Continuous carboplatin infusion during 6 weeks' radiotherapy in locally inoperable non-small-cell lung cancer: a phase I and pharmacokinetic study

Abstract

A phase I study was performed in 21 patients with previously untreated, locally inoperable, non-small-cell lung cancer (NSCLC) with ambulatory continuous carboplatin infusion together with continuous thoracic irradiation over 6 weeks. A dose range for carboplatin of 15 mg m-2 day-1 during the last 21 days (first level), during the last 31 days (second level), or during 6 weeks of the radiation period (third level) and thereafter 20 or 25 mg m-2 day-1 during 6 weeks of radiation (fourth and fifth level) was used. The total radiation dose was 60 Gy given as 2 Gy day-1 for 5 days week-1. The first three patients received radiotherapy without carboplatin. WHO grade III/IV leucopenia and thrombocytopenia occurred in the last two dose levels in two out of six and one out of six patients with 20 mg m-2 day-1 respectively, and in all three patients with 25 mg m-2 day-1 (dose-limiting toxicity). One local infection around the port and a subclavian vein thrombosis occurred. Radiation toxicity of the lung and oesophagus did not seem to be influenced by carboplatin treatment. Out of 21 patients one had a complete response (CR), ten partial response (PR), six stable disease (SD) and four progressive disease (PD). Total (TPt) and ultrafilterable plasma platinum (UPt) were measured in the last three dose levels with atomic absorption spectrophotometry with Zeeman correction. The mean (s.d.) level for TPt for 6 weeks at 15, 20 and 25 mg m-2 day-1 was 0.76 (0.15), 0.78 (0.19) and 0.90 (0.22) mg l-1 for UPt 0.10 (0.03), 0.12 (0.02) and 0.20 (0.03) mg l-1 respectively. TPt concentration levelled off after 3 weeks. The mean (s.d.) CLTB for UPt was 281 +/- 21 ml min-1 and correlated with glomerular filtration rate (r = 0.61, P = 0.03). As estimated with the sigmoid Emax model defined by the Hill equation the percentage reduction in platelets correlated with the area under the curve for UPt (r = 0.77). The maximum tolerable dose of carboplatin with concomitant continuous 60 Gy radiotherapy is 25 mg m-2 day-1; the recommended dose for phase II or III studies is 20 mg m-2 day-1 day for 6 weeks.