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.

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/m²), or with cisplatin (both on D1, q3w, from 3.6 mg/m² CBP501, 50 mg/m² 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/m² CBP501 and 75 mg/m² cisplatin, with 2 patients at the highest dose (36.4 mg/m² CBP501, 75 mg/m² 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.

Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, Liu Y, Blatter J, Visseren-Grul C, Stahel R.

Cardarelli Hospital, Medical Oncology, Via Cardarelli 9, 80100 Naples, Italy. giacomo.carteni@ospedalecardarelli.it

Abstract

Aim: Peritoneal mesothelioma (PM) has rarely been studied. The Expanded Access Program (EAP) provided access to 109 patients with PM.

Methods: This was a nonrandomized, open-label study conducted in chemo-naïve or previously treated patients with PM not amenable to curative surgery. Patients received pemetrexed (PEM) 500mg/m2 alone or with cisplatin (CIS) 75mg/m2 or carboplatin (CARBO) AUC 5 every 21 days, supplemented with standard vitamin B12, folate, and dexamethasone.

Results: Response rates (95% CI) for PEM, PEM/CIS, and PEM/CARBO were 12.5% (3.5, 29.0), 20.0% (7.7, 38.6), and 24.1% (10.3, 43.5), respectively. Median survival for PEM was 10.3 months. One-year survival rates for PEM/CIS and PEM were 57.4% (95% CI: 10.3, 100) and 41.5% (95% CI: 4.6, 78.4), respectively, and were not available for PEM/CARBO. Anemia was the most common serious adverse event (6.4%). Neutropenia (34.6%) was the most frequent CTC grade 3 or 4 toxicity reported.

Concluding statement: PEM with or without a platinum agent was both active and well tolerated in patients with peritoneal mesothelioma.

Keywords: Peritoneal mesothelioma, Pemetrexed, Platinum, Cisplatin, Carboplatin, Compassionate-use program, Expanded Access Program (EAP).

Berghmans T.

Département des Soins Intensifs et Oncologie Thoracique, Institut Jules-Bordet (Centre des Tumeurs de l’Université Libre de Bruxelles), 1 Rue Héger-Bordet, Brussels, Belgium. thierry.berghmanns@bordet.be

Abstract

Malignant pleural mesothelioma is a rare tumour of poor prognosis. Available therapeutics have restricted efficacy. Pleuro-pneumonectomy is the only treatment with curative intent but it could be offered to a limited and well selected group of patients. The role of radiotherapy is palliative and its preventive role on malignant seeding after invasive procedures is controversial. There are few active cytotoxic drugs in this disease. Currently, based on two randomised trials, the most efficacious chemotherapy regimen consists in a combination of cisplatin and an antifolate agent, pemetrexed or raltitrexed.

Keywords: Mesothelioma, Surgery, Radiotherapy, Chemotherapy

Lee CW, Murray N, Anderson H, Rao SC, Bishop W.

BC Cancer Agency – Fraser Valley Centre, 13750 96th Avenue, Surrey, British Columbia, Canada V3V 1Z2. clee@bccancer.bc.ca

Abstract

Cisplatin plus pemetrexed has been standard systemic therapy for malignant pleural mesothelioma (MPM) since the landmark randomized trial reported in 2003. However, the combination of cisplatin and gemcitabine was incorporated into clinical practice following publication of promising phase II trial results in 1999. The impact of these platinum-based regimens is assessed in this review of practice in the province of British Columbia. All cases of MPM diagnosed from 1999 to 2005 were identified in a provincial registry using ICD-O codes. The clinical records of individuals referred to the BC Cancer Agency were reviewed, and those treated with a platinum analog plus gemcitabine or pemetrexed as first-line therapy were included in survival analyses. During the selected period, 81 patients were treated first-line with a platinum analog plus gemcitabine (n=40) or pemetrexed (n=41). Characteristics of the entire cohort include: age at diagnosis, mean 65 years (median 66, range 43-84); gender, male 70 (86%); laterality of disease, right-sided 51 (63%); histology, epithelioid or not otherwise specified 69 (85%). Median survival was 10 months (95% confidence interval, 7.7-12.3), with 1- and 2-year survival rates 0.42 and 0.21, respectively. Survival did not appear to be influenced by the chemotherapy agent used. Survival outcomes with chemotherapy for MPM in the province are comparable to what is reported in the literature. No difference is seen combining platinum analogs with gemcitabine or pemetrexed. Platinum-based doublets might represent a therapeutic ceiling for cytotoxic chemotherapy in MPM.

Li L, Razak AR, Hughes A.

Department of Medical Oncology, Northern Centre for Cancer Treatment (NCCT), Westgate Road, Newcastle upon Tyne NE4 6BE, United Kingdom.

Abstract

Background: Malignant pleural mesothelioma is an aggressive cancer. Chemotherapy with cisplatin and pemetrexed can improve overall survival but has a toxic profile. Substitution of cisplatin with carboplatin may avoid some potential side-effects. Therefore, we undertook a retrospective review to assess the effectiveness and tolerability of carboplatin and pemetrexed in patients with malignant pleural mesothelioma in clinical practice.

Methods: Patients with malignant pleural mesothelioma who had been treated with carboplatin and pemetrexed were retrospectively identified from pharmacy databases. The endpoints were disease control rate, time to treatment failure, clinical improvement rate and overall survival. We also evaluated any significant haematological and non-haematological toxicities.

Results: A total of 49 patients were identified. Of 45 evaluable cases, the disease control rate was achieved in 34 patients (69%, 95% CI 55–82, intention to treat analysis). The clinical response rate was achieved in 34 out of 49 patients (69%, 95% CI 55–82). The median time to treatment failure was 4.6 months (95% CI 3.4–5.8) and median overall survival was 14 months (95% CI 9.5–18.5). Grade 3/4 haematological toxicities were observed in 7 patients (14.3%). Grade 3/4 non-haematological toxicities were seen in 12 patients (24.5%). No toxic deaths were recorded.

Conclusion: The combination of carboplatin and pemetrexed may be a viable option in the treatment of malignant pleural mesothelioma.

Keywords: Pleural; Mesothelioma; Pemetrexed; Carboplatin; Chemotherapy; Disease control; Retrospective; Survival

Abbreviations: CI, confidence interval; MPM, malignant pleural mesothelioma; IMIG, International Mesothelioma Interest Group; AUC, area under the curve; i.v., intravenous; DCR, disease control rate; CT, computed tomography; TTF, time to treatment failure; OS, overall survival

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.

Felip E, Rosell R.

Vall d’Hebron University Hospital Barcelona, Spain.

Abstract

NSCLC accounts for 80% of all cases of lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced, unresectable disease, which remains incurable. In advanced disease, chemotherapy with platinum (cisplatin or carboplatin) in combination with a third-generation cytotoxic drug (vinorelbine, gemcitabine, paclitaxel, or docetaxel) can provide a modest improvement in survival without impairing quality of life. In chemotherapy-naïve, advanced, non-squamous NSCLC patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. Response rates of 20%-40% can now be expected, with a median survival of 8-11 months and a 1-year survival rate of 30%-40%. In second-line treatment, docetaxel has shown superiority to best supportive care in terms of survival and quality of life. A pooled analysis comparing docetaxel administered weekly versus 3-weekly found similar survival rates between the schedules and a non-significant reduction in febrile neutropenia for the weekly regimen. Pemetrexed, a multitargeted antifolate agent, has shown clear activity in several tumors, including mesothelioma and NSCLC. In a phase III trial, second-line treatment with pemetrexed demonstrated overall survival comparable to docetaxel, with a more manageable toxicity profile.

Keywords: pemetrexed, second-line therapy, NSCLC

Cioffredi LA, Jänne PA, Jackman DM.

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Abstract

Peritoneal mesothelioma is a rare and often aggressive malignancy, mostly affecting asbestos exposed adults. We present four pediatric peritoneal cases treated with a cisplatin-based doublet regimen, the standard of care in the systemic therapy of adult mesothelioma. Treatment was well tolerated, and three of these patients have achieved long-term survival. The fathers of three of the patients worked in the construction industry and may have been the source of indirect asbestos exposure.

Keywords: chemotherapy, pediatric oncology, solid tumors