Management of Low and Intermediate Risk Prostate Cancer

Michael J Zelefsky M.D. Professor of Radiation Oncology

Chief, Brachytherapy Service Memorial Sloan Kettering Cancer Center

Weill Cornell Medical College, Cornell University, Division of Radiation Oncology

Early Stage Disease: Low and Intermediate Risk Disease

` Role of Active Surveillance for Low Risk Disease • Role of dose escalation for Low risk disease

• Comparison of tumor control outcomes and toxicity profiles between IMRT

and BRT. • Enhanced technologies or treatment delivery for EBRT: IGRT, Protons,

SBRT • Management of Intermediate risk disease

– Role of androgen deprivation therapy – Use of combined modality therapy (BRT+EBRT)

• Selection criteria for optimal radiotherapeutic management of low and

intermediate risk disease

NCCN- Very Low Risk Group

• Criteria

•T1c, Gleason score ≤6, PSA < 10

•fewer than 3 cores positive, ≤50% involved

•in each core, PSA density <0.15 ng/mL/g <20 years

Radical Prostatectomy Vs Observation for Localized Disease

(Wilt et al NEJM 2012)

• PIVOT trial enrolled 731 patients from 1994-2002 • Median age: 67 years • Median Follow-up: 10 yrs • Primary Outcome: All cause-mortality • Secondary Outcome: PC mortality • Initial design of the trial to accrue 2000 patients with

a median follow up of 15 years • Trial redesigned for a randomization goal of 740 and

with an expectation of a 25% reduction in mortality

Radical Prostatectomy Vs Observation for Localized Disease (Wilt et al NEJM 2012)

• Findings: – No significant difference in all-cause or PC

specific mortality in patients with low risk disease – Fewer deaths from PC or any cause among high

risk patients treated with surgery – Surgery arm had more complications including

urinary incontinence and ED – Bone metastases noted more often for the

observation group

Survival Outcomes-PIVOT

Improving Staging for Low and Intermediate Risk

The Role of Imaging

Benefit of MRI for Tumor Detection

• MRI sensitivity for disease detection ranges from 40-90%

• MRI sensitivity for disease > 1cm is noted to be 85%

• Accuracy for smaller tumors less clear • Repeat biopsy in low volume disease shows

upgrading or greater volume in 20% which was highly correlated with MRI findings with sensitivity of 90% (Vargas J Urol 2012)

2T Weighted MRI Identification of a Dominant Lesion

Added Value of Multi-parametric MRI in Tumor Staging

78-year-old: PSA= 6.3 ng/Ml, Stage T1C, Initial Biopsy Gleason 6 in 1 of 12 cores

Final pathology showed prostate cancer with Gleason score of 8 (4+4)

Tumor Detection in Prostate Cancer: Multi-Parametric Functional Imaging

• T2 Weighted imaging combined with DWI and DCE-MRI associated with 85% and 83% sensitivity and specificity for low risk disease.

• MRI can better detect anterior PC which comprise 21% of PC which are hard to detect on TRUS biopsy

• TZ directed needle biopsy does not detect a dominant anterior lesion in 80% of cases ( Harrer et al J Urol 2009)

Decision-Related Variable for Consideration of Therapy vs. Observation

• Pathology Variable – Presence of grade 4/5 – > 2 cores involved with >50% core involvement

• Imaging Variables – Evidence of capsular invasion or encroachment – Multi-focality, dominant lesion, larger volume

disease • PSA Kinetics • Patient age • Presence of co-morbidities

Treatment Interventions for Low Risk Disease

• Radical Prostatectomy, Robot-Assisted Prostatectomy

• Conventional fractionated IMRT/IGRT • Proton Therapy • Low Dose Rate Brachytherapy • HDR Monotherapy • SBRT (ultra-hypofractionated IGRT)

EBRT for Early Stage Disease

Randomized Trials of Dose Escalation with EBRT Series # Randomization PRFS Advantage

MDACC (2002, 2008)

301 78 Gy vs 70 Gy 73% vs 50% (10-yr)

Intermediate Risk ( PSA>10)

MGH/LLMC (2006, 2010)

393 79.2 vs 70.2 Gy (protons)

83% vs 68% (10-yr)

Low and Int Risk

Peeters (2006)

669 78 Gy vs 68 Gy 64% vs 54%

Intermediate Risk

Dearnelay (2007)

843 74 Gy vs 64 Gy (with ADT)

71% vs 60%

All risk groups

GETUG (2011)

306 80 Gy vs 70 Gy

72% vs 61%

Dose Escalation Advantage for Favorable Risk Disease Zietman et al JCO 2010

Favorable Risk

Intermediate Risk

Improved Targeting of Radiotherapy

( Zelefsky et al J Urol 2006)

• IMRT has radi

13%

2% P< 0.001

Risk Group 5-year (%) 10-year (%) Low risk* 97.70 93.40

Intermediate risk 89.10 75.50 High risk 76.10 65.80

Outcome of 1002 Patients Treated with 86.4 Gy IMRT

(Spratt et al IJROBP 2012)

Dose Constraints Used for 86.4 Gy

Structures Constraint To

Rectal Wall 53% of total volume V47 30% of total volume V75.6 97% - 99% Max Point Dose

Bladder Wall 53% of total volume V47

105% - 107% Max Point Dose Large Bowel 60Gy Max Point Dose Small Bowel 50Gy Max Point Dose

IGRT @MSKCC for Prostate Cancer • In 2008 gold fiducials routinely placed for all

definitive prostate cancer IMRT. • During this time our PTV margins were

maintained as 1 cm except at the prostate-rectal interface where a 6 mm margin used.

• In late 2010 PTV margins reduced to 6mm circumferentially

• Further margin reductions to 5 mm around the PTV and 3 mm posteriorly used for hypo-fractionated IGRT such as SRS and supplemental IMRT after brachytherapy

Comparison of Toxicity Outcomes Between IGRT and IMRT

(Zelefsky et al IJROBP- 2012)

Characteristics Non-IGRT (N=190) 2006-2008

IGRT (N=186) 2008-2010

Radiation Dose 86.4 Gy 86.4 Gy

CTV-PTV Margins 1 cm except at prostate rectal interface where 6 mm margin used

1 cm except at prostate rectal interface where 6 mm margin used

Use of Androgen Deprivation Therapy

54% 42%

Median IPSS Score 9 9

Actuarial Late Grade 2 or Higher Urinary Toxicity

( Zelefsky et al Int J Radiat Oncol Biol Phys- 2012)

P=0.024

Multivariable Analysis for Predictors of Late Urinary Toxicity

Variable Coefficient %95 Confidence (+/-)

Standard Error

P value Hazard Exponent

Use of Hormones

0.064 0.562 0.287 0.822 1.067

Non-IGRT vs IGRT

0.700 0.603 0.308 0.023 2.015

Age>65 0.138 0.636 0.325 0.670 1.148

Baseline IPSS >15

0.642 0.609 0.311 0.04 1.901

External Beam Radiotherapy 2014 for Low and Intermediate Risk

• High dose IMRT (>=78 Gy) recommended even for low risk disease.

• Target volume should include prostate (+ seminal vesicles) and not pelvis.

• Routine use of IGRT with fiducial marker

placement where margins can be tighter ( at MSKCC a 6 mm circumferential margin is used).

• Increasing interest in hypo-fractionated regimens

Dose-escalation Toxicity Randomized Trials

Institution Dose (Gy) 5-year Outcome Grade 3 Toxicity

MRC RT01 (1998-2002)

74 vs. 64 NED 60% vs 71% (SS) GI 6% vs 10% (SS) GU 2% vs 4% (NS)

Dutch CKVO96-10 (1997-2003)

78 vs. 68 NED 54% vs 64% (SS) GI 4% vs 5% (NS) GU 12% vs 13% (NS)

PROG 95-09 (1996-1999)

79.2 vs. 70.2 NED 79% vs 91% (SS) GI 1% vs 1% (NS) GU 1% vs 2% (NS)

MD Anderson (1993-1998)

78 vs. 70 FFP 75% vs 78% (SS) GI 1% vs 7% (SS) GU 5% vs 4% (NS)

Toxicity after High Dose IMRT- MSKCC

Grade 2+ GU Toxicity

Grade 2+ GI Toxicity

Toxicity Grade ≥2 5-year (%) 10-year (%) GU 16.0 26.7

10-year Crude Toxicity Grade 3 GU 2.2%

Spratt et al 2012- MSKCC

Impact of Dose to the Bladder Trigone on Long-Term Urinary Function after High Dose IMRT

( Ghadjar, Zelefsky and Spratt IJROBP 2014)

Factor Hazard ratio (95% confidence interval) (P)

IPSS sum baseline: >7 0.39 (0.20–0.79) (.009)

Trigone maximal dose: >90.9 Gy 2.70 (1.35–5.32) (.005

Brachytherapy for Early Stage Disease

Prostate Cancer Brachytherapy 2014 • Careful selection of patients to reduce the morbidity

of therapy. – Prostate size of 50 grams or less – IPSS < 18 – Post-void residual of 100 cc or less – No evidence of ECE on imaging

• Improved accuracy of seed delivery with

enhancements in image guidance and sophisticated intraoperative planning systems has resulted in excellent long-term outcomes.

• Use of combined treatment of brachytherapy with external beam radiotherapy to provide dose escalation for intermediate and high risk patients.

Brachytherapy for Low Risk Disease

• 10 year biochemical tumor control outcomes of > 90%.

• Results achieved with permanent interstitial I-125 or Pd-103 or HDR monotherapy.

• Optimal tumor control outcomes seen with proper application of dose – D90 > 140 Gy (for I-125) to the prostate associated

with improved long-term tumor control outcomes

Contemporary Series Reporting Proctitis Rates after Prostate Brachytherapy

Series # pts Median F/U

Grade 2 Grade 3

Phan 2008

263 5.5 yrs 3.7% 0.4%

Zelefsky 2010

448 6.5 yrs 5.1% 1.1%

Shiraishi 2011

458 4 yrs 9.7% NS

Keyes 2012

1006 5 yrs 7.3% 0.9%

Late Urinary Toxicity after Prostate Brachytherapy

Series # pts Median F/U

% G-2 % G-3 % G-4

Anderson (2009)

351 5.7 yrs 6.5% 1.7% 0.5%

Keyes (2009)

712 5 yrs 24% 6% 0.1%

Zelefsky (2010)

448 6.5 yrs 15.6% 2.2% 0%

Zilli (2011)

250 3 yrs 22% 1% -----

Sexual Function after Radiotherapy

• Approximately 30-50% of patients develop ED after RT.

• Almost all patients will develop significant reduction in the ejaculate

• Based on prospective QOL studies , patients who receive BRT may achieve better erectile preservation but this may be related to selection bias

• Sildenafil citrate associated with a 60-70% improvement in EF function.

• Results of randomized trial comparing prophylactic sildenafil versus placebo given to reduce ED after RT indicate especially after 1-2 years improvements of function noted ( Zelefsky et al J Urol in press)

Comparison of Outcomes Between Brachytherapy and

IMRT

Limitations of Comparisons • Lack of prospective randomized data leaves

us with retrospective data subject to selection bias.

• The use of hormone and patient age and co-morbidity differences make the comparison not as straightforward.

• Moving Target Phenomenon: Significant enhancements in treatment delivery over time confound comparisons of therapeutic interventions.

Patient Characteristics Between Treatment Groups

Characteristic Brachytherapy (n=448)

IMRT @ 81 Gy P Value

Age >65

58%

70%

P=0.002

Pre-Treatment PSA <4 >4

21% 79%

15% 85%

P=0.08

T Stage T1c

81%

70%

P=0.001

Use of Neoadjuvant Hormones

31% 32% P=0.81

PSA-Relapse Free Survival Favorable Risk Patients

( Zelefsky et al Urology 2011)

BRT vs EBRT: 95% versus 89% at 7 years Median PSA Nadir (ng/ml): 0.1 BRT; 0.6 EBRT

BRT

EBRT

Cox Regression Analysis for PSA-RFS

Factor UVA MVA HR P-value HR P-value

Mode (Brachy vs. EBRT) 0.30 <0.00001 0.517 0.0004

Age (continuous) 1.0 0.85

Age (>69 vs <=69) 0.993 0.96

HT (1 vs 0) 1.63 0.0003 0.82 0.18

Dose level (8640 vs 8100cGy)

1.03 0.86

Combined Brachytherapy and IMRT as an Effective Means of Dose Escalation

Comparison of LDR Brachytherapy vs IMRT @ 81 Gy

for Low Risk Patients Toxicity Brachytherapy IMRT P Value

GI Late Toxicity Grade 2 Grade 3

5.1% 1.1%

1.4% 0

0.01 0.19

GU Late Toxicity Grade 2 Grade 3

15.6% 2.2%

4.3% 1.4%

<0.001 0.62

Prostate Cancer Results Study Group

( Grimm BJU Int 2012)

• Meta-analysis of over 18000 identifying cohorts who were risk-stratified with 5 year follow-up

• Conclusions similar – Low risk: BRT provides superior biochemical

control – Intermediate Risk: combined EBRT+BRT

provide similar biochemical outcomes compared to selected patients undergoing BRT alone

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7

60

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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 F

ree

11

15

Protons

21

4

18

9

10

EBRT & Seeds

25

Robot RP 26

Prostate Cancer Center of Seattle

27

HDR

28 29

30

31 32 33

34

19 36

37

38

LOW RISK RESULTS Weighted >40 months follow-up or less than 100 patients

Trea

tmen

t Suc

cess

3 39

35

40

41

100

101

13

65

49

76

80

56

59 63

41

75

51

71 72

90

73

74

70

42

57

85 84

66

43 64

44 EBRT & ADT

53

82 81 62

54

79

86

87

88

45

58

69

78

77

46

48

91

+ Seeds & ADT

93

92

89

50

67

68

95 94

55 52 83 47

61

Brachy EBRT

Surgery

Hypo EBRT

96

103

102

97

98

60 6

16

104

105

106

99

107 108

17

Comparing Radiotherapeutic Interventions for

Intermediate Risk Disease

Comparing Outcomes for Intermediate Risk Disease

Sathya et al, JCO 2005

EBRT 66 Gy/33 fx to isocenter

LDR 35 Gy + EBRT of 40 Gy

vs.

EBRT 55 Gy/20 fx to isocenter (EQD2 65.3 Gy)

HDR 17 Gy /2 fx + EBRT of 35.75 Gy

vs.

Hoskin et al, Radiotherapy and Oncology, 2012

Two phase III RCT demonstrated biochemical control benefit of EBRT + brachy boost (combo-RT) over non-dose escalated EBRT alone

Combo

EBRT

41

33

37

21

26

16

11

4

Phase III Randomized Trial of HDR and EBRT vs EBRT alone for Localized Prostate Cancer

( Hoskin et al Radioth Oncol 2012)

Comparison of HDR+IMRT versus IMRT Alone

• 2 modalities of radiation dose escalation: – Ultra-high dose prostate IMRT to 86.4 Gy

• 470 patients, 53 months median followup (Zelefsky, IJROBP 2008)

• BED1.5 = 190.08 – HDR brachytherapy, 21 Gy in 3 fractions,

followed by prostate IMRT to 50.4 Gy • 160 patients, 47 months median followup • BED1.5 = 229

Intermediate Risk

p < 0.001

Deutsch et al Brachytherapy 2011

HDR

IMRT

Comparing EBRT vs Brachytherapy for Intermediate

Risk Disease

MSKCC Experience ( Spratt et al BJUI 2013)

Methods

• Retrospective analysis of consecutive patients

• Inclusion criteria: • 1997-2008 • Intermediate risk defined by NCCN

• PSA 10-20 ng/mL, Gleason Score 7, and/or T2b/c disease

• 870 patients

• 470 with high dose IMRT alone • 400 with combo-RT

• 260 LDR and 140 HDR

Time (years)

Prob

abili

ty o

f Bio

chem

ical

Con

trol

P = 0.00005

81.4%

92.0%

Comparison of Combined Brachy and IMRT vs IMRT Alone PSA-Relapse Free Survival

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6 7 8 9 10 11 12

IMRT

Combo-RT

COMBO

IMRT 86.4 Gy

Time (years)

Prob

abili

ty o

f Dis

tant

Met

asta

sis-

Free

Sur

viva

l

P = 0.044

97.2%

93.0%

Comparison of Combined Brachy and IMRT vs IMRT Alone Distant Metastasis-Free Survival

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6 7 8 9 10 11 12

IMRT

Combo-RT

IMRT 86.4 Gy

COMBO

Late Grade 2 Late Grade 3

Gastrointestinal

Genitourinary

Combo-RT IMRT P-Value Combo-RT IMRT P-Value

Gastrointestinal 4.1% 4.6% 0.89 1.4% 0.4% 0.36 Genitourinary 21.2% 19.4% 0.14 1.4% 3.1% 0.74

7 year actuarial rates

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

BrachySurgeryEBRTCRYOHIFU

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21

5 19

% P

SA P

rogr

essi

on F

ree

18

12

28

3 17

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 4

36

Prostate Cancer Center of Seattle

37

38

+

Seeds Alone

Seeds + ADT 40

Robot RP

41

42

44

43

45

46

INTERMEDIATE RISK RESULTS weighted >40 months follow-up or less than 100 patients

7

11

14

20

35

34

39

23 24

16

6

26

33

82

66

88

67

70

97 63

65 102 103

101

86

87 85

58 68

71 81 50

EBRT + ADT

94

93

92

77

91 51

69

Hypo EBRT 99

75

90

89

56 55

54

80

57

83

60

73 72

98

53

52

79

95 64

100

84

78

59

62 74

96

76

EBRT

Brachy

Surgery

EBRT & Seeds

EBRT, Seeds + ADT

Trea

tmen

t Suc

cess

104

105 30

27 47

48

49

150

151

106 107 31

109

108

Ultra-hypofractionated SBRT for Prostate Cancer

Ongoing Phase I Dose Escalation Study at

MSKCC • Ultra-hypofractionated IGRT Phase I dose escalation

study – 650 cGy x5- accrual completed – 700 cGy x 5- accrual completed – 750 cGy x 5- accrual completed – 800 cGy x 5- accrual initiated – 850 cGy x 5

• Primary endpoint is toxicity • Secondary endpoints included PSA tumor control and 2-

year biopsy outcomes • Eligibility includes IPSS< 17, Favorable/Intermediate

Risk, no prior ADT

Planning constraints – Converted from 8640 planning

protocols. RW max 3832 cGy D53 Rw 2400 cGy RW NTCP 12.5 ( Average NTCP of 8640cGy patient) Urethra max 4011 cGy Bladder wall 4100 cGy D53 BW 2400 cGy BOWEL S/L 2516 / 2899 cGy

1. Margins 3 mm at prostate rectal interface and 5 mm circumferentially 2. Patient simulated with catheter so urethra can be well delineated 3. Real time Tracking employed for each of the 5 fractions

PTV D95 = 3700

Color Wash of SHARP Dose Distribution

Ultra-Hypofractionated RT Tumor Control Outcomes

Study # Dose/Fx Fx Total Dose

Median F/u (mo)

PSA Control

Virginia Mason (2010)

40 6.7 5 33.5 Gy 41 90%

Stanford (2009)

41 7.25 5 36.25 Gy

33 100%

Naples (2009)

112 7-7.25 5 35-36 Gy

24 99%

Winthrop (2010)

304 7-7.25 5 35-36 Gy

30 99%

Boike (2011)

45 9-10 Gy 5 45-50 Gy

30 100%

Georgetown (2013)

100 7-7.25 5 35-36 Gy

27 99%

Ultra-Hypofractionated RT- Toxicity Outcomes

Study Dose/ Median F/u (mo)

Late GI Toxicity

Late GU Toxicity

King et al 2009

36.25Gy 33 48% G1-G2

65% G1-G2; 5% G3

Katz et al 2010

35 Gy 30 9% G1/G2 9% G1/G2 0.5%- G3

Bolzicco et al 2010

35 Gy 20 2.2% G-2 9% G1/G2 2.2%- G3

Freeman et al (2010)

36.25 Gy 60 15.5% G1-G2

32% G1/G2 2.5%- G3

King et al 2012

36.25 Gy 32 16% G1-G2

28% G1/G2 3.5%- G3

Adapted from Seisen et al 2013

Ultra-hypofractionated SBRT for Prostate Cancer

• So far excellent results reported albeit with shorter follow-up.

• Recent meta-analysis by King et al notes >90% PSA control rates in over 1000 patients treated (36.25 /4-5 fractions). PSA outcome for low, intermediate and high risk was 95%, 84% and 81%.

• Preliminary results also indicate excellent tolerance especially when using tight margins and intra-fraction motion tracking.

Protons for Early Stage Disease

Protons and Prostate Cancer • Between 2006-2009 there has been a doubling

of prostate cancer patients treated with proton therapy

• Increase in usage speculated to be related to the allure of new technology and high reimbursement per course of treatment

• No evidence in the literature of superior tumor control outcomes with protons compared to photons for treatment of prostate cancer

• University of Penn and MGH and other conducting randomized trial of IMRT vs proton for clinically localized disease

Comparison of Outcomes and Toxicity Between Proton Therapy and IMRT

( Sheets et al JAMA 2012) • Population=based study using SEER-

Medicare Linked data of treatments from 2000-2009

• Salient Findings: – IMRT patients had lower rates of GI toxicity

(absolute risk: 12.2 vs 17.8 per 100 person-years; RR-0.66)

– No significant differences in rates of other morbidities

– Comparable tumor control outcomes as reflected by need to receive additional cancer therapies

Comparison of Need for Additional Cancer Therapies Between Patients Treated Initially with Proton Therapy Vs IMRT

JAMA 2012

JAMA. 2012;307(15):1611-1620. doi:10.1001/jama.2012.460

The Physics Facts And Uncertainties About Protons ( Lawrence and Feng 2013)

• Bragg peak serves as advantage to reduced exit dose potentially leading to reduced normal tissue exposure and theoretically lower risk of secondary cancers

• Bragg peak of a single energy is too to treat a tumor so different energies must be used to broaden the peak increasing the entrance dose

• Uncertainty as to how far protons will travel, so the high dose region is typically extended several mm beyond the target

IMPT for Prostate Cancer

The Role of Androgen Deprivation Therapy for

Intermediate Risk Prostate Cancer

Intermediate Risk Prostate Cancer

• NCCN Intermediate Risk Factors – Clinical stage T2b-c – Gleason score 7 – PSA 10-20

• Multiple intermediate risk factors may be classified as high risk disease

• Optimum therapy is controversial

Randomized Trials of Short Term ADT with Intermediate Risk

Prostate CA

• RTOG 94-08 (Jones NEJM 2011) – 10 yr OS: 62% vs 57%, p = 0.03 – Benefit driven by intermediate risk patients

• DFCI Trial (D’Amico JAMA 2008) – 8 yr OS: 74% vs 61%, p=0.01 – ~75% of patients were intermediate risk

Can Dose Escalation Replace Short Term ADT?

• Low Doses Used in Both Trials – RTOG 94-08: ~63 Gy to 95% isodose line – DFCI Trial: 70.4 Gy to 95% isodose line

• Dose Escalation Trials

• Is ADT necessary in the dose escalation

era?

Adverse Sequelae of ADT • Adverse Quality of Life Sequelae

– Hot flashes, fatigue, sexual dysfunction, decreased libido, depression

• Adverse Medical Sequelae – Weight gain, muscle loss, diabetes – Anemia – Osteoporosis – Increased cardiovascular morbidity and

mortality is controversial

Improved Outcomes with SHORT COURSE ADT in Intermediate Risk Patients Treated with Dose Escalation

( Zumsteg et al IJROBP 2012- MSKCC)

P<0.001

Hormones

No Hormones

>=81 Gy

Impact of Short Course ADT on DMFS Prostate Cancer Death for Intermediate Risk Patients

( Zumsteg et al IJROBP 2012)

P = .011

DMFS Cause-Specific Survival

P = .032

Need for Adjunctive ADT with Radiotherapy for Low and Intermediate Risk Disease

• No role for using ADT in conjunction with low risk disease with EBRT or BRT.

• Data suggest benefit for using ADT with intermediate risk disease when using EBRT at dose levels of 81 Gy or higher.

• Data suggest that when using escalated intra-prostatic doses with BRT the use of ADT is not established.

Lack of Benefit of ADT When Using Brachytherapy

Intermediate Risk Disease

P=0.986

Is there a Benefit adding ADT with Brachytherapy?

Series # # IR % with ADT Treatment Outcome Benefit

Ash 2005 667 238 52% LDR None for IR

Stock 2010 432 432 81% LDR+EB No

Martinez 2005 934 NR 44% HDR+EB None for PSA , DM or OS

Merrick 2006 938 425 41% LDR or LDR+EB

None for PSA , DM or OS for IR

Beyer 2005 2378 787 20% LDR or LDR+EB

None for PCSM, reduced OS

Zelefsky 2011 1466 563 31% LDR or LDR+EB or HDR+EB

No for PRFS

Krauss 2011 575 417 47% LDR or LDR+EB or HDR+EB

Benefit for monotherapy, none for combined

MSKCC Treatment Algorithm for Intermediate Risk Prostate Cancer

Zumsteg & Zelefsky, Lancet Oncology 2012

RTOG 0815 • RCT of NCCN intermediate risk prostate

cancer receiving “dose escalated RT” +/- 6 months CAB – Excludes patients with all 3 intermediate RF’s

(T2b-c, GS = 7, and PSA 10-20) and ≥ 50% positive cores

– Planned accrual: 1520 patients • Dose escalated RT per physician choice:

– EBRT alone (79.2Gy/44fx to PTV) – Combination EBRT + brachy (either LDR or HDR)

• EBRT: 45Gy/25fx to prostate/SV • LDR: I-125 (110Gy) or Pd-103 (100Gy) • HDR: 21Gy/2fx

Conclusions-1 • Very Low Risk patients should be considered for AS;

MP MR imaging could provide valuable information re: volume of disease.

• Outcomes with EBRT has been improved with conformal therapies and dose escalation appears to be necessary for both low and intermediate risk disease.

• Outcomes with Brachytherapy for low and intermediate risk disease based on 2 randomized and retrospective comparisons appear to demonstrate superior biochemical tumor control outcomes and DMFS for BRT vs EBRT.

• Stereotactic hypofractionated radiotherapy demonstrates promise with excellent PSA-RFS for low and intermediate risk disease with excellent tolerance profiles; follow-up still short

• Proton therapy provide excellent dose distributions yet no clear data demonstrating any superiority over dose escalated photon therapy; toxicity not shown to be lower at this time.

• There is no role for ADT in low risk patients yet for intermediate risk patients short course ADT associated with improved survival outcomes when combined with EBRT.

• The role of ADT for intermediate risk patients treated with brachytherapy is unclear

• RTOG 0815 will address these issues as well as the role of ADT in intermediate risk patients when treated with dose escalation

Conclusions-2