Radiotherapy in the Treatment of Prostate Cancer€¦ · Radiotherapy of Prostate Cancer in 2017...

Radiotherapy in the Treatment

of Prostate CancerWhere are we now in 2017?

Melvin L.K. Chua, MBBS, FRCR, PhDClinician-Scientist, Consultant Radiation Oncologist

Division of Radiation Oncology, National Cancer Centre

Instructor, Duke-NUS Graduate Medical School, Singapore

Principal Investigator, Translational Radiation Oncology Group

(NCCS)

ESMO GU Preceptorship, 15 November 2017

Disclosure

I am a Radiation Oncologist who believes in

Multidisciplinary Care for all men with Prostate

Cancer….

Disclosure

I am a Radiation Oncologist who Believes in

Multidisciplinary Care for Men with Prostate

Cancer….

BUT I also get upset with every

Margin +ve GS 8-10 Prostate Cancer

with rising PSA who is referred

to my clinic

Prostate Cancer: Prognostication

TNM stage Tumour grade PSA

Intermediate

riskMetastatic

Localised cancers

Digital Rectal

Exam Imaging Biopsy Blood test

Reese, et al. 2012. J Uro.

Low risk

Active Surveillance

Intermediate risk

Radiotherapy or

Surgery

High risk

Radiotherapy or

surgery + additional

treatment

Prostate Cancer: Prognostication

Treatment of Prostate Cancer in 2017

Options

Active surveillance

Surgery (Radical prostatectomy, RadP – open vs

robotic)

Options

Active surveillance

Surgery (Radical prostatectomy, RadP – open vs

robotic)

Radiotherapy

▪ Image guidance

▪ Brachytherapy

▪ Stereotactic radiosurgery

▪ Proton beam therapy

Radiotherapy + hormonal therapy

Low cT1-T2a

PSA <10

GS ≤6

Intermediate cT2b-T2c

PSA 10-20

HighcT3-4

PSA >20

GS 8-10

Active

surveillance

Favourable

RadP vs IGRTUnfavourable

IGRT + ADTRadP +/- IGRT

IGRT + ADT

Radiotherapy of Prostate Cancer in 2017

IGRT (image-guided RT)

▪ SBRT – 36.25 Gy/5#

▪ Mod hypofract – 60 Gy (3 Gy/#)

▪ Conv fract – 74-78 Gy (2 Gy/#)

Brachy – LDR (seeds) vs HDR

Low cT1-T2a

PSA <10

GS ≤6

PSA 10-20

HighcT3-4

PSA >20

GS 8-10

Active

surveillance

Favourable

IGRT + ADT

RadP +/- IGRT

IGRT + LTAD

Low cT1-T2a

PSA <10

GS ≤6

PSA 10-20

HighcT3-4

PSA >20

GS 8-10

Active

surveillance

▪ SBRT – 37-40 Gy/5#

▪ Conv fract – 74-78 Gy (2

Gy/#) over mod hypofract

▪ RT to Pelvis???

Brachy – HDR boost

▪ SBRT – 36.25 Gy/5#

▪ Mod hypofract – 60 Gy

(3 Gy/#)

▪ Conv fract – 74-78 Gy

(2 Gy/#)

Brachy – LDR (seeds) vs

HDR mono

Favourable

IGRT + LTAD

Low cT1-T2a

PSA <10

GS ≤6

PSA 10-20

HighcT3-4

PSA >20

GS 8-10

Active

surveillance

▪ SBRT – 37-40 Gy/5#

(2 Gy/#) over mod

hypofract

▪ RT to Pelvis???

▪ SBRT – 36.25 Gy/5#

(3 Gy/#)

(2 Gy/#)

HDR mono

Favourable

IGRT + LTAD

IGRT (image-guided

▪ SBRT – 37-40

▪ Conv fract – 74-78

Gy (2 Gy/#) + 50-

54 Gy to Pelvis

1st LEVEL 1 evidence comparing local

tx in localised prostate cancers

UK-wide clinical trial of 1,500 men,

reported 2016ESMO GU Preceptorship, 15 November 2017

PROTECT cohort

PROTECT cohortMajority favourable-risk patients

Outcomes: low-risk and favourable

intermediate-risk prostate cancers

Hamdry et al. on behalf of PROTECT

investigators, NEJM, 2016

PROTECT: QOL post-RT

Incontinence

Erectile function

Leakage (Pads usage)

Sexual satisfaction

Donovan et al., NEJM, 2016

NC prospective: QOL post-RT

Chen, et al., ASTRO 2017

North Carolina Prospective Observational cohort

N = 1225; 2011-2013

PROTECT

NC prospective: QOL post-RT

Chen, et al., ASTRO 2017

▪ Contemporary data

▪ Consistent with PROTECT

▪ Highlights need for such high

quality data

Radiotherapy10 years of Technological Precision

Low cT1-T2a

PSA <10

GS ≤6

PSA 10-20

HighcT3-4

PSA >20

GS 8-10

Active

surveillance

IGRT (image-guided

▪ SBRT – 37-40 Gy/5#

(2 Gy/#) over mod

hypofract

▪ RT to Pelvis???

▪ SBRT – 36.25 Gy/5#

(3 Gy/#)

(2 Gy/#)

HDR mono

Favourable

IGRT + LTAD

IGRT (image-guided

▪ SBRT – 37-40

Gy (2 Gy/#) + 50-

54 Gy to Pelvis

Low cT1-T2a

PSA <10

GS ≤6

PSA 10-20

HighcT3-4

PSA >20

GS 8-10

Active

surveillance

IGRT (image-guided

▪ SBRT – 37-40 Gy/5#

(2 Gy/#) over mod

hypofract

▪ RT to Pelvis???

▪ SBRT – 36.25 Gy/5#

(3 Gy/#)

(2 Gy/#)

HDR mono

Favourable

IGRT + LTAD

IGRT (image-guided

▪ SBRT – 37-40

Gy (2 Gy/#) + 50-

54 Gy to Pelvis

What is the optimal

dose??

Hypofractionation in Prostate Cancer:

Tipping the Therapeutic Ratio Balance

Biological Effective Dose

BED = Total Dose(1+ dose per #/α/β) ▪ Assumption: α/β = 1.5 Gy for tumour & 3.0 Gy for normal

tissue

SBRT - 36.25 Gy/5#

EQD2tumour = 90.6 Gy

EQD2normal = 74 Gy

Conv fract

74-78 Gy/37-39# vs

Mod Hypofract - 60 Gy/20#

EQD2tumour = 77 Gy

EQD2normal = 72 Gy

Contemporary moderate hypofractionation RCTs

N = 6339CHHIP (UK) RTOG 0415 (US)

PROFIT (Canada/EU) HYPRO (Dutch)

N = 3216

N = 1206

N = 1115

N = 820

Contemporary moderate hypofractionation RCTs

N = 6339CHHIP (UK) RTOG 0415 (US)

PROFIT (Canada/EU) HYPRO (Dutch)

N = 3216

N = 1206

N = 1115

N = 820

Are all intermediate-risk prostate cancers the

same???

Dose escalation in the unfavourable risk group?

Evidence for a dose response for PSA control

Zelefsky et al J Urol 2006

Randomised trials of dose escalation

with Conventional Hyperfractionation

Randomised trials of dose escalation

with Conventional Hyperfractionation

Radiotherapy treatment protocol

NCCS GU Radiation Oncology Program

Low-risk

Active surveillance

Offer SBRT trial – PROSTAR

Intermediate-risk

Favourable – 60 Gy in 30# or PROSTAR

Unfavourable – 74-78 Gy in 39# +/- 6-mo ADT (STAD)

High-risk

74-78 Gy in 39# + 3-y ADT (LTAD) +/- 1-2 y combination Zytiga??

46 Gy + HDR boost (15 Gy) + 1 to 3-y ADT (LTAD)

ASCENDE-RT

NCCS GU RT Outcomes

Overall survival Biochemical control

(2006-2010)

10-y follow-up

Prostate Stereotactic Body Radiotherapy

Stereotactic Body Radiotherapy (SBRT)

▪ Precise and focused delivery of small number of

fractions of radiation in the ablative dose range to

extracranial targets

Stage I/II NSCLC

N = 67

MFU = 2.7y

36.25Gy in 5 fractions

over 1.5 weeks

Early data with Prostate SBRT

King, et al, IJORBP, 2012

N = 1100

“Comparable” outcomes with DE-EBRT

N = 304 (median fu = 5 y)

▪ Low risk 69.4%

▪ Int risk 26.6%

▪ High risk 0.7%

“Comparable” late toxicities with DE-EBRT

PROSTAR (PROstate STereotactic

Ablative Radiotherapy) NCCS prospective phase II trial

• Single institution; Single-arm

• NCCN Low-risk or single intermediate risk factor (DRE T2b-c

or Gleason 7 or PSA 10-20); organ-confined prostate

adenocarcinoma, with no MRI evidence of ECE and SV invasion

• 36.25Gy in 5 fractions over 1.5 weeks (EOD) delivered using

LINAC-based treatment system

• No hormonal therapy

• Primary end-point - severe late GI and GU toxicities

• Secondary end-points – Patient-reported QOL, acute RT

toxicities, biochemical relapse, prostate cancer specific mortality,

overall survival

PROSTAR: Early results

Summary

Low cT1-T2a

PSA <10

GS ≤6

PSA 10-20

HighcT3-4

PSA >20

GS 8-10

Active

surveillance

IGRT (image-guided

▪ SBRT – 37-40 Gy/5#

(2 Gy/#) over mod

hypofract

▪ SBRT – 36.25 Gy/5#

(3 Gy/#)

(2 Gy/#)

HDR mono

Favourable

IGRT + LTAD

IGRT (image-guided

▪ SBRT – 37-40

Gy (2 Gy/#) + 50-

54 Gy to Pelvis

ASCENDE-RT Ph III trial

Control arm

46 Gy EBRT to Pelvis

+ 32 Gy to Prostate

+ 12-mo ADT

Experimental arm

46 Gy EBRT to Pelvis

+ LDR 110 Gy to Prostate

+ 12-mo ADT

ASCENDE-RT Ph III trial

Intermediate-risk

High-risk

Contemporary data with HDR boost

UK MVCC Ph III (Hoskin et al., 2012)

Int-high-risk Prostate Cancers

55 Gy/20# vs

37.5 Gy/15# + 8.5 Gy x 2 HDR

Beaumont (Martinez et al., 2011)

Int-high-risk Prostate Cancers

46 Gy/23# to Pelvis ->

<8.5 Gy x 2 HDR vs >9 Gy x 2 HDR

Is HDR boost the best form of DE in GS 9-

10 high-grade disease??UCLA (Kishan et al., Eur Urol, 2016)

High-risk GS 9-10 Prostate Cancers

GS 9-10 consortium

Kishan et al., ASTRO, 2017

Distant Mets

Final Points

Low-risk and Favourable Int-riskActive surveillance

Treatment: 60 Gy/20# (Mod hypofract), 36.25 Gy/5# (SBRT)

Final Points

Unfavourable Int-riskProstate alone or Pelvis EBRT 74-78 Gy/39# +/- 6-mo ADT

Trial: Pelvis EBRT + HDR boost: 46-50 Gy/23-25# + HDR 15 Gy

Trial: Prostate EBRT + HDR boost: 37.5 Gy/15# + HDR 15 Gy

Final Points

Unfavourable Int-riskProstate alone or Pelvis EBRT 74-78 Gy/39# +/- 6-mo ADT

Trial: Prostate EBRT + HDR boost: 37.5 Gy/15# + HDR 15 Gy

High-riskProstate alone or Pelvis EBRT 74-78 Gy/39# + 3-y ADT

+ 1-3-y ADT

Systemic disease remains poorly addressed

Thank you!

Questions

Radiotherapy in the Treatment of Prostate Cancer€¦ · Radiotherapy of Prostate Cancer in 2017...

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