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Controversies in Prostate Cancer
Radiation Therapy
Curtiland Deville, MD
Assistant Professor
April 24, 2013
Lancaster General Health CME
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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Evolution of conformality
2D RT
IMRT
3DCRT
Rapid
Arc
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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
reference (simulation film)
online (port film)
co-registered (right)
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
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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 interest
Bottom: 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 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).
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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
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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
 Theoretical advantage is its
dose distribution.
 The physical characteristics of
the proton beam result in the
majority of the energy being
deposited at the end of a linear
track, “Bragg peak”
 Dose then falls rapidly to zero
beyond the Bragg peak.
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Proton Therapy vs. IMRT
 Dosimetric study:
 10 IMRT vs.10 proton
beam to 78 Gy
 Mean rectal dosevolume 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 IMRT
Yu 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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