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

Jackman DM, Kindler HL, Yeap BY, Fidias P, Salgia R, Lucca J, Morse LK, Ostler PA, Johnson BE, Jänne PA.

Dana‐Farber Cancer Institute, Boston, Massachusetts.

Abstract

Background: We conducted a phase 2, multicenter, open-label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non-small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity.

Methods: Eligible patients with mesothelioma who had previously received 1 chemotherapy regimen were treated with erlotinib 150 mg per os daily and bevacizumab 15 mg/kg administered intravenously on Day 1 of a 21-day cycle. Treatment continued until disease progression or development of significant toxicity. Tumor response was assessed after every 2 cycles using previously established mesothelioma response criteria from Byrne and Nowak.

Results: Twenty-four eligible patients initiated therapy with erlotinib and bevacizumab between February 2004 and October 2006. There were no complete or partial responses, although 12 patients achieved stable disease for at least 2 cycles of treatment. The median time to progression was 2.2 months (95% confidence interval [CI], 1.4 months-5.9 months). The median survival was 5.8 months (95% CI, 2.8 months-10.1 months). The most common toxicities were rash and diarrhea. There were no treatment-related deaths, intracranial bleeding, or hemoptysis.

Conclusions: The combination of erlotinib and bevacizumab was tolerated reasonably well, but there was no evidence of radiographic response. This study demonstrates the feasibility of conducting trials in mesothelioma patients who have failed first-line therapy. More therapeutic studies with effective agents are needed for these patients.

Somer RA, Sherman E, Langer CJ.

Department of Medical Oncology, Cooper Medical Center, Cherry Hill, NJ, USA.

Abstract

Background: In a previous randomized phase II trial evaluating carboplatin and paclitaxel with or without bevacizumab in patients naive to chemotherapy with advanced non-small-cell lung cancer (NSCLC), median survival ranged from 53 weeks to 76 weeks. Sudden life-threatening hemoptysis occurred in 6 of 66 patients receiving chemotherapy and bevacizumab; 4 episodes were fatal, all in patients with squamous cell histology. Squamous histology and bevacizumab therapy were the only factors associated with life-threatening hemorrhage. ECOG 4599 (Eastern Cooperative Oncology Group 4599), a randomized phase III trial of paclitaxel and carboplatin with or without bevacizumab ultimately excluded patients with squamous histology as well as brain metastases, ongoing therapeutic anticoagulation/nonsteroidal anti-inflammatory drugs, antecedent hemoptysis, and performance status (PS) of 2.

Patients and Methods: We performed a retrospective analysis during a defined period to determine the proportion of patients with newly evaluated advanced NSCLC seen at Fox Chase Cancer Center (FCCC) who would have been eligible for ECOG 4599. We reviewed new thoracic oncology patient visits (n = 260) at FCCC scheduled with 6 medical oncologists from March 1, 2002, through August 8, 2002.

Results: Forty-five patients had histology that made them ineligible (8 mesothelioma, 6 small-cell, 5 mixed histology, and 26 non-lung cancers). Of the remaining 215 patients with NSCLC, 8 had incomplete charts for review and 7 had stage I, 8 stage II, and 43 stage III NSCLC. Of the remaining 149 patients, 33 had received chemotherapy previously. Of the remaining 116, only 34 (29.3%) were eligible. Of 82 ineligible patients, 21 (25.6%) had PS > or = 2, 20 (24.3%) had central nervous system (CNS) metastases, 11 (13.4%) had squamous histology, 9 (10.9%) had therapeutic anticoagulation, and 21 (25.6%) had > or = 2 criteria (11 PS > or = 2/squamous histology; 3 PS > or = 2/CNS involvement; 2 PS > or = 2/anticoagulation, 2 CNS metastasis/anticoagulation, 2 PS > or = 2/squamous histology/anticoagulation, 1 PS > or = 2/squamous histology/CNS metastasis). Of 34 eligible patients, only 6 (17.6%) enrolled in the trial.

Conclusion: Based on the data reviewed, > 70% of patients who might otherwise have been eligible for standard advanced NSCLC trials were not candidates for ECOG 4599. Outcome with respect to this study must be interpreted in the context of eligibility restrictions.

Porret E, Madelaine J, Galateau-Sallé F, Bergot E, Zalcman G.

Service de Pneumologie, Pôle Coeur-Poumons-Vaisseaux, Université Basse-Normandie, CHU de Caen, France.

Abstract

Malignant pleural mesothelioma (MPM) is a rare tumour due to occupational asbestos exposure. The incidence of MPM will continue to increase until 2020-2030. The incidence reaches 100 cases/million/year in occupationally exposed populations as opposed to 1 case/million/year in the general population, leading to 800 to 1,000 cases per year in France. The molecular carcinogenesis of MPM is incompletely understood but alterations to genes NF2, c-met, WT1 RASSF and p16 have been described. These genes are involved in cell invasion and motility, cell division and apoptosis control. Histological diagnosis remains difficult and depends on immunohistochemical analysis as described by the French Mesopath group. Clinical diagnosis relies on thoracoscopy and large pleural biopsies, with increasing use of CT-PET for the evaluation of disease extent. Therapeutic strategy includes prophylactic irradiation following drainage or thoracoscopy to prevent tumour nodule development along drainage channels and puncture sites. In selected patients, extensive extra-pleural pneumonectomy can be performed with curative intent. First line chemotherapy is based on a combination of pemetrexed and cisplatin that has demonstrated an improvement in overall survival and quality of life in phase 3 trials. Antiangiogenic agents such as bevacizumab (Avastatin) may be of interest but need to be tested in phase 3 trials. The Mesothelioma Avastatin Pemetrexed Study (MAPS) is ongoing, coordinated by the French Thoracic Cancer Intergroup (IFCT).

Li Q, Yano S, Ogino H, Wang W, Uehara H, Nishioka Y, Sone S.

Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, Tokushima, Japan

Abstract

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive malignancy, which has a poor prognosis with a median survival of less than 1 year. The vascular endothelial growth factor (VEGF) has been reported to be an ideal therapeutic target, and a multitargeted antifolate, pemetrexed, has been clinically used for the treatment of MPM.

Experimental Design: We examined the therapeutic efficacy of the antihuman VEGF neutralizing antibody, bevacizumab, in combination with pemetrexed against two different human MPM cells, EHMES-10 and MSTO-211H, orthotopically inoculated into severe combined immunodeficient mice.

Results: Bevacizumab inhibited a VEGF-induced proliferation of the human endothelial cells in a dose-dependent manner, but it had no effect on the proliferation of the two MPM cell lines in vitro. The orthotopically inoculated EHMES-10 cells (VEGF high expressing) produced thoracic tumors and a large volume of bloody pleural effusion, whereas the MSTO-211H cells (VEGF low expressing) produced thoracic tumors and a small volume of bloody effusions. Treatment with bevacizumab effectively inhibited the production of thoracic tumors and dramatically prevented the production of pleural effusion by the EHMES-10 cells but not the MSTO-211H cells. Treatment with bevacizumab reduced the number of enlarged tumor-associated vessels and proliferating tumor cells. Moreover, treatment with bevacizumab in combination with pemetrexed more effectively suppressed the formation of the pleural effusion and prolonged the survival compared with the control and monotherapy in the EHMES-10 cell–bearing severe combined immunodeficient mice.

Conclusions: These results suggest that the combined use of bevacizumab and pemetrexed may therefore be promising for controlling the progression of MPM highly expressing VEGF.