Comparative Analysis of Second Malignancy Risk in Patients Treated with Proton Therapy versus Conventional Photon Therapy

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 22, 2008

Presenter: T. Yock
Presenter's Affiliation: Massachusetts General Hospital, Boston, MA
Type of Session: Scientific


  • Proton radiotherapy is rapidly gaining favor as a treatment modality in the setting of many cancers. Due largely to the physical nature of protons as particulate matter, proton radiation can improve dose distribution to treatment volumes while reducing dose to neighboring organs at risk.
  • Use of proton therapy is being examined in several clinical trials currently, and protons are being utilized for treatment of many different malignancies. Their benefit is potentially greatest when tumor tissue is within close proximity to organs at risk, and/or for specific subsets of the population for whom late effects to normal tissues may be more significant than expected for the general population (e.g. pediatric patients).
  • As use of protons has increased, and more proton centers are being constructed, concerns regarding late-effects from proton therapy have gained interest. Among these is a potentially increased risk of second malignant neoplasms (SMN) in patients treated with proton radiotherapy (Hall E, IJROBP, 2006).
    • The theoretical increased risk of SMN after proton radiotherapy results from scattered neutrons that may arise from the head of the treatment machine.
    • This risk may be greatest when proton radiotherapy is given using a passive scatter technique rather than a scanning technique; passive scatter technology is the most common type utilized in proton treatment machines, and the only type currently available at US centers. 
  • Although fairly large numbers of patients have been treated with proton therapy at select centers in the US having access to this technology, the magnitude of SMN risk in these patients when compared to those treated with photon radiation has not been reported.
  • This study was undertaken to attempt to quantify the risk of SMN associated with proton radiotherapy compared to photon radiotherapy.

Materials and Methods

  • The study described here was a matched retrospective cohort study comparing patients who received proton radiotherapy at the Harvard Cyclotron associated with Massachusetts General Hospital in Cambridge, MA to patients receiving photon therapy enrolled on the Surveillance, Epidemiology, and End Results (SEER) cancer registry.
  • Patients were matched according to age (+/- 10 years), year of treatment (+/ - 5 years), disease histology, and radiotherapy site.
  • Patients were required to have at least one year of follow-up.
  • Patients with eye tumors (mainly uveal melanomas and retinoblastomas) were excluded, as were patients who underwent radiosurgery.
  • The primary outcome of this study was SMN developing at any site following radiotherapy, regardless of histology or radiotherapy fields.
  • Multivariate Cox regression analysis and Poisson regression were used to analyze risk of SMN relative to other patient characteristics.


  • 1441 patients treated between 1974 and 2001 with proton radiotherapy at the Harvard Cyclotron were identified. Of these 503 were eligible to be considered in this study.
  • These 503 patients were matched in a 1:1 fashion to 503 patients registered in the SEER database.
  • The authors note that most patients treated with photons at the Harvard Cyclotron received 20% of their dose with photon radiation; this occurred because the Harvard Cyclotron is used for patient treatment only 4 days each week. On the 5th day, the machine is dedicated to research purposes and patients receive photon treatment rather than proton.
  • Median age in both groups was 62 years (range 1 year – 90 years).
  • Median follow up was 6.8 years for patients treated with protons, and 5.2 years for those treated with photons. This difference was statistically significant (p < 0.0001).
  • Median year of treatment was 1991 for both groups.
  • Second malignant neoplasms occurred in 6.4% (n = 32) of patients treated with proton therapy, and 13.1% (n = 66) of those treated with photon therapy. 
  • The incidence of SMN was 8.2 and 21.6 per 1000 person-years, respectively.
  • Multivariate analysis using Cox regression adjusting for age and gender demonstrated a hazard ratio of 3.01 for development of SMN with photon treatment versus proton (p < 0.0001).
  • Poisson regression was used to account for discrepancy in follow-up time, and again demonstrated increased SMN risk with use of photon therapy.

Author's Conclusions

  • The authors conclude that proton radiotherapy appears to be associated with decreased risk of SMN when compared to photon radiotherapy.
  • They note that the prolonged latency of second cancers will require ongoing close surveillance for improved understanding of SMN risk.
  • They note that their study is limited by its retrospective nature, but that these data represent the first comprehensive analysis of SMN following proton radiotherapy. Certainly, prospective data will be valuable, but will take many years to gather. In the meantime, these results are encouraging in that they do not indicate increased SMN risk with use of proton radiotherapy.

Clinical/Scientific Implications

  • Second malignant neoplasms are certainly of concern for any patient treated with radiotherapy. As new technologies become available, consideration of this risk must not be neglected.
  • This study represents an important effort to quantify the SMN risk following proton radiotherapy, and to compare this risk to that encountered by patients undergoing photon-based treatment.
  • This study does not demonstrate an increased SMN risk for the general population of patients receiving proton treatment. The data presented here may make us optimistic that such a risk will never be identified.
  • As the authors point out, the study presented here is limited by its retrospective nature; however, in the absence of prospective data (which will take at least 10 years to accumulate meaningfully) the data presented here are very important.
  • Subset analysis of the pediatric patients treated with proton versus photon treatment would certainly be of great interest. Children are acknowledged to be at greatly increased risk for SMN following cancer treatment than are adults, likely with risk approaching 10-fold. Analyzing this group separately would likely be interesting and meaningful. In addition, recognizing the genetic predisposition of retinoblastoma patients to development of SMN, comparison of treatment techniques for this population would be of interest.
  • Additionally, further analysis of details of SMN encountered by patients in this study would be of interest – the location (in-field versus out-of-field) and histology of SMN noted would likely shed light on the contribution of radiotherapy to their development.
  • Finally, the authors do not compare risk of SMN in either of the populations analyzed to the risk within the general population. This comparison would likely help to shape perspective regarding the data presented here.
  • Overall, this data is very interesting and important to the field of radiation oncology as proton treatment becomes more accessible and widely used. As more information becomes available, studies such as this will in all likelihood become more detailed and specific; in the meantime, however, this study may reassure us that SMN risk does not appear to be greatly increased with use of proton radiotherapy, and may in actuality be decreased.

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