My biopsy shows prostate cancer: How bad is it? How to stage prostate cancer

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1 My biopsy shows prostate cancer: How bad is it? How to stage prostate cancer Giuseppe Petralia Division of Radiology, IEO - European Institute of Oncology IRCCS, Milan Department of Oncology and Haematology, University of Milan

2 Case 70 years PSA = 7.98 ng/ml DRE = negative GS 3+3 in 3/14 cores (Right & Left, 25% max core involvement) In theory, eligible for AS (EAU criteria) <20% +ve cores, <50% core involvement, GS 3+3, PSA <10ng/ml, ct1c

3 mpmri PI-RADS 5 MDT Lesion (15mm), Rt CZ (cranial level) T2W ADC T2W = 5 Circumscribed hypointensity >1.5cm DWI = 5 Focal markedly hypo- on ADC / hyperintense on DWI >1.5cm DCE = neg DCE b1500

4 MR-GB is decided at MDT Histology after MR-GB GS 4+3 2/3 cores, 95% max core involvement, 80% Gleason pattern 4 Change in management From AS to RALP GS 4+3 pt3b pn0 R0

5 PCa management is aimed to PRECISION ONCOLOGY right treatment, right patient, right time, right duration

6 Low risk (PSA <10 ng/ml and GS < 7 (ISUP Grade 1) and ct1 T2a) 1. How good is MRI for enabling gland sparing therapies (AS/HIFU) or less invasive therapies (NS RALP or RT)?

7 N & M staging not needed N-staging not needed patients with low- and intermediate-risk PCa may be spared before potentially curative treatment (low-risk <10% 1-3 ) M staging not needed in asymptomatic patients Bone scanning should be performed in symptomatic patients 1. Pagliarulo V, et al. J Clin Oncol. 2006; 20; 24: Heidenreich A, et al. Eur Urol. 2007; 52: Haese A, et al. Cancer Sep 1;95(5):

8 T staging for Active Surveillance not needed EAU guidelines 2017 Perform mpmri before a confirmatory biopsy (LoE 2b, GR B) During confirmatory biopsy include systematic and targeted biopsies (LoE 2a, GR B) They however acknowledge that: mpmri high NPV value for lesion upgrading and for staging anterior prostate lesions Lawrentschuk, N., et al. BJU Int, : Schoots, I.G., et al. Eur Urol, : 627.

9 Current diagnostic process contributes to poor risk assessments in potential AS patients Prostatectomy examinations of low risk patients (potential AS candidates) finds unfavorable pathologic characteristics in a substantial proportion!* Patient numbers TRUS biopsy cores Organ confined Gl 7 Tosoian JJ et al. 2013* % 22% Epstein J, et al 2012* % Template biopsies with systematic sampling in potential AS candidates or AS patients (<1 year) indicate a 30-40% mis-classification rate** *Epstein J, et al. Eur Urol. 2012;61: ; *Tosoian JJ et al. J Urol 2013; 190: ; **Taira AV, et al. Am J Clin Oncol. 2013; 36: **Ayres BE, et al. BJU Int. 2012; 109:1170-6; **Barzell WE, et al. J Urol. 2012; 188:762-7

10 mpmri helps to select the right patient for AS Staging 135 AS patients Follow-up of 31 (6-80) months PSA/3 months, mpmri annually and re-biopsy at 1, 3 & 5 years PI-RADS v2 1-3 Baseline mpmri (PI-RADS v2) MV analysis: PI-RADS >3 and size >10mm are strongly associated with failure-free survival. PI-RADS v Sanguedolce F, et al. Clin Genitourin Cancer Apr;16(2):

11 T staging for Surgery & RT not needed EAU guidelines 2017 mpmri is not recommended for local staging in low-risk patients 1-3 However, mpmri can still be useful for treatment planning in selected low-risk patients (e.g. candidates for brachytherapy) 4 NS RALP (Extreme) HFX RT, brachytherapy 1. Wang, L., et al. Radiology, : D Amico, A.V., et al. J Urol, : Engelbrecht, M.R., et al. Eur Urol, : Albert, J.M., et al. Brachytherapy, : 30.

12 The «Gas & brake» rule Gas / Brake SEnsitivity / SPecificity

13 EPE in % 1-2 (25%) 3 Maximise SPecificity Assessment of ECE: low risk patient bgs 3+3, PSA 8, ct1) ESUR criteria for T3a 4 NV bundle thickening Bulge, loss of capsular outline Measurable EPE So as not to deny NS surgery 5 or (extreme) HFX RT, brachytherapy pt2c pn0 R0, GS Hong SK, et al. World J Urol 2009; 27(2): Tewari AK, et al. Indian J Urol 2011; 27(3): Somford DM, et al., J Urol May Barentsz JO, et al. Eur Radiol Apr;22(4): Cornud F, et al., Curr Urol Rep2012 Feb;13(1):82-92.

14 Intermediate risk group PSA ng/ml or GS 7 (ISUP Grade 2/3) or ct2b 1. How good is MRI for ruling out adverse features (primary Gleason 4 & pt3)?

15 N & M staging not needed EAU guidelines 2017 Patients with low- and intermediate-risk PCa may be spared N-staging before potentially curative treatment CT or MRI have a sensitivity of less than 40% 1-2 Partin tables and Roach formula % M staging is not needed in asymptomatic patients Bone scanning should be performed in symptomatic patients 1. Harisinghani, M.G., et al. N Engl J Med, : Hovels, A.M., et al. Clin Radiol, : 387.

16 Problem of categorization Intermediate risk is an heterogeneous group with widely variable outcomes (5 year survival 2-70%) 1-2 GS 3+3, PSA 16.2 ng/ml, ct1c = favourable GS 3+4, PSA 9.5ng/mL, ct2b = unfavourable T2W DCE T2W DCE ADC b 1000 b 1000 ADC pt2c pn0 R0, GS 3+4 pt3a pn0 R0, GS Mitchell JA, et al. J Urol. 2005;173: D Amico AV, et al. JAMA. 1998;280:969-74

17 MRI helps to select the right patient Unfavourable Primary Gleason 4 and/or >50% +ve biopsies and/or >1 intermediate risk factors Gene expressions like high risk 1 Increased risk of adverse final histology 2 pt3, GS 8, R1 resections Poorer outcomes 3 BCR, M+, poorer survival Unfavourable MRI High PI-RADS score Low ADC <800 µm 2 /s TCL with capsule >15mm Undiagnosed SVI/EPE Site Posterior-lateral Next to sphincter Multiple (>2) adverse MRI features 1. Singh D et al., Cancer cell 2002, 182): Nguyen PL, et al. Int J Radiat Oncol Biol Phys Mar 1;73; 3. Zumsteg ZS, et al. Eur Urol. 2013;

18 Courtesy of Prof. Padhani Why is it so important to select the right patient? To give the right treatment, at the right time and for the right duration Favourable mpmri characterization Unfavourable subgroup Gleason 4+3 and/or >50% positive biopsies and/or >1 intermediate risk factors Unfavourable mpmri Staging (TNM) Favourable MRI features Unfavourable MRI features (suggesting primary Gl 4, larger volume, undiagnosed T3a) Option Confirmed Favourable Guided Bx Potential for cure Recategorized Unfavourable AS (some centres) Surgery / EBRT + short course adjuvant ADT Surgery / EBRT ± Nodal RT / +long course adjuvant ADT D Amico AV. Euro Urol 2013; 64:903-4

19 T staging (intermediate risk) EAU guidelines 2017 PSA GS NOMOGRAMS ( MSKCC, Roach formula) DRE % (population) mpmri is the most useful method Single patient (PO) but low sensitivity (~50%) 1-3 cannot detect microscopic EPE 1. Wang, L., et al. Radiology, : D Amico, A.V., et al. J Urol, : Engelbrecht, M.R., et al. Eur Urol, : 300.

20 T staging (intermediate risk) Other MRI-derived parameters such as the tumour volume 1 or the contact length of the tumour with the capsule 2 [ ] could further improve the local staging MRI TCL 20 mm > conventional MRI criteria for predicting microscopic EPE (82% versus 67%, p=0.015) 1. Lim, C., et al. J Magn Reson Imaging, : Baco, E., et al. J Urol, : 466.

21 Assessment of EPE: intermediate risk patient EPE in 20-45% 1-2 (58%) 3 Maximise SEnsitivity ESUR criteria for T3a 4 Abutment Irregularity of the capsule pt3a pn0 R0, GS Hong SK, et al. World J Urol 2009; 27(2): Tewari AK, et al. Indian J Urol 2011; 27(3): Somford DM, et al., J Urol May Barentsz JO, et al. Eur Radiol Apr;22(4):

22 NS RALP

23 Problem in contact (T2) or beyond (T3a) the capsule Intrafascial resection plane pt3a Prostate cancer - beyond capsule - in contact pt2

24 mpmri directed IFS pts NS-RALP 134 mpmri +IFS 134 controls PSM rate from 18.7% to 7.5% (P=.01) 1. Petralia G, et al. Radiology Sep 29:

25 «Make a virtue of necessity»

26 High risk group PSA >20 ng/ml or GS >7 (ISUP Grade 4/5) or ct2c 1. How good is mpmri for enabling surgery? 2. How good is imaging for N & M assessment?

27 Case 61 years PSA 15 ng/ml DRE negative (ct1c) TRUS biopsy GS 4+4 (3/14, Right & Left) Bone and nodal imaging - negative for metastases HIGH risk group (surgery only in 5-15%)

28 mpmri Lesion of 28mm, AFMS & TZ (apex-mid level) T2W = 5 circumscribed, homogeneous moderate hypointense mass >1.5cm DWI = 5 focal markedly hypontense on ADC and markedly hyper- on DWI (b=1000) mass >1.5cm DCE = negative no early enhancement T2W b1000 DCE ADC PI-RADS 5

29 Q1: YES No extensive EPE/SVI Q1: Can I undergo surgery? Q2: Is nerve sparing feasible? Q2: NO ( in theory) No NS surgery when: PSA > 20 ng/ml GS 8 Palpable tumour in the side of NS

30 but with mpmri personalized surgery PO mpmri directed IFS In the AFMS IFS negative No SR needed R0 resection No evidence of disease in the posterolateral aspects (LT & RT) 1-2 : Bilateral NS 1. Park BH, et al., J Urol. 2014; 192: McClure TD, et al., Radiology. 2012; 262:

31 Bilateral NS RALP pt2c pn0 R0, GS 4+3 A high rate of downgrading exists between the bgs the GS of the resected specimen 1 mpmri has helped in selecting the right treatment for the right patient 1. Donohue, J.F., et al. J Urol, : 991.

32 Case 60 years PSA 29 ng/ml DRE positive (ct2c) TRUS biopsy GS 5+4 (8/8 cores, RT & LT) Bone and nodal imaging (CT abdomen-pelvis + BS) negative N0 M0 according to standard imaging HIGH risk group (surgery only in 5-15%)

33 EAU guidelines (N staging) Partin tables, Roach formula % Because of their low sensitivity (<40% 1-2 ), CT or MRI should [ ] be reserved for high-risk cancer patients single patient (PO) Diffusion-weighted MRI may detect metastases in normal-sized nodes, but a negative diffusion weighted MRI cannot rule out the presence of LN metastases 3 1. Harisinghani, M.G., et al. N Engl J Med, : Hovels, A.M., et al. Clin Radiol, : Thoeny, H.C., et al. Radiology, : 125.

34 DWI & morphologic T1W/T2W in clinical N0 120 patients with N0 disease; 3D T1W/T2W mm 3 and DWI b1000 (4mm) Prospective readings of b1000 SI (SI groin nodes) & morphology (shape/borders)); no ADC Template pelvic nodal dissections; median 37 nodes/ patient (12-134) 1. Thoeny HC, et al. Radiology 2014; 273:

35 DW-MRI for detecting metastases in clinical N0 disease - implications for high precision Rx Patient level & pelvic side LR-ve not low enough: Cannot avoid or lateralize lymphadenectomy Pelvic side LR+ve high: Change lymphadenectomy to a more extensive procedure if suspicious nodes are seen outside planned surgical field Individualised prophylactic pelvic nodal irradiation prescriptions by boosting doses to regions at higher risk of microscopic metastases (using IMRT approaches) Analysis level Preva lence Rule in metastasis Rule out metastasis Spec PPV LR+ Sen NPV LR- Patient 28% 86% 67% % 89% 0.32 Pelvic side wall 18% 90% 56% % 90% 0.5 Thoeny HC, et al. Radiology 2014; 273: Courtesy of Prof. Padhani

36 DWI + USPIO (75pts, 2993 LNs, 39 per patient)

37 EAU guidelines (M staging) Evidence shows that MRI is more sensitive than choline PET/CT and BS for detecting bone metastases 1 Sensitivity % Specificity % CI BS % ( ) Choline-PET/CT % ( ) WB-MRI % ( ) 1. Shen G, et al., Skeletal Radiol Nov;43(11):

38 mpmri + WBD-MRI

39 mpmri Lesion of 32mm, right PZpl and PZpm (apex-mid level-base) T2W = 5 DWI = 5 T2W T2W Extensive EPE & SVI (T3b) preclude radical surgery with R0 margins b1000 ADC Not suitable for surgery PI-RADS 5

40 WBD-MRI N1 Regional lymph node metastases M1b Non-regional LN metastases Bone (left rib) Not suitable for surgery

41 In this patient MRI promoted precision oncology After MRI, changes in: T staging mpmri from ct2c to ct3b N & M staging WBD-MRI from N0 M0 to N1 M1b Impact in management From curative surgery to palliative ADT + RT (++ sites for palliation over time) The right treatment to the right patient at the right time for the right duration

42 Staging PCa with MRI promotes precision oncology MRI: 1. Allows refinement of clinical risk stratification 2. Addresses clinical needs in every risk group 3. Integration between clinical & imaging risk factors is the key of success at the single patient level