Greillier L, Marco S, Barlesi F.

Service d’Oncologie Multidisciplinaire et Innovations Thérapeutiques, Université de la Méditerranée-Assistance Publique Hôpitaux de Marseille, Marseille, France.

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, whose exposure to asbestos fibers is the main etiology. The incidence of MPM is anticipated to increase worldwide during the first half of this century. MPM is notoriously refractory to most treatments, and the only standard of care is cisplatin and antifolate first-line chemotherapy. The urgent need for additional therapeutic agents, in parallel with advances in the knowledge of the molecular events of oncogenesis, has resulted in the development of the so-called ‘targeted agents’ that specifically inhibit critical pathways in malignant cells and in their microenvironment. We carried out a comprehensive review of the literature from January 2000 to May 2010 on studies that assessed targeted agents for the systemic treatment of MPM. Although tyrosine kinase inhibitors directed against the epidermal growth factor and the platelet-derived growth factor receptors did not show significant clinical activity in phase II studies, some other targeted therapies seemed promising, notably histone deacetylase inhibitors and antiangiogenic agents. However, none of these has yet reached daily practice. That is the reason why efforts must continue in the area of clinical and translational research for MPM.

Zucali PA, Giovannetti E, Destro A, Mencoboni M, Ceresoli GL, Gianoncelli L, Lorenzi E, De Vincenzo F, Simonelli M, Perrino M, Bruzzone A, Thunnissen E, Tunesi G, Giordano L, Roncalli M, Peters GJ, Santoro A.

Department of Oncology, Biostatistics Unit, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy. paolo.zucali@humanitas.it

Abstract

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients.

Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome.

Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted.

Yonemura Y, Tsukiyama G, Miyata R, Sako S, Endou Y, Hirano M, Mizumoto A, Matsuda T, Takao N, Ichinose M, Miura M, Hagiwara A, Li Y.

NPO Organization to Support Peritoneal Dissemination Treatment.

Abstract

A total of 521 patients with peritoneal carcinomatosis (PC) were treated by peritonectomy and perioperative chemotherapy. Each of the 95, 58, 316, 31, 10 and 11 patients were from gastric, colorectal, appendiceal, ovarian, small bowel cancer and mesothelioma, respectively. The distribution and volume of PC are recorded by the Sugarbaker peritoneal carcinomatosis index( PCI). Peritonectomy was performed with a radical resection of the primary tumor and all gross PC with involved organs, peritoneum, or tissue that was deemed technically feasible and safe for the patient. The postoperative major complication of grade 3 was found in 14%, and total 30 – day mortality was 2.7%. The survival of gastric cancer patients with a PCI score ≤ 6 was significantly better than those with a PCI score ≥ 7. In appendiceal neoplasm, patients with PCI score less than 28 showed significantly better survival than those with PCI score greater than 29. The survival of colorectal cancer patients with a PCI score ≥ 11 was significantly poorer than those with a PCI score ≤ 10. Among the various prognostic factors in appendiceal neoplasm and gastric cancer patients, CC – 0 complete cytoreduction was the most important independent prognostic factor. Peritonectomy is done to remove macroscopic disease and perioperative intraperitoneal chemotherapy to eradicate microscopic residual disease aiming to remove disease completely with a single procedure. Peritonectomy combined with perioperative chemotherapy may achieve long – term survival in a selected group of patients with PC. The higher mortality rate underlines this necessarily strict selection that should be reserved to experienced institutions.

Ceresoli GL, Zucali PA, De Vincenzo F, Gianoncelli L, Simonelli M, Lorenzi E, Ripa C, Giordano L, Santoro A.

Oncology Unit, Cliniche Humanitas Gavazzeni, Bergamo, Italy; Department of Oncology, Istituto Clinico Humanitas IRCCS, Rozzano (Milan), Italy.

Abstract

The role of second-line therapy in patients with malignant pleural mesothelioma (MPM) progressing after first-line pemetrexed-based chemotherapy (PBC) is currently undefined. Recent case series have suggested a possible role of re-treatment with PBC. In this observational study, the activity and safety of this therapeutic option was assessed in a consecutive series of cases. Patients with complete response (CR), partial response (PR) or stable disease (SD) lasting for at least 3 months after first-line PBC were retreated with PBC, either as second-line (2L) or further-line (>2L) therapy. Descriptive analyses of progression-free survival (PFS), overall survival (OS), response rate and toxicity are reported. Between October 2004 and July 2009, 31 patients (21 males and 10 females) received re-treatment with PBC as 2L (18 patients) or beyond 2L therapy (13 patients). Median age was 65 years (range 37-81). Fifteen patients were re-treated with pemetrexed alone, and 16 with a pemetrexed/platinum combination. An objective response was achieved in 6 patients (one CR and 5 PRs), for a response rate of 19%. Nine patients (29%) had SD after treatment. Overall, the disease control rate (DCR) was 48%. Median PFS and overall survival (OS) after re-treatment with PBC were 3.8 months and 10.5 months, respectively. PFS and OS after re-treatment with PBC were correlated with PFS achieved after first-line PBC (FL-PFS). Patients with a FL-PFS >12 months had a median PFS after re-treatment of 5.5 months, while patients with a FL-PFS =12 months had a median PFS after re-treatment of 2.5 months; no patient in this group was progression-free at 1 year. Toxicity was mild, with grade 3 or 4 hematological toxicity occurring in 9.7% of patients. In conclusion, re-treatment with PBC should be considered as second-line therapy in MPM patients achieving a durable (>12 months) disease control with first-line PBC. Further prospective evaluation of this therapeutic option is warranted.

Keywords: Malignant pleural mesothelioma; Second-line therapy; Pemetrexed; Re-treatment; Progression-free survival; Disease control.

Shapiro GI, Tibes R, Gordon MS, Wong BY, Eder JP, Borad MJ, Mendelson DS, Vogelzang NJ, Bastos BR, Weiss GJ, Fernandez C, Sutherland W, Sato H, Pierceall WE, Weaver D, Slough S, Wasserman E, Kufe DW, Von Hoff DD, Kawabe T, Sharma S.

Department of Medical Oncology, Dana Farber Cancer Institute.

Abstract

Purpose: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G2 checkpoint abrogator CBP501, as a single agent and in combination with cisplatin.

Experimental Design: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m&sup2;), or with cisplatin (both on D1, q3w, from 3.6 mg/m&sup2; CBP501, 50 mg/m&sup2; cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in ≤1 of 3-6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles.

Results: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10-60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine and loratadine. The MTD was 25 mg/m&sup2; CBP501 and 75 mg/m&sup2; cisplatin, with 2 patients at the highest dose (36.4 mg/m&sup2; CBP501, 75 mg/m&sup2; cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G3 rise of troponin in one patient. Grade 3-4 treatment-related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease.

Conclusions: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase 2 dose (RP2D) the combination is feasible and HRS manageable with prophylaxis. Evidence of anti-tumor activity was observed in platinum-resistant patients.

Dickgreber NJ, Fink TH, Latz JE, Hossain AM, Musib LC, Thomas M.

Hannover Medical School, Hannover, Germany. nicolas.dickgreber@gmx.de

Abstract

Purpose: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B₁₂ to the treatment regimen. We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation.

Experimental Design: Patients with malignant pleural mesothelioma or non–small cell lung cancer received pemetrexed doses from 500 to 900 mg/m² + 75 mg/m² cisplatin once every 21 days. Folic acid and vitamin B₁₂ were administered per label recommendations.

Results: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m² pemetrexed + 75 mg/m² cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1 death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m² pemetrexed + 75 mg/m² cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK.

Conclusions: Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m² + 75 mg/m² cisplatin. Based on this study, the recommended dose would be 800 mg/m² pemetrexed + 75 mg/m² cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m² single-agent pemetrexed versus 500 mg/m² and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.

Passot G, Cotte E, Brigand C, Beaujard AC, Isaac S, Gilly FN, Glehen O.

Service de chirurgie générale digestive et endocrinienne, centre hospitalier Lyon Sud (CHLS) – Lyon.

Abstract

Diffuse malignant peritoneal mesothelioma is a rare and lethal disease. Locoregional treatments combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) seem to improve prognosis.

Methods: Cytoreductive surgery and HIPEC was performed in 22 patients at the Centre Hospitalier-Lyon Sud between 1989 and 2006. A retrospective analysis of survival was carried out to assess clinical and histological prognostic factors.

Results: Nineteen patients with diffuse malignant peritoneal mesothelioma were included (16 epithelial, 3 biphasic and 3 multicystic forms). Sixteen patients presented stage 3 or 4 peritoneal carcinomatosis according to the Gilly classification. Optimal cytoreductive surgery was performed for 11 patients (complete macroscopic resection or residual tumor nodules less than 2.5mm). No post-operative deaths occurred but 9 patients (47%) presented grade III or IV post-operative complications. The overall median survival was 36.9 months; completeness of cytoreduction was the only significant prognostic factor.

Conclusion: Cytoreductive surgery combined with HIPEC may improve the length of survival for patients with diffuse malignant peritoneal mesothelioma; such patients should be treated in specialized centers.

Keywords: Peritoneal Mesothelioma , Treatment , Cytoreductive surgery , Hyperthermic intraperitoneal chemotherapy

Xanthopoulos A, Bauer TT, Blum TG, Kollmeier J, Schönfeld N, Serke M.

Respiratory Diseases Clinic Heckeshorn, Department of Pneumology, HELIOS Klinikum Emil von Behring, Berlin, Germany. torsten.bauer@helios-kliniken.de.

Abstract

Background: The aim of this study was to investigate the efficacy and safety of oxaliplatin +/- gemcitabine in patients with diffuse malignant pleural mesothelioma (MPM) pretreated with pemetrexed.

Methods: The study enrolled consecutive patients with relapsed MPM, all of them pretreated with a platin-pemetrexed-based chemotherapy. Oxaliplatin 80 mg/m2 was administered as monotherapy or in combination with gemcitabine 1000 mg/m2 given on day 1 and 8. Cycles were repeated every 21 days. The primary endpoints were response rate and disease control rate. Secondary endpoints included overall survival (OS), time to tumour progression (TTP), progression-free survival (PFS), time to treatment failure (TTF), and toxicity.

Results: Between February 2005 and September 2007 29 patients (median age: 65.0 years, World Health Organisation (WHO) performance status: 0-3) were enrolled. The follow-up period encompassed 5.4 to 97.4 weeks (median: 24.3 weeks). Out of these 29 patients, 15 were treated in second, 10 in third, 3 in fourth and 1 in fifth line, respectively. The majority of the patients received the combination oxaliplatin and gemcitabine (n = 25 vs. 4; 86.2 vs. 13.8%).The median overall survival (OS) was 71.7 weeks (30.6-243.3 weeks), whereas survival from the start of oxaliplatin/gemcitabine-treatment was 24.3 weeks (5.4-97.3 weeks). Median time to tumour progression (TTP) was 9.3 weeks (3.0-67.6 weeks).Partial response (PR) was observed in 2 patients (6.9%), stable disease (SD) for at least three courses of treatment in 11 patients (37.9%). Thus, disease control rate was 44.8%, whereas 16 of 29 patients exhibited progressive disease (55.2%).The toxicity profile was favourable, with no WHO grade 4-toxicities, only few dose-reductions were performed due to non-symptomatic haematotoxicities (neutropenia, thrombopenia). Mild WHO grade 2 neurotoxicity was seen in 6 patients.

Conclusion: Pemetrexed-pretreated patients with progressive MPM may benefit from a consecutive chemotherapy with oxaliplatin and gemcitabine without significant toxicity.

Baratti D, Kusamura S, Cabras AD, Dileo P, Laterza B, Deraco M.

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

Abstract

Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The issue of treatment failure has never been extensively addressed. The present study assessed the failure pattern, management, and outcome of progressive DMPM following comprehensive treatment. Clinical data on 70 patients with DMPM undergoing cytoreduction and HIPEC were prospectively collected; after a median follow-up of 43 months, disease progression occurred in 38 patients. Progressive disease distribution in 13 abdominopelvic regions was analyzed. In 28 patients undergoing adequate cytoreduction (residual tumor < or =2.5 mm), clinicopathological factors correlating to disease progression in each region were investigated. Median time to progression was 9 months [95% confidence interval (CI) 1.6-35.9]. Median survival from progression was 8 months (95% CI 4-16.2). The failure pattern was categorized as peritoneal progression (n = 31), liver metastases (n = 1), abdominal lymph-node involvement (n = 2), pleural seeding (n = 4). Small bowel was the single site most commonly involved (n = 27). Residual tumor < or =2.5 mm (versus no visible) was the only independent risk factor for disease progression in epigastric region (P = 0.047), upper ileum (P = 0.029), upper jejunum (P = 0.034), and lower jejunum (P = 0.002). Progressive disease was treated with second HIPEC in 3 patients, debulking in 4, systemic chemotherapy in 16, and supportive care in 15. At multivariate analysis, time to progression <9 months (P = 0.009), poor performance status (P = 0.005), and supportive care (P = 0.003) correlated to reduced survival from progression. We conclude that minimal residual disease, compared with macroscopically complete cytoreduction, correlated to failure in critical anatomical areas, suggesting the need for maximal cytoreductive surgical efforts. In selected patients, aggressive management of progressive disease seems worthwhile.

van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, Nowak AK, Lake RA.

National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. robbertvdm@gmail.com

Abstract

Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.

Keywords: Tumor immunity – Regulatory CD4+ T cells – Chemotherapy – Mesothelioma – Gemcitabine – Cyclophosphamide