Proton Radiation Therapy for Patients with Prostate Cancer

Reviewer: Geoffrey Geiger MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 13, 2009

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Presenter: C. Rossi
Presenter's Affiliation: Loma Linda, USA
Type of Session: Scientific

Background

  • The most effective treatment for clinically localized prostate cancer remains controversial, as no randomized trials comparing radiation therapy to surgical resection have been performed.
  • Options for the treatment of clinically localized prostate cancer include: radical prostatectomy and radiation therapy, the latter of which may be delivered via brachytherapy, external beam photon therapy, or proton therapy.
  • Protons interact more densely with tissue, result in a greater degree of ionization per unit volume and have a higher radiobiological effect (RBE) than photons.
  • Charged particle beam therapy with protons allows the delivery of higher doses of conformal radiation due to the dose characteristics of proton beam radiotherapy, including finite range and steep dose fall off beyond the Bragg peak.
  • Because of the superior conformality and higher radiobiological effectiveness, charged-particle radiation therapy is expected to deliver biologically equivalent doses with superior precision and with less radiation-induced morbidity than conventional photon radiation therapy.
  • Previously published photon dose escalation trials have suggested that higher doses (>72 Gy) typically confer increased rates of biochemical disease-free survival (bDFS).
  • This presentation focused on the past and present experiences as well as the future plans of the James M. Slater, M.D. Proton Treatment and Research Center at Loma Linda University with respect to their prostate cancer treatment program.

Materials and Methods

  • PROG 95-09 (1996-1999), published in JAMA 2005:
    • Randomized, phase III two-institution study of a combination of photons and protons to a total dose of 70.2 cobalt Gray equivalents (CGE) versus 79.2 CGE at MGH and LLUMC.
      • 392 patients, stage T1b-T2b, PSA <15 ng/mL (median PSA 6.3). Patients were randomized to either:
        • Arm 1) proton boost 19.8 CGE in 11 fractions, followed by photons 50.4 Gy in 28 fractions vs.
        • Arm 2) proton boost 28.8 CGE in 16 fractions, followed by photons 50.4 Gy in 28 fractions.
      • 5-year results published in JAMA in 2005 (Zietman, et. al.):
        • Median F/U 5.5 years.
        • 5-year biochemical NED (bNED): 70.2 CGE - 61% vs. 79.2 CGE - 80% (statistically significant).
        • No difference in overall survival (OS) 97% vs. 96% (not significant).
      • Late toxicity:
        • All grade 3+ toxicity: 70.2 CGE - 1% vs. 79.2 CGE - 2%.
        • GU Grade 2: 18% vs. 20% (NS).
        • GI Grade 2: 8% vs. 17% (SS).
        • Most GI toxicities appeared by 3 years; GU toxicity more likely to be continuous.
    • Conclusion: Men with clinically localized prostate cancer have better bNED with high dose, without worse severe toxicities.
  • PROG 95-09 Update (manuscript to be published in JCO 2009):
    • At 9-year median follow-up, higher dose arm continues to do better.
    • Effect of dose on PSA nadir profound: higher dose arm more likely to have PSA nadir < 0.5 ng/mL.
    • Higher dose patients more likely to be disease free at the 9-year mark, even in low-risk cancer patients.
      • 9-year biochemical NED (bNED) in low-risk patients, 70.2 CGE: 94% vs. 79.2 CGE: 80% (statistically significant).
    • No difference in patient reported morbidity between low and high dose arms at 9-years.
  • Loma Linda Experience (1991-1997), published most recently in IJROBP 2004 (Slater et. al.):
    • Retrospective, single-institution review of 1255 patients with clinically localized prostate cancer treated with protons +/- photons to a dose of 74-75 CGE.
    • 5-year bNED 73% and was 90% in patients with initial PSA <or=4.0; it was 87% in patients with post-treatment PSA nadirs <or=0.50. Rates dropped with rises in initial and nadir PSA values.
    • Conclusion: Proton therapy to 74-75 CGE produced minimal treatment-related toxicity and excellent PSA normalization and disease-free survival in patients with low initial PSA levels.
  • ACR 03-12, presented in abstract form at ASTRO 2008 (ongoing):
    • Prospective, two-institution phase I/II study of 85 men at MGH and LLUMC.
    • Patients had T1-2a tumors and a PSA of <15 ng/mL.
    • All treated with opposed lateral proton beams delivering 82 CGE total dose in 2 CGE daily fractions.
    • Primary endpoints were late rectal and GU late morbidity.
    • Results: no deaths at 23 months (median follow-up); Rates of grade 1, 2, and 3, acute GU/GI toxicity were 50%, 14%, and 1%, respectively.
    • Twenty-one patients (25%) experienced grade 2 late GU/GI toxicity, six (7%) had grade 3, and one (1%) had grade 4 (hemorrhagic cystitis and rectal ulcer) toxicities.
    • Longer follow-up necessary but suggests that more grade 3/4 events occurred compared to 79.2 CGE arm from PROG 95-05.

Author's Conclusions

  • Proton radiation therapy has been used since 1991 at Loma Linda University Medical Center (LLUMC) to treat prostate cancer.
  • Conformal proton beam radiation therapy can achieve bNED rates equivalent to those obtained with photon treatment.
  • In patients treated with a proton boost to 79.2 CGE, men with clinically localized prostate cancer have a lower risk of biochemical failure if they receive high-dose rather than conventional-dose conformal radiation (70.2 CGE).
    • This advantage was achieved without any associated increase in RTOG grade 3 acute or late urinary or rectal morbidity.
  • PSA nadir is a useful “early endpoint” for prostate cancer treatment.
    • Patients whose PSA nadirs were < 1.00 ng/mL had a statistically significant difference in their bNED rate as compared with those whose PSA nadirs never fell below 1.00 ng/mL.
  • Dose escalation to 82Gy can be given to the prostate using protons with acceptable morbidity.
  • Additional cautious dose-escalation and hypofractionation studies may be possible using more advanced proton beam techniques such as intensity modulation proton therapy (IMPT) to better define the maximum tolerable dose.

Clinical/Scientific Implications

  • In this session, the author presents a comprehensive experience of prostate cancer treatment using protons at Loma Linda University from 1991 onwards.
  • Proton beam therapy permits high doses of radiation to the target volume with limited scatter dose to surrounding normal tissues.
  • Although data exist for clinically localized prostate cancer only, 1255 men who received protons to 75 CGE with proton beam therapy alone or combined with photons had a five-year bDFS of 73 percent, and serious morbidity rates were similar to those expected with photons alone.
  • In a phase III trial conducted by the PROG of 393 men with stage T1b-2b prostate cancers, the proportion of men free from biochemical failure at five years was significantly higher in the higher-dose group (80 versus 61 percent at 5-years), who received a total of 79.2 CGE.
    • These improved outcomes were achieved without a substantial increase in severe acute or late rectal morbidity.
    • However, it should be noted that the contribution of the proton beam component is unclear, since the results of this study are similar in magnitude to those reported in a similar trial comparing 70 versus 78 Gy using photon beam RT (Pollack, 2002).
  • The improved dose conformality afforded by proton treatment of prostate cancer makes this modality amenable to dose escalation and hypofractionation studies, both of which are currently underway.