Risk Factors Predicting Failure and Survival in Lung Cancer Patients Treated with Definitive Dose Escalated Proton Radiation Therapy

Reporter: Lauren Hertan
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 4, 2013

Presenter: Quynh Nguyen
Presenter's Affiliation: University of Texas MD Anderson Cancer Center, Houston TX


  • For patients with locally advanced, inoperable, non-small cell lung cancer (NSCLC), multiple randomized trials have established definitive chemoradiation as the standard of care.
  • A minimum dose of 60 Gy has been considered standard over the past 30 years.
  • Multiple Phase II trials have suggested improved median survival with doses of 74 Gy (RTOG 0117, CALGB 30105, NCCTG N0028).
  • However, critical structures within the thorax often limit the ability to deliver higher doses.
  • The physical properties of proton beam radiation allow for better sparing of surrounding critical structures, potentially leading to the ability to safely dose escalate.
  • A phase II study done at the author's institution prior to the current study assessed stage III NSCLC patients treated with proton beam radiation to 74 CGE with weekly chemotherapy and found very good median overall survival (29.4 months) and no grade 4 or 5 toxicity (Chang et al, Cancer 2011).
  • The purpose of this study was to report survival outcomes and evaluate risk factors predicting for treatment failure in NSCLC patients treated with dose escalated proton beam radiation therapy (PBRT).


  • 176 NSCLC patients treated at a single institution with concurrent chemotherapy and PBRT.
  • Patients included were stage II-IV and post-operative recurrent. The majority of patients (66%) were stage III.
  • All patients included in this analysis were evaluated with PET/CT, EBUS, and mediastinoscopy.
  • All patients underwent a 4D CT simulation and daily IGRT. Adaptive replanning was done if dose distribution changed due to tumor shrinkage.
  • Toxicity and outcome data was collected prospectively.
  • Kaplan-Meier estimates and Cox regression analysis were used to calculate survival outcomes.


  • Median age at diagnosis 69.3 years.
  • Median KPS was 80 (range 60 – 100).
  • Median proton dose delivered was 74 CGE (range, 61 CGE – 87.5 CGE).
  • Median follow up time was 27 months.
  • All Patients:
    • Median overall survival (OS): 32.4 months
    • 3 year OS rate: 45%
    • 3 year local/regional failure rate: 43%
    • 3 year distant failure rate: 50%
  • Only stage III patients:
    • Median overall survival (OS): 30.4 months
    • 3 year OS rate: 42%
    • 3 year local/regional failure rate: 45%
    • 3 year distant failure rate: 55%
  • Older patients (age ? 65) had decreased overall survival on multivariate (p=0.008) analysis.
  • Patients with larger tumor size (GTV ? 55 cc) had decreased distant-metastasis free survival (DMFS) on multivariate (p=0.038) analysis.
  • Evaluating dose:
    • No difference in 3 year OS based on dose: 44% in patients treated with low dose (< 74 CGE) versus 47% in patients treated with high dose (? 74 CGE).
    • In only Stage III patients, there was an improvement in local/distant failures by dose: 73% in patients treated with low dose versus 53% in patients treated with high dose (p=0.047).
  • Toxicity (all patients):
    • Dermatitis:
      • Grade 1-2: 39.7%
      • Grade 3: 5.7%
      • Grade 4: 0%
    • Esophagitis:
      • Grade 1-2: 38.5%
      • Grade 3: 5.6%
      • Grade 4: 0.5%
    • Radiation Pneumonitis:
      • Grade 1-2: 47.1%
      • Grade 3: 1.1%
      • Grade 4: 0%

Author's Conclusions

  • Higher radiation doses appear to decrease local and distant failure in patients with stage III NSCLC.
  • Median survival seen in this study compare favorably to previously reported trials.
  • Despite dose escalation, toxicity was low.
  • Further research is being done to determine the optimal dose of radiation to be used in combination with chemotherapy for locally advanced NSCLC.

Clinical Implications

  • All data showing a benefit to dose escalation has been in either phase II or retrospective studies.
  • The only randomized, phase III study, RTOG 0617, which compared 60 Gy to 74 Gy, was presented at the ASTRO annual meeting in 2011. It failed to show a benefit to dose escalation and actually showed a decrease in survival with the higher dose arm (12 month OS: 81% for 60 Gy arm and 70% for 74 Gy arm). There was no significant difference in toxicity between the two arms and the cause of the difference seen in survival is still being investigated. Interestingly, both arms performed better than previous studies where 60 Gy was used with concurrent chemotherapy (12 month OS: 42 – 67%).
  • The current study showed that proton therapy appears to be a safe and effective method of dose escalation in patients being treated concurrently for NSCLC, with survival data that is improved compared to previous studies, including RTOG 0617.
  • However, there are many limitations to this study, including:
    • This was a non-randomized, single tertiary institution study whose results may not be generalizable to the average radiation oncologist. All patients were simulated using a 4DCT and underwent daily IGRT.
    • Many factors likely played a role in the physician's decision of what dose to use including the year the patient was treated, the size of tumor, patient's age, and patient's performance status. Given these factors, a comparison of outcome based on dose delivered is difficult to interpret.
    • Although it was mentioned that institution had dose constraint guidelines, no information was given about difference in dose to critical structures between the low dose and high dose patients. Additionally, no data were presented comparing toxicity in the low dose versus high dose patients.


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