EORTC

POSTOPERATIVE RADIOTHERAPY IMPROVES CLINICAL AND BIOCHEMICAL PROGRESSION FREE

SURVIVAL AFTER RADICAL PROSTATECTOMY : FIRST RESULTS OF EORTC TRIAL 22911

M. Bolla (Grenoble, France), H. van Poppel, L. Collette ,P.J. van Cangh, K. Vekemans, L. Da Pozzo, R.

Van Velthoven, JM Maréchal , P. Scalliet, , Th.M. de Reijke, A. Verbaeys, J.-F. Bosset, K. Haustermans, M.

Piérart

On behalf of the EORTC Radiotherapy and Genito-Urinary Groups

EORTC

For pT3 patients (cancer extending beyond the capsule) the risk of local failure varies from 10 to 50%.

PSA level, Gleason score and positive surgical margins are independant predictors of biochemical relapse.

Post operative radiotherapy reduces significantly the local relapse and PSA failure rates without any impact on disease-free survival.

EORTC

Trial Design

RANDOMIZATION andStratification for

Institution Capsule invasion Positive margins

Invasion of seminal vesicles

Wait and see until local failure

Post-op radiotherapy

(60 Gy/6wks)

SURGERY

1005 patients recruited between end 1992 and end 2001

Median follow-up: 5 years

EORTC

Selection Criteria

Age 75 years,

WHO performance status (PS) 0-1

T0-3 N0 M0 Prostate Cancer preoperatively

1 pathological risk factor of: capsule invasion positive surgical margins invasion of seminal vesicles

Informed consent

EORTC

Trial objectives

The trial is planned to demonstrate an increase of 7.5% of the 5-year biochemical progression free survival with post-operative radiotherapy with 80% power (2-sided Logrank test, =0.05)

Secondary endpoints Clinical progression-free survival Local control Overall survival Acute toxicity (WHO) and late Morbidity

EORTC

Yearly accrual

1

50

128

145

123

143131

10894

82

0

20

40

60

80

100

120

140

160

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Israel: 8

Switzerland: 31

Italy: 115

Spain: 19

France: 84

Belgium: 597

United Kingdom: 5

The Netherlands: 146

Accrual by Country

EORTC

Patient characteristics

The characteristics were well balanced between the groups

Median age 65 y (47 – 75)

WHO PS 0 : 93.8% - PS1: 5.5% - PS2: 0.3%

T0-1: 17.6% - T2: 65.1% - T3: 17.2% - Tx: 0.1%

WHO G1: 12.5% - G2: 62.7% - G3: 23.6% - Gx: 1.2%

Median PSA before surgery: 12.3 ng/ml (0.3-159.4)

Median PSA after surgery: 0.2 ng/ml (0.0 - 48.7)

EORTC

Pathological Risk factors

High Risk factors

Treatment Arm

Total(N=1005)

No RT(N=503)

 RT(N=502)

N (%) N (%) N (%)

Not pT3 0 ( 0.0) 2 ( 0.4) 2 ( 0.2)

Capsule only

127 (25.2) 139 (27.7) 266 (26.5)

Capsule + S.V.

40 ( 8.0) 26 ( 5.2) 66 ( 6.6)

Capsule + Margin 169 (33.6) 149 (29.7) 318 (31.6)

S.V. only 19 ( 3.8) 23 ( 4.6) 42 ( 4.2)

S.V. + Margin 8 ( 1.6) 16 ( 3.2) 24 ( 2.4)

Margin only

79 (15.7) 84 (16.7) 163 (16.2)

Capsule + S.V. + margin

61 (12.1) 63 (12.5) 124 (12.3)

EORTC

Treatment actually received

Treatment actually received

No Further Trt(N=503)

Post-op RT(N=502)

N (%) N (%)

No Further Trt 497 (98.8) 41* ( 8.2)

Post-op RT 5 ( 1.0) 457 (91.0)

Unknown 1 ( 0.2) 4 ( 0.8)

* Reasons were: ineligibility (10), post-operative complications (8), refusal (21), unspecified (2)

EORTC

Radiotherapy Treatment

N=457

Time from Surgery to d1 of RT (days) 90 (14-156)

Duration of RT (days) 44 (18-106)

Total Dose (Gy) 60.0 (50 – 74)

<57 Gy 3 ( 0.7%)

57-63Gy 420 (91.9%)

>63 Gy 34 ( 7.4%)

Total Number of Fractions 30 (26 – 39)

Interruptions for toxicity 14 (3.1%)

EORTC

Radiation treatment

Field size (square field-equivalent)

Post-op RT(N=457)

Large*-Large 247 (54.0)

Large-Small** 175 (38.3)

Small-Small 28 ( 6.1)

Missing 7 ( 1.5)

* > 9 cm² square-field equivalent

** 9 cm² square-field equivalent

EORTC

Data Maturity

The median follow-up is 5 years for both arms

A total of 351 of the 478 events of biochemical/ clinical progression-free survival needed per protocol were observed (73.4%)

The EORTC Independent Data Monitoring Committee recommended the early release of the results in December 2003

It is too early to assess the impact on time to distant metastases or survival (only 89 patients have died)

EORTC

Late toxicity

More gastro-intestinal toxicity grade 1 and genito-urinary toxicity grade 1-2 are observed with RT, few grade 3 are reported

years0 1 2 3 4 5 6 7 8 9 10 11

0102030405060708090

100

Time to first Grade >=1

0 1 2 3 4 5 6 7 8 9 10 110

102030405060708090

100

Time to first Grade >=3

54.3%

68.0%

years

No RT

RT

No RT: 2.6%

At 5 years:

RT: 4.2%

(years)

0 1 2 3 4 5 6 7 8 9 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment74 503 468 404 330 268 194 128 82 44 16

25 502 465 426 362 298 228 154 107 55 14

Wait-and-See

Irradiation

Cumulative incidence of loco-regional failure

Gray test P<0.0001

No further treatment: 15.4% at 5 years (98% CI: 11.2 –

19.6)

Post-operative RT: 5.4% at 5 years (98% CI: 2.7 – 8.0)

Clinical progression-free survival

(years)

0 1 2 3 4 5 6 7 8 9 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :113503 467 401 324 259 188 124 79 42 16

75 502 464 424 357 291 221 150 101 53 14

%

86.3% (82.2 – 90.4)

77.1% (72.1 – 82.0 )

HR=0.61 98% CI: (0.43, 0.87)Logrank P=0.0009

No further treatment

Post-operative RT

Biochemical progression-free survival

(years)

0 1 2 3 4 5 6 7 8 9 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :220 503 425 337 243 182 126 84 52 27 10

131 502 456 407 330 262 193 125 85 41 11

%

HR=0. 48 98% CI: (0.37, 0.62)

Logrank P<0.0001

No further treatment

Post-operative RT

74.0% (68.7 – 79.3)

52.6% (46.6 - 58.5 )

EORTC

Code and nameEvents / Patients

Post-op RT WawaStatistics

(O-E) Var.HR & CI

:(Post-op RT Wawa)|1-HR|% ± SD

SM+, ECE- 13/ 84 27/ 79 -9.7 9.8

SM-, ECE+ 34/ 139 40/ 127 -6.2 18.3

SM+, ECE- 33/ 149 74/ 169 -24.1 26.5

SV+ 51/ 128 79/ 128 -22.9 30.9

Total 131/ 500 220/ 503 -63 85.5(26.2 %) (43.7 %)

52% ±8reduction

0.25 0.5 1.0 2.0 4.0Post-op RT WawaTest for heterogeneity

better betterChi-square=4.41, df=3: p=0.2Treatment effect: p=0.00000Test for trend

Chi-square=0.06, df=1: p=0.8

Biochemical PFS by pT

EORTC

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Margin status22 76 65 34 12 6

22 33 21 10 4 2

11 40 30 19 13 5

57 119 86 48 23 6

Loc - / Rev -

Loc - / Rev +

Loc + / Rev -

Loc + / Rev +

B-PFSWait and See

Overall Wald test: p=0.0007 (df=3)

Margin statusPatients

(N)

ObservedEvents

(O)% at 5 Year(s)

(95% CI)

Local - / Review - 76 22 65.60 (50.89, 76.86)

Local - / Review + 33 22 45.27 (25.84, 62.88)

Local + / Review - 40 11 69.75 (50.34, 82.78)

Local + / Review + 119 57 49.44 (39.38, 58.72)

EORTC

ARO 96-02 : 385 patients

Southwest Oncology Group Trial : 431 patients

Other randomized studies

EORTC

ARO 96-02385 patients with pT3 N0 M0

1

0,75

0,5

0,25

00

p = 0,0010 HR : 0,49 (IC 95 0,3-0,75)

RT 81%

4-year biochemical progression free survival

Wiegler T et al et al ASCO 2005, abstract 4513

WW 60%

EORTC

SWOG 8794

1988-1995 - 473 pts pT3 prostate cancer randomized to RT - 60-64Gy or observation onlyThompson et al. AUA 2005 Abstract #1665

EORTC

Conclusion

Post-operative radiotherapy results in improved biochemical and clinical progression-free survival.

Today, T1c stages are most common and the rate of SM(+) is far lower as well as the median PSA before surgery.

The results of RP and immediate RT for pT3 R0-1 N0 might be improved by : i) accruing patients with a negative post-operative PSA, ii) replacing conventional RT by 3D-CRT, iii) promoting dose escalation.