A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617

Reporter: Saumil Gandhi, MD PhD
The Abramson Cancer Center at the University of Pennsylvania
Last Modified: June 7, 2013

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Presenter: Jeffrey D Bradley, MD
Presenter's Affiliation: Washington University School of Medicine

Background

  • Lung cancer is the leading cause of cancer death in the Unite States. 75-80% of all cases are non-small cell lung cancer (NSCLC).
  • The standard of care for locally-advanced (Stage IIIA and IIIB) NSCLC is radiation plus chemotherapy.
  • For more than 30 years, nationally accepted ";standard" radiation dose is around 60 Gy based on the RTOG 7301 trial.
  • For patients with Stage III NSCLC, local failure rate with concurrent chemoradiaiton at these doses is approximately 80-85%.
  • There are prospective phase I/II studies (RTOG 0117, NCCTG 0028, and CALGB 30105) that suggest that dose escalation up to 74 Gy is feasible with concurrent chemotherapy.
  • Phase II data also suggest median survival times approaching 24 months with dose escalation compared to about 17 months with conventional doses.
  • This trial was designed to study the role of: 1) dose escalation and 2) cetuximab, EGFR monoclonal antibody in improving overall survival (OS) of stage III NSCLC patients.
  • The primary objective here was to compare OS of patients treated with standard dose (SD)(60 Gy) versus high-dose (HD)(74 Gy). Results of the cetuximab arms are still pending.

Methods

  • 464 patients with Stage III NSCLC, with no supraclavicular or contralateral hilar disease, ECOG 0-1 PS and decent PFTs were randomized to either SD (60Gy) or HD (74Gy) arms prior to closure of the HD arm.
  • Four arms of the study are as follows:
  • Carbo/taxol with 60 Gy concurrent radiation
  • Carbo/taxol concurrent with 60 Gy + consolidation carbo/taxol and cetuximab
  • Carbo/taxol with 74 Gy concurrent radiation
  • Carbo/taxol + cetuximab concurrently with 74 Gy followed by consolidation chemotherapy
  • Concurrent CT included weekly paclitaxel(45 mg/m2) and carboplatin (AUC=2).
  • Patients randomized to cetuximab received a 400 mg/m2 loading dose on Day 1 followed by weekly doses of 250 mg/m2.

Results

  • 464 pts were accrued prior to closure of the HD arm in, of which 419 were eligible for analysis.
  • Median follow up was 17.2 months.
  • There were 2 grade 5 treatment-related adverse events (AEs) on the SD versus 10 on the HD arm.
  • Rates of Grade 3 AEs were not significantly different between the SD and HD arms (74.2% versus 78.2%, p=0.34).
  • There was a statistically significant difference in the local failures favoring the SD arm at 18 months (25.1% versus 34.3%, p=0.03).
  • There was a statistically significant difference in the local-regional failures favoring the SD arm at 18 months (35.3% versus 44%, p=0.04).
  • There was no statistically significant difference in distant failures between the two arms (42.4% versus 47.8%, p=0.16).
  • The median survival time favored the SD arm (28.7 versus 19.5 months, p=0.0007).
  • 18 month OS rate also favored the SD arm (66.9% versus 53.9%, p=0.0007).
  • There was no significant difference in the primary cause of death in either arm. A majority of patients died from lung cancer on both arms (72.2% versus 73.5%)(p=0.84).
  • Higher radiation dose, higher esophagitis grade, greater gross tumor volume, and heart volume >5 Gy predicted for less favorable OS on multivariate analysis.

Author's Conclusions

  • 60 Gy is superior to 74 Gy in terms of OS and local-regional control for locally-advanced Stage III NSCLC.
  • Patients on the 74 Gy arm had a 56% higher risk of death and 37% higher risk of local failure.
  • Higher local failure rate on the HD arm is not sufficient to account for the difference in OS.
  • There is no clear reason for the poorer survival on the HD arm.
  • The effect of the anti-EGFR antibody (cetuximab) awaits further follow up.

Clinical Implications

  • This randomized phase III trial of 60 Gy versus 74 Gy with concurrent chemotherapy has produced very surprising results. The high dose arm has performed worse than the standard dose in local/regional control as well as overall survival.
  • The authors do not have a very good explanation for this surprising result, except that a combination of multiple factor may have led to this result.
  • Although Grade 3 toxicity was not statistically significant between the two groups, rates of grade 5 toxicity were higher in the high dose arm. However, this is not sufficient to explain the difference in overall survival between the two groups.
  • One limitation of the study is the fact that recurrences were not biopsy proven. Therefore, it is possible that the HD arm had increased rate of fibrosis, which was misclassified as a recurrence on imaging.
  • It is also possible that Cetuximab had an adverse interaction with the HD arm, thus accounting for worse outcomes. However, complete results of the Cetuximab arms are needed to perform this analysis.
  • For now, there is no evidence to support dose escalation in treatment of Stage III NSCLC patients.


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