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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
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Disclosure
I am a Radiation Oncologist who believes in
Multidisciplinary Care for all men with Prostate
Cancer….
ESMO GU Preceptorship, 15 November 2017
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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
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Prostate Cancer: Prognostication
TNM stage Tumour grade PSA
Low
risk
Intermediate
risk
High
riskMetastatic
Localised cancers
Digital Rectal
Exam Imaging Biopsy Blood test
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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
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Treatment of Prostate Cancer in 2017
Options
Active surveillance
Surgery (Radical prostatectomy, RadP – open vs
robotic)
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Treatment of Prostate Cancer in 2017
Options
Active surveillance
Surgery (Radical prostatectomy, RadP – open vs
robotic)
Radiotherapy
▪ Image guidance
▪ Brachytherapy
▪ Stereotactic radiosurgery
▪ Proton beam therapy
Radiotherapy + hormonal therapy
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Treatment of Prostate Cancer in 2017
Low cT1-T2a
PSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20
GS 7
HighcT3-4
PSA >20
GS 8-10
Active
surveillance
Favourable
RadP vs IGRTUnfavourable
IGRT + ADTRadP +/- IGRT
IGRT + ADT
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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
mono
Low cT1-T2a
PSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20
GS 7
HighcT3-4
PSA >20
GS 8-10
Active
surveillance
Favourable
RadP vs IGRTUnfavourable
IGRT + ADT
RadP +/- IGRT
IGRT + LTAD
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Radiotherapy of Prostate Cancer in 2017
Low cT1-T2a
PSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20
GS 7
HighcT3-4
PSA >20
GS 8-10
Active
surveillance
IGRT (image-guided RT)
▪ SBRT – 37-40 Gy/5#
▪ Conv fract – 74-78 Gy (2
Gy/#) over mod hypofract
▪ RT to Pelvis???
Brachy – HDR boost
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 mono
Favourable
RadP vs IGRTUnfavourable
IGRT + ADTRadP +/- IGRT
IGRT + LTAD
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Radiotherapy of Prostate Cancer in 2017
Low cT1-T2a
PSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20
GS 7
HighcT3-4
PSA >20
GS 8-10
Active
surveillance
IGRT (image-guided RT)
▪ SBRT – 37-40 Gy/5#
▪ Conv fract – 74-78 Gy
(2 Gy/#) over mod
hypofract
▪ RT to Pelvis???
Brachy – HDR boost
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 mono
Favourable
RadP vs IGRTUnfavourable
IGRT + ADTRadP +/- IGRT
IGRT + LTAD
IGRT (image-guided
RT)
▪ SBRT – 37-40
Gy/5#
▪ Conv fract – 74-78
Gy (2 Gy/#) + 50-
54 Gy to Pelvis
Brachy – HDR boost
ESMO GU Preceptorship, 15 November 2017
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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
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PROTECT cohort
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PROTECT cohortMajority favourable-risk patients
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Outcomes: low-risk and favourable
intermediate-risk prostate cancers
Hamdry et al. on behalf of PROTECT
investigators, NEJM, 2016
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PROTECT: QOL post-RT
Incontinence
Erectile function
Leakage (Pads usage)
Sexual satisfaction
Donovan et al., NEJM, 2016
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NC prospective: QOL post-RT
Chen, et al., ASTRO 2017
North Carolina Prospective Observational cohort
N = 1225; 2011-2013
PROTECT
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NC prospective: QOL post-RT
Chen, et al., ASTRO 2017
▪ Contemporary data
▪ Consistent with PROTECT
▪ Highlights need for such high
quality data
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Radiotherapy10 years of Technological Precision
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Radiotherapy of Prostate Cancer in 2017
Low cT1-T2a
PSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20
GS 7
HighcT3-4
PSA >20
GS 8-10
Active
surveillance
IGRT (image-guided
RT)
▪ SBRT – 37-40 Gy/5#
▪ Conv fract – 74-78 Gy
(2 Gy/#) over mod
hypofract
▪ RT to Pelvis???
Brachy – HDR boost
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 mono
Favourable
RadP vs IGRTUnfavourable
IGRT + ADTRadP +/- IGRT
IGRT + LTAD
IGRT (image-guided
RT)
▪ SBRT – 37-40
Gy/5#
▪ Conv fract – 74-78
Gy (2 Gy/#) + 50-
54 Gy to Pelvis
Brachy – HDR boost
ESMO GU Preceptorship, 15 November 2017
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Radiotherapy of Prostate Cancer in 2017
Low cT1-T2a
PSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20
GS 7
HighcT3-4
PSA >20
GS 8-10
Active
surveillance
IGRT (image-guided
RT)
▪ SBRT – 37-40 Gy/5#
▪ Conv fract – 74-78 Gy
(2 Gy/#) over mod
hypofract
▪ RT to Pelvis???
Brachy – HDR boost
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 mono
Favourable
RadP vs IGRTUnfavourable
IGRT + ADTRadP +/- IGRT
IGRT + LTAD
IGRT (image-guided
RT)
▪ SBRT – 37-40
Gy/5#
▪ Conv fract – 74-78
Gy (2 Gy/#) + 50-
54 Gy to Pelvis
Brachy – HDR boost
What is the optimal
dose??
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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
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Contemporary moderate hypofractionation RCTs
N = 6339CHHIP (UK) RTOG 0415 (US)
PROFIT (Canada/EU) HYPRO (Dutch)
N = 3216
N = 1206
N = 1115
N = 820
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Contemporary moderate hypofractionation RCTs
N = 6339CHHIP (UK) RTOG 0415 (US)
PROFIT (Canada/EU) HYPRO (Dutch)
N = 3216
N = 1206
N = 1115
N = 820
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Are all intermediate-risk prostate cancers the
same???
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Dose escalation in the unfavourable risk group?
Evidence for a dose response for PSA control
Zelefsky et al J Urol 2006
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Randomised trials of dose escalation
with Conventional Hyperfractionation
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Randomised trials of dose escalation
with Conventional Hyperfractionation
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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
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NCCS GU RT Outcomes
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Overall survival Biochemical control
(2006-2010)
10-y follow-up
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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
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N = 67
MFU = 2.7y
36.25Gy in 5 fractions
over 1.5 weeks
Early data with Prostate SBRT
King, et al, IJORBP, 2012
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N = 1100
“Comparable” outcomes with DE-EBRT
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N = 304 (median fu = 5 y)
▪ Low risk 69.4%
▪ Int risk 26.6%
▪ High risk 0.7%
“Comparable” late toxicities with DE-EBRT
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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
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PROSTAR: Early results
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Summary
Low cT1-T2a
PSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20
GS 7
HighcT3-4
PSA >20
GS 8-10
Active
surveillance
IGRT (image-guided
RT)
▪ SBRT – 37-40 Gy/5#
▪ Conv fract – 74-78 Gy
(2 Gy/#) over mod
hypofract
Brachy – HDR boost
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 mono
Favourable
RadP vs IGRTUnfavourable
IGRT + ADTRadP +/- IGRT
IGRT + LTAD
IGRT (image-guided
RT)
▪ SBRT – 37-40
Gy/5#
▪ Conv fract – 74-78
Gy (2 Gy/#) + 50-
54 Gy to Pelvis
Brachy – HDR boost
ESMO GU Preceptorship, 15 November 2017
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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
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ASCENDE-RT Ph III trial
Intermediate-risk
High-risk
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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
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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
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GS 9-10 consortium
Kishan et al., ASTRO, 2017
Distant Mets
PCSM
12y
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Final Points
Low-risk and Favourable Int-riskActive surveillance
Treatment: 60 Gy/20# (Mod hypofract), 36.25 Gy/5# (SBRT)
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Final Points
Low-risk and Favourable Int-riskActive surveillance
Treatment: 60 Gy/20# (Mod hypofract), 36.25 Gy/5# (SBRT)
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
ESMO GU Preceptorship, 15 November 2017
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Final Points
Low-risk and Favourable Int-riskActive surveillance
Treatment: 60 Gy/20# (Mod hypofract), 36.25 Gy/5# (SBRT)
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
High-riskProstate alone or Pelvis EBRT 74-78 Gy/39# + 3-y ADT
Trial: Pelvis EBRT + HDR boost: 46-50 Gy/23-25# + HDR 15 Gy
+ 1-3-y ADT
Systemic disease remains poorly addressed
ESMO GU Preceptorship, 15 November 2017
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Thank you!
Questions