Phase 2 Study of Accelerated Hypofractionated Thoracic Radiation Therapy and Concurrent Chemotherapy in Patients With Limited-Stage Small-Cell Lung Cancer

Purpose

To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting.

Methods and Materials

Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 to 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate.

Results

Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation.

Conclusion

Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.

Introduction

Small-cell lung cancer (SCLC) accounts for approximately 13% of all lung cancers, and one-third of these patients present with limited stage SCLC (LS-SCLC) at diagnosis (1). Currently the standard of care for LS-SCLC is concurrent chemotherapy and thoracic radiation therapy (TRT), with prophylactic cranial irradiation (PCI) for those who achieve a good response after combined chemoradiotherapy, which has yielded a median survival of 15 to 23 months and 5-year survival rate up to 26% 2, 3.

The optimal TRT dose/fraction for LS-SCLC remains debatable (2). Intergroup study 0096 investigated once-daily and twice-daily TRT of 45 Gy in LS-SCLC, based on 2-dimensional radiation techniques, and the results showed that survival was improved significantly in the arm of twice-daily TRT over 3 weeks, which has become one of the standard treatments (3). However, a high local recurrence rate of 36% was observed despite using twice-daily TRT, indicating that more intensified TRT should be considered for LS-SCLC. With more advanced radiation planning techniques, Cancer and Leukemia Group B carried out a series of trials using daily TRT with a high dosage of 70 Gy over 7 weeks in LS-SCLC 4, 5, 6. Disappointingly, no significant improvement of treatment outcome was found in their pooled analysis, possibly owing to the prolonged overall radiation time (7).

Accelerated repopulation of tumor cells during radiation therapy has shown negative effects in several tumor types and is considered as one mechanism of resistance to treatment clinically 8, 9. For SCLC with the characteristic of rapid doubling time and high growth fraction, there is also evidence suggesting that prolonged or interrupted overall radiation time contributes to treatment failure and poor outcome because of accelerated repopulation 10, 11, 12. In our previous study we also found that overall radiation time might play an important role in the treatment of LS-SCLC and that patients treated with a high biologically effective dose (BED, including time factor) of >57 Gy have favorable local control and survival (13). Schild et al (14) investigated the relationship between 5-year survival and various dose-fractionation regimens used in phase 3 trials reported between 1997 and 2004. A strong positive correlation between BED and 5-year survival was found in LS-SCLC (Pearson correlation coefficient 0.81).

Besides dose escalation, an alternative strategy to obtain a higher intensive TRT regimen is use of hypofractionated thoracic radiation therapy (HypoTRT). In the era of 2-dimensional radiation therapy, HypoTRT has been used as a safe and effective treatment for LS-SCLC in Canada (40 Gy/15 fractions) 15, 16. The median survival time and 5-year survival rate were 21.2 months and 22% in Murray's report (15); however, the cumulative risk for local recurrence exceeded 50% beyond 3 years, which was partially attributed to the low radiation dose. Because of concerns that a fraction dose of more than 2 Gy may cause serious side effects and the limitation of 2-dimensional radiation techniques, the pace of exploring HypoTRT in LS-SCLC has slowed over the past few decades (17). With 3-dimensional conformal radiation techniques, a phase 1 study aimed to determine the maximal tolerated dose of HypoTRT for LS-SCLC was reported in 2006 (18). Acute esophagitis was the predominant dose-limiting toxicity, and a dose between 50 Gy and 58 Gy was recommended. In the present study a dose fraction of 55 Gy in 22 fractions over 30 days (BED, 62 Gy) was determined to explore our hypothesis that both high TRT dose and short overall radiation time are critical for the treatment of LS-SCLC.