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.

Barone-Adesi F, Ferrante D, Bertolotti M, Todesco A, Mirabelli D, Terracini B, Magnani C.

Unit of Cancer Epidemiology, CeRMS and Center for Oncologic Prevention Piemonte, University of Turin, Turin, Italy.

Abstract

Models based on the multistage theory of carcinogenesis predict that the rate of mesothelioma increases monotonically as a function of time since first exposure (TSFE) to asbestos. Predictions of long-term mortality (TSFE >/= 40 years) are, however, still untested, because of the limited follow-up of most epidemiological studies. Some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3,443 asbestos-cement workers, followed for more than 50 years. The functional relation between mesothelioma rate and TSFE was evaluated with various regression models. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers’ lungs.

Keywords: asbestos, mesothelioma, multi-stage model, latency, clearance

Elias D, Bedard V, Bouzid T, Duvillard P, Kohneh-Sharhi N, Raynard B, Goere D.

Département de chirurgie générale oncologique; Institut Gustave-Roussy, Villejuif.

Abstract

Objective: To report survival results in patients with diffuse malignant peritoneal mesothelioma (MPM) treated with maximal cytoreductive surgery followed by immediate intraperitoneal chemotherapy, and to compare them with the median survival of 12-24 months obtained with the standard treatment based on systemic chemotherapy.

Patients and methods: Twenty-six patients underwent this new regional approach and a median follow-up of 55 months was achieved after this treatment. Complete cytoreductive surgery (residual disease <2 mm) was performed in all but one patient. Intraperitoneal chemotherapy was performed with hyperthermia (4245°C) and oxaliplatin in 22 patients. The last 12 patients additionally received irinotecan. Data were prospectively verified and retrospectively analyzed.

Results: One patient died postoperatively (4%), and morbidity attained 54%. The median survival exceeded 100 months and the overall 5-year survival rate was 63%. This small series lacks the statistical power required to conduct a well-grounded study on prognostic factors, particularly as the completeness of the surgery is not analyzable here. However, the low-grade histological types had a better disease-free survival rate that was of borderline significance compared to their high-grade counterparts.

Conclusion: This new approach combining complete cytoreductive surgery considerably increases the survival of patients with MPM compared with the standard treatment based on systemic chemotherapy.

Hui K. Gan¹, Paul L. Mitchell¹, Peter Galettis², Ian D. Davis¹, Jonathan Cebon¹, Paul de Souza² and Matthew Links²

(1) Department of Medical Oncology and Ludwig Institute for Cancer Research, Austin Hospital, Level D, 3KZ Building, Studley Road, Heidelberg, Melbourne, VIC, Australia

(2) Department of Medical Oncology, St George Hospital and University of New South Wales, Gray Street, 2217 Kogarah, NSW, Australia

Abstract

Purpose: This dose escalation study aimed to determine the recommended doses, toxicity and pharmacokinetics of oxaliplatin and gemcitabine given on days 1 and 8 every 21 days. This schedule may maximize dose intensity of both drugs with acceptable or reduced toxicity.

Patient and methods: Eligible patients had solid malignancies, no more than two prior courses of chemotherapy, ECOG performance status 0–2, neurotoxicity ≤ NCI-CTC grade 1 and adequate organ function. Dose escalation commenced at oxaliplatin 40 mg/m² and gemcitabine 750 mg/m², both given on days 1 and 8 every 21 days, and reached oxaliplatin 80 mg/m² and gemcitabine 1,500 mg/m². The two highest dose levels were each expanded to six patients to gain additional toxicity data.

Results: There were no dose limiting toxicities related to treatment and an MTD was not reached. Five patients (24%) had grade 3 neutropenia, without associated infection, and seven patients (33%) had grade 3/4 thrombocytopenia. Neurotoxicity was mild and no worse than grade 1. Two patients with mesothelioma (10%) had partial responses and 11 patients (52%) had disease stabilization. No pharmacokinetic interaction between oxaliplatin and gemcitabine was detected. Dose intensity was maximal at level 4 (oxaliplatin 70 mg/m² and gemcitabine 1,250 mg/m²).

Conclusions: This schedule allows oxaliplatin and gemcitabine to be delivered at the full dose intensity of each drug with excellent tolerability and predictable pharmacokinetics. The recommended doses for phase II studies are oxaliplatin 70 mg/m² and gemcitabine 1,250 mg/m² on days 1 and 8 every 21 days.

Keywords: Gemcitabine – Oxaliplatin – Phase 1 – Neurotoxicity – Pharmacokinetics – Mesothelioma

Porta C, Zimatore M, Bonomi L, Imarisio I, Paglino C, Sartore-Bianchi A, Mutti L.

Medical Oncology, I.R.C.C.S. San Matteo University Hospital, Piazzale C. Golgi, I-27100 Pavia, Italy. c.porta@smatteo.pv.it

Abstract

Within a single-institution phase II trial, we investigated the antitumor activity of the Raltitrexed-Oxaliplatin combination as second-line therapy for malignant pleural mesothelioma (MPM). Fourteen patients were enrolled and all were assessable for response. The trial was then closed because chemotherapy, though well tolerated, yielded no objective responses. The best response observed was disease stabilization in 4 patients only (28.57%), while the other 10 patients (71.42%) progressed despite treatment. Median time to progression (TTP) was 8 weeks (average: 9.85, range: 7-20), while median overall survival was just 14 weeks (average: 21.69, range: 9-66+).