Clinical outcomes of proton beam therapy for early stage non-small cell lung cancer. A retrospective analysis of Shizuoka experiences

Reviewer: Geoffrey Geiger MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 13, 2009

Presenter: S. Murayama, H. Fuji
Presenter's Affiliation: Proton therapy division, Shizuoka Cancer Center Hospital, Nagaizumi, Shizuoka, Japan
Type of Session: Scientific


  • The standard of care for patients with operable stage non-small cell lung carcinomas (NSCLC) remains surgical resection.
    • The best surgical series have yielded 5-year overall survival rates of 63%-67% for Stage IA, 46%-57% for Stage IB, 52%-55% for Stage IIA, and 33%-39% for Stage IIB cancers (van Rens, 2000; Mountain, 1997).
    • However, eligibility for surgery depends not only on the clinical stage of the patient but also on their candidacy to undergo either pneumonectomy or lobectomy, which is frequently limited by these patients' concomitant pulmonary and cardiac comorbidities.
  • Several studies have reported a benefit to dose escalation, suggesting a dose-response relationship with respect to both local control and survival in early stage lung cancers, but significant toxicities can be potential sequelae in patients treated to high doses.
  • Photon-based intensity-modulatedradiation therapy (IMRT) may offer the benefit of dose escalation without causing greater toxicity to surrounding normal tissue in selected patients, but there are concerns regarding the delivery of low yet damaging doses of radiation to large volumes of non-cancerous lung tissue.
  • Charged particle beam therapy with either proton or carbon ion therapy allows the delivery of higher doses of conformal radiation due to the dose characteristics of proton beam radiotherapy, including finite range and steep dose fall off beyond the Bragg peak.
    • Protons can achieve an approximately 10-15% dose decrease per millimeter in the fall-off region.
  • The use of 4D CT scanning enables imaging of tumor and organ motion, which can aid in treatment planning. This is vital to proton treatment planning, as the range of protons is highly dependent on the density and amount of tissue they traverse. This is of great concern in treating lung tumors due to the significant respiratory motion.
    • Respiratory gating can therefore be used to spare normal lung tissue, with data demonstrating improvements in the volume of normal lung tissue being irradiated.
  • This study is a retrospective review of early stage lung cancer patients treated with proton beam therapy (PBT) with several beam ports using a respiratory gating irradiation system. The goal is to evaluate the safety and efficacy of definitive PBT for stage I NSCLC at Shizuoka Cancer Center Hospital about 5 years following the start of PBT.

Materials and Methods

  • Between November 2003 and April 2007, 24 patients with pathologically proven stage I NSCLC were treated at the Proton therapy division at the Shizuoka Cancer Center Hospital in Nagaizumi, Shizuoka, Japan
  • Patient characteristics and the number of subjects were as follows, and all patients were of ECOG 0-1 performance status:

    Patient Characteristics

    N =

    Median age

    75 (56-87)



    Stage IA/IB/Post-op recurrence


    Histology, Adeno vs. Squamous vs. Other


    Medically inoperable/refusal of surgery


  • The median duration of follow-up was 30 months (range 3-52 months).
  • Thoracic computed tomography images were obtained in the exhalation phase with a respiratory gating system used for PBT planning.


  • The planning target volume was defined as the clinical target volume with a setup margin and an internal margin for uncertainty of respiratory motion.


  • Daily verification of patient position was accomplished by the image subtraction method with digitally reconstructed radiography


  • Radiation was delivered to the target volume during the exhalation phase.


  • A hypofractionated schedule using a total dose of 80 GyE (GyE was defined as: proton Gy
  • RBE 1.1) was delivered in 20 fractions in all patients.


  • Overall, results were as follows:

    2-year overall survival (OS)


    2-year progression-free survival (PFS)


    2-year local control rate


  • One stage IB patient experienced local tumor re-growth nearly 5 years following an initial response to therapy.
  • Overall, a total of six patients experienced lymph node or distal recurrences in the period examined.
  • No serious acute toxicities were observed during the treatment period.
  • However, there were some longer-term toxicities reported, including patients with dyspnea on exertion, chest pain, and rib/costal fractures.

Author's Conclusions

  • Proton therapy is a very effective treatment for patients with NSCLC, especially for those with early stage tumors that have poor cardiopulmonary function or refuse surgical resection.
  • Excellent results were observed that are superior to early-stage operable patients during the period examined.
  • Furthermore, this regimen is very well tolerated on treatment and results in relatively little long term toxicity.
    • None of the reported patients suffered from radiation pneumonitis.

Clinical/Scientific Implications

  • Surgical resection has long been the standard of care for resectable, early stage non-small cell lung cancers since it confers generally superior outcomes compared to photon beam radiotherapy.
    • Historically, this has been thought to be secondary to inadequate doses to the primary tumor required to avoid unacceptable toxicity.
    • Two- and 5-year survival rates following conventional radiotherapy have typically ranged from 15-43% and 5-20% for stage I non-small cell carcinoma, with respective cause-specific survival rates of 31%-54% and 13%-32%. This is in contrast to surgery where lobectomy confers an approximate overall survival at 5 years of 63%-67% for Stage IA and 46%-57% for Stage IB.
  • These results should be interpreted in the context of stereotactic body radiation therapy (SBRT) for early-stage lung cancers, which has also yielded excellent results.
    • A Scandinavian multi-institutional study included 57 patients with stage I NSCLC (T1N0 or T2N0) who were deemed medically inoperable, primarily due to chronic obstructive pulmonary disease or cardiovascular disease.
      • At a median follow-up of 35 months, the three-year overall and lung-cancer specific survival rates were 60 and 88 percent, respectively. The estimated three-year local control rate was 92 percent (Baumann, 2009)
  • Given the limited availability of proton radiotherapy for early stage lung cancers and difficulties with respect to intrafractional motion and interfractional change in the context of excellent outcomes with SBRT, the data presented here appear interesting and promising, with potentially improved results as compared to historical data; however, the retrospective nature of the study, small sample size, and relatively short follow-up time preclude making statements regarding effectiveness in the definitive setting as compared to more readily available therapies.