radiotherapy in the treatment of prostate cancer€¦ · radiotherapy of prostate cancer in 2017...
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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
Disclosure
I am a Radiation Oncologist who believes in
Multidisciplinary Care for all men with Prostate
Cancer….
ESMO GU Preceptorship, 15 November 2017
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
ESMO GU Preceptorship, 15 November 2017
Prostate Cancer: Prognostication
TNM stage Tumour grade PSA
Low
risk
Intermediate
risk
High
riskMetastatic
Localised cancers
Digital Rectal
Exam Imaging Biopsy Blood test
ESMO GU Preceptorship, 15 November 2017
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)
ESMO GU Preceptorship, 15 November 2017
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
ESMO GU Preceptorship, 15 November 2017
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
ESMO GU Preceptorship, 15 November 2017
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
ESMO GU Preceptorship, 15 November 2017
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
ESMO GU Preceptorship, 15 November 2017
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
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
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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
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??
ESMO GU Preceptorship, 15 November 2017
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
ESMO GU Preceptorship, 15 November 2017
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
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
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)
ESMO GU Preceptorship, 15 November 2017
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
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
Thank you!
Questions