Intrafractional and Interfractional Range Variation in Charged Particle Therapy of Lung Cancer

Reviewer: Geoffrey Geiger MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

Presenter: S. Mori, L. Dong, G. Starkschall, R. Mohan, J.D. Cox, T. Chen
Presenter's Affiliation: National Institute of Radiological Sciences, Chiba, Japan
Type of Session: Scientific


  • The difference between charged particle and photon beams is their finite penetration and sensitivity to tissue density variations along a given pathway (Goitein, PTCOG 45).
  • The availability of 3D image data from computerized tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI) has enhanced the ability to perform conformal radiation treatment (RT) planning.
  • More recently, 4-dimensional (4D) planning has become increasingly utilized.
    • In f-4D-RT, temporal changes in the anatomy are taken into account during imaging, planning, and delivery of RT.
    • 4D treatment planning takes into account both intra- and interfraction motion.
    • 4D treatment planning with photons assesses geometric motion and ensures that the planning target volume (PTV) encloses the target volume, in the presence of both motion and setup error.
    • During treatment planning for a moving target, one may use the full range of motion during respiration and design a treatment plan irradiating the target (internal target volume or ITV) adequately during the full respiratory cycle (ungated mode).
      • If such a treatment plan is found to result in unacceptable irradiation of distal normal tissue, additional strategies must be employed such as turning the beam on only during a specific part of the respiratory cycle (respiratory gating).
    • 4D treatment planning with charged particle beams must also consider the range variations that occur during respiratory motion and setup, given their finite range.
      • Range is determined by both the extracted particle beam energy and the specific compensator constructed for a given beam direction.
      • Investigators have reported on 4D imaging techniques to incorporate organ motion directly into the diagnostic and therapeutic applications, but the assessment of range uncertainties in 4D treatment has not yet been fully explored.
    • Charged particle treatment planning includes beam specifications ( i.e. beam angle, aperture, weight, design of compensating bolus, etc.), but anatomical and changes tumor size can result in beam overshoot or undershoot.
      • Compensating bolus is designed to account for radiologic pathlength variations, with the goal of stopping the charged particle beam at the distal surface of the target from each beam direction.
      • Smearing (Wagner, 1982) is a well-established method of proton beam compensator design and involves the selection of the largest water equivalent pathlength (WEL) value within a given radius of the nominal beamlet.
      • Complete dosimetric assessment of the effects of motion on tumor and normal tissues is impractical on a routine basis.
      • Mori and Chen (2008) posited that many of the general features of the effect of motion on a treatment plan can be obtained by computing the variations in WEL.
    • This abstract examines the water equivalent pathlength variations due to both intrafractional and interfractional changes in anatomy and physical properties through weekly analysis of serial 4D CT scans to evaluate changes in anatomy over both inter- and intrafractional time scales.

Materials and Methods

  • Serial 4DCT scans were performed under free breathing conditions during 6 weeks of radiotherapy for 6 non-small cell lung cancer patients.
  • Evaluation metrics were variations in: WEL, lung density, CT number and chest wall thickness.
  • Metrics for the intrafractional changes and metrics from the initial CT scan (week 0) were compared with those from subsequent serial weekly CT scans (weeks 1-5) with peak exhalation as the reference.
    • The calculation region is defined by two planes, one at the entrance surface, the other just behind the target from a given beam direction.
    • The WEL difference (ΔWEL) was calculated by subtracting the WEL of the second CT scan from that of the first CT scan at the same respiratory phase.
    • Similarly, a lung density map was calculated to assess lung density changes by segmenting the lung from other anatomical structures by CT threshold and generating a lung density image (similar to a digitally reconstructed radiograph, or DRR) by calculating the average density along AP direction.


  • Mean WEL variations over the internal target volume region for all patients were -7.1mm and -15.5 mm due to intrafractional and interfractional changes, respectively.
  • Chest wall thickness variations of <-3.0 mm, -3.6 mm, -3.6 mm were observed during respiration in the upper, middle and lower lung fields, respectively.
  • WEL variations of -7.2 mm, -6.5 mm, -4.3 mm in the upper, middle and lower lung were observed in the interfractional data.
  • Lung density and soft tissue CT numbers did not show significant changes.
    • The change in lung density were less than 0.06 g/cc
  • Chest wall thickness showed variation from week to week; these variations could be attributed to patient setup.
    • For example, maintaining the arm-up position can be a challenge for physically weak cancer patients.
  • Additionally, the WEL values decreased gradually through the treatment course.
    • This trend could be explained by weight loss, muscle atrophy, lymphadenopathy, etc.

Author's Conclusions

  • WEL analysis is useful in the rapid assessment of range variations in the treatment of lung tumors.
  • Overall, intra- and interfraction variations were < 9 mm-WEL and <15 mm WEL, respectively, due to chest wall and thickness variation.
  • Chest wall thickness through respiration and course was identified as the biggest factor among all patients affecting range variations.
    • Intrafractional: rib position change and physical chest wall thickness change were the most important factors.
    • Interfractional: physical chest wall thickness change and patient positioning were the most important factors.
  • Future investigations will evaluate the merit of replanning and redesigning the bolus compensator to potentially improve the prescribed dose to the target and to avoid severe normal tissue toxicities by taking interfractional changes into account.
  • Additionally, immobilization and better reproducibility of the arm position may be important to minimize the changes in chest wall thickness, particularly in the upper chest region.

Clinical/Scientific Implications

  • Multiple factors in intrafractional motion and interfractional change impact range in charged particle therapy.
  • This study examines intra- and interfractional changes in WEL, lung density, CT number and chest wall thickness, with WEL serving as a surrogate for beam end of range in an effort to identify how intra- and interfractional changes in anatomy and physical properties affect particle treatment planning through the analysis of 4D CT scans.
  • Interfractional changes can result in significant beam overshoot if the initially planned compensating bolus is applied over the entire course of therapy.
  • As 4D CT-based treatment planning becomes increasingly utilized for photon radiotherapy, it becomes increasingly important to adapt those techniques to charged particle therapy, where the finite range of the particles makes the assessment of variations occurring during respiratory motion and setup crucial.
  • In view of the rapid progress of imaging techniques, quantitative information and interfractional changes should be evaluated and incorporated into image guided proton therapy.
  • Replanning and redesigning the bolus in consideration of the interfractional anatomical changes as well as intrafractional motion provide the ability to deliver treatment with greater accuracy, which can be accomplished with better quantitative understanding of intrafractional motion and interfractional change.