Low risk. Objectives. Case-based question 1. Evidence-based utilization of imaging in prostate cancer

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1 Evidence-based utilization of imaging in prostate cancer Fergus Coakley MD, Professor of Radiology and Urology, Vice Chair for Clinical Services, Chief of Abdominal Imaging, UCSF Objectives State the modalities, rationale, and indications for imaging local and distant spread of prostate cancer Describe the evidence-basis for imaging approaches to prostate cancer List the emerging modalities for prostate cancer imaging Low risk High risk - Summary Low risk Case-based question 1 A healthy 72 year old man is found to have a PSA of 8.4 ng/ml. DRE is unremarkable. Gleason 6 cancer is found in 15% of one sextant biopsy core. Based on existing guidelines, the following staging imaging is appropriate: A.CT of abdomen and pelvis B.Endorectal pelvic MRI C.Transrectal ultrasound D.No imaging E.Tc-99m bone scintigraphy

2 Existing guidelines Answer to question 1 Source Recommendations ACR Bone scan, CT, MRI if PSA > 10 or Gleason > 6 AUA Bone scan if PSA > 20, poorly differentiated, or T3 CT, MRI if PSA > 25 Utility of endorectal MRI/MRSI not determined AJCC Bone scan, CT, MRI if PSA > 20 or Gleason > 7-8 D: No imaging required for low risk disease Guidelines lack consensus! Indicates evidence mixed and conflicting National shift to less imaging, even when adjusted for risk migration Radiology 2007; 243: No imaging for low risk disease? Likelihood of T3 disease is low Lee et al, Int J Radiat Oncol Biol Phys 2007; 68: No imaging for low risk disease? Likelihood of nodal metastases very low Pettus et al. J Endourol 2008; 22: Risk group ECE SVI Risk group Node positive Low (PSA < 10, DRE < T2a, and Gleason <6) Intermediate (PSA 10-20, DRE < T2b, or Gleason = 7) High (PSA > 20, DRE 2c, or Gleason 8) 9% (64/712) 1% (8/712) 20% (137/686) 5% (35/686) 47% (72/152) 30% (45/152) Low (PSA < 10, DRE < T2a, and Gleason <6) 1.3% (5/374) Intermediate (PSA 10-20, DRE < T2b, or Gleason = 7) 6% (17/280) High (PSA > 20, DRE 2c, or Gleason 8) 20% (21/106)

3 No imaging for low risk disease? Utilization trends low risk Likelihood of bone metastases even lower Gleave et al, Urology 1996; 47: Rhoden et al, Int Braz J Urol 2003; 29: Hirobe et al, Jpn J Clin Oncol 2007; 37: PSA level Positive bone scan < 10 0% (0/290) 0% (0/71) 0% (0/161) % (4/88) 1.6% (1/61) 2.1% (2/95) > 20 21% (24/112) 41% (34/82) - J Urol 2002; 168: Is there any role for local imaging? Potential applications in low risk disease: Map tumor extent for focal therapy Select & monitor patients on active surveillance Available modalities: TRUS or MRI Shukla-Dave et al, Curr Opin Urol 2008; 18: Tumor mapping: TRUS or MRI? Comparison of Medline studies: Searched transrectal ultrasound prostate cancer localization and MRI prostate cancer localization Included original studies with localization results (by T2W for MRI) and 20+ patients Likely incomplete but fair comparison TRUS papers (last 10 years) = 1 MRI papers (last 5 years) = 7 TRUS scientifically moribund?

4 Tumor mapping: TRUS or MRI? Modality n Accuracy (A z ) Citation TRUS % Sedelaar et al. Urology. 2001; 57: Chen et al. Acta Radiol 2008; 49: Can imaging help select low risk patients for active surveillance? 26 61% Testa et al. Radiology 2007; 244: MRI Haider et al. AJR 2007; 189: Heijmink et al. Radiology 2007; 244: Graser et al. AJR 2007; 188: Maybe Fütterer et al. Radiology 2006; 241: % Kim et al. JCAT 2006; 30: 7-11 Active surveillance selection Definition of insignificant disease: Organ-confined (stage T1 or T2) Total volume 0.5cm 3 No poorly differentiated component present Accuracy (A z ) of predictive nomograms: PSA, DRE, Gleason score = 0.57 Above plus % +ve cores & gland volume = 0.73 Above plus MRI = 0.80 (significantly better) Can we monitor disease? Maybe Shukla-Dave et al, Curr Opin Urol 2008; 18: Shukla-Dave et al, BJU Int 2007; 99:

5 BASELINE FOLLOW-UP Disease monitoring by MRI/MRSI Monitoring active surveillance Serial TRUS (n = 180): TRUS change poor predictor of progression Serial MRI/MRSI (n = 68): MR classed as progressive (17) or stable (51) PSA velocity correlated with progression Mean velocity of 1.42 versus 0.42 ng/ml/year Hruby et al, BJU Int 2001; 87: Coakley et al, BJU Int 2007; 99: 41-5 Low risk imaging - summary DO NOT image for T3+, N+, M+ disease or focal therapy planning MAYBE image for selection and monitoring of active surveillance Low risk High risk - Summary High risk IF imaging, MRI (probably) better than TRUS

6 Case-based question 2 A 62 year old man presents with recent onset of low back pain. PSA is 56 ng/ml. TRUS shows extracapsular extension and Gleason 8 cancer is found in several sextant biopsy cores. The most appropriate choice of imaging is: A.CT of abdomen and pelvis B.Tc-99m bone scintigraphy C.Lumbar spine MRI D.B and C E.A and B Answer to question 2 E: CT of abdomen and pelvis and Tc-99m bone scintigraphy This combination provides robust evaluation of both nodal and bony spread Rationale for imaging in high risk disease: T3 disease dose escalation, extended ADT N+, M+ disease systemic therapy Predict outcome Imaging higher risk patients Utilization trends intermediate risk Likelihood of locally advanced or metastatic disease is high Risk group ECE SVI Node positive Positive bone scan Intermediate 20% 5% 6% % High 47% 30% 20% 21-41% Lee et al, Int J Radiat Oncol Biol Phys 2007; 68: Pettus et al. J Endourol 2008; 22: Gleave et al, Urology 1996; 47: Rhoden et al, Int Braz J Urol 2003; 29: Hirobe et al, Jpn J Clin Oncol 2007; 37: J Urol 2002; 168:

7 Utilization trends high risk Local staging: TRUS or MRI? Comparison of Medline studies: Searched transrectal ultrasound prostate cancer staging and MRI prostate cancer staging Included original studies with staging results based on pathological standard and 20+ patients TRUS papers (last 5 years) = 3 MRI papers (last 2.5 years) = 7 J Urol 2002; 168: T3 disease: TRUS or MRI? MRI findings in T3 disease Modality n Accuracy (A z ) Citation % Mitterberger et al. BJU Int 2007; 100: TRUS 55 26% Rinnab et al. BJU Int. 2007; 99: Focal irregular bulge NVB asymmetry Obliteration of RP angle Seminal vesicle invasion 25 88% Selli et al. Radiol Med (Torino) 2007; 112: % Tan et al. Ann Acad Med Singapore 2008; 37: % Park et al. J Comput Assist Tomogr 2007; 31: MRI 32 95% Bloch et al. Radiology 2007; 245: Heijmink et al. Radiology 2007; 244: % Latchamsetty et al. Can J Urol 2007; 14: Wang et al. AJR 2007; 188: Graser et al. AJR 2007; 188: % 21-38% 24-50% 43-71% Sens 77-88% 81-95% 81-95% 99% Spec 58-65% 56-70% 57-71% 95-97% Acc Radiology 1997; 202: and 2005; 237:

8 Nodal staging: At what PSA? Nodal staging: Can we do better? CT results in newly diagnosed untreated patients: N Positive CT PSA cut-off (3%) > 20 in (7%) > 15 in (3%) > 30 in 11 Huncharek et al, Cancer Invest 1995;13: 31-5 Lee et al. Urology 1999; 54: Huncharek et al. Abdom Imaging 1996; 21: Limited accuracy using size: Sensitivity 25-78%, specificity 77-98% using 1 cm short axis threshold Sensitivity 78%, specificity 87% using asymmetric 0.6 cm short axis threshold USPIO-enhanced MRI (n = 80): All proven nodal metastases in 33 patients correctly identified 45/63 +ve nodes below size criteria Radiol Clin N Am 2000; 38: Radiology 1994; 190: NEJM 2002; 347: T1 T2 Illustrative case Trial of hormones T1W T2*W after USPIOs Normal 3/12 Metastasis Courtesy of Dr Jelle Barentsz, Nijmegen UMC

9 M staging: Bone metastases False negative bone scan 80% stage IV is bone-only Rising PSA post-rrp Confirmed on MRI Little data on Tc-99m accuracy 18 F PET may be better (n = 34): 67 mets in 17 pts seen on 18F PET 29 mets in 11 pts on bone scan AUC of 0.99 versus 0.74 Tc-99m SUBTLE NEW LESION CT 7 months before Negative bone scan Dawson, Semin Oncol 1999; 26: Schirrmeister et al, J Clin Oncol 1999; 17: F PET What about PET? Standard FDG PET very limited: Detects only 18-65% of bone metastases Low glucose utilization in prostate cancer Bladder activity obscures locoregional disease Alternative radiotracers: C11 choline 86% accurate for nodal recurrence C11 acetate showed local, nodal, and bony recurrences in 15, 5, & 5 of 18 post-rrp patients Yeh et al, Nucl Med Biol 1996; 23: Shreve et al, Radiology 1996; 199: Yu et al, Radiol Clin North Am 2000; 38: Scattoni et al, Eur Urol 2007; 52: Kotzerke et al, Eur J Nucl Med Mol Imag 2002; 29: High risk imaging - summary T stage: May influence adjuvant therapy N and M stage: May influence definitive versus systemic therapy Choice of modality: T stage: MRI TRUS N stage: CT MRI (pending USPIOs?) M stage: Tc-99m bone scintigraphy (or 18 F PET?)

10 The BIG issue... The BIG issue... Gleason 6 left apex PSA 9.2 Gleason 6 left apex PSA 9.2 EIGHT years later PSA 11.9 WHO WILL Gleason 6 right apex PSA 5.8 PROGRESS? Gleason 6 right apex PSA 5.8 ONE year later PSA 10.8 Pre-EBRT MRI and outcome Pre-EBRT MRI/MRSI and outcome ECE measured on MRI pre-ebrt (n = 74) Mean follow-up = 42/12 ECE only independent predictor of metastases: 3/5 patients with > 5 mm ECE developed metastases at 24, 43, and 63 months McKenna et al, Radiology 2008; 247:141-6 Measurement of ECE 6 mm ECE ECE present ECE absent 100 months Multivariate Cox analysis (n = 67): Predictors: Standard clinical factors and MR tumor presence, stage & metabolic abnormality Endpoints (mean follow-up 44/12): Biochemical (19) or metastatic (6) failure Independent predictors: PSA: MRSI tumor volume Metastases: MRI tumor size and SVI on MRI Joseph et al, Int J Radiat Oncol Biol Phys Aug [Epub ahead of print] T3A T3B OC

11 Conclusions Thank you Difficult organ and disease to image TRUS remains key for biopsy/diagnosis CT and bone scan best and most widely available combination for N and M staging MR attractive for T and N staging and perhaps for prediction of prognosis? Fergus.Coakley@radiology.ucsf.edu