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Controversies in Prostate Cancer

Radiation Therapy

April 24, 2013

Lancaster General Health CME

Curtiland Deville, MD

Assistant Professor

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Disclosures

None

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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

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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)

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Background

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

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2D RT 3DCRT

IMRT Rapid Arc

Evolution of conformality

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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

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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”

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Motion Management (pre-IGRT era)

Rectal size at RT planning prognostic for PSA-free survival

de Crevoisier, Red Journal 2005

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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.

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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)

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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 interestBottom: prostate/sv represented by masked area.

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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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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.

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Motion management

Endorectal balloon • Used for prostate

immobilization/fixation • Ensures reproducibility of

rectal filling and spares posterior rectumTeh, Red Journal 2001

78 Gy IMRT plans without (left) and with balloon (right) Contours: rectal wall (green), anal wall (purple) and PTV (blue).

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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

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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

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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

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Hypofractionation

Multiple multi-institutional randomized trials are ongoing:• RTOG 0415 clinicaltrials.gov NCT00331773

– Patients: cT1-T2c, PSA <10– Arms: 73.8/41 vs. 70/28– Closed: 12/2009

• Ontario Clinical Oncology Group clinicaltrials.gov NCT00304759 – Patients: Intermediate risk PCA– Arms: 78/39 vs. 60/20– Target: 1204 patients, completion by 6/2013

• UK clinicaltrials.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

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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.

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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

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SBRT

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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

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Proton Therapy vs. IMRT

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Proton Therapy

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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

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Proton Therapy

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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

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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 IMRTYu JB, et al, JNCI 2013

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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

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Thank You

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