Phase I/II Trial Examining Dose-per-Fraction Escalation Using Intensity Modulated Radiation Therapy in the Treatment of Prostate Cancer
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: University of Wisconsin, Madison

 
 
 
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Phase I/II Trial Examining Dose-per-fraction Escalation using Intensity 
Modulated Radiation Therapy in the Treatment of Prostate Cancer 
 
 
 
 
 
 
 
A University of Wisconsin Tomotherapy Group Study 
 
 
 
University of Wisconsin Participants: 
 
Study Chair 
 
Mark A. Ritter, M.D., Ph.D. 
 
Radiobiology 
 
Jack F. Fowler, Ph.D., D.Sc. 
 
Statistician 
 
Richard Chappell, Ph.D. 
 
M.D. Anderson Cancer Center Orlando: 
 
Institutional PI: 
 
 Patrick Kupelian, M.D. 
 
Wayne State University: 
 
Institutional PI: 
 
Jeffrey Forman, M.D. 
 
Medical College of Wisconsin: 
 
 
Institutional PI: 
 
Dian Wang, M.D. 
 
 
 
 
 
 
 
INDEX 
 

 
 
 
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1.0 
2.0 
3.0 
4.0 
5.0 
6.0 
7.0 
8.0 
9.0 
10.0 
 
Appendix I 
Appendix II 
Appendix III 
Appendix IV 
Appendix V 
Appendix VI 
Appendix VII 
 
Schema 
Background 
Objectives 
Selection of Patients 
Registration Procedures 
Treatment Plan 
Measurement of Effect 
Study Parameters 
Statistical Considerations 
Records to be Kept 
References 
 
Patient consent form 
Fox Chase Bowel/Bladder Toxicity Questionnaire 
International Erectile Function Questionnaire 
The Spitzer Quality of Life Index (SQLI) 
Acute and Late Toxicity Data Sheet 
Eligibility Checklist 
Partin Tables 
 
 
 
 
 
 
 
 
 
 
 
STUDY CHAIR 
 
Mark Ritter, M.D., Ph.D. 
Clinical Science Center 
600 Highland Avenue, K4/B100 
Madison, WI  53792 
(608) 263-8500 
 
Protocol Information Network Contact Person 
 
Diana Trask – (608) 263-8500 
Wendy Walker- (608) 263-8500 

 
 
 
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SCHEMA 
 
 
 
 
 
4.3
Phase I/II HYPOFRACTIONATION TRIAL
Š 50 PTS                   
                 
S
    Š 50 PTS 
        Š 50 PT
≤50 PTS
50 PTS*a 
50 PTS a,b
50 PTS b 
 
 
 
* As described in Section 5.1, institutions joining the study after Level  I is filled will treat 
two patients at Level I before proceeding to enter patients at the level that the overall trial is 
currently accruing to.  
 
a 50 evaluable patients will be enrolled per dose/fraction level and followed for toxicity.  
These 50 patients will be analyzed for dose-per-fraction escalation and fraction-per-week 
escalation.  Additional patients may be enrolled in Levels one and two while waiting for 
higher dose level data and toxicity information to mature per Section 4.0 
 
b An additional 100 patients will be enrolled at the MTS (Maximum Tolerated Schedule) level 
in addition to the 50 patients already accrued at that level 
 

 
 
 
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1.0 BACKGROUND 
 
1.1 Introduction 
 
Prostate cancer is the most common non-skin cancer in American men, resulting in over 30,000 
deaths annually in this country.  Optimal treatment for localized, potentially curable, prostate 
cancer has not been determined, but radiation therapy has an established and major role in the 
management of localized disease, a role supported by evidence that disease control rates 
comparable to radical prostatectomy are achieved but with less toxicity.  
 
The probability of achieving biochemical control after radiation therapy is related to the pre-
treatment PSA, tumor grade and local stage, with PSA and grade being the most important factors.  
For example, patients with pre-treatment PSAs of less than 6 ng/ml and Gleason scores less than 
or equal to 6, have 5-year biochemical control rates of 87%, whereas patients with PSAs 10 – 20 
ng/ml and Gleason scores of 7 have control rates of only 45%. Radical prostatectomy outcomes 
are also influenced strongly by these same pre-treatment predictors. 
 
It has long been felt that one of the most important factors limiting the success of radiation therapy 
has been the inability to deliver adequate radiation dose without producing unacceptable toxicity.  
More recently, however, innovations in cancer imaging, radiation treatment planning and treatment 
delivery technology have created opportunities for safe dose escalation.  
 
 
1.2 The rationale for dose escalation 
 
Retrospective studies have indicated a substantial dose response for prostate cancer.  Hanks et al 
(1) examined Patterns of Care data and found actuarial local recurrence rates of 37% for Stage C 
patients treated to less than 60 Gy, 36% for doses of between 60-64.9 Gy, 28% for 65-69.9 Gy and 
19% for doses of 70 Gy or more.  Similarly, Perez et al (2) found 38% local recurrences for doses 
less than 60 Gy, 20% for doses between 60 and 70 Gy and only 12 % for doses of 70 Gy or 
greater.  More recently, a number of retrospective studies (3-7) and one randomized trial (8) have 
demonstrated superior PSA recurrence-free survival when doses higher than 70 Gy are delivered, 
at least for intermediate or higher risk patients (Figure 1).  These results and the unsatisfactorily 
high rates of disease persistence in intermediate to higher risk patients after conventional dose 
radiation therapy (66-70 Gy) provide a strong rationale for the delivery of higher than conventional 
radiation doses.   
 
 
 
 
 
 
 
 
 
 

 
 
 
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Figure 1.   
Tumor control probabilities for “intermediate 
risk” patients.  Data derived from 4 published 
series (Fowler, unpublished) 
 
 
 
 
 
 
 
 
When delivered with conventionally planned techniques, however, doses higher than 70 Gy are 
associated with higher complication risks (9). It has now become clear that 3D conformal 
radiotherapy demonstrates better than historically expected tolerance of normal tissues to higher 
doses (6, 10, 11) but complication rates, particularly rectal bleeding, can still be substantial. Various 
analyses suggest that the total area of rectal wall exposed to greater than 60 or 70 Gy predicts the 
rate of rectal bleeding or more severe grade 4 complications such as ulceration (Figure 2). 
Therefore, the implementation of intensity modulated radiotherapy, with its ability to further reduce 
rectal irradiation, should further reduce toxicities, as has indeed been reported by Zelefsky et. al. 
(12). 
 
 
 
 
 
 
 
 
Figure 2.  Grade 2 or higher rectal 
complications versus rectal area 
receiving higher than specified 
radiation doses.  A summary of 6 
clinical trials. (13) 
 
 
 
 
 
 
 

 
 
 
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With these advancements in delivery precision for radiation to a planned treatment volume, the 
minimizing of daily uncertainties regarding patient setup reproducibility and the change of position 
of the prostate within the pelvis because of rectal and/or bladder filling takes on a significant role. 
Currently at the University of Wisconsin Department of Radiation Oncology, we are using an 
optically guided 3D-ultrasound target localization system (SonArrayTM, Zmed, Inc., Ashland, MA) to 
correct daily for these misalignments at the time of treatment to within 2 mm along each axis 
(Tome, in press, 2001). As an alternative, the implantation of small metal seeds into the prostate to 
serve as fiduciaries during daily portal imaging has also proven reliable as a means of localizing 
the prostate 
 
In addition, it has been demonstrated that the use of a rectal balloon catheter can immobilize the 
prostate and facilitate localization on port films potentially allowing tighter margins for the treatment 
volume. Also, the lateral and posterior aspects of the rectal wall are displaced out of the high dose 
region by the rectal balloon, which should offer the potential for significant rectal sparing (14, 15). 
 
 
1.3 Hypofractionated Radiotherapy for prostate cancer 
 
While the above-described physical improvements in dose delivery have permitted larger total 
doses of radiation to be delivered to the prostate without undue toxicity, the added number of 
fractions of radiation required have produced an increasing burden in terms of cost, utilization of 
resources and inconvenience to the patient.  Some dose escalation regimens currently exceed 43 
treatments and exceed 8 weeks in duration. Evidence has emerged over the past two years, 
however, of a unique prostate cancer radiobiology that may offer the opportunity to dramatically 
improve the efficiency and safety with which radiation therapy is delivered.  
Conventional fractionation schemes employing fraction sizes of 1.8 – 2.0 Gy are based upon the 
premise that tumors typically are less responsive to fractionation than are late-responding normal 
tissues.  The α/β ratios are one measure of fractionation response, with low ratios (high β ‘s) being 
more associated with late responding normal tissues, indicating greater repair between fractions 
with an accompanying greater relative sparing with small fraction sizes than for tumors with their 
higher α/β ratios.  Under these conditions, an improved therapeutic ratio is achieved with multiple 
small fractions. 
 
In contrast, prostate cancers appear to be better able to repair radiation injury than late responding 
normal tissues. This is probably related to the very slow growth fractions and growth rates typical 
for prostate cancer. Growth fraction (or average cell cycle time) has often been associated with 
fractionation response, with slowly proliferating normal tissues (and some slowly proliferating 
tumors) generally displaying strong fractionation responses (low α/β ratios).  This relationship has 
been demonstrated for melanomas (16) and for some sarcomas (17), for example.  In the case of 
prostate cancer, there is ample evidence for slow proliferation, based both upon direct 
measurement of potential doubling times and labeling indices (18) and upon analysis of the kinetics 
of rising PSA during tumor recurrence (19).  Recent analyses of clinical tumor response data have 
argued for a low α/β ratio for prostate cancer as well (20, 21). Brenner and Hall (20), for example, 
analyzed dose response data for both external beam radiation and I-125 brachytherapy data and 
derived a very low α/β ratio of 1.5 Gy for prostate cancer.  Duschene and Peters (21) argue in 
analogous fashion that the α/β ratio for prostate cancer may be more similar to that expected for 
late responding normal tissue than for the typical, more rapidly proliferating tumor. 

 
 
 
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Our own analysis of tumor control versus dose response for external beam and brachytherapy also 
indicates a very low α/βratio of 1.49 (95% CI of 1.25 to 1.76) (22), significantly lower than the ratio 
of 3 expected for most late responding normal tissues. 
 
Under these unusual conditions, in which the α/β ratio of the tumor is lower (the radiation repair 
capacity is higher) than that for the limiting normal tissue, a new paradigm is created in which it 
becomes advantageous to use larger fractions; in other words, to use hypofractionation, rather 
than the traditionally larger number of smaller fraction size radiation treatments employed when 
treating most other tumor types.  In fact, the old way of fractionating would be the least efficient 
method.  Using the linear quadratic model, one can predict that it should be possible to improve the 
ratio of tumor control to normal tissue toxicity (the therapeutic ratio) for prostate cancer by using 
hypofractionation. 
 
Although begun before this unique prostate cancer radiobiology was understood, a relatively large 
clinical trial has already been carried out using hypofractionation for prostate cancer.  Cleveland 
Clinic investigators have carried out a trial of hypofractionation consisting of 28 fractions of 2.5 Gy 
each for a total dose of 70 Gy (23).  Intensity modulated radiotherapy (IMRT) and daily 
pretreatment ultrasound-based prostate localization were employed to improve treatment precision 
and reduce radiation dose to the rectum.  These investigators are now reporting 2-year follow-up in 
which rectal and bladder toxicities are no greater and likely lower that previously experienced with 
conventional fractionation of 2 Gy per day to 76 Gy using conventional 3D conformal radiotherapy 
techniques (Mohen, in press, 2002). Furthermore, these early results appear to indicate better 
tumor control (PSA recurrence-free survival) that was seen with standard fractionation, although 
follow-up is too short to reach definitive conclusions regarding tumor control.
 
1.4  Biomarkers of Prostate Cancer Radiation Response 
 
There is increasing evidence that cancers can have molecular alterations that render them poorly 
responsive to radiation therapy and that are associated with a significant proportion of treatment 
failures. Preliminary findings indicate, for example, the status of certain biomarkers, such as p53, 
and Bcl-2, correlate with success or failure of radiation therapy treatment for prostate cancer (30-
36) but more such studies are needed to further identify markers and to define the strength of 
these correlations with treatment outcome, particularly in favorable or intermediate risk patients, 
the type of patient most frequently diagnosed today and the type treated in this present study. 
 
We will therefore study certain biomarkers in the diagnostic biopsy specimens of patients treated 
on this protocol. These biomarkers have been selected based upon prognostically useful 
prevalences in early to intermediate risk prostate cancer and based upon their having pathways 
linked to radiation response. We will immunohistochemically measure the levels of p53, Bcl-2,  and 
Ki-67 in pre-treatment diagnostic biopsy specimens from patients enrolled on this study and will 
analyze correlations between these markers and clinical outcomes (freedom from biochemical and 
metastatic failure) in univariate and multivariate fashion, taking conventional prognosticators such 
as stage, grade and PSA into account.  
 
 
1.5 Study Rationale 

 
 
 
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Hypofractionation Trial 
The purpose of this study is to examine the clinical feasibility of using IMRT combined with daily 
pretreatment prostate localization to deliver increasingly hypofractionated treatment courses.  
Progressively larger fraction sizes will be delivered in a phase I design based on both acute and 
long-term tolerances to the treatment.  The dose-per-fraction escalation design utilizes schemas 
that maintain an isoeffective dose for late effects, while predicting that tumor control will actually 
improve.  A natural consequence of these constraints is that the total dose of radiation that can be 
delivered over an entire course of therapy must decrease as the dose delivered with each fraction 
increases.  
 
Late effects increase with fraction size and total dose delivered whereas acute toxicities increase 
with total dose and as overall treatment time is shortened.   Excessive shortening of overall 
treatment time could be a natural consequence of hypofractionation if treatments continue to be 
delivered daily even as fraction size is increased. Thus, any hypofractionation trial design must 
guard against an unacceptable increase in acute toxicities by considering whether treatments can 
continue to be delivered daily (5 days per week), as is generally the case with conventional 
treatment, or whether treatment frequency needs to be reduced.   The proposed study will 
therefore initiate treatment at each fraction size level with only 4 fractions per week and will only 
increase to 5 fractions per week if tolerated. 
 
The delivery of fewer, larger fractions of radiation, if proven effective and safe, would result in 
significant cost saving and a more efficient use of resources. In addition, patients would be spared 
the burden of undergoing the 40 or more treatments required in most current, conventionally 
fractionated, dose escalation regimens.  Time and effort saved could be applied to upgrading 
pretreatment verification of patient and organ position. 
 
Biomarker Study 
The purpose of the biomarker study is to identify tumor biomarkers useful in predicting 
which prostate cancers are or are not likely to respond to radiation therapy. If successful, 
this proposed study will define biomarkers that are clinically useful in predicting response 
to radiation therapy in favorable-to-intermediate risk patients.  This will provide insight into 
the mechanisms of resistance to radiation therapy and will potentially allow future 
therapies, including novel biologic/molecular therapy approaches, to be prospectively 
individualized to optimize clinical outcome.   
 
Participation in the tissue study is optional and is also dependent on the availability of 
tissue. The decision to participate in Biomarker study will not affect nor influence any 
patient treatment according to the remainder of this hypofractionation protocol.  Subjects 
agreeing to tissue study participation will sign a consent indicating this decision. 
 
2.0 OBJECTIVES 
 
2.1 
To evaluate acute and long-term tolerances to dose-per-fraction escalation in the treatment 
of prostate cancer using optimized treatment delivery that employs IMRT, daily rectal 
balloon displacement, and transabdominal ultrasound localization of the prostate. 

 
 
 
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2.2 
To clinically evaluate local tumor control and biochemical progression-free survival and 
metastasis-free survival. 
2.3 
To immunohistochemically measure the levels of p53, Bcl-2, and Ki-67 in pre-
treatment diagnostic biopsy specimens from patients enrolled on this study and will 
analyze correlations between these markers and clinical outcomes (freedom from 
biochemical and metastatic failure) in univariate and multivariate fashion, taking 
conventional prognosticators such as stage, grade and PSA into account. 
 
 
3.0 SELECTION OF PATIENTS 
• Histologically proven adenocarcinoma of the prostate.  
• Stage ≤ T2b disease, as defined by 1997 AJCC classification 
• Predicted risk of lymph node involvement (by standard nomograms) of 15% or less (24), OR 
histologically negative pelvic nodes   
• Gleason score ≤ 7 
• No evidence of distant metastasis 
• Age 18+ 
• Informed consent signed in accordance with institutional protocol 
• Pretreatment evaluations must be completed as specified in Section 7.0. 
• ECOG performance status 0-1 
• No previous or concurrent cancers, other than localized basal cell or squamous cell skin 
carcinoma, unless continually disease free for at least 5 years 
• No prior pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy 
• Gonadotropin-releasing hormone agonist (GnRH-a) use permitted (maximum of 6 months 
duration).  Anti-androgen therapy permitted concurrently with GnRH-a. 
• No previous or concurrent cytotoxic chemotherapy 
• No radical surgery or cryosurgery for prostate cancer 
• The absence of any co-morbid medical condition which would constitute a contraindication 
for radical radiotherapy 
• The absence of serious concurrent illness of psychological, familial, sociological, 
geographical or other concomitant conditions which do not permit adequate follow-up and 
compliance with the study protocol. 
• No current use of anticoagulation therapy, other than aspirin. 
 
 
 
4.0 REGISTRATION PROCEDURES 
 
Patients can be registered only after eligibility criteria are met.  Patients must have signed informed 
consent.  Patients are registered prior to any protocol treatment by faxing the registration page to 
608-263-3526 and calling 608-263-8500.  The UW data managers will verify eligibility, assign a 
case number, dose level, and confirm the number of fractions per week. 
 
Patients will be enrolled on the highest available dose level open to accrual.  If the highest dose 
level has reached full accrual with insufficient follow-up for further dose-per-fraction escalation, 
accrual will take place at one dose level lower, if one exists. 

 
 
 
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Enrollment will be permanently closed when the maximum tolerated dose per fraction is reached or 
when the dose per fraction escalation is complete.   
 
 
5.0 TREATMENT PLAN 
 
5.1 General 
 
The accrual goal will be 50 evaluable patients in each of the three dose levels. An additional  100 
patients will be enrolled at the determined MTS (Maximum Tolerated Schedule). An exception to 
this accrual target will be made for any new institutional participant joining the trial after Level I 
accrual has been completed, in which case that institution will  treat two patients to completion at 
Level I (22 fractions, 5 treatments a week) irrespective of the current  hypofractionation level the 
overall trial currently is treating. After two such patients have been treated, these institutions will 
then be allowed to accrue to the Level currently open in the trial. In addition, if the highest dose 
level has reached full accrual with insufficient follow-up for further dose-per-fraction escalation, 
accrual will take place at one dose level lower.  As a result, patients will be enrolled on the highest 
available dose level open to accrual.   
 
Both acute and late toxicities will be monitored and will dictate subsequent accrual.  The level of 
acute toxicity observed will dictate the number of fractions delivered per week, whereas the level of 
late toxicities will determine both whether accrual to a dose-per-fraction level is continued and 
whether escalation to the next dose-per-fraction level is allowed. The escalation rules are as stated 
in 5.2 and 5.3, with the statistical rationale being described in Section 8.  Given this study design, 
predicting the overall number of patients accrued is difficult.  Assuming we are able to complete 
Levels 1-3 without dose limiting toxicity and taking into account the possibility of further enrollment 
into a lower dose level per escalation rules, the enrollment could be as high as 400 patients.   
 
5.2  Dose-per fraction escalation 
 
Escalation to the next higher dose-per-fraction level (or the accrual of an additional 100 patients to 
the MTS) will only be allowed when there is at least 20 patient years of follow-up and at least 5 
patients have been followed for at least 12 months.  A rate of 20% grade 2 or higher late rectal 
toxicity per patient follow-up year will be considered dose limiting. Late toxicities will be scored > 90 
days from completion of therapy.  The statistical rationale and methodology for this dose-per-
fraction escalation strategy is described in section 8.0.  Of note, statistical fluctuations in measured 
toxicity rates could occasionally lead to an initial over- or underestimation of these rates.  
Therefore, cumulative toxicity rates will be updated every 6 months throughout the life of the 
protocol and will be utilized according to the rules stated above. 
 
The expected accrual timetable, the proposed dose-per-fraction and total fraction levels, and 
patient accrual goals for this phase I/II trial are shown in Table 1 below.  
 
 
 
 
Table 1:  Fraction size dose escalation protocol 

 
 
 
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Level 
Approx. 
Interval 
(mo) 
Dose per 
Fx (Gy) 
# Fxs 
# pts 
Treatments 
per week 
Total 
dose 
(Gy) 
Equiv. 
dose (Gy)
I 
1-15 
2.94 
22 
50* 
3         4        5  
64.68 
82.6 
II 
16 - 30 
3.63 
16 
50 
3       4        5 
58.08 
85.1 
III 
31 - 45 
4.3 
12 
50  
3       4        5 
51.6 
85.5 
* See section 5.1 for exceptions. Patients are initially treated 3 or 4 times per week, with this 
treatment frequency subsequently increasing, decreasing or remaining the same based upon the 
number of acute toxicities observed, as described in Section 5.3.  
 
All of the three above levels are predicted to be approximately isoeffective for late effects at BED3 
equals approximately 128 Gy3.  In other words, each of these dose-per-fraction levels would be 
predicted to produce about the same level of late toxicity, all other factors such as high dose rectal 
wall volume remaining constant.  Furthermore, the above schemas are all predicted to produce the 
same late toxicity as the fractionation regimen successfully piloted by Kupelian and Mohan(23) of 
2.5 Gy times 28 fractions.  
 
An additional 100 patients may be accrued to the MTS  if toxicities observed in the first patients at 
the level are within the limits specified in the standard escalation rules. 
 
The accrual intervals for each level stem directly from the escalation rules that will be followed, 
which are described in detail in Section 8.  While not shown, predicted tumor control at each of the 
levels can be extrapolated from the fitted model of actual tumor control data in Figure 1, combined 
with the increased biologically effective doses calculated for each dose-per fraction-level as shown 
in the last column of Table 1. Such calculations are theoretical, but provide the rationale to believe 
that the hypofractionation schemas proposed here may produce increasingly better tumor control 
with fewer fractions.  
  
5.3  Number of fractions per week and acute toxicities 
 
Acute toxicities, as defined in section 5.6, will be assessed to determine the number of fractions at 
the given fraction size that can be delivered per week.  The first 10 patients enrolled at each 
fraction size level will receive either 3 or 4 fx/week, depending upon how well tolerated previous 
fractionation levels and weekly treatment frequencies were tolerated. Acute toxicities will be 
reanalyzed and acted upon if necessary for subsequent groups of 10 patients. For toxicities 
observed within the first 10 patients at each hypofractionation level, ≥20% acute grade 3 or higher 
GI or GU toxicity will constitute a threshold toxicity level and will dictate a decrease in frequency of 
treatment by one treatment per week for the next 10 patients to be treated at that hypofractionation 
level. If > 20% acute toxicity is also observed in this second group of 10 patients,  treatment 
frequency will be further reduced by one treatment per week for all remaining patients in that 
hypofractionation level.  If excess toxicity is not seen after changing to a lower treatment 
frequency, then all remaining patients in that hypofractionation level will continue to be treated at 
that frequency. 
• If exactly 20% of patients within the first group of ten patients at any hypofractionation 
level experiences acute grade III or higher GI or GU toxicity, then the next ten patients at 
that hypofractionation level will remain at the same weekly frequency of treatment, 

 
 
 
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subject to the usual treatment frequency de-escalation if excess acute toxicities are 
observed. 
 
• If < 20% of the first ten patients within the level experience this threshold toxicities, then 
the subsequent patients will be treated at the next higher treatment frequency sublevel, 
again subject to de-escalation if excess acute toxicities are observed. 
 
• For an individual patient who develops acute toxicity at or above the Grade 3 level, that 
patient will be placed on treatment break for one week and treatments will then resume 
at the next lower treatment frequency.  For example, if that patient was being treated 4 
times per week at the time grade 3 or higher acute toxicities developed, he would 
subsequently be treated 3 times per week.  A longer treatment break can also be 
prescribed if the treating physician feels that it is clinically indicated. 
 
• At any hypofractionation level, a reduction in treatment frequency to two fractions per 
week will be allowed for a given patient if that patient experiences a threshold or higher 
toxicity at 3 fractions per week. 
 
 
• Acute toxicities will be scored from the start of treatment through 90 days post 
completion of radiation therapy.  Late radiation toxicities will be scored from 90 days post 
completion of radiation therapy. 
 
5.4 Target volume and rectal dose limits. 
 
Target volume.  The GTV will generally be defined to include the entire prostate gland as 
visualized on CT scan.  Seminal vesicles will be included in the GTV for 75% of the prescription 
dose if the estimated risk for seminal vesicle involvement is ≥15% (24). For situations where there 
is less than 15% risk of seminal vesicle involvement, the base of the seminal vesicles may be 
included in the GTV at the discretion of the treating physician.  The CTV will represent the same 
volume as the GTV plus a 0.3 cm margin in all dimensions except at the prostate-rectal interface, 
for which a margin of between 0 and 0.3 cm can be used. The PTV will include the CTV with a 
margin to account for patient and organ motion.  This margin beyond the CTV is expected to range 
between 0 – 0.4 cm depending upon the accuracy of the daily pretreatment localization method 
used. Some form of pretreatment prostate localization must be used, either transabdominal 
ultrasound, Megavoltage CT (using Tomotherapy) or fiducial markers. Block margins will be 
chosen to provide adequate coverage of the PTV with no more than 10% dose heterogeneity 
across the PTV.  At least 95% of the PTV must receive the prescription dose or higher.  All 
planning will be carried out using an intensity modulated radiation therapy treatment planning 
system and delivered with an IMRT capable LINAC or with the tomotherapy machine. 
 
Rectal dose limits.  The rectal wall volume (outer minus inner) will be contoured for a total length of 
11-12 cm beginning at approximately the inferior-most portion of the ischial tuberosities and 
extending to at least one cm above the most cranial extent of the treatment fields.  Rectal wall 
percent volumes versus dose, as derived from the dose volume histogram, should be kept at or 
below values given in Table 2 whenever possible: 
Table 2:  Rectal Percent Limits vs. Dose 

 
 
 
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Dose (Gy) 
Level 
Dose per 
Fx (Gy) 
# Fxs Total dose 
(Gy) 
30 
35 
40 
50 
55 
60 
I 
2.94 
22 
64.68 
- 
- 
37% 
25% 
- 
13.5
% 
II 
3.63 
16 
58.08 
- 
38% 
32% 
19% 
12% 
- 
III 
4.3 
12 
51.6 
40% 
- 
26.5%
12% 
- 
- 
 
 
5.5  Patient Positioning and Treatment delivery 
Patients will be positioned supine.  Use of a rectal displacement balloon is optional but  daily 
pretreatment prostate localization is required. Treatments will be carried out using Intensity 
Modulated Therapy with 6 MV or higher photons, using either a LINAC or tomotherapy. 
 
5.6  Adverse Effects 
5.6.1 Acute toxicity 
Acute toxicities will be scored from the start of radiation to 90 days after completion of radiation.    
Early urinary and GI toxicity will be used to determine the number of fractions deliverable per week 
as described in Section 5.2.  Toxicity grading will be based on a modified RTOG grading criteria 
(25) (see below).  
 
 
Grade 1 
Grade 2* 
Grade 3 
Grade 4 
Acute 
GU 
Requiring 
no 
medication 
Frequency of urination 
or nocturia, which is 
less frequent than 
every hour, dysuria, 
urgency, bladder 
spasm requiring local 
anesthetic. New 
obstructive 
symptoms requiring 
an alpha blocker 
Frequency with 
urgency and nocturia 
hourly or more 
frequently/dysuria, 
pelvis pain or bladder 
spasm requiring 
frequent narcotic; 
gross hematuria with 
or without clot 
formation. 
Hematuria requiring 
transfusion; acute 
bladder obstruction not 
secondary to clot 
passage, ulceration, or 
necrosis 
Acute 
GI 
Requiring 
no 
medication 
Diarrhea requiring 
parasympatholytic 
drugs; mucous 
discharge not 
necessitating sanitary 
pads; rectal or 
abdominal pain 
requiring narcotic 
analgesics. 
Diarrhea requiring 
parenteral support; 
severe mucous 
discharge 
necessitating sanitary 
pads, abdominal 
distension. 
Acute or sub-acute 
obstruction, fistula or 
perforation; GI bleeding 
requiring transfusion; 
abdominal pain or 
tenesmus, requiring 
tube decompression or 
bowel diversion 
* The pre-existing use of an alpha blocker for GU symptoms or of an antidiarrheal agent for GI 
symptoms does not constitute a Grade 2 toxicity 
 
 
5.6.2 Late toxicity  

 
 
 
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Rectal toxicities 
Late toxicities will be scored > 90 days from completion of radiation therapy. Late rectal 
complications will be used as the primary endpoint for dose-per-fraction escalation in this study, 
from which the maximum tolerated dose-per-fraction will be determined.  The most common 
clinical syndrome of radiation proctitis is rectal bleeding, urgency/tenesmus, and loose bowel 
movements.  Other, less common late complications include perforation, fistula, and bowel 
obstruction.  Toxicity grading will be based on the FC-LENT grading criteria (see below).  Patients 
will be monitored after treatment at regular intervals, and toxicity determined by history and 
physical examination.  Greater than 40% Grade 2 or higher late rectal toxicity at 2 years will be 
considered dose limiting and the escalation rules are described in section 8  
 
FC-LENT rectal toxicity scale* 
Grade 1 
Symptoms not requiring medication 
Grade 2 
>4 stools daily above baseline for ≥ 3 months; regular 
blood in stool for at least 6 months; pain not requiring 
narcotics; minor outpatient therapies (≤ 3 coagulations; 
enemas; steroids; antibiotics; opiates) 
Grade 3 
Dysfunction requiring non-surgical hospitalization for 
management; bleeding requiring transfusion and/or 
more than 3 coagulations; pain requiring narcotics 
Grade 4 
Dysfunction 
requiring 
surgery; 
perforation; 
life-
threatening bleeding 
Grade 5 
Fatal complications 
 
      * pre-existing use of opiates does not constitute Grade 2 toxicity 
 
 
Late GU toxicities 
 
Late 
GU 
Requiring 
no 
medication 
Moderate frequency; 
generalized telangiectasia, 
intermittent macroscopic 
hematuria 
Severe frequency and 
dysuria; severe generalized 
telangiectasia; frequent 
hematuria; reduction in 
bladder capacity (<150 cc) 
Necrosis; contracted 
bladder (capacity 
<100 cc); severe 
hemorrhagic cystitis 
 
5.6.3 Serious Adverse Events 
 
Serious adverse events (SAE) will be defined as all Grade 4 and Grade 5 toxicity. SAE’S will be 
phoned in to the Study Chairman at 608-263-8500 within one working day of the event.   SAE’s will 
be reported by the UW data managers to the DSMB and the Clinical Trials Monitoring Committee 
administrator within one business day of notification of SAE.  These will also be discussed at 
regularly scheduled Disease Oriented Working Group meetings. 
 
5.6.4 Quality of Life 
 
Quality of life will be assessed by three separate questionnaires with special emphasis on bowel, 
bladder, and erectile function. Questionnaires will be performed prior to treatment, one , two and 
three years after completion of treatment.  Overall quality of life will be assessed using The Spitzer 
Quality of Life Index (SQLI) (26).  Bowel and bladder quality of life will be assessed using a 
questionnaire developed at Fox Chase Cancer Center (27).  Erectile function will be assessed 

 
 
 
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using the International Index of Erectile Function Questionnaire (IIEF) (28).  Data will be used to 
compare these patients to those who received conventional external beam radiation therapy. 
 
 
5.7  Supportive Care 
 
All supportive measures consistent with optimal patient care will be given throughout the study. 
 
5.8  Duration of Therapy 
 
Study treatment will be stopped if: 
• The patient refuses the study treatment 
• The patient’s physician feels that continuing the study treatments would not be in the 
patient’s best interest. 
• The patient experiences severe treatment related toxicities as outlined in section 5.6.3. 
• There is clear evidence of progressive disease. 
• Treatment interruption more than 2 weeks. 
 
All patients will be followed for disease status until progression and for survival until death.   
 
5.9  Biomarker Assessment 
 
Biomarker studies will be carried out at UW Hospital by performing immunohistochemistry 
analyses on the original diagnostic biopsy material whenever this is available. In most cases, this 
will be needle biopsy material. The emphasis will be on a proliferation markers, Ki-67 and apoptotic 
pathway markers (e.g., p53, bcl-2, bax and mdm-2).  The apoptotic markers are all involved in 
molecular radiation response pathways and have shown promise in predicting prostate cancer 
patient outcome after radiotherapy, while the proliferation marker, Ki-67, may have particular 
relevance for hypofractionation since the slow proliferation typical of many prostate cancers is 
thought to be causally related to their high capacity for interfraction repair and their suitability for a 
hypofractionated radiotherapy approach. All of these markers will be determined by quantitative 
immunohistochemistry, using the ACIS Chromavision system, as has been used, for example, in 
immunohistochemistry studies carried out in RTOG 86-10 (37).  
 
Clinical outcomes (biochemical control) determined from the trial described here will not be ready 
for correlative analysis comparisons with these biomarker analysis for approximately 7 years.   This 
analysis is for research purposes only and is not expected to have an impact on the patients 
enrolled on this study. 
 
 
6.0 
MEASUREMENT OF EFFECT 
 
6.1 General 
 
The primary objectives of this study are to potentially establish the maximum tolerated 
hypofractionation intensity (or to determine whether the most hypofractionated schedule tested in 
this study is tolerated) for prostate cancer patients and to determine clinical response. Analyses for 

 
 
 
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clinical tumor control and PSA disease free survival will be performed when median 5-year follow-
up is obtained. Data will be collected for efficacy evaluation as stated in section 6.2 and 6.3. 
 
6.2 Disease-free Status 
 
Patients will be considered to be without biochemical recurrence if either the PSA is still declining 
or the PSA nadir has been reached and is below 1.0 ng/mL, there is no palpable or radiologic 
evidence of disease, PSA is not rising (defined as 3 successive increases in measured PSA levels 
each at least two months apart) and there is no evidence of metastasis.  Patients not meeting 
these criteria will be judged to have a recurrence. 
 
6.3 Progressive Disease 
 
Any patient with rising PSA on 3 successive serum measurements will be considered to have 
recurrent or progressive disease. The date of failure will be taken as midway between the nadir 
PSA date and the date of the first of the three rising PSAs. 
 
7.0 STUDY PARAMETERS 
 
7.1 All pre-study laboratory tests must be done within 6 weeks of registration. 
 
7.2 Patients will be evaluated weekly during radiotherapy by one of the clinical study investigators 
to assess acute toxicities and functional status 
 
7.3.  The follow-up schedule and evaluations are outlined below:  
 
 
 
Pre-
study 
Weekly 
during 
RT 
4 weeks 
post-RT 
3 months 
post-RT 
Subsequent 
follow-upa
H & P 
X 
 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
PSA 
X 
 
X 
X 
X 
CBC/platelets 
X 
 
 
 
 
Toxicity notation 
X 
X 
X 
X 
X 
QOL assessment 
X 
 
 
 
Xb
IPSS score 
X 
 
X 
X 
X 
 
a  
Subsequent follow-up will be every 3 months x 1 year post-treatment, every 4 months during years 2 - 3, every 6 
months years 4 – 5 and then annually.  Follow-up frequency can be increased if thought medically necessary by 
the treating physician
b 
QOL assessment will be completed pre-treatment and at 12, and 24 and 36 months post-treatment. 
* 
For patients for whom travel to the treating institution creates a hardship, scheduled follow-ups, with the exception 
of the 4 week and all annual follow-ups, can be conducted via telephone interview with PSA and any other 
indicated testing being carried out at a facility near to the patient. 
 
 

 
 
 
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8.0 STATISTICAL CONSIDERATIONS 
 
8.1 Treatment and Toxicities 
 
This phase I/II trial will be conducted with three potential fraction size levels, with a potential of 50 
patients per level (plus an additional 100 patients at MTS if permitted by the escalation rules) and 
an accrual rate of approximately 50 patients per year anticipated. This may estimate the maximum 
tolerated dose-per-fraction (MTD), defined as that fractionation schema that yields at most a 40% 
rate of late grade 2 rectal toxicity at 2 years. A modified LENT grading system for rectal toxicity will 
be used (28). That outcome is chosen for its clinical relevance; however, the extended follow-up 
makes the standard sequential designs impractically long at 3 years (one year accrual plus two 
years follow-up for each of three cohorts). We therefore use the simply modified class of prorated 
designs (R. Chappell and K. Cheung, Simple designs for phase I clinical trials of long-term 
toxicities, abstract presented at the 1998 meeting of the Society for Clinical Trials). Proration 
implies, for example, that two patients observed for one year each, constituting two patient-years 
of follow-up, are equivalent in information to one patient followed for two years. This implicitly uses 
the result of Teshima (29) that the cumulative incidence of late grade 2 rectal complications 
reaches 50% of the final value within twelve months of treatment and that the cumulative incidence 
of complications is approximately linear with time. 
 
The prorated design will require the following conditions for escalation: at least twenty patient-
years of observation; and a minimum of 5 patients followed for one year; and at most a 40% 
toxicity rate per two years (i.e., at most 2 toxicities per 10 patient-years) observed. Proration allows 
a great reduction in the overall time of the trial - with fifty patients accrued at a uniform rate over 
each year, the first two conditions will be satisfied after 15 months. Thus the entire study will take 
at most 45 months. The requirement of 5 patients being followed for one year is made for safety's 
sake. The situation may arise that the maximum 50 patients have been accrued at a particular 
dose-per-fraction step, but there is insufficient follow-up to allow escalation to the next dose-per-
fraction step. Under these circumstances, additional patients may be accrued at the previous (next 
lower) dose-per-fraction level until follow-up conditions for the next escalation are met. 
 
8.2 Disease-free Survival 
 
A primary endpoint is Disease-Free Survival (DFS), as defined in Section 6.2.  The 95% 
confidence interval for DFS observed on 150 fully followed patients will have half-width of 8% or 
less; that is, it will be the observed DFS rate plus or minus 8%.  This figure is conservative 
in that the width will be less for DFS rates far from 50%.  It is slightly anticonservative in the 
presence of loss to follow-up. 
 
The DFS estimate and its confidence interval will be compared to similar statistics observed for 
patients treated with standard care fractionation schedules such as those presented in [Zelefsky et 
al. High dose rate radiotherapy delivered by intensity modulated conformal radiotherapy improves 
the outcome of localized prostate cancer, J. Urol. 166: 876, 2001].  In addition, efficacy in these 
data will be modeled with the linear-quadratic formula [Chappell, R., Nondahl, D., and Fowler, J.F.  
Modeling dose and local control in radiotherapy. Journal of the American Statistical Association.  
Vol. 90 (1995), pp. 829-838] to examine the hypothesis, which underlies the logic of fractionation, 
that prostate cancers have an alpha/beta ratio which makes them better able to repair radiation 
injury than surrounding late responding tissues. 

 
 
 
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8.3 Correlation of Biomarkers with Clinical Outcome 
 
The percent labeling observed immunohistochemically with each biomarker studied will ultimately 
be analyzed for correlations with clinical outcome once sufficient clinical follow-up is achieved 
(median follow-up of at least 5 years. Three markers (p53, bcl-2, and Ki-67) will be analyzed for 
prognostic significance using a Cox proportional hazards regression analysis accounting for each of the 250 
patients' follow-ups, and adjusting for pretreatment PSA and tumor grade.  For purposes of power 
calculations only, we will assume that marker scores will be divided at their medians and modeled as binary 
covariates, so that prevalences are by definition 50%.  Also, we compute power using binary failure/no-
failure five year outcomes; these produce conservative (slightly too small) estimates of power.  We invoke 
the usual two-sided test of significance at the conducted .05 level, divided by three using a Bonferroni 
adjustment to avoid bias due to multiple comparisons. 
 
 Suppose that the relative risk induced by positive markers is 3.  This, by the proportional hazards 
assumption, implies five-year failure rates of approximately 22% vs. 8% which average to 15%, a failure 
rate consistent with that reported in a patient population such as this treated with dose-escalated 
radiotherapy.  Then by the above assumptions the power to detect each marker's effect, after adjusting for 
multiple comparisons, is approximately 79%.  This is reasonable for an exploratory study. Should failure 
rates be higher than the assumed 15%, then the power would be greater. 
 
8.4     DSMB 
 
Hypofractionation of radiation therapy for prostate cancer was identified in the funded Tomotherapy 
Program Project Grant as a key investigational area, irrespective of whether the treatment was 
delivered by a tomotherapy device or by conventional LINAC-based equipment.  Therefore, the 
DSMB established for tomotherapy-related protocols will also be utilized in this study.  This Data 
Safety Monitoring Board (DSMB) has been formally constituted for the “Improving Cancer 
Outcome With Adaptive Helical Tomotherapy” NIH grant.  The DSMB consists of one statistician 
who will chair the Board (Associate Professor Mary Lindstrom, Ph.D.), one radiation oncologist 
(Professor Emeritus Richard Steeves, Ph.D., M.D.), and one medical physicist (Heath Odau).  
None of these individuals are involved with this study.  The DSMB meetings will be held semi-
annually and more often depending on the nature and progress of the trial.  The DSMB will be 
responsible for recommendations regarding specific actions or no action for the continuing conduct 
of this trial.  The DSMB will be notified immediately (within 24 hours) if any grade 4-5 toxicities are 
observed.  
 
 
9.0 DATA COLLECTION 
 
This protocol will be conducted according to Good Clinical Practice Guidelines.  Participating 
investigators/institutions agree to permit trial related monitoring, audits, IRB review, and regulatory 
inspections, providing direct access to source documents/data.  
 
All data identified in patient evaluation table, section 7.0 will be collected. The following dosimetry 
data will be collected within 10 days of the end of radiation:  copy of DVH plan, copy of daily 
treatment record, and axial CT cuts at several levels with superimposed isodose curves. Follow-up 
data and signed informed consents will be kept for a minimum of five years.  Forms will be labeled 
with name codes and sequence numbers. 

 
 
 
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For patients that agree to participate in the Biomarker study the following info will be collected:  one 
paraffin tissue block containing tumor* (*any unused tissue will be returned to the site) and the 
corresponding pathology report.  Tissue and report will be labeled with name codes and sequence 
numbers.  
 
 
10.0 REFERENCES 
 
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3. 
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Ling, C. C.; Fuks, Z. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int 
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Pollack, A.; Zagars, G. K.; Kavadi, V. S. Prostate specific antigen doubling time and disease relapse after radiotherapy for 
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