1. PRESENT STATUS OF PROSTATE CANCER TREATMENT AND THE ROLE OF IMAGING CÉSAR DAVID VERA-DONOSO Department of Urology

2. WHO IS IN THE LINE OF FIRE?

3. WE NEED TO COLLABORATE IN MANY FIELDS

4. WE NEED RELIABLE IMAGES TO TAKE DECISIONS

5. INCIDENCE EUROPE In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men, outnumbering lung and colorectal cancer PCa is currently the second most common cause of cancer death in men Prostate cancer affects elderly men more often than young men

6. ESTIMATED NEW CASES OF CANCER IN USA 2012: 1,638,910 UROLOGIC TUMORS PROSTATE BLADDER KIDNEY AND RENAL PELVIS URETER TESTIS PENIS AND OTHERS 382,880 (23,3 %) 241,740 73.510 64770 2860 8590 1570

8. 250 200 150 100 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S.

9. FIRST MESSAGE WE HAVE TO TALK A LOT AND WORK TOGETHER

10. Prostate Cancer: Natural History Prostate cancer pts can have a long history – Opportunity for multiple therapies – Toxicities and quality of life important – Issues of co-morbid disease and aging Philosophy of chronic disease management New therapies are identified continuously

11. Natural History of Prostate Cancer Typical patient presentation as they move through different stages Under the care of ONCOLOGIST Under UROLOGIST care NonmetastaticMetastatic Local therapy Androgen deprivation Therapies after LHRH agonists and antiandrogens First-line therapy Salvage therapy Death Under ONCOLOGIST care Higano C, et al. In: Figg WD, et al. Drug management of prostate cancer; 2010. Burden of disease Asymptomatic Symptomatic Castrate sensitiveCastrate resistant

12. HOW IS THE DIAGNOSTIC ITINERARY?

13. Digital Rectal Examination A – Central zone B – Fibromuscular zone C – Transitional zone D – Peripheral zone E – Periurethral zone Seminal Vesicles Prostate

14. In about 18% of all patients, PCa is detected by a suspect DRE alone, irrespective of the PSA level A suspect DRE is a strong indication for prostate biopsy as it is predictive for more aggressive (Gleason score > 7) prostate cancer

15. SCREENING – PSA IS ASSOCIATED: With an increased diagnosis of PCa With more localized disease and less advanced PCa (T3-4, N1, M1) From the results of five RCTs, with more than 341,000 randomized men, no PCa- specific survival benefit was observed From the results of four available RCTs, no overall survival benefit was observed

16. Molecular Images to discharge prostate cancer To avoid unnecessary biopsies > 1,000.000 of biopsies are done every year in USA Just 30 % of biopsies are positive for cancer

17. The role of Imaging in Diagnosis Multiparametric MRI Results need further confirmation, and the cost-effectiveness of mMRI as a triage test before the first biopsy has not been assessed Inter-reader variability

18. Prostate cancer missed by multi- parametric MRI: Correlation with whole-mount pathology Nelly Tan, Steven Raman, Los Angeles, CA Systematic biopsy continues to reveal prostate cancer (CaP) in areas not deemed suspicious by MRI 122 patients with mp- MRI prior to radical prostatectomy Matched each MRI lesion to its whole-mount pathology counterpart 135/283 histologically confirmed CaP tumors were identified by mp-MRI (48% sensitivity). Of 148/283 (52%) tumors in 74/122 (61%) men that missed MR detection, 110 (74%) were GS 6, 23 (16%) GS 3+4, 9 (6%) GS 4+3, 6 (4%) GS ≥8. Missed CaP foci were smaller in size

19. WHAT IS THERE ABOUT PET?

20. CASE 1 57 years old man 2009 Systemic Vasculitis 2002 Silicosis. bilateral pulmonary conglomerates March 2011 purple with renal, neurological compromise PET-CT (Nov 2013) asked by his specialist doctor

21. CASE 1 He refers a weak and interrupted urine stream DRE: normal. Left lobe shows a slightly increased size but without palpable nodules Hypermetabolic focus on posterior - inferior left prostatic lobe

23. EVALUATION PSA 0,78 ng/mL NEXT STEP : levofloxacin 250 mg every 12 hours 7 days PET CT 2 months after (Febr 2014)

25. Focus of diffusion restriction is observed in the left side periphery of the base medium-third of the gland

26. 06/06/2014 PROSTATIC BIOPSY Symmetrical, homogeneous prostate. Prostate Volume: 30cc TZ Volume: 16cc Prostatic Adenocarcinoma affecting a single core of Left Prostatic Lobe - Gleason score 6 (3 + 3) Percentage of GLOBAL TUMOR LOAD: 0.5%

27. Incidental prostate 18F-FDG uptake without calcification indicates the possibility of prostate cancer ONCOLOGY REPORTS 31: 1517-1522, 2014 HIROKO et al Hirosaki Japan 3,236 male subjects who underwent 18F-FDG PET/CT scans from 2008 to 2012 in order to identify cases of incidental prostate FDG uptake Incidental FDG uptake of the prostate was observed in 53 cases (2%) 49 cases were included in the present study. Of the 49 cases, 8 (16%) had prostate cancer, while 41 (84%) were benign Urologists performed a biopsy for suspicious cases, and 12 patients underwent biopsy

28. NUCLEAR MEDICAL DOCTORS UROLOGISTS

29. SECOND MESSAGE WE HAVE TO CREATE NEW PARADIGMS

30. STAGING

31. LOCAL STAGING: Multiparametric MRI Given its low sensitivity to microscopic invasion, MRI is not recommended in the local staging of low-risk patients MRI may be useful in selected patients with intermediate- to high-risk cancers

32. CLINICAL NODAL STAGING Since CT or MRI cannot detect microscopic lymph node invasion, detection rates are typically < 1% in patients with a Gleason score < 8 cancer, PSA < 20 ng/mL or clinically localized disease They should therefore not be performed in low-risk patients and reserved for patients with high-risk cancers

33. TREATMENTS: ACCORDING TO RISK OF RECURRENCE RISK VERY LOW RISK AND LOW RISK (40%) INTERMEDIATE RISK (20 %) HIGH RISK (40 %) TREATMENT ACTIVE SURVEILLANCE ACTIVE SURVEILLANCE, RADICAL PROSTATECTOMY, RADIOTHERAPY ( EBRT +/- BRACHYTHERAPY) EBRT, RADICAL PROSTATECTOMY, HORMONAL TREATMENT

34. TREATMENT: WATCHFUL WAITING/ACTIVE MONITORING In patients with the lowest risk of cancer progression: cT1-2a PSA < 10 ng/mL biopsy Gleason score< 6 ( 10 cores) < 2 positive biopsies minimal biopsy core involvement (< 50% cancer per biopsy).

35. ACTIVE SURVEILLANCE might mean NO TREATMENT at all for patients older than 70 years in younger patients, it might mean a possible treatment delayed for years PRESERVING QUALITY OF LIFE AND AVOIDING REPEATED BIOPSIES WHY IS IMPORTANT ACTIVE SURVEILLANCE?

37. TREATMENT: RADICAL PROSTATECTOMY COMPLICATIONS

38. COMPLICATIONS DEFINITIVE RADIOTHERAPY Any significant toxicity (> grade 2) 22,8 % Erectile Disfunction 52 % Increased risk of developing secondary rectum cancer 1.7 -fold in comparison with the surgery group Bladder cancer increased by 2.34-fold in comparison with a healthy control population

39. Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study More than 4500 patients right now Prostatic Biopsy is necessary at years 1,4,7 At 2 years 81% of patients stay on AS WE NEED A RELIABLE IMAGE TO REPLACE BIOPSY IN THE FOLLOW UP THIRD MESSAGE

40. SENTINEL NODE IN RADICAL PROSTATECTOMY TREATMENT

41. Lymphadenectomy It is the gold standard for N-staging lymph node dissection limited to the obturator fossa will miss about 50% of lymph node metastases The primary removal of the so-called sentinel lymph node (SLN), has the main aim of reducing the eventual morbidity associated with an extended pelvic node dissection It remains experimental in 2014

42. Different reports mention that 19-35% of positive lymph nodes are found exclusively outside the area of the traditionally limited LND Besides being a staging procedure, pelvic eLND can be curative, or at least beneficial, in a subset of patients with limited lymph node metastases A recent prospective study randomized 360 consecutive patients to receive extended LND versus standard LND. After a median follow-up of 74 months, this study confirmed that an extended LND positively affected BPFS in intermediate and high-risk PCa GUIDELINES EAU 2014

43. Distribution of SLNs (percentage)

46. The Optimal Tracer Hybrid radioactive + fluorescent radiocolloid + PSMA antibody

47. LAST NEWS

48. 38 patients prior to planned RP with intermediate or high- risk After injection of 122±17 MBq 68Ga-HBED-PSMA a fully- diagnostic PET/MRI including multiparametric prostate MRI Results Despite unremarkable conventional imaging 68Ga-HBED- PSMA PET/MRI revealed metastasized disease in two patients Tumor involvement of the prostate could be visualized by 68Ga-HBED-PSMA PET in 95% of patients (36/38) 68Ga-HBEDPSMA PET/MRI detected 6 out of 11 patients with histological lymph node involvement (sensitivity: 55%) and correctly classified 24 out of 25 patients without histological evidence of lymph node metastases (specificity: 96%).

49. A comparison of 111In-J591 SPECT with 89Zr-J591 PET imaging for Prostate Cancer patients. Sandhya Chalasani*, Douglas Scherr, Cornell University,New York, NY To compare pilot cohorts of men scheduled for radical prostatectomy imaged with novel antibody conjugates: Cohort 1 Eight patients (111In-J591) (SPECT) or Cohort 2 Eleven patients (89Zr-J591/PSMA) PET

50. Conclusions 111In-J591 demonstrated targeting in localized disease in prostatectomy specimen, but pathologic validation was only inferred by quadrant due to low soft tissue contrast and the inherent resolution limits 89Zr-J591/PSMA-PET can identify discrete intra- prostatic tumor foci, and in our cohort, visualized most of the index lesions. Additionally, high-grade tumors are generally better visualized with this novel imaging agent There is a relationship between SUV on the 89Zr- J591-PET of tumor foci and their aggressiveness as defined by Gleason score

51. New imaging modalities: USPIO Ultra-small particles of iron oxide (USPIO) can dramatically improve the detection of microscopic lymph node metastases on MRI MR sensitivity improved from 35.4% to 90.5% with the use of USPIO This approach may be cost-effective, but is limited by the lack of availability of USPIO in Europe

52. CONCLUSIONS: MI for Treatment Treatment of prostate cancer is a moving target Most patients die with prostate cancer not from prostate cancer Side effects of treatments: sexual dysfunction and incontinence Active surveillance or watchful waiting  You can help us to select the correct patient for this treatment providing us an image that identifies any perceptible change

53. FUNCTIONAL IMAGES ARE THE FUTURE!