Stereotactic Body Radiation Therapy for Low and Intermediate Risk Prostate Cancer

A new therapy called stereotactic body radiation therapy (SBRT) for treating prostate cancer
which provides fewer treatments but higher doses of radiation per treatment. This is a
radiation therapy technique that uses special equipment to position the patient and precisely
deliver a large radiation dose to a tumor and not to normal tissue. This research is being
done because although SBRT is used to treat a variety of cancers, it hasn't been used
extensively to treat prostate cancer and needs more investigation. Stereotactic body
radiation therapy (SBRT) for low- to intermediate-risk prostate cancer involves several weeks
of treatment sessions.

Blood samples will also be collected before, during, and after treatment as part of this
trial. These samples will be collected in patients who chose to participate within 1 week
prior to therapy, immediately after first treatment, immediately before second treatment,
immediately after fifth treatment, and 6 months after fifth treatment. a doctor, nurse, or
licensed technician will collect 50 teaspoons of blood by vein total over the course of the
study. investigators may ask for a second blood sample if the research laboratory cannot
process the first sample.

Primary End Point:

Phase-I: The primary endpoint of the phase I portion is to either reach the maximum tolerated
dose (MTD) or a dose of 50 Gy total (whichever comes first) by escalating the dose of SBRT
toward the tumorcidal dose of 50 Gy total. Patients will be treated in cohorts of seven to
fifteen.

The phase I portion of the study will be completed when either of the following events occur:

1. The MTD for a cohort is reached or

2. When the highest protocol dose level is treated and tolerated (10 Gy per fraction, total
50 Gy) where we consider the therapy likely to be tumorcidal per determination of the
investigators.

Phase-I Dose Escalation: The phase I study is designed to end if the rate of dose limiting
toxicity (DLTs) within 90 days from the start of treatment is 33% or higher. For each dose
level cohorts, a total of seven to fifteen patients will be enrolled. If zero out of the
first seven with 90 day follow-up, two or fewer out of the first nine with 90 day follow-up,
three or fewer out of the first twelve with 90 day follow-up, or four or fewer out of the
first fifteen of patients with 90 day follow up experience a DLT as defined above, then the
dose will escalate to the next dose level. If three or more of the first nine patients, four
or more of the first twelve, or five or more of the first fifteen patients experience a DLT,
then the MTD will be considered to have been exceeded. The MTD will be defined as the
immediately previous lower dose level tolerated. The probability that at least two of nine
patients will experience a DLT when the true rate of acute DLTs is 33% is 0.80; that is, the
probability of making the correct decision if the true DLT rate is at least 33% is 0.80.

Phase I Waiting Periods:

Dose escalation on the phase I portion of this study should not occur until a sufficient
waiting period has occurred after patients have been treated. A period of 90 days must pass
in order to assess toxicity. If 90 days have transpired without DLT in each of the first
seven (7) patients enrolled to a specific dose level, then dose escalation to the next level
may proceed. Patients will continue to be enrolled to each dose level (up to a maximum of 15
patients) with ongoing assessment of those reaching 90 day follow-up so long as either
criteria for defining the MTD or criteria for further dose escalation is not reached. If
fifteen patients are enrolled to a given dose level yet criteria for adequate follow-up are
not reached in a representative sample of patients, further enrollment to the protocol will
be suspended until adequate follow-up is reached.

Phase-II: Patients will be treated at either the MTD or highest dose from the phase I study.

Primary Endpoint:

Late severe Genitourinary (GU) and Gastrointestinal (GI) toxicity is defined as grade 3-5 GU
and GI toxicity occurring between 270-540 days (i.e., 9-18 months) from the start of the
protocol treatment. It is graded based on Common Terminology Criteria for Adverse Events
(CTCAE v3.0). Grade 3-5 GU or GI toxicity that originally occurred prior to 270 days from
start of protocol treatment will only be considered late severe GU or GI toxicity if it
persists at a severity grade of 3-5 based on CTCAE v3.0 after 270 days.

Secondary Endpoints:

- Acute severe GU and GI toxicity is defined as grade 3-5 toxicity occurring prior to 270
days from the start of protocol treatment. It is graded based on CTCAE v3.0.

- Non GU and GI toxicity.

- Biochemical failure Radiation Therapy Oncology Group (RTOG)-American Society for
Therapeutic Radiology and Oncology (ASTRO) definition (also known as Phoenix definition)
- Thus, when the PSA rises by more than 2 ng/ml above the lowest level (nadir) achieved
after treatment,, biochemical failure has occurred and the date of the failure is
recorded at the time the nadir plus 2 ng/ml level is reached.

- Overall survival

- Disease-specific survival

- Clinical progression including local/regional and distant relapse

Sample Size:

1. The sample size of the phase I component of this study will not exceed 45 patients.

2. The sample size of the phase II component of this study will not exceed 50 patients.

Sample Size Estimation: The phase II component of this study is designed to test whether late
GU/GI toxicity at 270-540 days from the start of treatment following the protocol treatment
is above 10%. The sample size is determined so that the probability of rejecting the
treatment because of excessive late toxicity is 90% if the true late toxicity rate is 23% or
higher. Assuming an exponential distribution for time from the end of the acute period (270
days from the start of protocol treatment) to the occurrence of late toxicity, the hazard
rate for the expected 10% toxicity rate and the unacceptable 23% toxicity rate is 0.006/month
and 0.015/month, respectively. Following the asymptotic property of the observed hazard and
using Z-test for the logarithm of the hazard ratio, we require 12 cases with severe late
GU/GI toxicity. Thus, 47 patients are required to be accrued within three to four years and
be followed for 270 days after the acute period (i.e., a total of 540 days) to have a
statistical power of 90% with a one-sided significance level of 0.05. Considering 5%
ineligible cases and lack-of-data cases, the sample size of the phase II component of this
study is 50 patients. Patients treated in phase I at the dose level ultimately used in phase
II will be included in the phase II analysis as part of the 50 patient trial.

Study Analysis: This analysis will be carried out when each patient has had at least 270 days
(i.e., 9 months) of follow-up after the end of the acute period, a total of 540 days (i.e.,
18 months) of follow-up. The hazard rate will be estimated by the life table approach with a
time span of 18 months. The one-sided Z-test will be used to test the significance of the
difference between the logarithm of the observed hazard rate and the logarithm of the
hypothesized hazard rate of 0.006/month with variance equal to the reciprocal of the number
of cases with late toxicity observed. Because of the lead time of 9 months for the acute
period, the 18-month late toxicity will be estimated by the 9- month toxicity rate using the
cumulative incidence approach to the defined time to severe late GU/GI toxicity.

Inclusion Criteria:

- Patients (Male) who satisfy all of the following conditions will be eligible for this
study:

- All patients must be willing and capable to provide informed consent to
participate in the protocol

- Eligible patients must have appropriate staging studies identifying them as
American Joint Committee on Cancer (AJCC) stage T1 (a, b, or c) or T2 (a and b
only) adenocarcinoma of the prostate gland. The patient should not have direct
evidence of regional or distant metastases after appropriate staging studies.
Histologic confirmation of cancer will be required by biopsy

- The patient's Zubrod performance status must be 0-2

- The Gleason score should be less than or equal to 7

- The serum PSA should be less than or equal to 20 ng/ml prior to starting hormonal
therapy (if given) for patients with Gleason score 2-6. For patients with Gleason
score of 7, PSA should be less than or equal to 15 ng/ml prior to starting
hormonal therapy (if given). As such, the risk of pelvic lymph node involvement
according to the Roach formula would be under 20%

- Patients may have used prior hormonal therapy, but it should be limited to no
more than 9 months or therapy prior to enrollment

- Patients should not have significant urinary obstructive symptoms; American
Urological Association (AUA) score must be ≤ 15 (alpha blockers allowed)

- The ultrasound or CT based volume estimation of the patient's prostate gland
should not be greater than 60 grams

- Male of reproductive potential may not participate unless they agreed that they
or their partner use an effective contraceptive method such as condom/diaphragm
and spermacidal foam, intrauterine device (IUD), or prescription birth control
pills

Exclusion Criteria:

- Patients (Female) are not eligible for this study. Patients (Male) with one or more of
the following conditions also are ineligible for this study:

- Positive lymph nodes or metastatic disease from prostate cancer

- Prior invasive malignancy unless disease free for a minimum of 3 years (carcinoma
in situ of the breast, oral cavity, or cervix, or non-melanomatous skin cancer
are all permissible)

- T2c, T3, or T4 tumors

- Previous pelvic radiotherapy

- Previous surgery or chemotherapy for prostate cancer

- Previous transuretheral resection of the prostate (TURP) or cryotherapy to the
prostate

- Previous hormonal therapy given for more than 9 months prior to therapy

- Concomitant antineoplastic therapy (including surgery, cryotherapy,
conventionally fractionated radiotherapy, and chemotherapy) while on this
protocol

- History of Crohn's Disease or Ulcerative Colitis

- Previous significant obstructive symptoms; American Urological Association (AUA)
score must be ≤ 15 (alpha blockers allowed)

- Significant psychiatric illness

- Men of reproductive potential may not participate unless they agree to use an
effective contraceptive method

- Ultrasound or CT estimate of prostate volume > 60 grams

- Severe, active co-morbidity as defined in the following:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration

- Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days before
registration

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for liver function and coagulation
parameters are not required for entry into this protocol

- Acquired Immune Deficiency Syndrome (AIDS) based upon current Center for Disease
Control and Prevention (CDC) definition; note, however, that Human
Immunodeficiency Virus (HIV) testing is not required for entry into this
protocol. The need to exclude patients with AIDS from this protocol is necessary
because the treatments involved in this protocol may be significantly
immuno-suppressive. Protocol-specific requirements may also exclude
immuno-compromised patients

- History of treatment with potent immuno-suppressive drugs for such conditions as
post organ transplant, severe rheumatoid arthritis, etc. within the past 6 months