Protons and Other Charged Particles: What Is the Potential Impact on Radiotherapy Practice?

Eric Shinohara, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: August 8, 2007

Presenter: Jay S. Loffler
Presenter's Affiliation: Harvard University
Type of Session: Scientific


  • There are treatment limitations which are independent of radiation.
    • Limitations in diagnostic imaging to define the tumor
    • How sensitive the tumor is to radiation
    • How close the tumor is to normal organs
    • Is the tumor truly localized or are there occult metastases
  • There are also factors which can be controlled for to reduce “collateral damage” from radiation (reducing acute toxicities to normal tissues).
    • The spatial distribution of treatments: improvements in conformality
    • The fractionation and total dose of treatments
    • How dose is delivered temporally, i.e. can we control when the beam is on to limit dose to normal structures, such as with respiratory gating.
    • The intensity of therapy, i.e. can we limit radiation toxicity such that it can be used in conjunction with chemotherapy to improve outcomes.
  • Radiation treatment modalities have been shifting towards greater conformality with reduced integral dose.
    • 3D conformal therapy delivers a fairly large integral dose with limited conformality. -> Intensity modulated radiation therapy (IMRT) improved conformality without increasing integral dose. -> 3D conformal proton therapy significantly reduces integral dose and may also improve conformality. -> Intensity modulated proton therapy (IMPT), such as with a scanning beam may further improve conformality. -> Heavy ion beams, such as carbon beams may further improve conformality.
  • Over the past 5-10 years there has been a dramatic increase in the number of patients treated with proton therapy. Is level one evidence necessary for the wide spread use for this technology?
    • Prior techniques to improve the dose homogeneity and conformality of radiation have been adopted previously without level one evidence.
      • The progression from 2D -> 3D conformal radiation -> IMRT -> Image Guided Radiation Therapy (IGRT) occurred without level one evidence. There have only been two randomized studies which have compared IMRT to 3D conformal therapy, one in breast and one in head and neck cancer.
      • The use of higher energy photon beams was adopted without level one evidence.
      • Protons can be considered a “sustained technology”, meaning that they improve the performance of an established technique, rather than causing a paradigm shift in radiation oncology.
  • Is proton therapy an experimental modality? -> No
    • Protons and photons have a similar relative biological effect (RBE). Hence, treatment doses are comparable making for a smooth transition from photons to protons.
    • Decreasing the dose outside of the treatment volume is logical and cost effective.
    • However, further studies are needed to show that protons are more effective or are less toxic to justify their cost.
    • Due to protons improved conformality and reduced integral dose, dose escalation will be of greater interest, however, these treatments should be done on protocol.
  • What is the 30 year experience at Harvard and what are the gains achieved?
    • The Harvard proton experience is limited by the use of lower energy protons and the use of a fixed beam which limited proton use to shallow tumors.
    • Furthermore, the data was “contaminated” as the majority of patients had 20% or more of their dose given using photons due to the limited availability of protons.
    • Nonetheless, the results from Harvard have been promising suggesting improvements in local control in a variety of tumors such as tumors of the base of skull and uveal melenomas.
    • Preliminary data investing the incidence of secondary malignancies after proton therapy is to be presented at ASTRO 2008. The study was comprised of 647 patients treated at Harvard encompassing 6893 person years. Results suggest that there is a decrease in secondary malignancies in patients treated with protons.
      • The in field risk of secondary malignancies was lower compared with photon therapy and the risk of malignancy outside of the treatment field was similar to the risk of malignancy in the normal population.
      • This suggests that the neutrons produced from the scatter foils used to widen the proton beam do not cause more secondary malignancies.
  • What about the cost of protons?
    • Protons do not cost as much as the public perceives. The new University of Pennsylvania proton facility was published to cost 140 million dollars. The proton portion of this facility was 70 million dollars.
    • A recent publication examining the cost of proton therapy found that it costs 1,330 dollars per fraction compared with IMRT which costs 565 dollars per fraction. However, with improvements in proton therapy, treatment times should be reduced, leading to a decrease in cost per fraction.
    • This same publication found that the annual cost of radiation therapy in the US was approximately 1.1 billion dollars. This is equivalent to the total annual expenditure of some individual biological agents, such as Avastin.
    • Further improvements in proton technology, creating more compact, potentially less expensive accelerators is on the horizon.
  • How will heavy ions affect radiation oncology?
    • Heavy ions are a paradigm shift in the field of radiation oncology as they have a significantly higher RBE compared with photons or protons in addition to improved conformality.
    • This may render many previously radio-resistant tumors radiosensitive. Preliminary data from Japan have shown that excellent local control with heavy ions in radio-resistant cancers, such as melanoma, can be achieved.

Author's Conclusions

  • Protons are part of the natural evolution of radiation oncology and no class one evidence is need for their use.
  • However, as the use of protons expands, it is vital to document changes in side effects and outcomes to justify their cost.
  • In the future, hopefully, the cost of protons will continue to decrease.
  • Heavy ions represent a paradigm shift in the field of radiation oncology and may represent the final frontier of radiation therapy.
  • Heavy ions are still experimental and their use is limited by their higher cost.

Clinical/Scientific Implications

  • With improvements in conformality there also needs to be an improvement in the accuracy and reproducibility of patient immobilization. Otherwise, the improvements in conformality and decreased normal tissue toxicity may be offset by marginal misses. Traditionally used margins may need to be reevaluated.
  • As protons improve conformality and decrease normal tissue dose, there may be an increase in the use of larger fractions and hypofractionation. Previous studies with photons have shown an increase in toxicity with hypofractionation. However, this may not be the case with proton therapy.