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82804218.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ORIGINAL ARTICLE Single-Agent Pemetrexed or Sequential Pemetrexed/Gemcitabine as Front-Line Treatment of Advanced Non-small Cell Lung Cancer in Elderly Patients or Patients Ineligible for Platinum-Based Chemotherapy: A Multicenter, Randomized, Phase II Trial Cesare Gridelli, MD,* Eckhard Kaukel, MD,† Vanessa Gregorc, MD,‡ Maria Rita Migliorino, MD,§ Thomas R. Mu¨ller, MD,͉͉ Christian Manegold, MD,¶ Adolfo Favaretto, MD,# Andrea Martoni, MD,** Orazio Caffo, MD,†† Alexander Schmittel, MD,‡‡ Antonio Rossi, MD,* Francesca Russo, MD,§§ Patrick Peterson, PhD,͉͉͉͉ Marı´a Mun˜oz, PhD,¶¶ and Martin Reck, MD## hematologic toxicity consisted of neutropenia (4.5% pemetrexed; 2.3% Introduction: This randomized phase II trial evaluated single-agent pemetrexed/gemcitabine), febrile neutropenia (4.5% pemetrexed; pemetrexed or sequential pemetrexed/gemcitabine in patients with non- 4.7% pemetrexed/gemcitabine), thrombocytopenia (4.5% pem- small cell lung cancer (NSCLC) who were elderly (Ն70 years) or etrexed; 7.0% pemetrexed/gemcitabine), and anemia (6.8% pem- younger than 70 years and ineligible for platinum-based chemotherapy. etrexed; 4.7% pemetrexed/gemcitabine). No grade 3/4 nonhema- Methods: Chemonaive patients with stage IIIB/IV NSCLC and an tologic toxicities exceeded 4.7% in either arm. Eastern Cooperative Oncology Group performance status of 0 to 2 received either 500 mg/m2 of pemetrexed (day 1, every 3 weeks) for Conclusions: Single-agent pemetrexed and sequential pemetrexed/ eight cycles, or the same dosage of pemetrexed for cycles 1 and 2 gemcitabine have shown moderate activity and are well tolerated as and then 1200 mg/m2 of gemcitabine (days 1 and 8, every 3 weeks) first-line treatments for advanced NSCLC in elderly patients or for cycles 3 and 4 (repeated once for a total of eight cycles). All patients unsuitable for platinum-based combination chemotherapy. patients were given vitamin B12 and folic acid supplementation. Key Words: Advanced NSCLC, Elderly patients, PS 2 patients, Results: From July 2003 to July 2004, 87 patients (44 pemetrexed; 43 Pemetrexed, Gemcitabine. pemetrexed/gemcitabine) received treatment. The median time to pro- gression was 4.5 (95% confidence interval: 3.0–9.3) and 4.1 months (J Thorac Oncol. 2007;2: 221–229) (95% confidence interval: 1.7–5.8) for the pemetrexed and pemetrexed/ gemcitabine arms, respectively, and the median progression-free sur- vival time was 3.3 months for both arms. Tumor response rates for the on-small cell lung cancer (NSCLC) represents approxi- pemetrexed and pemetrexed/gemcitabine arms were 4.5% and 11.6%, Nmately 80% to 87% of all lung cancers.1 Because the respectively. The median overall survival time was 4.7 months for the majority of patients present with metastatic NSCLC, pallia- pemetrexed arm and 5.4 months for the pemetrexed/gemcitabine arm, tive treatment is often the only therapeutic option. with respective 1-year survival rates of 28.5% and 28.1%. Grade 3/4 Platinum-based combination chemotherapy is currently the standard treatment for patients with advanced NSCLC. *Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy; †Asklepios However, two categories of patients, the elderly and patients Klinik Harburg, Hamburg, Germany; ‡Division of Medical Oncology, San with poor performance status (PS; Յ2), are often not candi- Raffaele Hospital, Milan, Italy; §Pneumo-oncology Division, Forlanini Hospital, dates for platinum-based combinations because of poor gen- Rome, Italy; ͉͉Krankenhaus Hofheim am Taunus, Hofheim, Germany; ¶Heidel- eral conditions and comorbidities. berg University Medical Center, Mannheim, Germany; #Division of Medical Oncology, University Hospital, Padova, Italy; **Division of Oncology, Mal- More than 50% of advanced NSCLC cases are diag- pighi Hospital, Bologna, Italy; ††Division of Medical Oncology, Santa Chiara nosed in patients older than 65 years, and approximately 30% Hospital, Trento, Italy; ‡‡Charite´, Campus Benjamin Franklin, Department of to 40% of cases are diagnosed in patients older than 70 Hematology and Oncology, Berlin, Germany; §§Eli Lilly and Company, Flo- years,2,3 yet disproportionately low numbers of elderly par- rence, Italy; ͉͉͉͉Eli Lilly and Company, Indianapolis, IN; ¶¶Eli Lilly and Com- 4–7 pany, Madrid, Spain; and ##Hospital Grosshansdorf, Grosshansdorf, Germany ticipants are included in clinical trials. Three phase III Disclosure: Sponsored by Eli Lilly and Company, Indianapolis, Indiana. Carol J. trials constitute the published evidence-based literature for Shipley is the authorized representative signing on behalf of the Eli Lilly and the elderly.8–10 Chemotherapy treatment in the elderly is Company authors, only as work made for hire. Francesca Russo and Maria complicated by a number of age-related issues. Decreased Munoz are employees of Eli Lilly and Company. No other authors have financial disclosures to report. hepatic, renal, and bone marrow functions increase toxicity, Address for correspondence: Cesare Gridelli, MD, Division of Medical Oncol- particularly cisplatin-related toxicity.7,8 Furthermore, comor- ogy, S.G. Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy. bid diseases, which may significantly affect functional E-mail: [email protected] status, general health, and tumor symptoms, are frequently Copyright © 2007 by the International Association for the Study of Lung 11,12 Cancer present. Because of these complications, single-agent ISSN: 1556-0864/07/0203-0221 chemotherapy is often the recommended treatment, even by Journal of Thoracic Oncology • Volume 2, Number 3, March 2007 221 Gridelli et al. Journal of Thoracic Oncology • Volume 2, Number 3, March 2007 American Society of Clinical Oncology guidelines, for el- Additionally, eligible patients met the following criteria: no derly patients with advanced NSCLC.6,8,10,13,14 The findings prior chemotherapy (prior surgery and radiotherapy were of the two phase III trials that compared single-agent versus permitted as long as relapse or disease progression had combination therapy in the elderly8,9 produced different con- occurred after the procedure or therapy); measurable disease clusions: the Multicenter Italian Lung Cancer in the Elderly according to Response Evaluation Criteria in Solid Tumors Study showed that the combination of gemcitabine and vi- criteria32; age Ն70 years or Ͻ70 years for patients who, in the norelbine was not more effective or tolerable than either investigator’s opinion, were ineligible for platinum-based agent alone, whereas the Southern Italy Cooperative Oncol- chemotherapy because of poor PS or comorbidities; an East- ogy Group found that the combination of gemcitabine and ern Cooperative Oncology Group PS of 0 to 2; an estimated vinorelbine was associated with significantly better overall life expectancy of at least 12 weeks; and adequate bone survival than vinorelbine alone. Nevertheless, the difference marrow, renal, and hepatic function. Patients with symptom- in sample sizes between the two trials (698 versus 120 atic brain metastases were ineligible for the study (whereas patients for the Multicenter Italian Lung Cancer in the Elderly patients with a history of brain metastases were permitted to Study and the Southern Italy Cooperative Oncology Group participate in the study), as were patients with an inability to trial, respectively) should be noted. interrupt nonsteroidal antiinflammatory drugs (2 days before, The proportion of patients with PS 2 enrolled in clinical the day of, and 2 days after receiving pemetrexed), uncon- trials is often less than 20% of the whole study population, trolled pleural effusions, or inability or unwillingness to take even though the proportion of PS 2 patients is consistently steroids or vitamin supplementation. The protocol was ap- higher in population-based studies.15 For these patients, no proved through institutional ethical review boards, and all treatment is widely accepted as standard. A subgroup analysis patients provided written informed consent before treatment. of several randomized trials16 suggests that several new- The study was conducted in accordance with the ethical generation cytotoxic drugs (gemcitabine, vinorelbine, and principles in the Declaration of Helsinki and good clinical taxanes) are superior to supportive care in this patient cate- practice. gory. Therefore, single-agent chemotherapy with these drugs may be the preferred option for palliative treatment of PS 2 Study Design and Sample Size patients.13,16–18 This open-label phase II study was designed to ran- Pemetrexed, a novel multitargeted antifolate, inhibits domly assign 90 patients to one of two regimens (single-agent three enzymes involved in pyrimidine and purine synthesis: pemetrexed or single-agent pemetrexed followed sequentially thymidylate synthase, dihydrofolate reductase, and glyci- by single-agent gemcitabine), and the trial was not considered namide ribonucleotide formyl transferase.19 Pemetrexed has complete until at least 73 patients progressed. This sample shown activity as a single agent in several phase II trials and size was chosen on the basis of a selection design using the one phase III trial in patients with NSCLC.20–23 Supplemen- primary endpoint of TtPD. The selection design assumed that tation with folic acid and vitamin B12, which is required to the primary goal of the trial was to select a regimen for a reduce pemetrexed toxicity,24 results
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