# Radiation Oncology/Prostate/Hypofractionation

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Hypofractionation in Prostate Cancer

## Randomized

* PROFIT (Ontario) (2006-2011) -- 78/39 (2.0 Gy/fx) vs 60/20 (3.0 Gy/fx)
** Randomized. 1206 patients, intermediate risk. ADT not allowed. Arm 1) 78/39 vs Arm 2) 60/20, IMRT encouraged but 3D-CRT allowed, IGRT required, CTV included proximal seminal vesicles for some patients.
** 2017 PMID 28296582 -- "Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer." (Catton CN, Journal of Clinical Oncology. 2017 March 15). Median F/U 6.0 years
*** Outcome: 5-year biochemical failure DFS conventional 85% vs hypofx 85% (HR 0.96 - meeting noninferiority criteria)
*** Toxicity: Late GI G2 conventional 11% vs hypofx 7.4% (SS), GU G2 19% vs 20% (NSS)
*** Conclusion: In intermediate risk prostate cancer hypofractionated treatment not inferior to conventional fractionation for efficacy, not associated with increased toxicity.
* CHHiP (UK) (2002-2011) -- 74/37 (2.0 Gy/fx) vs 60/20 (3.0 Gy/fx) vs 57/19 (3.0 Gy/fx) - 1:1:1 randomization
** Randomized. 3216 patients, 73% intermediate risk, 15% low risk, 12% high risk. Short term ADT (optional for low risk), IMRT and IGRT required, Proximal or entire seminal vesicles (depending on risk) were treated to a lower dose in an initial field (48 Gy for 60 Gy arm).
** 2016 PMID 27339115 -- "Conventional Versus Hypofractionated High-dose Intensity-modulated Radiotherapy for Prostate Cancer: 5-year outcomes of the randomized, non-inferiority, phase 3 CHHIiP Trial." (Dearnaley D, Lancet Oncology. 2016 August). Median F/U 5 years
*** Outcome: 5-year biochemical/clinical failure free: 74Gy 88.3%, 60Gy 90.6%, 57Gy 85.9% (60Gy met non-inferiority, 57Gy arm did not)
*** Toxicity: No significant differences in 5-year clinician reported or patient reported side effects. Late GI G2 or higher - 74Gy 13.7%, 60Gy 11.9, 57Gy 11.3%; GU G2 or higher 74Gy 9.1%, 60Gy 11.7%, 57Gy 6.6%.
*** Conclusion: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation.
* HYPRO (Dutch Cancer Society) (2007-2010) -- 78.0/39 (2.0 Gy/fx) vs 64.6/19 (3.4 Gy/fx - 3 fx per week)
** Randomized. 820 patients, intermediate-high risk, ADT optional (64% received ADT, usually long-term), SV treated according to risk, to a lower dose (cone down after 16 fx or SIB)
** 2016 PMID 27339116 -- "Hypofractionated versus conventionally fractionated radiotherapy for patients with localized prostate cancer (HYPRO): final efficacy results from a randomized, multicentre, open-label, phase 3 trial." (Incrocci L, Lancet Oncol 2016 Aug 17). Median F/U 5 years.
*** Outcome: 5-yr relapse-free survival conventional 77%, hypofx 80% (NSS)
*** Conclusion: Hypofractionated radiation does not have superior outcomes at 5-years.
** 2016 PMID 26968359 -- "Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomized, non-inferiority, phase 3 trial." (Aluwini S, Lancet Oncol 2016 Apr 17). Median F/U 5 years.
*** Toxicity: 3-yr Grade >2 GI conventional 17.7%, hypofx 21.9, 3-yr Grade >2 GU conventional 39%, hypofx 41.3%, neither met non-inferiority criteria.
*** Conclusion: Could not confirm that hypofractionation non-inferior to conventional radiation for late toxicity.
* RTOG 0415 (NRG) (2006-2009) -- 73.8/41 (1.8 Gy/fx) vs 70/28 (2.5 Gy/fx)
** Randomized. 1115 patients, low risk (GS 2-6, PSA >10 ng/ml, T1b-T2c). ADT not allowed. Arm 1) 73.8/41 vs Arm 2) 70/28, 3D-CRT or IMRT allowed, IGRT required, CTV = prostate only (no SV).
** 2016 PMID 27044935 -- "Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer." (Lee WR, Journal of Clinical Oncology. 2016 April 4). Median F/U 5.8 years
*** Outcome: 5-year DFS conventional 85.3% vs hypofx 86.3% (HR 0.85 - meeting noninferiority criteria)
*** Toxicity: Late GI G2 conventional 11% vs hypofx 18% (SS), GU G2 21% vs 26% (SS)
*** Conclusion: In low-risk prostate cancer hypofractionated treatment noninferior to conventional fractionation for efficacy, but increased late GI and GU toxicity.
* MD Anderson (2001-2010) -- 75.6/42 (1.8 Gy/fx) vs 72/30 (2.4 Gy/fx)
** Randomized. 222 patients, localized prostate cancer (71% intermediate risk, 1% high risk), 24% received ADT. RT to prostate and proximal SV.
** 2014 PMID 24661661 -- "Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results from a Randomized Trial." (Hoffman K, Int J Radiat Oncol Biol Phys. 2014 Apr). Median F/U 6.0 years.
*** Toxicity: 5-yr toxicity >2 GI conventional 5.1%, hypofx 10.0% (P=0.11), >2 GU 16.5%, hypofx 15.8% (NSS)
*** Conclusion: Hypofractionation safe; minimizing moderate and high-dose rectal constraints may decrease late rectal toxicity.
* Italy, Regina Elena NCI Rome (2003-2007) -- 80/40 (2 Gy/fx) vs 62/20 (3.1 Gy/fx)
** Randomized. 168 patients, high-risk (GS 8-10, PSA >20 ng/ml, or 2+ of PSA 10-20, T ≥ T2c, GS7), but PSA ≤ 100. All patients neoadjuvant/concurrent/adjuvat ADT x9 months. Arm 1) 3D-CRT 80/40 vs Arm 2) 3D-CRT 62/20, CTV = prostate + SV.
** 2017 PMID 28355113 -- "Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial." (Arcangeli G, JCO 2017 March). Median F/U 9 years
*** Outcome: 10-year bPFS conventional 65% vs hypofx 72% (NSS)
*** Toxicity: Freedom from > G2 GI conventional 84, hypofx 86.5%, freedom from > G2 GU conventional 79%, hypofx 86% (NSS)
*** Conclusion: Failed to show superiority of hypofractionation for either reducing toxicity or improving efficacy.
** 2010 PMID 20047800 -- "A Prospective Phase III Randomized Trial of Hypofractionation Versus Conventional Fractionation in Patients with High-Risk Prostate Cancer." (Arcangeli G, Int J Radiat Oncol Biol Phys. 2010 Jan 2. [Epub ahead of print]). Median F/U 2.7 years
*** Outcome: 3-year bPFS conventional 79% vs hypofx 87% (SS); very high risk subset (GS 8-10, PSA ≥ 20, or ≥ T2c) 76% vs 88% (SS)
*** Toxicity: 3-year late GI G2 conventional 16% vs hypofx 17%, GU G2 11% vs 14%
*** Conclusion: Hypofractionated schedule superior for biochemical control, comparable for late toxicity
* Vilnius University, Lituania (2004-ongoing) -- 74/37 (2 Gy/fx) vs. 57/17 (3 Gy/fx + 4.5 Gy/fx)
** Randomized. 91 patients, clinically localized prostate cancer, risk of SV/LN involvement <15%. No neoadjuvant ADT. Arm 1) 74/37 vs. Arm 2) 57/17 (39/13 + 18/4). CTV = prostate + base SV. PTV margin 8-10 mm. 3D-CRT using 5 fields
** Acute Toxicity; 2009 PMID 19899003 -- "A randomized trial comparing hypofractionated and conventionally fractionated three-dimensional external-beam radiotherapy for localized prostate adenocarcinoma : a report on acute toxicity." (Norkus D, Strahlenther Onkol. 2009 Nov;185(11):715-21. Epub 2009 Nov 10.) Min F/U 3 months
*** Toxicity: No acute G3-4 toxicity. GU Grade 2 toxicity HFRT 19% vs. CFRT 48% (SS). Median duration of GI acute toxicity 3 weeks vs 6 weeks (SS)
*** Conclusion: Hypofractionated schedule feasible, lower acute toxicity
** 1-year; 2009 PMID 19605967 -- "A randomized trial comparing hypofractionated and conventionally fractionated three-dimensional conformal external-beam radiotherapy for localized prostate adenocarcinoma: a report on the first-year biochemical response." (Norkus D, Medicina (Kaunas). 2009;45(6):469-75.)
*** Outcome: 1-year PSA nadir <1.0 HFRT54% vs. CFRT 50% (NS); 1-year PSA nadir <0.5 18% vs. 25% (NS)
*** Conclusion: Preliminary results suggest comparable biochemical response
* Fox Chase -- 76/38 (2 Gy/fx) vs. 70.2/26 (2.7 Gy/fx)
** Randomized. (2002-2006) Intermediate-high risk. Neoadjuvant ADH x4 months permitted. Arm 1) conventional 76/38 (@ 2 Gy/fx) vs. Arm 2) hypofractionated 70.2/26 @ 2.7 Gy/fx)
** 2013 PMID 24101042 -- "Randomized Trial of Hypofractionated External-Beam Radiotherapy for Prostate Cancer." (Pollack A, JCO 2013 Nov). Median F/U 5.7 years. 303 patients.
*** Toxicity: No statistically significant differences in late toxicity for overall group, but subgroup with "compromised" urinary function prior to treatment had 2-yr GU >2 conventional 5%, hypofx 10.6% (SS)
*** Outcome: 5-yr biochemical/clinical failure conventional 21.4%, hypofx 23.3% (NSS)
*** Conclusion: Hypofx not superior for efficacy, may cause more toxicity in men with significant urinary symptoms prior to treatment.
** 2006 PMID 16242256 -- "Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial." (Pollack A, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):518-26. Epub 2005 Oct 19.)
*** Toxicity: Slight increase in acute GI toxicity, no difference in GU toxicity
*** Conclusion: Hypofractionation well tolerated acutely
* Mount Vernon, UK (1997-2005) -- 55/20 vs 35.75/13 + 17/2
** Randomized. 220 patients, prostate cancer T1-T3M0 (T3 26%), PSA <50. Arm 1) EBRT 55/20 vs Arm 2) EBRT 35.75/13 + HDR 17/2. ADT 76%.
** Initial; 2007 PMID 17531335 -- "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." (Hoskin PJ, Radiother Oncol. 2007 Aug;84(2):114-20. Epub 2007 May 24.) Median F/U 1.25
*** Outcome: Mean bRFS combined modality 5.1 years vs EBRT 4.3 years (SS). Improvement seen in all risk groups
*** Toxicity: Acute GI toxicity better in combined group, other acute and late toxicities comparable. QoL FACT-P score better in combined group
*** Conclusion: HDR brachytherapy + EBRT results in improved outcome with less acute toxicity and improved QoL
* Adelaide (Australia)(1996-2003) -- 64/32 (2 Gy/fx) vs. 55/20 (2.75 Gy/fx)
** Randomized. 217 patients, T1-2N0 PCA. No ADT. Arm 1) conventional 64/32 vs. Arm 2) hypofractionated 55/20.
** 4-years; 2006 PMID 16965866 -- "Hypofractionated versus conventionally fractionated radiation therapy for prostate carcinoma: updated results of a phase III randomized trial. (Yeoh EE, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):1072-83. Epub 2006 Sep 11.) Median F/U 4 years
*** Outcome: 5-year biochemical/clinical PFS conventional 55% vs. hypofractionated 57% (NS), OS 84% vs 86% (NS)
*** Toxicity: GI urgency worse with hypofractionation, otherwise (NS). GU significantly worse with hypofractionation
*** Conclusion: Hypofractionated schedule equivalent in efficacy, toxicity somewhat worse
** Colonic motility; 2010 PMID 20153122 -- "Disturbed Colonic Motility Contributes to Anorectal Symptoms and Dysfunction After Radiotherapy for Carcinoma of the Prostate." (Yeoh EK, Int J Radiat Oncol Biol Phys. 2010 Feb 10. [Epub ahead of print])
*** Subset analysis, 38 patients, colonic transit scintigraphy, assessment of anorectal symptoms, anal sphincteric morphology (EUS) before, at 1 month and at 1 year
*** Outcome: Colonic transit increased at 1 month and persisted at 1 year after RT. Frequency and urgency of defecation, fecal incontinence, and rectal bleeding increased at 1 month and persisted at 1 year. No difference in basal anal pressures, but progressive reduction in anal squeeze pressure and increased intra-abdominal pressure. Progressive decreased rectal compliance. No impact on morphology of anal sphincters
*** Conclusion: Colonic dysmotility contributes to anorectal dysfunction after RT for prostate CA
* NCI Canada (1995-1998) -- 66/33 (2 Gy/fx) vs. 52.5/20 (2.62 Gy/fx)
** Randomized. 936 men, T1-T2, PSA <40, no AST. Technique 3D-CRT, 4F
** 5-years; 2005 PMID 16135479 -- "Randomized trial comparing two fractionation schedules for patients with localized prostate cancer." (Lukka H, J Clin Oncol. 2005 Sep 1;23(25):6132-8.). Median F/U 5.7 years
*** Outcome: 5-year FFP standard 47% vs. hypofractionated 40% (NS); no difference in post-RT biopsy rate or OS
*** Toxicity: Grade 3 late toxicity 3.2% both arms (NS)
*** Conclusion: Current hypofractionated regimen may be inferior to standard fractionation

## Non-randomized

* Princess Margaret (2001-2005)
** Long-term Results; 2017 PMID 27838147 -- "Long-term Outcomes of a Phase II Trial of Moderate Hypofractionated Image-guided Intensity Modulated Radiotherapy (IG-IMRT) for Localized Prostate Cancer." (Lieng H, Radiotherapy and Oncology 2017 Jan 122(1):93-98)
*** Phase II. 96 treated with 60 Gy in 20 fx (median F/U 10.6 years), 27 treated with 66 Gy in 22 fx (median F/U 9 years). 66 Gy arm stopped early due to high late G3-4 toxicity.
*** Toxicity: 60Gy: 8 yr cumulative late Grade >2 GI 4%, GU 12%; 66 Gy 8 yr cumulative late Grade >2 GI 21%, GU 4%
*** Outcome: 5-yr FFBF 60Gy 81%, 66Gy 88%; 8-yr FFBF 60Gy 66%, 66Gy 80%
*** Conclusion: 60 Gy had low late toxicity, although there were late recurrences. 66 Gy arm had high late toxicity.
** Initial Results; 2007 PMID 17606331 -- "Phase II Trial of Hypofractionated Image-Guided Intensity-Modulated Radiotherapy for Localized Prostate Adenocarcinoma." (Martin JM, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1084-9. Epub 2007 Jul 2.)
*** Phase II. 92 patients with T1c-T2c, median PSA 7, GS <=7 (32% low risk, 61% intermediate risk, 7% high risk). RT 60/20 @ 3 Gy/fx. Median F/U 3.2 years
*** Toxicity: Acute G3-4 toxicity in <1%; Late toxicity no G3-4
*** Outcome: 3-year bNED (old ASTRO definition) 76%
*** Conclusion: HFX-RT feasible, low toxicity, bNED comparable to conventional
* Christie Hospital, UK; 2009 (2002-2003) PMID 19131179 -- "Hypofractionated intensity-modulated radiotherapy for carcinoma of the prostate: analysis of toxicity." (Coote JH, Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1121-7. Epub 2009 Jan 7.)
** Phase I/II. 60 patients, high risk prostate cancer, T3N0 with any GS and PSA <=50, or T2N0 GS >=7 and PSA 20-50. ADT 6 months. Cohort I 57/19 -> Cohort II 60/20. PTV expansion 0.7 posterior, 1 cm otherwise. IMRT 5 fields.
** Acute toxicity: No Grade 3-4 GI/GU; Grade 2 GI 15%; Grade 2 GU 10%
** Late toxicity (2 years): Grade 3 GU 4% (1 patient), no Grade 3 GI; Grade 2 GI 9%, Grade 2 GU 4%. LENT/SOMA general worsening of bowel function
** Conclusion: Hypofractionated IMRT minimal late toxicity at 2 years
* Colorado; 2009 PMID 19362783 -- "Toxicity Assessment of Pelvic Intensity-Modulated Radiotherapy with Hypofractionated Simultaneous Integrated Boost to Prostate for Intermediate- and High-Risk Prostate Cancer." (McCammon R, Int J Radiat Oncol Biol Phys. 2009 Apr 11. [Epub ahead of print])
** Retrospective. 30 patients. Pelvic IMRT 50.4/28 with simultaneous integrated boost 70/28 @ 2.5 Gy/fx. Median F/U 2 years
** Toxicity: Late Grade 3 in 2/30 patients, Grade 4 in 1/30 patients. Bowel toxicity associated with bowel volume >= 50 Gy
** Conclusion: Well tolerated
* Italy Multi-Institutional; 2008 (2004-2006) PMID 18538488 -- "Clinical and Dosimetric Predictors of Acute Toxicity after a 4-Week Hypofractionated External Beam Radiotherapy Regimen for Prostate Cancer: Results from a Multicentric Prospective Trial." (Arcangeli S, Int J Radiat Oncol Biol Phys. 2008 Jun 4. [Epub ahead of print])
** Phase II. 102 patients, 3 institutions. RT 56/16 @ 3.5 Gy/fx
** Toxicity: GU Grade 2 39%, Grade 3+ 4%; GI Grade 2 38%, no Grade 3+
** Conclusion: Acute GU and GI toxicity comparable to other series
* Montreal; 2008 (2001-2002) PMID 18406883 -- "Combined hypofractionated radiation and hormone therapy for the treatment of intermediate-risk prostate cancer." (Yassa M, Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):58-63.)
** Phase II. 42 patients, intermediate-risk PCA. RT 57/19 @ 3 Gy/fx. Neoadjuvant/concomitant ADT. Median F/U 3.8 years
** Outcome: 4-year bPFS 79%
** Toxicity: Grade 3 8%
** Conclusion: Hypofractionation with concomitant ADT is well tolerated
* US Multi-Institutional 2005 ASCO Abstract -- "A multi-institutional phase I/II trial of hypofractionated radiation therapy for localized prostate cancer." (Ritter MA, ASCO 2005)
** Dose escalation. The planned HFX levels I, II and III are 64.7 Gy/ 22 fx @ 2.94 Gy, 58.08 Gy/ 16 fx @ 3.63 Gy, and 51.6 Gy/ 12 fx @ 4.3 Gy. Three increasingly HFX levels were designed per LQ modeling to maintain constant predicted late toxicity relative to 76 Gy in 38 fractions. IMRT is used.
** Conclusion: First level completed, low level toxicity. Accrual for higher levels ongoing
* Cleveland Clinic; 2007 (1998-2005) PMID 17544601 -- "Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience." (Kupelian PA, Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1424-30. Epub 2007 Jun 4.)
** Retrospective. 770 patients, localized PCA. RT 70/28. Median F/U 3.7 years
** Outcome: 5-year bPFS 82%; low risk 95%, intermediate risk 85%, high risk 68%
** Late Toxicity: GI Grade 3+ 1%, GU Grade 3+ 5%
** Conclusion: Acceptable outcomes and toxicity
* Christie Hospital, UK; 2009 (1995-1998) PMID 14630259 -- "Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis." (Livsey JE, Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1254-9.)
** Retrospective. 705 men with T1-T4N0 PCA, 4F conformal RT, dose 50/16 @ 3.13 Gy/fx. No ADT. Median PSA 13 ng/ml. Median F/U 4 years
** Outcome: 5-year bPFS low risk (T1-T2 or PSA <=10 or GS <7) 82%, intermediate (1 risk) 56%, high risk (2-3 risks) 39%
** Toxicity: Grade 2+ GI 5% and GU 9%
** Conclusion: Similar tumor control and toxicity to standard 65-70 Gy. However, now treating on a dose-escalation trial due to other evidence for higher dose benefit
* St. Thomas Hospital; 1991 (UK)(1964-1984) PMID 2069876 -- "Radical external beam radiotherapy for localised carcinoma of the prostate using a hypofractionation technique." (Collins CD, Clin Oncol (R Coll Radiol). 1991 May;3(3):127-32.)
** Retrospective. 232 patients, clinically localized PCA. RT 36/6
** Conclusion: Comparable results to other series, early and late morbidity acceptable

## SBRT
### Clinical: Definitive

* Yale / Medicare review (2008-2011) -- Retrospective
** Toxicity; 2014 No PMID yet -- "Stereotactic Body Radiation Therapy Versus Intensity-Modulated Radiation Therapy for Prostate Cancer: Comparison of Toxicity." (Yu JB, J Clin Oncol -- online before print, 2014 Mar 10.)
*** Medicare database. Compared pts receiving SBRT (n=1335) vs IMRT (n=2670). Pts were matched with those with similar follow-up time. Reviewed claims indicative of GU toxicity (urethritis, incontinence, obstruction).
*** Mean treatment cost $13,645 for SBRT vs $21,023 for IMRT.
*** At 6 months: GU toxicity rate 15.6% SBRT vs 12.6% IMRT (OR 1.29; SS). At 24 months, 43.9% vs 36.3% (OR 1.38, SS). on.
*** Conclusion: "Although SBRT was associated with lower treatment costs, there appears to be a greater rate of GU toxicity for patients undergoing SBRT compared with IMRT, and prospective correlation with randomized trials is needed."
* Winthrop University, USA; 2010 (2006-2008) PMID 20122161 -- "Stereotactic body radiotherapy for organ-confined prostate cancer." (Katz AJ, BMC Urol. 2010 Feb 1;10(1):1. [Epub ahead of print])
** Retrospective. 304 patients, clinically localized PCA (low risk 69%, intermediate risk 27%, high risk 4%). SBRT dose 35/5 (first 50 patients, 16%) or 36.25/5 (84%). Median F/U 2.5 years for 35/5 cohort and 17 months for 36.25/5 cohort
** Outcome: PSA failure in 4 patients. PSA bounce 16%
** Toxicity: No acute Grade 3+ toxicity. Acute Grade 2 toxicity 5%. One patient late G3 GU toxicity. Late G2 GU toxicity 6%, G2 GI toxicity 3%
** Conclusion: Low toxicity and maintained QoL; additional F/U needed for biochemical control
* Drexel University; 2010 PMID 20065849 -- "Toxicity After CyberKnife-Delivered Hypofractionated Radiotherapy for Treatment of Prostate Cancer." (Townsend NC, Am J Clin Oncol. 2010 Jan 8. [Epub ahead of print])
** Retrospective. 50 patients, of which 37 treated with 35/5 to 37.5/5, and 11 patients treated as boost 17.6 to 25 Gy in 2-5 fractions
** Outcome: Acute GU toxicity Grade 2 in 10%, Grade 3 in 6%. No acute GI Grade 2-3 toxicity
** Conclusion: Cyberknife RT acceptable acute toxicity profile
* Naples Radiation Oncology, USA; 2009 (2005-2006) PMID 19754215 -- "Stereotactic body radiotherapy: an emerging treatment approach for localized prostate cancer." (Friedland JL, Technol Cancer Res Treat. 2009 Oct;8(5):387-92.)
** Retrospective. 112 men, localized PCA (GS 6 in 81%, mean PSA 6.0). Cyberknife RT 35-36/5 @ 7-7.2 Gy/fx. Median F/U 2 years
** Outcome: bPFS 98% (2 biopsy-confirmed local relapse, 1 distant mets)
** Toxicity: Grade 3 GI (bleeding) in 1 patients. Sexual potency in 82%
** Conclusion: Additional follow-up is required
* Stanford (2003-2008)
** Phase II. Men with low risk PCA (cT1c-T2b, PSA <=10, GS <=6; GS 7 allowed if 1-2/12 cores ). Cyberknife RT 36.25/5 @ 7.25 G/fx; initially over 5 days, then 3x/week. End points early and late GI and GU toxicity, QoL, and patterns of PSA response
** 2006 ASTRO Abstract -- "Hypofractionated Stereotactic Radiotherapy for Prostate Cancer: Early Results" (Hara W, Int J Radiat Oncol Biol Phys. 2008 66(3):S324, Abstract 2206)
*** Interim update. 26 patients.
*** Outcome: 18-month PSA 0.22, bounce in 23%
*** Toxicity: Late GU Grade 2 4%, late rectal Grade 2 0%; no Grade 3-4
*** Conclusion: Acute sequelae for SBRT acceptable; early PSA results promising
** Interim; 2009 PMID 18755555 -- "Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial." (King CR, Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1043-8. Epub 2008 Aug 26.)
*** Interim update. 56 patients enrolled, 41 analyzed. Median F/U 2.7 years
*** Outcome: No PSA failure so far. 78% nadir <0.4 ng/ml. PSA bounce (median 0.4 ng/ml) in 29%, occurring at median 18 months after treatment
*** Toxicity: Late GU Grade 3 toxicity 5%, no Grade 4. No late GI Grade 3 toxicity. Reduced rectal toxicity with 3/week vs 5/week treatments (0% vs. 38%, SS).
*** Conclusion: Early and late toxicity, and PSA response highly encouraging
** Sexual fn; 2010 PMID 20137864 -- "Sexual Function after Stereotactic Body Radiotherapy for Prostate Cancer: Results of a Prospective Clinical Trial." (Wiegner EA, Int J Radiat Oncol Biol Phys. 2010 Feb 3. [Epub ahead of print])
*** Subset analysis, 32 consecutive patients. EPIC QoL scale, at baseline, and at 4, 12, 20, and 50 months after RT. No ADT. Median F/U 3 years, min F/U 1 year
*** Outcome: Mean EPIC score decreased for sexual domain summary by 45%, sexual function by 49%, and sexual bother by 25%. Decrease became clinically relevant by 20 months after SBRT. ED increased from baseline 38% to 71% (SS); use of ED meds baseline 3% increased to 25%. Satisfactory ED by age if <70 60% vs. >70 12% (SS)
*** Conclusion: Rates of ED appear comparable to other reported modalities of RT
* Messina, Italy; 2009 PMID 19246151 -- "CyberKnife in the Treatment of Prostate Cancer: A Revolutionary System." (Morgia G, Eur Urol. 2009 Feb 23. [Epub ahead of print])
** Brief report. 6 patients. Cyberknife RT. Dose 38/4 @ 9.5 Gy/fx
* Seoul; 2007 (2002-2005) ASTRO Abstract -- "Stereotactic Radiation Therapy of Localized Prostate Cancer Using Cyberknife" (Choi C, Int J Radiat Oncol Biol Phys. 2007 69(3):S375, Abstract 2307)
** Retrospective. 44 patients, 10 low risk, 9 intermediate risk, 25 high risk. RT 32-36/4. Median F/U 13 months
** Outcome: 3-year bPFS 78%, OS 100%
** Conclusion: Cyberknife feasible
* Virginia Mason; 2007 (2000-2004) PMID 17336216 -- "Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results." (Madsen BL, Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1099-105.)
** Phase I/II. 40 patients, localized PCA. SBRT 33.5/5 in 5 days. Median F/U 3.4 years
** Outcome: Actuarial 4-year bPFS (ASTRO) 70%, (nadir+2) 90%
** Toxicity: Late G1-2 toxicity GU 45%, GI 37%; no Grade 3-4 toxicity; impotence 23%
** Conclusion: SBRT feasible, with minimal toxicity

### Clinical: Boost

* Barcelona; 2009 (2001-2004) PMID 19910135 -- "Hypofractionated Boost to the Dominant Tumor region with Intensity Modulated Stereotactic Radiotherapy for Prostate Cancer: A Sequential Dose Escalation Pilot Study." (Miralbell R, Int J Radiat Oncol Biol Phys. 2009 Nov 10. [Epub ahead of print])
** Phase I. 50 patients. Initial conventional 3D-CRT/IMRT 64-64.4 in 1.8-2 Gy/fx, follwed by SBRT boost. 10/2 -> 12/2 -> 14/2 -> 16/2 @ 8 Gy/fx. Rectal balloon with 60 cc air. ADT 66%.
** Outcome: 5-year bDFS 98%
** Toxicity: 5-year Grade 2+ GI 28%, Grade 2+ GU 18% and not correlated with dose
** Conclusion: Hypofractionated boost dose escalation is feasible, with excellent outcomes and acceptable long-term toxicity
** Comment: See PMID 19250768 for same institution, concurrent protocol on HDR boost

### Dosimetry

* UC San Francisco
** 2008 PMID 18841856 -- "Simulated real time image guided intrafraction tracking-delivery for hypofractionated prostate IMRT." (Hossain S, Med Phys. 2008 Sep;35(9):4041-8.)
*** Treatment planning. Review of intrafraction prostate movements during 50-70 min Cyberknife treatment time, then virtually treated with IMRT plan based on the observed motion over time. Nominal single fraction 9.5 Gy
*** Outcome: For most cases, DVH impact minimal (~2%). However, with sporadic movements >5mm, significant change. V100 could be reduced to <85%
*** Conclusion: Due to observed large amplitude sporadic prostate motion, online target correction is necessary for hypofractionated IMRT-SBRT
** 2010 PMID 20133073 -- "Dose Gradient Near Target-Normal Structure Interface for Nonisocentric CyberKnife and Isocentric Intensity-Modulated Body Radiotherapy for Prostate Cancer." (Hossain S, Int J Radiat Oncol Biol Phys. 2010 Feb 2. [Epub ahead of print])
*** Treatment planning. 8 patients treated with Cyberknife replanned with 9-field IMRT
*** Outcome: CK plans better conformity (1.18 vs 1.44) but higher dose inhomogeneity (1.45 vs 1.28). Dose fall-off posterior CK 2.9%/mm vs IMRT 3.1%/mm, all directions 3.6%/mm vs 3.6%/mm
*** Conclusion: Cyberknife capable of producing comparable dose gradient as IMRT
* San Diego CyberKnife Center; 2008 PMID 18374232 -- "Virtual HDR CyberKnife treatment for localized prostatic carcinoma: dosimetry comparison with HDR brachytherapy and preliminary clinical observations." (Fuller DB, Int J Radiat Oncol Biol Phys. 2008 Apr 1;70(5):1588-97.)
** Dosimetry. 10 patients treated with CyberKnife. Used HDR protocol 38/4
** Comparison: CK had comparable PTV, less V125 and V150, lower urethral dose, lower bladder Dmax but slower dose fall-off, similar rectal doses, and sharper dose fall-off
** Outcome: 4-month PSA decreased 86%
** Toxicity: acute toxicity mainly GU, IPSS median increase 10 points, return to baseline by 8 weeks, minimal GI toxicity
** Conclusion: It is possible to construct and deliver Cyberknife plans that closely recapitulate HDR dosimetry
* Stanford
** 2008 PMID 18722274 -- "Intrafractional motion of the prostate during hypofractionated radiotherapy." (Xie Y, Int J Radiat Oncol Biol Phys. 2008 Sep 1;72(1):236-46.)
** 2008 PMID 19147028 -- "Testicular dose from prostate cyberknife: a cautionary note." (King CR, Int J Radiat Oncol Biol Phys. 2008 Apr 1;70(5):1588-97.)
** 2007 PMID 17472885 -- "Investigation of linac-based image-guided hypofractionated prostate radiotherapy." (Pawlicki T, Med Dosim. 2007 Summer;32(2):71-9.)
** Comparison of Varian Trilogy and CyberKnife
* Virginia Mason; 2003 PMID 14630263 -- "Intrafractional stability of the prostate using a stereotactic radiotherapy technique." (Madsen BL, Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1285-91.)
** Retrospective. 47 patients, each with 3 fiducial markers. 227 RT fractions reviewed. Also ragiographs at 6 min intervals
** Outcome: sup/inf 2.0 mm, ant/post 1.9 mm, right/left 1.4 mm. Radiographs 0-6 min 1.5 mm greatest, >6 min 0.9 mm greatest
** Conclusion: Average intrafractional movement 2.0 mm or less. Most movement early, and recommend settling-in period before treatment

### Review

* ASTRO; 2010 PMID 20338473 -- "Stereotactic body radiotherapy for primary management of early-stage, low- to intermediate-risk prostate cancer: report of the American Society for Therapeutic Radiology and Oncology Emerging Technology Committee." (Buyyounouski MK, Int J Radiat Oncol Biol Phys. 2010 Apr;76(5):1297-304.)
* Stanford; 2007 PMID 17641522 -- "Prostate cancer therapy with stereotactic body radiation therapy." (Pawlicki T, Front Radiat Ther Oncol. 2007;40:395-406.)

## Dose Modeling

* Medical College of Wisconsin; 2008 PMID 18039721 -- "Designing equivalent treatment regimens for prostate radiotherapy based on equivalent uniform dose." (Li XA, Br J Radiol. 2008 Jan;81(961):59-68. Epub 2007 Nov 26.)
** Modelling. EUD using two sets: a/b = 3.1 Gy and alpha = 0.15 Gy-1; a/b = 1.5 Gy and alpha = 0.04 Gy-1
** Outcome: Multiple equivalent alternative regimens calculated (e.g. EBRT 76/38 == EBRT 63/21 == I-125 156 Gy == Pd-103 128 Gy == HDR 42/4)