Reduction of Normal Tissue (NT) Toxicity in Patients with Locally Advanced (LA) NSCLC treated with Concurrent Chemotherapy (ChT) and Proton Beam Therapy (PBT) compared to Intensity Modulated Radiation Therapy (IMRT)

Reviewer: Curtiland Deville, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 28, 2010

Presenter: Ritsuko Komaki, MD
Presenter's Affiliation: University of Texas M.D. Anderson Cancer Center


  • Lung cancer is the leading cause of cancer mortality with a 5 year overall survival of 15%.
  • Local control with standard photon therapy is less than 50%.
  • Improvements in radiation treatment planning and delivery, in addition to combined modality treatment, have led to an increase in median survival from 9.8 months in the 1980's to as high as 22.7 months in the recent Phase I/II RTOG protocol 0324. This protocol evaluated concurrent chemotherapy, radiation, and Cetuximab, an IgG1 monoclonal antibody, in patients with Stage III non-small cell lung cancer (NSCLC).
  • Multiple prospective randomized trials have demonstrated a survival benefit with concurrent chemotherapy and radiation over sequential treatment, but at the cost of increased normal tissue toxicity, including esophagitis, pneumonitis, and bone marrow suppression with concurrent treatmemt.
  • Strategies to improve the therapeutic ratio – increasing the dose to tumor and/or reducing the dose to normal tissues – continue to be investigated.
  • A retrospective review from the MD Anderson Cancer Center group of 496 patients with LA-NSCLC treated from 1999-2006 showed an overall survival benefit to patients treated with 4D/IMRT in comparison to 3D conformal therapy, as well as a reduction in grade 3 treatment-related pneumonitis.
  • The physical properties of proton therapy allow for unique dose deposition with no exit dose, potentially reducing the dose to normal tissues.
  • The objective of this study was to evaluate the incidence of severe esophagitis, pneumonitis, and bone marrow suppression in patients with LA NSCLC treated with concurrent chemotherapy and PBT versus concurrent chemotherapy and IMRT.


  • This was a single institution, nonrandomized, retrospective review of NSCLC patients treated at the M.D. Anderson Cancer Center from 2003 – 2008.
  • There were 132 patients: 67 in the PBT arm and 75 in the IMRT arm.
  • 4D planning was implemented in 2004.
  • Inclusion criteria included concurrent chemotherapy, dose > 60 Gy/60 Gy (RBE), and no previous radiation.
  • Patients receiving mixed photon and proton therapy were excluded.
  • Toxicity was scored based on Common Terminology Criteria for Adverse Events (CTACE) Version 3.0.


  • Median follow-up was 16.9 and 9.8 months for PBT and IMRT, respectively.
  • Median age was lower in the PBT arm at 62 versus 67 in the IMRT arm (p<0.07).
  • Nodal involvement was significantly increased in the IMRT group (83%) compared to PBT (42%) (p<0.001)
  • Median doses prescribed were 63 Gy and 74 Gy(RBE) for the IMRT and proton therapy arms, respectively.
  • Grade 3 esophagitis and pneumonitis were significantly decreased at 6% and 0% respectively in the PBT group compared to 40% and 9% in the IMRT group (p<0.001).
  • Bone marrow suppression was significantly reduced in the PBT group, with respect to hemoglobin, overall white blood cell, neutrophil, and lymphocyte counts.

Author's Conclusions

  • PBT significantly reduced grade 3 or greater normal tissue toxicity – esophagitis, pneumonitis, and bone marrow suppression – compared to IMRT for patients with LA NSCLC treated with concurrent chemotherapy
  • These data suggest that patients treated with proton therapy may be offered more aggressive chemotherapy regimens.

Scientific Implications

  • This single institution, retrospective, nonrandomized comparison of PBT and IMRT in NSCLC provides preliminary evidence for potential improvement in the therapeutic ratio of combined modality treatment with proton therapy by reducing normal tissue toxicity.
  • However, given the advanced stage and larger target volumes in the IMRT arm, it is unclear that the advantages of PBT would be as dramatic in stage- and volume-matched cases.
  • The ongoing prospective randomized phase II study of IMRT vs PBT (P-01 CA 021239) for patients with Stage III NSCLC treated with concurrent chemotherapy should further clarify these issues.