Jackson Lau
Dos 741 Protocols & Studies
10/29/2012
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RTOG 0938 is a Phase II trial to assess quality of life
outcomes of two hypofractionated radiotherapy
regimens for prostate cancer as compared to standard
radiotherapy treatment
• Research strongly suggests that early stage prostate cancer can
be effectively treated with hypofractionated radiotherapy
 Deliver higher doses of radiation in fewer treatments
• To obtain information on bowel, urinary and sexual side effects
of the study treatment vs standard treatments
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Radiation Therapy Oncology Group (RTOG)
• National clinical cooperative multidisciplinary group consisting of physicians and
researchers from over 300 academic and medical facilities in the US, Canada and
internationally.
• Mission – to increase the survival outcome and quality of life of adults with cancer
through high quality clinical trials
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Funded by the National Cancer Institute
Established in 1968 for the purpose of conducting radiation therapy
research and clinical investigation
RTOG continues to provide an infrastructure for investigators to
seek more effective treatments for cancer
Successful trials in this protocol will:
• Fulfill RTOG’s mission of improving survival and quality of life for cancer patients
• Increase awareness and participation by investigators and patients in subsequent
phases and trials
• Continued financial support from National Cancer Institute
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Majority of prostate cancer is diagnosed in the early
stage
• Have not spread to lymph nodes or other organs
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Much research is focused on the best treatment strategy
for these patients
• Propose hypofractionated radiotherapy as an alternative to
standard treatment
• Common radiotherapy regimen
 5 days/wk, 39 to 41 treatment sessions for 7-8 weeks
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Studies show prostate specific antigen (PSA) control is significantly
affected by the dose fractionation used
Dose response of tumors and normal tissues to fractionated
irradiation is described by the “α/βratio ”
• Indication of the fractionation sensitively of a particular cell type
• Clinical results suggest that the fractionation sensitivity of prostate
tumors is very high
 α/βratio for prostate tumor much lower than most other tumors
α/βratios of Human Tumors1
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Radiosensitivity
• Cells with high proliferation rates have little time to repair
 High alpha-beta ratio (ie skin, mucosa and most tumors)
 Not very sensitive to fraction size
• Cells with slow proliferation rates have long cell cycle time
allowing plenty of time for intracellular repair between
successive fractions
 Low alpha-beta ratio (ie connective tissues, muscles, prostate tumors)
 Very sensitive to fraction size
• The lower α/βratio for prostate tumors than the surrounding late
responding normal tissues creates the potential for therapeutic
gain
α/βratio for prostate tumor and normal tissue1
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Most tumors have rapid proliferation rates: use large # of small doses
while keeping damage to late reacting normal tissues low
However, prostate cancer have slow proliferation rates: use fewer and
larger fractions
Decreasing the # of fractions
• Increases the biochemical non-evidence of disease (bNED) - % of patients with
5 yr success rate
• Biological Effective Dose (BED) remains the same with no increase in toxicity
for normal tissues (ie rectum)
Hypofractionated schedule1
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Hypofractionated regimens could be designed with
fewer but larger doses, to maintain equivalent late
reactions while yielding improved tumor control
• Possible with highly conformal technologies (ie IMRT)
A
phase II randomized trial to assess quality of
life outcomes of two different hypofractionated
regimens
• Regimen #1
 36.25 Gy in 5 fractions of 7.25 Gy 2x/wk over 2.5 weeks (15-17 days)
• Regimen #2
 51.6 Gy in 12 daily fractions of 4.3 Gy over 2.5 weeks (16-18 days)
• Control Group
 Prostate cancer patients receiving standard treatment
 Treatment
• High potential for therapeutic gain
• Potential to significantly affect the future treatment of
early stage prostate cancer
 Logistics
• More convenient for patients by reducing the
number of clinic visits for treatment
 Economic
• Fewer treatments leads to health care cost savings
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Sample size for this study = 174 patients
Conditions of eligibility
• Diagnosis of adenocarcinoma of the prostate
• History/physical examination with digital rectal examination of the
prostate
• Prostate biopsy with Gleason scores 2-6
• Clinical stage T1-2a
• PSA < 10 ng/mL
• Zubrod Performance Status 0-1
• Age ≥ 18
• Provide study specific informed consent
• Willingness and ability to complete the Expanded Prostate Cancer
Index Composite (EPIC) questionnaire
 Assess patients urinary, bowel, sexual functions
 Conditions for ineligibility
• Prior or concurrent invasive malignancy
• Evidence of distant metastases
• Regional lymph node involvement
• Previous radical surgery
• Previous pelvic irradiation or prostate brachytherapy
• Previous hormonal therapy
• Previous or concurrent cytotoxic chemotherapy
• Severe active co-morbidity
• Hepatic insufficiency
• Acquired Immune Deficiency Syndrome
 Regimen
#1:
• 7.25 Gy/fraction for 5 fractions of radiation
• Total dose = 36.25 Gy
• Delivered 2x a week
• A minimum of 72 hours and a maximum of 96 hours
between each treatment
• No more than 2 fractions will be delivered per week
• Total duration of treatment will be no shorter than 15
days and no longer than 17 days
 Regimen
#2:
• 4.3 Gy/fraction for 12 daily fractions
• Total dose = 51.6Gy
• Treated 5 days a week
• The total duration of treatment will be no shorter
than 16 days and no longer than 18 days
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Require the use of IMRT or related techniques
(Tomotherapy, VMAT, Cyberknife)
Treatments are required to be performed with an
image guided technique for target localization
• A computerized method for image registration is required for
determination of patient shift information
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Recommended photon energies 6-10MV
• Beams with higher energies are discouraged
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Patients are positioned supine
Minimum immobilization apparatus will be a pillow under the
knees
Use of rectal balloons are allowed by not required
Degree of bladder fullness should be made to duplicate what is
anticipated for daily treatment
Acceptable IGRT techniques should be utilized for initial
localization and tracking or periodic monitoring to ensure beam
positioning is maintained throughout long treatments
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Computed Tomography (CT) will be the primary image
platform for treatment planning
Axial cuts of 2.5 mm or less will be acquired throughout the
pelvis and prostate from the top of the iliac crests superiorly to
the perineum inferiorly
Definition of volumes in accordance to ICRU report #50 and
#62
Planning target volume (PTV) is defined as the CTV plus a 3mm
margin posteriorly and 5mm in all other dimensions
• To meet dose constraints, the anterior margin can be reduced to 3mm
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Isodose line used for the prescription dose should cover a
minimum of 95% of the PTV
Minimum dose within the PTV to a point that is 0.03 cc in size
must be ≥95% of the prescribed dose
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Static gantry IMRT beam arrangements will be
designed with a minimum of 5 gantry angles
The use of non-coplanar beams is encouraged
The maximum dose within the PTV is 7% above the
prescribed dose for a point that is 0.03cc in size
• Must not occur outside of the PTV
• Hotspots should be manipulated to avoid the prostate-rectal and
prostate-bladder interfaces as defined by the CTV
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Urethra dose shall not exceed 107% of the prescription
dose
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Normal tissue volume to be contoured include:
• bladder, rectum, bilateral femora, seminal vesicles, penile bulb,
skin and urethra
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The bladder should be contoured from its base to the
dome
The rectum should be contoured from the anus for a
length of 15cm or to the rectosigmoid flexure
The following table lists the maximum critical organ
dose limits for both regimens
• Treatment delivery that do not meet these limits will constitute
either a variation (acceptable) or deviation (unacceptable
protocol violation)
 Documentation
• CTV, PTV and designated organs at risk, dosimetry and DVHs
are reviewed for compliance with protocol
• For IMRT, at least one port film from each orthogonal film along
with the DRRs shall be included
 Compliance
Criteria
• Minimum allowable dose within PTV is > 95% of the prescribed
dose to a volume that is at least 0.03cc
• The maximum dose volume of the PTV must not be shared by a
normal critical structure
• Dose to the prostate rectal interface and prostate bladder
interface shall not exceed the dose constraint parameters from
the previous slide
 Small
bowel or rectal irritation
• Abdominal cramping, diarrhea, rectal urgency, or
proctitis
 Bladder
complications
• Urinary frequency/urgency, dysuria, hematuria,
urinary tract infection, and incontinence
 Radiation
dermatitis
 Expanded
Prostate Index Composite (EPIC)
questionnaire
• Assess patients urinary, bowel, sexual functions
 Optional
EQ-5D questionnaire
• A self assessment survey
 Covers mobility, self care, usual activities, pain/discomfort,
anxiety/depression and current overall health
1.
Fowler JF. The radiobiology of prostate cancer
including new aspects of fractionated radiotherapy.
Acta Oncol. 2005;44:265-276.