International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationProspective Study of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Concurrent With Individualized Radiotherapy for Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer
Introduction
It is well known that chemotherapy as a systemic treatment plays an important role in ameliorating survival and quality of life for patients with cancer. However, it is still a dilemma for patients who are medically unfit for, refractory to, or intolerant of their latest chemotherapy regimen. Therefore, it is necessary to develop a specialized novel treatment model for these entities.
Modern radiotherapy (RT) that includes three-dimensional conformal radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and stereotactic body radiotherapy (SBRT) as primary local treatment in definitive and palliative radiation has had more and more important roles in controlling primary or distant sites, alleviating uncomfortable symptoms, and ameliorating survival for patients with non–small-cell lung cancer (NSCLC). In patients with early-stage and locally advanced NSCLC, CRT and SBRT showed a favorable local control and brought survival benefit 1, 2, 3, 4.
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, targeting the EGFR signal pathway, have shown encouraging efficacy in advanced or metastatic NSCLC, thus offering a novel alternative in systemic treatment for these patients. Phase I studies of EGFR-TKIs demonstrated similar dose-limited toxicities and common toxicities 5, 6, 7. Phase II studies demonstrated that EGFR-TKIs showed antitumor activity, with response rates of 12% to 28%, median survival time (MST) of 7.0–13.5 months, and 1-year overall survival (OS) rates of 27% to 57% 8, 9, 10, 11. Phase III trials showed that EGFR-TKIs could prolong survival, and the MST ranged from 5.6 to 7.6 months in advanced NSCLC patients 12, 13, 14, 15. Additionally, preclinical studies showed that EGFR-TKIs could enhance radiosensitizing effects when combined with radiation 16, 17. In view of the superiority of local control with RT and the roles of systemic treatment with EGFR-TKIs, a definitive advantage of EGFR-TKIs concurrent with RT in advanced or metastatic NSCLC needs to be ascertained and confirmed in a prospective study.
In our previous pilot study, concurrent treatment with EGFR-TKIs and RT was well tolerated and had promising outcomes (18). The purpose of the present investigation was to clear the safety profile and to analyze treatment outcomes and the possibility of concurrent treatment as a novel alternative combined-modality treatment.
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Patient characteristics
Between June 2007 and January 2010, 26 patients with histologically or cytologically confirmed locally advanced/metastatic (Stage III/IV) NSCLC were enrolled in the study. The main inclusion criteria were as follows: age ≥18 years; life expectancy ≥3 months; Eastern Cooperative Oncology Group performance status scores ≤2; refractory to or in relapse after chemotherapy; medically unfit; refusal of chemotherapy; measurable lesions; retain a posture for irradiation; and adequate organ function.
Treatment characteristics
Twenty-six patients were treated with EGFR-TKIs concurrent with thoracic RT. Nineteen patients were receiving geftitinib, and 7 patients were receiving erlotinib. Among them, only 1 patient experienced the determination with EGFR mutation. For the reason of EGFR exon 19 mutation, gefitinib was administered to him. There were 18 patients receiving EGFR-TKIs maintenance. The median time of maintenance treatment was 7.3 months (range, 1.9–29.0 months). Among patients who received thoracic RT,
Discussion
The present study demonstrated that EGFR-TKIs concurrent with individualized thoracic RT is well tolerated in locally advanced or metastatic NSCLC. Toxicities related to skin, digestive tract, and hematology were manageable. There was no occurrence of serious pulmonary toxicities. Promising outcomes were observed, with MST of 21.8 months and 1-, 2-, and 3-year OS rates of 57%, 45%, and 30%, respectively (Fig. 1). This is the first prospective study to show that concurrent treatment is safe and
Acknowledgments
The authors thank Mr. Nai Bin Fan, Mr. Zuo Ren Wang, Ms. Xiu Mei Zhu, and Ms. Jing Yu, Department of Radiation Oncology, Air Force General Hospital, Beijing, for their assistance with data collection.
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Conflict of interest: none.