Hypofractionation for Prostate Cancer: the Present Luca Incrocci, MD PhD Professor of Genito-Urinary Radiotherapy Erasmus MC Cancer Institute Rotterdam, The Netherlands Themadag Prostaatcarcinoom 15 maart 2018
Outline What is hyprofractionation Why hyprofractionation The Dutch HYPRO trial Recent hypofractionation trials Take home messages
External-Beam Radiotherapy (EBRT)
Hypofractionation What is it and Why? Hyprofractionation: Decrease of the total dose by increasing the fraction dose PCa has extremely low proportion of cycling cells, with low potential doubling time (40 days vs 5 of other tumours) Haustermans KM et al. IJROBP 1997;37:1067-1070 Disparity between PCa cells and late complications widens the therapeutic window by hypofractionation Reduced number of fractions improves patient comfort
95% 85% 68% 82% Late GU and GI toxicity Grade 2 similar
N=303 38x2 vs 26x2.7 Gy
The HYPRO Trial
The HYPRO Trial Purpose To detect an absolute reduction of 10% of the relapse rate at 5 years in the hypofractionation arm (19x3.4 vs 39x2 Gy) To demonstrate the non-inferiority of the hypofractionated schedule with respect to the cumulative incidence of grade 2 acute and late toxicity (8% difference)
The HYPRO Trial Inclusion and Exclusion Criteria Histologically proven adenocarcinoma of the prostate No evidence of node or bone metastases WHO performance status 0-2 Intermediate and high risk PCa: T1b-T4, Gleason score 6, PSA 60 ug/l 3 risk groups according to seminal vesicle involvement Low risk excluded (T1c-2a and Gleason 3+3 and PSA 10 ug/l) Concomitant hormonal therapy according to local protocols
The HYPRO Trial End-points 1. Relapse-Free Survival (RFS), either biochemical (Phoenix definition), clinical, loco-regional or distant, or start of hormonal treatment 2. Acute and late gastro-intestinal (GI) and genito-urinary (GU) toxicity by using the RTOG/EORTC scoring system 3. Highest score registered from both CRFs and patient questionnaires 3. Quality of life by using the EORTC-PR25 prostate module and the International Index of Erectile Function (IIEF) 4. Alpha=0.05 level of statistical significance
The HYPRO Trial Inclusion March 2007-December 2010 Fiducials, IMRT 3-10mm CTV to PTV Boost: 0mm to the rectum, 3-5mm in other directions
22% 13% Acute GI Toxicity Acute GU Toxicity GI: 42% in HF vs 31% in SF
The HYPRO Trial Late toxicity Cumulative percentage 100 A N 387 F 172 190 SF HF 395 Logrank P =0.16 100 B N 387 F 82 SF HF 395 96 Logrank P =0.26 75 75 50 25 HF SF 50 25 HF SF 0 SF HF 0 12 24 36 48 mon. 60 At risk: 387 395 301 282 254 240 208 208 166 172 97 102 0 SF HF 0 12 24 36 48 mon. 60 At risk: 387 395 362 360 320 309 276 274 230 232 131 141 GU Grade 2: 39% in SF vs 41% HF (p=0.16) GI Grade 2: 18% SF vs 22% HF (p=0.26) Aluwini S et al. Lancet Oncol 2016;17:464-474
The HYPRO Trial Late toxicity: Grade 3 SF N (%) HF N (%) p-value SF HF p-value Pain needing medications Bleeding needing treatments Frequency at day 16 Frequency at day 32 Frequency at night 4-6 56 (14 5%) 68 (17 2%) 0 33 9 (2 3%) 12 (3 0%) 0 66 30 (7 8%) 40 (10 1%) 0 26 5 (1 3%) 8 (2 0%) 0 58 75 (19 4%) 92 (23 3%) 0 19 Pain needing medications Diarrhea needing medications 31 (8 0%) 32 (8 1%) 1 00 9 (2 3%) 6 (1 5%) 0 44 Frequency 6 13 (3 4%) 27 (6 8%) 0 03 Use of pads 45 (11 6%) 63 (15 9%) 0 09 Frequency at night 6 5 9 (1 3%) 24 (6 1%) <0 001 Incontinence 46 (11 9%) 58 (14 7%) 0 29 Incontinence 52 (13 9%) 75 (19 7%) 0 04 Bleeding needing ACT* 9 (2 3%) 18 (4 6%) 0 11 GU 19% in HF vs 13% in SF GI 3% in both arms Aluwini S et al. Lancet Oncol 2016;17:464-474
The HYPRO Trial Relapse-Free Survival Relapse free survival (RFS) 100 75 80% Hypro Standard 77% 50 25 0 Standard Hypro N Standard 397 Hypro 407 Logrank P =0.36 At risk: 397 407 386 384 F 89 80 0 12 24 36 48 mon. 60 356 350 314 309 HR= 0.86 (95% CI 0.63-1.16) 247 254 127 142 Incrocci L, Wortel RC et al. Lancet Oncol 2016;17:1061-1069
The HYPRO Trial Overall Survival Over all survival (OS) 100 75 Standard Hypro 86% 50 25 0 Standard Hypro N Standard 397 Hypro 407 Logrank P =0.92 At risk: 397 407 391 396 F 59 61 0 12 24 36 48 mon. 60 382 384 354 360 Incrocci L, Wortel RC et al. Lancet Oncol 2016;17:1061-1069 306 311 177 185
J Sex Med 2016;13:1695-703
The HYPRO Trial Conclusions The hypothesized superiority of the hypofractionated treatment regimen (19x3.4 Gy) over conventional treatment (39x2 Gy) could not be confirmed (absolute increase in RFS <10%) The use of long-term (>12 mos) ADT might have obscured potential differences between study arms Acute (at 3 mos) and late Grade 2 toxicity (end points) for both GU and GI was not different Late grade 3 toxicity was higher in the hypofractionation arm as regarding urine incontinence (20 vs 14%), nocturia (6 vs 1%), and stool frequency (7 vs 3%).
The HYPRO Trial Conclusions (cont d) Baseline symptoms equal to Grade 2 RTOG-EORTC toxicity scores were the strongest baseline predictor of acute and late toxicity 19 fractions of 3.4 Gy can be offered to intermediate- and high risk patients with limited GU and GI baseline symptoms Although the hypofractionated schedule shows no superiority over conventional treatment, reduction in fractions means a step forward in patient s comfort 18-03-2016: Landelijk Platform voor Radiotherapie van Urologische Tumoren (LPRU) "Bij uitwendige bestraling voor het prostaatcarcinoom kan er in overleg met patiënt gekozen worden voor het hypofractioneren (19x3.4 Gy) volgens de HYPRO trial. Dit schema geeft vergelijkbare uitkomsten met mogelijke toename van toxiciteit (max 10%)"
Non-inferiority; n=3216 pts T1b-3a; Seminal vesicle invasion <30%; PSA 30 ug/l 37x2Gy; 20x3Gy; 19x3Gy ADT short-course recommended intermediate-high risk End-point: Progression at 5 yrs Late Toxicity Grade 2, clinician reported, 5 yrs GI 74Gy: 13.7% 60Gy: 11.9% 57Gy: 11.3% GU 74Gy: 9.1% 60Gy: 11.7% 57Gy: 6.6% Grade 3: < 1%
88.3% 90.6% 88.3% 85.9%
J Clin Oncol 2017;35:1-7 n=1206, non-inferiority Intermediate risk, no ADT: T1-2a, Gleason 6, PSA 10-20ug/L T2b-2c, Gleason 6, PSA 20 ug/l T1-2, Gleason 7, PSA 20ug/L 39x2 Gy vs 20x3 Gy, 5 weekly fractions Follow-up: 6 yrs
Catton CN et al. J Clin Oncol 2017;35:1-7
Catton CN et al. J Clin Oncol 2017;35:1-7
J Clin Oncol 2016;34;2325-32 86% 85% RTOG 0415 n=1092, low risk 41x1.8Gy (73.8) vs 28x2.5 Gy (70) Follow-up 5.8 yrs Late Grade 2 Toxicity: GU 22% vs 30%, and GI 14% vs 23%
Fonteyne et al Interim analysis, phase III, GI acute toxicity end point n=160, T1-4 R: arm A 16x3.5 (56) Gy 4/weekly vs arm B 25x2.68 (67) Gy 5 weekly
Take Home Messages Hypofractionation as effective as conventional fractions Improved treatment outcome? Toxicity is similar to standard regimens Patient selection is paramount Is slight increased toxicity clinically relevant? Less expensive Improves patient comfort