Multi-Institutional Phase II Study of Proton Beam Therapy for Organ Confined Prostate Cancer in Japan, Focusing on the Incidence of Late Rectal Toxicities

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 13, 2009

Presenter: Dr. K. Nihei
Presenter's Affiliation: Shizuoka Cancer Center, Shizuoka, Japan
Type of Session: Scientific


  • At present, IMRT is the predominant modality used to treat prostate cancer using radiation
  • Dose escalation has been shown to provide higher rates of biochemical free survival in numerous studies (Zietman et al., JAMA 2005; Pollack et al., JCO 2000)
  • Proton beam therapy has been shown to provide a good dose distribution using simple opposed lateral fields.  There are data suggesting that the use of opposed laterals does not increase the dose to the rectum and bladder compared with IMRT (Vargas et al., IJROBP, 2008)
  • However, the majority of the data available are dosimetric, and prospective data regarding the use of protons in prostate cancer are lacking.  It is not clear that the use of protons will lead to a clinically meaningful reduction in toxicity.  
  • The present group reports the results of a multi-institutional phase II trial that examined the incidence of late grade 2 or greater rectal toxicity in patients treated with proton therapy.

Materials and Methods

  • Eligibility Criteria
    • Histologically proven prostate cancer
    • Gleason score of 7 or less
    • Clinical stage T1-2N0M0
    • PSA of 20 ng/ml or less
    • Patients could not be treated with hormone therapy or have had hormone therapy within the 12 months prior to entry into the trial
    • All patients were required to have written informed consent
  • Patients were divided into low and intermediate risk patients as follows:
    • Low risk patients
      • Patients with a Gleason score of less than 7
      • Patients with a PSA of less than 10
    • Intermediate risk patients
      • Patients with Gleason 7 disease
      • Patients with a PSA of greater than 10
  • The primary endpoint of this study was the incidence of late grade 2 or greater rectal toxicity at 2 years
  • The calculated sample size was 150 patients, and was set such that the upper limit of the 95% confidence interval (CI) was below 16% when the actual incidence of toxicity was below 10%
  • Planned accrual was over two years
  • Three Japanese institutions contributed patients to this study after approval by the IRB
  • Radiation
    • Patients were treated to a total dose of 74 CGE in 37 fractions using carbon ions
    • An RBE of 1.1 was used
    • Daily orthogonal imaging was used for positioning
    • Target volumes:
      • Low risk patients: Prostate alone
      • Intermediate risk patients: Proximal seminal vesicles and prostate (to 50 CGE) then boost to prostate only (24 CGE)
    • Follow up:
      • Patients were assessed prospectively for toxicity and had repeat PSA’s drawn at one month after treatment and then every three months for the first two years. After this time point, patients were assessed every six months
      • NCI-CTC version 2.0 was used to assess acute and late toxicities


  • 151 patients were enrolled from March 2004 to March 2007
  • Patients characteristics:
    • Median age 67 (range 51-82)
  • Tumor Risk






    Tumor Stage












    Gleason Score
















    Hormone Therapy






  • Median follow up was 43.4 months (range 3-62 months)
  • At two years, four patients had been lost to follow up
  • Acute grade 2 rectal toxicity was seen in 0.7% patients and acute grade 2 bladder toxicity was seen in 12% of patients.
  • Of the 147 patients who were followed for greater than 2 years results are as follows:
  • Late Rectal Toxicity (grade)



    27 (18.4%)


    5 (3.4%)


    0 (0%)

    Late Bladder Toxicity (grade)



    9 (6.1%)


    8 (5.4%)


    2 (1.4%)

    Late Rectal Toxicity at 2 years


    Grade 2 or greater

    2.0% (95% CI 0-4.3%)

    Late Rectal Toxicity at last follow up


    Grade 2 or greater

    4.1% (95% CI 0.4-7.7%)

    Late BladderToxicity at 2 years


    Grade 2 or greater

    4.1% (95% CI 0.9-7.3%)

    Late Bladder Toxicity at last follow up


    Grade 2 or greater

    7.8% (95% CI 2.9-12.8%)

  • Rectal toxicity appeared to plateau after a few years
  • Bladder toxicity appeared to continue even after several years of follow up
  • bPFS was 94% at 3 years (95% CI 90-98%)

Author's Conclusions

  • The results of this study suggest that the use of proton beam radiation given in opposed laterals results in relatively low rates of rectal and bladder toxicity
  • Data were collected in a prospective fashion
  • Follow up is too short to draw conclusions regarding biochemical free survival
  • It appears that rectal toxicity plateaus while bladder toxicity continues to rise even after several years

Clinical/Scientific Implications

  • Proton therapy has the potential to decrease treatment-related rectal and bladder toxicity and to decrease the integral dose to normal tissues, potentially decreasing the risk of secondary malignancies
  • Data up to this point have largely been dosimetric in nature, with conflicting results regarding whether the doses to the bladder and rectum are better when using proton therapy compared with IMRT
  • The present study discusses important prospective data examining the use of opposed lateral beams in the treatment of prostate cancer. However, there are some limitations to this study which make the interpretation of its results a bit more complicated. As this is not a randomized trial, it requires comparison with historical controls to provide a context for its toxicity data, limiting its interpretation. Also, the toxicity grading system used is different from those used in many other prior trials, which can make comparison of toxicities difficult. Furthermore, the fractionation and total dose are slightly different that those used at many institutions, which may also complicate interpretation. Lastly, the daily imaging with orthogonal films may not have been optimal, and as better on-board imaging begins to be available with protons as well as devices such as rectal balloons, these results may become obsolete. Nonetheless, the results from this study suggest that proton therapy is well tolerated and should be studied further with more in-depth assessment of quality of life issues.