Toxicity Analysis of RTOG 0236 Using Stereotactic Body Radiotherapy to Treat Medically Inoperable Early Stage Lung Cancer Patients

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 31, 2007

Presenter: Robert Timmerman, MD
Presenter's Affiliation: University of Texas Southwestern
Type of Session: Scientific


  • The treatment of patients with non-small cell lung cancer (NSCLC) who are unable to undergo surgery can be very difficult as these patients often have poor lung function which limits radiation dose and volumes.
  • Disappointing results with conventional fractionation has led to studies investigating the use of stereotactic radiation and dose escalation.
  • Based on Phase I data from Indiana University, a Phase II trial (RTOG 0236), was initiated.
  • RTOG 0236 is the first study conducted in North American investigating the use of stereotactic radiation for the treatment of early stage lung cancer. 
  • The present abstract presents the toxicity in this group of medically inoperable patients and efficacy data is to follow when available.

Materials and Methods

  • Study criteria
    • All patients accrued for this study had biopsy proven NSCLC.
    • All patients had T1 or T2 disease except for T3 disease which involved the chest wall. Patients could not have nodal or metastatic disease.
    • All patients were required to have documented medical conditions such as emphysema or diabetes which precluded them from surgery. 
    • All patients had peripherally located tumors, defined as those located greater than 2 cm from the central bronchial tree.
  • Radiation:
    • All patients were treated to a PTV margin dose of 60 Gy in three 20 Gy fractions. 
    • No heterogeneity correction used. Subsequent analysis of dose with heterogeneity corrects demonstrated that actual dose delivered was 54 Gy in three doses of 18 Gy. 
    • All radiation plans were centrally reviewed.
  • The primary endpoint of this study was local control.
  • Secondary endpoints included disease free survival, overall survival, and toxicity.
  • Early stopping rules stated that Grade 3 treatment related toxicity could not exceed 25%. Grade 3 toxicities which were examined included pulmonary toxicity, such as fibrosis or pleural effusions, esophageal toxicity, cardiac toxicity, and neurologic toxicity.


  • A total of 59 patients were accrued from May of 2004 to October 2006. 55 patients were evaluated.  One patient withdrew and four patients were found to be ineligible for the study.
  • 44 patients had T1 disease and 11 had T2 disease. The majority of patients were female (62%) and had a Zubrod performance status of 1 (64%). 
  • The majority of patients were treated per treatment protocol or with only minor deviations (91%).
  • Three interim analyses of toxicity were conducted. None reached the threshold for stopping the study.
  • Median follow up was 12.6 months.
  • Toxicity:
    • No grade 5 toxicity (death) occurred.
    • One patient had grade 4 toxicity with a decreased in pulmonary function to <25% of predicted.
    • There were five grade 3 pulmonary toxicities. Two patients had decreased pulmonary function tests.
    • Five grade 3 non-pulmonary toxicities were noted comprised of rib fractures and dermatitis. 
    • A problem with toxicity criteria was that the CTC version 3 criteria were used. However, this criteria assumes a normal baseline pulmonary function (90-100% or predicted) which is inappropriate for this study group as they were medically inoperable and often had worse starting pulmonary function. 

Author's Conclusions

·        Stereotactic radiation to a dose of 54 Gy in three fractions was well tolerated and safe with 6/55 (11%) of patients having grade 3 or 4 toxicity.
·        This treatment regimen appears to be safe in a frail, inoperable patient population.
·        An improved protocol for evaluating toxicity needs to be used to assess treatment related toxicity going forward as the previously selected protocol is inappropriate. Clinically relevant toxicity may be lower than that detected in this study. The majority of patients with decreased pulmonary function tests were not symptomatic. 
·        Continued toxicity follow up is required as previous data has found that late toxicity can occur with stereotactic radiation in lung cancers. Though the median follow up has been greater than 1 year, previous studies of centrally located lung cancers treated with stereotactic radiation have suggested that late toxicities can occur beyond this time point.
·        There is presently a new trial being planned examining treatment with five fractions for central lung cancer lesions.
·        It is too early to report recurrence data; however the authors report, preliminarily, there has been one recurrence to date which is encouraging.

Clinical/Scientific Implications

  • Though early, these results are encouraging as they suggest that, even in patients with comorbidities which preclude surgery, stereotactic radiation can be used safely in peripherally located lung cancers. The results do not seem to be compromised by the inappropriate use of the CTC toxicity criteria as a large portion of the patients who had decreased pulmonary function tests (which comprised a large amount of the toxicity seen) were not symptomatic.
  • Data is not yet available, but response based on tumor size would aid in determining if further dose escalation may be necessary. Previous studies have found that with stereotactic radiation there was decreased local control with larger tumors.
  • The present study did not comment on how respiratory motion was accounted for. It is also unclear as to what margin was used for treatment. These factors are important as the use of respiratory gating or other techniques could allow the volume of normal lung treated to be reduced.  In this group of patients who may have limited pulmonary reserve, this may further reduce toxicities.  
  • Hypofractionated proton therapy for early stage lung cancer has been examined in multiple studies and appears to have limited toxicity as well. Proton based treatment may allow sparing of more normal lung and decrease toxicity further. There is also the potential for further dose escalation with the use of protons.
  • The present results support the use of stereotactic radiation in treating peripheral lung cancers but further follow up is needed to determine late toxicities. Efficacy data is also required and it will be interesting to see if they demonstrate that stereotactic radiation is comparable to surgery. If these data are compelling a Phase III randomized trail should be initiated.

Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.