Late Effects of Particle Radiation

Reviewer: Christine Hill-Kayser, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

Presenter: E. Blakely
Presenter's Affiliation: Berkeley Laboratory, San Francisco, California
Type of Session: Scientific


Dr. Blakely gave a comprehensive discussion of the published literature regarding late effects of radiation with protons and other particles. Populations at risk for such late effects include both patients requiring particle radiation and individuals participating in space travel. The former may be exposed to high radiation doses to the partial body, with lower doses to nearby normal tissues, for relatively short periods of time. The latter will be exposed to much lower doses (less than 1 Gray (Gy)) to most if not all parts of the body, sometimes over a period of years. The effects that these two different populations experience may thus be quite different. In addition, space travelers may be exposed to mixed radiation types and various ionization qualities that may not be well understood; this is in contrast to patients treated with radiation, for whom radiation delivered is likely much better defined.

Biologic Aspects of Radiation Damage

  • Effects of radiation may be defined sequentially. Acute damage may occur during or immediately following a course of therapeutic radiation, and is generally followed by a period of recovery. Degenerative late effects may begin to develop months to years after radiation exposure.
  • Immediate effects are likely largely mediated by DNA damage in rapidly proliferating cells. Early effects may include necrosis, denudation, hematopoiesis, and decreased spermatogenesis. Late effects may be considered in three tissue-based categories:
    • Epithelial: Atrophy, necrosis, atypia, dysplasia, neoplasia
    • Stromal: Fibrosis
    • Vascular: Alterations in capillaries and arterioles
  • Radiation sensitivity of a given organ is determined partially by the radiation sensitivity of the stem cells of that organ. Degree of radiation damage may also be based on dose size, mode of dose delivery, dose rate, dose fractionation, and volume of tissue irradiated.
  • Although the period of recovery was once felt to be a quiescent period, many molecular pathways are now known to be active during this time.
    • These may include cytokine cascades, remodeling of the extracellular matrix, growth factor activation, and activation of proteases. Pathways are likely activated by combinations of DNA damage and production of reactive oxygen species.
    • The result of molecular activity may range from cell death to cell repair and recovery. Transformation resulting in dysplasia or neoplasia may also occur.
  • Radiation may also trigger autocrine, paracrine, and endocrine changes.

Recognized Late Effects of Particle Radiation

  • In bioastronautics, a Critical Pathway Roadmap exists, ranking risks of space travel associated with radiation. Malignancy is the most highly-ranked risk, followed by central nervous system damage, chronic degenerative disease, and acute radiation risks.
  • Other recognized risks of particle radiation include cataract formation, cardiovascular damage, gastrointestinal toxicity, neurotoxicity, fibrosis, immune effects, endocrine effects, and hereditary effects.
  • Tolerance doses vary according to tissue type.
  • Cataractogenesis represents one of the most studied radiation-induced late effects.
    • The risk of cataract formation following radiation was first documented in the 1960s, at which time a threshold radiation dose for development of cataracts of 2 Gy was identified.
    • A more recent review of cases has demonstrated that any threshold, if one in fact exists, is likely far below 1 Gy (Ainsbury, 2009).
    • This review demonstrates a linear relationship between dose and risk of cataract formation, and also identifies a longer period of latency before cataract development when lower doses are used.
  • Radiation-induced cancers are also recognized to be of significant concern. Recently, Imaoka and colleagues (2007) have demonstrated influence of strain on risk of induction of mammary tumors in rats. This work demonstrates a clear genetic variability, which renders Sprague-Dawly rats more susceptible to development of radiation-related malignancies.
  • Genetic variability likely plays a role in risk for other radiation-related late effects. This is supported by the identification of certain genotypes identified as increasing risk for urinary morbidity following radiation for prostate cancer (Suga, 2008).

Research at the Berkeley Lab

  • Particle therapy was initiated at the Berkeley Laboratory in 1955, with treatment of pituitary tumors. From 1975 – 1992, patients were treated at the Berkeley Lab with several types of particle therapy, including fast neutrons, helium, carbon, silicon, argon, and neon.
  • Several phase I-II trials were initiated, the lattermost of which was a phase I-II trial directly comparing treatment with neon versus helium.
  • Patients enrolled on these trials represent the earliest cohort of patients treated with particle therapy. Follow-up of these trials was closed in 1993, and data has not been accessed since that time.
  • 1465 patients were treated with helium, carbon, neon, argon, and silicon. At the time of closure, in 1992, 516 patients remained alive, 276 of whom were male.
  • Support has now been obtained for a retrospective evaluation of these patients, and such a study has recently been initiated.
    • Phase 1 of the study will consist of a chart review process, during which survival data will be obtained from public records.
    • Phase 2 will ensue if the cohort of patients is felt to be adequate for analysis from a statistical standpoint.  At this point, after institutional approval, patients will be contacted and invited to participate in a clinical analysis of late particle radiation effects.

Clinical/Scientific Implications

  • Dr. Blakely’s discussion was a very interesting overview of the data that is available regarding late effects of particle radiation.
  • Unfortunately, there is a relative paucity of data regarding this topic, and there are no studies directly comparing late effects from photon radiation versus particle.
  • As the availability of particle therapy becomes more widespread, and this type of therapy becomes potentially applicable to a wide variety of patients, understanding of late risks is clearly of utmost importance.
  • As more and more centers continue to treat patients with particle therapy, data will be gathered to provide information on late effects; however, due to the sheer length of time over which many such effects develop, such data will not be available for many years.
  • Several centers have performed theoretic and dosimetric analyses regarding risk of second cancer development following particle therapy, which may serve a surrogate role until more data is available.
  • As we await the accrual of more data, examination of the Berkeley patient cohort is potentially of great importance. Although differences in technique and type of radiotherapy within this cohort compared to patients treated in the modern era must be taken into account, further understanding of the late effects experienced by this early cohort may be quite informative.