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.

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 100mg/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.

Phase I study with dose escalation of gemcitabine and cisplatin in combination with ifosfamide (GIP) in patients with non-small-cell lung carcinoma.

Gemcitabine (G) and cisplatin (P) are active reference agents in patients with non-small-cell lung cancer (NSCLC). Ifosfamide (I) has also been approved for NSCLC treatment. This phase I trial aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose [maximum tolerated dosage (MTD)], and recommended dose (RD) of a GIP combination in patients with advanced/metastatic NSCLC. In this study, one cycle of chemotherapy combined the following: ifosfamide: 3 g/m2 fixed dose (24-hour intravenous infusion) combined with mesna, day 1; gemcitabine: starting dose 1,000 mg/m2/d, escalating by 250 mg/m2 increments, days 1 and 15; cisplatin: starting dose 80 mg/m2, subsequently 100 mg/m2, day 15; in cohorts of at least 3 patients. Cycles were repeated every 28 days and no hematopoietic growth factors were administered. DLT was evaluated after the first chemotherapy cycle. Thirty-three patients (30 men, 3 women) with stage III (14 patients)/IV (19 patients) NSCLC were treated at eight dose levels, receiving 109 cycles of chemotherapy. Neutropenia was the only DLT reported. Although the MTD was not reached at the highest tested dose level, the RD chosen corresponds to the full doses of the GP3000 doublet standard (G: 3,000 mg/m2; P: 100 mg/m2 per cycle) every 28 days. Nonhematologic toxicities were mainly grade I-II. Relative dose intensities of G, I, and P at the RD were 96%, 98%, and 96%, respectively. Sixteen of 33 patients with measurable/evaluable disease had an objective response including two complete responses. In conclusion, GIP chemotherapy is safe and appears to be active in patients with NSCLC. The RD is gemcitabine: 1,500 mg/m2 days 1 and 15; ifosfamide: 3 g/m2 day 1; cisplatin: 100 mg/m2 day 15. A confirmatory phase II study is currently under way, before a phase III trial of GIP versus GP.

Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma.

PURPOSE: We report the 5-year survival and late toxicity results of a randomized clinical trial, which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma, using concomitant radiochemotherapy (arm B), compared with standard radiotherapy (arm A). PATIENTS AND METHODS: A total of 226 patients were entered onto a phase III multicenter randomized trial comparing radiotherapy alone (70 Gy in 35 fractions; arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil; arm B). Prognostic factors were evaluated by univariate and multivariate analysis. Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity, hearing, taste, mandibula, and teeth damage, and Radiation Therapy Oncology Group toxicity criteria for skin, salivary gland, and mucosa. RESULTS: Five-year overall survival, specific disease-free survival, and locoregional control rates were 22% and 16% (log-rank P =.05), 27% and 15% (P =.01), and 48% and 25% (P =.002), in arm B and arm A, respectively. Stage IV, hemoglobin level lower than 125 g/L, and standard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis. One or more grade 3 to 4 complications occurred in 56% of the patients in arm B, compared with 30% in arm A (P was not significant). CONCLUSION: Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms.

Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems.

PURPOSE: To prospectively assess 5-year late toxicity in patients treated by concomitant radiochemotherapy for locally advanced oropharynx carcinoma using three different toxicity scales. METHODS AND MATERIALS: A total of 226 patients were entered in a Phase III multicenter, randomized trial comparing radiotherapy alone (70 Gy in 35 fractions: Arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil: Arm B). Five living patients, free of local or distant recurrences, could not be evaluated for late toxicity. Forty-four patients were eligible for late toxicity with a median follow-up of 5 years. Late toxicity was evaluated by the radiation oncologist using a large questionnaire containing 120 mixed items of three scales (NCI-CTC, LENT/SOMA, and RTOG). The data were then transposed on separate scales using corresponding grades. RESULTS: The 5-year overall survival rate was 22% in Arm B and 16% in Arm A (p = 0.05). The 5-year locoregional control rate was 48% in Arm B and 25% in Arm A (p = 0.002). The spinal cord was not affected by the concomitant adjunct of chemotherapy, and no deaths were caused by late toxicity. Using the three late toxicity scales, 100% of the patients treated with the combined modality (Arm B) developed one or more late complications vs. 94% in the radiotherapy-alone arm (Arm A). The difference was not statistically significant. The most commonly damaged organs (all Grade 1-4) were the salivary glands (100% in Arm B vs. 82% in Arm A, p <0.05), skin (78% vs. 47%, p <0.05), teeth (67% vs. 18%, p <0.05), mucosa (59% vs. 63% p = not significant), and mandible (44% vs. 12%, p <0.05). One or more Grade 3-4 complications occurred in 82% of the patients in Arm B vs. 47% in Arm A (p = 0.02) but concerned only the teeth. The correlation between the RTOG and LENT/SOMA scale and between the NCI-CTC and LENT/SOMA scale were low for Grade 1-4 toxicity (near 30%). The transposability of a patient's symptoms was significantly greater using the LENT/SOMA or RTOG/EORTC scaling systems than using the NCI-CTC system. CONCLUSION: Concomitant radiochemotherapy increased overall survival and locoregional control rates. The difference between the two treatment groups for Grade 3-4 complications was only significant for the teeth. The late toxicity assessment of a treatment may depend on the toxicity scale used. The LENT/SOMA scale seems to be the most accurate scale, but most of the score results were not concordant with those obtained with other scales. The results of this study confirm the necessity of using a common late toxicity scale in clinical trials.