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2. Controversies in Prostate Cancer Radiation Therapy April 24, 2013 Lancaster General Health CME Curtiland Deville, MD Assistant Professor

3. 3 Disclosures  None

4. 4 Outline  Objective: to review current controversies and hot topics in prostate RT: Background Conformality –3DCRT vs. IMRT Motion management (IGRT) Dose escalation –Hypofractionation –SBRT Modality –Proton vs. IMRT

5. 5 Outline  Controversies and Hot Topics in Prostate RT (not covered): Erectile dysfunction prophylaxis using a PDE-5 inhibitor Brachytherapy: –Role in high risk prostate cancer –Benefit of androgen deprivation (ADT) Post-prostatectomy RT –Adjuvant vs. early salvage Clinically node positive (N1M0) –Benefit of definitive RT with ADT Intermediate risk prostate cancer –Benefit of short-term ADT in the setting of dose escalation High risk prostate cancer –Benefit of elective pelvic nodal irradiation –Duration of long-term ADT (are 28-36 months needed)

6. 6 Background  The role of radiotherapy across all risk groups as curative management for prostate cancer is well-established.

7. 7 2D RT 3DCRT IMRT Rapid Arc Evolution of conformality

8. 8 IMRT vs. 3D-CRT  No randomized trials comparing IMRT with 3D-CRT for localized prostate cancer.  Retrospective data suggest an improved toxicity profile. Medicare Surveillance, Epidemiology, and End Results (SEER) analysis of 12,000 men. –IMRT less GI “morbidity,” hip fractures, and additional cancer therapy Sheets NC, et al, JAMA 2012 MSKCC series of 1571 men –IMRT 81 Gy vs. 3D-CRT at lower doses (358 at ≤70.2 Gy and 472 at 75.6 Gy). –IMRT significantly reduced grade ≥2 GI toxicity at 10 years (5% vs. 13% 3D-CRT). Zelefsky M, et al, Red Journal 2008

9. 9 Motion Management  Interfraction Motion Changes in position between fraction, “day to day” External: set-up error Internal: Mostly due to daily changes in rectal and bladder volume Image-guided radiotherapy (IGRT) - daily imaging to provide prostate localization to account variable motion  Intrafraction Motion Changes in position while the treatment beam is on, “second by second”

10. 10 Motion Management (pre-IGRT era)  Rectal size at RT planning prognostic for PSA-free survival de Crevoisier, Red Journal 2005

11. 11 Motion Management  Daily localization IGRT techniques to account for interfraction motion: intraprostatic fiducial markers with daily imaging transabdominal US daily in-room CT imaging endorectal balloon immobilization  All of these methods employ daily imaging of the prostate in the treatment room.

12. 12 Motion Management In this technique, the isocenter is shifted until the bony contours (setup error) or the implanted markers are in agreement (total error). Graf, RO Journal 2009 reference (simulation film)online (port film) co-registered (right)

13. 13 Motion Management  Cone beam computerized tomography (CBCT) allows volumetric visualization of the prostate and adjacent organs. Daily online correction allows for PTV margins: –4 mm in all directions and 3 mm posterior (Pawlowski, Red Journal 2010) –5 mm all around and 3 mm posterior (Hammoud, Red Journal 2008) 2 stages of image registration: Top: pelvic bone region of interest Bottom: prostate/sv represented by masked area.

14. 14 Motion Management  Intrafraction Motion Changes in position while the treatment beam is on (“second by second”) Mostly from peristalsis/gas, pelvic floor movement, respiration coughing, etc. Techniques to account for intrafraction motion: –RGRT (radiofrequency-guided RT techniques) –Rectal balloon –Bowel prep (anti-gas tablets and daily bm) –Consistent Bladder filling

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24. 24 Motion management  Electromagnetic transponders  Benefits: localize the prostate similar to fiducial markers but without additional radiation dose real-time tracking, allowing for immediate intervention if prostate moves outside the radiation field.  Limitations: Subsequent difficulty of prostate post-treatment follow-up with MRI Patient factors: pacemakers, obese/abdominal girth.

25. 25 Motion management  Endorectal balloon Used for prostate immobilization/fixation Ensures reproducibility of rectal filling and spares posterior rectum Teh, Red Journal 2001 78 Gy IMRT plans without (left) and with balloon (right) Contours: rectal wall (green), anal wall (purple) and PTV (blue).

26. 26 Dose escalation  Biologic models support dose escalation beyond 80 Gy  Improved conformality and IGRT techniques have allowed for dose escalation  Multiple randomized trials show improved control rates: MD Anderson: 8-yr freedom from biochemical or clinical failure improved significantly with dose escalation from 70 to 78 Gy (59% vs. 78%). Kuban, Red Journal 2008 Proton Radiation Oncology Group (PROG) 95-09 collaborative trial compared 70.2 GyE to 79.2 GyE using proton beam after standard photon 50.4/28, finding significantly improved 10-year biochemical PFS. Zietman, JCO 2010

27. 27 Hypofractionation  Shorter courses of RT using larger treatment fractions 2.5 - 3.1 Gy per fraction, rather than standard 1.8 - 2.0 Gy  Method of dose escalation  Preliminary reports suggest similar outcomes and favorable toxicity profiles: Fox Chase Cleveland Clinic Italian NCI

28. 28 Hypofractionation  Italian NCI randomized trial 168 men with high-risk prostate cancer. 3DCRT + 9 mo ADT 80 Gy/40 vs. 62 Gy/20 fractions Median f/u 70 months No differences in biochemical, local, or distant failure (right). No differences in toxicity. Arcangeli, Red Journal 2010, 2012

29. 29 Hypofractionation  Multiple multi-institutional randomized trials are ongoing: RTOG 0415 clinicaltrials.gov NCT00331773clinicaltrials.gov NCT00331773 –Patients: cT1-T2c, PSA <10 –Arms: 73.8/41 vs. 70/28 –Closed: 12/2009 Ontario Clinical Oncology Group clinicaltrials.gov NCT00304759clinicaltrials.gov NCT00304759 –Patients: Intermediate risk PCA –Arms: 78/39 vs. 60/20 –Target: 1204 patients, completion by 6/2013 UK clinicaltrials.gov NCT00392535clinicaltrials.gov NCT00392535 –Patients: cT1b-T3a, PSA <= 30, risk of SV+ <30% –Arms: 37 fxs vs. 20 fxs vs. 19 fxs –Target: 2163 men, completion by 9/2012  Long-term results are required before hypofractionation can be considered a standard alternative

30. 30 Hypofractionation (at Penn Medicine)  Mild Hypofractionation With Proton Therapy or Intensity Modulated Radiation Therapy (IMRT) for Intermediate-Risk Prostate Cancer  70 Gy/ 28 fractions (2.5 Gy per fractions)  currently recruiting  Abramson Cancer Center of the University of Pennsylvania  ClinicalTrials.gov Identifier: NCT01352429  Eligibility: Clinical stages T1a-T2c N0 M0 Gleason score must be in the range 2-7 PSA values < 20 ng/ml within 90 days prior to registration.  Androgen deprivation at discretion of the treating radiation oncologist.

31. 31 Stereotactic Body Radiotherapy (SBRT)  Extreme hypofractionation  Entire dose is administered in a very limited number (~5) of fractions.  Requires high degree of precision in defining the target and administering the radiation Immobilization Imaging Motion management

32. 32 SBRT

33. 33 SBRT  Longer follow-up in larger numbers of patients is required to establish the safety and efficacy of this approach  Presently SBRT should be performed within the context of a clinical trial

34. 34 Proton Therapy vs. IMRT

35. 35 Proton Therapy

36. 36 Proton Therapy vs. IMRT  Dosimetric study:  10 IMRT vs.10 proton beam to 78 Gy  Mean rectal dose- volume histograms Vargas et al. IJROBP 2007

37. 37 Proton Therapy

38. 38 Proton Therapy vs. IMRT  No randomized trials comparing proton therapy to photon therapy or brachytherapy in men with clinically localized prostate cancer.  Retrospective analyses have not established whether proton beam therapy (either alone or in combination with photon therapy) is less toxic than photon therapy alone or brachytherapy

39. 39 Proton Therapy vs. IMRT (retrospective)  Medicare-SEER analysis of 684 men treated with proton therapy 2002-2007 vs. matched IMRT cohort IMRT associated with less GI “morbidity” No significant differences in other toxicities No difference in additional cancer therapy Sheets NC, et al, JAMA 2012  Medicare analysis of 421 men treated with proton therapy with 842 2008-2009 vs. matched IMRT cohort Less GU toxicity at 6 mo for protons, which disappeared by 1 yr No other significant differences Proton therapy associated Medicare reimbursement costs were 75% higher than IMRT Yu JB, et al, JNCI 2013

40. 40 Proton Therapy vs. IMRT (at Penn Medicine)  Proton Therapy vs. IMRT for Low or Low-Intermediate Risk Prostate Cancer  Currently recruiting  Sponsor: Massachusetts General Hospital  Collaborators: University of Pennsylvania National Cancer Institute (NCI)  ClinicalTrials.gov Identifier: NCT01617161  Anticipated enrollment: 461  Primary Outcome Measures: Compare the reduction in mean EPIC bowel scores at 24 mo

41. 41 Thank You

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