanism.

Keywords: Asbestos, doxorubicin resistance, hypoxia-inducible factor-1{alpha}, iron, mesothelioma, P-glycoprotein

Hesdorffer ME, Chabot JA, Keohan ML, Fountain K, Talbot S, Gabay M, Valentin C, Lee SM, Taub RN.

Division of Oncology, Columbia University New York, New York, USA. mhesdorffer@curemeso.org

Abstract

Objective: We report a single-institution Phase I or II trial of surgical debulking, intraperitoneal chemotherapy, and immunotherapy followed by whole abdominal radiotherapy in patients with malignant peritoneal mesothelioma.

Methods: Between 1997 and 2000, 27 patients with malignant peritoneal mesothelioma were enrolled: 23 with epithelial subtype and 4 with sarcomatoid or mixed subtype. The treatment regimen consisted of surgical debulking followed by 4 intraperitoneal courses of cisplatin alternating with 4 courses of doxorubicin, 4 doses of intraperitoneal gamma interferon, a second laparotomy with resection of residual disease plus intraoperative intraperitoneal mitomycin and cisplatin heated to 41 degrees C, and finally whole abdominal radiotherapy.

Results: The median overall survival was 70 months with a 3-year survival of 67% (95% confidence interval, 46%-81%). Fourteen patients have died of their disease with a median time to death of 17 months (range, 0.4-71 months) after consenting to treatment. Seven patients are alive without evidence of disease with a median follow-up of 90 months (range, 71-110 months), and 6 are alive with disease with a median follow-up of 86 months (range, 70-106 months). The regimen was well tolerated. There were no patients with Grade III or IV hematological toxicities, 2 patients with Grade III ototoxicity, and 3 patients with Grade III gastrointestinal toxicity.

Conclusion: Based on the results of this study, intensive multimodality therapy appears feasible and effective in this group of patients.

Lee JE, Raines RT.

Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USADivision of Biology, California Institute of Technology, Pasadena, California, USA.

Abstract

Ranpirnase, a cytotoxic ribonuclease from the frog Rana pipiens, is the archetype of a novel class of cancer chemotherapeutic agents based on homologs and variants of bovine pancreatic ribonuclease (RNase A). Ranpirnase in combination with doxorubicin is in clinical trials for the treatment of unresectable malignant mesothelioma and other cancers. The putative mechanism for ranpirnase-mediated cytotoxicity involves binding to anionic components of the extracellular membrane, cytosolic internalization, and degradation of transfer RNA leading to apoptosis. The maintenance of ribonucleolytic activity in the presence of the cytosolic ribonuclease inhibitor protein is a key aspect of the cytotoxic activity of ranpirnase. The basis for its specific toxicity for cancer cells is not known. This review describes the development of ranpirnase as a cancer chemotherapeutic agent.

Baratti D, Kusamura S, Nonaka D, Oliva GD, Laterza B, Deraco M.

Department of Surgery, National Cancer Institute, Milan, Italy.

Abstract

Background: Multicystic peritoneal mesothelioma (MPM) and well-differentiated papillary peritoneal mesothelioma (WDPPM) are exceedingly uncommon lesions with uncertain malignant potential and no uniform treatment strategy. The aim of the current study was to review our experience with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in these clinical settings.

Methods: Four women with MPM and eight with WDPPM underwent 13 procedures of cytoreduction and close-abdomen HIPEC with cisplatin and doxorubicin. Seven patients had recurrent disease after previous debulking (one operation in five patients, two in one, four in one). Potential clinicopathological prognostic factors were assessed.

Results: Optimal cytoreduction (residual tumor nodules ≤2.5 mm) was performed in 12 of 13 procedures. Median follow-up was 27 months (range 6–94). One grade 4 postoperative complication (NCI/CTCAE v.3.0) and no operative mortalities occurred. One patient underwent the procedure twice due to locoregional MPM recurrence. Transition of typical WDPPM to malignant biphasic mesothelioma was documented in one patient who died of disease progression following incomplete cytoreduction and HIPEC. Following multimodality treatment, 5-year overall and progression-free survival were 90.0% (standard error = 9.0) and 79.7% (11.9), respectively. Progression-free survival following previous debulking surgery (median 24 months; range 2–87) was statistically worse (P = .0156). Incomplete cytoreduction and poor performance status correlated to both reduced overall and progression-free survival after cytoreduction and HIPEC.

Conclusions: MPM and WDPPM are borderline tumors capable of transformation into potentially lethal processes. Definitive tumor eradication by means of cytoreduction and HIPEC seems more effective than debulking surgery in preventing disease recurrence or transition to aggressive malignancies.

Keywords: Multicystic peritoneal mesothelioma – Well-differentiated papillary peritoneal mesothelioma – Peritonectomy – Hyperthermic intraperitoneal chemotherapy; HIPEC