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
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 20, 2003
Presenter: Minesh Mehta
Presenter's Affiliation: University of Wisconsin/ ECOG
Type of Session: Scientific
The current standard of care for patients with inoperable NSCLC is combined modality chemotherapy and thoracic irradiation. Research is ongoing, however, to establish the optimal scheduling and dose fractionation of the radiation component of therapy. Failures following standard radiation schemes (ie: 2 Gy fractions once daily) have been attributed in part to the accelerated tumor cell repopulation that is induced during the time period 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 total 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
- Study open from 6/98 to 6/00; closed prematurely due to poor accrual
- 141 pts enrolled, 119 pts randomized, 112 eligible for analysis
- Induction chemotherapy consisted of 2 three-week cycles of carboplatin (AUC 6) and paclitaxel (225 mg/m2)
- 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 (initial on-cord fields were treated 8 hours apart)
- 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
- 3-yr survival 14% vs. 23%
- Distant relapse rates 39% vs. 21%
- 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) and Pulmonary (6 vs 0)
- The use of HART following initial chemotherapy shows a provocative median survival improvement to 20.3 months, compared to the 14 months seen with standard, sequential chemotherapy and radiation in Stage IIIA/IIIB NSCLC patients.
- HART appears to have an acceptable toxicity profile.
- It appears to decrease distant failure rates over standard radiation.
The benefit of HART on the median survival of patients with inoperable stage IIIA/IIIB NSCLC is supported by this study. Furthermore, the use of induction chemotherapy followed by an accelerated radiation regimen does not show substantially increased toxicity over induction chemotherapy followed by standard radiation. Unfortunately, the study closed prematurely secondary to poor patient accrual, and thus the data presented here do not have the statistical power to reach statistical significance. The poor accrual was attributed to the reluctance of both physicians and patients to have treatments 3 times a day, a logistical challenge for most US radiation oncology practices. However, while not statistically significant, the clinical significance of this data and its possible ramifications for future management paradigms is quite real. By reducing the overall radiation course from the standard 7 weeks to 2.5 weeks, as well as addressing the issue of tumor repopulation as a major mechanism of treatment 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 patient accrual and thus help answer this and other related questions. A future study might also address one of the study's criticisms regarding the lack of biological equivalence between the doses administered in the two arms (ie: control arm to 64 Gy is not high enough and thus not a fair comparison arm).
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