Posibilităţi şi limite ale radioterapiei în

cancerul de prostata

Gabriel KACSÓ

UMF „Iuliu Hatieganu”, Cluj-Napoca;

RTC Amethyst Cluj;

Rezi curs 2020

 Radioterapia
• Radioterapie externa (RTE)
– Fotoni (3D conformal  IMRT SBRT)
– Protoni or particule grele (ioni Carbon)

• Brahiterapie (BT)
– Low dose rate = LDR ( implant permanent 125I or 103
Pd)
– High dose rate = HDR (implant temporar 192Ir)

• Combo RTE + BT boost

1809 p, retrospective, US+ Norwaw
 LOW RISK RESULTS Weighted
>40 months follow-up or less than 100 patients

100
6851 50
68
97 66 2592 96
110 46 11314
27 ++ Seeds & ADT
22 13 8
3
75
2014 816 62 86
44 86
37 48
60
11435 LDR Brachy
% PSA Progression Free

203 6985 41 82 33 32 EBRT & ADT

90 HDR 98 89
71 33
6584 31 72 99 29 101 39103 11228 1067 111
61 93 42 94 95 16
93 18 88102 115
Treatment Success

105 24
19 47
38
73
54 36
43 55
5 EBRT & Seeds
78 2 26 64
202 58 40 12 83
Seeds 52
80 76 56 1 100
7 87 106 Robot RP
107 106
107 Surgery
104
Proton 77
77
70 80 9
EBRT 108
41
15 45 57 74 79
70 EBRT/IMRT 109 59 20

53
90 17
Surgery
63
CRYO
60 7
HIFU
1 2 3 4 5 6 7 8 9 10 11 12 13
34 14 15 Protons
← Years from Treatment → Hypo EBRT
91 49
11 HDR

• Prostate Cancer Results Study Group

• Numbers within symbols refer to references
06/01/2024 Update of 7
BJU Int, 2012, Vol. 109(Supp 1) Prostate Cancer Center of Seattle
 INTERMEDIATE RISK RESULTS weighted
>40 months follow-up or less than 100 patients

LDR SEEDS ALONE EBRT + ADT

100 54
10459 56
111
66 55 14 24 23 13 37 Robot RP
% PSA Progression Free

35
79
49 158 35
90 111 92
151 92 156 98
161 1544 96 153 F163 34 ++ Seeds + ADT
4 40
57
57 16
80 25 10930 36 45 68 69 38 58 EBRT & Seeds
HDR
99
99 77
Treatment Success

39 83
111105 152
82 97 612
107
42 73 27 Brachy
160
160
108 51 156 31 91
3 72 64 Hypo EBRT
43 Surgery
6218 6393 47
62 86 71 17
70 74 67 50 28 150
81 95 Seeds Alone
5 90 926 52 150 EBRT
152 78 70 7 155
103 29
65 EBRT & SEEDS
CRYO
157

60 76 102 41
411 154
60 100 159
48 32 HIFU
Surgery
110

48
85 88 53 8 87 2
75 10101 11 19
50 46
84
84
EBRT 8994
89 20
40 HDR
1 2 3 4 5 6 7 8 9 10 11 12 13
155 14 15
EBRT, Seeds +
← Years from Treatment →
21 ADT
80 22 Protons
• Prostate Cancer Results Study Group
• Numbers within symbols refer to references
06/01/2024 Update of 8
BJU Int, 2012, Vol. 109(Supp 1) Prostate Cancer Center of Seattle
 HIGH RISK RESULTS Weighted
>40 months follow-up or less than 100 patients

EBRT, Seeds & ADT

92 65
99 94 81 20 16 109
EBRT + Seeds Surg & EBRT
80 19 18
4 Surg & ADT
% PSA Progression Free

74 32 112 108 EBRT & ADT

78
137 22
123
123
136 122 67
123 17
55 123 131 EBRT & Seeds
Treatment Success

4075 112
125 44 85
3
7212454 60 4376 37
91 66 4134 135 127 47 Hypo EBRT
EBRT + ADT 711251364
79 68
68
48 128
48
2
59 10 114
134
114 42
57 104
50 56 1 12 24 28
53 25 132 136
8 61
90
90 32 110 9 89 133
101 113
EBRT 45 21 9345 36
62 113
106 12933 111
111 126
5 120
118 14
70 39 119 95
98 31 11
103 115 96
83 7 8226
35 6 138
52 63 36 84
116
130 Protons
73
73 30 58 27
77 46
88 86 87 107
102 15
HDR
51 105
23 29
← Years from Treatment
69 → Surgery EBRT Seeds +
ADT
49
Robot RP

• Prostate Cancer Results Study Group HIFU

• Numbers within symbols refer to references HDR + ADT
06/01/2024 Update of 9
BJU Int, 2012, Vol. 109(Supp 1) Prostate Cancer Center of Seattle
 PLAN
I. Escaladarea dozei

II. IMRT vs. 3D-CRT

III. Brahiterapia mono/ boost al RTE

 Tumor Monitorizarea pacientului in
Board timpul tratamentului si follow-up

Verificare
Stadiu radioterapie
cancer
Aplicare Radioterapie

Imagistica Lantul de Monitorizare

Securizare camp
tratament
radioterapeutic Auxiliare Radioterapie
Definirea volumului &
Identificarea organelor de Imobilizare
risc Markeri anatomici

Planificare
tratament Simulare
Miscarea organului / planificarea
marginilor Masuri pacient
Tehnic / selectie plan Masuri pozitionare in timpul tratamentului
Fascicule si intensitate Evaluari camp radioterapie
Calcul computerizat distributii
Optimizarea planului de tratament
 RT basic principles in the 3rd
millennium

1. TREAT what you SEE (GTV) + what might harbour microscopic disease (CTV):
in brachy CTV = whole prostate, GTV= boost to 150 % dose (or more for
brachy!)

2. SEE what you TREAT(= IGRT): in brachy = real time ultrasound/ MRI fusion

3. Control target (prostate) movements (CTV PTV): for brachy CTV= PTV
- target moves together with the radioactive source(s)
 Premize: imagistica de incredere
(RMN mp, PET-CT, fuziune de imagini...)
Better imaging- Dose painting/ sculpting
Moriggi et al, J Nucl Med 2015

Much lower detection

rates than previously
reported

Afshar Oromieh et al, Eur J

Nucl Med Mol Imaging 2014
 PLAN
I. Escaladarea dozei

II. IMRT vs. 3D-CRT

III. Brahiterapia HDR vs. LDR

 Phase III Dose Escalation Trials
Randomized Dose Escalation Trials
ADT Freedom from Subgroup
Trial/Author N (HT) Biochemical Failure Overall survival benefit
MD Anderson 73% v 50% 78% v 79%
301 No PSA>10
Kuban (2011 IJROBP) (10y, p=0.004) (8y, p=0.32)

GETUG 61% v 72%

306 No No difference PSA>15
Beckendorf (2011, IJROBP) (5y, p=0.036)

PROG 83% v 68% 78% v 83%

393 No All (low,Int)
Zietman ( JCO 2010) (10y, p=0.0001) (10y, p=0.41)

Netherlands
54% v 47% 75% v 75%
Al-Mamgani (2014, 664 Some Int, High
(7y, p=0.04) (7y, p=0.45)
Radioth& Oncol)
MRC
55% v 43% 71% v 71%
Dearnaley (2014, Lancet 843 All All
(10y, p=0.0003) (10y, p=0.96)
Oncol)

RTOG 70% v 55% 64% V 65%

1499 No Int risk
Michalski (2014) (10y, P<0.0001) (10y, p=0.98)

+ 15 %
Late GI/GU Toxicity from Phase III Conformal Dose Escalation Trials

Late ≥ grade Late ≥ grade

2 2
Trial/Author Dose GI Toxicity 2x GU Toxicity 1.5 x
MD Anderson 70Gy 13% 8%
p=0.013 p=ns
Kuban 2007 78Gy 26% 13%

GETUG 70Gy 14% 10%

Beckendorf 80Gy p=0.22 p=0.046
2005 20% 18%

70.2Gy
E 8% 18%
PROG
p=0.005 p=ns
Zietman 2005 79.2Gy
E 17% 20%

Netherlands 68Gy 25% 40%

Al-Mamgani 78Gy p=0.04 p=0.6
2008 35% 41%

MRC 64Gy 24% 8%

p=0.005 p=0.14
Dearnaley 2007 74Gy 33% 11%

RTOG 70.2Gy 16% 10%

p=0.0063 p=0.001
Michalski 2014 79.2Gy 22% 15%
Cresterea dozei control local mai bun
(919 p T1-3N0M0)

Kupelian PA et al. IJROBP 2008; 71: 16-22.

Cresterea dozei scad meta (la 7 ani):
9 vs. 6 vs. 1%

Kupelian PA et al. IJROBP 2008; 71: 16-22.

 Meta-analiza escaladarii dozei in
cancerul de prostata
• Viani, 2012  scade mortalitatea specifica...
but Int J Radiat Oncol Biol Phys. 2013 Mar 15;85(4):899.RETRACTED: High-dose conformal
radiotherapy reduces prostate cancer-specific mortality: results of a meta-analysis Int J
Radiat Oncol Biol Phys 2012;83:e619-e625

..pentru moment nu avem beneficiu de SV globala pentru escaladarea dozei prin

RTE.

- + Brachy (?)
- + HT (?)
- (+ CT) ?
 PLAN
I. Escaladarea dozei

II. IMRT vs. 3D-CRT

III. Brahiterapia HDR vs. LDR

 Beneficiul IMRT
izodoze “concave pe mijloc”

I. conformalitate mai mare pe “tinta”

II. protecţia ţ. Sănătoase
III. “boost-in-field” simultan (GTV/ CTV /PTV)
- D/fr mai mare  hipofractionare
- etalare mai scurta
- un singur plan (nu exista “MT”....)

 Doza mai mare cu toxicitate egala/mai mica

 Indicaţii IMRT
Cancere in zone cu mobilitate fiziologica mica
 cu corelatie doza-efect demonstrata!

1. Volume ţintă neregulate, cel puţin parţial concave

2. --//--- în proximitatea structurilor critice

3. --//-- în imediata vecinătate/ în zona deja iradiata

0 &1 & 2  (Tu cerebrale), ORL, (prostata)

3  Re-iradieri in intentie curativa
 Limitele IMRT
• Experienţă clinică relativ limitată  QA & QC!!!

• Volume mici cu doză mare vs. volume mari cu doză

mică  efecte pe termen lung “?”

• Multiplicarea cauze/ posibilitati de eroare (MLC,

algoritmi de calcul....)

• Incertitudinile de delimitare a vol. tinta si a org. risc

riscă să aibă un răsunet mai mare în:
– rata recidivelor
– rata complicaţiilor
 IMRT vs. 3DCRT
 Dozimetria (HDV) e mai buna

scade toxicitatea severa vs. aceeasi doza in

3DCRT, in analize retrospective
Tox (%) G2 GI G3 GI G2 GU G3 GU
“Standard 8- 23 1-2 6-18 1-8
dose”
2x
High-dose 7 - 30 1-7 10- 30 1- 15
(non-IMRT)
High-dose 1- 23 0- 3 (1 %) 9 - 23 0 – 6 (3%)
IMRT

Cahlon, Seminar in Radiation Oncology 2008

 (GTV) –CTV- PTV
Tinta Low risk intermediate High risk + very high
CTV1 P +/- prox SV P+ prox SV Idem + ECE (“GTV”T3-4)
 PTV: +1 cm/ 0.5 cm post 76 Gy/38 fr 78 Gy/39fr 76- 80 Gy/38- 40 fr
CTV2 - Distal SV Proximal SV (if T3b, SV =
 PTV: +1 cm/ 0.5 cm post 56 Gy/28fr full dose)
CTV3 - +/- ggl +Ggl pelvini (Iliaci int/
 PTV: + 0.5 - 0.7 cm 50.4 Gy/28fr ext, prresacrati S1-S3)
(45 Gy/25 fr….)

V95 > D95

(95 % PTV gets > 95 % of total dose)

BOOST SIB vs SECVENTIAL

 GTV, CTV, PTV prostata
• GTV invizibil CT, except. masiv EC sau VS.
- fuziunea cu MRI / MRI mp ......

• CTV= prostata in toto generos pe exteriorul

limitei vizibile fereastra de pelvis ( > RMN)
- delicat la baza & apex
 GTV, CTV, PTV prostata

• PTV=  5 (10) mm post , 10 (15 mm) restul

- mobilitatea internă: 10 mm AP & CC
< 5 mm lateral
- incertitudinile de poziţionare zilnică !
Marginile sunt functie de media erorilor, in raport cu
mijlocul de verificare folosit (nimic vs. R-grafie vs.
CBCT)  Izotrop 5- 7 mm?
 GTV, CTV, PTV vezicule seminale

• Aceleaşi principii, deşi mobilitatea lor > P.

• Posibil omise dacă risc invazie < 10 %
• 1/3 cranială rarisim invadată microscopic pt.
cT2 (50 % max 1 cm, 90% max 2 cm)
Kestin, IJROBP 2002; 54: 686.
• Pt. cT3b  56 Gy  68- 76 Gy (full dose)
Michalski, RTOG 9406, 2003
 GTV, CTV, PTV ggl.
• GTV= imaginea CT patologică

• CTV = 7 mm in jurul GTV

sau/si pedicul vascular iliac
intern; extern- 10 mm antlat;
18 - 20 mm largime in aria
obturatorie

• PTV= CTV + 5-7 mm

• Limitele ggl 
Taylor et al. Int. J. Radiation Oncology Biol. Phys., 2005, Vol. 63, No. 5, pp. 1604–1612
 RTE- organe la risc
(structuri critice)
Rect, separat de sigmoid si de canalul anal.
Vezica urinara
Intestin subtire
Bulb penian (?)
Capete femurale: V55< 5% ; V50 < 10 %

Maduva osoasa (  Docetaxel mai devreme)

 CONTURAJ ggl iliaci ext/ int
Ganglionii ilaci externi

 Grup lateral- posterior de V iliaca pe peretele pelvin

 Grup medial- anteromedial de V. iliaca externa
 Grup anterior – anterolateral de Art iliaca externa

Ganglionii iliaci interni

!!!Atentie !!!
incizura m piriform/perete pelvin
 Conturaj ggl presacrati (CTV)
1. Daca vas de sg prezent: = limita ant a acestuia

2. Daca exista doar tesut grasos: = banda de 10 (max 15 mm)

3. Daca exista o ansa intestinala, delinierea va urma limita

posterioara a ansei si aceasta se va exclude din volum

4. Foramenuri sacrate- se includ “rezonabil” (complet doar

daca exista imagini ggl imediat adiacent)

De la promontoriu la baza artc sacro-iliace (= S1-S3)

 POST- PROSTATECTOMIE
• Sediu recidive locale:
- anastomoza U-V (mai ales post)= 63%
- retrovezical (17%)
- colul vezical (10%)
- alte (VS restante etc) = 10 %

- ggl pelvini : 1/3 recidive biochimice

- pNx/ p No suboptimal
- pN1 (≤ 2 N+/ > 2 LN) = Indic de RT
Extinderea extracapsulara (EEC)

Pe 712 piese de Prostatectomie :

- EEC < 2 mm = 57.2 %
93 %
2- 5 mm= 36.1 %
> 5 mm = 6.7 %

- toate cele > 2 mm= post- lat !

Teh BS, et al. Cancer J 2003;9: 454-60.

 Ghiduri de conturaj postop
• EORTC (Poortmans P, Radiother Oncol, 2007;84:121-7)

• Canada ( Wiltshire KL, Int J Radiat Oncol Biol Phys. 2007;69:1090-9)

• Australia (2008)

• RTOG (Michalski J, Int J Radiat Oncol Biol Phys. 2010, Feb 1;76(2):361-8)
 Elemente utile (...indispensabile)
• Imagistica preop (cu prostata en place/ preferabil RMN);

• Protocol op in detaliu/ clipuri chrg

• Ana-pat piesa op./ biopsii initiale

Solicitati completari ! Dialog cu uro& ana-pat.
- ! La vezicule seminale reziduale (20%)
- Sedii & nr de ggl (MINIM 8 ggl dr şi 8 stg)
- Invazia perineurala, margini de rezectie

• Imagistica postop (Preferabil RMN cu difuzie)

 Vol tinta postop: “GTV”
• de obicei nu exista....(R2/ depinde de imagistica -
Vizibil pe MRI difuzie, PSMA-PETCT)

- daca exista GTV: CTV high risk= +5 mm izotrop,

editat la muschi/oase

- Daca pT3b si vedeti rest de VS., considerati-l GTV

- Daca fara limfadenectomie sau suboptimala si vedeti
ggl suspecti  GTV –N (preferabil staging laparo)
 Vol tinta postop: “CTV”
- aveti deja CTV HR, prin expansiunea GTV
- identificati anastomoza V-U, col vezical, zona retro-trigonala;
- desenati CTV loja prostatica. Includeti VS. restante si clipuri non-vasc

- identificaţi (fuzionati) pozitia prostatei (baza & apex) & VS pe imag

preop, in raport cu repere os (simfiza, capete femurale) = “CTV Prostata
Preop”

- daca R1- definiti zona CTV IR (intermediate risk)

- integrati CTV loja P cu CTV boost, CTVHR si CTV preop  CTV low risk
CTV Preop
 Vol tinta postop: “PTV”

• PTV LR= CTVLR + 5 mm daca IGRT protocol

(clips MV/ CBCT)  60 Gy/30fr
+ 10 mm daca fără IGRT

PTV IR= CTV IR + 5 mm izotrop 70 Gy/35fr

PTV HR= CTV boost + 5 mm 74-76 Gy

 CTV loja P+/-VS. (+, daca pT3b)
- ANT: simfiza, pana la H = 1cm deasupra colului
vezical iar mai apoi, pe l.m. = interiorul peretelui
post al vezicii iar paramedian la 1.5 cm anterior
de acesta (max pana la lig acetabular)

- POST: pana la fata ant rect pe linia mediana iar

pararectal 5 mm post, incluzand clipurile.
- mai sus de simfiza, lim post = fascia
mezorectala (daca nu iradiati si ggl)
 CTV loja P+/-VS. (+, daca pT3b)
- LAT: - plan musculo-osos (ridicatori, LSRGP)

-SUP: - vas deferens daca pT3b,

- 1 cm sub el pt VS neg
- INF: 10 mm sub anastomoza U-V
- daca R1 apex, pana la prima sectiune
(3mm) deasupra bulbului penian;
 Vol tinta postop: “N”
• Daca pNo si ≥ 8 ggl: nu exista CTV/ PTV ggl

• Daca pNx, cN0: L1 ,% pN+>15 % (Roach)

- optional (CMD) in rset

• Daca pN+: daca < 3 ggl pN+ si IGRT/ IMRT

- optional (CMD) in rest (tt standard=
HT)
Institution
RECT constrangeri
Dose Volume/ lenght
de
DVH
doza
MDAH (US) 78 Extern/ 11 cm V40 < 60 %
V45 < 50%
V60 < 40 %
V70 < 25
V75.6 < 15 % si < 4 cc
V78 < 5 % si < 2cc

GETUG (Fr) 80 Perete (max 5 mm) Doza max (1.8 cc) ≤ 76 Gy

L = CTV1 + 2 cm V50 < 50 %
V72 < 25 %
Milan (IEO) vs. 76 Extern, golit V40 < 60 % vs. < 35%
Fox Chase V50< 50 %
V60 < 25 % vs. V65 < 17%
V72 < 15 %
V76 < 5 %
QUANTEC In toto, anatomic V50 < 50%
V60 < 35 %
V65<25%
V70<20 %
V75 < 15 % !!
 Structuri critice
• Gay HA1, Barthold HJ, O'Meara E, et al. Int J Radiat
Oncol Biol Phys. 2012 Jul 1;83(3):e353-62. Pelvic
normal tissue contouring guidelines for radiation
therapy: a Radiation Therapy Oncology Group
consensus panel atlas.
Constrangeri de doza vezica urinara
Institution Dose Volume definition DVH
MDAH 78 In toto, plina V70 < 20%
GETUG 14- 18 80 Perete (7 mm) V70 < 50 %
D max (1.8cc)≤ 80 Gy
IEO (Milano) 76 Perete (5mm) V76 < 50%
QUANTEC 76+ In toto V65 ≤ 50 %
(IJROBP 2010; 76) V70 ≤ 35 %
V75 ≤ 25%
V80≤ 15 %
SFRO 76 In toto, plina V70 ≤ 25 %
V60 ≤ 50 %
V45≤ 35%
Fox Chase 76-78 In toto, ½ plina (eco) V65 ≤ 25 %
V40 ≤ 50 %
IMRT “step & shoot” secvential 46/56/76 Gy
5 campuri  Gantry 0, 75, 135, 225, 285 o
“Boost Simultan integrat” SIB-IMRT
70 Gy/28 fr Prostata; 56 Gy/ distal VS & 50.4 Gy/ ggl
CC prostata oligometastatic (1)- VMAT
CC prostata oligometastatic (2)- VMAT
 PLAN
I. Escaladarea dozei

II. IMRT vs. 3D-CRT

III. Brahiterapia ca boost al RTE

 Pros & Cons: 3DCRT vs. IMRT vs. BT

3DCRT IMRT IGRT BT

Target definition - - - +

Interfraction movements - -  *

Intrafraction --//-- - - (4D) - (4D) 

“Dose painting” (SIB) - + (4D) + (4D) ++

Irradiated Volume (2nd K) - - - 

Bladder & rectum sparing - ++ + +++

Recomandarile societatilor americana/
europeana de BT
Criterii de excludere ale BT in ADKP

Skowronek J, J Contemp Brachy 2013

 BT cc prostata
• LDR (Iod125): mono=145 Gy; boost 110 Gy
• HDR (Ir192): mono 2 fr a 13.5-14 Gy/fr
boost 1 fr 13.5-14 Gy.

CTV1= contur extern prostata, vizibil eco endorectal

 dozimetrie previzionala  nr/pozitie ace 
 Implantare  incertitudini…. (edem, rotatie etc)

 Reconturezi CTV2 sau « PTV »= CTV + 1-2 mm

3 Trialuri randomizate(2LDR , 1 HDR): + PFS, OS=….., toxicitate (LDR>HDR)

“we estimate that the local recurrence rate of LDR-PB in our
study cohort likely lies in the range of 1.8% to 2.7%.”

“In the context of the limitations of our study design, this population-
based analysis indicates that the local recurrence rate after LDR-PB
appears to be as low or lower than that following RP in our jurisdiction. ”

IJROBP, Vol 91, Issue 4, 15 March 2015, Pages 745–751

 Long term results of LDR prostate
BT – selected (mono or boost)
Author Nb pts Risk group Time point CSS bDFS (%)
Zelefsky (2007) 367 T1-2, PSA ≤ 10, G < 7 5y 100 L: 96; Int 88
Blasko (2000) 103 T1-2 5y 98 L94; Int 82; H 65
Kacso (2017) 222 T1-3a 5y 99 L 95; Int 83 H 63

Battermann(2004) 351 T1-2 7y 97.7 L89 ; Int 75; H 57

Hinnen (2010) 921 T1-2 (10 % + HT na 6 mo) 10 y 96/87/69 88/ 61/30
Critz (2004) 1469 T1-2 (100% +RT) 10 y ND 93/80/61
Potters (2005) 1449 T1-2 (20 % +RT, 27 % +HT) 12 y 93 89/78/63
Taira (2011) 1656 T1-3a 12 y 98.2 98.6/96.5/90.5
Sylvester (2011) 215 T1-2 (mono) 15 y 84 86/80/62.2
Sylvester (2007) 225 T1-3 (boost) 15 y ND 85.8/80.3/67.8
Intermed risk – LDR mono or boost, no HT

• RTOG 0232 (Prestidge B, et al. IJOBP 2016) – phase III

5 y FFBF: 80 % (=)

any ≥ G2 tox: 37 vs. 53 %

G3 7 vs. 12 %
Phase III trials Brachy Boost (+EBRT +/- HT)

Sathya et al. JCO 2005;23:1192-9

Hoskin et al. Radiother Oncol 2012;103:217-22
Morris et al. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):275-285
)
Trial Randomizat: EBRT vs EBRT + HDR boost
Hoskin PJ et al. Radioth Oncol, 2007;84: 114-120.
2012; 103: 217-22

108 p.

110 p.
 Toxicitatea “=“
(Hoskin PJ et al; 2007.
updated 2012)

a) Late Bladder ≥ G2 Tox.

b) Late GI ≥ G2 Toxicity
Results: Biochemical PFS
(Ascende trial- IJROBP 2017)
Intent-to-treat analysis of the primary endpoint
1.0
proportion free of recurrence

0.8 LDR-PB ARM

Log rank P =0.001; HR:0.5

0.6
DE- LDR-
EBRT PB
0.4 DE-EBRT ARM
83.8 88.7
5 yr
(±5.6) (±4.8)
75.0 86.2
0.2 7 yr
(±7.2) (±5.4)
62.4 83.3
9 yr
(±9.8) (±6.6)
0.0 9 y RFS: IR: 94 vs 70 %
HR: 78 vs. 58 %
0 2 4 6 8 10 12
time since first LHRH injection (yrs)
LDR Toxicity :: ( global perspective) EORTC QLQ-C30, EPIC

• GU toxicity is ubiquitary, (generally G1-2)

• Urinary Grade > 3 toxicity rates: Urinary global : MONO <5 % - BOOST: 2-3 x (20 % ASCENDE!)
– Acute urinary retention: 10% (5-34%) = highest incidence

– Urinary incontinence: 1.5% (0-17%)

– Urinary bother (detrusor OA) 1-3%

– Stricture 1-3 %
– Hemorr. cystitis <<<1%
– Infection <<<1%
– Fistula <<<1%
• Rectal Grade > 3 toxicity rates: <1% MONO  BOOST < 3&
• Erectile dysfunction: 24 % at 5 years (meta-analysis mono) 2x (+EBRT) 3-4x
(+HT)
Anderson et al. Urol 2009;74:601-5
Gore et al. JNCI 2009;101:888-92
Bottomley et al. RO 2007;82-46-9
Chen et al. JCO 2009;27:3916-22
Robinson JW et al. IJROBP 2002; 54: 1063- 8
 HDR vs. LDR (Pd) Efficacy &Toxicity
[Martinez et al. (2009) on 454 matched patients]

LDR (206) HDR(248)

• 5y bRFS 89 %89-91%

• Acute toxicity (more dysuria and or urgency/ rectal pain)

• Late toxicity ≥ G2
Dysuria (ns) 22% 15%
Freq/urgency (ns) 54% 43%
Impotence (p<0.05) 30% 20%

Courtesy of Ghilezan M.
 HDR vs LDR prostate brachytherapy

Better radiation safety for patient, family, personnel

Excellent clinical outcome
The steeper learning curve is due to online feedback
Technically, possibility to cover potential extracapsular tumor extension or base of SV
Eliminates the issue of seeds migration, post-implant seeds clumping, counting, etc
Radiobiologically superior based on alpha/beta ratio
Both acute and chronic GU toxicity profile is more favorable, confirmed by better QoL
Younger patients more likely to preserve their erectile function
Financially appealing (patient-volume dependent), source can be used for other sites
Applicable to all stages of prostate cancer (monotherapy or boost +EBRT), except M1
Really “real-time” intra-operative dosimetry and dose optimization
Brachytherapy External Beam Surgery

Less work time loss 8 weeks of treatment 6 -12 weeks recovery

+ recuperation

Continence unaffected Continence unaffected 50% immediate continence

Mild LUTS in 70% Mild LUTS in majority 75% by 3 months
Moderate LUTS in 30% Moderate LUTS in 50% 90-95% by 6 months

Very low gastro-intestinal Moderate GI toxicity in majority Extremely low GI toxicity

toxicity Severe GI toxicity low, but dose
related

Preservation of potency Relative preservation of potency Potency never the same

Preservation of ejaculation Preservation of ejaculation True ejaculation does not
but may be reduced but may be reduced occur
Fertility is preserved Potential impact on fertility Infertile (need IVF)

Caveat: - additive toxicity of several therapies (! HT)

QoL BT > RP ( Crook JM et al, JCO 2011/ SPIRIT) …. at long term “=“ (Donovan, NEJM 2016/ PROTECT)
• Int J Radiat Oncol Biol Phys. 2015 Feb 1;91(2):295-302.
• Risk of second cancers according to radiation therapy technique and modality in
prostate cancer survivors.
• Berrington de Gonzalez A1, Wong J2, Kleinerman R2, Kim C2, Morton L2, Bekelman JE3.
• Author information
• , National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:
berringtona@mail.nih.gov.
• METHODS AND MATERIALS:
• The cohort was constructed using the Surveillance Epidemiology and End Results-Medicare database. We included cases
of prostate cancer diagnosed in patients 66 to 84 years of age from 1992 to 2004 and followed through 2009.
• RESULTS:
• During an average of 4.4 years' follow-up among 5-year prostate cancer survivors … 2933 second solid cancers were
diagnosed. …
• Rates of second solid cancers for higher- and lower-energy RT were similar overall (RR = 0.97, 95% CI: 0.89-1.06), as
were rates for site-specific cancers.

• There were significant reductions in colon cancer and leukemia rates in the first
decade after brachytherapy compared to those after external beam RT.

• Comments ; short follow-up ! …..

Salvage LDR Brachytherapy in teritoriu anterior RT:
 70-75% 5 bRFS with 10- 15 % G3 late tox
AUTHOR Nb pts Follow-up (mo) bRFS (%) G3/4 Toxicity (%)
Nguyen (2007) 25 47 70 30
Lee (2008) 21 36 38 0
Aaronson (2009) 24 30 88 4
Burri (2010) 37 86 54 11
Battermann (2010) 31 73 23 3.6
Crehange (2010) 24 25 87.5 0
Lopez (2010) 42 48 80.6 21
Peters (2013) 129 29 20 30
Vargas (2014) 69 60 73.8 (nonCRPC) 8.7
Henriquez (2014) 56 48 77 24
Candidati “ideali” pt BT de salvare
(Zaorsky NG et al, Nature Reviews/Urology 2017)
 Salvage LDR Brachytherapy after RP
= only for nodular recur. (visible on US/ MRI DCE endorectal coil1)
- locally isolated, biopsy confirmed
- low Gleason (6 or 7=3+4) – brachy alone; the others:
EBRT+BT+/- HT

 5y bDFS: 88 % 2, 3,4 ( +EBRT; bioch failure = PSA nadir +2 ng/ml);

- <10 % G3 GU tox.
1
Rischke HC et al. Radiat Oncol 2012; 7: 185-192;
2 Losa A et al. Urology 2003; 62:1068-1072;
3
Gomez-Veiga F et al. BJU int 2012;109:17-21
4
Kumar et al. J Contemp Brachy 2015;7: 241-246.
3 single-fraction or 2 multi-fraction implants

EQD2 of 65-78 Gy3

BED of 108-130 Gy3

Tselis N et al,2017
Biochemical control Iridumknife
<15% late grade 3 GU
74-95% at 2 years < 5% late grade 3 GI
51-77% at 5 years

Biochemical control Surgery

Rectal injury Ø 6.8%
47-87% at 2 years Anastomotic stricture Ø 18.3%
37-66% at 5 years
Incontinence Ø 47.8%

Tselis N et al,2017
 Take home messages:
• RT (Inclusiv BT) este standard pt. toate stadiile de cc prostatic
(curativ pt NoMo oligomets N/M…. paliativ )

• BT boost (HDR≥ LDR)  + 20 % bRFS

• BT mono =OK pt grup rsic scazut/ intermediar- scazut vs active

surveillance

• Re-iradierea de considerat case by case (rectal spacer…./ HDR –BT,

SBRT)
 Asocierea HT +RT
1) PSA < 10, ≤ T2b 2002, G ≤ 6 – doar pt downsizing  brahi.

2) T2c, PSA:10- 20, G7: 6 luni BAC, na + c

3) PSA> 20, T3-4, N1, G≥ 8: + LHRH 2-3 ani sau

Bicalutamida 150 mg

Adj: Bria et al. Cancer 2009 OS : +5 % ( RL↓cu 36%

M+ ↓ cu 28 %)

Neoadj: Shelley et al. Cancer Treat Rev 2009  OS :+ RT(GS≤ 6)

(nu si pt. PR)
 Asocierea HT scurtă- RTE
► RTOG 86-10: T2- T4,N0-1, 4 luni BAC na/conc. RT standard
 + SV8 pt. G ≤ 6: (70 vs. 52 %)
 + DFS orice Gleason (Pilepich, 2001)

► Canada: T2- 3, 3 vs. 10 luni vs. No HT (Laverdiere, 2004)

 + bPFS7 (66 vs. 42 %); 3 = 10 luni

► D’Amico: PSA= 10-40 sau G> 6 sau T3, 3D-CRT

(2004) 6 luni BAC (2-2-2)  + SV5 (88 vs.78%)

► TROG 96-01: 3 vs. 6 vs. 0 BAC  + 6 luni (Denham, 2005)

► RTOG 94-13: 4 luni na/c > 4 luni adj bPFS8 ( Lawton, 2007)
 Asocierea HT lungă- RT
►EORTC (Bolla): 3 ani LHRH c/adj. vs. -HT
T3-4/ Grad 3 + SV5 (78 vs 62 %)
+ SVs (94 vs.79 %)

► RTOG 85-31 (Pilepich 2005): LHRH ∞

T3/ N1  + SV10 (53 vs. 38 %), + SVs

► Suedez (Granfors): OB, N1  + SV9 (69 vs 39 %)

► EPC (150 mg): T3-4/ orice N+  + SV 7

► RTOG 92-02 : 2 ani adj, +PFS, OS?

 LHRH (Zoladex) adjuvant radioterapiei
(studiul EORTC 22863)

Supravieţuirea generală la 5 ani

% 100
pacienţi 90
în viaţă 78%
80
(72-84%)
70
60
50 58 %
40
30
Radioterapie + Zoladex 3,6 mg (n=203) 62%
20 (52-72%) 40 %
10 Radioterapie (n=198)
0
0 1 2 3 4 5 6 7 8 9 10
Timp (ani)
HR 0.51; 95% CI 0.36-0.73, p =0.0002 Bolla M et al. Lancet 2002;360:103-8

Bolla M et al. Lancet Oncol 2010; 11: 1066

 HT adj. scurta vs. lunga
► RTOG 92-02 (Hanks): T2c- T4, BAC2+2
+ 2 ani BAC vs. Θ
 + PFS pt. adj. DAR!

 + SV 5 doar pt. G ≥ 8 (80 vs 69 % )

pt G ≤ 7: detrimentală !! († CV)
QoL
 HT adj. scurtă vs. lungă
• EORTC 22961
- 970 pMo Tc-2bN+ sau pN+ sau T2c-4N0-2
- PSA < 150 ng/ml
- RTE 70 Gy

- 6 L vs. 3 ani (NA-C +/- A)

 bPFS: 58 vs. 78 %
mortalitatea la 5 ani: 19 vs. 15.2%

Bolla M et al. NEJM 2009; 360: 2516 – 27.

 CONCLUZII
• Tehnicile de RT – modernizare continuă IGRT

•  preciziei = logistică/ aparatură sofisticată

= resurse umane antrenate
= control riguros al calităţii
= studii clinice de validare/ optimizare

 Responsabilitate dar şi satisfacţii profesionale 

* BT ramane cea mai conformationala iradiere si mai

putin iatrogena