Induction chemotherapy followed by standard thoracic radiotherapy (Std. TRT) vs. hyperfractionated accelerated radiotherapy (HART) for patients with unresectable stage IIIA and B non-small cell lung cancer (NSCLC): Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597)
Reviewer: Neha Vapiwala, MD
Last Modified: June 1, 2003
Presenter: C.P. Belani Presenter's Affiliation: ECOG Type of Session: Scientific
The current standard of care for patients with locally advanced NSCLC is combined modality chemotherapy and thoracic irradiation. What has not been clearly established is the optimal scheduling and dose fractionation of radiation with respect to chemotherapy. Failures following standard radiation have been attributed in part to accelerated repopulation of tumor cells that is induced between radiation fractions. The concept of continuous HART or hyperfractionated accelerated radiotherapy stems from its apparent radiobiological advantage of combating this tumor repopulation as well as its logistical advantage of shortening the radiation course. Saunders et al(Lancet 1997) demonstrated a reduction in relative risk of mortality and a 2-yr survival benefit using continuous HART compared to standard radiation. ECOG 2597 is a phase III trial aimed to evaluate the efficacy of standard thoracic radiation compared to HART following induction chemotherapy in pts with unresectable stage III NSCLC.
Materials and Methods
141 pts enrolled, 119 pts randomized
Induction chemotherapy consisted of 2 three-week cycles of carboplatin and paclitaxel
Subsequent randomization to one of two study arms
Arm I received 64 Gy in 2 Gy daily fractions
Arm II received 57.6 Gy in 1.5 Gy tid (3 times a day) fractions, with each fraction given at least 4 hours apart
Pts stratified for histology (squamous vs. nonsquamous), ECOG performance status (0 vs. 1), and stage IIIA vs. IIIB
Designed to find 50% increase in median survival from 14 mos to 21 mos
Both arms well matched for pt characteristics except notably more T4 pts were in the HART arm
Results of Std. TRT vs. HART:
Median survival was 13.7 vs 20.3 months
Time to progression was 9.3 vs 8.4 months
Complete response rate was 4% in both arms
3-yr survival was 14% vs 23%
No statistically significant survival differences due to low number of pts in trial
Toxicities (# pts) for arm 1 vs arm 2:
Esophagitis (9 vs 14)
Pulmonary (6 vs 0)
Relapse patterns Arm 1 vs Arm 2
Local 32% vs 30%
Distant 39% vs 21%
CNS only 13% vs 20%
Local + Distant 7% vs 7%
The use of HART post-chemotherapy shows a provocative median survival improvement to 20.3 months.
HART appears to have an acceptable toxicity profile.
It appears to increase distant disease control.
The benefit of HART on median survival of pts with inoperable stage IIIA/IIIB NSCLC appears to be supported by this study. Furthermore, the use of induction chemotherapy followed by this accelerated radiation regimen does not show substantially increased toxicity over induction chemotherapy and subsequent standard radiation. Unfortunately, the study closed prematurely secondary to poor pt accrual and thus the data presented here do not have the statistical power to reach statistical significance. This was due to the reluctance of both physicians and patients to have treatments 3 times a day, which is logistically difficult. The clinical significance, however, and its possible ramifications for future management guidelines, is quite real. By shortening the overall radiation course from standard 7 weeks to 2.5 weeks, as well as addressing the issue of tumor repopulation as a major mechanism of treatent failure, HART offers a promising and perhaps superior alternative for unresectable, good performance status NSCLC pts. Should it be adopted in modern-day treatment regimens in lieu of standard radiation? The authors suggest that an Intergroup trial investigating this topic would perhaps achieve higher pt accrual and thus help answer this and other related questions. However, 3 times a day radiation is very difficult to deliver logistically in the United States as an outpatient treatment regimen. For those patients that are treated with this regimen in Europe, the patients are admitted to the hospital for the duration of treatment.
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