1. Department of Radiation Oncology, Shuang Ho Hospital Yu Jen Wang MD
Role of Salvage Intensity Modulated Radiation Therapy for Biochemical Failure after Radical Prostatectomy
加IIMRT 前面減少 後面加入oncotarget
Department of Radiation Oncology, Shuang Ho Hospital
Yu Jen Wang MD

2. In 1853 Emperor Xian Feng of the Ching Dynasty
About prostate ca
Was a Very Rare Disease
Prostate cancer…
Rare disease…
1853清咸豐三年
太平天國 臺灣天地會
Queen Victoria
40 VS. 80
In 1853 Emperor Xian Feng of the Ching Dynasty

3. Introduction Epidemiology: Primary treatment: 46% OP, 30% RT, 60% ADT
US in 2014: 233,000 new cases / 29,480 patients death from prostate cancer
Taiwan: in 2013: 4,804 in 2013, 1207 dying of the disease.
More advanced disease, higher PSA
Primary treatment:
Life expectancy/Risk Groups (T stage, Gleason Score, PSA)
Active Surveillance
Radical prostatectomy (RP)
Radiotherapy
Young, Hugh H. "THE CURE OF CANCER OF THE PROSTATE BY RADICAL PERINEAL PROSTATECTOMY (PROSTATO-SEMINAL VESICULECTOMY)-HISTORY, LITERATURE AND STATISTICS OF YOUNG OPERATION." Journal of Urology 53.1 (1945):
46% OP, 30% RT, 60% ADT
Taiwan Cancer Registry
United States Cancer Statistics

4. Surgery technique Traditional radical prostatectomy
Localized patients
Life expectancy ≥10 years
No serious comorbidity
Laparoscopic radical prostatectomy
Robotic radical prostatectomy
Adverse effects
Blood loss
Erectile dysfunction
Urine incontinence
. "Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study." A multinational, multi-institutional study comparing positive surgical margin rates among open, laparoscopic, and robot-assisted radical prostatectomy patients."
Nam, Robert K., et al. The lancet oncology 15.2 (2014):
Sooriakumaran, Prasanna, et al. European urology 66.3 (2014):

5. After Radical prostatectomy (RP)
Overall survival
Disease free survival
Biochemical failure rate 15-30%
Risk factors: positive surgical margins, seminal vesicle invasion (SVI), extraprostatic extension (EPE) and higher Gleason scores
AUA/ASTRO Guideline 2013
Stephenson AJ, et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. European urology 2012;61:

6. Adjuvant RT vs. Postop surveillance
 Decreases the risk of biochemical relapse
 Administering RT to some patients who would otherwise never require treatment
SWOG 8794 ( ) 425 patients
EORTC ( ) 1005 patients
ARO 9602 ( ) 268 patients
Pathological risk factors
Extraprostatic disease
S.V.+
Margin+
AUA/ASTRO Guideline 2013

7. Adjuvant Radiation Therapy Results
Freedom Biochemical
from
Relapse
Local
Control RP
RP+RT
Actuarial Endpoint
ARO 54
72* NS
5 yrs
EORTC 53
74* 85
95*
SWOG 44 78
92* 25
51*
10 yrs
*Statistically significant with RT
All numbers are in percentages

8. Adjuvant Radiation Therapy Results
Clinical
Free
Disease
Survival
Metastasis Survival
Overall RP
RP+RT
Actuarial Endpoint
ARO NS 95 97
5 yrs
EORTC 81
91* 94 93 92
SWOG 70
84* 82 87 90 91 49
70* 61
71* 66
74*
10 yrs
*Statistically significant with RT
All numbers are in percentages

9. Salvage treatment Salvage RP Salvage RT Cryotherapy HIFU ADT
The 2017 NCCN® clinical practice guidelines in oncology on prostate cancer.

10. Biochemical Relapse: Salvage Prostate Bed Radiation Therapy Results
Author
Pt., No.
Salvage RT Dose Median (Gy)
Biochemical Response %
BCR-free%
Endpoint
actuarial
Neuhof
171
63.0 83 35
5-yr
Ward
211
64.0 90
48-66
5-yr.
Brooks
114 69 33
6-yr.
Stephenson
1540
64.8 59 32
Maier
170
68.0 - 44
7-yr.
Buskirk
368 30
8-yr.
Pazona
223 73 25
10-yr.
Update一下

11. RTOG 9601

12. Rtog 9601
, 760 pts
Post prostatectomy with a lymphadenectomy T2 margin+, T3
RT+ADT (24 months bicalutamide) vs. RT (64.8Gy, 2D or 3DRT)
Median f/u: 12 years
OS: 76.3% vs. 71.3% (p=0.04)
Death from prostate cancer: 5.8% vs % (p<0.001)
Metastatic prostate cancer: 14.5% vs. 23% (p=0.005)
Toxicity: Gynecomastia 69.7% vs. 10.9%
Shipley, William U., et al. New England Journal of Medicine (2017):

13. Shipley, William U. , et al. New England Journal of Medicine 376

14. GETUG-AFU 16 2006-2010 743 pts, pT2, pT3, and pT4a
RT (66Gy, 3D or IMRT)+ goserelin (6m) vs. RT free of biochemical progression: 80% vs. 62% (p<0.0001)
Toxicity: hot flushes, sweating
Carrie, Christian, et al. The Lancet Oncology 17.6 (2016):

16. Nomogram

17. Biochemical failure 2460 pts Median f/u : 5 yrs
24% GS≤6, 56% GS=7, 56% pT3a, 58% margin+
16% with ADT
5-yr FFBF rate was 56%
Concordance index, 0.68
"Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy."
Tendulkar, Rahul D., et al. Journal of Clinical Oncology (2016):

18. estimating 5- and 10-year rates of distant metastases after salvage radiotherapy
Concordance index, 0.74
Tendulkar, Rahul D., et al. Journal of Clinical Oncology (2016):

19. Our study
IMRT: Definitive IMRT in localized Pca results in lower acute and late toxicities compared with conventional conformal RT techniques
Prostate cancer (PCa) patients undergoing salvage intensity modulated radiation therapy (IMRT) for post-radical prostatectomy (RP) biochemical failure
Prognostic factors in IMRT era?
Goenka A, Magsanoc JM, Pei X, Schechter M,
Kollmeier M, Cox B, Scardino PT, Eastham JA and
Zelefsky MJ. Improved toxicity profile following highdose
postprostatectomy salvage radiation therapy with
Oncotarget
intensity-modulated radiation therapy. European urology.
2011; 60:
Goenka A,.et al European urology.
2011; 60:
The 2017 NCCN® clinical practice guidelines in oncology on prostate cancer.

20. Methods Inclusion criteria From 2004 to 2012 Exclusion Criteria
Patients underwent post-RP IMRT at NTUH: 69
Prostate adenocarcinoma
Received salvage RT
Exclusion Criteria
Adjuvant intent: 16
LN+: 3
Total 50 patients enrolled
Update: Inclusion criteria
From 2004 to 2016: n=111, without HT: 44

21. methods Definition for post-RP biochemical failure
PSA level of >0.20 ng/ml by two consecutive measurements.
PSADT and PSA velocity (PSAV) between the post-RP PSA nadir and the initiation of salvage RT were calculated using at least two PSA measurements with a 3-month interval and log calculations on the website of the Memorial Sloan Kettering Cancer Center

22. RT technique All IMRT Dose: Median 70 Gy, range: 63-74 Gy
CTV: prostatic and seminal vesicle bed plus periprostatic tissues as the EORTC guideline
PTV: expansions were 6 mm posteriorly (rectum), 6 mm inferiorly, 10 mm anteriorly, bilaterally, and superiorly from CTV
60-ml air-filled endorectal balloon was placed
100% of prescribed radiation dose covering >95% of the PTV, with the maximum not exceeding 110%
Constraint . "Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group."
Poortmans, Philip, et al Radiotherapy and Oncology 84.2 (2007):

23. Initial clinical T stage before RP
P staging T1 2 4 T2 22 44 T3 25 50 T4 1
Initial Gleason score 6 10 20 7 24 48 8 9 12
Total
Age at IMRT 50
100
< 65 15 30
65-75 28 56
>75 7 14
Initial clinical T stage before RP T1 18 36 T2 T3 4 8
Wang et al. 2016

24. PSA before RP <10 ng/ml 19 38 10-20 ng/ml 16 32 >20 ng/ml 15 30
<10 ng/ml 19 38
10-20 ng/ml 16 32
>20 ng/ml 15 30
Surgical type
Open RP 76
Laparoscopic RP 12 24
PSA doubling time
<3 months 21 42
3-6 months 14 28
6-12 months 10 20
≥12 months 5
Nadir PSA after RP
<0.1 ng/ml
ng/ml
ng/ml
>0.5 ng/ml 6
PSA velocity
ng/ml/year 11 22 18 36 9
>1.0 12 24
PSA before IMRT
<0.2 ng/ml
ng/ml 15 30
>0.5 ng/ml 23 46
IMRT dose Gy Gy Gy 1 2
70-74 Gy 26 52
Wang et al. 2016

25. ADT at biochemical failure
Yes 36 72 No 14 28
ADT duration
≤ 6 months 11 22
6-12 months 5 10
12-24 months
24-36 months 6 12
Wang et al. 2016

26. Median BFFS time: 70 months
survival
5 y/o OS: 91%
5 y/o DFS: 88%
5 y/o BFFS: 60%
Median BFFS time: 70 months
Wang et al. 2016

27. toxicity GI toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Acute
25 (50%)
20 (40%)
5 (10%)
Late
42 (84%)
1 (2%)
2 (4%)
GU toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Acute
31 (62%)
14 (28%)
5 (10%)
Late
35 (70%)
Wang et al. 2016

28. Prognostic factors PSA at salvage IMRT Initial PSA before RP
PSA nadir after RT
PSA doubling time
PSA velocity
Pathological T stage
Gleason score
Initial PSA before RP
ADT at BCF
Salvage IMRT dose
Surgical margin on RP
ADT duration

29. Univariate and Multivariate analysis
Variable
Five-year BFFS
p value
HR (95% CI)
PSA at salvage IMRT
>0.5 ng/ml
37.0%
0.003
0.340 ( )
0.016
≤0.5 ng/ml
78.3%
PSA nadir after RP
>0.1 ng/ml
44.4%
0.346 ( )
0.018
≤0.1 ng/ml
74.0%
Wang et al. 2016

30. Univariate and Multivariate analysis
PSA doubling time
≥6 months
75.9%
0.211
<6 months
50.8%
PSA velocity
<0.5 ng/ml/year
54.5%
0.358
>0.5/ng/ml/year
68.4%
Pathological T stage
T3-T4
58.4%
0.844
T1-T2
63.6%
Wang et al. 2016

31. Univariate and Multivariate analysis
Gleason score
8-10
58.3%
0.931 ≤7
61.3%
Initial PSA before RP
≥20 ng/ml
67%
0.831
<20 ng/ml
56%
ADT use at BCF
Yes
65.5%
0.267 No
50.0%
Salvage IMRT dose
<70 Gy
67.0%
0.245
≥70 Gy
52.4%
Wang et al. 2016

32. Univariate and Multivariate analysis
Surgical margin on RP
Positive
62.3%
0.261
Negative
56.6%
ADT duration
≦6 months
72.9
0.451
> 6 months
61.9
Wang et al. 2016

33. Multivariate analysis PSA nadir< 0.1
5 y/o BFFS
74% vs. 44%
Wang et al. 2016

34. PSA level at salvage RT<0.5
5 y/o BFFS
78% vs. 37%
Wang et al. 2016

35. Favorable Group
5 y/o BFFS
83% vs. 43%
Wang et al. 2016

36. Patients characteristics (without Ht)
Median age at RP: 62 years
Median age at RT: 66 years
Pathological T stage: 45% T2, 50% T3
Median RT dose: 70Gy (63-73Gy)
Gleason score=7: 50%
Median f/u: 24 months

37. survival
3 y/o MFS: 95%
3 y/o BFFS: 69%

38. toxicity GI toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Late
40 (91%)
3 (7%)
1 (2%)
GU toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Late
37 (84%)
4 (16%)
2 (4%)
1 (2%)

39. Comparison of Late GI Toxicity
Pro/Retrospective Adjuvant/Salvage Trials
# pts.
F/U mths.
Grade 2
Grade 3
Grade 4
Our results 44 24 2% 0%
Bolla et al.
EORTC 22911
1005 45
2.5%
Thompson et al.
SWOG 8794
214
127
3.3%
Feng et al.
959 55 4%
0.4%
0.3%
Zelefsky et al. 42 5%
Choo et al. 98 50
Forman et al. 16 -

40. Conclusion
Biochemical failure rate 15-30% after RP consider adjuvant RT or salvage RT (risk factors: Extraprostatic disease, S.V.+, Margin+), early salvage?
Prediction factors: ADT, GS, Margin, pT3a or pT3b, pre-RT PSA, RT dose<6600cGy
GETUG 16/RTOG 9601: ADT+RT better than RT, early salvage ADT? Standard of care for all men with BCR undergoing sRT?
Salvage IMRT for PCa patients with post-RP biochemical failure:
good outcome (5 yr BFFS after SRT: 50-60%) and low toxicity
The patients with post-RP PSA nadir ≤0.1 ng/ml and PSA ≤0.5 ng/ml at salvage IMRT could be benefited the most by salvage IMRT

41. Thank you for your attention
John of Arderne