looking into the future for recurrent cancer - canm … speaker presentations/2017 pet... ·...

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!



Staging

Response assessment


Directed biopsyFocal therapyImage guided surgery




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)


SBRT to Pelvic Nodes (5/2014)

• Prophylactic pelvic nodes to 25Gy/5#

• Grossly visible pelvic node boost to 30Gy/5#


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


Routine Scans (6/2015)


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



Staging

Response assessment


Directed biopsyFocal therapyImage guided surgery




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

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