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

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

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

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

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

>75 yo

Urinary

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

Overall

IR-PCa

HR-PCaLower failures

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%

Limited DE: Boost to DIL

MRI DIL DWI

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

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

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

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

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

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 (melvin.chua.l.k@singhealth.com.sg)

Advances in Radiotherapy modalities in Prostate Cancer · Division of Radiation Oncology, National...

Documents

8.01.47 Intensity-Modulated Radiotherapy of the Prostate ......Localized Prostate Cancer: Radiotherapy (RT) as Definitive Treatment Localized prostate cancer can be defined as cancer

Altered Fractionation Radiotherapy in Head-Neck Cancer

Break out session: Radiotherapy - World Cancer Congress€¦ · Session code: Break out session: Radiotherapy Global Task Force on Radiotherapy for Cancer Control International Atomic

Early breast cancer treatment radiotherapy

Cervical Cancer Screening Modalities

Radiotherapy in Lung Cancer

Radiotherapy for Nasopharyngeal Cancer

New technologies, new toxicities: New radiotherapy modalities

New radiotherapy techniques - Cancer Australia

NEW IMAGING MODALITIES IN BREAST CANCER MANAGEMENT

Breast Cancer Radiotherapy Brochure

RADIOTHERAPY FOR BREAST CANCER

Radiotherapy In Early Breast Cancer

Application of nanotechnology to cancer radiotherapy

LONDON CANCER RADIOTHERAPYlondoncancer.org/media/76382/london-cancer-skin-radiotherapy... · Skin Cancer Radiotherapy Guidelines ... Merkel cell carcinoma ... Squamous Cell Carcinoma

Advances in Radiotherapy for Prostate Cancer Treatmentdownloads.hindawi.com/journals/specialissues/350875.pdf · ProstateCancer Advances in Radiotherapy for Prostate Cancer Treatment

Motion Management in Lung Cancer Radiotherapy

Breast cancer (early) - intrabeam radiotherapy system

Radiotherapy in Lung Cancer Dr. Vassilis Kouloulias 1 Radiotherapy in Lung Cancer Dr. Vassilis Kouloulias ... target volumes used in radiotherapy according to ICRU 50 guidelines are

Radiotherapy in Breast Cancer: Current Issues