Kristin Higgins, MD
Department of Radiation Oncology
Winship Cancer Institute of Emory University
Locally advanced non-small cell lung cancer (NSCLC) remains a challenging disease to treat, with a 5-year survival rate for patients with unresectable stage III disease of approximately 20%,1
even after definitive radiation therapy and concurrent chemotherapy. Yet the repertoire of tools for managing patients continues to grow, as researchers investigate novel strategies in radiation therapy as well as the introduction of molecularly targeted agents for this population.
High-Dose Regimen Ruled Out
The Radiation Therapy Oncology Group (RTOG) tackled important questions about dosing through RTOG 0617, a randomized phase III trial for patients with stage IIIA/B NSCLC that completed accrual in November 2011. This trial investigated standard chemoradiation to 60 Gy with concurrent carboplatin and paclitaxel, and consolidation chemotherapy, compared with high-dose radiation to 74 Gy with the same chemotherapy regimen. A second randomization was also performed after consolidation chemotherapy, with the trial arms consisting of cetuximab versus observation.
Preliminary results, presented in abstract form at the 2013 American Society of Clinical Oncology Annual Meeting, demonstrated inferior survival (median survival 19.5 months vs 28.7 months) and increased local regional failure at 18 months (25.1% vs 34.3%) in the high-dose, 74 Gy arm.2
Additionally, preliminary results have also demonstrated no improvement in overall survival with the addition of cetuximab after consolidation chemotherapy.3
On multivariate analysis, factors associated with reduced survival included 74 Gy, squamous histology, grade 3 or higher esophagitis, larger gross tumor volume, radiation dose to the heart (heart V50%), and heart contour not per protocol. There is no clear reason as to why patients in the high-dose radiation arm experienced poorer survival outcomes.
Possible reasons include the extension of overall treatment time in the high-dose arm, increased radiation dose to the heart, increased grade 5 events, and unreported toxicities.
Technology Boosts Outcomes
It is now clear from RTOG 0617 that high-dose radiation to 74 Gy delivered at 2 Gy/day does not improve outcomes for unresectable stage III NSCLC. However, median overall survival for the 60 Gy arm was quite high at 29 months, the highest median survival for this population yet reported in a phase III trial. This study is also one of the first large studies in NSCLC to report nearly half of patients were treated with intensity- modulated radiation therapy (IMRT), an advanced technology that has not been utilized in prior phase III trials in NSCLC. It is likely that improvements in technology, including more accurate staging with FDG/PET and improvements in radiation delivery (Figure
), are responsible for the excellent performance of the 60 Gy arm in RTOG 0617.
The RTOG is now investigating the use of in-treatment FDG PET/CT to determine if tumor dose can be escalated to improve the locoregional failure rate at 2 years. RTOG 1106 is a randomized phase II study that utilizes an FDG PET/CT obtained after 40 Gy to 46 Gy of external-beam radiation, and uses this PET/CT to reduce the volume of tissue that is incorporated in the radiation fields that receive high dose.4
This is the first randomized study to perform individualized, adaptive radiation planning based on metabolic changes that occur during radiation therapy. This study is currently actively enrolling patients.
Targeted Agents Introduced
Other strategies for improving outcomes for patients with unresectable stage III NSCLC include the use of molecularly targeted agents. Molecular testing on tumor specimens is now standard clinical practice for lung adenocarinomas. For patients with stage III adenocarcinomas with targetable genetic abnormalities, such as EGFR mutations or EML4-ALK translocations, it is unknown if the use of targeted therapy with agents such as erlotinib or crizotinib, respectively, confers a benefit beyond that of standard chemoradiation.