Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule–Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non–Small-Cell Lung Cancer

Purpose

We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non–small-cell lung cancer.

Methods and Materials

Paclitaxel at escalating doses of 15 mg/m², 20 mg/m², and 25 mg/m² were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography.

Results

Dose-limiting toxicities included 3 of 18 patients with Grade 3 pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m²), II (20 mg/m²), and III (25 mg/m²), the mean peak plasma level was 0.23 ± 0.06 μmol/l, 0.32 ± 0.05 μmol/l, and 0.52 ± 0.14 μmol/l, respectively; AUC was 0.44 ± 0.09 μmol/l, 0.61 ± 0.1 μmol/l, and 0.96 ± 0.23 μmol/l, respectively; and duration of drug concentration >0.05 μmol/l (t > 0.05 μmol/l) was 1.6 ± 0.3 h, 1.9 ± 0.2 h, and 3.0 ± 0.9 h, respectively.

Conclusion

Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 μmol/l for a minimum of 1.6 h was sufficient for effective radiosensitization.

Introduction

Combination chemoradiation therapy has improved survival in patients with Stage III inoperable non–small-cell lung cancer (NSCLC) when compared with radiation treatment alone 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. Despite the promising improvement by combined-modality therapy, investigations using various chemoradiotherapy combinations have yielded an average 5-year survival of <25%. Although chemotherapy combinations have reached the plateau for NSCLC (11), intrathoracic disease control is even more disappointing, with an average low rate of control of 40–50% at best by radiographic criteria 1, 4, 6 and a control rate of only 15–17% by tumor biopsy through post-treatment bronchoscopy (4). Because locoregional failure can serve as a continuous source of distant metastasis, improving chest disease control is critical in the management of locally advanced NSCLC.

We previously conducted preclinical studies of the cell cycle and apoptotic effects of low-dose paclitaxel on human lung cancer cell lines. We found that pulsing low-dose paclitaxel every 48 h resulted in the restitution of G2/M cell cycle arrest, the most radiosensitive phase of the cell cycle. The cell cycle effect started at approximately 4 h after drug treatment and peaked at 24 h. This was followed by a gradual recovery of G2/M effect after 36 h and a return to baseline cell cycle distribution at 48 h after treatment. In addition, the apoptotic effect of paclitaxel peaked at 48 h after in vitro treatment of lung cancer cell lines 12, 13. Clinical data from a Phase II investigation showed a 100% gross tumor response rate at 4 to 6 weeks post-therapy, with an absolute in-field tumor control rate of 97.6% and a 3-year survival rate of 21% 12, 13.

To our knowledge, complete toxicity detail and pharmacokinetic profile using paclitaxel in such a low dose range for radiosensitization has not been reported. The toxicity and pharmacokinetic profiles of low-dose paclitaxel combined with chest irradiation, as well as the clinical implications of this Phase I study, will be discussed.