Phase I-II Trial of Hypofractionated Conformal Proton Beam Radiation Therapy for Favorable-risk Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: Loma Linda University

IRB #58116  
 
 
 
 
 
 
RMPT  0801 
 
 
Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy  
for favorable-risk prostate cancer 
 
Loma Linda University Medical Center 
Department of Radiation Medicine  
 
 
**NCT# 00831623 
 
Protocol 
Version:  11/21/14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
Jerry D. Slater, MD 
 
 
 
 
 
 
 
 
Study Co-Investigators 
 
 
 
 
 David Bush, MD 
 
 
 
 
 Ben Jabola, MD 
 
 
 
  
 Joseph Kang, MD, PhD 
 
 
 
 
 Ivan Namihas, MD 
 
 
 
 
 Gary Yang, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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1.0 INTRODUCTION 
1.1 Rationale for Hypofractionation 
 
Radiation therapy has a long and established role in the curative treatment of organ-
confined prostate cancer[1]. However, the optimal radiation dose and treatment 
schedule remain unknown[2]. Typically, patients treated with external beam radiation 
therapy [EBRT] receive daily treatment five days per week for a total duration of 7-8 
weeks[3]. More recently, published non-randomized and randomized data strongly 
suggests that radiation doses in the range of 78-81 Gy result in an improvement in 
five year biochemical freedom from relapse, even in “low risk (for regional/distant 
metastasis) patients [4] [5]. Delivery of these doses via highly conformal radiation 
techniques (including conformal proton beams) has been associated with minimal and 
acceptable significant acute and late treatment-related morbidity. At LLUMC, our 
current institutional standard for early-stage disease is to treat the prostate and 
immediately adjacent paraprostatic tissues with conformal proton beams alone to a 
radiation dose of ~81 CGE [Cobalt-Gray Equivalent, in which 1 proton Gy is 
assumed to equal 1.1 photon Gy], delivered over a period of nine weeks. This 
prolonged course, although well tolerated, can lead to logistical difficulties in terms 
of requiring patients (many of whom reside outside of the immediate area) to remain 
at LLU for periods of up to three months; this can serve as an absolute treatment 
barrier to some patients who would otherwise be candidates for conformal proton 
beam therapy but who are unable to remain at LLU for such a prolonged treatment 
course. A reduction in treatment time could therefore allow more patients to take 
advantage of this treatment modality that is currently possible. 
 
Radiation induced mammalian cell death (including human cells) is classically 
described according to the linear-quadratic equation. Per this formula, the survival 
rate of a given cell will depend upon multiple factors including the overall radiation 
dose, the dose per treatment fraction, and the overall treatment time. The dose-
response of tumors and normal tissue to fractionated radiotherapy can be described 
according to the alpha-beta ratio. This ratio is a parameter which numerically 
describes the fractionation sensitivity of a particular cell type. For example, the  
ratio is typically high (>10 Gy) for early-responding normal tissues (skin, mucosa) 
and most tumors, and low (< 5 Gy) for late-responding normal tissues (spinal cord, 
brain, bone). An obvious implication of the difference in  ratios between tumor 
and normal tissue is that it may therefore be possible to increase the “therapeutic 
ratio” by employing unconventional fractionation schedules. 
 
Over the last 5-10 years there have been several published reports suggesting that the 
 ratio for prostate cancer cells is very low and is in fact lower than that for some 
of the surrounding adjacent normal tissues (bladder, rectum) [6] [7]. Although the 
absolute number varies, most publications suggest that the  ratio is between 1 and 
3 [8] [9]. Should this be true, then treatment with hypofractionated regimens (shorter 
overall treatment time, larger treatment fractions) may prove to be more effective 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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than conventional fractionation. As will be mentioned below, this hypothesis has 
already been successfully tested in conformal proton beam treatment of numerous  
malignancies. This protocol is designed to investigate the safety and efficacy of 
conformal proton beam therapy of early stage prostate cancer in which treatment is 
administered via a hypofractionated regimen designed to be biologically equivalent to 
our current conventional fractionation schemata. 
 
1.2 Hypofractionated Conformal Proton Beam Therapy of other tumors 
 
The use of hypofractionation has a long and generally successful history in conformal 
proton beam therapy. Its use has been predicated by both the superior physical 
characteristics of protons as compared to x-rays (i.e., low entrance dose, sharply 
defined high dose area, lack of exit dose) and, until recently, the limited number of 
proton beam treatment centers in existence. Hypofractionated conformal proton beam 
therapy is routinely employed in the treatment of intra-ocular tumors, intra-cranial 
tumors (both benign and malignant), lung cancer, and early breast cancer. It is, 
therefore, reasonable to assume that an analogous level of success can be achieved in 
treatment of organ-confined prostate cancer, and this hypothesis is worthy of testing 
in a Phase I-II clinical trial. 
 
1.3 Calculation of Biologically Equivalent Dose [BED] 
 
In order to facilitate a comparison between our current institutional standard (81 
CGE/45 Fractions) and the fractionation schedule to be employed in this protocol (60 
CGE/20 Fractions) biologically equivalent doses [BED] will be calculated and the 
isoeffect model using the linear-quadratic equation will be used. Also, for the 
purposes of calculating the BED and isoeffective doses in this protocol two 
underlying assumptions will be made 1) complete repair of radiation-induced DNA 
injury between fractions and 2) there is no time factor. The calculated BED depends 
on the assumed  ratio, which in this protocol will be assumed to be 1.5 for tumor, 
4.0 for rectum (a late responding tissue), and 10 for early responding tissues. The 
assumed  ratio used in each calculation will be indicated by a subscript e.g., BED 
1.5 indicates that the BED reported was calculated using an  of 1.5. The calculated 
BED’s for the hypofractionated treatment and our current institutional protocol are as 
follows: 
 
 
               
BED 1.5                                  
BED 4.0                                 BED 10.0 
 
Conv 
178 
 
 
 
117 
 
 
 
96 
 
Hypofx 
180 
 
 
 
105 
 
 
 
78 
 
 
 
 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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1.4 Phase I-II Trials of Hypofractionation Regimens in Prostate Cancer 
 
Several reports detailing the efficacy and safety of hypofractionated conformal 
radiation therapy (with x-rays) of prostate cancer can be found in the literature. In the 
United States, Kupelian et al have recently reported five year bNED survival and 
morbidity in a group of patients treated with hypofractionated radiotherapy delivered 
via an IMRT approach [10]. One hundred patients with organ-confined prostate 
cancer were treated to 70 Gy delivered in 28 fractions (2.5 Gy/fx). Patients were 
treated in 1998, and the median follow up was 66 months. Androgen deprivation 
therapy was administered to 51% of the patients, with the duration of ADT limited to 
no more than six months. The PTV-CTV margin was 4mm posteriorally and 5-8 mm 
elsewhere. Freedom from biochemical failure was reported using both the ASTRO 
Consensus definition [11] and the RTOG Phoenix definition (nadir + 2 ng/ml). 
Results were reported according to prognostic groups, and the RTOG morbidity 
scoring system was used to report GI and GU morbidity. 
 
The estimated rate of FFBR at five years post-treatment was 85% according to the 
ASTRO definition and 88% per the Phoenix definition. These biochemical results 
were similar to a group of contemporaneously treated patients who were treated with 
3-D CRT to 78 Gy/39 fx. In the hypofractionated patients the combined rate of Grade 
2-3 rectal morbidity was 11% at five years; again, this compares favorably to patients 
treated in a conventional manner to 78-80 Gy. 
 
LLUMC has treated sixty-two patients with low-risk prostate cancer on a Phase I-II 
hypofractionation trial, in which they received 60 Gy/20 fractions. With a minimum 
follow-up of one year, to date there have been no Grade >3 complications, and the 
rate of Grade 2 GI/GU morbidity is 1.6%. These toxicity numbers compare favorably 
with those from our randomized dose-escalation trial and strongly suggest that further 
dose-escalation via hypofractionated techniques is medically feasible. 
 
1.5 Randomized Trials of Hypofractionation 
 
To date, the preliminary results from two randomized trials have been published. The 
Australian Trial compared 64 Gy/32 fx to 55 Gy/20 fx in men with favorable risk 
stage T1-T2 prostate cancer [12]. The primary trial endpoint was morbidity, and the 
total sample size of 220 patients (110 per arm) was powered to determine a difference 
in the frequency of mild late radiation morbidity of 20% with 90% power. Efficacy 
was considered to be a secondary endpoint. An interim analysis included the first 120 
consecutively treated men. Median follow up was 43 months (range 23-62 months). 
Two dimensional EBRT was employed in each arm; no 3-D or IMRT was used or 
allowed. Morbidity was measured with the LENT-SOMA questionnaires. The GI 
component of this questionnaire emphasizes six symptoms (stool frequency, stool 
consistency, rectal pain, mucus discharge, tenesmus, and rectal bleeding). GU 
morbidity measures four symptoms (urinary frequency, urgency, dysuria, and 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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hematuria). Treatment efficacy was assessed both clinically and biochemically; the 
latter utilized PSA nadir and three consecutive rises as indications of biochemical 
relapse. 
 
Of the ten symptoms measured only the prevalence of rectal bleeding at two years 
was different between the two arms, with bleeding reported in 42% of the 
hypofractionated patients vs. 24% in the conventionally treated arm (p<0.05). The 
prevalence of late rectal bleeding in the conventionally treated arm is higher than 
expected and is most likely due to the two-dimensional methods employed. If one 
only considers those patients experiencing moderate to severe bleeding there is  
no difference between the arms (20 vs. 14%, P < 0.05). In terms of efficacy, there was 
no difference in the nadir PSA and the PSA levels 2 years following treatment 
between the arms. Using the ASTRO definition the 4-year estimated freedom from 
biochemical failure was 85.5% in the conventionally treated arm (BED10 76.8, BED 
1.5 149.3) and 86.2% in the hypofractionated arm (BED 10 70.1, BED 1.5 155.8). 
 
Preliminary results of a Canadian randomized trial have also been recently published 
[13]. This trial compares 66 Gy/33 fx (standard arm) to 52.5 Gy/20 fx 
(hypofractionated arm) in patients with low and intermediate risk prostate cancer. 
Dose was prescribed to isocenter and the CTV-PTV margin was 15 mm, except, 10 
mm posterioraly (at investigators discretion). Patients were treated via a four-field 
arrangement and although CT data was used for treatment planning in most patients, 
IMRT was not performed. It must be noted that the two arms were not designed to be 
isoeffective and that the biologically equivalent dose of the short arm is considerably 
less than the long arm (BED 10 66.3 vs. 79.2, BED 1.5 of 144 vs. 154). It is therefore 
not surprising that the five year failure rate (biochemical or clinical) is higher in the 
hypofractionated arm (59.95% vs. 52.95%, P < 0.05). At a median follow up of 5.7 
years there is no difference in five year actuarial rate of grade 3+ GI/GU toxicity 
between the two arms. 
 
 
1.6 Trial Justification 
 
As has been previously described, hypofractionated conformal proton beam radiation 
therapy has become our institutional routine for the treatment of numerous solid 
tumors. Conformal proton beams, by virtue of their physical characteristics, permit a 
degree of normal tissue sparing that is simply not possible with x-rays [14]. In the 
treatment of prostate cancer, this difference is almost exclusively in the volume of 
normal tissue which receives a low to moderate radiation dose. This difference may 
and probably does have a profound impact in late normal tissue morbidity as 
radiation-induced late effects are moderated by many factors including total dose, 
dose per fraction, and volume of organ receiving any radiation dose. Given the degree 
of normal tissue sparing possible with protons, it is reasonable to assume that results 
achieved with x-ray therapy can be duplicated and quite possibly exceeded (in terms 
of reducing late effects) by treating in a similar fashion with conformal proton beams. 
Since ample support exists in the medical literature regarding the safety and apparent 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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efficacy of hypofractionated prostate cancer treatment via x-rays, it is reasonable and 
desirable to pursue an identical strategy with protons. 
 
1.7 Patient Selection 
 
This trial will be restricted to patients with low-risk prostate cancer, defined as Stages 
T1-2C, and Gleason Score 2-6 and PSA < 10. In this patient population the risk of 
seminal vesicle and lymph involvement is low enough (< 10%) to permit excluding 
these structures from the treatment volume. 
 
 
1.8 Dose Selection 
 
The hypofractionated dose of 60 CGE/20 Fx has been chosen because, as per the 
linear-quadratic equation (and assuming a BED of 1.5 for prostate cancer cells) it 
should be isoeffective in terms of biochemical DFS with our current institutional 
standard of 81 CGE/ 45 fractions [4]. In addition, the hypofractionated dose is similar 
to that which has been reported by Kupelian et al. 
 
  
2.0 Objectives 
 
2.1 Primary Objective 
 
To determine if hypofractionated conformal proton beam radiation therapy of prostate 
cancer can result in late RTOG > Grade 3 treatment-related morbidity which is no worse 
than that engendered by our current institutional standard with conventional fractionation 
(81 CGE/45 fx). In PROG 9509, late Gr 2 and Gr3+ GI toxicity was 17 & 1 % 
respectively, Gr2 & Gr3+ GU toxicity was 20 & 3%.  
 
 
2.2 Secondary Objectives 
 
2.2.1. To determine if hypofractionated conformal proton beam treatment will result 
in local progression (5-year rate in PROG was 7%), disease-specific survival, 
freedom from biochemical failure (3-Year Actuarial rate in PROG was 96% for low 
risk patients, 90% for intermediate/high risk patients), and overall survival (5 year OS 
in PROG was 97%) that are no worse than those achieved with our current 
institutional standard. 
 
2.2.2. To determine the incidence of acute and late GI and GU morbidity treated with 
hypofractionated conformal proton beam treatment. 
 
 
 
 
 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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3.0 Patient Selection 
 
3.1. Criteria for eligibility 
 
3.1.1. Histologically confirmed adenocarcinoma within 180 days of registration. 
3.1.2. History and Physical Examination, including digital rectal exam, within eight 
weeks prior to registration 
3.1.3. Histologic evaluation of prostate biopsies at LLUMC with assignment of Gleason’s 
Score to the specimen 
3.1.4. Clinical stage T1-T2C as per the AJCC, 6th edition, and Gleason Score 2-6, and  
PSA < 10 ng/ml within 180 days prior to registration 
3.1.5. KPS > 90 
3.1.6  Age > 18 
3.1.7 Patient must sign study-specific informed consent 
 
 
3.2 Conditions for Ineligibility 
 
3.2.1. Prior or concurrent invasive malignancy (excluding non-melanomatous skin 
cancer) or lymphomatous or hematologic malignancies unless continuously disease-free 
for a minimum of five years 
 
3.2.2. Evidence of distant metastasis 
 
3.2.3. Regional lymph node involvement 
 
3.2.4. Previous radical surgery (radical prostatectomy) or cryosurgery for prostate cancer 
3.2.5. Previous pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy 
 
3.2.6. Previous hormonal therapy 
 
3.2.7. Previous or concurrent cytotoxic chemotherapy for prostate cancer 
 
3.2.8. History of Ulcerative Colitis or Crohn’s Disease 
 
3.2.9. Concurrent Coumadin administration 
 
3.2.10. AIDS 
 
 
4.0 Pretreatment Evaluation. 
 
4.1. History and Physical Examination, including digital rectal examination. 
4.1.1. Completion of baseline urinary status questionnaire. 
4.1.2. Evaluation of pelvic lymph node status by non-contrast CT 3-D planning scan. 
4.1.3. MRI/MRS. Endo-rectal MRI/MRS is optional and recommended in patients who are 
clinically stage T2B-T2C. MRI evidence of upstaging to T3a-T3b will not be taken into 
account for eligibility determinations unless these findings are collaborated pathologically 
however, MRI/MRS data on staging will be used to analyze impact of MRI upstaging on 
biochemical freedom from relapse, disease-specific survival, and overall survival. 
4.1.4. Pre-treatment PSA as per Section 3.1.5. 
4.1.5. Histologic review of biopsy specimens as per Section 3.1.3. 
 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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5.0 Registration 
 
5.1 Patient registration as per LLUMC institutional standards for participation in clinical 
trials. 
 
 
 
6.0 Radiation Therapy 
 
6.1. All treatment will be delivered with conformal proton beams. Minimum beam energy 
will be 225 MeV. 
 
6.1.1. All fields will be treated daily. 
 
 
6.2 Immobilization, and CT Scanning 
 
6.2.3. All patients will be immobilized in a full body immobilization device, while 
positioned supine. A water balloon will be placed into the rectum at the time of 
immobilization as per our institutional standard.  
6.2.4. Following immobilization a treatment planning CT will be performed as per our 
institutional protocol, with scanning beginning at the iliac crests superiorly and extending 
inferiorly to beyond the perineum. Image thickness will be 3mm, with images acquired 
every 2mm, thus providing sufficient image overlap to minimize the effects of patient 
motion on image quality and to provide for the creation of a high-resolution DRR. 
Patients will be encouraged to fill their bladder by drinking 8-16 ounces of fluid prior to 
CT scan, but no specific bladder filling guidelines will be mandated. 
6.2.5. Daily treatment localization will be achieved by acquiring orthogonal radiographs 
immediately prior to each daily treatment. To ensure adequate coverage of the prostate 
gland, wherein daily position can be influenced by varying amounts of bladder and rectal 
filling, the daily patient alignment will be performed with reference to bony landmarks. 
Alignment via reference to bone landmarks will remain our primary alignment 
technique.All positioning images and table shifts are to be reviewed by a physician prior 
to each day’s treatment. 
 
6.3 Treatment Planning/Target Volumes 
6.3.1. The GTV is defined by the physician as all known disease as defined by the 
planning CT scan, additional imaging studies (ultrasound, MRI) and clinical information. 
The GTV for the purposes of this protocol is the prostate gland only. 
6.3.2. The CTV is the GTV plus areas considered to be at risk for containing microscopic 
tumor. The CTV for the purposes of this protocol is the GTV. 
6.3.3. The PTV (Planning Target Volume) will provide a margin around the CTV to 
compensate for patient motion, variations in daily set-up position, and beam physics. For 
the purposes of this protocol, the PTV will be defined as the CTV + 12 mm in all 
directions.  

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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6.3.4. Treatment will be administered to the PTV via multiple conformal proton beams, 
with all fields being treated daily. It is anticipated that for most if not all patients a lateral 
beam arrangement will be employed, although other beam configurations may be 
permitted subject to the normal tissue constraints listed in section 6.3.6. and the approval 
of the principal investigator. 
 
 
6.3.5. Critical Normal Structures 
 
 
6.3.5.1. DVH data will be generated for the following normal tissues: 
Bladder-with organ contoured from dome to neck. 
Rectum-Contoured from the recto-sigmoid junction to the inferior border of the 
ischial tuberosities. The entire outer circumference should be contoured. 
Femoral heads-Contoured from the acetabular roof to the inferior edge of the 
greater trochanter. 
6.3.6. Normal Tissue Constraints (adapted from arm II of the RTOG 0415 Study, 
assumes an / of rectum and bladder=3). 
 
 
 
No more than  
No more than  
No more than No more than 
 
 
15% volume  
25% volume  
35% volume 50% volume 
 
 
exceeds 
 
exceeds 
 
exceeds 
exceeds 
 
Bladder 
60 CGE 
 
55 CGE 
 
51 CGE 
48 CGE 
Rectum 
60 CGE 
 
55 CGE 
 
50 CGE 
45 CGE 
 
6.3.7. The prescription dose is to the isocenter of the PTV. The maximum dose to the 
PTV should not exceed the Rx dose by >5%, and the minimum dose to the PTV should 
not be < 90% of the Rx dose. 
The Rx is 3 CGE/Day to isocenter, one treatment per day, 5 days per week, for 20 
treatments (=60 CGE to isocenter/20 fractions). 
 
6.4 Radiation Toxicity 
6.4.1. All patients will be seen and examined weekly by their attending radiation 
oncologist during treatment. Any and all observations regarding radiation reactions will 
be recorded and should include particular attention to the following side effects: 
6.4.1.1. Small bowel or rectal irritation manifesting as abdominal cramping, 
diarrhea, rectal urgency, proctitis, or hematochezia. 
6.4.1.2. Bladder complications including urinary frequency/urgency/dysuria, 
hematuria, urinary tract infection, incontinence, nocturia. 
6.4.1.3. Radiation dermatitis. 
6.4.1.4. Clinical discretion may be exercised to treat radiation-induced side effects 
with the appropriate OTC and/or prescription medications. 
 
7.0 Drug Therapy-N/A 
 
8.0 Surgery-N/A 
 
9.0 Other Therapy 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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9.1. Neoadjuvant or Adjuvant Hormonal Therapy. 
Neoadjuvant or adjuvant hormonal therapy is not allowed in this trial. The patient 
population for this trial was chosen to include only those patients who did not 
stand to benefit from the use of hormonal therapy (by virtue of their favorable 
disease status). As a secondary goal of this trial is to determine the effect of 
hypofractionated conformal proton beam radiation therapy on bNED survival, 
hormonal therapy would simply confound the impact of hypofractionated 
radiation on bNED survival and freedom from relapse. 
 
 
9.2 Subsequent disease progression. 
Patients who have failed as defined by criteria described in Sections 11.4 (criteria 
for biochemical recurrence), 11.5 (criteria for local recurrence), or 11.6 (criteria 
for non-local recurrence) may receive additional medical and/or surgical therapy 
as appropriate for the clinical situation. These would include salvage 
prostatectomy, salvage cryosurgery, androgen-ablation therapy, cytotoxic 
chemotherapy, observation, or participation in an appropriate clinical trial. 
 
 
11.0 Patient Assessments 
11.1 Study parameters 
 
 
Assessments 
 
Pre- 
Entry 
 
Weekly 
During 
RT 
 
 
Follow-Up (months) 
 
 
3 6 9 
12 
15 
18 
21 
24 
History, physical exam 
X 
X 
X X X 
X 
X 
X 
X 
Xc 
Prostate biopsy with Gleason Score 
X 
 
 
 
 
 
 
 
 
Xd 
PSA 
Xa 
 
X X X 
X 
X 
X 
X 
Xc 
Digital Rectal Exam 
X 
 
X X X 
X 
X 
X 
X 
Xc 
MRI/MRS  
Xb 
 
 
 
 
 
 
 
 
 
Baseline urinary status evaluation 
X 
 
 
 
 
 
 
 
 
 
Toxicity evaluation 
 
X 
X X X 
X 
X 
X 
X 
Xc 
Bone scan 
 
 
 
 
 
 
 
 
 
Xe 
 
a. PSA < 10 ng/ml within 180 days of registration 
b. Per Section 4.1.3 
c. Follow-up will continue every 6 months for the next 3 years, then annually thereafter 
d. Per Section 11.3.4 
e. Per Section 11.3.3 
 
 
 
11.2. Evaluation During Treatment 
11.2.1. Patients will be seen and evaluated at least weekly during treatment with 
documentation of treatment tolerance and the presence/absence/magnitude of 
acute reactions. 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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11.3 Evaluation Following Treatment 
11.3.1. At each visit the patient will have an interval history, disease-focused 
physical examination (including DRE) and assessment of any specific GI/GU 
toxicity. 
11.3.2. PSA will be drawn at each follow up visit: 3 months post radiation 
therapy, then every three months for two years, then every six months for three 
years, then annually. 
11.3.3. A Bone scan will be performed as clinically indicated e.g., if the patient 
develops a PSA recurrence with a rapid doubling time (< 6 months) or if the 
patient develops symptoms suggestive of metastatic disease. 
11.3.4. A needle biopsy is encouraged from the site of original tumor within the 
prostate and/or other sites or within the gland as identified by TRUS and/or MRI 
for rising PSA or clinical failures (see Sections 11.5.1. and 11.6.1). 
 
 
11.4 Criteria for Biochemical Recurrence 
11.4.1. Biochemical (PSA) recurrence will be defined as per the new 
RTOG/ASTRO criteria known as the RTOG Phoenix definition: an increase of 
the PSA level of at least 2 ng/ml greater than the post-treatment nadir. To ensure 
valid comparisons with our institutional data, the ASTRO Consensus Conference 
definition (three successive > 10% rises in PSA above a nadir) will also be used, 
although this definition will not be the primary definition of biochemical failure. 
 
 
11.5 Criteria for Local Recurrence 
11.5.1. Clinical criteria for local recurrence are progression (increase in size of a 
palpable abnormality) at any time, failure of regression of the palpable tumor by 
two years post-treatment, and redevelopment of a palpable abnormality after 
complete disappearance of the previously appreciated abnormality. The presence 
of palpable disease must be recorded on the data collection forms for initial and 
follow up patient evaluations. 
11.5.2 Histologic criteria for local recurrence are presence of prostate carcinoma 
upon biopsy and positive biopsy of the palpably normal prostate > 2 years from 
the end of treatment. 
 
 
11.6 Criteria for non-local recurrence. 
11.6.1. Distant metastasis will be documented if clinical, bone scan, or other 
imaging studies (Prostascint, MRI) demonstrates evidence of its existence. 
Whenever possible, distant metastasis should be documented by histologic 
confirmation. In addition, TRUS/ biopsy of the prostate is recommended at the 
time distant metastasis are reported. 
11.6.2. Regional metastasis will be documented if there is imaging evidence of 
lymphadenopathy and histologic confirmation. 
 
 
12.0 Statistical Considerations 
 
12.1 Study Endpoints 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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12.1.1.  Rate of late GI and GU toxicities > grade 3 (see Appendix for scoring 
scheme) 
12.1.2.  Three-year actuarial rate of freedom from biochemical failure. 
 
 
12.2. Sample Size 
12.2.1. Sample Size  
12.2.1.1. Phase I Component:  Between 1990 and 2007, we have treated 4260 
patients with early stage prostate cancer (clinical stage T1 or T2, initial PSA <10 
ng/ml, KPS 90 or 100) with protons only. The 3-year actuarial rectal/urinary 
grade 3 toxicity rate was 0.69% ± 0.15% SE in this cohort. We will 
conservatively assume the standard toxicity rate 
0p  to be 1% and set the 
unacceptable toxicity rate
1p  at 5%. Statistical error rates will be set at =10% for 
a false positive result (calling the treatment too toxic when it is not) and =10% 
for a false negative result (accepting that the treatment is not too toxic when in 
reality it is) when using a one-sided test of significance. The sample size meeting 
these requirements is 105 patients.  
12.2.1.2. Phase II Component:   In the same patient cohort, the 3-year actuarial 
rate of biochemical progression free survival (bPFS) was 96%. We will 
conservatively assume the standard 3-year biochemical failure rate 
0p  to be 5% 
and set the unacceptable failure rate
1p  at 10%. Statistical error rates for false 
positive and false negative results will again be set at 10%. The required sample 
size is 187 patients, which exceeds the required sample size for the toxicity 
endpoint. An additional 35% will be added to this number to guard against 
ineligible or inevaluable cases, resulting in 288 patients. In order to be 
conservative the sample size for the Phase I/II study will be set to 300 patients. 
12.2.1.3. Assuming we accrue the target goal of 187 evaluable patients, a 5% late 
toxicity rate equates to 9.34 patients with toxicity. If we have 9 or fewer patients 
with toxicity, the protocol therapy will be considered for further study. In 
addition, we must also meet the goals for tumor control. Assuming the target goal 
of 187 patients, tumor control will be considered acceptable if 12 or fewer 
patients have biochemical failure within the first three years. For the protocol 
therapy to be recommended for further study, both the toxicity and tumor control 
outcomes must be considered acceptable. This equates to 9 or fewer patients with 
late toxicity, and 12 or fewer patients with recurrence. If the study accrues more 
or less than 187 evaluable patients, these cut-off numbers will be adjusted 
accordingly.  
With a sample size of 187 patients and an assumed late toxicity rate of 2%, we 
have an upper = 95% confidence limit of 5% for (grade >3) late toxicity. This 
upper bound corresponds to the limit we would accept in terms of toxicity. 
 
 
12.3. Stopping Rules for Excessive Acute Effects 
The acute toxicity rate (>=grade 2) in our previously treated patient with early 
stage prostate cancer was less than 15% (12.6% grade 2, 0.8% grade 3) . We wish 
to ensure that the hypofractionation treatment does not increase the acute toxicity 
rate within the first three months after treatment commenced. The following table 

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gives the numbers of patients with acute toxicity (>= grade 2) that are considered 
unacceptable at interim check points as calculated by the method of Fleming. For 
example, if there are 17 or more acute toxicities reported in the first 50 patients, 
the accrual will be stopped and the treatment protocol will receive a special 
review. Note that these are the first 50 patients entered (and eligible) 
consecutively onto the trial and not the first 14 patients for whom we have 
collected data up to three months. The last column lists the power to detect a 10% 
increase from an assumed 15% toxicity rate to 25%  based on the number of 
patients available at each stage.  
 
Number of Patients 
with acute Toxicity 
Number of Patients 
Available 
Power (%) 
(1-) 
15 
50 
20.7 
22 
100 
75.6 
30 
150 
92.1 
35 
187 
97.6 
 
 
 
 
12.4 
Patient Accrual 
It is projected that there will be approximately a 2-month period with initial slow 
accrual (5-10 patients per month) at the beginning of this study to allow for 
establishing the procedures. After this initial period, it is projected that this study 
will accrue approximately 25 patients per month. At this rate, it will take 13 
months to complete accrual. If the average monthly accrual is less than 15 patients 
per month, the study will be reevaluated with respect to feasibility. 
 
12.5 
Analysis Plan 
12.5.1 Interim Analyses of Accrual and Toxicity Data 
• Interim reports will be prepared every six months until the final analysis. In 
general, the interim reports include information about: 
• accrual rate with projected completion date 
• Pre-treatment characteristics of patients accrued 
• frequency and severity of toxicity. 
12.5.2 Analysis and Reporting of Initial Treatment Results 
The analysis to report the initial results of treatment will be undertaken when each 
patient has been potentially followed for a minimum of 15 months. The emphasis 
of this analysis will be on acute toxicity. The usual components of this analysis 
are: 
• patients excluded from the analyses with their reasons for exclusion 
• distribution of the important baseline prognostic variables 
• patient accrual rate 
• observed results with respect to the endpoints described in Section 12.1 
12.5.3 Analysis and Reporting of Final Treatment Results (10/29/01) 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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The analysis to report the final results of treatment will be undertaken when each 
patient has been potentially followed for a minimum of 3 years. The emphasis of 
this analysis will be on biochemical control. The usual components of this 
analysis are: 
• patients excluded from the analyses with their reasons for exclusion 
• distribution of the important baseline prognostic variables 
• patient accrual rate 
• observed results with respect to the endpoints described in Section 12.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OSR#58116 Phase I-II trial of hypo-fractionated conformal proton beam radiation therapy for favorable-risk prostate cancer 
 
 
 
 
 
 
 
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