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%, even after definitive radiation therapy and concurrent chemotherapy.
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.
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.
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.
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.
RTOG 1306 is a phase II randomized study comparing standard chemoradiation to 60 Gy versus 12 weeks of induction therapy with erlotonib or crizonitib in EGFR-mutated or ELM4-ALK translocated adenocarcinoma, respectively.5 This is the first clinical trial to examine molecularly targeted agents in a selected population for locally advanced adenocarinoma of the lung, and the results will be informative.
Lastly, stereotactic body radiation therapy (SBRT) has yielded great success in the early stage, medically inoperable NSCLC population. SBRT specifically refers to delivery of radiation using 3D localization of the target lesion, allowing very high doses per fraction (10-20 Gy) of radiation to be delivered with a high degree of precision and accuracy. The success of SBRT lies in the high dose per fraction and sharp dose gradients associated with this treatment technique that allow for normal tissue sparing from high-dose radiation regions. SBRT techniques have not been applied to the locally advanced patient population, but as radiation delivery technologies continue to improve, using SBRT techniques in patients with stage III disease is feasible.
At Winship Cancer Institute of Emory University, we recently opened a phase I study with a primary endpoint of defining the maximum tolerated dose of an SBRT boost after 44 Gy of concurrent chemoradiation.6 We hope to complete accrual by the end of 2015.
IMRT-based planning is illustrated in the FDG PET/CT image, left, which allows for more precise delineation of radiation target volumes, as seen contoured in the inner red line on the radiation planning CT. At right, the heart is largely not included in the color wash, which represents the high-dose radiation isodose line.