Looking into the future for recurrent cancer
Glenn Bauman, MD
April 2017
Radical Prostatectomy
Prostate Brachytherapy
External beam RT
Image guided interventions
HIFU, Cryo, FLA, TULSA...
Prospective Phase II trial, n=56Majority intermediate risk (47/56); median PSA 7.4Index lesion defined by MRI (PiRADS 4-5 on 2 of T2W, ADC, DCE) + biopsy (TRUS or TPM)Focal ablation of the index lesion with HIFUFollow-up MRI at 2 weeks, 6mo, 12mo and biopsy at 6mo
EUROPEAN UROLOGY 68 (2015) 927–936
Focal therapy for localized prostate cancer
Biochemical Failure Post RP+ RT
RP or RP + Adjuvant RT Primary RTStephenson, J Clin Oncol. 2007
5
Biologic characterization
Intra-prostatic lesion delineation
Staging
Response assessment
Therapy selection• Surveillance• RT/Sx• ADT/systemic Rx
Directed biopsyFocal therapy/boostImage guided surgery
Salvage post RT/RPHigh risk RP
SurveillancePost RTPost ADT/systemic Rx
Potential role of imaging in CaP
Imaging in Prostate Cancer
• CT/Bone Scan– staging+restaging+response
• Ultrasound – systematic biopsy guidance
• mpMRI
– Biopsy guidance for TRUS bx –ve, cancer suspicion
Potential for Image Guided Therapy in Prostate Cancer
mpMRI• DIL identification for Bx/FT/FB• Whole body MRI for metastates
Positron Emission Tomography (PET)• DIL identification for FT/FB• Identification and quantification of metastases
New PET tracers and hybrid imaging• Choline derivatives (11C, 18F)• FACBC (Fluciclovine)• PSMA (68Ga, 18F)• Acetate (18F)
PET/MRI – “One Stop Shopping” for CaP
Complete response
Partial response
Cellini et al. 2002; Int. J. Radiat. Oncol. Biol. Phys. 53:595-599
Importance of DIL in XRT
76% of cancers >0.1cm3 identified by at least 1 observers
An automated pipeline for model-based prostatecancer radiotherapy
Planned doseDose prescription
Tumor probability
Ktrans
ADC
T2
Slide courtesy of Dr. Uulke van der Heide
Systematic Review DIL boost
Bauman, Rad Onc. 2013 107(3):274• N=13, 833 patients; mainly MRI For target definition• mean boost 150% (brachy); 89 Gy (EBXRT)• significant heterogeneity • acceptable toxicity; short follow-up
Von Eyben, Clin. Genitoruinary Cancer, 2016, 14(3):189• N=11, 988 patients• significant heterogeniety• 464 patients>5 year follow-up• Low toxicity, bDFS/cDFS >80%
FeasibilityNeed for prospective studies
T2 MRI DCE-MRI DW-MRI
FLAME: focal dose escalationmulti-center phase III randomized trial
Prostate 77 Gy
Tumor 95 Gy
Number of GTVs
defined per patient
1 71%
2 21%
>3 8%
571 patients
Trial is now closed
Use of Choline PET for DIL identification
Nuc Med Comm, 2017• Biopsy and whole mount gold standards• Sensitivity: 55-90%; Specificity: 45-86%; Accuracy: 60-85% • ↑performance with ↑ tracer dose, delayed imaging, PET/MRI
What about other tracers?
Int J Radiation Oncol Biol Phys, 91(5):2015
Nat Rev Urology, Feb 2016
PSMA imaging
21
Prostate Specific Membrane Antigen
• Type II trans-membrane protein• FOLH1 gene on Chromosome 11• Expressed on prostate epithelium• 100-1000x over-expression in CaPp;
increased expression with GG, AD
18F-DCFPyL• Hopkins + Canadian Consortium develop
2 stage automated synthesis
First Case – Gleason Pattern 4
Simplifying the pipeline for model-based prostatecancer radiotherapy
Planned doseDose prescription
Modified from Dr. Uulke van der Heide
PET DIL identification(PET/CT or PET/MRI)
But that’s not all you also get!
Biologic characterization
Intra-prostatic lesion delineation
Staging
Response assessment
Therapy selection• Surveillance• RT/Sx• ADT/systemic Rx
Directed biopsyFocal therapyImage guided surgery
Salvage post RT/RPHigh risk RP
SurveillancePost RTPost ADT/systemic Rx
Potential role of imaging in CaP
Biochemical Failure Post RP
RP or RP + Adjuvant RT Primary RTStephenson, J Clin Oncol. 2007
28
Sites of recurrent disease at BF
Local failure
• Prostate/prostate bed
Regional failure
• Pelvic nodes
Distant failures
• Extra-pelvic nodes
• Bone
Restaging CT and bone scan have poor sensitivity if PSA <10 and low PSA velocity (when recurrence is most likely to be localized or limited)
UROLOGY 61: 607–611, 2003.29
Challenges in Recurrent Disease
• Routine hormone therapy at the time of BF exposes men who have limited disease to morbidity of ADT
• Observation until symptomatic metastases denies men a potential therapeutic window for treatment and exposes them to morbidity from recurrence
• Lack of a well established post-RT salvage pathways also influences upstream treatment decisions (RP vs. RT). Variable use of adjuvant and salvage RT post RP
• Conventional restaging is relatively insensitive with early BF thus limiting ability to detect isolated local recurrence vs. oligometastatic vs. extensive metastatic disease
30
IGPC-003 Trial
Post RP (n=10)6 none/bed3 pelvic nodes1 extra-pelvic
Post RT (n=10)2 none6 prostate2 pelvic nodes1 extra-pelvic
Improving the treatment of recurrent CaPRestaging with 18F-Fluorocholine PET/MRI
32
Movember GAP-2
N=96; 10 sites worldwide• London• UHN• Laval University
Accrual completeAnalysis underway
Improving outcomes of post RP salvage RT
Modality 3-5 yr bDFS Toxicities
Salvage RP 47-71% Incontinence: 50%Rectal injury: 5-15%Stricture: 30-30% RSRP
Salvage Cryotherapy 34-77% Incontinence: 11-40%Fistula: 1-3%Obstruction: 11-73% With focal Cryo
Salvage HIFU 46-61% Incontinence: 7-50%Fistula: 3-7%Obstruction: 9-36% With focal HIFU
Salvage Brachytherapy 34-89% Incontinence: 0-30%Gr 3/4 GU: 14-47%Gr 3/4 GI: 0-24% With focal Brachy
Management of Local Recurrence post RT
37
HDR Salvage Brachytherapy
• MRI with mapping biopsies
• Directed to tumour only
• 2 brachytherapy implants (13 Gy x 2) separated 7-10 days apart
Slide courtesy of Dr. Peter Chung
40
Biochemical profile
Salvage HDR brachytherapy
Post treatment biopsy
Time41
Slide courtesy of Dr. Peter Chung
Composite PTV defined on PSMA-PET+MRI18Gy/single HDR treatment
6mo PSA 5.65 -> 0.67; CR on mpMRI and PET/CT
Annals of Oncology 24: 2881–2886, 2013
N=140, biochemical recurrence post RPSurvival from time of detection of metastases
Improving the treatment of recurrent CaPManagement of Oligometastatic Disease
44
Patterns of salvage:• Nodal – 78%• Bone – 21%• Visceral – 1%
Staging• 98% choline PET/CT
Heterogeneity of Rx• 61% adjuvant ADT• 49% elective nodal Rx
“For MDT to be successful, three main prerequisites should be fulfilled: (1) accurate imaging to detect early metastases, (2) complete eradication of all oligometastaticsites, and (3) acceptable toxicity”
Improving the treatment of recurrent CaPMx of Oligometastatic Disease – Systematic Review
45
Treatment of oligometastatic disease
0 0.03 0.09 0.16 0.08 0.17
0.58
1.07
1.65
2.48 2.39
3.99
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Jul-
05
Dec
-05
May
-06
Oct
-06
Mar
-07
Au
g-0
7
Jan
-08
Jun
-08
No
v-0
8
Ap
r-0
9
Sep
-09
Feb
-10
Jul-
10
Dec
-10
May
-11
Oct
-11
Mar
-12
Au
g-1
2
Jan
-13
Jun
-13
No
v-1
3
PSA Salvage
radiotherapy
Re-staged
46Slide courtesy of Dr. Hans Chung
Metastatic Workup (3/2014)
47Slide courtesy of Dr. Hans Chung
SBRT to Pelvic Nodes (5/2014)
• Prophylactic pelvic nodes to 25Gy/5#
• Grossly visible pelvic node boost to 30Gy/5#
48Slide courtesy of Dr. Hans Chung
PSA Trend
0 0.03 0.08 0.08 0.17
0.58
1.071.3
1.65
2.39
3.99
1.94
0.360.55
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Jul-
05
Jan
-06
Jul-
06
Jan
-07
Jul-
07
Jan
-08
Jul-
08
Jan
-09
Jul-
09
Jan
-10
Jul-
10
Jan
-11
Jul-
11
Jan
-12
Jul-
12
Jan
-13
Jul-
13
Jan
-14
Jul-
14
Jan
-15
Jul-
15
PSA
Pelvic nodal SBRT
49Slide courtesy of Dr. Hans Chung
Routine Scans (6/2015)
50Slide courtesy of Dr. Hans Chung
Improving the treatment of recurrent CaPComparison of PET restaging (meta-analysis)
Am J Nucl Med Mol Imaging 2014;4(6):580-601
RT
RP
51
N=532 men with BF post RP (452) or RT (107) imaged with 68Ga-PSMA PET/CTIncreasing lesion detection with increasing PSA:
Post RP failures: 52% overall detection; 35% nodal; 13% local; 11% bone
Post RT failures: 95% overall detection; 71% local; 34% nodal; 17% bone
Didn’t track outcomes
Mainly post RP BF failures (80%) +/-prior salvage prostate bed RT (50%)
N=131, median PSA 2.2 ng/ml
76% management impact (99/131)
ADT to lesion directed therapy (44)Switch to surveillance (29)Switch from to ADT (14)Therapy modification (8)
68Ga
DCFPyL
Mol Imaging Biol (2015) 17:575
[18F]-DCFPyl advantages: availability, production amount, and image resolution
N=14 biochemical recurrence post RT or RP
All Ga68 lesions detected by DCFPyLDFCPyL detected additional lesions vs. Ga68DFCPyL had higher SUVmax to background
“Our results indicate that the [18F]-labeled compound [18F]DCFPyL is a highly promising alternative to [68Ga]- Ga-PSMA-HBED-CC for PSMA-PET/CT imaging in relapsed prostate cancer. Based on significantly higher SUVvalues in the PSMA-avid lesions, [18F]DCFPyLPET/CT may represent a valuable tool to detect small prostate cancer lesions with high sensitivity.”
Improving the treatment of recurrent CaP[18F]-DCFPyL vs. [68Ga] PSMA Imaging for restaging
55
Biochemical failure after primary RT (n=80)
[18F]DFCPyL PET/CT (optional PET/MRI)
Number of men with extra-prostatic recurrenceNumber and sites of recurrence
Impact on proposed management plan
CT Thorax + abdomen + bone scan + mpMRI pelvis
Number of men with extra-prostatic recurrenceNumber and sites of recurrence
Proposed management plan
Actual management at 6,12,24,26 months• Biopsy • Salvage therapies• HROQOL and Toxicity
Canadian trials of 18F-DCFPyL
PICsLondon, Hamilton, PMCC, OCC• N=80, BF post RT
PSMA PET/CT for Prostate CancerBC Cancer agency• N=200, BF post RP or RT
First PICs Patient
Biologic characterization
Intra-prostatic lesion delineation
Staging
Response assessment
Therapy selection• Surveillance• RT/Sx• ADT/systemic Rx
Directed biopsyFocal therapyImage guided surgery
Salvage post RT/RPHigh risk RP
SurveillancePost RTPost ADT/systemic Rx
Potential role of imaging in CaP
Imaging systemic disease
Kwee et al, J Nuc Med, 2014
• MATV = SUV>3.0; 40%
Castration Resistant Prostate Cancer (CRPC)18F-FCH pre and post chemotherapy
18F-Choline 3mo 18F-Choline
Now Open
MISTR N=40, Hamilton + London
18F-DCFPyL PET/CT vs. 18F-FDG PET/CT pre and post CTX
Imaging-based response evaluation. Clemens Kratochwil et al. J Nucl Med 2016;57:1170-1176
(c) Copyright 2014 SNMMI; all rights reserved
PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617
Conclusions
Increasing role for imaging in directing therapy in prostate cancer:
• DIL directed focal therapy or boost
• Selection of patients for local salvage
• Treatment of oligo-metastatic disease
• Prognosis and response in CRPC
mpMRI: early/localized CaP
PET/CT: advanced/recurrent/metastatic CaP
PET/MRI: “one stop shopping”
Lu177-PSMA: treatment
THANK YOU