Kindler HL.

Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu

Abstract

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients
with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival.
The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed
to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.

Eric K. Rowinsky¹, Muralidhar Beeram¹, Lisa A. Hammond¹, Garry Schwartz², Johann De Bono¹, Baharam Forouzesh¹, Quincy Chu¹, Jane E. Latz³, Shengyan Hong³, William John³ and Binh Nguyen³

Authors’ Affiliations: ¹ Institute for Drug Development, Cancer Therapy, and Research Center, San Antonio, Texas; ² Brooke Army Medical Center, Fort Sam Houston, Texas; and ³ Eli Lilly and Company, Indianapolis, Indiana

Abstract

Purpose: The main objectives of this phase I and pharmacokinetic, open-label study were to characterize the principal toxicities and determine the maximum tolerated dose of the multitargeted antifolate pemetrexed administered in combination with irinotecan. The study also sought to detect major pharmacokinetic drug-drug interactions between these agents and preliminary evidence of antitumor activity in patients with advanced solid malignancies.

Experimental Design: Pemetrexed was administered as a 10-min i.v. infusion followed by irinotecan given i.v. over 90 min every 3 weeks to patients with advanced solid malignancies. The study objectives were first pursued in heavily pretreated patients and then in lightly pretreated patients who also received vitamin supplementation.

Results: Twenty-three heavily pretreated patients enrolled in the first stage of the study, and the maximum tolerated dose level of pemetrexed/irinotecan without vitamin supplementation was 400/250 mg/m²; further dose escalation was precluded by severe neutropenia that was protracted and/or associated with fever. In the second stage of the study, 28 lightly pretreated patients were administered pemetrexed/irinotecan with vitamin supplementation; these patients tolerated pemetrexed/irinotecan at a dose level of 500/350 mg/m², which reflected clinically relevant single-agent doses of both agents. No major pharmacokinetic interactions between the agents were evident. Four patients, two patients each with colorectal cancer refractory to fluoropyrimidines and advanced mesothelioma, had partial responses.

Conclusions: The pemetrexed/irinotecan regimen is well tolerated in patients with advanced solid malignancies at clinically relevant single-agent doses. The recommended dose level of pemetrexed/irinotecan for subsequent disease-directed evaluations involving lightly pretreated patients is 500/350 mg/m² every 3 weeks with vitamin supplementation.

Fennell DA, Steele JP, Shamash J, Evans MT, Wells P, Sheaff MT, Rudd RM, Stebbing J.

Lung and Mesothelioma Unit, Department of Medical Oncology, St Bartholomew’s Hospital, West Smithfield, London, UK.

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rapidly progressive lethal tumor. Treatment options remain limited and the outcome in recurrent disease is poor.

Methods: A Phase II open-label noncomparative study was conducted to assess the safety and efficacy of the triplet combination irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy in untreated patients and in those with previous exposure to chemotherapy.

Results: In 62 patients an objective response rate of 25% was observed. In the first-line setting progression-free survival measured 6.4 months (95% confidence interval [CI]: 4.5-7.3) and overall survival was 10.8 months (95% CI: 7.9-13.7). In the second-line setting progression-free survival was 7.3 months (95% CI: 3.4-11.2) and overall survival was also 7.3 months (95% CI: 4.8-9.8). Psychosocial well-being improved during chemotherapy and the main toxicity observed was neutropenia (40%).

Conclusions: IPM appeared to have a reasonable response rate with an acceptable toxicity profile in the first- and second-line treatment of MPM.

Keywords: mesothelioma, irinotecan, cisplatin, mitomycin C, phase II, first-line, recurrence

Nesti M, Marinaccio A, Gennaro V, Gorini G, Mirabelli D, Mensi C, Merler E, Montanaro F, Musti M, Pannelli F, Romanelli A, Tumino R; ReNaM Working Group.

ISPESL – National Institute for occupational safety and prevention, Occupational Medicine Department, Epidemiology Unit Rome, Italy.

Abstract

Background: The Italian National Mesothelioma Registry (ReNaM) was set up at the National Institute for Occupational Safety and Health (ISPESL) to estimate Italian incidence of malignant mesothelioma (MM), define modalities of asbestos exposures, assess impact and diffusion of MM, identify underestimated sources of environmental contamination.

Objectives: To describe ReNaM activity, database dimension and epidemiological characteristics of the caselist.

Methods: Regional Operating Centers (COR) in 16 Italian regions were set up to identify and investigate all cases of MM diagnosed in each region, applying national guidelines. COR collect cases in health care institutions. Occupational history, lifestyle and residence are obtained by direct interview using a standard questionnaire. Exposure modalities are classified by industrial hygienists, evaluating whether work, private life or any particular environmental condition could have involved asbestos exposure.

Results: Data refer to 3,446 cases collected in 9 Italian regions during 1993-2001. Pleural mesothelioma affected 94% cases, pleural/peritoneal ratio was 16:1. Gender ratio (M/F) was 2.7:1 (1.3:1 for peritoneum). There was a variety of occupational exposures, some already known as high risk sectors and others unexpected. The most common exposures occurred in building and construction, metallurgy and steel, shipbuilding, and railway stock. High risk categories were encountered such as bricklayers, plumbers, carpenters, electricians, welders, installers and maintenance workers in metallurgy and the steel industry, general labourers, tool makers and painters in shipbuilding/repair/demolition.

Conclusions: Despite some ReNam’s limitations, identification of MM cases and analysis of modality of exposure, with standardized criteria, are a fundamental tool for primary prevention of asbestos related diseases.

Kindler HL, Herndon JE, Zhang C, Green MR; Cancer and Leukemia Group B.

University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu

Abstract

Purpose: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the activity of irinotecan in malignant mesothelioma (CALGB protocol 9733).

Patients and Methods: Twenty-eight patients accrued between January 1998 and January 1999 received irinotecan 125 mg/m2 by intravenous infusion over 90 min weekly for 4 weeks, every 6 weeks. Eligibility included a performance status of 0-2 by CALGB criteria, and no prior chemotherapy. Twenty-five patients had pleural mesothelioma; two patients had peritoneal mesothelioma, and one patient had pericardial mesothelioma. Sixty-one percent of patients had epithelial histology.

Results: There were no complete or partial responders. Thirty-three percent of patients had stable disease and 52% were shown to have progressive disease at the first reassessment. One patient was not evaluable for response. Median survival from study entry was 9.3 months (95% CI 4.5-13.2 months); 1-year survival was estimated at 46% (95% CI 28-65%). Toxicity was moderately severe. Grade 3 or 4 toxicities included neutropenia in 28% of patients, lymphopenia in 43%, and diarrhea in 18%. Three patients died of treatment-related toxicities. All three experienced grade 4 diarrhea, two also had neutropenic sepsis.

Conclusion: Single-agent irinotecan in this dose and schedule has considerable toxicity in patients with malignant mesothelioma and has no anti-tumor activity. The relatively long median survival seen in this study principally reflects the prognostic features of the accrued patients.