Radiation Oncology/Prostate/Protons

Proton Therapy in Prostate Cancer

Primary Treatment

 * Kobe University (Hyogo)
 * 2007 (2003-2004) PMID 17482768 -- "Acute morbidity of proton therapy for prostate cancer: the Hyogo Ion Beam Medical Center experience." (Mayahara H, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):434-43. Epub 2007 May 7.)
 * Retrospective. 287 patients, cT1-T4N0 PCA. Treated with 190-230 MeV protons, lateral-opposed technique, 74 GyE. Acute toxicity evaluated by NCI CTC2.0. Neoadjuvant AST 71%
 * Acute Toxicity: GI 0% G2+, GU 39% G2 and 1% G3. Most relieved by alpha-1 blocker
 * Predictors for acute toxicity: large CTV, AST
 * Conclusion: Low incidence of GI toxicity, comparable GU toxicity to photons
 * 2004 (2001) PMID 15289722 -- "Experience with conformal proton therapy for early prostate cancer." (Hara I, Am J Clin Oncol. 2004 Aug;27(4):323-7.)
 * Initial Phase I. 16 patients, T1-T2b. Median F/U 12 months
 * Outcome: 4/16 patients normal PSA, no change. 12/16 PSA CR by PSA; no PSA failures
 * Toxicity: No acute Grade 3-4 toxicity
 * Outcome: Minimum toxicity and good short-term responses


 * Loma Linda (1991-1997)
 * 2004 PMID 15491710 -- "Influence of patient age on biochemical freedom from disease in patients undergoing conformal proton radiotherapy of organ-confined prostate cancer." (Rossi CJ, Urology. 2004 Oct;64(4):729-32.)
 * Retrospective. 1038 patients with cT1-T2c (AJCC 1992), definitive conformal protons. <60 years (12%) vs. >60 years (88%), comparable distribution. Median F/U 5.2 years
 * Outcome: 5-year bNED <60 82% vs. >60 75% (NS)
 * Conclusion: Patient age does not impact bNED
 * 2004 PMID 15145147 -- "Proton therapy for prostate cancer: the initial Loma Linda University experience." (Slater JD, Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):348-52.)
 * Retrospective. 1255 patients with Stage Ia-III, no prior surgery or AST. Photons 45 Gy + proton boost 30/15 CGE to prostate/pelvic LN n=731, protons only 74/37 CGE to prostate/SV n=524. Protons delivered opposed laterals, typically one field/day. Water balloon in rectum. Median F/U 5.2 years
 * Outcome: 5-year bNED 73%, if PSA <=4.0 90%
 * Toxicity: G3 late toxicity 1%, G4 late toxicity 0.2%; no difference between mixed treatment vs protons only
 * Conclusion: Conformal PRT comparable to other local therapy, with minimal toxicity
 * 2002 (1991-1996) PMID 10650829 -- "Value and perspectives of proton radiation therapy for limited stage prostate cancer." (Schulte RW, Strahlenther Onkol. 2000 Jan;176(1):3-8.)
 * Retrospective. 911 patients with limited stage PCA.
 * Outcome: 5-year bNED 82%
 * Toxicity: no Grade 3/4; Grade 2 rectal 3.5%, Grade 2 bladder 5.4%
 * Conclusion: Improved bNED and better late effects
 * 1999 PMID 10394406 -- "Conformal proton beam therapy of prostate cancer--update on the Loma Linda University medical center experience." (Rossi CJ, Strahlenther Onkol. 1999 Jun;175 Suppl 2:82-4.)
 * Retrospective. 643 patients with localized PCA, protons alone or photons/protons. Dose 74-75 CGE
 * Outcome: 5-year bNED 79%, better in "early" (T1b-2b, PSA <15) vs. "advanced" (PSA >15, or T2c-T4)
 * Toxicity: minimal proctitis 21%, greater toxicity <1%
 * Conclusion: Conformal proton beam high rate of response, minimal toxicity
 * 1999 PMID 10223493 -- "Conformal proton therapy for early-stage prostate cancer." (Slater JD, Urology. 1999 May;53(5):978-84.)
 * Retrospective. 319 patients, T1-T2b and PSA <15, protons to 74-75 CGE. No hormones until disease progression
 * Outcome: 5-year bNED 88%, clinical NED 97%
 * Conclusion: Comparable outcomes to radical prostatectomy, with no significant toxicity


 * Tsukuba; 1993 (1983-1990) PMID 8380147 -- "Clinical results of fractionated proton therapy." (Tsujii H, Int J Radiat Oncol Biol Phys. 1993 Jan;25(1):49-60.)
 * Phase I-II. 147 patients treated, various primaries
 * Conclusion: Potential advantage in lung, esophageal, liver, uterine cervix, prostate, and head and neck malignancies; possible value in treatment of high-grade gliomas, and gastric, urinary bladder, and pediatric tumors.

Proton Boost

 * National Cancer Center Hospital East; 2005 (Japan)(2001-2003) PMID 16314345 -- "Phase II feasibility study of high-dose radiotherapy for prostate cancer using proton boost therapy: first clinical trial of proton beam therapy for prostate cancer in Japan." (Nihei K, Jpn J Clin Oncol. 2005 Dec;35(12):745-52. Epub 2005 Nov 28.)
 * Phase II. 30 patients, cT1-3N0. RT photon to prostate & SV 50/25 and proton boost 26/13 GyE. Boost PTV = prostate + 5mm + 5mm penumbra margin. Lateral opposed beams. Photon treatment to prostate/SV. PTV = prostate + 10 mm margin + 5 mm penumbra margin. 240 degree dynamic conformal arc. Hormonal therapy allowed. Median F/U 2.5 years
 * Toxicity: no acute or late Grade 3 GI/GU toxicity. Acute G1-2 GI toxicity 57%, acute G1-G2 GU toxicity 80%. Late G1-2 GI toxicity 37%, G1-G2 GU toxicity 17%
 * Conclusion: Proton boost is feasible, multi-institutional PII trial in progress


 * PROG 95-09 (1996-1999) -- Proton/photon 70.2 Gy vs. 79.2 Gy
 * Randomized. 2 institutions (Harvard and Loma Linda). 392 patients, stage T1b-T2b, PSA <15 ng/mL (median PSA 6.3). Arm 1) proton boost 19.8/11 GyE followed by photons 50.4/28 vs. Arm 2) proton boost 28.8/16 followed by photons 50.4/28. Proton CTV = prostate + 5 mm margin. PTV = CTV + 7-10 mm. Loma Linda used opposed lateral beams, 250 MeV protons; Harvard used perineal boost, 160 MeV protons. Rectal Lucite probe, inflated with 25-50 mL saline. Photons were 4F plan, photon CTV = prostate/SV + 10 mm margin.
 * 5-years; 2005 PMID 16160131 -- "Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial." (Zietman AL, JAMA. 2005 Sep 14;294(10):1233-9.) Median F/U 5.5 years
 * Outcome: 5-year bNED 70.2 Gy 61% vs. 79.2 Gy 80% (SS), 50% reduction in risk of failure. LC (defined as PSA <1.0) 48% vs. 67% (SS) No difference in OS 97% vs 96% (NS)
 * Risk stratification: low risk (PSA <10, stage <=T2a, GS <7) 60% vs. 80% (SS); high risk 63% vs. 79% (SS). Contemporary intermediate risk 63% vs. 81% (SS), but contemporary high risk (NS, but small number)
 * Late toxicity: Grade 3+ 70.2 Gy 1% vs. 79.2 2%; GU Grade 2 18% vs. 20% (NS), GI Grade 2 8% vs. 17% (SS). Most GI toxicity by 3 years; GU toxicity continuous
 * Conclusion: Men with clinically localized PCA have better bNED with high dose, without worse severe toxicity
 * 10-years; 2010 PMID 20124169 -- "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." (Zietman AL, J Clin Oncol. 2010 Mar 1;28(7):1106-11.) Median F/U 8.9 years
 * Outcome: 10-year ASTRO (backdating) bPFS low-dose 68% vs. high-dose 83% (SS). For low-risk disease 72% vs 93% (SS); for intermediate-risk 58% vs. 70% (p=0.06). No difference in OS (78% vs 83%)
 * Toxicity: Late Grade 2+ low-dose 29% vs. high-dose 39% (SS); Grade 3+ 2% in both arms (NS)
 * Conclusion: Long-term advantage for high dose in low/intermediate risk PCA patients, with comparable Grade 3 toxicity


 * Loma Linda (1991-1997)
 * 2004 PMID 15145147 -- "Proton therapy for prostate cancer: the initial Loma Linda University experience." (Slater JD, Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):348-52.)
 * Retrospective. 1255 patients with Stage Ia-III, no prior surgery or AST. Photons 45 Gy + proton boost 30/15 CGE to prostate/pelvic LN n=731, protons only 74/37 CGE to prostate/SV n=524. Protons delivered opposed laterals, typically one field/day. Water balloon in rectum. Median F/U 5.2 years
 * Outcome: 5-year bNED 73%, if PSA <=4.0 90%
 * Toxicity: G3 late toxicity 1%, G4 late toxicity 0.2%; no difference between mixed treatment vs protons only
 * Conclusion: Conformal PRT comparable to other local therapy, with minimal toxicity
 * 1998 PMID 9788407 -- "Conformal proton therapy for prostate carcinoma." (Slater JD, Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):299-304.)
 * Retrospective. 643 patients, localized PCA. Protons +/- photons, 74-75 CGE
 * Outcome: 5-year clinical NED 89%; bNED PSA <4 100%, PSA 4-10 89%, PSA 10-20 72%, PSA >20 53%; nadir <0.5 91%, 0.5-1.0 79%, >1.0 40%
 * Toxicity: minimal proctitis 21%, severe proctitis <1%
 * Conclusion: Minimal toxicity and excellent DFS with low initial PSA
 * 1997 (1991-1993) PMID 9054873 -- "Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: preliminary results of a phase I/II study." (Yonemoto LT, Int J Radiat Oncol Biol Phys. 1997 Jan 1;37(1):21-9.)
 * Phase I/II. 106 patients, T2b-T4Nx. Proton 30/15 CGE prostate boost via opposed lateral fields, followed by photons 45/25 Gy to pelvis. No break. Target prostate/SV + 0.7 cm prescribed at 90% isodose line. 250 MeV proton beam. Median F/U 1.7 years
 * Toxicity: 2-year Grade 3-4 0%, Grade 1-2 12% (8% rectal, 4% urinary)
 * Outcome: 2-year PSA normalization: PSA 4-10 96%, PSA 10-20 97%, PSA >20 63%
 * Conclusion: Low incidence of side-effects, despite 75 CGE dose


 * Harvard (1982-1992) -- Proton (dose escalated) vs. photon boost
 * Randomized. 202 patients, Stage T3-T4Nx,0-2. Standard photons 50.4 Gy four-field, then Arm 1) Conformal protons 25.2 CGE (total 75.6 CGE) vs. Arm 2) Photons 16.8 Gy (total 67.2 Gy). Median F/U 5.1 years
 * 1993 PMID 8514551 -- "Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma" (Benk VA, Int J Radiat Oncol Biol Phys. 1993 Jun 15;26(3):551-7.) Median F/U 3.7 years
 * Rectal bleeding (none Grade 3-4): high dose 34% vs. low dose 16% (SS)
 * DVH evaluation: significant bleeding risk if >40% anterior rectum gets >75 CGE
 * 1995 PMID 7721636 -- "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." (Shipley WU, Int J Radiat Oncol Biol Phys. 1995 Apr 30;32(1):3-12.)
 * Outcome: 5-year LC photon+proton 92% vs. photons 80% (NS), no difference in OS, DSS, TRFS. GS 4/5 patients 94% vs. 64% (SS)
 * Toxicity: Rectal bleeding photon+proton 32% vs. photons 12% (SS), urethral stricture 19% vs. 8% (p=0.07)
 * Conclusion: Boosting dose with protons increased LC in poorly differentiated tumors, but also worsened late toxicity
 * 2002 PMID 11743288 -- "Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer." (Gardner BG, J Urol. 2002 Jan;167(1):123-6.)
 * Retrospective. 39/42 patients alive from original cohort of 167 patients, T3-T4, treated with 4 field box photons to 50.4 Gy, follower by perineal proton boost to 27 Gy in 11 fractions. Median F/U 13.1 years
 * GU toxicity: G2+ GU 59% at 15 years but persisted in 18%. G2+ hematuria 21% at 5 years, 47% at 15 years. G3+ hematuria 3% and 8%. Urethral stricture 10%, urinary incontinence 8% (strongly associated with prior/subsequent prostate surgery)
 * GI toxicity: G2+ GI 13% at 15 years; G1 rectal bleeding in 41%
 * Conclusion: High dose RT results in high rate of low-grade rectal bleeding, but low rate of G2+ GI toxicity; stable after 5 years. GU morbidity continues to worsen over time, but high grade uncommon


 * Harvard (1976-1979)
 * 1983 PMID 6299503 -- "Protons or megavoltage X-rays as boost therapy for patients irradiated for localized prostatic carcinoma. An early phase I/II comparison." (Duttenhaver JR, Cancer. 1983 May 1;51(9):1599-604.)
 * Phase I/II. 180 patients (Photons n=116, photons + proton boost n=64). Proton beam 160 MeV, boost single perineal portal. Photon dose 67 Gy vs. proton dose 74 Gy.
 * Outcome: No difference in LRC, DFS, or OS
 * Toxicity: no difference
 * Conclusion: 10% increase in dose, but minimal complications. Plan to perform an RCT
 * 1979 PMID 107338 -- "Proton radiation as boost therapy for localized prostatic carcinoma." (Shipley WU, JAMA. 1979 May 4;241(18):1912-5.)
 * Retrospective. Initial report. 17 patients with localized PCA. Proton boost 20-25 Gy. F/U 12-27 months
 * Outcome: no significant rectal toxicity, 2/17 urethral strictures, 16/17 locally controlled
 * Conclusion: Proton boost feasible

Treatment Techniques

 * Geneva, Switzerland
 * 2009 PMID 19740429 -- "RapidArc, intensity modulated photon and proton techniques for recurrent prostate cancer in previously irradiated patients: a treatment planning comparison study." (Weber DC, Radiat Oncol. 2009 Sep 9;4(1):34.)
 * Treatment planning. RapidArc vs IMRT vs IMPT. 7 patients with recurrent PC after RT. Dose 56/14
 * Outcome: GTV V95% RA 93% vs. IMRT 89% vs. IMPT 90%, PTV V95% RA 84% vs. IMRT 77% vs. IMPT 86%
 * Toxicity: Urethra V35 RA 5% vs. IMRT 10% vs. IMPT 4%
 * Conclusion: RapidArc and IMPT improved indices over IMRT
 * 2001 PMID 11770521 -- "New techniques in hadrontherapy: intensity modulated proton beams." (Cella L, Phys Med. 2001;17 Suppl 1:100-2.)
 * Comparative planning between intensity modulated XRT and PRT
 * Outcome: Equally homogenous dose of PTV, equally low NTCPs, but less integral dose and reduced low-to-medium dose for protons
 * 2001 PMID 11163518 -- "Potential role of intensity modulated proton beams in prostate cancer radiotherapy." (Cella L, Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):217-23.)
 * Four treatment plans to deliver 81 Gy: 1) 3D-CRT 18 MV 6 fields, 2) 214 MeV protons 2 fields, 3) IMRT 15 MV 5 fields, 4) 177-200 MeV IMPT 5 fields. Further dose escalation to 99 Gy
 * Conclusion: Both IMRT and IMPT could optimize target dose and NTCP constraints; protons reduced low-to-medium dose and improved PTV dose heterogeneity


 * Florida
 * 2009 PMID 19619961 -- "Dosimetric Study of Pelvic Proton Radiotherapy for High-Risk Prostate Cancer." (Chera BS, Int J Radiat Oncol Biol Phys. 2009 Jul 18. [Epub ahead of print])
 * Treatment planning. 5 high-risk prostate patients, treated to prostate, proximal SV, and pelvic LNs. IMRT vs IMRT+PT boost vs PT. Prescribed to 46 CGE pelvis and 78 CGE prostate/SV
 * Outcome: PT plans reduced mean dose to rectum, rectal wall, bladder, bladder wall, small bowel, and pelvis by 40-70%
 * Conclusion: PT significantly reduced dose to normal tissues in pelvis, while maintaining adequate target coverage compared with IMRT
 * 2007 PMID 17967305 -- "Rectal dose-volume differences using proton radiotherapy and a rectal balloon or water alone for the treatment of prostate cancer." (Vargas C, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1110-6.)
 * Retrospective. 30 proton plans for 15 patients, T1-2N0, both CT and MRI with rectal balloon (100ml saline) or water alone (100ml saline with contrast). Doses 78-82 GE to PTV. Planning done with Eclipse
 * Conclusion: Rectum and rectal wall doses were low, regardless of water or rectal balloon; small difference for few patients
 * 2007 PMID 17904306 -- "Dose-Volume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer." (Vargas C, Int J Radiat Oncol Biol Phys. 2007 Sep 26 [Epub ahead of print])
 * Retrospective. First 10 patients treated on Phase II low-risk prostate protocol. Comparison between proton plans and IMRT plans. Dose to 78 GE
 * Conclusion: Proton therapy reduced dose to rectum and bladder, while maintaining excellent PTV coverage


 * NCC Korea
 * 2009 PMID 19647628 -- "Characteristics of movement-induced dose reduction in target volume: a comparison between photon and proton beam treatment." (Yoon M, Med Dosim. 2009 Fall;34(3):191-201. Epub 2008 Sep 24.)
 * Treatment planning. Target displaced 3mm - 20 mm in a scanned phantom. Photon vs proton comparison
 * Outcome: 6mm lateral movement: coverage worse by 9% for protons and 1% for photons; 15 mm lateral movement: coverage worse by 34% and minimally for photons. EUD and homogeneity index similar characteristics
 * Conclusion: Movement-induced dose reduction differs significantly for proton and photon beams
 * 2009 PMID 19616746 -- "Microscopic gold particle-based fiducial markers for proton therapy of prostate cancer." (Lim YK, Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1609-16.)
 * Visibility comparison, two gold particles
 * Outcome: x-ray - good visibility, proton beam - <5% dose distortion. CT artifacts reduced for gold particle mixture
 * Conclusion: Mixture of gold particles and polymers have excellent potential


 * MD Anderson
 * 2009 PMID 19550003 -- "Comparison of surface doses from spot scanning and passively scattered proton therapy beams." (Arjomandy B, Phys Med Biol. 2009 Jul 21;54(14):N295-302. Epub 2009 Jun 23.)
 * Treatment planning. Proton plan, planned with scanning beam with scattered beam. Surface dose in phantom measured to estimate skin dose
 * Outcome: Scanning beam dose lower by ~12% compared with scattered beam, equivalent to 4 CGE during 76 CGE course
 * 2009 PMID 19427561 -- "Risk of secondary malignant neoplasms from proton therapy and intensity-modulated x-ray therapy for early-stage prostate cancer." (Fontenont JD, Int J Radiat Oncol Biol Phys. 2009 Jun 1;74(2):616-22.)
 * Treatment planning. Proton plan vs 6-MV IMRT plan for 3 patients with early stage PCA. Primary doses determined from treatment plans, secondary doses from Monte Carlo and measured data. Risk of second malignancy estimated on organ-by-organ basis
 * Outcome: PT reduced risk of SMN by 26%-39% compared with IMRT, due to substantial sparing of rectum/bladder
 * Conclusion: PT can reduce risk of second malignancies in prostate patients
 * 2009 PMID 19223836 -- "Dose perturbations from implanted helical gold markers in proton therapy of prostate cancer." (Giebeler A, J Appl Clin Med Phys. 2009 Jan 27;10(1):2875.)
 * Gold fiducial marker evaluation. Small (0.35 mm), medium (0.75 mm), and large (1.15mm) marker with length of 10 mm implanted in phantom. Monte Carlo simulation
 * Outcome: Perturbation of dose large marker 31%, medium marker 23%, so not well suited. Small marker too fragile for transrectal implantation
 * 2007 PMID 17505081 -- "Monte Carlo simulations of the dosimetric impact of radiopaque fiducial markers for proton radiotherapy of the prostate." (Newhauser W, Phys Med Biol. 2007 Jun 7;52(11):2937-52. Epub 2007 May 2.)
 * Compared various types of implantable markers for visibility on kV imagins, and reviewed dosimetry models by Monte Carlo
 * Outcome: gold and stainless steel markers visible, titanium not so much. Stainless steel and titanium didn't perturb beam much, gold large shadow
 * Conclusion: 0.9 mm diameter, 3.1 mm long stainless steel marker has good visibility on kV and <8% beam pertuberance
 * 2007 PMID 17236979 -- "Effect of anatomic motion on proton therapy dose distributions in prostate cancer treatment." (Zhang X, Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):620-9.)
 * Dosimetric impact, 10 patients, 8 daily CT scans each. Comparison of IMRT and proton dosimetry
 * Conclusion: Interfractional anatomic motion has similar impact on both modalities


 * Wollongong, Australia; 2008 PMID 19239059 -- "A comparison of proton therapy and IMRT treatment plans for prostate radiotherapy." (Dowdell SJ, Australas Phys Eng Sci Med. 2008 Dec;31(4):325-31.)
 * Treatment planning. Passive vs IMPT vs 7-F IMRT step-and-shoot vs 7-F IMRT sliding window. 78 CGE
 * Outcome: Homogeneity and rectal sparing best for IMPT
 * Conclusion: PT is suitable treatment option


 * Harvard
 * 2007 PMID 17513063 -- "Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison." (Trofimov A, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):444-53. Epub 2007 May 21.)
 * Retrospective. 10 patients with early-stage PCA. Treated with 3D-CPT (two parallel-opposed lateral fields) and IMRT (7 coplanar fields). Dose 79.2 Gy/CGE
 * Outcome: 98% of PTV received prescription dose. IMRT better dose conformity, 3D-CPT better dose homogeneity.
 * Normal organs: Bladder dosimetry: V30 better with protons, V70 better with IMRT. Rectal dosimetry: V70 comparable
 * Conclusion: Above 60 Gy, IMRT better than protons for bladder, rectum comparable. Doses <50% significantly better with protons
 * Comment from PSI (PMID 17967323)
 * 1996 PMID 8948358 -- "Conformal irradiation of the prostate: estimating long-term rectal bleeding risk using dose-volume histograms." (Hartford AC, Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):721-30.)
 * 41 patients treated with photons + perineal boost. Review of DVH for anterior rectal wall. Min F/U 4 years
 * Toxicity: 14/41 (34%) rectal bleeding. Found dose-volume relationship between 60 - 75 CGE; development of low/moderate/high risk groups
 * 1990 PMID 2157240 -- "Considerations in fractionated proton radiation therapy: clinical potential and results." (Austin-Seymour M, Radiother Oncol. 1990 Jan;17(1):29-35.)
 * Comparative evaluation of X-ray and proton plans


 * Paul Scherrer Institut
 * 2007 PMID 17459608 -- "The impact of dose escalation on secondary cancer risk after radiotherapy of prostate cancer." (Schneider U, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):892-7. Epub 2007 Apr 24.)
 * 23 patient plans. Comparison of TCP and NTCP for 3D-CRT (n=7), 6 MV or 15 MV IMRT (n=8), and spot-scanned proton RT (n=8). Doses modeled 70 - 100 Gy, baseline 70 Gy 3D-CRT
 * Outcome: Secondary cancer risk compared with 70 Gy 3D-CRT: 6 MV IMRT +18%, 15 MV IMRT +25%, spot-scanned protons -41%
 * Conclusion: Spot-scanned protons can halve risk of secondary cancers with dose escalation
 * 2006 PMID 17072522 -- "The impact of IMRT and proton radiotherapy on secondary cancer incidence." (Schneider U, Strahlenther Onkol. 2006 Nov;182(11):647-52.)
 * 30 patient plans. 15 MV 3D-CRT (n=11), 6 MV IMRT (n=11), spot-scanned protons (n=8). Secondary cancer risk estimated based on organ equivalent dose (OED)
 * Outcome: Secondary cancer risk compared with 15 MV 3D-CRT: 6 MV IMRT +15%, 15 MV IMRT +20%, 18 MV IMRT 60%, spot-scanned protons -50%
 * Conclusion: IMRT risk not as dramatic as expected, particularly at 6 MV. Spot-scanned protons treatment of choice
 * 2004 PMID 15587667 -- "Treatment planning and verification of proton therapy using spot scanning: initial experiences." (Lomax AJ, Med Phys. 2004 Nov;31(11):3150-7.)
 * Overview of 160 patients treated with spot-scanning, including some prostates. Mean 3 beams per plan, with 200-45,000 Bragg peaks per field. Treatment time few seconds to 20-25 minutes
 * Mean width of beam at Bragg peak ~8mm; Precision: orthogonal +/- 1mm, range +/- 1.5 mm


 * Loma Linda
 * 2006 PMID 16551129 -- "Innovative strategies for image-guided proton treatment of prostate cancer." (Schulte RW, Technol Cancer Res Treat. 2006 Apr;5(2):91-100.)
 * Review of rationale for reduction of high dose PTV margins
 * 2006 PMID 16488552 -- "Patient tolerance of rectal balloons in conformal radiation treatment of prostate cancer." (Ronson BB, Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1367-70. Epub 2006 Feb 20.)
 * Retrospective. 3561 patients, protons for prostate/SV and photon pelvis as necessary
 * Outcome: 98% tolerated balloon throughout treatment, 2% declined balloon for at least one treatment but tolerated it on average for 85% of their treatments. Better tolerance if protons alone 99.5% vs combination 95.7% (SS)
 * Conclusion: Intrarectal balloons well tolerated
 * 2003 PMID 14529309 -- "Range, range modulation, and field radius requirements for proton therapy of prostate cancer." (Moyers MF, Technol Cancer Res Treat. 2003 Oct;2(5):445-7.)
 * Analysis of 240 treatment fields from >5,000 patients treated
 * Range typically <290 mm water, modulation width <120 mm, radius <75 mm


 * Cambridge (UK) PMID 16510958 -- "Margins for treatment planning of proton therapy." (Thomas SJ, Phys Med Biol. 2006 Mar 21;51(6):1491-501. Epub 2006 Mar 1.)
 * Evaluation of margins for H&N and prostate plans, for single field, parallel opposed fields, and four fields
 * Good dose distributions can be obtained with one or two fields


 * Vienna; 2005 (Austria) PMID 15995838 -- "Comparative treatment planning on localized prostate carcinoma conformal photon- versus proton-based radiotherapy." (Mock U, Strahlenther Onkol. 2005 Jul;181(7):448-55.)
 * Comparison. 5 patients. 3D proton plan (2 lateral beams) vs. 3D conformal photons (4 field box) vs. IMRT (seven beams). PTV = CTV + 5 mm. Total dose 70 Gy.
 * Outcome: PTV: similar dose distribution. Conformity indices photon 1.4-1.5, proton 1.1-1.4. OAR received more dose (>=1.7x) with photons, mainly at low and medium dose levels
 * Conclusion: PTV comparable, for OAR 2 field protons > IMRT > 3D-CRT


 * Alberta; 2002 (Canada) PMID 11865989 -- "Intensity and energy modulated radiotherapy with proton beams: variables affecting optimal prostate plan." (Yeboah C, Med Phys. 2002 Feb;29(2):176-89.)
 * Influence of energy, beamlet width, number of beams, and beam orientation on treatment plans
 * Conclusion: Need maximum 3-4 beams, but then beam orientation becomes important

Cost-Effectiveness

 * Please see Radiation_Oncology/Prostate/Utilization

Radiobiology

 * Wisconsin; 2003 PMID 12602558 -- "What can we expect from dose escalation using proton beams?" (Fowler JF, Clin Oncol (R Coll Radiol). 2003 Feb;15(1):S10-5.)
 * Evaluation of tumor dose-response curves, and dose escalation benefit if normal tissue complications can be avoided

Review

 * Harvard
 * 2009 PMID 19672148 -- "Life, liberty, and the pursuit of protons: an evidence-based review of the role of particle therapy in the treatment of prostate cancer." (Efstathiou JA, Cancer J. 2009 Jul-Aug;15(4):312-8.)
 * 2009 PMID 19434101 -- "Proton radiation for localized prostate cancer." (Coen JJ, Nat Rev Urol. 2009 Jun;6(6):324-30. Epub 2009 May 12.)
 * 2007 PMID 17921728 -- "High-dose external beam radiation for localized prostate cancer: current status and future challenges." (Nguyen PL, Cancer J. 2007 Sep-Oct;13(5):295-301.)


 * Loma Linda; 2007 no PMID full text -- "Conformal proton beam radiation therapy for prostate cancer: concepts and clinical results" (Rossi CJ, Commun Oncol 2007; 4:235-240)