Giorgio Arcangeli

Highlights in the Management Highlights in the Management of Urogenital Cancerof Urogenital Cancer

Rome May 9-10, 2008Rome May 9-10, 2008

Radiation Therapy is the bestRadiation Therapy is the best

treatment approach for treatment approach for

localized prostate cancerlocalized prostate cancer

Radiation Therapy is the bestRadiation Therapy is the best

treatment approach for treatment approach for

localized prostate cancerlocalized prostate cancer

CARCINOMA OF THE PROSTATE

risk to treat scarcely aggressive

indolent tumors

risk to treat scarcely aggressive

indolent tumors

multiple therapeutic options

multiple therapeutic options

High probabilityof cure in

localized tumors

High probabilityof cure in

localized tumors

CRITERIA FOR TREATMENT CHOICE

TUMOR RELATED (Stage - G.S. - PSA)

PATIENT RELATED (age - P.S.)

TREATMENT RELATED (Acute and late side effects, QOL)

Clinical Staging of prostate cancer

Clinical Staging of prostate cancer

Clinical Staging of prostate cancer

Clinical Staging of prostate cancer

SISTEMA DI GLEASON (1974) SISTEMA DI GLEASON MODIFICATO (ISUP 2005)

CARCINOMA OF THE PROSTATADefinitive treatment options in localized tumors

HIGH DOSE RADIOTHERAPY±

ANDROGEN DEPRIV.

HIGH DOSE RADIOTHERAPY±

ANDROGEN DEPRIV.

RADICALPROSTATECTOMY

RADICALPROSTATECTOMY

0

500

1000

1500

2000

2500

3000

3500

84 85 86 87 88 89 90 91

SurgeryRadiotherapy

AGE < 70 years

(Harlan: J Clin Oncol, 1995)YEARS OF DIAGNOSIS

CARCINOMA OF THE PROSTATE

0

500

1000

1500

2000

2500

3000

84 85 86 87 88 89 90 91

SurgeryRadiotherapy

YEARS OF DIAGNOSI(Harlan: J Clin Oncol, 1995)

AGE > 70 anni

CARCINOMA OF THE PROSTATE

A Multi-institutional* Pooled Analysis of Radiation Therapy For Clinically Localized Prostate Cancer

(Shipley, JAMA 281:1598, 1999)

* Fox Chase; Mass General; Michigan University; Washington University; EVMS; Stanford

ACR Patterns of Care Study :Risk of Grade 3-4 Complications by Radiation

Dose in Carcinoma of the Prostate

Dose # Patients % Complications

<70 Gy 428 3.5%

>70 Gy 174 6.9%

p = 0.03

Modified from Leibel SA, Hanks GE, Kramer S. IJROBP, 10, 401, 1984

120100806040200

20

40

60

80

100

Prescription Dose

Pro

bab

ility

(%

)

Shifting The Organ Toxicity Curveby Decreasing the Irradiated Volume

TumorControl Organ

Toxicity

Multileaf Collimator for Conformal or Intensity Modulater Radiation Therapy

Dynamic Multileaf ( “Sliding window”)• le lamelle si muovono in modo continuo ed unidirezionale durante l’erogazione, sempre da sinistra verso destra, fino ad una velocità di 2.5 cm/s;

• ogni lamella si sposta a velocità diversa dalle altre, ricongiungendosi alla lamella opposta nella posizione finale;

• l’erogazione è continua durante il movimento delle lamelle.

Fluence Matrix

Why IMRT ???• Creation of concave or convex isodose surfaces with

sharp dose gradients• Higher dose to target volume• Specific sparing of sensitive volumes (organs at risk)

within complex treatment geometries

With IMRT dose distribution can be shaped to the target to spare Organs at Risk

Beam Profile #1 1

Beam Profile # 2

Beam

Profile #3

Dose Intensity

PTV

RORO

PTV

3-field IMRT

Prescribed Dose (typical distribution)

3-field RT

Isodose comparison betwen CRT or IMRT 20-30%40-50%60-70%80-90%90-100%>100%

20-30%40-50%60-70%80-90%90-100%>100%

Dose prescription: 80 Gy to isocentre, 2 Gy per fractions, 5 fr/week

6 FIELDS-3DCRT 5 FIELDS-IMRT

bladdder6 fields-3DCRT

5 fields-IMRT

PTVrectum

Per

cen

t G

rad

e 2

Rec

tal

Ble

edin

g

0 12 24 36 48 60 72 84 96 108

Time (months)

0

5

10

15

20

6480 cGy (96)

7020 cGy (268)

7560 cGy (446)

8100 cGy (61)

Zelefsky 1999

Pe

rce

nt

≥ G

rad

e 2

GI T

ox

icit

y

0 12 24 36 48 60 72 84 96

Months

5

10

15

20

p< 0.001

81 Gy IMRT (171)

81 Gy Conventional 3D-CRT (61)

0

Zelefsky 2001

Dose escalationwith External BeamRadiation Therapy

Biochemical Failure-Free

Zietman AL, JAMA 2005

All Pts. Intermediate to high risk

Low risk70.2 Gy vs 79.2 Gy

Peeters STH et al. JCO 2006

Conventional vs. High dose 3D-CRT in pts with prostate cancer receiving 3-6 mos NCADT

Randomized phase III study (MRC RT01)

74 Gy

64 Gy

HR=0.67(0.53-0.85)P=0.0007

Dearnaley, Lancet Oncol 2007

External Beam Radiation Therapy

VsRadical Prostatectomy

bNed for surgically and radiation-managed patients stratified into risk groups

low risk

intermediaterisk

high risk

D’Amico A, IJROBP 1997

bRFS in pts with favorable tumors (T1-T2A, bGS< 6, iPSA< 10 ng/ml)

Kupelian PA, JCO 2002

bRFS in pts with unfavorable tumors (T2b-T2c, bGS> 6, iPSA>10 ng/ml)

Kupelian PA, JCO 2002

Akakura K, Jpn J Clin Oncol 2006

bNED OS

P=0.25 P=0.30

RP: 46 pts – EBRT (60-70 Gy): 49 pts (2 month neoadjuv DES 300mg and adjuv LHRH until progress)

Characteristics of Pts with high risk prostate cancer

Variable RP EBRT p-value

Median Age 65.5 75.0 <0.001bGS < 6 29 (24%) 17 (10%) 7 82 (67%) 105 (65%) <0.001 > 8 11 (9%) 40 (25%)cT-Stage <T2c 110 (90%) 70 (43%) T2c 4 (3%) 71 (48%) <0.001 >T2c 8 (7%) 21 (9%)iPSA <10 2 (1%) 44 (27%) 11-20 57 (47%) 55 (34%) <0.001 >20 63 (52%) 63 (39%)Median FU 30.5 mos 30.7 mos 0.56

EAU Guidlines for follow-up after treatment with curative intent

•After RP a serum PSA level > 0.2 can be associated with residual or recurrent disease (grade B recommendation)

•After EBRT a rising PSA level 2.0 ng/ml above the nadir value, rather than a specific threshold value, is the most reliable sign of persistent or recurrent disease (grade B recommendation)

•Both a palpable nodule and rising PSA level can be signs of local disease recurrence (grade B recommendation)

Eur Urology 2008

p=n.s. p=n.s. p=n.s.(238 pts.)

(46 pts.) (238 pts.)(104 pts.)(180 pts.) (46 pts.)

FFBF in high risk prostate tumors according to different scores of clinical prognostic factors

IRE Apr 2008

bGS iPSAcT-stage

(123 pts.)

(159 pts.)

FFBF as a function of Age in pts with high risk prostate cancer treated with RP or EBRT

IRE Apr 2008

p = 0,0012

(162 pts.)

(122 pts.)

FFBF after RP or EBRT in pts with high risk prostate cancer

IRE Apr 2008

RP

p=n.s.= 0.06p=n.s

EBRT

p=0.005p=n.s.

FFBF according to bGS ± 8 and iPSA ± 20 ng for RP and EBRT

(11 pts)

(111 pts)

(40 pts)

(122 pts)

(63 pts)

(59 pts)

(63 pts)

(99 pts)

p = 0.0161

FFBF of Pts with worst prognosis according to the treatment received

IRE Apr 2008

(152pts.)

(10pts.)

p= 0.001

FFBF according to nPSA in Pts treated with EBRT

IRE Apr 2008

p=0.62

p=0.06

p=0.0001(162 pts.)

(83pts.)

(39 pts.)

FFBF of Pts treated with EBRT, RP only or RP + Adjuvant Treatment

IRE Apr 2008

p=n.s.

p=n.s.

p=0.008

p=n.s.

FFBF according to different scores of pathologic factors

(88 pts)(23 pts)

(17 pts)

(96 pts)

(25 pts)

(71 pts)

(8 pts)

(103 pts)

Univariate analysis of RP patient

Variable 3-yr FFBF rate p-value

bGS (≥8 vs <8) 72% vs 77% 0.74

cT (>T2c vs <T2c) 37% vs 77% 0.08

iPSA (>20 vs < 20) 68% vs 81% 0.06

SM+ vs SM- 79% vs 72% 0.73

pGS (>8 vs <8) 53% vs 81% 0.008

pN+ vs pN- 60% vs 73% 0.53

pT (>T2c vs <T2c) 72% vs 78% 0.74

Adjuv Treatm (Y vs N) 65% vs 87% 0.06

Univariate analysis of EBRT patient

Variable 3-yr FFBF rate p-value

bGS (>8 vs <8) 77% vs 93% 0.005

cT (>T2c vs <T2c) 83% vs 93% 0.66

iPSA (>20 vs < 20) 86% vs 91% 0.26

nPSA (>0.5 vs <0.5) 40% vs 94% 0. 001

Fractionation

(standard vs hypo) 76% vs 96% 0.06

Univariate analysis of all patients

Variable 3-yr FFBF rate p-value

bGS (> 8 vs < 8) 73% vs 85% 0.17

cT (>T2c vs <T2c) 74% vs 83% 0.82

iPSA (>20 vs < 20) 76% vs 81% 0.01

Age (>70 vs <70) 84% vs 80% 0. 61

Treatment

(RP vs EBRT) 80% vs 92% 0.001

Summary of Multivariate Analysis

Group Variable p-value

RP pGS (<7 vs =7 vs >7) 0.04

EBRT nPSA (continuous) 0.0002

All PTS iPSA (continuous) 0.01

Treatment (RP vs EBRT) 0.007

Rectal and urinary late toxicity

Incidence of grade >2 late toxicity

rectal

urinary

convent

convent

hypo

hypo

IRE, Oct 2007

Radiation Proctitis Related Factors

Radiation related factors•Total dose•Dose per fraction•Dose/volume relationship•PTV size•RT technique•N° of RT fields•Rectal motion

Patient related factors•Previous history of proctitis•Previous abdominal surgery•Cardiovascular disease•Arterial hypertension•Peripheral vascular disease•Diabetes•Hemorrhoids•Prostate size•Long term ADT

99

Non confluent multipleTelangectasia

Freedom from rectal toxicity as a function of rectal volume receiving > 70 Gy (V70)

Pollack IJROBP 2002

Disfunzione erettile

Sexual potency preservation

– Radiotherapy: 73%

– Radiotherapy (high doses): 61%

– Radiotherapy + neoadiuv ADT: 79%

– Radioterapia + adiuvant ADT: 0%

Pilepich 1999, D’Amico&Zelefsky ASTRO2004

Radiation mediated impotence is multifactorial. Of pts. evaluated for impotence, 63% had arteriogenetic dysfunction, 31% cavernosal dysfunction, and only 3% had a neurogenic impotence

Merrick GS ASTRO 2004

Merrick GS ASTRO 2004

Tsai HK, JNCI 2007

EBRT, age≥65 yrEBRT, age<65 yr

RP, age<65 yr RP, age≥65 yr

Quality of life-Prospective evaluation-Patient/Physician evaluation-Validated instruments

Litwin Cancer 007

BrachytherapyEBRTRP

BrachytherapyEBRTRP

Actuarial analysis of the subjects returned to baseline HRQOL scores

Litwin Cancer 2007

All Pts

Pts initiallypotent

Actuarial analysisof the subjects returned to baseline sexual scores

BrachytherapyEBRTRP

BrachytherapyEBRTRP nerve-sparingRP non nerve-spar

Grazie per la VostraGrazie per la VostraAttenzione!Attenzione!

Grazie per la VostraGrazie per la VostraAttenzione!Attenzione!

Ringrazio:

Pr. M Gallucci, Dr. P De Carli, Dr. R Papalia (Div. Urologia), Dr. L Strigari, Dr V Landoni, Pr. M Benassi (Lab Fisica Medica) e i miei collaboratori della SC Radioterapia: Dr. B Saracino, Dr. MG Petrongari M, Dr. S Gomellini, Dr. S Arcangeli.