LA RT NEL PAZIENTE AD ALTO RISCHIO E CON

RECIDIVA BIOCHIMICA

Alessio G. MorgantiIV meeting urologico

RT dose-effect

Creak A et al. Br J Cancer 2013

random trial:

126 patients

med. FUP: 13.7 years

T1b-T3b

neoadjuv. ADT + 3D-RT

64 Gy vs 74 Gy

1.0 vs 1.5 cm margin

64 vs 74 Gy:

no differences in:

PSA control

PC-specific surv.

OS

1.0 vs 1.5 cm:

no differences

Dearnaley DP et al. Lancet Oncol 2014

random study (RT01):

862 patients

med. FUP: 10 years

T1b-T3a

neoadjuv. ADT + 3D-RT

64 Gy vs 74 Gy

64 vs 74 Gy:

BDFS: 43% vs 55%

p=0.0003

OS: 71% vs 71%

p=0.96

Hou Z et al. J Cancer Res Clin Oncol 2014

metanalysis:

6 randomized trials

higher vs convent. dose

prolonged follow-up

2822 patients

3D-CRT

higher dose:

> BDFS

= OS

= PCSS

> G > 2 GI late tox.

> G > 2 GU late tox.

Ghadjar P et al. J Clin Oncol 2015

SAKK 09/10 random trial:

resected PC with BF

salvage RT: 64 vs 70 Gy

350 pts

G3 acute GU toxicity:

0.6% vs 1.7% (p:0.2)

G3 acute GI toxicity:

0.6% vs 2.3% (p:0.8)

70 Gy: > urinary symptoms

Denham JW et al. Radiother Oncol 2015

TROG 03.024 RADAR

randomized trial:

impact on loc. progr. (LP)

dose: 66, 70, 74 Gy +/-

BRT boost

ADT: 6 vs 18 months (±

zoledronate)

both > dose & > ADT

(independently):

< LP

> urethral strictures

hypofractionation

Pollack A et al. J Clin Oncol 2013

randomized trial:

favorable to high risk

303 pts

med. FUP: 68.4 mts

76/2 Gy vs 70.2/2.7 (84.4 Gy)

high risk LT ADT

standard vs hypofr. < treatm. time 2.5 wks

5-y-BCDF: 21.4% vs 23.3%

= late toxicity

< urinary funct. with HF in

pts with < urinary function

Botrel TE et al. Core Evid 2013

metanalysis:

9 studies

hypofract. vs standard

2702 patients

hypofractionation:

= BF

> acute GI toxicity

= acute GU toxicity

= late toxicity

Norkus D et al. Radiation Oncol 2014

randomized trial:

interim analysis: 124 pts

high risk PC 76 Gy (2 Gy/fr.) vs

63 Gy (3.15 Gy/fr., 4 fr/w)

LT adjuvant ADT

hypofractionation:

earlier toxicity

earlier recovery

> G>1 GU acute tox

Hoffman KE et al. Int J Radiat Oncol Biol Phys 2014

randomized trial:

low-intermediate risk

203 pts

med. FUP: 6 yrs

75.6/1.8 Gy vs 72/2.4

standard vs hypofract.

5-yrs grade > 2 tox.: GU 16.5% vs 15.8% (p: NS)

GI: 5.1% vs 10.0% (p: NS)

Koontz BF et al. Eur Urol 2014

systematic review:

6 studies

superiority designed

standard vs moderate HF

= BDFS

= late GI toxicity

= late GU toxicity non-inferiority studies pending

Wilkins A et al. Lancet Oncol 2015

CHHiP randomized

(non-inferiority) trial:

2 year PROs,

74 Gy (37 fr) vs 60 GY (20 fr)

vs 57 Gy (19 fr)

VCLA-PCi, FACT-P, EPIC

2100 pts in QOL sub-study

no difference in bowel scores

if same efficacy:

hypofractionation not inferior

Aluwini S et al. Lancet Oncol 2015

HYPRO randomized trial

(non-inferiority):

820 pts: IR-HR PC

78 Gy (2 Gy/fr) vs 64.6 GY (3.4 Gy/fr)

G>1 acute GI toxicity. standard : 31.2%

hypofr: 42.0% (p:.0015)

hypofractionation is not

non-inferior to standard

RT technique

Heemsbergen WD et al. Radiother Oncol 2013

randomized study: rectang. vs conform. fields

164/266 high risk pts

FUP: 34 months

66 Gy to: prost. + sem. vesc. + 1.5 cm

clinical failures:

rectangular: 9

conformal: 24

p: 0.012

failures out of prostate

rectangular: 7

conformal: 19

p: 0.025

Mariados N et al. Int J Radiat Oncol Biol Phys 2013

randomized study: 222 T1-2 PC

perirectal spacer injection vs not

RT: 79.2 (1.8 Gy/fr)

hydrogel placement:

success rate: 99%

V70Gy: 12.4%3.3% (p<0.001)

< acute rectal pain (p:0.02)

< late rectal toxicity (p:0.04)

Michalski JM et al. Int J Radiat Oncol Biol Phys 2013

randomized trial: RTOG 0126

763 pts

79.2 Gy

3D vs IMRT

IMRT < acute tox G>2 GU/GI

= acute G>2 GU tox

= late GU/GI tox

Bruner DW Cancer 2015

RTOG 0126 random trial: 763 pts

PRO, scores: FACE, IIEF

3D: 55.8 Gy to prostate + SV

23.4 Gy to prostate

IMRT: 79.2 Gy to prostate and SV

IMRT:

significant < of dose/volume

no differences in FACE & IIEF

Blanchard P et al. Int J Radiat Oncol Biol Phys 2016

secondary analysis of :

GETUG 12 randomized

trial:

358 pts receiving ADT (3

years) or ADT + docetaxel

+ estromustine + RT ± ENI

ENI

no difference in bPFS

even in pN0 pts

no difference in

toxicity

Habl G et al. Int J Radiat Oncol Biol Phys 2016

randomized phase II trial: 92 pts: localised PC

protons vs carbon ion

66 Gy (RBE) in 20 fractions

comparable acute tox. & QoL

urinary cath. during RT: 8%

2 G3 rectal fistula (protons)

organ motion

Ki Y et al. Int J Radiat Oncol Biol Phys 2013

randomized trial:

40 pts:

78/2 Gy, tomotherapy

probiotic lactobacillus

acidophilus vs placebo

probiotic group:

rectal volume

< median value

< % volume change

den Harder AM et al. Strahlenther Onkol 2014

randomized trial:

92 pts:

77/2.2 Gy, IMRT

magnesium oxide vs placebo

no differences:

prostate motion

rectal filling

rectal air pockets

magnesium oxide:

not recommended

hormonal therapy

Mason M et al. Clin Oncol (R Coll Radiol) 2013

randomized trial

244 pts

T2b-4

NA ADT: degarelix vs

goserelin + bicalutamide

degarelix: = prostate shrinkage

> urinary symptom relief

in symptomatic patients

Denham JM et al. Radiother Oncol 2013

randomized trial

TROG 9601

802 pts, T2-4N0

T2b-4

NA ADT:

NO vs 3 months vs 6 months

incidence of dist. failures

first 4 years FUP

DF: 39, 40, 26

subsequently

DF: 25, 20, 11

mets not prevented by 3 mo NA ADT

Mydin AR et al. Int J Radiat Oncol Biol Phys 2013

randomized trial

4 vs 8 months NA HT

secondary analysis

salvage HT, 3 groups:

A: PSA < 10, M0

B: PSA > 10, M0

C: M1

OS from: enrol. - 10-year:

A: 78%

B: 42%

C: 29%

salvage HT – 6-year: A: 70%

B: 47%

C: 22%

p: < 0.0005

Denham JW et al. Lancet Oncol 2014

TROG 03-04 RADAR

random:

6 (STAS) vs 18 (ITAS) mo ASD

± 18 mo zoledronic acid (ZA)

1071 pts loc. adv. PC

PC mortality: STAS: 4.1%, STAS ZA: 7.8%, ITAS:

7.4%, ITAS + ZA: 4.3% (p:NS)

STAS + ZA: > risk of bone PD

compared to STAS

ITAS + ZA: < secondary

interventions compared to STAS

Mason MD J Clin Oncol 2015

NCIC PR3/MRC PR07

randomized trial:

1205 pts locally advanced PC

life long ADT ± RT (64-69)

ADT + RT:

> OS: HR: 0.70, 95% CI: 0.57-0.85

< death PC: HR: 0.48, 95%

CI: 0.35-0.61

Brundage M et al. J Clin Oncol 2015

NCIC CTG PR3/MRC PR07

randomized trial:

1205 pts with loc. adv. PC

ADT vs ADT + RT

RT:

improved OS

6 months: > diarrhea, <

urinary function, > erectile

dysfunction

3 years: no differences

Pisansky TM et alJ Clin Oncol 2015

RTOG 9910 randomized

trial:

1579 pts: IR PC

8 ws ADT RT + 8 ws ADT vs

8 wks ADT RT + 28 ws ADT

8 vs 28 wks ADT:

10 year LF: 6% vs 4%

(p:0.07)

10 year DM: 6% vs 6%

(p:0.8)

10 year BF: 17% vs 27%

(p:0.77)

Zapatero A et al. Lancet Oncol 2015

DART 01/05:

355 pts IR or HR PC

3D-CRT (76 Gy) + 4 mo

vs 28 mo of ADT

long term ADT:

> 5y-bRFS: 90% vs 81%

(p:0.01)

> 5y-OS: 95% vs 86%

(p:0.009)

> 5y-MFS: 94% vs 83%

(p:0.01)

James ND et al. JAMA Oncol 2016

secondary analysis of:

control ARM of randomised STAMPEDE

trial

721 pts with HR PC

hormonal therapy +/- RT

failure-free survival:

better in RT pts:

N0: HR 0.33 (95% CI: 0.18-0.61)

N1: HR 0.48 (95% CI: 0.29-0.79)

Voog JC et al. Eur Urol 2016

secondary analysis of

RTOG 94-08 trial:

1979 pts, localized PC

RT vs RT + ADT (4 mo)

evaluation of cardiovasc.

mortality (CVM)

ADT: improved OS

10 year CVM

RT: 11.0%

RT + ADT: 10.0%

adjuvant chemotherapy

Sandler HM et al. ASCO 2015

RTOG 0521 random:

RT + ADT vs

RT + ADT + docet. + predn.

562 evaluable pts with

G5 7-8 & PSA >20 or

GS 9-10

RT + ADT + chemo

> 4y-OS: 93% vs 89%

(p: 0.03)

acceptable toxicity

Rosenthal SA et al. Int J Radiat Oncol Biol Phys 2016

NRGOncology/RTOG 9902:

397 pts with HR PC

RT + ADT vs RT + ADT + CT

CT: paclit/estram/etopos.

> thromboemb. in CT arm

early closure of trial

10 year OS: 65% vs 63% (p: 0.81)

BF: 58% vs 54% (p: 0.82)

DFS: 22% vs 26% (p:0.61)

erectile disfunction

Ilic D et al. J Med Imaging Radiat Oncol 2013

randomized study

27 pts

Sildenafil for 6 months

after RT

International Index of

Erectile Function (IIEF)

IIEF:

improved @:

4 weeks

6 months

no differences @:

2 years

Yang L et al. Urol Int 2013

systematic review: 4 randomized studies

phosphodiesterase-5 inhibitors

treatment of erectile disfunction

after RT

PDE5: improved:

IIEF

Global Efficacy Questions

Sexual Encounter Profile

side effects:

mild to moderate

Pisansky TM et al. JAMA 2014

randomized study

242 pts

Tadalafil for 24 weeks

starting with ERT or BRT

IIEF:

not improved @:

28-30 weeks

12 months

Zelefsky MJ et al. J Urol 2014

randomized study

279 pts

Sildenafil for 6 months

from 3 days before RT

@ 2 years

IIEF:

no differences

functional erection +/- medication:

Sildenalfil: 81.6%

Placebo: 56.0%

> sexual desire

radiation proctitis

Yeoh E et al. Int J Radiat Oncol Biol Phys 2013

randomized study: 30 pts with

intractable rectal bleeding

argon plasma coagulation vs

topical formalin

end-point:

< 1 bleeding/month

VAS < 25/100

no need of transfusion

endpoint achieved:

APC: 94%

topic formalin: 100%

comparable efficacy

Nascimiento M et al. Int J Radiat Oncol Biol Phys 2014

randomized study: 20 pts with

3D-CRT

Lactobacillus reuteri symbiotic powder

vs placebo

EORTC QLQ-PRR23

symbiotics during RT:

< proctitis symptoms

> QoL

Chruscielewska-Kiliszek MR et al. Colorectal Dis 2013

randomized study: 122 pts with

chronic emorragic RT proctitis

argon plasma coagulation +

oral sucralfate vs placebo

in both groups:

severity score:

4 2

bleeding score:

2 0

APC safe & effective

clin. & endosc. results not affected by sucralfate

Maggio A et al. Int J Radiat Oncol Biol Phys 2014

randomized study: 166 pts

sodium butirate enemas vs placebo

during RT + 2 weeks

no differences:

proctitis

incidence,

severity

duration

endoscopic data

predictive factors

Cury FL et al. Cancer 2013

RTOG 9413: 1070 pts

@ the end of ST ADT + RT

PSA-CR (PSA < 0.3 mg/mL)

pts without PSA-CR:

< diseas.-spec. surv.

> distant mets

> bioch. failures

LT ADT?

Verhoven B et al. Int J Radiat Oncol Biol Phys 2013

RTOG 9408

468 pts

low-intermediate risk

RT +/- ST ADT

Ki-67 staining index

high Ki-67 SI (>Q3):

< DSS

> DM

> BF

stratification factor

in future trials

surgery versus radiotherapy

Van Tol-Geerdink JJ et al. BJU Int 2013

240 pts

eligible for RP or RT

randomized:

usual care

decision aid

treatment choice:

hospit.& decision aid

RP remained preferred

decision aid

> brachytherapy

< undecided

Petrelli F et al. Clin Genitourin Cancer 2014

RP vs RT:

metanalysis 17 studies:

16 retrospective

1 randomized

evaluated:

OS, PCSM, non-PCSM, BF

RP:

= BF

> OS

> PCSM

> non-PCSM

Lennernas B et al. Acta Oncol 2015

swedish multicenter random trial

89 pts: T1b- T3a, N0

PSA ≤ 50

RP vs RT (EBRT + HDR boost)

+ 6 months TAB

no differences in:

health related QoL

complications

• > dose > BDFS = survival

• hypofractionation = BDFS > toxicity?

• RT technique: probiotics < organ motion

• NAD ADT: 6 mo > 3 mo

• early salvage ADT: useful in terms of OS

• proctitis: APC effective

• new predictive factors: Ki-67, PSA-CR

summary