Phase I study of cisplatin, vinorelbine, and concurrent thoracic radiotherapy for unresectable stage III non‐small cell lung cancer

Abstract

To determine the recommended phase II dose of vinorelbine in combination with cisplatin and thoracic radiotherapy (TRT) in patients with unresectable stage III non-small cell lung cancer (NSCLC), 18 patients received cisplatin (80 mg/m 2 ) on day 1 and vinorelbine (20 mg/m 2 in level 1, and 25 mg/m 2 in level 2) on days 1 and 8 every 4 weeks for 4 cycles. TRT consisted of a single dose of 2 Gy once daily for 3 weeks followed by a rest of 4 days, and then the same TRT for 3 weeks to a total dose of 60 Gy. Fifteen (83%) patients received 60 Gy of TRT and 14 (78%) patients received 4 cycles of chemotherapy. Ten (77%) of 13 patients at level 1 and all 5 patients at level 2 developed grade 3-4 neutropenia. Four (31%) patients at level 1 and 3 (60%) patients at level 2 developed grade 3-4 infection. None developed ≥ ≥ ≥ ≥grade 3 esophagitis or lung toxicity. Dose-limiting toxicity was noted in 33% of the patients in level 1 and in 60% of the patients in level 2. The overall response rate (95% confidence interval) was 83% (59-96%) with 15 partial responses. The median survival time was 30.4 months, and the 1-year, 2-year, and 3-year survival rates were 72%, 61%, and 50%, respectively. In conclusion, the recommended dose is the level 1 dose, and this regimen is feasible and promising in patients with stage III NSCLC. tage III locally advanced non-small cell lung cancer (NSCLC) accounts for about 25% of all lung cancer cases. 1)Successful treatment of this disease rests on the control of both clinically apparent intrathoracic disease and occult systemic micrometastases, and therefore a combination of systemic chemotherapy and thoracic radiotherapy is indicated in many patients with good performance status and no pleural effusion.2) Concurrent chemoradiotherapy is superior to the sequential approach, as shown by recent phase III trials in unresectable stage III NSCLC, in which the median survival time was 15.0 to 17.0 months in the concurrent arm and 13.3 to 14.6 months in the sequential arm, although acute esophagitis was more severe in the concurrent arm.3-5) Chemotherapy regimens combined with simultaneous thoracic radiotherapy have consisted of cisplatin plus etoposide and cisplatin plus vinca alkaloids, 3,4) and a combination of cisplatin plus vindesine, with or without mitomycin, has been widely used in Japan. [5][6][7][8] Vinorelbine, a new semisynthetic vinca alkaloid with a substitution in the catharanthine ring, interacts with tubulin and microtubule-associated proteins in a manner different from the older vinca alkaloids, and it more selectively depolymerizes microtubules in mitotic spindles. 9) Several randomized trials have shown vinorelbine to be more active against advanced or metastatic NSCLC than vindesine as a single agent or in combination with cisplatin.10-13) Thus, incorporation of vinorelbine into concurrent chemoradiotherapy instead of vindesine is an important strategy for the treatment of locally advanced NSCLC. The objective of this study was to determine the maximum tolerated dose (MTD) and reco...

Phase I study of weekly cisplatin, vinorelbine, and concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer

“…Therefore we conducted a phase I study of weekly cisplatin and vinorelbine with standard TRT. The studies described above 29,[31][32][33] reported that esophagitis and neutropenia were the major toxicities. The present study showed that the DLTs of our regimen were esophagitis, fatigue, infection, and hyponatremia.…”

“…32 In the cisplatin-vinorelbine arm, the doses reported by Masters et al 31 were used, and the CALGB concluded that induction chemotherapy followed by concomitant chemoradiotherapy was feasible, with the observed survival rates exceeding those of previous CALGB trials for all treatment arms. Sekine et al 33 conducted a phase I study and reported that the recommended dose of cisplatin was 80 mg/m 2 on day 1 and that of vinorelbine was 20 mg/m 2 on days 1 and 8 every 4 weeks with TRT including a 4-day interval. The Czech group 29 used the following schedule and dose: cisplatin 80 mg/m 2 on day 1 and vinorelbine 12.5 mg/m 2 on days 1, 8, and 15 every 4 weeks with standard TRT starting on day 4.…”

Phase I Study of Oral S-1 Plus Cisplatin With Concurrent Radiotherapy for Locally Advanced Non–Small-Cell Lung Cancer

“…The other wellknown cisplatin-based regimen with concurrent radiotherapy is vinorelbine plus cisplatin. Because this regimen is considered to be safe and active regimen, it is currently often concurrently used with radiotherapy for locally advanced NSCLC (28,29). However, toxicity is well known to increase with greater myelotoxicity in such a concurrent treatment modality.…”

Overview of chemoradiation clinical trials for locally advanced non-small cell lung cancer in Japan

“…Whereas a full dose of the oldgeneration combination chemotherapy can be combined with concurrent radiotherapy, 4,5 a reduced-dose (weekly or daily administration) of new-generation chemotherapy must be used in combination with TRT. [8][9][10][11] Chemoradiation based on full-dose old-generation chemotherapy has not yet been directly compared with that based on reduced-dose new-generation chemotherapy. Well-designed multicenter clinical trials to determine how to integrate newer platinumbased regimens into chemoradiation protocols are thus urgently needed.…”