Radiation Therapy Oncology Group (RTOG) 0617 was a study initially designed to address an important issue in radiation oncology regarding the treatment of stage III non–small cell lung cancer (NSCLC): Are outcomes improved with high-dose as opposed to standard-dose thoracic radiation therapy? The additional study objective, testing the possible benefit of cetuximab ­(Erbitux), followed encouraging results seen in a prior RTOG phase II study.¹ Findings in RTOG 0617 were recently reported by Bradley and colleagues² and are reviewed in this issue of The ASCO Post.

The study was closed regarding the question of high-dose (74 Gy) vs standard-dose (60 Gy) when the first interim analysis demonstrated that the study had crossed the boundaries for futility. However, the study continued as a two-arm study, with randomization to cetuximab or no cetuximab, with all patients receiving 60 Gy.

Surprising Findings

Given the suboptimal rates of local tumor control and survival following standard-dose radiation therapy, the radiation community was surprised and disappointed to learn of the poorer survival outcome associated with higher-dose radiation. So far, it appears that the poorer survival following high-dose radiation therapy is related to tumor recurrence/progression as opposed to treatment toxicity. Since the study results are somewhat counterintuitive, Bradley et al put forward several hypotheses to account for this poorer outcome:

• Fewer patients on the high-dose arm completed consolidation chemotherapy.
• High-dose radiation given over 7.5 weeks allowed tumor repopulation to occur.
• Concern regarding treatment toxicity in the high-dose setting may have prompted inappropriately tight radiation fields.
• Higher-dose radiation was associated with a higher heart dose.
• Attributions of cause of death were inaccurate. For example, could higher heart doses have led to undetected treatment-related cardiac deaths?

Further analysis of RTOG 0617 regarding the effect of heart dose on treatment outcome will be forthcoming. Although heart dose was an independent negative predictor of survival, it does not yet fully account for the poor results seen in the high-dose arm. Nevertheless, radiation oncologists need to look more critically at their radiation plans in terms of heart dose. 

Debate Over Radiation Dose Continues

The authors concluded that the high dose of 74 Gy was “potentially harmful.” However, the findings should discourage prescription of doses higher than the standard 60 Gy outside of a study protocol. Pending the results of RTOG 0617, many radiation oncologists have been prescribing doses in the range of 64 to 66 Gy. This study cannot determine whether such doses are better or worse than 60 Gy, but these intermediate doses are now more difficult to rationalize. And, despite the results of RTOG 0617, the radiation dose issue will continue to be controversial.

An important ongoing study is RTOG 1106/ACRIN 6697, a randomized phase II study comparing standard 60 Gy of radiation therapy with high-dose radiation therapy using adaptive (shrinking) radiation therapy techniques. Patients on the high-dose arm will receive up to 80 Gy in 6 weeks, or a dose delivering a mean lung dose of 20 Gy or less. The study will determine the feasibility, treatment toxicity, and survival associated with high-dose radiation therapy using adaptive radiation fields. The high doses are delivered only to tumor sites that remain fluorodeoxyglucose positron emission tomography (FDG-PET)–positive following the initial 4 weeks of concurrent chemoradiotherapy. 

Role of Cetuximab

The other issue addressed in RTOG 0617 was the role of cetuximab in the treatment of stage III NSCLC. RTOG 0617 was initiated at a time when it was not standard of care to perform molecular analysis on tumor specimens in such patients. Epidermal growth factor receptor (EGFR) mutation analysis was not necessary for trial entry, and tissue was available for subsequent EGFR H-score testing (see sidebar on page 23) in less than 50% of accrued patients.

No survival difference was seen in the whole study set when comparing the cetuximab and no-cetuximab arms. This is disappointing given the improvement in survival outcome observed in an unselected population (regarding EGFR status) of patients with squamous cell cancer of the head and neck.³ Bradley et al reported no difference in survival outcomes according to H-score. However, a planned subset analysis determined that for patients with an H-score greater than 200, cetuximab was associated with statistically significant longer overall survival. The authors of RTOG 0617 caution against using cetuximab outside of the protocol setting.

‘Positive’ Outcomes and Beyond

The “positive” outcomes of RTOG 0617 should not be ignored. The median survival of 28.7 months in the 60-Gy study arms is excellent when compared with prior cooperative group studies in stage III NSCLC. The use of PET scans in approximately 90% of enrolled patients may account somewhat for this good survival.

RTOG 0617 also supports the benefit of intensity-modulated radiation therapy in the treatment of lung cancer. Although critics have pointed to the high financial cost associated with intensity-modulated radiation therapy, a plenary session presented at the 2013 American Society for Radiation Oncology (ASTRO) Annual Meeting by Movsas et al⁴ reported the improved quality of life experienced by patients on RTOG 0617 at 3 and 12 months following intensity-modulated radiation therapy as opposed to three-dimensional computed tomography planning. Intensity-modulated radiation therapy is often helpful in reducing the heart dose.

The possible benefit of cetuximab in patients with high H-scores is also intriguing. It should prompt enthusiastic support of RTOG 1306, in which patients with EGFR tyrosine kinase mutations or EML4-ALK fusion arrangements are treated with neoadjuvant erlotinib or crizotinib (Xalkori), respectively. RTOG 0617 and ongoing RTOG studies underscore the goal of defining the best treatment for individual patients. ■

Disclosure: Dr. Gaspar reported no potential conflicts of interest.

References

1. Blumenschein GR Jr, Paulus R, Curran WJ, et al: Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 29:2312-2318, 2011.

2. Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617). Lancet Oncol 16:187-199, 2015.

3. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.

4. Movsas B, Hu C, Sloan J, et al: Quality of life analysis of the randomized radiation dose escalation NSCLC trial (RTOG 0617): The rest of the story. 2013 American Society for Radiation Oncology Annual Meeting. Plenary Session. Presented September 23, 2013.

Dr. Gaspar is Professor in the Department of Radiation Oncology at the University of Colorado School of Medicine in Aurora, Colorado.