rt for high-risk and post- operative prostate cancer · rt for high-risk and post- operative...

RT for High-Risk and Post- operative Prostate Cancer ASTRO Refresher Course 2014

Stanley Liauw MD

Associate Professor University of Chicago

Dept of Radiation and Cellular Oncology

Objectives • Review evidence regarding the role of RT for

high-risk (locally advanced) prostate cancer • Review evidence regarding the role of RT after

radical prostatectomy • Review treatment factors which influence

outcomes (disease control, toxicity) • Review technical aspects of post-operative

radiation planning and treatment

High-Risk, Intact Prostate Cancer

Definitions: NCCN risk category

• Life expectancy estimation is less critical for men with high risk prostate cancer

Recurrence risk Features Consider surveillance, if expectancy:

Very low 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

Low T1-2a, Gleason score ≤6, PSA < 10 <10 years

Intermediate T2b-c OR Gleason score 7 OR PSA 10-20 <10 years

High T3a OR Gleason score ≥8 OR PSA >20 Not specified

Very high (locally advanced)

T3b-4 Not specified

Metastatic Any nodal or distant metastasis

Management of high-risk disease

• EBRT (+/- brachytherapy) with long term ADT • Radical prostatectomy (if no fixation) and LND

+/- RT • ADT alone only for very-high risk disease who

are not candidates for local therapy

NCCN guidelines 2014

Local therapy can improve survival

RT/ADT vs. ADT SPCG-7

Widmark Lancet Onc 2009 NCIC/MRC

Warde Lancet 2011

Eligibility T3 or T1b-2b/WHO G2-3; PSA<70; pN0 if PSA > 11

T3-4, or T2 with PSA>40, or GS8 with PSA>20; cN0/Nx

Patients n=875 78% T3

Median PSA 16 19% WHO G3

n=1205 83% T3

Median PSA 28 18% GS 8-10

Treatment 70 Gy (no pelvic RT) 65-69 Gy (45 Gy pelvis)

Indefinite ADT Anti-androgen (3 mo LHRH)

LHRH agonist (2+ wk anti-androgen)

Median fu 7.6 y 6.0 y

RT/ADT vs. ADT

• RT improves survival, with limited Grade 3 toxicity (≤2%) – Perhaps a wider risk/benefit ratio with newer technology

SPCG-7

24%

12%

Cause specific mortality NCIC/MRC

Overall survival 74%

66%

At 10 years RT/ADT ADT p

PSA failure 26% 75% <0.001

CSS 88% 76% <0.001

OS 70% 61% 0.004

At 7 years RT/ADT ADT p

Time to progr NR 6.8 y 0.0001

CSS 91% 81% 0.001

OS 74% 66% 0.03

What about surgery?

RP has traditionally been reserved for lower risk disease Cooperberg, JCO 2010

Low risk Intermediate risk High risk

Surgery vs. RT • Retrospective studies of biochemical control

Kupelian, IJROBP 2004

n=2991, Median follow-up 56 mo

T1-T2 disease: Surgery and dose escalated RT offer similar bRFS

Surgery vs. RT • Retrospective studies of late endpoints,

including high risk disease

– HRs favor RP (1.5-2.8), largest for high-risk disease

Outcome Endpoint Reference

MSKCC, n=2380 RP > EBRT Metastasis Zelefsky JCO 2010

CapSURE, n=7538 RP > EBRT Cancer mortality Cooperberg, Cancer 2010

Mayo/FCCC, n=1847 RP > EBRT (RP = EBRT/ADT)

Cancer mortality Boorjian, Cancer 2011

CCF/WashU, n=10429 RP > EBRT Cancer mortality Kibel, J Urol 2012

PCOS, n=1655 RP > EBRT Cancer mortality Hoffman, JNCI 2013

Surgery vs. RT • Time from metastasis to cancer death

depends on primary modality of therapy

SEER-Medicare data n=574 with int/high risk disease Median follow-up 33 mo

Shao, Eur Urol 2013

RP

RT

Limitations with comparative data • Imbalances in the two groups are likely • Contribution of salvage therapies can

influence analysis • Comparisons may be outdated (suboptimal RT

dose, imaging, ADT by today’s standards) • Quality of life and toxicity are not considered

A safe conclusion: with primary RT, maximize efforts to safely obtain local control

RT dose • Supported by several randomized trials

to improve biochemical control

Kuban, IJROBP 2008

78 Gy 73% at 10 y

70 Gy 50% at 10 y

RT dose n Eligibility RT dose (Gy)* FFBF at 5 y

MDACC (2002,2008)

301 T1b-3 78 vs. 70 73/50 (10 y); trend FFDM and CSS

Harvard/LLMC (2005,2010)

393 T1b-2b, PSA<15

79.2 vs. 70.2 83/68 (10 y)

Dutch (2006,2013)

669 T1b+, GS6+, PSA<60

78 vs. 68* 49/43 (10 y)

MRC (2007)

843 T1b-3a, PSA<50

74 vs. 64* 71/60

GETUG (2011)

306 T1b-3, PSA<50 80 vs. 70 72/61

*ADT allowed

• Dose escalation is supported for all risk categories • Local control remains a problem even with dose

escalation to 78-80 Gy

RT dose

Kuban, IJROBP 2011

Distant failures after 78 Gy

• MDACC study: median follow-up 9.7 years

0% 0% 3%

Combination EBRT/brachytherapy • 848 outcomes studies (n=14,793 high risk pts)

Grimm, BJUI 2012

• Suggestion of improved outcomes with EBRT + seeds in comparison to EBRT or RP

EBRT

EBRT+seeds+ADT

EBRT+seeds

RP

EBRT vs. EBRT/brachytherapy • Dose escalation with brachytherapy boost is

supported by a few smaller RCTs

n Eligibility RT dose (Gy)* FFBF at 5 y Mt Vernon, UK (2007)

220 T1-T3 35.75/13 fx + HDR vs. 55/20 fx

79/64

McMaster, Ont (2005)

51 T2-T3 40/20 fx + HDR vs. 66/33 fx

71/39 +biopsy at 2 yr: 24/51

– BED was relatively low in the EBRT alone arm – UBC trial compares 46 Gy + brachy vs. 78 Gy in

int/high risk disease (analysis planned in 2014)

Role of ADT with RT • Several randomized trials test RT/ADT vs. RT

n Eligibility ADT Important endpoints affected EORTC (1997,2010)

412 T3-4, WHO G3

36 m vs. 0 m bRFS, LC, DM, CSS, OS

RTOG 8531 (1997,2005)

997 T3, or N+ (non-bulky)

Indef. vs. none bRFS, LC, DM, CSS [OS for GS7-10]

RTOG 8610 (1995,2001)

456 T2-4 bulky, or N+

4 m vs. 0 m bRFS, [LC, DM, CSS, OS for GS2-6]

TROG 9601 (2005,2011)

818 T2b-4; N0 0 vs. 3 vs. 6 m bRFS, LC [DM, CSS, OS for 6 m]

Harvard (2004,2010)

206 PSA 10-40, or GS7+, T1b-2b

6 m vs. 0 m FFbF, FF salvage, CSS, OS

RTOG 9408 (2011)

1979 T1b-2b, PSA≤20; cN0

4 m vs. 0 m FFbF, DM, CSS [OS for int-risk] +biopsy at 2 y

RT is conventional fractionation, 66-70 Gy; whole pelvic RT for high risk patients

The addition of ADT (dual agent) to RT improves survival

High

-risk

In

t-ris

k

Role of ADT with RT • Other randomized trials test length of ADT

n Eligibility ADT Important endpoints affected RTOG 9202 (2003,2008)

1554 T2c-4, N0; PSA<150

28 m vs. 4 m bRFS, LC, DM, CSS [OS for GS8-10]

EORTC (2009)

970 T2c-4, or N+ PSA<160

36 m vs. 6 m CSS, OS

Quebec (abs 2013)

630 T3 or PSA>20 or GS8, N0

36 m vs. 18 m No differences

Canadian (2004,2009)

378 Any M0 8 m vs. 3 m No differences [DFS for high-risk]

RTOG 9910 (abs 2012)

1579 GS6+PSA>10; GS7+PSA<20; T1, GS8-10, P<20

9 m vs. 4 m No differences

Using conventional RT to treat high risk disease, there is a survival advantage with longer term ADT

RT is conventional fractionation, 66-70 Gy; whole pelvic RT for high risk patients

High

-risk

In

t-ris

k

Role of ADT with RT • For prostate cancer with high-risk features:

– ADT ↑local control, distant control, and survival

66-70 Gy Int-risk

4-6 months

18-36 months

High-risk

76-80 Gy

≤4-6 months?

≤18-36 months?

Dose escalated EBRT +/- ADT

– After dose escalated RT, long term ADT is associated with better biochemical and distant control

Feng IJROBP 2013

Retrospective analysis of 234 men treated with 75-79.2 Gy and varying ADT

>≥1 year

0.00.10.20.30.40.50.60.70.80.91.0

FFbF

0 12 24 36 48 60Time (months )

PSA response as a prognostic variable?

These potential biomarkers to guide duration of ADT must be further tested

Pre-RT PSA halving time ≤ 2 weeks

4yr FFbF 96%

4yr FFbF 81%

Pre-RT PSA nadir ≤0.3

Post-RT PSA nadir ≤0.5

8yr PCSM 4-7%

8yr PCSM 27-28%

10yr FFDM 86%

10yr FFDM 79%

D’Amico Lancet Onc 2012 Malik IJROBP 2011

Zelefsky IJROBP 2013

Biomarkers as a (future) variable?

Karnes J Urol 2013

22- gene classifier for distant metastasis after RP (via RNA micro dissection)

Low GC score

High GC score

Pros

tate

ca su

rviv

al

Hormonal therapy

Hormonal therapy SEER-Medicare

Keating, JCO 2006; JNCI 2012

ADT can cause: ↓Insulin sensitivity ↑LDL, HDL and TG ↑Fat mass (↓lean mass)

Veterans Affairs

Absolute Excess Risk: ↑15 cases/1000 patient years

Hormonal therapy

– Joint statement: referrals to cardiology for “ADT clearance” are not necessary (Levine, Ca J Clin 2011)

Nguyen JAMA 2011

• In 8 RCTs, ADT did not ↑risk of CV mortality

RT volume • Pelvic nodes can be involved in high risk disease

– Incidence ~22% from extended LN dissection data

Lymph node involvement goes beyond ‘standard’ US template >50% of time

Weckerman J Urol 2006

RT volume

n Eligibility Arms Endpoints affected RTOG 9413 (2003,2007)

1292 T2c-4 GS6+, or LN+ risk >15%; PSA<100

Whole Pelvis vs. Px only Neoadj HT vs. Adj HT

Trend PFS for WPRT/NHT (and PORT/AHT)

GETUG-01 (2007)

444 T1b-3 Low pelvis RT vs. Px only (ADT allowed)

None

• Does pelvic radiation improve outcomes?

Lawton IJROBP 2007

WP/NHT vs. PO/NHT p=0.066 WP/AHT p=0.022 PO/AHT p=0.75

RT volume

5-year rates of late toxicity

WPRT (n=309)

Mini-pelvis (n=170)

Prostate (n=131)

P value

Gastrointestinal: Grade 2 Grade 3

15% 4%

9% 1%

7% 0%

0.002 0.006

Genitourinary: Grade 2 Grade 3

15 3%

15% 2%

6% 0%

0.03 0.24

• Pelvic radiation adds toxicity

• The risk benefit ratio for 2D pelvic RT is unfavorable • Today, careful patient selection and technology may

influence the decision to include pelvic lymph nodes

Roach IJROBP 2006

Summary: High risk, intact prostate cancer

• Role of RT+ADT well established by RCTs – Long term ADT superior to short term ADT

• Dose escalation improves outcomes – Brachytherapy boost may be an attractive

alternative in select cases

• Pelvic nodal RT (2D) demonstrates an unfavorable risk-benefit ratio

• The “standard of care” may change with incorporation of newer technology (IMRT, IGRT), and new drugs

UCMC guidelines for Intact prostate cancer

• Comorbidity can downstage treatment (~1 category) • Consider protocol enrollment a priority when eligible

Always weigh comorbidity (and consider surveillance)

Low-risk Intermediate risk High risk NCCN risk category:

EBRT:

ADT:

brachy:

78 Gy at 2/fx Prostate only

No

Monotherapy preferred if age<65

<50% cores ≥50% cores <T3 T3; GS9-10; high vol; N1

78 Gy at 2/fx Prostate/SV

No

Monotherapy preferred if age<65


6 mo

Boost considered if age<65


6 vs. 28 mo


79.2 Gy at 1.8/fx Pelvic LN, Px/SV

28 mo


Discuss: Treatment vs. no treatment, Surgery vs. RT

Post-operative Prostate Cancer

Outcomes after prostatectomy Overview Risk factors %bNED-10 y

8 centers Karakiewicz Urol 2005

N=5831

1983-2000 Med fu 25 mo

bNED 61% at 10 y 0% adj RT

+ margins ECE, +/- margins SVI, +/- margins LNI, +/- margins

36 25/46 12/20 14/8

Wash U Roehl J Urol 2004

n=3478

1983-2003 Med fu 65 mo

bNED 68% at 10 y 6% adj RT

Stage cT3 Gleason score ≥8 ECE, +/- margins

SVI LN

15 32

53/62 26 12

Baylor Hull J Urol 2002 n=1000

1983-1998 Med fu 47 mo

bNED 75% at 10 y 0% adj treatment

+margins ECE alone

SVI LN

36 71 37 7

Men with +margins, pT3 disease have >50% risk of failure at 10 yrs

Randomized trials: adj RT vs obs

EORTC 22911 Bolla Lancet 2012

SWOG 8794 Thompson J Urol 2009

ARO 9602 Wiegel JCO 2009/ GU ASCO 13

Eligibility pT2-3N0 ece, svi, or psm

pT2-3N0 ece, svi, or psm

pT3N0 ece, svi, psm

Patients n=1005 1992-2001 Age 65 y

Med preop PSA 12 Postop PSA ≤0.2 in 70%

n=425 1988-1997 Age 65 y

Med preop PSA ~10 Postop PSA <0.2 in 66%

n=307 1997-2004 Age 65 y

Median preop PSA ~9 Postop PSA ≤0.2 in 100%

RT techniques 60 Gy Conventional Prostate bed Within 4 mo

60-64 Gy Conventional Prostate bed Within 4 mo

60 Gy 3D conformal Prostate bed Within 3 mo

Median fu 10.6 y 11.5 y 9.3 y

EORTC 22911 SWOG 8794 ARO 9602

bNED

Endpoints (primary)

bPFS, LRF-10 y (7/17) DM (~11), OS-10 y (~78) bPFS: all except age>70 cPFS: age<65, +margins OS: none (worse if >70)

Clinical PFS-10 y (~70/50) On ADT- 5y (10/21) MetFS-15 y (46/38)

OS-15 y (47/37)

bPFS

bPFS: +margins, PSA>10, pT3b, GS≥7

RT toxicity Acute Late

~20% Gr2; ≤5% Gr3 ~10% Gr2; ≤2% Gr3

Any grade 24% (vs 12%)

proctitis, stricture, incontinence

12% Gr2; 3% Gr3

~ 5% Gr 2; 1% Gr3

Randomized trials: adj RT vs obs

61% at 10 y

41% at 10 y

~50% at 10 y

~25% at 10 y

56% at 10 y

35% at 10 y

Quality of life • Health related QOL: Adj RT vs obs. (n=217)

Global HRQOL: “rating of how life is affected by your state

of health”

Moinpour, JCO 2008

Frequent (mild) rectal Tenderness or urgency

Urinary frequency 9x/day

Insufficient erectile function (Normal) Global HRQOL

RT

RP

ASTRO/AUA joint guidelines • 3 guidelines regarding adjuvant RT:

Valicenti, IJROBP 2013

Statement Recommendation

Clinical principle Counsel men on possibility of recurrence after RP

Clinical principle Inform men that adjuvant RT can be beneficial

Grade A evidence Offer men with negative features at RP adjuvant RT

Have these RCTs changed practice?

– No change in use of adjuvant RT for high-risk disease

Hoffman, J Urol 2011

Concerns with adjuvant RT exist 1. “Observation” group did not routinely

receive early salvage RT after failure

– Original protocol specified salvage treatment at LF – If early salvage RT were routinely given, perhaps

we would not detect a benefit with adjuvant RT Bolla, Lancet 2005

Median time 2.2 years

Subgroups: Adjuvant vs. ‘early salvage’

SWOG

EORTC

~30% of men were enrolled with a postop PSA >0.2

bPFS

Metastasis-FS

“Early” salvage RT • Matched paired analysis of adjuvant and observation

with early salvage (PSA ≤ 0.5) as needed

– Early salvage RT ≈ adjuvant RT; avoids overtreatment – Trials are accruing to address this issue

Salv RT: 5-year FFBF 78%

Briganti Eur Urol 2012

n=890, Median FU 47 mo

Adj RT: 5-year FFBF 82%

65 Gy Bed alone Med PSA 0.2 at salvage

Concerns with adjuvant RT exist 2. A large percentage of men may be treated unnecessarily

– Risks of therapy – Costs of therapy – Surgeons may be especially sensitive to a therapy

which could compromise their patients’ recovery

With adjuvant RT?

Sanda NEJM 2008

Does RT adversely affect continence? • Subset of men on EORTC 22911 (n=100)

– Pad weight measured with adj RT vs. no RT:

– Full continence recovery was not required at randomization

– Rate of full continence (Grade 0) was similar in both groups at time of last follow-up

Van Cangh, J Urol 1998

Pre-RT Post-RT

Does RT adversely affect continence? • Retrospective comparison, Milan (n=361)

RT dose 70.2 Gy at 4.5 mo after RP

81%

51%

Suardi, Eur Urol 2013

The Ideal candidate for adjuvant RT (?) • High risk for recurrence:

– Positive margins or pT3 – Consider for post-RP LN+ disease

• Reasonably good recovery of continence • Longer life expectancy • Patient who understands potential pros/cons

of therapy

The Ideal candidate for adjuvant RT (?) • Hypotheses: Adjuvant RT is better because …

– Adjuvant treatment is less toxic than salvage RT 60-64 Gy without ADT vs. ~68+ Gy +/- ADT

– A delay in treatment might ↑risk of DM – PSA does not reliably report disease burden or

growth kinetics in all cases – Follow-up anxiety can be minimized

Caveat: We cannot confirm that early salvage RT is an inferior approach

Adjuvant RT for LN+ disease • Matched, retrospective comparison, Milan

– Preop PSA ~30; 25% had > 2 LN+

Briganti, Eur Urol 2011


10-y CSS 86%

10-y CSS 70%

Adj RT 3 mo after RP; ~68.4 Gy + long term ADT

Salvage RT • Retrospective data support salvage RT vs obs

n Patients Treatment Important endpoints affected Johns Hopkins JAMA 2008

635 Observation or RT Median PSA ~0.8

43% margin + 28% GS 8+; 20% N1

Median 66.5 Gy 12% ADT

RT improves CSS 10 yr CSS, ~85% vs. 62% [best for PSA DT < 6 mo]

Mayo Clinic J Urol 2009

2657 Observation or RT Median PSA 0.8 45% margin +

11% GS 8+; No N1

RT dose not reported No ADT

RT reduces DM

Duke Cancer 2011

519 Observation or RT 59% margin +

29 GS 8+; No N1

Median 66 Gy 16% ADT

RT improves OS

Salvage RT is associated with ↑CSS and OS

Salvage RT

PSA ≤ 0.5 PSA > 1.5

48% 18%

FFP-6 y FFP associated with: • Gleason score • Pre-RT PSA • LN involvement • Margin status • PSA DT • Use of ADT

Stephenson, JCO 2007

– Similar to intact prostate (T/N, Gleason, PSA) + two post-op factors (margins and PSA DT)


Salvage RT • Meta-analysis of 41 salvage RT studies

King IJROBP 2012

– Best outcomes with lower pre-RT PSA (0.2 probably better than 0.5)

2.6% loss of RFS per ↑0.1 ng/mL PSA

Salvage RT: patient selection • Clinical factors are used to prognosticate outcome

6-year progression-free probability after salvage radiotherapy

Stephenson JCO 2007

• Output typically 30-70% • Largest impact for PSA DT,

pre-RT, GS, LN status, ADT

These men (e.g. short PSA DT) may actually have the biggest gain in CSS

New referral with a post-op PSA • “Post-op active surveillance” analogy

– Weighing natural history of disease vs. life expectancy

Freedland JAMA 2005

15-y CSS 94%: BF > 3 y after RP, PSA DT ≥ 15 mo, GS < 8

ASTRO/AUA joint guidelines

– Limited by quality of evidence available

Statement Recommendation

Clinical principle PSA recurrence post-op is associated with clinical failure

Clinical principle PSA failure post-op is defined as ≥0.2 and rising

Grade C evidence Consider restaging men with biochemical failure

Grade C evidence Offer men with rising PSA post-op salvage RT

Clinical principle Salvage RT is most successful for a low PSA

Clinical principle Post-op RT has possible acute and late toxicity

Valicenti, IJROBP 2013

• 6 guidelines regarding salvage RT:

Salvage RT: imaging Recommended? Comment

Ultrasound and biopsy

No Moderate sensitivity only; only evaluates prostate bed

CT abdomen/pelvis No Low sensitivity with low PSA

Bone scan If PSA >10, PSADT<6 mo, velocity >0.5 ng/mL/mo; or sx

Low sensitivity with low PSA; indeterminate findings possible

RIS (e.g. Prostascint) Not routinely Accuracy questionable; does not predict better salvage RT response

PET (C11, F18) Not routinely Accuracy low for PSA <2

MRI (Endorectal, DCE, DWI)

Consider, especially for pT3 and positive margins

Most favorable sensitivity and specificity (Lymphotropic nanoparticles not approved)

Adapted from: Beresford, Clin Onc 2010

Salvage RT: Endorectal MRI

• 88 men evaluated for salvage RT, median PSA 0.3 – Radiographic abnormalities in prostate bed in 24% (α PSA) – Abnormalities seen on T2 MRI (90%) > DWI or DCE

• Still unclear whether MRI findings should influence patient selection or treatment

Liauw IJROBP 2013

“Local recurrences” as seen on endorectal MRI:

Optimizing salvage RT • Data driven approach towards ‘intensification’

of therapy to improve outcomes

Available data RT dose Retrospective

RT volume Retrospective Combined ADT Limited prospective, and

Retrospective

RT dose • Can dose escalation be extrapolated from the

intact setting?

King IJROBP 2012

70 Gy is better than 60 Gy

RT dose

Ohri IJROBP 2011

70 Gy

65 Gy

Higher RT doses might compensate for a higher pre-RT PSA

PSA 1.2+70 Gy=50%

PSA 0.75+65 Gy=50%

PSA 1.2+65 Gy=35%

RT dose • Is there an upper limit to the dose response?

Goenka IJROBP 2012

… but dose ≥70 Gy was associated with lower rate of local failure men with LF on eMRI (p=0.07)


Median pre-RT PSA 0.4

RT dose

• High dose IMRT is tolerated with limited G3 tox (Smaller, MRI defined prostate bed + 4-7 mm with IGRT)

Ost Eur Urol 2011

n=136, Med follow-up 60 mo

5 year FFBF 56%

Toxicity: Gr2-3 GU 22% Gr2-3 GI 8%

• 76 Gy to the post-operative bed

Median pre-RT PSA 0.8

RT volume • Does inclusion of pelvic lymph nodes improve

efficacy of salvage RT? – With a median PSA 0.5, 23% of men had +LNs on

nanoparticle MRI (Ross, Clin Imaging 2009)

Shih IJROBP 2005

RT volume

– Certain subsets may benefit from pelvic nodal RT

Spiotto IJROBP 2007 Moghanaki Cancer 2013

Stanford Duke/VCU Subset: pT3, GS8+, preop PSA>20 (with ADT)

Subset: PSA >0.4 (no ADT)

WPRT

PBRT n=139, median follow-up 4 y

n=114, median follow-up >5 y

Use of ADT • RTOG 9601

771 pts, pT2-3N0 with PSA 0.2-4.0

64.8 Gy + 2 years of bicalutamide 150 mg daily

64.8 Gy alone

– Median follow-up 7.1 years – No difference in overall survival – ADT ↑7-year FFBF and ↓DM (13% vs. 7%)

Shipley ASTRO 2010

Use of ADT

• Retrospective ADT data generally indicate ↑FFBF but results are mixed

• Randomized trials are accruing to test ADT and volume

n Eligibility RT ADT Important endpoints Sunnybrook (2009)

78 pT3 or R1 60-70 Gy

2 years (adj CAB/LHRH)

Adjuvant: FFBF-5 y 100% Salvage: FFBF 5-y 85%

Sunnybrook (2009)

75 pT3 or R1, PSA detectable

60-66 Gy

2 years (adj CAB/LHRH)

Salvage: FFBF 5-y 92%, 7-y 79%

SWOG S9921 (2011)

481 PSA >15, pT3b, N1, GS8-10, R1

Only in 27%

2 years (CAB) FFBF-5 y 93%

• Prospective, single arm studies

UCMC guidelines for Post-op RT

• Consider boosting eMRI defined or gross disease to ~72 Gy • Consider protocol enrollment a priority when eligible

Adjuvant RT (PSA undetectable)

Salvage RT (PSA detectable)

EBRT:

ADT:

64 Gy at 2/fx Prostate bed

No, but fair to consider

Only if pT3 or margin+; N0

N1 Favorable (e.g. margin+, lower GS, older age)

Unfavorable (e.g. higher GS, younger age, N1)

64 Gy at 2/fx Pelvic LN, bed

4-28 mo (consider 28 mo if age <65)

68 Gy at 2/fx Prostate bed

No

68.4 Gy at 1.8/fx Pelvic LN, bed

4 mo (consider 28 mo if N1 and age <65)

Always assess comorbidity (and consider surveillance)

Late Toxicity (Grade)

• Comparable toxicity rates to intact setting • Treatment factors including volume and dose

likely have impact

RT Modality (+/- ADT as indicated)

GI Toxicity GU Toxicity References

Gr2 Gr3 Gr2 Gr3

Adjuvant RT 5 2 5 2 EORTC

Salvage RT Standard dose 76 Gy with IMRT

5 8

1 1

10 22

1 3

Multi-institutional Belgium

Toxicity (Symptom Scores) • Patient reported QOL shows stability at 4 years

Melotek, submitted

Toxicity (Symptom Scores) • Post-op IMRT does not clearly worsen continence

Corbin, PRO 2013

Contouring: Prostate bed

• RTOG guidelines are online for prostate bed and pelvic LNs

• Guidelines have been proposed by 4 groups – Differences mainly regard coverage of anterior

and superior prostate bed

Wiltshire, IJROBP 2007

PMH

Planning guidelines • DVH relationships are less established for the

post-op setting compared to the intact setting – RTOG 0534:

Metric Goal

PTV V100 ≥95%

Dmax 115%

Rectum V65 Gy ≤35% (+10)

V40 Gy ≤55% (+10)

Bladder (minus CTV) V65 Gy ≤50% (+7.5)

V40 Gy ≤70% (+7.5)

Femoral heads V50 Gy ≤10%

IMRT • SEER-Medicare: 2000-2009

Goldin, JAMA Int Med 2013

82%

0%

IMRT vs. 3DCRT

– No difference in procedures or diagnosis codes between IMRT and 3DCRT

Goldin, JAMA Int Med 2013

• SEER-Medicare analysis of 251,787 men

IMRT vs. 3DCRT • MSKCC

– 176 pts IMRT (≥70 Gy); 109 pts 3DCRT (66-70 Gy)

2%

10%

16% 17%

• Treatment primarily to prostate bed alone • Median follow-up 60 months

IMRT may allow for safer escalation of dose to ~70 Gy Goenka Eur Urol 2011

Gra

de 2

+ G

I to

xici

ty

IGRT for post-op RT Comments

Bony anatomy Most widely available PTV margin ~ 0.6-1.5 cm not always reliable due to soft tissue movement

Ultrasound Monitor bladder, rectal filling; No additional radiation exposure Inter-observer variability in use

Surgical clips or fiducial markers in prostate bed (kV)

Easily seen and quickly imaged Does not evaluate soft tissue anatomy

Cone beam CT See entirety of prostate bed volume More time on treatment table

IGRT for post-op RT • Surgical clips in the prostate bed

Song Rad Onc 2012

– Clips are reproducibly identified – Rectal DVH improved with 5 mm vs 10 mm margin

UCMC guidelines on IGRT use

Prostate bed alone Prostate bed and pelvic LNs*

PTV margin, bed:

6 mm lateral 8 mm ant/post 9 mm sup/inf

No surgical clips Surgical clips No surgical clips Surgical clips

5 mm uniform

Post-operative RT planned

IGRT: kV: set up to bony anatomy; At least weekly CBCT (after d1,2 confirms reproducibility)

Daily kV: set up to clips



kV; set up to bony anatomy At least weekly CBCT (after d1,2 confirms reproducibility) to ensure bed is within PTV margin

Daily kv: Set up to bony anatomy but ensure clips are within PTV margin

*after initial field completed, see bed alone

On treatment imaging • CBCT can identify differential rectal filling

Differential rectal filling

Daily cone beam CT Reference (CT simulation)

Required a shift of > 1 cm ant/post … consider daily imaging and/or replanning

Conclusions: EBRT for postop prostate • Adjuvant RT is better than observation for

men with pT3, +margins • Early salvage RT (if needed) is an alternative to

adjuvant RT • Salvage RT is moderately effective, and could

impact biochemical control and survival • Uncertainty regarding timing of RT, and best

use of dose, volume, ADT will hopefully be addressed with future trials

rt for high-risk and post- operative prostate cancer · rt for high-risk and post- operative...

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