advances in radiotherapy modalities in prostate cancer · division of radiation oncology, national...

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


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)


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


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


PSA 10-20GS 7

HighcT3-4

PSA >20GS 8-10

Active surveillance



RadP +/- IGRTIGRT + LTAD



Low cT1-T2aPSA <10

GS ≤6


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/#)







Low cT1-T2aPSA <10

GS ≤6


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???




(2 Gy/#)






(2 Gy/#) + 50-54 Gy to Pelvis



UK PROTECT

UK-wide clinical trial of 1,500 men, reported 2016



UK PROTECT

Outcomes: low-risk and favourableintermediate-risk prostate cancers

Hamdry et al. on behalf of PROTECT investigators, NEJM, 2016


QOL post-RTIncontinence

Erectile function

Leakage (Pads usage)

Sexual satisfaction

Donovan et al., NEJM, 2016


Same observation in other prospective cohorts

Chen, et al., JAMA 2017

North Carolina Prospective Observational cohortN = 1225; 2011-2013

UK PROTECT


NC prospective: QOL post-RT

Chen, et al., JAMA, 2017

Contemporary data Consistent with PROTECT Highlights need for such high

quality data


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



Low cT1-T2aPSA <10

GS ≤6


PSA 10-20GS 7

HighcT3-4

PSA >20GS 8-10

Active surveillance


(2 Gy/#) over mod hypofract

RT to Pelvis???




(2 Gy/#)





IGRT (image-guided RT) SBRT – 37-40

Gy/5# Conv fract – 74-78

Gy (2 Gy/#) + 50-54 Gy to Pelvis


What is the optimal dose??


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


Contemporary moderate hypofractionation RCTsN = 6339

CHHIP (UK) RTOG 0415 (US)

PROFIT (Canada/EU) HYPRO (Dutch)

N = 3216

N = 1206

N = 1115

N = 820


HYPRO trial

2016


HYPRO trial

2016


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


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


Mod hypofr in the elderly

2018

>75 yo

Urinary

Bowel

Wilson, et al. IJROBP, 2018


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


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



2017

Overall

IR-PCa

HR-PCaLower failures



2017

Overall

IR-PCa

HR-PCaLower failures

Fav IR-PCa

Unfav IR-PCa


RCTs of DE vs non-DE RT


RTOG 0126: Largest DE study with 10 Gy dose response

No overall survival

Improved PSA control of 10-15%

2018


Limited DE: Boost to DIL

2014

MRI DIL DWI

GI

GU

2018

DIL


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


N = 67MFU = 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


HYPO-RT-PC trial

2019


2019


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


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


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


Surgery Study cohort

Tan and Chua, et al. Presented at ASCO GU 2019


Surgery Study cohort



PSMA-PET Contouring

RT plan

Daily matching –transverse

Coronal

RT planning process

ContouringMRI CT


Small overlap

Small overlap


RectumBladderFem heads

Urethra Penile bulb

OAR contouring


Minimum PTV coverage by 95% of prescribed dose

Plan optimisation for PTV coverage against OAR doses

Prostate target

RectumBladder


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


Dosimetric comparison37.5 Gy/5 fr 36.25 Gy/5 fr

37 Gy IDL 37 Gy IDL

38 Gy IDL 38 Gy IDL


SurgeryAcute & Late toxicities



SurgeryPatient-reported QOL



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


SurgerySBRT dose-response


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


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???


Alpha-beta

Other technological advances

HDR brachytherapy boost as an effective dose intensification strategy

ASCENDE-RT Ph III trial(Morris et al., IJORBP, 2017)


HDR brachytherapy boost as an effective dose intensification strategy

Intermediate-risk

High-risk


Contemporary data with HDR brachy boost


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


SurgeryPET-imaging (PSMA)Bone

Lymph nodesTypes of Tracers

PSMA (Overall) F-Choline (LN) Na-F (Bone) Fluciclovine

PET staging in prostate cancer


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


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


Thank you!Collaborations/positions ([email protected])


advances in radiotherapy modalities in prostate cancer · division of radiation oncology, national...

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