Phase I study of pemetrexed and cisplatin with concurrent high-dose thoracic radiation after induction chemotherapy in patients with unresectable locally advanced non-small cell lung cancer

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 80; no. 1; pp. 68 - 74
• Main Authors: Mornex, Françoise, Peignaux, Karine, Germain, Thierry, Wautot, Virginie, Chouaki, Nadia, Bourayou, Nawel, Tourani, Jean-Marc
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ireland Ltd 01-04-2013; Elsevier
• Subjects: Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; Chemoradiotherapy - adverse effects; Chemoradiotherapy - methods; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glutamates - administration & dosage; Glutamates - adverse effects; Guanine - administration & dosage; Guanine - adverse effects; Guanine - analogs & derivatives; Hematology, Oncology and Palliative Medicine; Humans; Induction; Induction Chemotherapy; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymphopenia - etiology; Male; Medical sciences; Middle Aged; Neoplasm Staging; Neutropenia - etiology; NSCLC; Pemetrexed; Phase I trial; Pneumology; Pulmonary/Respiratory; Radiotherapy; Radiotherapy Dosage; Treatment Outcome; Tumors; Tumors of the respiratory system and mediastinum; Vomiting - etiology; Phase I trial; NSCLC; Radiotherapy; Induction; Pemetrexed; Cisplatin; Antineoplastic agent; Human; Lung disease; Respiratory disease; Concurrent; Malignant tumor; non-small cell lung carcinoma; Induction treatment; Cancerology; Unresectable; Bronchus disease; High dose; Cancer; Non small cell carcinoma; Pneumology
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2012.12.007

Abstract Purpose This is a phase I, escalating-dose trial targeting exclusively patients with non-small cell lung cancer (NSCLC), investigating pemetrexed and fixed-dose cisplatin concurrently administered with high-dose radiotherapy (RT) after induction chemotherapy (CT). Primary objective was to determine the maximum tolerated dose and recommended phase II dose of pemetrexed. Patients and Materials Patients with unresected stage III NSCLC, planned V20 ≤ 35%, and FEV ≥ 1.3 L, were treated every 21 days for 2 cycles (pemetrexed 500 mg/m2 ; cisplatin 75 mg/m2 ), followed by 2 cycles of concurrent CT-RT: pemetrexed starting dose was 400 mg/m2 , escalated up to 800 mg/m2 per 100 mg/m2 dose level (DL), cisplatin at 75 mg/m2 and RT at fixed dose of 66 Gy/33 fractions. Results Nine of 10 enrolled patients (age range 46–68 years; 6 men; ECOG PS 0 [6 patients], PS 1 [4] ; stage IIIA [1] , IIIB [9] ; 6 adenocarcinomas, 3 squamous cell carcinomas, 1 large cell carcinoma) were entered on 3 DLs. Dose escalation of pemetrexed was conducted up to 600 mg/m2 based on the independent safety monitoring board recommendation. One dose-limiting toxicity occurred at DL3: Grade 4 septic shock. Grade 3 related toxicities: 2 neutropenia at DL3, 2 lymphopenia per DL (3 recurrent), 2 leukopenia (1 recurrent) at DL3, 1 gastric pain (DL3), 1 nausea and 1 recurrent vomiting (DL2). No Grade 3/4 radiation-related toxicities were observed. No toxic death was observed. Disease control rate was 77.7% (1 CR, 4 PR, 2 SD). One-year survival rate was 90%. Conclusions This phase I report of pemetrexed is dedicated to NSCLC with induction therapy and fixed high-dose RT. Pemetrexed at 500 mg/m2 , concurrently given with cisplatin and RT was well tolerated and appears to be the only third-generation agent that can likely be recommended safely at full dose in future trials with concurrent RT.