A Phase II Trial of Stereotactic Body Radiation Therapy for Operable T1N0M0 Non-small Cell Lung Cancer: Japan Clinical Oncology Group (JCOG0403)

Reviewer: Geoffrey Geiger, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2010

Authors: Y. Nagata, M. Hiraoka, T. Shibata, H. Onishi, M. Kokubo, K. Karasawa, Y. Shioyama, R. Onimaru, E. Kunieda, S. Ishikura
Institution: Hiroshima University,, Hiroshima, Japan, Kyoto University, Kyoto, Japan, JCOG Data Center, National Cancer Center, Tokyo, Japan, Yamanashi University, Yamanashi, Japan, Institute of Biomedical Research and Innovation, Kobe, Japan, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan, Kyushu University, Fukuoka, Japan, Hokkaido University, Sapporo, Japan, Keio University, Tokyo, Japan, National Cancer Center, Tokyo, Japan


  • Lung cancer is the most common cancer and cause of cancer-related deaths worldwide with an estimated overall survival of only 15% at 5 years.
  • Widespread use of computerized tomography (CT) has resulted in the detection of increasing numbers of patients with early-stage disease.
  • Surgical resection of early-stage non-small cell lung cancers (NSCLC) offers a chance of cure with 5-year survival rates ranging from 50% to nearly 80%, depending on the series.
    • Lobectomy currently remains the "gold standard" for definitive treatment of early-stage NSCLC.
  • Unfortunately, many patients with early stage lung cancers are not candidates for aggressive surgical management due to underlying medical comorbidities.
    • For these patients, stereotactic body radiation therapy (SBRT) is a treatment modality has emerged as an excellent option for definitive treatment for medically inoperable stage I NSCLC.
      • SBRT allows for the delivery of higher biologically effective doses (BED) than possible with more traditional and protracted external beam radiation techniques.
    • Although local control has been excellent in this population of patients, 3-year overall survival numbers have been suboptimal, possibly because of deaths from underlying illness.
  • More recently, data have emerged regarding the use of SBRT in operative candidates.
    • The purpose of this trial (JCOG0403) was to evaluate the safety and efficacy of SBRT in patients with both operable and medically inoperable T1N0M0 NSCLC (UICC 6th ed., 2002).
      • Two questions were to be answered with this trial: 1) Can SBRT be a standard treatment for medically operable patients? and 2) Can SBRT be an alternative to lobectomy for operable patients?

Materials and Methods

  • This study was a prospective phase II trial conducted across 15 different institutions in Japan.
  • The eligibility criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Patients had to have an ECOG performance status of 0-2, ?20 years old, PaO2 ?60 torr, FEV1.0 ?700 mL, and written informed consent.
  • Patients analyzed in this study were operable patients that had to have been assessed for surgical candidacy by thoracic surgeons. The prescription was 48 Gy at the isocenter delivered in 4 fractions over 4-8 days
    • 4-10 MV X rays were allowed.
    • Heterogeneity corrected doses by pencil beam algorithms were used.
  • The GTV included the primary tumor only, CTV margin was not considered; an ITV margin and 5 mm setup margin were added.
  • As a quality assurance program, credentialing of institutions and an individual case review using the Image-guided Therapy Center (ITC) remote review tool were performed.
  • The primary endpoint was three-year overall survival.
  • The secondary endpoints included overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS), event-free survival (EFS), toxicity, and patterns of failure. The sample size was determined so that the 95% confidence interval for the estimated 3-year OS would be +/- 10% around an expected value of 80%.


  • Between July 2004 and January 2007, 65 patients were registered in this study from 15 institutions, of which 64 were analyzable.
  • The patients characteristics were: male 45, female 20; median age 79 (range, 50-91); median tumor size 21 mm (range, 10-30 mm); 40 patients had adenocarcinomas, 21 squamous cell carcinomas, and the remaining four patients had other histologies. Performance status (Eastern Cooperative Oncology Group) breakdown: 0/1/2, 43/20/2. All patients completed the protocol treatment.
  • At the last follow-up in November 2009, median follow-up of censored cases was 45.4 months.
  • For the eligible 64 patients, the 3-year overall survival was 76.0% (95% CI: 63.3% - 84.8%).
  • The 3-year PFS, LPFS, and EFS were 54.5% (95% CI: 41.5% - 65.7%), 68.5% (95% CI: 55.5% -78.4%) and 51.4% (95% CI: 38.6% - 62.9%), respectively.
  • Grade 3 toxicity was observed in 6 patients: chest pain 1 (1.5%), dyspnea 2 (3.1%), hypoxia 1 (1.5%), and pneumonitis 2 (3.1%). No grade 4 and 5 toxicity was observed.
  • There were a total of 25 failures observed among the patient population.
    • 9 patients (14%) had local failures.
    • 13 patients (20%) had nodal failures.
    • 17 patients (27%) had distant failures.

Author's Conclusions

  • Few data exist regarding the efficacy of SBRT for operable early-stage lung cancer patients.
  • This trial demonstrates that SBRT for operable stage I NSCLC is highly effective with mild toxicity.
  • This treatment has the potential to be an alternative to surgery and should be considered as a treatment option especially in elderly patients.

Clinical Implications

  • Although several articles have been published on the use of SBRT for stage I NSCLC, almost all treated patients were medically inoperable and overall survival confounded by underlying medical comorbidities.
  • This trial is one of few examining the role of SBRT for patients that are medically operable, as assessed by thoracic oncologists and represents one of the first to examine patients prospectively.
  • Overall, the treatments were very well tolerated with no grade 4 or 5 toxicities and only 6 patients suffering grade 3 toxicities.
  • Of the eligible 64 patients, the 3-year overall survival was 76%, which is similar to that observed in surgical series.
  • The use of SBRT for the definitive treatment of early-stage NSCLC in patients that are not candidates for surgical resection has been rapidly increasing, but the role of SBRT in operable patients is much more controversial.
    • The conclusion that this treatment is a potential alternative to surgery is an interesting hypothesis that will need to be tested in larger phase III studies comparing surgery versus SBRT.
      • In North America, the RTOG is nearing completion of accrual to a smaller phase II study, RTOG 0618, of SBRT in operable patients and there are two phase III trials that are ongoing assessing SBRT or surgery for patients with stage I lung cancer: the Randomized Clinical Trial of Either Surgery or Stereotactic Radiotherapy for Early Stage (IA) Lung Cancer (ROSEL) trial in the Netherlands and the Accuray Cyberknife worldwide trial. However, it will be several years before the results of any of these trials are available.
      • Until longer follow-up from larger phase III trials is available, SBRT for patients that are candidates for lobectomy should only be utilized within the context of a clinical trial.