Proton boost of 20？Gy in daily 5？Gy fractions followed by external beam radiotherapy (EBRT) of 50？Gy in daily 2？Gy fractions were given to 278 patients with prostate cancer with T1b to T4N0M0 disease. Fifty-three percent of the patients received neoadjuvant androgen deprivation therapy (N-ADT). The medium followup was 57 months. The 5-year PSA progression-free survival was 100%, 95%, and 74% for low-, intermediate-, and high-risk patients, respectively. The toxicity evaluation was supported by a patient-reported questionnaire before every consultant visit. Cumulative probability and actuarial prevalence of genitourinary (GU) and gastrointestinal (GI) toxicities are presented according to the RTOG classification. N-ADT did not influence curability. Mild pretreatment GU-symptoms were found to be a strong predictive factor for GU-toxicity attributable to treatment. The actuarial prevalence declined over 3 to 5 years for both GU and GI toxicities, indicating slow resolution of epithelial damage to the genitourinary and gastrointestinal tract. Bladder toxicities rather than gastrointestinal toxicities seem to be dose limiting. More than 5-year followup is necessary to reveal any sign of true progressive late side effects of the given treatment. Hypofractionated proton-boost combined with EBRT is associated with excellent curability of localized PC and acceptable frequencies of treatment toxicity. 1. Introduction One of the first-line curative treatment options of prostate carcinoma is radiotherapy (RT), which can be considered for organ-confined disease as well as for locally advanced tumors. The message of the potential benefit of dose escalation for disease-free survival announced by Hanks [1] and Perez et al. [2] from retrospective studies became a milestone for the current successful outcome in the use of radiotherapy for curative intent. Since then, several mature randomized trials have proven that dose escalation up to 79？Gy to the prostate is advantageous with regards to clinical disease control [3–14]. Further dose escalation to 81？Gy delivered in a phase II study using intensity modulated radiotherapy (IMRT) resulted in excellent 8-to-10-year tumors control and acceptable late toxicity [15, 16]. A feasibility study of proton beam therapy (PBT) suggested that daily proton fractions of 2？Gy to 82？Gy might be the maximal dose that can be delivered with acceptable late morbidity [17]. It is noteworthy that in phase II studies, to 81 and 82？Gy the dose was prescribed to the planning target volume (PTV). That means a 5 to 10% higher dose if prescribed
References
[1]
G. E. Hanks, “Optimizing the radiation treatment and outcome of prostate cancer,” International Journal of Radiation Oncology Biology Physics, vol. 11, no. 7, pp. 1235–1245, 1985.
[2]
C. A. Perez, G. E. Hanks, S. A. Leibel, A. L. Zietman, Z. Fuks, and W. R. Lee, “Localized carcinoma of the prostate (stages T1B, T1C, T2, and T3): review of management with external beam radiation therapy,” Cancer, vol. 72, no. 11, pp. 3156–3173, 1993.
[3]
W. U. Shipley, L. J. Verhey, J. E. Munzenrider et al., “Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone,” International Journal of Radiation Oncology Biology Physics, vol. 32, no. 1, pp. 3–12, 1995.
[4]
A. Pollack, G. K. Zagars, G. Starkschall et al., “Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial,” International Journal of Radiation Oncology Biology Physics, vol. 53, no. 5, pp. 1097–1105, 2002.
[5]
D. A. Kuban, S. L. Tucker, L. Dong et al., “Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer,” International Journal of Radiation Oncology Biology Physics, vol. 70, no. 1, pp. 67–74, 2008.
[6]
D. A. Kuban, L. B. Levy, M. R. Cheung et al., “Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease?” International Journal of Radiation Oncology Biology Physics, vol. 79, no. 5, pp. 1310–1317, 2011.
[7]
J. R. Sathya, I. R. Davis, J. A. Julian et al., “Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate,” Journal of Clinical Oncology, vol. 23, no. 6, pp. 1192–1199, 2005.
[8]
A. L. Zietman, M. L. DeSilvio, J. D. Slater et al., “Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial,” Journal of the American Medical Association, vol. 294, no. 10, pp. 1233–1239, 2005.
[9]
A. L. Zietman, K. Bae, J. D. Slater et al., “Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1106–1111, 2010.
[10]
S. T. H. Peeters, W. D. Heemsbergen, P. C. M. Koper et al., “Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy,” Journal of Clinical Oncology, vol. 24, no. 13, pp. 1990–1996, 2006.
[11]
A. Al-Mamgani, W. L. J. van Putten, W. D. Heemsbergen et al., “Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer,” International Journal of Radiation Oncology Biology Physics, vol. 72, no. 4, pp. 980–988, 2008.
[12]
D. P. Dearnaley, M. R. Sydes, J. D. Graham et al., “Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial,” Lancet Oncology, vol. 8, no. 6, pp. 475–487, 2007.
[13]
P. J. Hoskin, K. Motohashi, P. Bownes, L. Bryant, and P. Ostler, “High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial,” Radiotherapy and Oncology, vol. 84, no. 2, pp. 114–120, 2007.
[14]
P. J. Hoskin, A. M. Rojas, P. J. Bownes, G. J. Lowe, P. J. Ostler, and L. Bryant, “Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer,” Radiotherapy and Oncology, vol. 103, no. 2, pp. 217–222, 2012.
[15]
M. J. Zelefsky, H. Chan, M. Hunt, Y. Yamada, A. M. Shippy, and H. Amols, “Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer,” Journal of Urology, vol. 176, no. 4, pp. 1415–1419, 2006.
[16]
Z. A. Alicikus, Y. Yamada, Z. Zhang et al., “Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer,” Cancer, vol. 117, no. 7, pp. 1429–1437, 2011.
[17]
J. J. Coen, K. Bae, A. L. Zietman et al., “Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology Phase II study 03-12,” International Journal of Radiation Oncology, Biology, Physics, vol. 81, no. 4, pp. 1005–1009, 2011.
[18]
D. J. Brenner and E. J. Hall, “Fractionation and protraction for radiotherapy of prostate carcinoma,” International Journal of Radiation Oncology Biology Physics, vol. 43, no. 5, pp. 1095–1101, 1999.
[19]
E. F. Miles and W. Robert Lee, “Hypofractionation for prostate cancer: a critical review,” Seminars in Radiation Oncology, vol. 18, no. 1, pp. 41–47, 2008.
[20]
G. Arcangeli, B. Saracino, S. Gomellini et al., “A Prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer,” International Journal of Radiation Oncology Biology Physics, vol. 78, no. 1, pp. 11–18, 2010.
[21]
J. J. Coen and A. L. Zietman, “Proton radiation for localized prostate cancer,” Nature Reviews Urology, vol. 6, no. 6, pp. 324–330, 2009.
[22]
A. Trofimov, P. L. Nguyen, J. J. Coen et al., “Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison,” International Journal of Radiation Oncology Biology Physics, vol. 69, no. 2, pp. 444–453, 2007.
[23]
S. Falkmer, B. Fors, B. Larsson, A. Lindell, J. Naeslund, and S. Stenson, “Pilot study on proton irradiation of human carcinoma,” Acta Radiologica, vol. 58, pp. 33–51, 1962.
[24]
B. Fors, B. Larsson, A. Lindell, J. Naeslund, and S. Stenson, “Effect of high energy protons on human genital carcinoma,” Acta Radiologica: Therapy, Physics, Biology, vol. 2, pp. 384–398, 1964.
[25]
J. R. Duttenhaver, W. U. Shipley, and T. Perrone, “Protons or megavoltage X-rays as boost therapy for patients irradiated for localized prostatic carcinoma. An early phase I/II comparison,” Cancer, vol. 51, no. 9, pp. 1599–1604, 1983.
[26]
J. D. Slater, C. J. Rossi, L. T. Yonemoto et al., “Proton therapy for prostate cancer: the initial Loma Linda University experience,” International Journal of Radiation Oncology Biology Physics, vol. 59, no. 2, pp. 348–352, 2004.
[27]
J. L. Mohler, “The 2010 NCCN clinical practice guidelines in oncology on prostate cancer,” JNCCN Journal of the National Comprehensive Cancer Network, vol. 8, no. 2, p. 145, 2010.
[28]
J. J. Pavy, “Late effects toxicity scoring: the SOMA scale,” Radiotherapy and Oncology, vol. 35, no. 1, pp. 11–15, 1995.
[29]
J. D. Cox, J. Stetz, and T. F. Pajak, “Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC),” International Journal of Radiation Oncology Biology Physics, vol. 31, no. 5, pp. 1341–1346, 1995.
[30]
M. Roach III, G. Hanks, H. Thames Jr. et al., “Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference,” International Journal of Radiation Oncology Biology Physics, vol. 65, no. 4, pp. 965–974, 2006.
[31]
U. Isacsson, K. Nilsson, S. Asplund, E. Morhed, A. Montelius, and I. Turesson, “A method to separate the rectum from the prostate during proton beam radiotherapy of prostate cancer patients,” Acta Oncologica, vol. 49, no. 4, pp. 500–505, 2010.
[32]
L. L. Kestin, N. S. Goldstein, F. A. Vicini, D. Yan, H. J. Korman, and A. A. Martinez, “Treatment of prostate cancer with radiotherapy: should the entire seminal vesicles be included in the clinical target volume?” International Journal of Radiation Oncology Biology Physics, vol. 54, no. 3, pp. 686–697, 2002.
[33]
M. S. Pepe, G. Longton, and M. Thornquist, “A qualifier Q for the survival function to describe the prevalence of a transient condition,” Statistics in Medicine, vol. 10, no. 3, pp. 413–421, 1991.
[34]
L. ？str？m, D. Pedersen, C. Mercke, S. Holm？ng, and K. A. Johansson, “Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer,” Radiotherapy and Oncology, vol. 74, no. 2, pp. 157–161, 2005.
[35]
W. M. Mendenhall, B. S. Hoppe, R. C. Nichols, R. H. Henderson, and N. P. Mendenhall, “When is elective pelvic lymph node irradiation indicated in definitive radiotherapy for localized prostate cancer?” American Journal of Clinical Oncology. In press.
[36]
E. S. Antonarakis, A. L. Blackford, E. Garrett-Mayer, and M. A. Eisenberger, “Survival in men with nonmetastatic prostate cancer treated with hormone therapy: a quantitative systematic review,” Journal of Clinical Oncology, vol. 25, no. 31, pp. 4998–5008, 2007.
[37]
M. Bolla, G. Van Tienhoven, P. Warde et al., “External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study,” The Lancet Oncology, vol. 11, no. 11, pp. 1066–1073, 2010.
[38]
J. W. Denham, A. Steigler, D. S. Lamb et al., “Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial,” The Lancet Oncology, vol. 12, no. 5, pp. 451–459, 2011.
[39]
L. Bud？us, M. Bolla, A. Bossi et al., “Functional outcomes and complications following radiation therapy for prostate cancer: a critical analysis of the literature,” European Urology, vol. 61, no. 1, pp. 112–127, 2012.
[40]
A. A. Aizer, N. S. Anderson, S. C. Oh et al., “The impact of pretreatment prostate volume on severe acute genitourinary toxicity in prostate cancer patients treated with intensity-modulated radiation therapy,” International Journal of Radiation Oncology Biology Physics, vol. 79, no. 2, pp. 379–384, 2011.
[41]
J. M. Michalski, H. Gay, A. Jackson, S. L. Tucker, and J. O. Deasy, “Radiation dose-volume effects in radiation-induced rectal injury,” International Journal of Radiation Oncology Biology Physics, vol. 76, no. 3, pp. S123–S129, 2010.
[42]
I. Turesson, “The progression rate of late radiation effects in normal tissue and its impact on dose-response relationships,” Radiotherapy and Oncology, vol. 15, no. 3, pp. 217–226, 1989.
[43]
I. Turesson, “Individual variation and dose dependency in the progression rate of skin telangiectasia,” International Journal of Radiation Oncology Biology Physics, vol. 19, no. 6, pp. 1569–1574, 1990.
