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Martha K. Terris, MDWitherington Distinguished Professor and Chair

Medical College of Georgia UrologyNovember 5, 2018

Elevated PSA and/or nodule on digital rectal examination

Prostate biopsies If initial biopsy shows

no cancer, a variety of other tests may be performed

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3T Multiparametric MRI of the Prostate ◦ Identifies lesions in patients with negative biopsy

and persistent concern for cancer◦ Use as an initial evaluation is controversial◦ Biopsies directed at MRI lesions do not replace

random systematic biopsies

Blood◦ 4Kscore Measures kallikrein proteins: total PSA, free PSA, intact

PSA, and human kallikrein related peptidase 2 to assess a patient’s risk of having a Gleason score ≥ 7 on prostate biopsy.

◦ Prostate Health Index (phi) score includes PSA, free PSA, and proenzyme PSA (proPSA) to

estimate probability of cancer on biopsy

Urine◦ Progensa® (Gen-Probe, San Diego, CA) prostate

cancer antigen-3 (PCA3) urine assay Following a DRE, PCA3 score is calculated from a

patient’s urine to estimate the risk for prostate cancer on a subsequent biopsy.

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Biopsy Tissue◦ ConfirmMDx Uses the methylation status of three biomarkers

(GSTP1, RASSF1, and APC) from negative prostate biopsy tissue to help determine the chance of prostate cancer on a subsequent biopsy.

Low Risk◦ PSA level <10 ng/mL◦ Biopsy Gleason score of ≤6, ◦ Clinical stage of ≤T2a

Intermediate Risk ◦ PSA level of 10.1 to 20 ng/mL◦ Gleason score of 7◦ and/or a clinical stage of T2b

High Risk ◦ PSA level >20 ng/mL, ◦ Gleason score of ≥8, ◦ and/or a clinical stage of T2c-3a

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Organization Low Risk Intermediate Risk

High Risk

AUA, EAU, D’Amico

<T2a, PSA<10, and GS<6

T2b and/or PSA >10-20 and/or

GS=7

>T2c or PSA>20 or GS 8-10

GUROC, NICE <T2a, PSA<10, and GS<6

T1-T2 and/or PSA <20 and/or GS<7

>T3a or PSA>20 or GS 8-10

CAPSURE <T2a, PSA<10, and GS<6

T2b and/or PSA >10-20 and/or

GS=7

>T3a or PSA>20 or GS 8-10

Very High T3b-4NCCN <T2a, PSA<10,

and GS<6Very Low: <3cores

+ <50%

T2b or T2c and/or PSA >10-20 and/or GS=7

T3a or PSA>20 or GS 8-10

Very High T3b-4

ESMO <T2a, PSA<10, and GS<6

Any between Lowand High

>T3a or PSA>20 or GS 8-10

AUA=American Urological Association, EAU=European Association of Urology, D’Amico=Harvard, GUROC=GU Radiation Oncologist of Canada, NICE=National Institutes of Health and Clinical Excellence, Capsure=UCSF, ESMO=European Society of Medical Oncology

Oncotype Dx/genomic prostate score (GPS) ◦ Consists of 12 cancer-related genes and 5 reference

genes to evaluate cancer aggressiveness. Prolaris Score◦ Measures RNA expression of 31 genes involved in cell

cycle progression compared to 15 house keeping genes to quantify prostate cancer cellular aggression.

ProMark◦ Proteomic prognostic test that incorporates eight

biomarkers from a prostate biopsy sample to predict an individual’s risk of favorable or nonfavorable/aggressive prostate cancer.

Considered Experimental

Low Risk◦ No Staging Studies necessary◦ If choosing active surveillance may have serial MRI

and/or biopsies Intermediate Risk◦ Abdominal/Pelvic imaging (CT or MRI)◦ Bone scan if T2 and PSA >10

High Risk◦ Abdominal/Pelvic imaging (CT or MRI)◦ Bone scan if T2 and PSA >10

*NCCN Guidelines

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Very healthy 63 year old African American gentleman

Prostate Cancer on TRUS bx for elevated PSA 4.3 GS 4+4 in 7/15 cores in 2008

Treated with Brachytherapy (age 54) PSA nadir at <0.01 and was undetectable

until 2014 when PSA was found to be 0.2 Repeat PSA in 2/2017 was 4.87 and 3/2017

was 6.37.

ROS: negative PMH: prostate cancer, hypertension,

hyperlipidemia PSH: rotator cuff repair, brachytherapy Med: amlodipine, aspirin, lipitor, FH: no hx of PCa SH: non-smoker, social drinker

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IMPRESSION 1. Brachytherapy seeds identified within the

prostate gland. The prostate gland is within normal limits of size.

2. A 1.2 x 1.6 cm intermediate density structure is identified adjacent to right external iliac vein, which is highly concerning for pathologically enlarged right pelvic lymph node (i.e. nodal metastatic disease).

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Patient underwent repeat Ultrasound guided prostate biopsy

Pathology Report: Benign prostatic tissue showing treatment effect in all cores

He was advised by his urologist that Lupron was next step but was opposed to hormone treatment at this point

He presented to MCG for a 2nd opinion AXUMIN PET/CT

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Intensely increased activity in a conglomerate right external iliac lymph node group 1.3 cm short axis x 2.4 cm craniocaudal

Numerous brachytherapy seeds throughout the prostate gland. No abnormal focal uptake.

IMPRESSION: Intense regional right external iliac tumor

lymphadenopathy No other significant active lymphadenopathy or

distant metastasis

F-18 fluciclovine (AXUMIN) PET/CT

F-18 fluciclovine (AXUMIN) PET/CT

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30-40% biochemical recurrence rate after RP and 36-50% for brachytherapy within 10 years

Management Options:◦ Androgen deprivation therapy- standard Unfavorable side effect profile Progression to castration-resistant disease Significant toxicity at long term Continuous vs Intermittent◦ Salvage radiation therapy◦ Salvage ablation procedures◦ Salvage lymphadenectomy

More favorable outcome than those with metsto bone or other visceral organs

Long-term follow-up studies: good cancer-specific survival of patients with limited node-positive disease after RP ◦ Even without ADT

Removal of node may have beneficial impact on cancer progression

Tilki et al. J Urol. 2015; 193:484-490.Karnes et al. J Urol. 2015; 193:111-116.Suardi et al. Eur Urol. 2015 67:299-309.Winter et al. BMC Urol. 2015; 15:10.

Rigatti et al. 2011

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Salvage PLND after primary treatment ◦ Prolong recurrence-free survival◦ Delay systemic therapies

Efficient and precise imaging for identification of suspicious LNs would optimize salvage

Traditional CT and MRI – low sensitivity Tilki et al. J Urol. 2015; 193:484-490.Karnes et al. J Urol. 2015; 193:111-116.Suardi et al. Eur Urol. 2015 67:299-309.Winter et al. BMC Urol. 2015; 15:10.

PET/CT Scan◦ 18-fluorodeoxyglucose ◦ 11C-choline ◦ 18F-fluoroethylcholine◦ 11C-acetate ◦ Sensitivity 58% ; Specificity 69% ◦ Small (>5mm) LN metastasis◦ Limitations: 20 min t ½ ◦ Requires on-site cyclotron

Jadvar H. J Nuc Med.2011;52(1):81-89. Almeida et al. Am J Nucl Med Mol Imaging. 2017;7:1-11.

PET/CT ◦ 18F-fluciclovine (AXUMIN) - amino acid

transporter analogue Sensitivity 58% and Specificity 81% 109.7 min t ½◦ 68Ga-PSMA - transmembrane protein Prostate-specific membrane antigen (PSMA) 55% detection PSA 0.2-0.5 ng/ml 76% detection PSA 0.5-1.0 ng/ml

Pultrone et al. J Urol. 197, 4S, 2017. Maurer et al. J Urol. 197, 4S, 2017. Maurer et al. Nature Rev Urol 13, 226-235. 2016

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Diffusion-weighted MRI combined with ultra-small particles of iron oxide (USPIO) ◦ high sensitivity between benign and malignant lymph

nodes even in normal sized nodes.◦ Identified intraoperatively with hand-held magnetometer◦ Intraprostatic injection limits use in salvage setting.

Winter et al. Ann. Surg. Oncol. 2014; 21: 4390–6. Harisinghani et al. N. Engl. J. Med. 2003; 348: 2491–9.

99mTc-labeled colloids ◦ Albumin◦ Sulphur◦ Phytate◦ Require intraoperative gamma camera

Hybrid ICG and 99m Tc-nanocolloid◦ Intraoperative imaging without gamma camera

All require injection into primary tumor

Buckle et al. J. Nucl. Med. 2012;53:1026–33.

Near-infrared (NIR) intraoperative molecular imaging with indocyanine green (ICG) ◦ Intraoperative, intraprostatic injection of ICG◦ Complexity of lymphatic drainage◦ U Penn: 5 mg/kg IV ICG one day prior to node dissection

Xia et al. Urology. 2017. 106 , 133 - 138

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Future imaging with prostate-specific fluorescent compounds◦ Anti-Prostate-Specific Membrane Antigen (PSMA)

antibody (J591) linked to ICG◦ YC-27, a near-infrared-emitting fluorophore

targeted to PSMA◦ Antibody fragment (cys-diabody, cDb) against

prostate stem cell antigen (PSCA) conjugated to far-red fluorophore, Cy5

Nakajima et al. Bioconjug Chem. 2011 22:1700-5.Neuman et al. Clin Cancer Res. 2015 21:771-80.Son et al. Clin Cancer Res. 2016 22:1403-12.

Experimental treatment option for PCapatients with nodal recurrence localized on PET/CT after primary treatment failure ◦ Lack of current guidelines

Two main aims: ◦ Delay further cancer recurrence◦ Postpone use of systemic treatments

Suardi et al. Eur Urol. 2015 67:299-309.Winter et al. BMC Urol. 2015; 15:10.

To maximize oncological outcomes, avoid unnecessary morbidity [1,3]

Ideal candidate: [3,5,6]

◦ Young patients ◦ Path stage pT2◦ Gleason score ≤ 7◦ PSA < 4 ng/ml ◦ Castration-sensitive disease◦ Low LN burden limited to pelvis

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Abdollah et al. 2015

50-80% of patients achieve complete BR after SLND (defined as PSA < 0.2 ng/mL)

Significant predictor of cancer progression◦ Rigatti et al: Mean time to clinical progression Persistently elevated PSA: 28.8mo Complete BR: 64.8mo

Predictors of BR:◦ PSA <4 ng/ml◦ RP to BCR time <24mo◦ Node-negative at RP

Most invariably progress to biochemical recurrence after SLND, despite initial BR [3]

◦ Definition: PSA> 0.2 ng/ml and rising ◦ Median 18mo

9-31% BCR-free survival rate at 5 yrs◦ Suardi et al: 23% at 8 yrs

Winter et al: 3/13 complete remission (PSA<0.01) for 7 yrs◦ Potential for “cure”

Suardi et al. Eur Urol. 2015 67:299-309.Winter et al. BMC Urol. 2015; 15:10.

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Positive PET/CT after SLND + rising PSA 35%-50% CR-free survival rate at 5 yrs [3,6,7]

◦ Suardi et al: 38% CR-free survival at 8 yrs Pre-op predictors of CR: ◦ PSA >4 ng/ml at SLND [1,3]

◦ Retroperitoneal uptake at PET/CT scan Post-op predictors of CR: ◦ Pathologic nodes in retroperitoneum◦ Higher # of positive nodes◦ Incomplete PSA response to SLND

• Most reported complications were mild• No post-op mortality has been reported

Suardi et al. Eur Urol. 2015 67:299-309.

Constraints on sensitivity of current imaging techniques to detect LN recurrence

No literature currently on SLND s/p brachytherapy specifically

Studies: retrospective, small sample sizes, heterogeneous population, no controls ◦ Current randomized prospective trial ongoing Salvage Treatment or Active Clinical Surveillance for

Oligometastatic Prostate Cancer: a Randomized Phase II Trial (NCT01558427)

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A) LYMPH NODES, RIGHT PELVIC (DISSECTION):-Metastatic prostatic adenocarcinoma (2.6cm) involving one of ten lymph nodes (1/10)

B) LYMPH NODES, LEFT PELVIC (DISSECTION):-Five lymph nodes, negative for malignancy (0/5)

Tolerated procedure without complication Good biochemical response to SLND◦ Pre-op PSA: 6.37◦ 1 month post-op PSA: 0.32◦ 2 months post-op PSA: 0.04◦ 3 months post-op PSA: 0.03◦ 6 months post-op PSA: 0.02◦ 9 months post-op PSA: 0.02

New imaging techniques help localize disease recurrence after primary prostate cancer treatment.

More exact staging in recurrence increases the opportunities for directed treatment and prolonged results to salvage therapy

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