Traditionally: treating the entire prostate. LDR brachytherapy. Radical prostatectomy EBRT. Active surveillance vs. radical whole-gland treatment.

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1 Traditionally: treating the entire prostate Choice of therapy FOCAL THERAPY: A RADIOTHERAPY PERSPECTIVE Piet Dirix MD, PhD Department of Radiation Oncology, LKI LDR brachytherapy Radical prostatectomy Active surveillance vs. radical whole-gland treatment. EBRT LR-IR patients: comparable outcome with all 3 modalities, provided that at least 7 Gy is delivered to the prostate. Choice depends on age, patient preference, and expertise of treatment center. HR patients: EBRT + ADT, increasing role for surgery. Kupelian A. P. et al. Int J Radiat Oncol Biol Phys 004. Prostate cancer outcomes study (POCS) What about an intermediate option? Focal therapy Resnick M.J. et al. N Engl J Med 013. de la Rosette J. et al. J Endourol 010. Valerio M. et al. Eur Urol

2 Relinquishing the CTV concept Prostate cancer is multifocal Secondary lesions do not predict PSA relapse after RP Multifocality is reported in 50 87% of cases in contemporary radical prostatectomy series. However, only the index lesion determines disease progression (Stanford data). Meiers I. et al. Urology 007. Nogushi M. et al. J Urol 003. The size of the index lesion does predict PSA relapse after RP As in most solid tumors, local failures occur mostly in GTV This does not mean that CTV coverage does not matter Too soon to abandon treatment of the whole-prostate CTV? Johnson S.B. et al. Int J Radiat Oncol Biol Phys 013. Chopra S. et al. Int J Radiat Oncol Biol Phys 01. Heemsbergen W.D. et al. Radiother Oncol 013.

3 Focal brachytherapy (1) Focal brachytherapy () We need to deliver a high enough dose to the entire prostate Nguyen P.L. et al. J Urol 01. Nguyen P.L. et al. J Urol 01. Vainshtein J. et al. Radiat Oncol 01. Dose-escalation above 7 Gy Trial N Design Results Evolution in RT techniques SEER database: IMRT dose-escalation improves outcome Pollack 00 Kuban 008 M.D. Anderson vs. 78 Gy 8-year bdfs significantly better in high-dose group (78% vs 59%); D-RT 3D-CRT IMRT VMAT Zietman 005 MGH/Loma Linda Peeters 006 Al-Mamgani 008 Dutch trial vs. 79. Gy 5-year bdfs significantly better in high-dose group (91.3% vs 78.8%) vs. 78 Gy 7-year bdfs significantly better in high-dose group (56% vs 45%) Dearnaley 007 MRC RT vs. 74 Gy 5-year bdfs significantly better in high-dose group (71% vs 60%) At least 4 randomized trials demonstrated a 10% to 0% improvement in biochemical control with doses 74 Gy. No survival benefit to date. D-RT 3D-CRT IMRT VMAT Sheets N. C. et al. JAMA 01. 3

4 How high? Every Gy counts! Even with escalated doses, some IR-HR patients recur To further improve tumor control: focus on index lesions Need to further improve radio-therapeutic ratio in prostate cancer Cancer outcomes related to gross tumor-bearing sub-regions Approach Tumor-targeting Need Accurate technique Eade T. N. et al. Int J Radiat Oncol Biol Phys 007. Peeters S.T. et al. J Clin Oncol 006. Cellini N. et al. Int J Radiat Oncol Biol Phys 00. Dose limited by (rectal) NTCP Diffusion-weighted imaging (DWI) DWI: clinical example Housri N. et al. Int J Radiat Oncol Biol Phys 011. Koh D. M. et al. Radiol Clin North Am 01. 4

5 DWI: meta-analysis Dynamic contrast-enhanced (DCE) MRI DCE-MRI: clinical example Wu L. M. et al. AJR 01. Verma S. et al. AJR 01. DCE-MRI: comparison with T MR spectroscopy (MRSI) Multi-parametric MRI Prostate cancer on multi-parametric MRI: Anatomic T-weighted: T DCE: fast T1 contrast enhancement & washout DW: diffusivity ( ADC) MRS: choline + creatine/citrate T diffusivity fast T1 contrast enhancement & washout choline/citrate Alonzi R. et al. Eur J Radiol 007. Claus F. et al. RadioGraphics

6 Clinical example Multiparametric MRI for GTV delineation MRI can detect all clinically significant lesions Kozlowski P. et al. JMRI 006. Mazaheri Y. et al. Radiology 009. Turkbey B. et al. Radiology 010. Groenendaal G. et al. Radiother Oncol 010. Pucar D. et al. Int J Radiat Oncol Biol Phys C-Choline-PET-CT Prospective study in Leuven Methodology Tw MRI DCE MRI Resection specimen = gold standard 11 C-Choline PET-CT Prostate was cut into 3 mm sections, perpendicular to urethra Tumor delineated on H&E-staining DWI: b1000 DWI: ADC map Bauman G. et al. Prostate Cancer Prostatic Dis 01. 6

7 Tumor localization: octant-grid 7 6 Histology MRI X X X X X X Visual analysis PET-CT SUV max Results 175 octants analyzed 708 (40.4%) malignant octants Characteristics Pathological T stage (00 TNM) b c 3a 3b 4 Gleason score 7 (3 + 4) 7 (4 + 3) 8 9 (4 + 5) 9 (5 + 4) 10 Tumor volume (median + range) Absolute (cc) Relative (%) Tumor localization Peripheral zone (PZ) Transition zone + PZ Number of patients (n = 73) ( ) 7.1 ( ) 66 7 Results: MRI Tw DCE DWI mp-mri TP TN FP FN Sensitivity % Specificity % Accuracy % High specificity, but low sensitivity for each MRI modality separate. Combination of different MRI modalities: higher sensitivity (p < 0,01). Isebaert S. et al. JMRI 013. Results: combination MRI & PET-CT Accuracy MRI (%) Highest accuracy MRI SUV max combined with PET (%) threshold Tw DCE DWI Tw+DCE+DW Van den Bergh L. et al. Int J Radiat Oncol Biol Phys 01. Less than 1% improvement in accuracy Use imaging to boost in IR-HR patients? Number of case series, mostly IR to HR Variable MRI and GTV delineation technique Whole prostate doses ranged from Gy GTV boosts ranged from Gy; majority delivering 80 Gy Planning constraints mainly driven by rectal dose constraints Toxicity reported ranged from 0 10% > Gr 3 acute GU/GI and 5 15% > Gr 3 late GU/GI Bauman G. et al. Radiother Oncol 013. Several promising RCT running FLAME Utrecht (also in Leuven) van Vulpen & van der Heide, N=566 Ph3 RCT: IB 95Gy/35 fractions vs. 77Gy/35 fractions DCE- and DW-MRI Endpoint - BNED HEIGHT Miami Pollack, N=7 Ph RCT: CTV 76Gy, GTV 90Gy IB (in 38 fractions) DCE-MRI only Endpoint biopsy at years TARGET Princess Margaret Menard, N=80 Ph (case-control): CTV 76Gy, GTV 95Gy IB (in 38 fractions) DWI + T (+ DCE) Endpoint biopsy at 3 years Slide courtesy of C. Menard (Princess Margaret). 7

8 FLAME trial Conclusions Even with escalated doses, some IR-HR patients recur locally. The gross tumor-bearing sub-regions largely determine disease progression. However, local recurrences can occur in the whole-prostate CTV outside the index lesion. It is therefore too soon to abandon whole-prostate RT. But to improve outcome after RT, it seems logical to focus on the index lesion. This can be done by focal boosting. Thank you Radiation Oncology otom Budiharto olaura Van den Bergh osofie Isebaert okarin Haustermans Urology ohein Van Poppel olorenzo Tosco osteven Joniau ofilip Ameye Pathology oevelyne Lerut Radiology oraymond Oyen ofilip Claus olies De Wever ofrederik De Keyzer Nucleair medicine Christophe Deroose omichel Koole ofelix Mottaghy Medical imaging Frederik Maes Pieter Slagmolen Biostatistics okris Bogaerts 8