# Radiation Oncology/Prostate/External Beam RT/Dose Escalation

| Front Page: Radiation Oncology | RTOG Trials | Randomized Trials | Edit this |
| Prostate: Main Page | Prostate Overview | Screening and Prevention | Workup | Natural History | External Beam RT | IMRT | Androgen Suppression Therapy | Brachytherapy | Protons | Prostatectomy | Adjuvant RT after Prostatectomy | Salvage RT | Chemotherapy | Localized prostate cancer | Node Positive | Advanced disease | Recurrence after RT | Cryotherapy | RTOG Prostate Trials | Randomized Evidence | |
Prostate Cancer Dose Escalation Studies

## Overview

* Standard 2D dose cannot reasonably exceed 70Gy due to bowel toxicity.
* Prospective dose escalation studies (RTOG 94-06, French, Dutch, Memorial Sloan Kettering, and Fox Chase) have shown reasonably good tolerance to doses of at least 81 Gy; GI and GU side effects appear to show more a volume effect.
* As a result, several Phase III trials evaluated 3D-CRT to escalate dose above 70Gy. All except for the initial Harvard Proton Boost trial in locally advanced disease showed a biochemical progression free survival benefit for higher dose
* Because they used different doses, it is not clear what actual dose should be used, or whether further dose-escalation would be beneficial
* The Dutch trial allowed ADT for high risk disease, the MRC trial mandated neoadjuvant ADT; the other trials did not use ADT
* A prospective non-randomized risk-adapted data from Spain argues for benefit of dose escalation in the presence of ADT

## Randomized

Meta-Analysis
* Sao Paulo, Brazil; 2009
** Meta-analysis. 7 trials, 2812 patients
** Outcome, reduction in bPFS (SS), no difference in PCSM (p=0.45), or OS (p=0.38). Low, intermediate, and high risk all benefited. Linear correlation between total dose and bPFS
** Toxicity: Increased G3+ late GI toxicity
** Conclusion: High dose RT superior to conventional dose RT, and should be offered for all patients, regardless of risk status
** PAPER RETRACTED - Int J Radiat Oncol Biol Phys. 2013 Mar 15;85(4):899.Zietman AL, Viani GA.
Individual Trials
| Institution | Stage | Dose (Gy) | 5-year Outcome | Grade 3 Toxicity |
| MRC RT01 (1998-2002) | T1b-T3a | 64 vs 74 | NED 60% vs 71% (SS) | GI 6% vs 10% GU 2% vs 4% |
| Dutch CKVO96-10 (1997-2003) | T1b-T4 | 68 vs 78 | NED 54% vs 64% (SS) | GI 4% vs 5% (NS) GU 12% vs 13% (NS) |
| PROG 95-09 (1996-1999) | T1b-T2b | 70.2 vs 79.2 | NED 79% vs 91% (SS) | GI 1% vs 1% (NS) GU 1% vs 2% (NS) |
| MD Anderson (1993-1998) | T1-T3 | 70 vs 78 | FFP 75% vs 78% (SS) | GI 1% vs 7% (SS) GU 5% vs 4% (NS) |
| Ontario LDR Boost (1992-1997) | T2-T3 | 66 vs 75 | FFP 39% vs 71% (SS) | GI 2% vs 4% (NS) GU 4% vs. 14% (NS) |
| Harvard Proton Boost (1982-1992) | T3-T4 N0-2 | 67.2 vs 75.6 | LC 92% vs 80% (NS) | GI bleeding 15% vs 32% (NS) GU stricture 8% vs 19% (NS) |
* RTOG 01-26 -- "A Phase III Randomized Study of High Dose 3D-CRT/IMRT vs. Standard Dose 3D-CRT/IMRT in Patients Treated for Localized Prostate Cancer"
** 3D-CRT/IMRT to 79.2 Gy in 44 fractions vs. 70.2 Gy in 39 fractions; intermediate prognosis tumors
** Activated March 2002, ongoing, no publications yet
* GETUG (France) (1999-2002)
** Randomized. 306 patients, intermediate risk (T2-T3, or T1 and GS 7+ or PS >10, PSA <50 ng/mL). Arm 1) 70/35 Gy vs. Arm 2) 80/40 Gy. 3D-CRT 4F 46/23 then multi-field technique. Rectum wall Dmax 76 Gy, bladder wall Dmax 80 Gy
** 2004 PMID 15519775 -- "The GETUG 70 Gy vs. 80 Gy randomized trial for localized prostate cancer: feasibility and acute toxicity." (Beckendorf V, Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1056-65.)
*** Acute GI toxicity: low dose Grade 2 27%, Grade 3 2% vs. high dose 28%, 2% (NS)
*** Acute GU toxicity: low dose Grade 2 31%, Grade 3 5% vs. high dose 30%, 7% (NS)
*** Conclusion: Acute toxicity acceptable
* MRC RT01 (UK)(1998-2002) -- 3D-CRT 64 Gy vs. 74 Gy
** Randomized. 843 men, T1b-T3a (T3 in <20%), PSA <50 ng/mL. . Neoadjuvant AST 3-6 months, then RT Arm 1) 64/32 Gy vs. 74/37 Gy. GTV = prostate +/- SV (depending on risk). CTV = GTV + 0.5 cm. PTV = CTV + 0.5-1.0 cm
** Pilot 2005 ASCO Abstract -- "Phase III pilot study of dose escalation using conformal radiotherapy (CFRT) in prostate cancer: PSA control and side effects" (Dearnaley, 2005 ASCO)
*** Single institution pilot for MRC RT01 using 2x2 dose (64 Gy vs. 74 Gy) and margin design (1.0 cm vs. 1.5 cm); median follow-up 6.5 years
*** 5-year PSA-DFS dose 74 Gy vs. 64 Gy: 71% vs. 59% (p=0.1)
*** 5-year PSA-DFS margin 1.0 cm vs. 1.5 cm: 67% vs. 63% (p=NS)
*** Acute side effects: GU greater in 74 Gy and 1.5 cm, GI greater in 1.5cm
*** Late side effects: GU (p=NS), GI greater in 1.5cm
*** Conclusion: "Dose escalation from 64 Gy to 74 Gy using CFRT may improve long term PSA control but a treatment margin of 1.5cm is unnecessary and is associated with increased bowel and bladder side effects."
** 2004 PMID 15297138 -- "Implementing the UK Medical Research Council (MRC) RT01 trial (ISRCTN 47772397): methods and practicalities of a randomised controlled trial of conformal radiotherapy in men with localised prostate cancer." (Sydes MR, Radiother Oncol. 2004 Aug;72(2):199-211.)
** Early toxicity; 2007 PMID 17391791 -- "The early toxicity of escalated versus standard dose conformal radiotherapy with neo-adjuvant androgen suppression for patients with localised prostate cancer: Results from the MRC RT01 trial (ISRCTN47772397)" (Dearnaley DP, Radiother Oncol. 2007 Mar 26)
*** Early toxicity measured using physician-reported instruments (RTOG, LENT/SOM, Royal Marsden Scales) and patient-reported questionnaires (MOS SF-36, UCLA Prostate Cancer Index, FACT-P)
*** Grade 2 standard vs. escalated: bladder 38% vs. 39%, bowel 30% vs. 33%. Urinary frequency improved from pre-AST, but bowel and sexual function deteriorated
*** 6-month outcomes: RTOG side effects <1%; 6 rectal ulceration (6/6 escalated), 6 hematuria (5/6 escalated), 8 urethral stricture (6/8 escalated)
*** Conclusion: Escalated group broadly similar early toxicity, except immediately post-RT
** 5-years; 2007 PMID 17482880 -- "Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial." (Dearnaley DP, Lancet Oncol. 2007 Jun;8(6):475-87.) Median F/U 5.2 years
*** Outcome: PFS high dose 71% vs. standard dose 60% (SS); clinical PFS 90% vs. 87% (NS)
*** By risk group: low-risk 85% vs. 79%, intermediate-risk 79% vs. 70%, high-risk 57% vs. 43%; benefit across all groups
*** Toxicity: GI Grade 2+ high dose 33% vs. standard dose 24% (SS); GU Grade 2+ 11% vs. 8% (NS); sexual dysfunction prevalent
*** Conclusion: Escalated dose with neoadjuvant AST seems clinically worthwhile, but increased incidence of long-term adverse events
** Bcl-2; 2010 PMID 20092961 -- "Expression of Bcl-2, p53, and MDM2 in Localized Prostate Cancer with Respect to the Outcome of Radical Radiotherapy Dose Escalation." (Vergis R, Int J Radiat Oncol Biol Phys. 2010 Jan 19. [Epub ahead of print])
*** Subset analysis. 308 patients, neoadjuvant ADT and RT. Tumor expression of Bcl-2, p53, and MDM2 evaluated. Median F/U 7 years
*** Outcome: Univariate, Bcl-2 and p53 but not MDM2 associated with 5-year bPFS. Bcl-2 associated on MVA. For Bcl-2+ tumors, 7-year bPFS 64 Gy 41% vs 74 Gy 61% (SS). For Bcl-2- tumors, 81% vs 87% (NS)
*** Conclusion: Bcl-2 positive patients had worse biochemical control, and benefited from dose escalation
* 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
* Dutch CKVO96-10 (1997-2003) -- 68 Gy vs. 78 Gy
** Randomized. 664 patients, T1b-T4, with PSA < 60 (excluded low risk: T1a, T1b-c with GS<5 and PSA <=4; excluded pN+). Arm 1) 68/34 Gy vs. Arm 2) 78/39 Gy. Both 3D-CRT. CTV = prostate +/- SV (depending on risk group); PTV = 1.0 cm margin to 68 Gy, then 0.5 mm and 0 mm posteriorly. Prescription dose was to the isocenter. Stratified by risk group. Hormonal therapy in 22%
** Toxicity, 2005 PMID 15752881 — "Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy." (Peeters ST, Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1019-34.)
*** No acute toxicity differences (p=NS)
*** No late GI and GU toxicity difference (p=NS), except for rectal bleeding requiring laser treatment or transfusion (p = 0.007) and nocturia (p = 0.05)
*** Conclusion: Acute and late toxicity higher, but not NS except late rectal bleeding and late nocturia
** 5-years, 2006 PMID 16648499 — "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." (Peeters ST, J Clin Oncol. 2006 May 1;24(13):1990-6.). Median F/U 4.2 years
*** Outcome: 5-year FFS high-dose 64% vs low-dose 54% (SS). Clinical failure both groups 76% (NS), OS 82% vs. 83% (NS)
*** Toxicity: GI Grade 2+ high-dose 32% vs. low-dose 27% (NS), GI Grade 3+ 5% vs. 4% (NS). GU Grade 2+ 39% vs. 41% (NS), GU Grade 3+ 13% vs. 12% (NS).
*** Conclusion: Significantly improved FFS, with comparable toxicity
** Sexual fn, 2007 PMID 17331667 -- "Sexual function after three-dimensional conformal radiotherapy for prostate cancer: results from a dose-escalation trial." (van der Wielen GJ, Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):479-84.)
*** 268 patient subset. Baseline ED 28%
*** ED in pretreatment potent men: at 1 year 27%, at 2 years 36%, at 3 years 38%. No difference between low and high dose.
*** 2-year outcome: 30% had considerable/very much sexual desire; 14% used sexual aids
*** Conclusion: Lower % of ED than previously reported
** Urinary obstruction; 2010 PMID 20056354 -- "Urinary Obstruction in Prostate Cancer Patients From the Dutch Trial (68 Gy vs. 78 Gy): Relationships with Local Dose, Acute Effects, and Baseline Characteristics." (Heemsbergen WD, Int J Radiat Oncol Biol Phys. 2010 Jan 5. [Epub ahead of print])
*** Subset analysis. 40 patients with urinary obstruction (19 low dose arm and 21 high dose arm). Dose-difference maps
*** Outcome: Early events within 2 years (47%) predicted by baseline complaints and TURP. Late events after 2 years (53%) predicted by bladder surface receiving ≥ 80 Gy and especially with dose to bladder neck in the trigone
*** Conclusion: Late urinary obstruction associated with local dose to trigone
** Risk factors; 2010 PMID 20227123 -- "Subgroup analysis of patients with localized prostate cancer treated within the Dutch-randomized dose escalation trial." (Al-Mamgani A, Radiother Oncol. 2010 Mar 11. [Epub ahead of print])
*** Subset analysis. Two prognostic models: Chism risk group (low risk T1-T2 and GS ≤ 6 and PSA ≤ 10; high risk T3-T4 or GS 8-10 or PSA >20) and PSA-level (<10 and ≥ 10)
*** Outcome: 6-year bPFS 68 Gy 51% vs 78 Gy 63% (SS). Low-risk 84% vs 80% (NS); intermediate risk 54% vs 78% (SS); high risk 40% vs 49% (NS). If PSA <10 no difference; if PSA &ge: 10, 62% vs 40% (SS); PSA optimal cut-off for no benefit 8 ng/ml. For patients treated with ADT, bPFS improved with high dose
*** Conclusion: Intermediate-risk group derived greatest benefit from dose escalation, though no indication was found to exclude low-risk or high-risk patients from high-dose RT
* 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); 75% GS <7. Low risk 58%, intermediate risk 37%. 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 + 10 mm margin. No hormones
** 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.). Note erratum published after incorrect analysis of failures during initial publication, which changes outcomes. Values below are corrected values. Median F/U 5.5 years
*** Outcome: 5-year bNED 70.2 Gy 79% vs. 79.2 Gy 91% (SS), 59% reduction in risk of failure. LC 48% vs. 67% (SS) No difference in OS 97% vs 96% (NS)
*** Risk stratification: low risk (PSA <10, stage <=T2a, GS <7) 83% vs. 97% (SS); high risk 74% vs. 82% (NS). When high risk sub-analyzed: contemporary intermediate risk 75% vs. 87% (SS), but contemporary high risk not significant, but small number of patients)
*** 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 intermediate-risk clinically localized PCA have better bNED with high dose, without worse severe toxicity and with only small increase in G2 GI 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
** Patient surveys; 2010 PMID 20233822 -- "Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer." (Talcott JA, JAMA. 2010 Mar 17;303(11):1046-53.)
*** Post-hoc analysis. 280 patients surveyed (83% of surviving cohort). Main outcome: Prostate Cancer Symptom Indices. Median F/U 9.4 years
*** Outcome: No difference in urinaty obstruction/irritation, urinary incontinence, bowel problems, sexual dysfunction, and most other outcomes. Patients receiving standard dose had less confidence that their dose was under control (76% vs 86%, SS). Many patients reported their function as normal, despite substantial symptoms
*** Conclusion: Higher dose not associated with increase in patient-reported symptoms
** Rectal DVH; 2010 PMID 20207497 -- "Gastrointestinal Quality of Life After Conventional and High-Dose Radiation for Prostate Cancer: A Subgroup Analysis of a Randomized Trial." (Nguyen PL, Int J Radiat Oncol Biol Phys. 2010 Mar 5. [Epub ahead of print])
*** Subset analysis. 50 men with >7 year follow up, QoL questionnaire and DVH data. Anterior rectal wall correlated with patient-reported QoL
*** Outcome: Trend toward association between higher V60, V65, V70, and V75 and long-term GI QoL. No difference between conventional and high-dose arms
*** Conclusion: DVH constraints rather than total prescribed dose have impact on long-term bowel function
* MD Anderson (1993-1998) -- 70/35 vs. 78/39
** Randomized. 301 T1-T3 patients, stratified by PSA <10 (65%), 10-20 (35%), >20 (few). Arm 1) 70 Gy vs. Arm 2) 78 Gy. Technique 4F 46/23, Arm 1) 4F RF 24/12, Arm 2) 3D-CRT 6 fields 32/16. CTV = prostate/SV, margin 1.5 cm anterior/inferior, 1.0 cm posterior/superior. No hormones
** Preliminary; 1996 PMID 8621278 -- "Conventional vs. conformal radiotherapy for prostate cancer: preliminary results of dosimetry and acute toxicity." (Pollack A, Int J Radiat Oncol Biol Phys. 1996 Feb 1;34(3):555-64.)
** Toxicity; 2000 PMID 11020558 -- "Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial." (Storey MR, Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):635-42.) Median F/U 40 mo.
** 6-years; 2002 PMID 12128107 -- "Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial." (Pollack A, Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1097-105.). Median F/U 5 years
*** Outcome: 6-year overall FFF 64% vs. 70% (p=0.03); however: 6-year FFF if PSA < 10 ~75% in both groups (NS), but FFF if PSA >10 43% vs. 62% (p=0.01). No difference in clinical DFS or OS
*** Toxicity: Grade 2+ rectal toxicity 12% vs. 26% (p=0.001); Grade 2+ bladder toxicity NS
*** Conclusion: Highly significant FFF improvement for intermediate-to-high risk patients, no benefit if PSA <10. Increased rectal toxicity
** 8-years; 2008 PMID 17765406 -- "Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer." (Kuban DA, Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):67-74. Epub 2007 Aug 31.) Median F/U 8.7 years
*** 8-year outcome: FFF 78 Gy 78% vs. 70 Gy 59% (SS); if PSA >10 78% vs. 39% (SS), clinical failure 7% vs. 15% (SS); if PSA <10 78% vs. 66% (NS)
*** By risk group: low risk 88% vs. 63% (SS); intermediate risk 86% vs. 76% (NS); high risk 63% vs. 26% (SS). OS 78% vs. 79% (NS)
*** 10-year toxicity: GI Grade 3 7% vs. 1% (SS); GI Grade 2+ 26% vs. 13% (SS); GU Grade 3 5% vs. 4% (NS), GU Grade 2+ 13% vs. 8% (NS)
*** Conclusion: Dose escalation improved PSA and clinical control, particularly if PSA >10 ng/ml
* Ontario EBRT/LDR (1992-1997) -- EBRT 66/30 vs. EBRT/LDR 75 (LDR 35 + EBRT 40/20)
** Randomized. 104 patients, locally advanced T2-T3. All underwent staging pelvic lymphadenectomy. Arm 1) EBRT 66/33 vs. Arm 2) LDR 35 Gy (delivered via 18 needles over 48 hours) + EBRT 40/20 for total 75 Gy (>80% of prostate received 80 Gy)
** 5-years; 2005 PMID 15718316 -- "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." (Sathya JR, J Clin Oncol. 2005 Feb 20;23(6):1192-9.). Median F/U 8.2 years
*** Outcome: 5-year FFP high dose 71% vs. standard dose 39% (SS); positive biopsy 24% vs. 51% (SS). OS 94% vs. 92% (NS)
*** Late toxicity: Grade 3 GU high dose 14% vs. standard dose 4% (NS); Grade 3 GI 4% vs 2% (NS)
*** Conclusion: Higher doses of radiation over shorter duration results in better control
* Harvard Proton Boost (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. No impact on DFS or OS
** 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

## Prospective Dose-Escalation

* Memorial Sloan Kettering
** 86.4 Gy; 2012 (1997-2008) PMID 22795805-- "Long-term Survival and Toxicity in Patients Treated With High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer." (Spratt DE, Int J Radiat Oncol Biol Phys. 2012 Jul 12. Epub 2012.)
*** Started as prospective trial. 1002 patients. NCCN very low risk 10%, low risk 10%, intermediate risk 46%, high risk 34%. RT 86.4/48. PTV 0.6 cm rectal, otherwise 1 cm, weekly portal imaging. ADT x 3-6 months at discretion. Median F/U 5.5 years
*** 7-year bRFS very low risk 100%, low risk 97.7%, intermediate risk 85.6%, high risk 67.9%
*** 7-year DMFS very low risk 100%, low risk 98.9%, intermediate risk 94.1%, high risk 82%
*** 7-year PCSM very low risk 0%, low risk 0%, intermediate risk 3.3%, high risk 8.1%
*** Late toxicity: Actuarial 7-yr late Grade 3 GI and GU, 0.7% and 2.2% respectively.
*** Of 427 men with full potency at baseline, 74% retained sexual function at time of last follow-up.
*** Conclusions: Ultra-high dose escalation to 86.4 Gy is safe and effective with remarkable long term outcomes, especially for the lower risk groups.
*** Strengths: Highest EBRT dose published in the literature with over 1000 patients. It is the largest IMRT series to date (when published) with remarkably low late toxicities despite dose escalation. One of the first reports to include the very low risk group (requires prostate volume measurements).
** 81 Gy; 1998 PMID 9635694 -- "Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer." (Zelefsky MJ, Int J Radiat Oncol Biol Phys. 1998 Jun 1;41(3):491-500.
*** 743 patients with clinically localized PCA (T1-2 74%); median follow-up 3 years. Dose escalation: 64.8 Gy (96 pts) -> 70.2 Gy (266 pts) -> 75.6 Gy (320 pts) -> 81.0 Gy (61 pts)
*** Toxicity: urinary (18% Grade I/II, 1% Grade III), rectal (22% Grade I/II, 1% Grade III)
*** Initial clinical response (PSA nadir <=1.0): 56% (64.8 Gy) vs. 76% (70.2 Gy) vs. 90% (75.6 Gy and 81.0 Gy) (p<0.001)
*** 5-year PSA outcomes: 85% favorable (PSA <=10, T1-2, GS <=6) vs. 65% intermediate (1 risk) vs. 35% unfavorable (2+ risks) (p<0.001)
*** Dose response: escalation to 75.6/81.0 Gy improved PSA-DFS of intermediate (p=0.04) and unfavorable (p=0.03) patients, but not favorable (p=0.5) patients
*** Positive follow-up prostate bx (2.5+ years): 57% (64.8 Gy) vs. 45% (70.2 Gy) vs. 48% (75.6 Gy) vs. 7% (81.0 Gy) (p<0.05)
*** Neoadjuvant AST: No impact on PSA outcome, significant impact (p<0.001) on local control but also impotence (p<0.001)
*** Conclusion: "The data provide evidence for a significant effect of dose escalation on the response of human prostate cancer to irradiation and defines new standards for curative radiotherapy in this disease."
* RTOG 94-06 Protocol (1994-2000) - Dose escalation
** Phase I dose escalation. 1055 men. 3D Conformal. 3 patient groups. Group 1 (T1-T2, low risk of SV) treated to prostate only; Group 2 (T1-T2, >15% of SV involvement) treated to prostate + SV, then prostate boost; Group 3 (T3 tumors) treated to prostate+SV. No Group 3 in Levels III-V. Doses: 68.4 Gy (1.8 Gy/fx; level I), 73.8 Gy (1.8 Gy/fx; level II), 79.2 Gy (1.8 Gy/fx; level III), 74 Gy (2 Gy/fx;level IV), 78 Gy (2 Gy/fx; level V). PTV margins 5-10 mm. see RTOG 94-06 page
** Long-Term Toxicity; 2010 PMID 19577865 -- "Long-Term Toxicity Following 3D Conformal Radiation Therapy for Prostate Cancer from the RTOG 9406 Phase I/II Dose Escalation Study." (Michalski JM, Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):14-22.) Median F/U 6.1 years (Level V) to 12.1 years (Level I)
*** Late Grade 3+ GI/GU toxicity:
**** Group 1 (prostate only): 68.4 - 3%; 73.8 - 4%; 79.2 - 6%; 74 - 7%; 78 - 9% (SS)
**** Group 2 (prostate + SV): 68.5 - 6%; 73.8 - 2%; 79.2 - 6%; 74 - 9%; 78 - 12% (SS)
*** Conclusion: Excellent tolerance; more toxicity with 2 Gy/fx than 1.8 Gy/fx
** Clinical results; 2012 PMID 22633552 -- "Clinical Outcome of Patients Treated With 3D Conformal Radiation Therapy (3D-CRT) for Prostate Cancer on RTOG 9406." (Michalski J, Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):e363-70.)
*** Median f/u 9.2-11.8 yrs. 5-yr OS 90%, 87%, 88%, 89%, and 88% for dose levels I-V. 5-yr clinical DFS (excluding PSA definition) 84%, 78%, 81%, 82%, and 82%.
*** 5-yr biochemical failure (Phoenix): 68%, 73%, 67%, 84%, and 80% (low risk); 70%, 62%, 70%, 74%, and 69% (intermediate risk); and 42%, 62%, 68%, 54%, and 67% (high risk)
*** Conclusion: "Dose-escalated 3D-CRT yields favorable outcomes for localized prostate cancer. This multi-institutional experience allows comparison to other experiences with modern radiation therapy."
* Fox Chase
** PMID 12243818 -- Dose response in prostate cancer with 8-12 years' follow-up. (2002 Hanks GE, Int J Radiat Oncol Biol Phys. 2002 Oct 1;54(2):427-35.)
*** 229/233 assessable patients; median follow-up 9.2 years; favorable definition (T1-T2a, GS 2-6, no PNI)
*** Dose escalation: 68-79 Gy in 2 Gy steps (<70 Gy 50 pts, 70-72.5 Gy 80 pts, 72.5-75 Gy 28 pts, 75- 77.5 Gy 56 pts, 77.5-80Gy 21 pts)
*** Toxicity: dose response for rectal Grade II, none for rectal Grade III and urinary Grade II/III
*** PSA-DFS was 55% at 5 years, 48% at 10 years, and 48% at 12 years (median dose 74 Gy)
*** 8-year PSA-DFS if PSA <10: 68% (<70 Gy) vs. 74% (70-72 Gy) vs. 68% (>72 Gy) (p=NS)
*** 8-year PSA-DFS if PSA 10-20: 19% vs. 31% vs. 84% (p=0.003) Only dose-response seen.
*** 8-year PSA-DFS if PSA >20: 8% vs. 23% vs. 11% (p=NS)
*** Dose response subgroups: unfavorable PSA <10 (p=0.04) and favorable PSA 10-20 (p=0.002), (p=NS) for all other groups
*** Dose response for DM: yes for entire cohort (p=0.03), borderline for PSA <10 (p=0.05), significant for PSA 10-20 (p=0.01), not significant for PSA >20
*** Conclusion: "The long-term results of the original Fox Chase radiation dose escalation study with >9 years of median follow-up confirm the existence of a dose response for both bNED control and FDM. The dose response in prostate cancer is real, and the absence of biochemical recurrence after 8 years demonstrates the lack of late failure and suggests cure."
** PMID 9635695 -- Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. (1998 Hanks GE, Int J Radiat Oncol Biol Phys. 1998 Jun 1;41(3):501-10.)
*** 233 patients (T1-2 90%), median follow-up 5 years
*** Dose escalation: 68-79 Gy in 2 Gy steps (<70 Gy 50 pts, 70-72.5 Gy 80 pts, 72.5-75 Gy 28 pts, 75- 77.5 Gy 56 pts, 77.5-80Gy 21 pts)
*** Toxicity: RTOG grade 3,4 GI morbidity at 5 years was <1%.
*** 5-year PSA-DFS if PSA <10: 86% (<70 Gy) vs. 77% (70-72 Gy) vs. 84% (>72 Gy) (p=NS)
*** 5-year PSA-DFS if PSA 10-20: 29% vs. 57% vs. 73% (p=0.02)
*** 8-year PSA-DFS if PSA >20: 8% vs. 28% vs. 30% (p=0.02)
*** For each 1 Gy increase in dose, the hazard of bNED failure decreased by 8%
*** Conclusion: "A dose response was observed for patients with pretreatment PSA >10 ng/ml based on 5-year bNED results. No dose response was observed for patients with pretreatment PSA < 10 ng/ml. Dose response was observed for FC-LENT grade 2 and grade 3,4 GI sequelae and for LENT grade 2 GU sequelae. Optimization of treatment was made possible by the results in this report. The improvement in 5-year bNED rates for patients with PSA levels > 10 ng/ml strongly suggests that clinical trials employing radiation should investigate the use of 3DCRT and prostate doses of 76-80 Gy."
** PMID 9112451 -- Optimization of conformal radiation treatment of prostate cancer: report of a dose escalation study. (1997 Hanks GE, Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):543-50.)
*** 233 patients (T1-2 90%), minimum 3-year follow-up
*** Dose escalation: 68-79 Gy in 2 Gy steps (<70 Gy 50 pts, 70-72.5 Gy 80 pts, 72.5-75 Gy 28 pts, 75- 77.5 Gy 56 pts, 77.5-80Gy 21 pts)
*** Toxicity: urinary (8% Grade II, <1% Grade III), rectal (24% Grade II, 5% Grade III)
*** 3-year PSA-DFS in <71.5 Gy vs >=71.5 Gy: PSA <10 90% vs. 87% (NS), PSA >10 39% vs. 71% (p=0.02)
*** Dose response: none if PSA <10, PSA 10-20 (69% 70 Gy vs. 80% 75 Gy vs. 89% 80 Gy), PSA 20+ (36% 70 Gy vs. 46% 75 Gy vs. 57% 80 Gy)
*** Dose response toxicity: Grade III/IV (4% 70 Gy vs. 9% 75 Gy vs. 19% 80Gy)
*** Conclusion: "Patients with pretreatment PSA < 10 ngm/ml do not benefit from dose escalation, and the serious late morbidity of conformal radiation at 70 Gy is < 3%. Patients with PSA values 10-19.9 ngm/ml and 20+ ngm/ml benefit from dose escalation beyond 70 Gy. Treatment beyond 75 Gy results in > 10% serious morbidity unless special precautions are taken to protect the rectal mucosa. All levels of severity of radiation morbidity show a dose response and combined with the dose response for bNED survival these data allow the optimization of treatment."
* French Multi-Institutional PMID 10974470 -- Dose escalation with 3D-CRT in prostate cancer: French study of dose escalation with conformal 3D radiotherapy in prostate cancer-preliminary results. (2000 Bey P, Int J Radiat Oncol Biol Phys. 2000 Sep 1;48(2):513-7.)
** 5 French cancer centers in Dijon, Lyon, Marseille, Nancy, and Nice; 164 patients
** Dose escalation: 66 Gy (18 pts) -> 70 Gy (28 pts) -> 74 Gy (49 pts) -> 78 Gy (48 pts) -> 80 Gy (21 pts); (max 72 Gy to SV and 75 Gy to rectal wall). Follow up 32 months (66-70 Gy) and 17.5 months (74-80 Gy)
** GI toxicity: [66-70 Gy Grade I 19.5%, Grade II 6.5%, Grade III 0%] vs. [74-80 Gy Grade I 26.3%, Grade II 9.3%, Grade III 0%] (p=NS)
** GU toxicity: [66-70 Gy Grade I 17.3%, Grade II 2%, Grade III 6.5%] vs. [74-80 Gy Grade I 16%, Grade II 3.3%, Grade III 0.8%] (p=NS)
** Probability to achieve nadir <1ng/ml: better in 74-80 Gy (p=0.003)
** Conclusion: "This multi-institutional study demonstrated the feasibility of escalating the dose of radiation to 80 Gy in prostate cancer patients."
* Dutch Multi-Institutional PMID 9588921 -- Estimation of the incidence of late bladder and rectum complications after high-dose (70-78 GY) conformal radiotherapy for prostate cancer, using dose-volume histograms. (1998 Boersma LJ, Int J Radiat Oncol Biol Phys 1998; 41:83-92.)
** Conclusion: "These data show that dose escalation up to 78 Gy, using a conformal technique, is feasible. However, these data have also demonstrated that the incidence of severe late rectal bleeding is increased above certain dose-volume thresholds."
* Wayne State Hyperfractionation PMID 8621290 -- Hyperfractionated conformal radiotherapy in locally advanced prostate cancer: results of a dose escalation study. (1996 Forman JD, Int J Radiat Oncol Biol Phys 1996; 34:655-62.)
** 25 patients with locally advanced PCA treated to 78 Gy at 1.3 Gy bid in 6 weeks, followed by 24 patients treated to 82.8 Gy at 1.15 Gy bid in 7 weeks; 30-month follow-up
** 30-month toxicity: Grade II rectal 17%, Grade II GU 16%, no Grade III/IV
** 12-month outcome: 84% had PSA <= 4; and 53% < or = 1 ng/ml; 71% had post-RT biopsies that were either negative (55% or showed a marked therapeutic effect (16%).
** Conclusion: "The use of hyperfractionated conformal radiotherapy facilitated dose escalation with no increase in chronic toxicity compared to standard doses. The initial tumor response based on prostate specific antigen measurements and postradiation biopsies is highly encouraging. Based on these results, an increase in dose to 87.4 Gy has been planned according to the schema of this ongoing dose escalation study."

## Retrospective

* Multi-institutional (1994-5) PMID 15667961 -- Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: the combined experience of nine institutions in patients treated in 1994 and 1995. (2005 Kupelian P, Int J Radiat Oncol Biol Phys. 2005)
** 1325 patients, 1061 treated with <72 Gy and 264 with >=72 Gy during 1994 and 1995
** Conclusion: "With similar follow-up duration, higher than conventional radiotherapy doses were associated with improved PSA-DFS when controlled for the influence of pretreatment PSA levels, biopsy GS, and clinical T stage."
* Michigan PMID 12957249 -- Dose escalation for localized prostate cancer: substantial benefit observed with 3D conformal therapy. (2003 Symon Z, Int J Radiat Oncol Biol Phys 2003; 57:384-90.)
** Retrospective review of 1473 patients treated with 3D-CRT (1987-2000); median follow-up 35 months
** Intermediate risk patients (T1-T2 and GS 7 or PSA 10-20): each 1-Gy increment in total radiation dose was associated with a highly significant 8% reduction in the probability of failure (hazard RATIO = 0.92, p = 0.005).
** Conclusion: "Dose escalation using 3D-CRT significantly reduces the risk of biochemical/disease failure among intermediate-risk prostate cancer patients."
* RTOG (1975-92) - PMID 10894874 (Full text) — Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials. (2000 Valicenti R, J Clin Oncol. 2000 Jul;18(14):2740-6.)
** Retrospective analysis of 4 Phase III RTOG trials: 75-06, 77-06, 85-31, and 86-10. Included 1465 pts treated with RT alone (no hormonal therapy). Not randomized to dose.
** Doses: range 10 Gy - 77.7 Gy (median 68.4; 25-75% range, 66 - 70.2 Gy).
** Higher radiation dose associated with improved DSS and OS only for Gleason 8-10.
* Multi-institutional PMID 3198435 -- The effect of dose on local control of prostate cancer. (1988 Hanks GE, Int J Radiat Oncol Biol Phys. Dec;15(6):1299-305.)
** 1516 patients from three patterns of care outcome surveys retrospectively reviewed
** Stage A (168 patients): no dose-response
** Stage B (725 patients): dose 60-70Gy appropriate; dose <60Gy significant increase in local failure; dose >70 Gy no demonstrable improvement in local control, but increase in complications
** Stage C (624 patients): appear to require dose >= 70 Gy
** Conclusion: "The policy of treating all stages of prostate cancer with the same dose is not supported by these data."
* Memorial Sloan Kettering Cancer Center, 2003 (1988-2001).
** 1684 pts. 3D-CRT. Dose increased from 64.8 to 86.4 Gy by 5.4 Gy increments.
** PMID 14571409 — "Technological Advances in External-Beam Radiation Therapy for the Treatment of Localized Prostate Cancer." Leibel SA et Al. Semin Oncol 30:596-615.
** Results:
*** Late Toxicity (Grade III)
**** Group 64.8-70.2 Gy -- 3% (364 pts)
**** Group 75.6-81 Gy -- 2.2% (507 pts)
**** Group (only IMRT)>=81 Gy -- 1.4% (772 pts )
*** PSA relapse free survival
**** -Favorable(F) ;-----Intermediate(I); unfavorable (U)
***** group 64.8-70.2 Gy -- 65% (F) ; -- 44%(I);--22%(U)
***** group 75.6 Gy -- 86% (F) ; --61%(I);--43%(U)
***** group 81-86.4 Gy -- 96% (F); --87%(I);--69%(U)
* Fox Chase Retrospective Dose-Response Update Abstract, Pollack, JUrol 2004
** 839 patients, 3D-CRT, 63-month median follow-up, retrospective
** RT analyzed as categorical (dose groups <72, 72-75.9 and >=76 Gy) variable
** Conclusion: RT dose escalation to 76 Gy or greater improved patient outcome for all prognostic groups except those at the favorable (PSA <10 and Gleason 2-6) and unfavorable (PSA >20 and stage T3-T4) extremes.
* Fox Chase Retrospective Lymph Node Risk Study Abstract Jacob, IJRBOP 2005
** 420 patients, >15% risk of LN+ (but negative radiologically), 3D-CRT to whole pelvic (WP), partial pelvic (PP), or prostate only (PO) fields. +/- short term androgen deprivation. Median follow-up 43 months
** RT analyzed as categorical (dose groups <73, 73-76.9 and >=77 Gy) variable
** 5-year FFBF rate by dose group was 48% for <73 Gy, 64% for 73-76.9 Gy, and 74% for >=77 Gy (p = 0.002).
** Conclusion: The radiation dose was the most significant determinant of FFBF in patients with a lymph node risk >15% in the patient population studied. These data suggest that the primary tumor takes precedence over lymph node coverage or the use of STAD. Doses >70 Gy are of paramount importance in such intermediate- and high-risk patients.

## Biology

* Fox Chase; 2007 PMID 17398026 -- "What dose of external-beam radiation is high enough for prostate cancer?" (Eade TN, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):682-9. Epub 2007 Mar 29.)
** Dose modeling. 1530 consecutive patients, treated 1989-2002 with 3D-CRT. Four isocenter groups <70 Gy (3%), 70-75 Gy (36%), 75-80 Gy (37%), and >80 (24%)
** Outcome: Adjusted 5-year Phoenix bNED 70%, 81%, 83%, 89%. 10-year FFDM 93%, 93%, 95%, 96%. Dose-response curve increasing benefit >80 Gy
** Conclusion: Doses >=80 Gy recommended for most men with prostate cancer
* MD Anderson
** Low/Intermediate risk; 2005 PMID 15752878 -- Dose-response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy. (Cheung R,Int J Radiat Oncol Biol Phys 2005; 61:993-1002.)
*** 235 low-risk (<=T2a, PSA<10, GS<=6) and 387 intermediate-risk (T2b-c, PSA 10-20, GS=7) treated with EBRT 1987 - 1998
*** Low risk: TCD(50): ASTRO def 57.3Gy, dose-response using ASTRO but not using CN+2 definitions. The dose-response curves essentially plateaued at 78 Gy
*** Intermediate risk: TCD(50): ASTRO def 67.5Gy, CN+2 def 57.8Gy
*** Most benefit seen by patients with PSA >7.5
*** Conclusion: Marginal improvement for Phoenix failure definition; little gain with doses >78 Gy for low risk patients. Dose-response for intermediate-risk patients
** High risk; 2003 PMID 12873666 -- "Dose-response for biochemical control among high-risk prostate cancer patients after external beam radiotherapy." (Cheung R, Int J Radiat Oncol Biol Phys 2003; 56:1234-40.)
*** 363 high risk patients (T3, PSA >20, GS 8-10) treated with EBRT 1987-1998.
*** TCD(50) was 75.5Gy; Gamma50 was 1.7. 78 Gy dose at the steep portion of dose-response curve. 78 Gy -> 83 Gy may improve PSA control by 10%
*** Conclusion: Benefit to dose escalation in this group.
* MSKCC PMID 12065099 -- "Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer." (Levegrun S, Radiother Oncol. 2002)
** Failure determined by post-treatment prostate bx >2.5 years after treatment
** TCD(50) for high risk patients is ~10Gy higher than for low risk patients (~65Gy vs. ~75Gy)
** TCD(95) is 78Gy, 83Gy, and 88Gy for low, intermediate and high risk groups
** Gamma50 for the entire cohort is 2.9, but increases to ~5 for risk groups stratified by 2-3 factors. This supports that the shallowness of overall RT dose-response is a summation of steeper subgroups
** Conclusion: "Dose-response of prostate cancer, quantified by TCD(50) and gamma(50), varies by prognostic subgroup."
* Multi-institutional PMID 7607946 -- "Radiation dose-response of human tumors." (Okunieff P, Int J Radiat Oncol Biol Phys 1995; 32:1227-37.) using data published in PMID 3967982 -- "Patterns of care studies: dose-response observations for local control of adenocarcinoma of the prostate." (Hanks GE, Int J Radiat Oncol Biol Phys. 1985 Jan;11(1):153-7.)
** 574 patients treated 1973-1975; failure determined by DRE and at that time standard imaging
** T1: TCP(50) 28.34Gy; Gamma50 1.00; optimal control at <=60Gy
** T2: TCP(50) 45.18Gy; Gamma50 1.16; optimal control at 60-65Gy
** T3: TCP(50) 46.29Gy; Gamma50 0.95; optimal control at 65-70Gy
** T4: TCP(50) 41.78Gy; Gamma50 0.60; optimal control at >70Gy
** Conclusion: "A change in institutional policies to treat with optimal doses as indicated by this study would result in an overall increase in local control and a decrease in complications."
* PMID 7410129 -- Irradiation of carcinoma of the prostate localized to the pelvis: analysis of tumor response and prognosis. (1980 Perez CA, Int J Radiat Oncol Biol Phys. 1980 May;6(5):555-63.)

## Conventional EBRT

Excessive toxicity with conventional RT:
* Netherlands (1983-85) - PMID 2298625 — "Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose." Smit WG et al. Int J Radiat Oncol Biol Phys. 1990 Jan;18(1):23-9.
** 2-yr incidence of moderate or severe proctitis was <22% for 70-75 Gy but increased to 60% when the dose at the anterior rectal wall was > 75 Gy.

## Dose Escalation and ADT

See also: Adjuvant ADT
See also: Localized Prostate Cancer (Dose Escalation vs ADT)
* GICOR; 2005 (Spain)(1999-2001) PMID 16170164 -- "Risk-adapted androgen deprivation and escalated three-dimensional conformal radiotherapy for prostate cancer: Does radiation dose influence outcome of patients treated with adjuvant androgen deprivation? A GICOR study." (Zapatero A, J Clin Oncol. 2005 Sep 20;23(27):6561-8.)
** Prospective, nonrandomized. 416 patients assigned to low, intermediate, and high risk groups. Low risk: 3D-CRT only; Intermediate risk: 3D-CRT and 4-6 months ADT; High risk: 3D-CRT and 2 years ADT. RT dose varied per institution (median 72 Gy, 64.8-82.6). Median F/U 3 years
** Outcome: 5-year bDFS low risk 80%, intermediate risk 73%, high risk 79%.
** By dose (<72 vs. >=72 Gy): low risk (no ADT) 66% vs. 96% (SS); intermediate risk (ST-ADT) 56% vs. 94% (NS); high risk (LT-ADT) 63% vs. 84% (SS)
** Conclusion: Additional benefit of high-dose (>=72 Gy) when combined with ADT

## Patient Preference

* Nijmegen, Netherlands
** Prospective. 150 patients with T1-3N0 prostate cancer. Asked if they wanted to choose dose, and if so what dose (70 Gy vs 74 Gy). Decision aid used to show higher cure but higher toxicity for 74 Gy dose. Control group of 144 treated with fixed dose without choice. Follow up at baseline, after choice, at 2 weeks and 6 months after RT completion
** 2008 PMID 17765404 -- "Offering a treatment choice in the irradiation of prostate cancer leads to better informed and more active patients, without harm to well-being." (van Tol-Geerdink, Int J Radiat Oncol Biol Phys. 2008 Feb 1;70(2):442-8. Epub 2007 Aug 31.)
*** Outcome: Involved group increased participation (SS), increased knowledge (SS), improved risk perception (SS), higher satisfaction with quality of information (SS), and appropriateness of treatment (SS). No difference in well-being
*** Conclusion: Offering a choice with decision aid led to better-informed patient; no overall impact on well-being
** 2007 PMID 17634489 -- "Doctors' and patients' preferences for participation and treatment in curative prostate cancer radiotherapy." (Stalmeier PF, J Clin Oncol. 2007 Jul 20;25(21):3096-100.)
*** Physicians gave substitute judgments (their estimate of what the patient would want) after initial consultation, but prior to patient decision
*** Outcome: MDs believed 66% wanted to choose (vs. actual 79%). Lower dose favored by 20% of physician preference, 51% of physician substitute preference, and 71% of patient preference (SS)
*** Conclusion: Physicians had problems predicting patient preference, and underestimated patients preference for less toxic treatment
** 2006 PMID 17008699 -- "Do patients with localized prostate cancer treatment really want more aggressive treatment?" (van Tol-Geerdink JJ, J Clin Oncol. 2006 Oct 1;24(28):4581-6.)
*** Outcome: 79% wanted to choose dose. In these, 75% chose lower dose. Lower dose chosen more often by older, low-risk, no hormone, or low anxiety/depression score
*** Conclusion: Most patients with localized PCA prefer lower radiation dose; many patients attach more weight to QoL aspects than improving survival