Radiation Therapy Protocol Deviations are Associated With Inferior Clinical Outcomes: A Meta-analysis of Cooperative Group Clinical Trials

Reporter: Abigail T. Berman, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 30, 2012

Presenting Author: Nitin Ohri, MD
Presenting Author Affiliation: Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA


  • Quality assurance procedures are commonly incorporated into modern radiotherapy trials, but their importance has not been quantified.
  • Several reports have linked noncompliance with radiotherapy (RT) protocol guidelines with inferior clinical outcomes.
  • The purpose of this study was to perform a systematic review and a meta-analysis of prospective cooperative group trials to determine the impact of RT quality assurance (QA) deviations on disease control and overall survival (OS).


  • The authors searched MEDLINE and the Cochrane Central Register of Controlled Trials for multi-institutional trials that reported clinical outcomes in relation to RT quality assurance (QA) results.
  • They looked for the terms “radiotherapy”, “quality assurance”, “survival”. Criteria included reports relating to clinical outcomes in multi-institutional clinical trials to RT QA results.
  • Primary outcome was overall survival and secondary outcomes were local control and event-free survival, which were grouped together.
  • Hazard ratios (HRs) from time-to-event outcomes were extracted directly from the original studies or were estimated directly describing the impact of RT protocol noncompliance on outcomes were extracted directly from the original studies or calculated from survival curves (Parmar et al, Statistics in Medicine, 1998).
  • Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p<0.10 using Cochran's Q test).


  • Initially 600 publications were identified but 8 studies met all inclusion criteria and were incorporated into this analysis.
  • Of these 8 studies, 4 were pediatric trials (POG 8346, Ewing's sarcoma; SFOP.TC 94, medulloblastoma; POG 9031, medulloblastoma; SIOP/UKCC PNET-3, supratentorial PNET), and 4 studied adult patients (RTOG 73-01, non-small cell lung cancer; SWOG 7628, small cell lung cancer; TROG 02.02, head and neck cancer; RTOG 97-04, pancreatic cancer).
  • Six of these trials reported the impact of RT QA deviations on overall survival, and six described the effects of RT QA deviations on secondary endpoints (local control, event-free survival).
  • The frequency of RT QA deviations ranged from 8% to 71% (median: 40%).
  • In 5 out of 6 trials, RT deviations were associated with worse overall survival (outlier: POG 9031). Using a random effects model, RT deviations were associated with a significant decrease in OS (HR = 1.74, 95% CI: 1.28 to 2.35, p<0.001).
  • A similar effect was seen for secondary endpoints (HR = 1.79, 95% CI: 1.15 to 2.78, p=0.009). This was seen in 5 of 6 trials (again, outlier is POG 9031).
  • No evidence of publication bias was detected using the Egger test (p=0.361 for OS, p=0.468 for secondary endpoints).

Author's Conclusions

  • In clinical trials, RT protocol deviations are associated with increased risk of treatment failure and overall mortality.
  • The magnitude of these effects demonstrates that RT QA results should be considered in the interpretation of clinical trial results.
  • The delivery of high-quality RT is critical for the successful treatment of cancer patients.

Clinical Implications

  • This is an impressive study with a very broad group of patients and trials included: 8 cooperative group trials that covered over 1500 patients, adults and children, epithelial and non-epithelial tumors, multiple disease sites, and studies from various parts of the world.
  • There was a clear overall survival decrement with RT deviations.
  • Several recent publications have specifically address this issue:
    • TROG 02.02 (Peters et al. JCO 2010). They found that in patients who received at least 60 Gy, those with major deficiencies in their treatment plans had decreased 2 year overall survival, 50% v 70%; HR 1.99; P < .001; and decreased 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001.
    • RTOG 9704 (Abrams et al. IJROBP 2012) found that patients treated per protocol were associated with decreased risk of failure (p = 0.016) and, for gemcitabine patients, there was also a trend toward reduced Grade 4/5 non-hematologic toxicity.
    • These examples highlight that the results of this study are not only statistically significant but also clinically significant with up to a 20% difference in overall survival per the TROG study.
  • One potential confounder is that patients perhaps did not have improved survival because of better compliance with the RT plan, but because overall their physicians were delivering better, more compliant care including chemotherapy and supportive care. Therefore, these are potential unmeasured confounders.
  • Limitations of this study include that it incorporated study-level data and the possibility of publication bias although this was not detected using the Egger test.
  • It is clear from this study that protocol adherence needs to be increased, but it leaves open-ended the ways to accomplish this. An important first step will be to understand the causes of non-adherence.
  • This study also raises the broader point that quality radiotherapy improves patient outcomes. Therefore, as a community, we should all continue to strive to deliver quality radiotherapy for patients on and off-study.