International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationToxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule–Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non–Small-Cell Lung Cancer
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.
Section snippets
Phase I clinical study of pulsed, low-dose paclitaxel for radiosensitization
A Phase I clinical study of pulsed low-dose paclitaxel with daily fractionated thoracic irradiation for inoperable NSCLC was conducted between 1998 and 2001 through a clinical protocol approved by the University of Rochester Institutional Review Board. All patients had given informed consent for participation. All patients were given standard premedications (cimetidine, dexamethasone, and diphenhydramine) before paclitaxel infusion to reduce the risk of hypersensitivity reactions. Low-dose
Patient characteristics
In all, 17 patients completed the 7.5 weeks of chemoradiation, and 1 patient completed 6 weeks of the planned chemoradiation before evidence of distant disease progression. Patient characteristics are shown in Table 1. The definition of “inoperable” NSCLC in this study includes the majority of Stage III NSCLC patients who are not operable because of tumor stage, as well as a smaller population with Stage I to II disease who are deemed inoperable by the thoracic surgeons because of poor
Discussion
Improving chest disease control can improve survival of patients with Stage III NSCLC. The best example is the randomized Phase III study incorporating low-dose sensitizing cisplatin to chest radiation conducted by Schaake-Koning et al. (1). There were three treatment arms of this European study: radiotherapy alone, radiotherapy with weekly cisplatin (30 mg/m2), and radiotherapy with daily cisplatin (6 mg/m2). There was no treatment arm administering systemic doses of cisplatin; thus the
Conclusion
In summary, schedule-dependent, pulsed, low-dose paclitaxel chemoradiation is an effective regimen for improving local tumor control and is associated with very low rates of toxicity. We found that all three of the dose levels resulted in a similar degree of tumor shrinkage, and that there appeared to be a trend of increasing toxicity with dose escalation. The pharmacokinetics, clinical efficacy, and toxicity demonstrated in this trial suggest that effective radiosensitization may be achieved
Acknowledgments
The authors thank Dr. Merrill Egorin for the pharmacokinetic analyses and feedback on the manuscript preparation, Dr. Richard Raubertas of Merck Pharmaceuticals for the design of the Phase I study, and Ms. Laura Brumbaugh for editorial assistance. This study was supported in part by a grant from Bristol-Myers Squibb Oncology and by General Clinical Research Center Grant 5MO1 RR0004 from the National Center for Research Resources, National Institutes of Health.
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Conflict of interest: Dr. Yuhchyau Chen was supported in part by a grant from Bristol-Myers Squibb Oncology and by General Clinical Research Center Grant 5MO1 RR0004 from the National Center for Research Resources, National Institutes of Health.