advances in radiotherapy modalities in prostate cancer · division of radiation oncology, national...
TRANSCRIPT
NCCS 2022
Melvin L.K. Chua, MBBS, FRCR, PhDClinician-Scientist, Senior Consultant Radiation OncologistDivision of Radiation Oncology, National Cancer Centre SingaporePrincipal Investigator, Tan Chin Tuan Laboratory of Optical Imaging, Photodynamic and Proton Therapy & Precision Radiation Oncology Program (NCCS)Asst Professor, Duke-NUS Medical School, Singapore
Advances in Radiotherapy modalities in Prostate Cancer
ESMO Advanced Course on Prostate Cancer,6 Sep 2019, Singapore
Structured research agreement/Research funding: GenomeDx Biosciences, PVMed, Ferring Singapore, Varian, MedLever Inc., ImmunoScape
Speakers’ fees/Honorarium:Varian, AstraZeneca, Janssen
Advisory/Consultancy roles:Varian, Janssen, Astellas
SurgeryDisclosures
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
RT in the management of localised PCa Intermediate-risk vs High-risk vs M1 disease
Advancement in RT techniques Technological advances – SBRT; PSMA PET-fusion Dose escalation and fractionation regimes HDR brachytherapy – more than just dose escalation?
SurgeryOutline
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Treatment of Prostate Cancer in 2019OptionsActive surveillanceSurgery (Radical prostatectomy, RadP – open vs
robotic)Radiotherapy Does dose matter? Brachytherapy Stereotactic body ablative radiotherapy
Radiotherapy + hormonal therapy (including novel anti-androgens)
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Treatment of Prostate Cancer in 2019
Low cT1-T2aPSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20GS 7
HighcT3-4
PSA >20GS 8-10
Active surveillance
FavourableRadP vs IGRT
UnfavourableIGRT + ADT
RadP +/- IGRTIGRT + ADT
NCCN Zumsteg-Spratt critieria (Eur Urol, 2013)Sub-stratification for IR-PCa ≥50% +ve biopsy cores Primary GG 4 ≥2 NCCN IRF – cT2b,c; GS 7; PSA 10-20 ng/ml
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Radiotherapy of Prostate Cancer in 2019
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-T2aPSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20GS 7
HighcT3-4
PSA >20GS 8-10
Active surveillance
FavourableRadP vs IGRT
UnfavourableIGRT + ADT
RadP +/- IGRTIGRT + LTAD
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Radiotherapy of Prostate Cancer in 2019
Low cT1-T2aPSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20GS 7
HighcT3-4
PSA >20GS 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
FavourableRadP vs IGRT
UnfavourableIGRT + ADT
RadP +/- IGRTIGRT + LTAD
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Radiotherapy of Prostate Cancer in 2019
Low cT1-T2aPSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20GS 7
HighcT3-4
PSA >20GS 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
FavourableRadP vs IGRT
UnfavourableIGRT + ADT
RadP +/- IGRTIGRT + 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 Advanced Course on PCa, 6 Sep 2019, Singapore
UK PROTECT
UK-wide clinical trial of 1,500 men, reported 2016
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
UK PROTECT
Outcomes: low-risk and favourableintermediate-risk prostate cancers
Hamdry et al. on behalf of PROTECT investigators, NEJM, 2016
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
QOL post-RTIncontinence
Erectile function
Leakage (Pads usage)
Sexual satisfaction
Donovan et al., NEJM, 2016
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Same observation in other prospective cohorts
Chen, et al., JAMA 2017
North Carolina Prospective Observational cohortN = 1225; 2011-2013
UK PROTECT
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
NC prospective: QOL post-RT
Chen, et al., JAMA, 2017
Contemporary data Consistent with PROTECT Highlights need for such high
quality data
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
RT outcomes post-AS: Toronto exp
2017
Propensity-matched analysis LDR brachytherapy; N = 165 IGRT-EBRT; N = 394 (Dose: 75.8 Gy to 79.8 Gy) 50% Unfavourable IR-PCa
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Radiotherapy of Prostate Cancer in 2019
Low cT1-T2aPSA <10
GS ≤6
Intermediate cT2b-T2c
PSA 10-20GS 7
HighcT3-4
PSA >20GS 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
FavourableRadP vs IGRT
UnfavourableIGRT + ADT
RadP +/- IGRTIGRT + 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 Advanced Course on PCa, 6 Sep 2019, Singapore
Fractionation studies
SurgeryComparative BED between # schedules
Lymph nodes
Biological Effective DoseBED = Total Dose(1+ dose per #/α/β)
Assumption: α/β = 1.5 Gy for tumour & 3.0 Gy for normal tissue
SBRT - 40 Gy/5#EQD2tumour = 108.6 GyEQD2normal = 88 Gy
Conv fract74-78 Gy/37-39# vs
Pelvic RT (54 Gy) + Brachy boost (21 Gy/3#)EQD2tumour = 101.9 GyEQD2normal = 93.8 Gy
Mod Hypofract - 60 Gy/20#EQD2tumour = 77 GyEQD2normal = 72 Gy
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Contemporary moderate hypofractionation RCTsN = 6339
CHHIP (UK) RTOG 0415 (US)
PROFIT (Canada/EU) HYPRO (Dutch)
N = 3216
N = 1206
N = 1115
N = 820
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Contemporary moderate hypofractionation RCTsN = 6339
CHHIP (UK) RTOG 0415 (US)
PROFIT (Canada/EU) HYPRO (Dutch)
N = 3216
N = 1206
N = 1115
N = 820
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
HYPRO trial
2016
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
HYPRO trial
2016
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Designed as a superiority study Intermediate-to-High risk 78 Gy (DE) vs
64.6 Gy/19fr (EQD2 = 90.4 Gy) 3D-CRT technique
HYPRO trial
2019
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Designed as a superiority study Intermediate-to-High risk 78 Gy (DE) vs 64.6 Gy/19fr (EQD2 = 90.4 Gy) 3D-CRT technique
HYPRO trial no benefit across subgroups
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Mod hypofr in the elderly
2018
>75 yo
Urinary
Bowel
Wilson, et al. IJROBP, 2018
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Summary (Mod-hypofr) Moderate hypofractionation is efficacious and
safe (even in the elderly) in most IR PCa No clear winner (choose a well-defined
treatment protocol to adopt in your institution) Long-term data is needed True range of alpha-beta ratio in prostate cancer
is still unknown
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Dose escalation & Ultra-hypofraction
Dose escalation in the unfavourable risk group?Evidence for a dose response for PSA control
Zelefsky et al J Urol 2006
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Dose escalation in the unfavourable risk group?Evidence for a dose response for PSA control
2017
Overall
IR-PCa
HR-PCaLower failures
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Dose escalation in the unfavourable risk group?Evidence for a dose response for PSA control
2017
Overall
IR-PCa
HR-PCaLower failures
Fav IR-PCa
Unfav IR-PCa
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
RCTs of DE vs non-DE RT
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
RCTs of DE vs non-DE RT
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
RTOG 0126: Largest DE study with 10 Gy dose response
No overall survival
Improved PSA control of 10-15%
2018
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Limited DE: Boost to DIL
2014
MRI DIL DWI
GI
GU
2018
DIL
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Radiotherapy treatment protocolNCCS GU Radiation Oncology ProgramLow-risk
Active surveillance SBRT on progression or patient’s request
Intermediate-risk Favourable – 60 Gy in 20# or SBRT (36.25-37.5 Gy) Unfavourable – 74-78 Gy in 39# or SBRT (37.5 Gy) +/- 6-mo ADT
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
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
N = 67MFU = 2.7y
36.25Gy in 5 fractions over 1.5 weeks
Early data with Prostate SBRT
King, et al, IJORBP, 2012
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
N = 1100
“Comparable” outcomes with DE-EBRT
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
N = 304 (median fu = 5 y) Low risk 69.4% Int risk 26.6% High risk 0.7%
“Comparable” late toxicities with DE-EBRT
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
HYPO-RT-PC trial
2019
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
2019
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Initially designed as a superiority study
Intermediate-to-High risk 78 Gy (DE) vs
42.7 Gy in 7fr (EQD2 = 92.7 Gy) 80% 3D-CRT
HYPO-RT-PC trial
2019
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Initially designed as a superiority study Intermediate-to-High risk 78 Gy (DE) vs
42.7 Gy in 7fr (EQD2 = 92.7 Gy) 80% 3D-CRT
Is the alpha-beta ratio of prostate cancer really 1.5 Gy???
HYPO-RT-PC trial
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Bowel
GU
HYPO-RT-PC trial
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
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Surgery Study cohort
Tan and Chua, et al. Presented at ASCO GU 2019
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Surgery Study cohort
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Tan and Chua, et al. Presented at ASCO GU 2019
PSMA-PET Contouring
RT plan
Daily matching –transverse
Coronal
RT planning process
ContouringMRI CT
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Small overlap
Small overlap
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
RectumBladderFem heads
Urethra Penile bulb
OAR contouring
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Minimum PTV coverage by 95% of prescribed dose
Plan optimisation for PTV coverage against OAR doses
Prostate target
RectumBladder
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
PSMA-PET Contouring
RT plan
Daily matching –transverse
Coronal
Precise targeting of prostate & pelvisRT plan – Prostate + Pelvis Dose constraints
Ability to limit doses to rectum even if we RT the SVs
Low dose bath to the bladder and rectum with pelvis RT
SIB plan – 25 Gy to Pelvis; 35 Gy to Prostate
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Dosimetric comparison37.5 Gy/5 fr 36.25 Gy/5 fr
37 Gy IDL 37 Gy IDL
38 Gy IDL 38 Gy IDL
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
SurgeryAcute & Late toxicities
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Tan and Chua, et al. Presented at ASCO GU 2019
SurgeryAcute & Late toxicities
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Tan and Chua, et al. Presented at ASCO GU 2019
SurgeryPatient-reported QOL
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Tan and Chua, et al. Presented at ASCO GU 2019
SurgeryPROSTAR vs other SBRT studies 230 low-risk treated with Cyber-knife; 35Gy & 36.25Gy in 5 consecutive days; 10 yr DFS 93%;
10% G2-3 GU; 4% G2 GI; EPIC sexual score declined by 40%
EPIC Sexual QOLEPIC GU QOL EPIC GI QOL
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
SurgerySBRT dose-response
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Zelefsky, et al. IJROBP, 2019
2019
Summary (Ultra-hypofr) Ultra-hypofractionation is efficacious and safe
(even in the elderly) in most IR PCa Long-term data is needed
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Summary (Ultra-hypofr) Ultra-hypofractionation is efficacious and safe
(even in the elderly) in most IR PCa Long-term data is needed Is there a dose-response???
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Alpha-beta
Other technological advances
HDR brachytherapy boost as an effective dose intensification strategy
ASCENDE-RT Ph III trial(Morris et al., IJORBP, 2017)
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
HDR brachytherapy boost as an effective dose intensification strategy
Intermediate-risk
High-risk
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Contemporary data with HDR brachy boost
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
SurgerySBRT boost to replace HDR Brachy boost?
Lymph nodes
Biological Effective DoseBED = Total Dose(1+ dose per #/α/β)
Assumption: α/β = 1.5 Gy for tumour & 3.0 Gy for normal tissue
Pelvic RT + SBRT boost (19.5 Gy/3#)EQD2tumour = 98.6 GyEQD2normal = 91.1 Gy
Pelvic RT (54 Gy) + Brachy boost (21 Gy/3#)EQD2tumour = 101.9 GyEQD2normal = 93.8 Gy
Axial – 19.5 Gycolour wash
Sag – 19.5 Gycolour wash
*Courtesy of Ashley Ong
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
SurgeryPET-imaging (PSMA)Bone
Lymph nodesTypes of Tracers
PSMA (Overall) F-Choline (LN) Na-F (Bone) Fluciclovine
PET staging in prostate cancer
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
SurgeryPET utility for RT planning in PCaPET-fusion for target delineation RT plan
Requires deformable registration due to different CT slice thickness
Image guidance and distance from bowel allows safe dose escalation
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Summary Contemporary techniques have resulted in optimal local
control and favourable toxicity profiles in localised prostate cancer
Dose escalation and fractionation require a risk-adapted approach
Modern technologies from imaging to enhance target contouring; precision matching and dose escalation permit novel RT strategies in high-risk disease
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore
Thank you!Collaborations/positions ([email protected])
ESMO Advanced Course on PCa, 6 Sep 2019, Singapore