Prostate Cancer Comparative EffectivenessJohn Sylvester M.D. 21st Century Oncology

Eliminate Cancer -

- High Total Dose to Prostate Cancer

Avoid Significant Side Effects- Low Dose per Day- Limit Rectal Volume/Dose

Cone Beam-CT

Linear accelerator

Partin TablesStudy of > 5,000 patients that underwent Radical Prostatectomy

Risk of microscopic disease

T Stage (DRE) ECE

Gleason Score SV

PSA Lymph Nodes

TRUS Volume Study

05/00 Seattle Prostate Institute

Transperineal Interstitial Permanent Prostate Brachytherapy(seed implant)

Quality & Experience is Critical

Day 1 post-implant dosimetry

Prostate

Full DoseRadiationInside and outside of prostate

Seeds Inside and outside of prostate

Post Operative

Discharge to home 1 hour later with: • Alpha-blockers, NSAIDs, Antibiotics• Ice bag on perineum 20minutes on/off repeat all day• Light lunch, normal dinner • Post-op dosimetry CT the next day.• Return to work in ~3-4 days• Avoid strenuous activities and sex for ~ 2 weeks• Avoid upright bike seat 2 months

Cone Beam-CT Image Guided-IMRT (BEAM)

Cone Beam-CT

Linear accelerator

Multiple fields (>100-200)

Doses

4 field: 68 Gy

3dCrt: 74 Gy

IMRT: 78 Gy

IGRT: 81 Gy

• Normal structures significantly spared (e.g. rectum V70 19% vs 1.7%)

• Side effects Graded 1 (very mild)-5 (severe)

• Acute grade 2 toxicity (mild) : Rectal 80% vs 13% p=0.004. Bladder 60% vs. 13%, p=0.014.

• No grade 3-5 toxicity

• Conclusion: IMRT with daily image (IGRT) results in lower dose to normal structures which means less side effects

Prostate Cancer IMRT +/- IGRT Chan LW et al IJROBP ;69,No 3 2007,abstr.#2242

Rectal Balloon

Rectal Balloon1) Lower rectal dose2) Less movement3) Normal diet4) Lower small bowel dose

CBCTIGIMRT

Cone-beam CTImage GuidedIntensity Modulated Radiation Therapy

SpaceOARFDA approved 2:1 randomized trial

SpaceOAR

Low Intermediate High

PSA < 10 PSA 10.1-20.0 ng/ml PSA > 20 ng/ml Gleason < 7 and/or Gleason = 7 Gleason 8-10 T1c-T2a and/or Stage T2b Stage > T2c,T3

RISK Groups

Don’t Use MSKCC Nomogram to compare results!!!

5-YR Relapse-free Survival Low risk usually seeds

alone

Intermed. ebrt

+ seeds

High risk ebrt+seeds +/-

hormones

Seeds MSKCC (IJROBP 2009) 97% 89% ------------

Seeds Cleveland Clinic (IJROBP ;2008) ------------- 89% -----------

Seeds Sylvester Seattle (IJROBP 1;2007) -------------- 80% (15-yr) 68% (15-yr)

Seeds Sylvester Seattle (Brachy 5;2009) --------------- 92% (9-YR) --------

Seeds Frank..Sylvester (Cancer Epub 2011) 99.1% (7-yr) ----------------- ------------

Seeds Multi-institutional study IJROBP Feb 2009 --------------- 86%

HDR Demanes- (UCLA JCO 2009 ) (10-yr) 92% 87% 63%

RP Mayo Clinic RP (J. Urol April 2008) 82% 10-yr 65% (10yr) 55% (10yr)

RP JHU RP (Hernandez J Urol 2007) 94% 76% 54%

RP Cleveland Clinic RP (IJROBP 69,3,2007) 86% (10yr) 79% (5yr)

EBRT Protons- IJROBP 78,3 s146 ASTRO 2010 (10-yr) 92% 69% -----------

IMRT MSKCC (81Gy) J Urol; 176, Oct 2006 89% (8yr) 78% (8yr) 67% (8yr)

Immune Baylor Prostatak + 76Gy IMRT 2006 100% (~6yr) 95% (~6yr) 80% (~6yr)

HiFU HiFU European Urology 65 (2014) 76% (8yr) 63% (8yr) 57% (8yr)

Cryo Dhar et al BJU int, 2011 Jul 1 (Epub) 79.4% 61.4% 58%

HIFU Dickinson et al; Mar 2016 Urology

• 569 patients 8 hospitals academic registry

• 29% required re-treatment

• 5-yr relapse free survival

• Low risk = 87%

• Intermediate= 63%

• High risk = 58%

• Impotency = 71%

• Incontinence = 12%

Comparative Analysis of Prostate Specific Antigen Free Survival Outcomes for Patients with Low, Intermediate and High Risk Prostate Cancer Treated By Radical Therapy.

Results of the Prostate Cancer Results Study Group. Grimm, Sylvester et al IJROBP 2009. Updated BJU Int 2012;109(sup1):22-29

12/11/2020 16

7

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Seeds

Surgery

EBRT

5

22

← Years from Treatment →

CRYO

• Prostate Cancer Results Study Group • Numbers within symbols refer to references

1

12 24

14 8

2

23

HIFU

% P

SA P

rogr

essi

on

Fre

e

11

15

Protons

21

4

18

9

10

EBRT & Seeds

25

Robot RP

26

27

HDR

2829

30

313233

34

1936

37

38

LOW RISK RESULTS

3 39

35

40

42

43

13EBRT

Brachy

Surgery

Trea

tmen

t Su

cces

s

John Sylvester MD21st Century Oncology

12/11/2020 17

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Brachy

Surgery

EBRT

CRYO

HIFU

29

22

21

519

% P

SA P

rogr

essi

on

Fre

e

18

12

28

317

10

32

9

8 2

25

1

13

Protons

HDR

← Years from Treatment →

• Prostate Cancer Results Study Group • Numbers within symbols refer to references

15

436

37

38

+

Seeds Alone

Seeds + ADT40

Robot RP

41

42

44

43

45

46

INTERMEDIATE RISK RESULTS

7

11

14

20

35

34

39

2324

16

6

26

33

EBRT & Seeds

EBRT Surgery

Brachy

EBRT & Seeds

Hypo EBRT

EBRT, Seeds + ADT

Trea

tme

nt

Succ

ess

John Sylvester MD21st Century Oncology

Comparative Analysis of Prostate Specific Antigen Free Survival Outcomes for Patients with Low, Intermediate and High Risk Prostate Cancer Treated By Radical Therapy.

Results of the Prostate Cancer Results Study Group. Grimm, Sylvester et al IJROBP 2009 Updated BJU Int 2012;109(sup1):22-29

12/11/2020

611

36

25

15

5

EBRT Seeds +ADT

19

30

16 20

18

29% P

SA P

rogr

essi

on

Fre

e

17

21

8

9

22

24

26

37

41

12

Protons

HDR

← Years from Treatment →

• Prostate Cancer Results Study Group • Numbers within symbols refer to references

42

4344

45

46

47

Robot RP

48

49

101

102

103

104

105

106

107

109

HIGH RISK RESULTS

10

23

35

108 4

2

31

39

32

33

34

38

EBRT, Seeds & ADT

Brachy

EBRT Surgery

EBRT & ADT

EBRT & Seeds

Hypo EBRT

Trea

tmen

t Su

cces

s

1

7

John Sylvester MD21st Century Oncology

Comparative Analysis of Prostate Specific Antigen Free Survival Outcomes for Patients with Low, Intermediate and High Risk Prostate Cancer Treated By Radical Therapy.

Results of the Prostate Cancer Results Study Group. Grimm, Sylvester et al IJROBP 2009 Updated BJU Int 2012;109(sup1):22-29

HiFU

ASCENDE-RT RCT Trial

For the Brachytherapy Blast Issue this month, Dr. Mira Keyes has graciously written a summary of the ASCENDE-RT RCT trial, PI Dr. James Morris, that was presented both at the ASCO GU Symposium this year, as well as the

April ABS meeting in Orlando. This RCT is a "game changer" in the management of intermediate- and high-risk prostate patients. All GU

oncologists should be very familiar with the study design and results. In this study of nearly 400 men, both groups received 12 months of ADT and pelvic RT to 46 Gy. They were than randomized to either an EBRT boost of 32 Gy (total EBRT dose of 78 Gy) or an LDR-PB boost of 110 Gy. At over 6

years of follow-up the PSA PFS curves dramatically diverge with a 50% reduction in the failure rates for those who received a LDR-PB boost. The

absolute difference at 9 years for the intermediate-risk LDR-PB group was 24%, and for the high-risk group 20% (P = 0.001 - 0.05). The prevalence of

GU 3 toxicities were 8.6% vs 2.2% for LDR vs EBRT - primarily urethral strictures in which 50% resolved with dilatation. These results are

staggering and practice changing. We thank the vision and leadership of Dr. Morris and the British Columbia Cancer Agency for conducting this sentinel work. At the ABS, we predict this RCT, as well as the results of other critical

studies, will solidify the importance of dose escalation with BT.

Daniel Petereit, MD, FASTRODavid K. Gaffney, MD, PhD, FASTRO, FACR

ASCENDE-RT RCT Trial

Radical prostatectomy, external beam radiotherapy, or EBRT with Brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 cancer

Kishan et al JAMA march 6, 2018 .vol 319, N9

• 1,809 patients at 12 teriary medical centers

• 5-year Prostate cancer specific mortality: 3% Brachy boost, 13% EBRT, 12% Surgery

• 5-Year metastatic disease: 8% Brachy boost, 24% Surgery, 24% EBRT

• 7.5-year overall mortality: 10% Brachy boost, 18% EBRT, 17% surgery

• Only 41% of EBRT patients received greater than 70Gy and 2 years ADT

Acute Temporary Side Effects – IMRT (Beam)

• Obstructive Urinary Symptoms ~ few weeks s/p tx--- Usually mild

• Retention (Catheter) --- much less than 1% of patients

• Increase BM frequency --- common

• Diarrhea --- Mainly if lymph nodes treated

• Fatigue --- usually mild

Brachytherapy (Seeds)

• Obstructive urinary symptoms –moderate

• Catheter 6-35% of patients (~2-4 weeks)

• Alpha blockers usually for 3- 6+ months

• Pain with Urination ~ 24-72 hours

• Time off work ~ 1-2 days

• Diarrhea – very rare

• Fatigue – usually mild if any

• O.R. Procedure and anesthesia

Possible Late / Long Term Side Effects

- Rectal: bleeding ~ 1 yr s/p treatment.- More frequent BM’s, looser stools, more

sensitivity to roughage in diet- Impotency: age and current function dependent- Reduced volume ejaculate- Bladder: Permanent frequency urgency- Radiation induced malignancies (rare)- Dysuria (burning sensation during urination)- Stricture (restricted flow)- Incontinence - rare

Later Possible Side EffectsIMRT (81Gy) (Beam)MSKCC (Zelefsky et al J Urol 2010 Dec)

SeedsMSKCC(Zelefsky et al J Urol 2010 Dec)

Protons(EuropeanUrology 60 (2011)Pp 908-916)

Number Patients 281 448

Grade 2 rectal 1.4% 5.1% Highesttoxicity

Grade 3 Rectal 0% 1.1% Highesttoxicity

Grade 4 rectal 0% 0%

Grade 2 GU 4.3% (Stricture- tx Flomax)

15.6%

Grade 3 GU 1.4%(Stricture- tx Dilation)

2.2%

Proton Beam therapy has higher gastrointestinal

Toxicity any other radiation option

John Sylvester M.D. 21st Century Oncology-Lakewood Ranch Oncology Center

Late Gastrointestinal Toxicities Following Radiation Therapy for Prostate CancerKim et al European Urology 60 (2011) 908-816

John Sylvester M.D. 21st Century Oncology-Lakewood Ranch Oncology Center

0

20

40

60

80

100

Urinary Function Bowel Function Sexual Function

Prostatectomy

Brachytherapy

EBRT

Controls

Surgery

Seeds +/- EBRT

Old form of EBRT

controls

HRQOL: UCLA-PCIProstatectomy vs brachytherapy vs EBRT (not IMRT)Measured QOL 2.5 years post treatmentHigher the bar = better the function

* = poor functioning

Davis JW, et al. J Urol. 2001;166:947-952.

**

*

*-Statistical Significance

(Surgery & Seed patients are younger than ebrt pts)

Used 3dCrt , (Modern IMRT has less side effects)

SexualBowelUrinary

At 5 Years, Brachytherapy Shows Quality-of-life Advantages over Radical Prostatectomy for Favorable-risk Prostate Cancer Crook et al JCO;September 1, 2011, Volume 2, Issue 13

P < 0.05 = significant

*

*

*

*

*

*

*

*

New Radiation Therapy Innovations

• Stranded Seeds: - prevents seed migration

• Cs-131 Seed shorter 1/2life- maybe shorter duration side effect?

• Rectal Balloon - reduces rectal side effects and prostate

motion

· CT/MRI Fusion planning

– reduces side effects

John Sylvester M.D. 21st Century Oncology-Lakewood Ranch Oncology Center