10/30/2018. Martha K. Terris, MD Witherington Distinguished Professor and Chair Medical College of Georgia Urology November 5, 2018

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1 Martha K. Terris, MD Witherington Distinguished Professor and Chair Medical College of Georgia Urology November 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 1

2 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. 2

3 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 3

4 Organization Low Risk Intermediate Risk AUA, EAU, D Amico GUROC, NICE CAPSURE NCCN ESMO <T2a, PSA<10, and GS<6 <T2a, PSA<10, and GS<6 <T2a, PSA<10, and GS<6 <T2a, PSA<10, and GS<6 Very Low: <3cores + <50% <T2a, PSA<10, and GS<6 T2b and/or PSA >10-20 and/or GS=7 T1-T2 and/or PSA <20 and/or GS<7 T2b and/or PSA >10-20 and/or GS=7 T2b or T2c and/or PSA >10-20 and/or GS=7 Any between Low and High High Risk >T2c or PSA>20 or GS 8-10 >T3a or PSA>20 or GS 8-10 >T3a or PSA>20 or GS 8-10 Very High T3b-4 T3a or PSA>20 or GS 8-10 Very High T3b-4 >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 4

5 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 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 5

6 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). 6

7 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 2 nd opinion AXUMIN PET/CT 7

8 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 8

9 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 mets to bone or other visceral organs Long-term follow-up studies: good cancerspecific 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: Karnes et al. J Urol. 2015; 193: Suardi et al. Eur Urol : Winter et al. BMC Urol. 2015; 15:10. Rigatti et al

10 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: Karnes et al. J Urol. 2015; 193: Suardi et al. Eur Urol : 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): 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% min t ½ 68Ga-PSMA - transmembrane protein Prostate-specific membrane antigen (PSMA) 55% detection PSA ng/ml 76% detection PSA ng/ml Pultrone et al. J Urol. 197, 4S, Maurer et al. J Urol. 197, 4S, Maurer et al. Nature Rev Urol 13,

11 Diffusion-weighted MRI combined with ultrasmall 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: Harisinghani et al. N. Engl. J. Med. 2003; 348: mTc-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: 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 ,

12 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 farred fluorophore, Cy5 Nakajima et al. Bioconjug Chem : Neuman et al. Clin Cancer Res : Son et al. Clin Cancer Res : Experimental treatment option for PCa patients 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 : 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 12

13 Abdollah et al % 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 : Winter et al. BMC Urol. 2015; 15:10. 13

14 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 : 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 (NCT ) 14

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16 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: month post-op PSA: months post-op PSA: months post-op PSA: months post-op PSA: 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 16

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