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.

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).

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.

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

Ryad AY, Mostafa E, Salem DA, Al-Adwy ER, Margerges M.

The Departments of Radiation Oncology&Nuclear Medicine, Ain Shams University.

Abstract

Purpose: To evaluate the efficacy, safety, and clinical benefit of combined gemcitabine and carboplatin in patients with previously untreated malignant pleural mesothelioma (MPM).

Patients and Methods: This prospective phase II study was performed on 42 eligible patients with histologically or cytologically proven MPM presenting to Ain Shams University hospitals and Sohag Cancer Center between January 2002 and April 2006. They were assigned to receive combined gemcitabine (1250mg/m2) on days, 1 and 8 and carboplatin (AUC 6) on day 1. The regimen was repeated every 21 days. The treatment continued until disease progression or intolerable drug toxicity.

Results: The patients received a total of 227 cycles of chemotherapy (median 5.4 cycles and range from 2 to 9 cycles). The chemotherapy was generally well tolerated. Neutropenia, thrombocytopenia and anemia were the most severe (Grade 3 or 4) toxicities recorded during therapy and were reported in (14%), (9.5%), and (9.5%), respectively. Twelve patients (29%) achieved partial response, 18 patients (42%) had stable disease and the disease progressed in the remaining 12 patients (29%). The median follow-up duration was 11 months (range 5 from 20 months). The overall survival (OS) and progression free survival (PFS) at one year was 44.5% and 33.2%, respectively. The median survival and time to disease progression were 11 months and 8.5 months respectively. Of 32 patients assessed for clinical benefit, 20 patients (62.5%) were considered clinical benefit responders.

Conclusion: The combination of gemcitabine and carboplatin is a safe and tolerable treatment with reasonable response rate, OS, and PFS compared with the historical phase II single agents and combined chemotherapy studies in patients with MPM.

Keywords: Mesothelioma , Gemcitbine , Carboplatin.

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

Santoro A, O’Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, Eberhardt W, Paz-Ares L, Sundstrom S, Liu Y, Ripoche V, Blatter J, Visseren-Grul CM, Manegold C.

Istituto Clinico Humanitas, Rozzano, Italy. armando.santoro@humanitas.it

Abstract

Introduction: Previously published results from a randomized phase III study of pemetrexed plus cisplatin in patients with malignant pleural mesothelioma (MPM) demonstrated a significant survival benefit and higher response rate compared with cisplatin. Although pemetrexed was under review by regulatory agencies, an International Expanded Access Program (EAP) provided more than 3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin in 13 countries. This manuscript reports the safety and efficacy data from the nonrandomized open-label study in chemonaive patients receiving pemetrexed plus platinum under the EAP.

Methods: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m2 in combination with either cisplatin 75 mg/m2 or carboplatin AUC 5, once every 21 days with standard premedication. Efficacy data were recorded at the end of study participation.

Results: A total of 1704 chemonaive patients received pemetrexed plus cisplatin (n = 843) or pemetrexed plus carboplatin (n = 861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumor response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% versus 64.0%) and median time to progressive disease (7 months versus 6.9 months). The most common grade 3/4 hematologic toxicity was neutropenia in 23.9% of the pemetrexed plus cisplatin group and 36.1% of the pemetrexed plus carboplatin group.

Conclusion: This large EAP confirmed the activity of pemetrexed plus cisplatin and pemetrexed plus carboplatin in chemonaive patients with MPM, demonstrating clinically similar time to progressive disease and 1-year survival rates.

Ceresoli GL, Castagneto B, Zucali PA, Favaretto A, Mencoboni M, Grossi F, Cortinovis D, Conte GD, Ceribelli A, Bearz A, Salamina S, De Vincenzo F, Cappuzzo F, Marangolo M, Torri V, Santoro A.

1Department of Oncology, Istituto Clinico Humanitas IRCCS, Rozzano, Milano, Italy.

Abstract

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m^-2 and carboplatin AUC 5 mg ml^-1 min^-1 intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those >/=70 years old. A total of 178 patients with an ECOG performance status of </=2 were included. Median age was 65 years (range 38-79), with 48 patients >/=70 years (27%). Grade 3-4 haematological toxicity was slightly worse in >/=70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.

Keywords: malignant pleural mesothelioma; elderly patients; chemotherapy; carboplatin; pemetrexed

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.

Small GR, Nicolson M, Buchan K, Broadhurst P.

Department of Cardiology, University of Aberdeen, Aberdeen, Scotland AB25 2ZN, United Kingdom.

Abstract

Pericardial diseases can be difficult to differentiate from myocardial conditions. Diagnosis can be challenging and often requires the use of different imaging modalities. Here, we describe a case which presented with common cardiac symptoms which were shown to be the result of a rare condition. A 62-year-old lady presented with left femoral artery embolism. Post-embolectomy she developed cardiac failure. Three months previously an acellular, sterile pericardial effusion had been drained. In 1993 a left mastectomy and axillary node clearance was performed for breast cancer. Adjuvant chemotherapy and radiotherapy were administered. Examination revealed a raised jugular venous pressure (JVP) with rapid Y descent and Kussmaul’s sign. CT chest and abdomen found no recurrence of breast carcinoma. Cardiac MRI demonstrated thickened pericardium. At cardiac catheterisation haemodynamic responses consistent with constrictive pericarditis were seen. Pericardectomy was performed. Histology revealed pericardial epithelioid malignant mesothelioma. 18-FDG-PET CT post-operatively was negative in the pericardium and pleura. Chemotherapy with pemetrexed and carboplatin was given. The patient died 9 months after presentation. Radiotherapy and asbestos exposure are both associated with pericardial mesothelioma and the aetiology in this case was not clear. The condition carries a poor prognosis and is invariable fatal although newer chemotherapeutic regimens have prolonged survival times.

Keywords: Pericardium; Mesothelioma; Radiotherapy