Neadjuvant Hormonal Therapyin Men Being Treated with

Radiotherapy for Localized Prostate Cancer

Mack Roach III, MDProfessor, Radiation Oncology & Urology

University of California, San FranciscoUCSF/Mt. Zion NCI-Designated Comprehensive Cancer Center

San Francisco, California

Background

Several prospective Phase III randomized trials have demonstrated that the addition of long-term adjuvant HT to EBRT prolongs survival for patients with high-risk Prostate Cancer, including:– EORTC (Bolla)EORTC (Bolla)– Swedish Trial N+ (Granfors)*Swedish Trial N+ (Granfors)*– RTOG 8531 (Pilepich) updatedRTOG 8531 (Pilepich) updated

*Granfors et al. J Urol. Jun 1998;159(6):2030-2034.

All Patients

RT+ Adj LHRH RT+ Adj LHRH (n=477)(n=477)

RT+HT at RT+HT at Relapse Relapse (n=468)(n=468)

5 yr5 yr 10 yr10 yr 5 yr5 yr 10 yr10 yr PP

Local FailureLocal Failure 15%15% 23%23% 30%30% 39%39% <0.0001<0.0001

Distant FailureDistant Failure 15%15% 25%25% 29%29% 39%39% <0.0001<0.0001

NED SurvivalNED Survival 62%62% 36%36% 44%44% 22%22% <0.0001<0.0001

Absolute Absolute SurvivalSurvival

76%76% 47%47% 71%71% 38%38% 0.00430.0043

Prostate Cancer Prostate Cancer DeathDeath

9%9% 17%17% 13%13% 22%22% 0.00530.0053

Pilepich et al. Proc Am Soc Clin Oncol. 2003;22:381(Abs1530).

Years from Randomization

Per

cent

(%

)

0 3 6 9 12

RT+ImmediateHormones

RT+Hormonesat Relapse

P=0.042

Absolute Survival Central Gleason 7

Pilepich et al. Proc Am Soc Clin Oncol. 2003;22:381(Abs1530).

0

25

50

75

100

P=0.0061

Absolute SurvivalCentral Gleason 8-10

Pilepich et al. Proc Am Soc Clin Oncol. 2003;22:381(Abs1530).

Years from Randomization

Per

cent

(%

)

0 3 6 9 12

RT+ImmediateHormones

RT+Hormonesat Relapse

0

25

50

75

100

Purpose

Several prospective randomized trials have demonstrated that men with localized prostate cancer benefit from the use of short-term NHT in combination with EBRT

The optimal timing and total duration of NHT remain controversial

This review critically analyzes the major randomized trials incorporating NHT with EBRT reported to date

1. Is there consistent evidence NHT is beneficial?

2. Is there evidence of a sequence dependent biologic interaction between HT and EBRT?

3. Is there a sub-population of patients treated with EBRT in which NHT is not justified?

4. If justified how long should NHT be used?

5. Should adjuvant HT be added as well?

6. What volume should be irradiated?

7. Should high-risk patients receive NHT?

All major prospective randomized trials published to date were critically reviewed in an

attempt to answer the following questions:

Materials and Methods

Seven randomized trials reported in six papers including patients treated with NHT in combination with EBRT on one or more arms were identified

In total 17 arms compared either EBRT alone (n=3); NHT & concurrent hormonal therapy (N&CHT) (n=12) +/- short-term adjuvant hormonal therapy (SAHT) (n=5) or long term HT (n=1)

The Features of the Major HT Trials

In total >4300 patients were treated on all 17 arms Doses of EBRT used were similar @ 65 to 70 Gy Three trials omitted pelvic EBRT in all patients

(both Quebec series & Harvard series) One study included WPRT in patients with a risk

of + nodes >10 to 15% (Princess Margaret) Two studies used WPRT in all patients (RTOG

8610 & 9202) & in the remaining study half of the patients received WPRT (RTOG 9413)

The Major Features of the Trials

RTOG trials were: – Larger (456-1514 vs 161-378 patients). – Patients on RTOG had more advanced Dz:

Higher Median preTx PSAs– 20 to 26 vs ~10 to 12 ng/mL

Higher T-stages with <T2c– 0 to 30% vs 52 to 100%

Higher grade tumors GS=7-10 in: – 60 to 73% vs 28 to 74%

Phase III RTOG Randomized Trials

RTOG 8610: WP & PO RT +/- NHT RTOG 9202: NHT WP+Prostate RT +/-

Adj LHRH x 2 years RTOG 9413: Four Arm Trial WP vs PO &

N&CHT vs AHT (4 months) RTOG 9408 (analysis pending)

– Prostate RT +/- NHT

First Author (Year)

Total / No. patients with NHT +/- concurrent HT

No HT

Short / Long Term Adjuvant HT (no.)

T-StagesT1-2bT2cT3-4

GS#2-67

8-10

PreTx PSA

(Med)^Comments:

Pilepich (2001) RTOG 8610

456 / 226 230 0 / 00%

30%70%

--

28%26

ng/mL

Survival advantage for

GS <7, Included N+

patients

Hanks (2003) RTOG 9202

1514 / [761 vs753 (+adjuvant)] 0 0 / 753

045%55%

40%35%26%

20 ng/mL

Disease-specific

survival and Overall for GS = 8-10.

Roach (2003) RTOG 9413

1291 / 645 0 646 / 033%NRNR

28%NRNR

23 ng/mL

Progression-free survival advantage with short follow-up

Randomized Trials Using NHT

Phase III RTOG Trial 8610 of Androgen Deprivation Adjuvant to Definitive Radiotherapy in Locally

Advanced Carcinoma of the Prostate

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

RT + NHT

RT alone

Sur

viva

l (%

) G

leas

on 2

-6

Years

P=0.015

Pilepich MV et al. Int J Radiat Oncol Biol Phys 2001; 50(5): 1243-52.

Arm 1:Arm 1: goserelin and flutamide goserelin and flutamide2 months before and during 2 months before and during standard RT (STAD)standard RT (STAD)

Arm 2:Arm 2: goserelin and flutamide goserelin and flutamide2 months before and during2 months before and duringstandard RT, followed bystandard RT, followed bygoserelin alone for 24 months (LTAD)goserelin alone for 24 months (LTAD)

T2c-T4T2c-T4PreRx PSA PreRx PSA

<150 <150 ng/mLng/mL

RANDOMIZE

RTOG 92-02

Overall SurvivalAll Patients RTOG 9202

Years since randomization

Sur

viva

l rat

e

STAD+RT

LTAD+RT0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8

159 22

169 28P=0.73

9202 Prostate Cancer Survival

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8

Failed/Total

STAD+RT 87/762

LTAD+RT 55/755

Years Since Randomization

Sur

viva

l Rat

e

P=0.006

RTOG 9413 Scheme: Timing

FirstMonth

HTT HT HT HT none none

EBRT EBRT none none

HT HT HT HT

EBRT EBRT

Arms 1 & 2

Arms 3 & 4

2 months different Rx duration

SecondMonth

ThirdMonth

FourthMonth

FifthMonth

SixthMonth

Progression-Free Survival Arm 2 vs Arm 4 (RTOG 9413)

Years since randomizationApproximatelytwo months

N&CHT+PO RT

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

0 1 2 3 4 5

Non

-fai

lure

rat

e

PO RT+AHT

Progression-Free SurvivalArm 1 vs Arm 2 (RTOG 9413)

Years since randomization

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

0 1 2 3 4 5

Non

-fai

lure

rat

e

N&CHT+WP RTN&CHT+PO RT

Randomized Trials Using NHT

First Author (Year)

Total / No. patients with NHT +/- concurrent HT

No HT Short / Long Term Adjuvant HT (no.)

T-Stages

T1-2b

T2c

T3-4

GS#

2-6

7

8-10

PreTx PSA

(Med) Comments:

Laverdeire (2004)

Quebec Trials

161 / 63

296 / 148(3 months)

43

0

55 / 0

148 / 0

NA

NA

30%

NA

NA

13.5%

(7-10) = 26%^

(7-10) = 28%

10 ng/mL

12 ng/mL

PSA failure rates higher with EBRT

alone, otherwise no difference s

D’Amico (2004)

Harvard Study

206 / 104 102 0 / 0 100%,

0%

35%

59%

15%11

ng/mL

Overall & disease specific survival

advantage

Crook (2004)

Princess Margaret

378 / 378 (3 vs 8 months)

0 0

~52%

~35%

13%

50%

38%

11%~10

ng/mL

Overall no difference in PSA failure

rates

Laverdiere Scheme:Timing of Hormonal Therapy (HT)

Arm (no.)

Group 1Study 1

EBRT EBRT none none none none

Group 2Study 1

HT HT HT EBRT EBRT none

Group 3Study 1

HT HT HT HT

EBRT

HT

EBRT

HT*

Maximum field size 10 x 10 cm to 64 Gy.

*HT = Combined Androgen Blockade with a LHRH & Flutamide

*10 months. Laverdiere J et al. J Urol 2004; 171(3): 1137-40.

FirstMonth

SecondMonth

ThirdMonth

FourthMonth

FifthMonth

Sixth-Tenth

The Efficacy and Sequencing of Short Course of Androgen Suppression on Freedom from Biochemical Failure When

Administered with Radiation Therapy for T2-T3 Prostate Cancer

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0

Months

bNE

D S

urvi

val (

%)

3 month NHT

N&CHT+Adj (10 months)

EBRT Alone

Laverdiere J et al. J Urol 2004; 171(3): 1137-40.

Laverdiere Scheme: Timing of Hormonal Therapy (HT)

Group 1Study 2 HT HT HT

HT

EBRT

HT

EBRTnone

Group 2Study 2 HT HT HT

HT

EBRT

HT

EBRTHT*

*HT = Combined Androgen Blockade with a LHRH & Flutamide

Maximum field size 10 x 10 cm to 64 Gy.

*10 months. Laverdiere J et al. J Urol 2004; 171(3): 1137-40.

Arm (no.) FirstMonth

SecondMonth

ThirdMonth

FourthMonth

FifthMonth

Sixth-Tenth

6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients

with Clinically Localized Prostate Cancer

0

10

20

30

40

50

60

70

80

90

100

0.0 1.0 2.0 3.0 4.0 5.0 6.0

3D-CRT + Hormones

3D-RT alone

Sur

viva

l (%

)

Years

P=0.04

D’Amico et al. JAMA. 2004;292:821-827.

The Results

Every study comparing EBRT alone vs EBRT + NHT (n=3) demonstrated a benefit to patients treated with the addition of NHT

One trial demonstrated no advantage to using longer NHT (3 versus 8 months)

Two studies demonstrated no benefit to adding concurrent & short-term adjuvant HT (3 months NHT vs N&C&SAHT (total time, 10 months) &5 months N&CHT vs N&C&SAHT (10 months)

The Results

Considering using prostate only EBRT, N&CHT appears to be equal to SAHT (9413)

Patients with very high-risk disease did better if treated with longer term adjuvant HT (n=1) &a trend to do better with longer NHT (8 months) (n=1) (P >0.05)

Despite variability in study design & definitions of PSA failure there is consistent evidence for a benefit to NHT in patients with intermediate risk disease

RTOG 9413

RTOG 9202RTOG 8610

Princess Margaret

Quebec StudiesHarvard Study

Rel

ativ

e E

x ten

t o f

Dis

ease

-50

-40

-30

-20

-10

0

10

20

30

40

Low Risk Intermediate High Risk Very High Risk Dz

Impact of Short Term NHT on SurvivalImpact of Disease on survivalNet Impact of Dz & HT

Model and Literature on the Impact of Short-TermNHT and EBRT on Outcome in Treatment ofClinically Localized from Prostate Cancer

Based on the data from these studies the following conclusions seem reasonable:

1. NHT is beneficial with EBRT in intermed risk patients (RTOG 8610, Quebec study #1, Harvard study)

2. Biologic interactions between NHT & PO RT may not be sequence dependent (Arms 2 vs 4 of RTOG 9413)

3. Interactions between HT & WPRT are sequence dependent (Arms 1 vs 3 RTOG 9413)

4. NHT without long term adj HT is inadequate for very high-risk patients (RTOG 9202, subset RTOG 9413)

Based on the data from these studies the following conclusions seem reasonable:

5. Two to 3 months of NHT + EBRT appears to be adequate for intermediate risk patients with no additional benefit with concurrent & / or SAHT(Quebec studies, Princess Margaret study)

6. Patients with a risk of + nodes > 15% should undergo prophylactic WP EBRT with NHT(RTOG 9413, RTOG 8610 & RTOG 9202)

7. High-risk patients should probably receiveshort-term NHT & long-term adjuvant HT(RTOG 9413, RTOG 9202, RTOG 8610)

8. The role of NHT in low-risk patients has not been defined (RTOG 9408)

Final Conclusions

The composite findings from these 7 prospective Phase III randomized trials are remarkable because:– There are NO contradictory studiesThere are NO contradictory studies– As a body of evidence they should establish a As a body of evidence they should establish a

standard of carestandard of care– Few comparable examples of evidence-based Few comparable examples of evidence-based

practices can be found elsewhere in GU practices can be found elsewhere in GU OncologyOncology