Systematic Review Evaluating the Timing of Thoracic Radiation Therapy in Combined Modality Therapy for Limited-Stage Small-Cell Lung Cancer

Authors: Fried et al.
Source: Journal of Clinical Oncology, Volume 22, Number 23, December 1, 2004

Introduction

Meta-analyses by Payne, Pignon and Warde have helped to confirm the benefit of adding thoracic irradiation to chemotherapy for limited-stage small cell lung cancer. However, there is still some controversy regarding the timing of thoracic irradiation (TRT), specifically whether TRT should be administered up-front at the start of chemotherapy, (early) or later towards the end of chemotherapy (late). This study by Fried et al seeks to address this issue by conducting a meta-analysis of 7 randomized trials published in peer-reviewed journals after 1985.

Methods

• Purpose: meta-analysis to evaluate the timing of thoracic radiation therapy (TRT) - early (E) vs. late (L) in limited-stage small-cell lung cancer (LS-SCLC)
• Methods: analysis of 7 randomized trials (81-335 patients) published after 1985 that addressed timing of TRT.
• • Analysis by risk ratio (RR), risk difference, and number-needed-to-treat (NNTT)
  • E-TRT was defined as beginning before 9 weeks and before 3rd cycle of chemo
  • L-TRT was defined as beginning 9 weeks or more after initial chemo (Jeremic)
  • Treatment response: responders if CR or PR, non-responders if no response or progression
• Overall Survival was analyzed 2 ways:
• • Risk ratio: probability of survival at given time point for E-TRT divided by probability of survival at that time point for L-TRT
  • • RR > 1 indicates improved survival in E-TRT
  • Risk Difference (absolute risk reduction): actual difference in survival rates between E-TRT and L-TRT
  • Number Needed to Treat (NNNT): estimated number of patients that would need to be treated on the more beneficial study arm to prevent an adverse outcome
• Seven randomized trials with 81 to 335 patients, for a total of 1,524 patients
• Limited stage: disease confined to one hemithorax +/- mediastinal nodes (2 of 7 included contralateral or bilateral supraclav nodes)
• Chemo varied (5 of 7 included platinum-based chemo)
• RT doses ranged from 40 to 50 Gy [3 of 7 were hyperfractionated (HRT) and 1 of 7 used an alternating RT/chemo schedule]
• PCI: 4 of 7 studies included PCI as part of therapy for CRs, and 2 of the 4 included patients with PRs (1 of 7 studies included PCI in all patients)

Results

• OS risk ratios (RRs) were 1.17 (95% CI 1.02 to 1.35, P=0.03) at 2 years and 1.13 (95% CI 0.92 to 1.39, P=0.20) at 3 years
• Subset analysis:
• • HRT OS RRs for ERT vs. LRT were 1.44 (95% CI 1.17 to 1.77, P=0.001) at 2 years and 1.39 (95% CI 1.02 to 1.90, P=0.04) at 3 years
  • Platinum-based chemo OS RRs were 1.30 (95% CI 1.10 to 1.53, P=0.002) at 2 years and 1.35 (95% CI 1.07 to 1.70, P=0.01) at 3 years

Author's Conclusions

• There is significant survival benefit at 2 years for early thoracic radiation in LS-SCLC, and there is a trend at 3 years when analyzing all 7 trials
• There is significant survival benefit at 2 and 3 years for early thoracic radiation when given in a hyperfractionated schedule
• There is significant survival benefit at 2 and 3 years to early thoracic radiation when given with platinum-based chemotherapy
• There is an 18% absolute survival benefit of E-TRT at 2 years when given hyperfractionated and with a platinum-based chemotherapy

Discussion

This meta-analysis concludes that early thoracic irradiation for limited-stage small cell lung cancer has a significant survival benefit. The major criticism of this study is that data were abstracted from the published articles, rather than from the original individual patient data. Using original individual patient data would have been the preferred approach and would have lent more credibility to the conclusions. Also, the benefit seen with early TRT loses significance when analyzed at three years. Regardless, the conclusions generally support our current treatment practice. The subgroup analysis confirms that hyperfractionated TRT with a platinum-based chemotherapy regimen is superior to daily fractionation with non-platinum-based chemotherapy.