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11.6 criteria for nonlocal failure

11.6.1 Regional Metastasis Regional metastasis will be documented if there is radiographic evidence (CT or MRI) of lymphadenopathy (lymph node size ≥ 1.5 cm) in a patient without the diagnosis of a hematologic/lymphomatous disorder associated with adenopathy. Histologic confirmation is not required, although it is recommended in the setting of freedom from biochemical failure.  
11.6.2 Distant Metastasis Distant metastasis will be documented if by imaging (e.g., bone scan, CT, MRI) there is evidence of hematogenous spread.  
Time to Distant Failure The time to distant failure will be measured from the date of randomization to the date of documented distant disease.  
11.7 Other Response Parameters 11.7.1 Secondary Biochemical Failure Endpoint A more common biochemical endpoint used in the post-prostatectomy setting is a PSA ≥ 0.4 ng/mL and rising (see Section 1.3). This endpoint requires that the PSA is detectable and rising for at least two values with the second value at 0.4 ng/mL or greater.  
Time to Secondary Biochemical Failure The time to a PSA of 0.4 ng/mL and rising will be calculated from the time of randomization to this event, with a minimum follow-up from randomization of 2 years.  
Hormone Refractory Disease The development of hormone disease will be defined as three rises in PSA after the institution of salvage hormone therapy. Time to Hormone Refractory Disease The time to hormone refractory disease will be calculated from the date of randomization to the date of the third rise in PSA.  
11.7.3 Cause-Specific Mortality Time to cause-specific mortality will be measured from the date of randomization to the date of death due to prostate cancer. Causes of death may require review by the study chair or their designee. Death due to prostate cancer will be defined as:
- Primary cause of death certified as due to prostate cancer or
- Death in association with any of the following conditions:
- Further clinical or biochemical tumor progression occurring after initiation of
"salvage" anti-tumor (e.g., androgen deprivation) therapy;
- Three consecutive rises in the serum PSA level at > 3-month intervals that occur during or after "salvage" androgen suppression therapy;
- Disease progression in the absence of any anti-tumor therapy;
- Death from a complication of therapy.  
11.7.4 Overall Mortality Time to overall mortality will be measured from the date of randomization to the date of death from any cause. A post-mortem examination will be performed whenever possible and a copy of the final post-mortem report will be sent to NRG Oncology.  
11.8 Health-Related Quality of Life (HRQOL) (12/10/13)
Note: The Quality of Life component of this study closed to patient accrual on March 22, 2012. If the patient provided consent to participate in the quality of life component of this study prior to closure to new patient accrual, the site is required to administer the QOL assessments in follow up as specified in Appendix I of the protocol.  
11.8.1 Prostate Cancer-Specific Health-Related Quality of Life: EPIC
The Expanded Prostate Cancer Index Composite (EPIC) is a prostate cancer health-related quality of life (HRQOL) patient self-administered instrument that measures a broad spectrum of urinary, bowel, sexual, and hormonal symptoms related to radiotherapy and hormonal therapy.57 Instrument development was based on advice from an expert panel and prostate cancer patients, which led to expanding the 20-item University of California-Los Angeles Prostate Cancer Index
(UCLA-PCI) to the 50-item EPIC. Summary and subscale scores were derived by content and factor analyses. Test-retest reliability and internal consistency were high for EPIC urinary, bowel, sexual, and hormonal domain summary scores (each r ≥ 0.80 and Cronbach's alpha ≥ 0.82) and for most domain-specific subscales. Correlations between function and bother subscales within domains were high r > 0.60). Correlations between different primary domains were consistently lower, indicating that these domains assess distinct HRQOL components. EPIC domains had weak to modest correlations with the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12), indicating rationale for their concurrent use. Moderate agreement was observed between EPIC domains relevant to the Functional Assessment of Cancer Therapy Prostate module (FACTP) and the American Urological Association Symptom Index (AUA-SI), providing criterion validity without excessive overlap.89 Utilization of Sexual Medications/Devices will be collected to provide a context for interpreting the sexual domain score of the EPIC questionnaire. EPIC is a robust prostate cancer HRQOL instrument that measures a broad spectrum of symptoms; however, to decrease patient burden we will only use the domains most pertinent to this study: urinary, bowel, sexual, and hormonal. The domains were validated separately, and since each domain will be used intact, there is no threat to validity. Dutch and Japanese translations of the EPIC are available, and a Spanish translation is planned but not yet available.  
Sites can contact the Quality of Life/Outcomes Co-Chair, Dr. Bruner, deborah.w.bruner@emory.edu, to obtain translations.  
11.8.2 Mood and Depression: HSCL-25 The 25-item version of the Hopkins Symptom Checklist (HSCL-25)
90 will be used as a baseline and follow-up measure of depressive symptoms.90-92 The patient self-administered measure is closely related to the Brief Symptom Inventory93 and is widely used as a screening instrument in the cancer patient population. Using a cutoff of 44 and above for caseness, Hough and colleagues90 found that the HSCL-25 was comparable or superior to the Center for Epidemiological Studies–Depression Scale in detecting psychiatric disorder. **Note**: If the research nurse (or other person administering the QOL assessments) determines that a patient scores 44 or greater on the HSCL-25, they should bring to the attention of the treating radiation oncologist that the patient is possibly depressed. The treating physicians should evaluate the patient and consider treatment or a referral to a psychiatrist.  
The HSCL-25 has demonstrated reliability (Cronbach's alpha >.90) and validity across a variety of general and medical populations.94 Patients can complete the HSCL-25 in approximately 3-5 minutes. The HSCL-25 has been translated into Bosnian, Cambodian, Japanese, Laotian, and Vietnamese. These translations can be ordered for a cost at http://www.hprtcambridge.org/Layer3.asp?page_id=10.  
11.9 Neurocognitive Test Battery **(12/10/13)**
Note: The neurocognitive test battery component of this study closed to patient accrual on March 22, 2012. If the patient provided consent to participate in the neurocognitive test battery component (a part of Quality of Life component) of this study prior to closure to new patient accrual, the site is required to administer the neurocognitive assessments in follow up as specified in Appendix I of the protocol.  
The tests in the neurocognitive test cognitive battery were selected because they are widely-used standardized psychometric instruments that have been shown to be sensitive to the neurotoxic effects of cancer treatment in other clinical trials.  
95 The tests have published normative data that takes into account age, and where appropriate, education and gender. All of the tests have been translated into multiple languages. Sites can contact the Neuropsychology Co-Chair, Dr. Wefel, jwefel@mdanderson.org, to obtain translations.  
The tests are given by trained site administrators (see Section 11.9.5), and the total time for the cognitive assessment is approximately 20 minutes, as follows:  
| Cognitive Domain                    | Test                             | Administration  Time (minutes)   |          |              |    |
|-------------------------------------|----------------------------------|----------------------------------|----------|--------------|----|
| Memory                              | Hopkins                          | Verbal                           | Learning | Test-Revised | 5  |
| (HVLT-R)                            |                                  |                                  |          |              |    |
| Verbal fluency                      | Controlled Oral Word Association | Test                             | 5        |              |    |
| (COWAT)                             |                                  |                                  |          |              |    |
| Cognitive                           | Trail Making Test, Part A        | 2                                |          |              |    |
| Processing Speed Executive Function | Trail Making Test, Part B        | 5                                |          |              |    |  
11.9.1 *Hopkins Verbal Learning Test-Revised (HVLT-R)*96 The patient is asked to recall a list of 12 words in three semantic categories over three trials. After a delay of at least 15 minutes, the patient is asked to recall the words. The patient is then asked to identify the list words from distractors (both semantically related and unrelated). There are six alternate forms of this test to minimize practice effects. The test measures learning efficiency (total words recalled, Trials 1–3), delayed memory retrieval (delayed recall), and consolidation (storage) of the information (delayed recognition). This measure has been widely used in clinical trials.  
11.9.2 Controlled Oral Word Association Test *(COWAT)*
97 This is a test of phonemic verbal fluency. The patient is asked to produce as many words as possible in 60 seconds beginning with a specified letter. There are two alternate forms of this test.  
11.9.3 *Trail Making Test, Part A*98 This is a measure of visual-motor cognitive processing speed, requiring the patient to connect dots in numerical order from 1 to 25 as fast as possible.  
11.9.4 *Trail Making Test, Part B*98 This is similar to Trail Making Test Part A, with the additional requirement of shifting mental set
(an executive function). The patient connects dots alternating numbers and letters as fast as possible.  
11.9.5 Quality Assurance for Neurocognitive Test Administration **(1/17/12)**
All persons administering the cognitive test battery must be certified. Previous certification for RTOG 0212, RTOG 0214, RTOG 0424, or PCYC-0211A is not sufficient as the administration of the HVLT-R has been changed. However, previous certification for RTOG 0525, 0614, or 0825 within the past 6 months will be accepted. Instructions for accessing the training video and posttest are available from NRG Oncology (see "Neurocognitive Training Procedure Letter" on the NRG Oncology/RTOG website, www.rtog.org). Dr. Wefel, Neuropsychology Co-Chair and Chief ad interim of Neuropsychology at M.D. Anderson Cancer Center, will oversee the training and will be available to answer questions. Certification procedures and test instructions are provided in Appendix V. The instructions must be reviewed and retained for reference. Data forms are available from NRG Oncology. With training, administrators of the neurocognitive test battery should be able to complete testing in approximately 20 minutes. **Note**: Participation in the neurocognitive test battery is optional for the institution as well as the patient. Institutions participating in the neurocognitive test battery must follow the certification process (See Appendix V).
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11.10 beta-amyloid (abeta) and measures

As a correlative study, serum levels of beta-amyloid (Abeta) will be assessed at the same time points as the HSCL-25, the HVLT-R, the COWAT, and the cognitive test battery; associations among Abeta levels and cognitive tests will be evaluated. Beta-amyloid levels will be correlated with testosterone levels to further elucidate the mechanism of any cognitive decline.  
Note: Participation in the neurocognitive test battery is optional for the institution as well as the patient. However, even if participation in the neurocognitive test battery is declined, blood drawing for biosample collection and banking will continue as specified in Section 10.0 of the protocol for patients that agree to participate in banking.  
11.11 **Cost Utility Analysis: EuroQol (EQ-5D)**
The EQ-5D is a two-part patient self-administrated questionnaire that takes approximately 5 minutes to complete.99 The first part consists of 5 items covering 5 dimensions including: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Each dimension can be graded on 3 levels including: 1-no problems, 2-moderate problems, and 3-extreme problems.  
Health states are defined by the combination of the leveled responses to the 5 dimensions, generating 243 (35) health states to which unconsciousness and death are added.100 The second part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable health state is scored as 100 at the top. The Quality of Life/Outcomes Co-Chair, Dr.  
Bruner, will review and specify the VAS score for each case.  
Both the 5-item index score and the VAS score are transformed into a utility score between 0
"Worst health state" and 1 "Best health state." The index score or the VAS score or the cost-utility equation, can be used in the quality adjusted survival analysis depending on the health state(s) of interest.101 For this study we will plan to report both the multidimensional and the VAS utilities for comparative purposes between standardized HRQOL and current health state but will only use the multidimensional utilities for the cost-utility analysis. The EQ-5D has now been translated into most major languages, with the EuroQol Group closely monitoring the translation process; translations can be accessed at http://www.euroquol.com.  
12.0 DATA COLLECTION **(15-Jan-2019)**
Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave via iMedidata, the site user must have an active CTEP-IAM account (check at <
https://ctepcore.nci.nih.gov/iam >) and the appropriate Rave role (Rave CRA, Read-Only, CRA
(Lab Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the enrolling site. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Users that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1888-823-5923 or by e-mail at ctsucontact@westat.com.**Data is to be entered into the legacy**
RTOG Data Center Logon.
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if a data form is

Attention-Data Management 1818 Market Street, Suite 1720 Philadelphia, PA 19103 Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be used (first-last). Last names with apostrophes will be identified by the first letter of the last name.
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12.1 summary of data submission

Item Due Demographic Form **(A5)** Within 2 weeks of study entry Initial Evaluation Form **(I1)** Pathology Report **(P1)** Slides/Blocks **(P2)**
American Urological Association Symptom Index (AUA SI) **(PQ)**
HRQOL:
EPIC **(FA)**; HSCL-25 **(HP)**; EQ-5D **(QF)** Utilization of Sexual Meds/Devices **(SA)**
Neurocognitive Evaluation Summary Form **(CS)**:
HVLT-R; Trail Making Test, Parts A & B; COWAT
Interim Follow-up Form **(F0)** Arms 2 and 3 only: Prior to RT start, 3 months after RT (includes report of androgen suppression treatment)  
Follow-up Form **(F1)** Arm 1: 3, 6, and 12 months after RT; then  
every 6 months x 6 years; then annually  
| every 6 months x 6 years; then annually Arms 2 and 3: 6 and 12 months after RT, then  every 6 months x 6 years; then annually   |
|---------------------------------------------------------------------------------------------------------------------------------|  
Radiotherapy Form **(T1)** Within 1 week from end of RT  
(AUA SI) **(PQ)** Arm 1: During week 6 of RT; 3, 6, and 12 months after RT; then every 6 months x 6 years; then annually Arms 2 and 3: 2 weeks prior to RT start; during week 6 of RT; 3, 6, and 12 months after RT; then every 6 months x 6 years; then annually  
Neurocognitive Evaluation Summary Form  
(CS):  
During week 6 of RT, 1 year and 5 years postRT  
HVLT-R; Trail Making Test, Parts A & B; COWAT  
| Neurocognitive Evaluation Summary Form  (CS): HVLT-R;  Trail Making Test, Parts A & B;  COWAT HRQOL:  EPIC (FA); HSCL-25 (HP);  EQ-5D (QF) Utilization of Sexual Meds/Devices (SA) Autopsy Report (D3)   | As applicable   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|  
During week 6 of RT, 1 year and 5 years postRT
12.2 **Summary of Dosimetry Digital Data Submission for 3D-CRT or IMRT (Submit to TRIAD; see**
Section 5 for account access and installation instructions) **[12/31/14]**  
| Item Preliminary Dosimetry Information (DD) Digital Data Submission - Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Due Within 1 week of  start of RT   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|
| Digital data submission includes the following, all in DICOM format: - CT data, all critical normal structures, CTV and PTV contours - Digital beam geometry for initial and boost beam sets - Doses for initial, boost and composite concurrently treated beams - Digital DVH data for all required critical normal structures, CTV, and PTVs  for total dose plan - All required structures MUST be labeled per the table in Section 6.4 Upon submission of the digital data via TRIAD, complete an online Digital  Data Submission Information Form (DDSI) (Form located on RTOG/NRG  Oncology web site at http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study= 0534) Final Dosimetry Information Radiotherapy Form (T1) Daily Treatment Chart (T5) [copy of RT treatment chart to HQ] | Within 1 week of  RT end            |
| Note: All simulation and portal images will be kept by the institution and submitted  to NRG Oncology ONLY if specifically requested.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                     |
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13.0 statistical considerations 13.1 study

Freedom from progression (FFP): FFP (Section 11.4), will be the first occurrence of biochemical failure by the Phoenix definition (PSA ≥ 2 ng/ml over the nadir PSA),43 clinical failure (local, regional or distant), or death from any cause.  
13.1.2 Secondary Endpoints
- Secondary biochemical failure: See Section 11.7.1; - Hormone-refractory disease: See Section 11.7.2;
- Local Failure: See Section 11.5.1;
- Distant metastasis: See Section 11.6.2; - Cause-specific mortality: See Section 11.7.3; - Overall mortality: See Section 11.7.4; - Incidence of "acute" adverse events (based on CTCAE, v. 3.0.): The acute adverse events will be the first occurrence of worst severity of the adverse event ≤ 90 days of the completion of RT.  
- Time to "late" grade 2+ and 3+ adverse events (based on CTCAE, v. 3.0.): The time of a first late grade 2+ or 3+ adverse event, defined as > 90 days from the completion of RT.  
- Comparison of disease-specific health related quality of life (HRQOL) change by EPIC, HVLTR, Trail Making Test, parts A & B, and COWAT;
- Assessment of mood and depression change using QOL measured by the HSCL-25;
- Assessment and comparison of Quality Adjusted Life Year (QALY) and Quality Adjusted FFP
Year (QAFFPY);
- Evaluation and comparison of the cost-utility using EQ-5D;
- Association between serum levels of beta-amyloid (Abeta) and measures of HSCL-25, the HVLT-R, Trail Making Test, parts A & B, or the COWAT.  
- Prognostic value of genomic and proteomic markers for the primary and secondary clinical endpoints.  
- To collect paraffin-embedded tissue blocks, serum, plasma, urine, and whole blood for future translational research analyses.  
- To assess the relationship(s) between the American Urological Association Symptom Index
(AUA SI) and urinary morbidity (Adverse Event terms: Urinary frequency/urgency) using the CTCAE v. 3.0 grading system.  
13.2 Sample Size
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13.2.1 stratification and randomization (1/8/09)

Patients will be stratified before randomization according to seminal vesicle involvement (No vs.  
Yes); prostatectomy Gleason score (≤ 7 vs. 8-9); pre-radiotherapy PSA (≥ 0.1 and ≤ 1.0 ng/ml vs.  
>1.0 and <2.0 ng/ml), and pathology stage (pT2 and margin negative vs. all others). The treatment allocation scheme described by Zelen102 will be used because it balances patient factors other than institution. Patients will be randomized to PBRT alone (Arm 1), PBRT+NCSTAD (Arm 2), or PLNRT+PBRT+NC-STAD (Arm 3). The patients are randomized to one of three arms until a treatment effect is detected or the total information time is reached. If a decision is made regarding treatment effect during the accrual, patients will be randomized as specified in Section 13.5.7.  
13.2.2 Sample Size Derivation The sample size calculation is based on the primary endpoint FFP rate by 5 years and the assumption that patients are randomized to all three arms until the end of accrual. Based on the prior results from a multi-institutional pooled analysis35-36 we project that the rate of 5-year FFP of Arm 1, p1 is 70% and hypothesize a 10% improvement in patients treated in Arm 2, i.e., p2=80%,
and a 20% improvement in patients treated in Arm 3, i.e., p3=90%. The sample size calculation is based on the backward elimination decision rule in Chen and Simon103 because this approach has the least favorable configuration property. We assume that the three treatment arms are ranked with Arm 1 as the least favorable arm, Arm 2 as the second one, and Arm 3 as the most favorable arm (p1 > p2 > p3). We define the probability of selecting Arm i under hypothesis i (i=1, 2, 3) as P (D=i | Hi) = 1- αi. The three hypotheses are as follows:
H1: p1 = p2 = p3 where, P (D=1 | H1) = 1- α1 H2: p1 + δσ = p2 = p3 where, P (D=2 | H2) = 1- α2 H3: p1 + δσ = p2 + δσ = p3 where, P (D=3 | H3) = 1- α3 Assume that the rates for all three arms are independently approximately normally distributed and have the same variance σ2/n= 0.25/n. We wish to detect a difference of 10% (δ*σ = δ*0.5 = 0.1).  
Assume that α1 =0.025, α2 =α3=0.15, and ζ=3.25 (from Table 4 in Chen and Simon103), the sample size for each treatment arm, n=2*ζ 2/ δ2 = 2*3.252/ 0.22 = 529 patients are needed to have a statistical power of 90.1%. Three interim analyses and a final analysis are planned for early stopping for efficacy and futility.  
For efficacy, testing will be done at the significance level of 0.001, which is similar to the HaybittlePeto test104,105 and the futility testing is based on the Freidlin and Korn106 method. Guarding against an ineligibility or lack-of-data rate of up to 10%, the final targeted accrual for this study will be 1764 (588 per arm) patients.  
13.3 Patient Accrual **(11/23/11)**
The proposed trial, RTOG 0534, builds on the experience obtained in RTOG 96-01. RTOG 96-01 involved a similar group of patients treated postoperatively with salvage radiotherapy and accrued 840 patients over 5 years at an average rate of 14 cases per month. As described above, we anticipate at the minimum a similar accrual rate; however, what is notable about the accrual in RTOG 96-01 is that at the end of the trial over 30 patients were being entered per month. There was an extended ramp-up period in RTOG 96-01; it took 2.5 years for accrual in RTOG 96-01 to reach 20 patients per month, and the trial reached targeted accrual and closed in less than five years. We anticipate that accrual to RTOG 0534 will be faster during the ramp-up period because the group has experience in accruing postoperative patients to randomized trials. Moreover, in RTOG 0534, androgen deprivation therapy is only used for 4 months, whereas in RTOG 96-01, it was used for 2 years. Many men are reluctant to take prolonged androgen deprivation, and for this reason accrual to the new study might be more robust. We are conservatively estimating an average of 16 cases per month in the new trial. We expect to complete accrual in 9.2 years.  
Based on patient accrual in previous RTOG randomized prostate studies, there will be relatively few entries during the initial 6 months while institutions are obtaining IRB approval. The total duration of the study is expected to be 15 (14.7) years from the time the first patient is entered to the final analysis with 5 years of follow-up for each patient, and a uniform accrual rate of 16 patients per month.  
The NRG Oncology Data Monitoring Committee (DMC) will begin evaluating patient accrual semiannually following the anticipated quiet period. In accordance with CTEP policies for slowly accruing trials, if the average monthly accrual rate for the trial in the fifth and sixth quarters after study activation (i.e., in months 13-18) is less than 20% of the rate projected in the paragraph above (i.e., less than 4 patients per month), the study will close to further accrual. If the average monthly accrual rate is greater than 20% but less than 50% of projected (i.e., less than 8 patients per month), the trial will be placed on probation for six months. If the average monthly accrual rate at the end of the probationary period is less than 50% of projected, the study will close to future accrual. The participation of non-NRG Oncology institutions through CTSU is expected to follow a similar pattern as seen in NRG Oncology.
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13.4 power calculations for selected

13.4.1 Secondary Biochemical Failure The prior results from a multi-institutional pooled analysis35-36 show that Arm 1 has a 59% rate of 5-year freedom from biochemical failure, and we project Arm 2 will have a 5-year freedom from biochemical failure rate of 69%, and Arm 3 will have a 7-year freedom from biochemical failure rate of 79%. With 529 analyzable patients per arm, we would have at least 87% statistical power of detecting at least a 10% absolute improvement in the biochemical failure rate in Arm 2 by 5 years compared to Arm 1 using a Z-test for the difference between the two rates with the standard errors estimated by Greenwood's method at the 0.0125 significance level. Also, with 529 analyzable patients per arm, we would have at least 93% statistical power of detecting at least a 10% absolute reduction in the biochemical failure rate in Arm 3 at 5 years compared to Arm 2 using a Z-test for the difference between the two rates with the standard errors estimated by Greenwood's method at the 0.0125 significance level.  
13.4.2 Overall Mortality **(1/8/09)**
The prior results from a multi-institutional pooled analysis36 show that Arm 1 has an 85% rate of 10 year overall survival, which translates to a yearly hazard rate of 0.0163. Based on this result,  
we project Arm 2 will have a 10-year overall survival rate of 90%, which translates to a yearly hazard rate of 0.0105, and Arm 3 will have a 10-year overall survival rate of 95%, which translates to a yearly hazard rate of 0.0051. With 529 analyzable patients per arm, we would have at least 47% statistical power of detecting at least a 6% (or a hazard rate of 0.648) relative reduction in the yearly overall survival rate using a one-sided log-rank test at the 0.0125 significance level for patients in Arm 2. Also, with 496 analyzable patients per arm, we would have at least 46%
statistical power of detecting at least a 6% (or a hazard rate of 0.487) relative reduction in the yearly overall survival rate using a one-sided log-rank test at the 0.0125 significance level for patients in Arm 3 compared to Arm 2.  
13.4.3 Genomic and Proteomic Biomarkers **(1/8/09)**
Genomic or proteomic biomarkers will be categorized into either overexpressed or underexpressed. At a minimum, the analyses will include DNA-ploidy, Ki-67, p53, MDM2, bcl-2, bax, p16 and Cox-2. These biomarkers have shown promise in complementing the standard clinical parameters of PSA, Gleason score, and stage in prior analyses of men treated primarily for prostate cancer with RT. While these markers have been selected based on prior analyses, it is likely that some other markers and/or methods will be investigated when the proposed trial matures. Group 1 denotes a group with a better survival rate and Group 0 denotes the adverse group with the overexpressed or underexpressed marker. Tests will be performed to determine whether there is a difference in the survival functions for the primary endpoint, secondary biochemical failure, hormone refractory disease, distant metastasis, cause-specific survival, and overall survival. The number of events needed to obtain 1-β statistical power under these assumptions is calculated based on Schoenfeld.  
107 In treatment efficacy trials, the targeted hazard ratios are usually not that large and the Schoenfeld formula works well.
Nd = (z + z)
2/[(log())2P0P1]
Where Pi = the proportion of patients allocated to group I. i=0,1 Λ = λ0/ λ1 (>1)
nd = The number of events (failure)
Zu=the uth percentile of the standard normal distribution Tables 2 through 9 show the number of events for each biomarker required to demonstrate the hazard ratio Λ at a significance level α = 0.025 with statistical power of 80% and 90%. P0 or P1 values for each biomarker are based on the previous studies.
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table 2 number of events

| HAZARD RATIO ( Λ)   |     |      |    |
|---------------------|-----|------|----|
| STATISTICAL POWER   | 1.5 | 1.75 | 2  |
| 90%                 | 258 | 136  | 89 |
| 80%                 | 193 | 101  | 66 |  
HAZARD RATIO ( Λ)
Table 3: Number of events for p53: P0 or P1**=22%**
HAZARD RATIO ( Λ)  
| STATISTICAL POWER   | 1.5   | 1.75   | 2   |
|---------------------|-------|--------|-----|
| 90%                 | 373   | 196    | 128 |
| 80%                 | 279   | 147    | 96  |  
Table 4: Number of events for MDM2: P0 or P1**=50%**
HAZARD RATIO ( Λ)  
| HAZARD RATIO ( Λ)   |     |      |    |
|---------------------|-----|------|----|
| STATISTICAL POWER   | 1.5 | 1.75 | 2  |
| (ZΒ) 90%            | 256 | 135  | 88 |
| 80%                 | 191 | 101  | 66 |  
Table 5: Number of events for Bcl-2: P0 or P1**=20%**
HAZARD RATIO ( Λ)  
90% 400 210 137  
| STATISTICAL POWER (ZΒ)   |
|--------------------------|  
| 1.5                                             | 1.75   | 2   |
|-------------------------------------------------|--------|-----|
| Table 6: Number of events for Bax: P0 or P1=47% |        |     |  
80% 299 157 103  
Table 6: Number of events for Bax: P0 or P1**=47%**
HAZARD RATIO ( Λ)  
90% 257 135 88 80% 192 101 66  
| STATISTICAL POWER (ZΒ)   |
|--------------------------|  
| 1.5   | 1.75   | 2   |
|-------|--------|-----|  
Table 7: Number of events for Cox-2: P0 or P1**=50%**
HAZARD RATIO ( Λ)  
| STATISTICAL POWER   | 1.5   | 1.75   | 2   |
|---------------------|-------|--------|-----|
| (ZΒ) 90%            | 256   | 135    | 88  |
| 80%                 | 191   | 101    | 66  |  
Table 8: Number of events for DNA-ploidy: P0 or P1**=40%**
HAZARD RATIO ( Λ)  
90% 267 140 92  
| STATISTICAL POWER (ZΒ)   |
|--------------------------|  
| 1.5   | 1.75   | 2   |
|-------|--------|-----|  
80% 199 105 69  
Table 9: Number of events for p16: P0 or P1= 27%
HAZARD RATIO ( Λ)
STATISTICAL POWER  
90% 325 171 111  
80% 243 128 83  
| (ZΒ)   |
|--------|  
| 1.5   | 1.75   | 2   |
|-------|--------|-----|  
13.5 Analysis Plan (22Jun2017)
All eligible patients who are randomized to the study will be included in the comparison of treatment arms (intent-to-treat analysis).  
13.5.1 Analysis of the Primary Endpoint **(1/8/09)**
FFP failure will be the first occurrence of local failure, regional failure, distant metastasis, biochemical failure defined by the Phoenix definition (PSA ≥ 2 ng/ml + nadir PSA), or death from any cause. Patients who are event free with less than 5 years of follow-up or who receive any secondary salvage therapy (e.g., salvage androgen deprivation, vaccine therapy, biologic/small molecule therapy, or chemotherapy) will be censored. The primary endpoint FFP rate by 5 years is defined as the proportion of patients with a FFP failure by 5 years from the randomization among all eligible patients at baseline and will be estimated by the Kaplan-Meier method. The Ztest statistic for the difference between the two rates with the standard errors estimated by Greenwood's method will be used with an overall significance level of 0.025. The following test statistics will be used for testing between Arm i and Arm j.  
  
$$\begin{array}{r l}{\mathrm{i,j}}&{{}=1,2,3}\end{array}$$  
where, i,j =1,2,3 eq (1)
where, i p is FFP rate of Arm i estimated by Kaplan-Meier method, ri is the number of patients who are at risk and fi is the number of patients who have FFP events. Using the backward elimination decision procedure, we will first compare Arm 3 with Arm 2 at a critical value (Z-score)
of 1.6249. The following hypotheses are of interest to be tested, where, p1, p2, and p3 are the rate of 5-year FFP of Arm 1, Arm 2 and Arm 3, respectively.  
H01: p3 ≤ p2 vs. HA1: p3 > p2 If Arm 3 is not better than Arm 2 (p3 ≤ p2), then we compare Arm 2 with Arm 1. If Arm 3 is better than Arm 2 (p3 > p2), then we compare Arm 3 with Arm 1. If H01 is rejected (T23 > 1.6249), then we conclude that Arm 3 is better than Arm 2 and the following hypotheses are tested.  
H02: p3 ≤ p1 vs. HA2: p3 > p1 If the H02 is rejected (T13 > 2.0768), then we conclude that the 5-year FFP of Arm 3 will be better than Arm 1. If the H02 is not rejected (T13 ≤ 2.0768), then we conclude that the 5-year FFP of Arm 3 will not be better than Arm 1. If H01 is not rejected (T23 ≤ 1.6249), then we conclude that Arm 3 is not better than Arm 2 and the following hypotheses are tested.  
H02: p2≤ p1 vs. HA2: p2 > p1 If the H02 is rejected (T12 > 2.0768), then we conclude that the 5-year FFP of Arm 2 will be better than Arm 1. If the H02 is not rejected (T12 ≤ 2.0768), then we conclude that the 5-year FFP of Arm 2 will not be better than Arm 2.  
In addition, univariate and multivariate logistic regression108 will be used to compare the treatment differences in each hypothesis. Odds ratios from univariate and multivariate logistic regression and the respective 97.5% confidence intervals will be computed. Treatment arm, SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage, age, and race (as appropriate) will be adjusted for in the Multivariate analysis.  
13.5.2 Biochemical Failure-Related Endpoints **(1/8/09)**
The secondary biochemical failure (BF) endpoint is defined as having a detectable PSA (PSA
≥ 0.1 ng/ml) and rising for at least two values with the second value at 0.4 ng/ml or greater, or the initiation of salvage therapy. Hormone refractory disease is defined as three rises in PSA after the institution of second salvage hormone therapy. The rate pi (i=1, 2, 3) is defined as the proportion of patients with an event among all eligible patients at baseline in Arm i. The Z-test statistics for the difference between the two rates with the standard errors estimated by Greenwood's method, eq. (1), will be used with an overall significance level of 0.025. In the test statistics, i p is the rate of Arm i estimated by Kaplan-Meier method, ri is the number of patients who are at risk and fi is the number of patients who have events by 5 years. Using the backward elimination decision procedure, we first compare Arm 3 with Arm 2. The following hypotheses are of interest to be tested, where, p1, p2, and p3 are the rate of 5-year of Arm 1, Arm 2 and Arm 3, respectively.  
H01: p3 ≤ p2 vs. HA1: p3 > p2 If Arm 3 is not better than Arm 2 (p3 ≤ p2), then we compare Arm 2 with Arm 1. If Arm 3 is better than Arm 2 (p3 > p2), then compare Arm 3 with Arm 1.  
If H01 is rejected (T23 > 1.6249), then we conclude that Arm 3 is better than Arm 2 and the following hypotheses are tested. H02: p3 ≤ p1 vs. HA2: p3 > p1 If the H02 is rejected (T13 > 2.0768), then we conclude that the 5-year rate of Arm 3 will be better than Arm 1. If the H02 is not rejected (T13 ≤ 2.0768), then we conclude that the 5-year rate of Arm 3 will not be better than Arm 1.  
If H01 is not rejected (T23 ≤ 1.6249), then we conclude that Arm 3 is not better than Arm 2 and the following hypotheses are tested.  
H02: p2≤ p1 vs. HA2: p2 > p1 If the H02 is rejected (T12 > 2.0768), then we conclude that the 5-year rate of Arm 2 will be better than Arm 1. If the H02 is not rejected (T12 ≤ 2.0768), then we conclude that the 5-year rate of Arm 2 will not be better than Arm 2.  
In addition, the univariate and multivariate logistic regression will be used to compare the treatment differences in each hypothesis. Odds ratios from the univariate and multivariate logistic regression and the respective 97.5% confidence interval will be computed. The treatment arm, SV
involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology staging, age, and race (as appropriate) will be adjusted for in the multivariate analysis.  
13.5.3 Time to Failure of Secondary Survival Endpoints **(1/8/09)**
The time to failure for secondary endpoints (second biochemical failure, hormone refractory disease, distant metastasis, cause-specific mortality, and overall mortality) will be measured from the date of randomization to the date of the event of interest. The events for secondary endpoints and time-to-events are defined in Sections 11.4-11.7. Using the backward elimination decision procedure, we will first compare Arm 3 with Arm 2 at the significance level of 0.0125. If Arm 3 is not better than Arm 2, then Arm 2 will be compared with Arm 1 at the significance level of 0.0125. If we conclude that Arm 2 will be better than Arm 1, then we can conclude that the 5-year FFP of Arm 2 will be the best. If Arm 3 is better than Arm 2, then Arm 3 will be compared with Arm 1 at the significance level of 0.0125. If we conclude that Arm 3 will be better than Arm 1, then we can conclude that Arm 3 will be the best. The time-to-event distribution of overall mortality will be estimated using the Kaplan-Meier method109 and the log-rank test110-111 will be used to test whether the overall mortality rate in one arm is higher than the other arm for each hypothesis at the significance level of 0.0125. However, the treatment effect on other types of failure may impact the observable measures of distant metastasis and cause-specific mortality and other competing risks may dilute the sensitivity of hormone refractory disease, distant metastasis and cause-specific mortality.  
106 We will use the cause-specific hazard rate112-113(the instantaneous rate of cause-specific mortality in the presence of competing failure types as a function of time)
approach to consider the competing events. Freidlin and Korn106 showed that the cause-specific hazard rate approach is better than other approaches, for example, the cumulative incidence method, 114in most cases. The log-rank test on the times to the specific type of failure, which considers the presence of competing events, will be used to test whether the survival rates of these secondary endpoints in one arm are higher than that of the other arm for each hypothesis at a significance level of 0.0125. In this approach, patients who experience other failure first are censored.112 In addition, the Cox regression model115 will be used to compare the treatment differences. Both unadjusted and adjusted hazard ratios and the respective 97.5% confidence interval will be computed. At least the treatment arm, the stratification variables (SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage), age, and race (as appropriate) will be adjusted for in this analysis.  
13.5.4 Comparison of the Incidence of Acute Toxicity and Time to Late Grade 3+ Toxicity **(1/8/09)**
Adverse events are scored according to CTCAE, v. 3.0. An acute adverse event will be defined as the worst severity of the adverse event occurring less than or equal to 90 days of treatment.  
Both acute grade 2+ and 3+ toxicity will be examined separately. Univariate logistic regression107 will be used to model the distribution of acute adverse events. Multivariate logistic regression107 will be used to model the distribution of acute adverse events, adjusting for covariates. Treatment arm, SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage, and age (as appropriate) will be adjusted for in the multivariate analysis. Both unadjusted and adjusted odds ratios (H1: Arm 1 vs. Arm 2 and H2: Arm 2 vs. Arm 3, respectively) and the respective 97.5% confidence interval will be computed and tested using a one-sided chi-square test with the significance level of 0.025 for each hypothesis.  
Late grade 2+ or 3+ adverse events will be defined as an a grade 2+ or 3+ adverse events occurring more than 90 days of the completion of treatment. The time to late grade 2+ or 3+ adverse events will be measured from the time protocol treatment started to the time of the worst late grade 2+ or 3+ adverse event, respectively. If no such late adverse event is observed until the time of the analysis, the patient will be censored at the time of the analysis. The distribution of time to late grade 2+ or 3+ adverse events will be estimated using the Kaplan-Meier method109 and tested using a one-sided log-rank test110-111 with the significance level of 0.025 for each hypothesis. A multivariate Cox regression model115 will be used to compare the treatment differences of time to late adverse event. Both unadjusted and adjusted hazard ratios (H1: Arm 1 vs. Arm 2 and H2: Arm 2 vs. Arm 3, respectively) and the respective 97.5% confidence interval will be computed. Treatment arm, SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage, age, and race (as appropriate) will be adjusted for in this analysis.  
A Chi-square test will be used at a significance level of 0.05 to test the correlation between the common toxicity categories in the American Urological Association Symptom Index (AUA SI) and urinary morbidity (Adverse Event terms: Urinary frequency/urgency) using the CTCAE v. 3.0.  
13.5.5 Modeling the Relationship of Genomic and Proteomic Biomarkers to the Study Endpoints **(1/8/09)**
At the time of data maturity of this study, we will propose specific details of the markers to be investigated. We will address the assays that will be used and a list of specific correlative aims with appropriate statistical considerations. The following is a general guideline for the statistical consideration for this analysis. This analysis will be done in each arm separately to test the prognostic vales of biomarkers.  
A genomic or proteomic biomarker will be categorized into two subgroups based upon previously defined (or hypothesized) cut-off points and these two groups will be referred to as favorable and unfavorable risk groups. The patients with genomic and proteomic biomarkers will be compared with the patients without a value for that biomarker to determine if there are any differences with respect to distribution of baseline variables (SV involvement, prostatectomy Gleason score, preradiotherapy PSA, and pathology stage). We want to know if there is a difference in survival rate between these two groups. The null (H0) and alternative (HA) hypotheses for survival distribution
(S) are
arm 1 pbrt alone pbrt
h0 s0 (t) >= s1(t)

Tests will be performed to see if one group is statistically significantly better than the other in the primary endpoint and secondary endpoints that are related to time to failure (hormone refractory disease, distant metastasis, cause-specific survival, and overall survival). However, the selection of the cut-off point for each biomarker is not established. If the hypothesized cut-off points do not yield statistical significance, other cut-off points may be evaluated. Therefore, various cut-off points are evaluated for their statistical significance. To correct the problem from the multiple testing, the Bonferroni correction will be used. The overall survival functions will be estimated by the Kaplan-Meier method and will be tested for the overall survival difference between the favorable and unfavorable groups using the log-rank test. We will use the cause-specific hazard rate approach106 to estimate other survival/failure distributions and test the survival/failure difference between the two groups using the cause-specific log-rank test. The multivariate analysis will be performed using the Cox proportional hazards model115for both groups. Potential covariates evaluated for the multivariate models are SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage, and assigned treatment. A stepwise procedure will be used to develop the base model for each outcome endpoint prior to evaluating the prognostic impact of the biomarkers. This approach will be employed to account for as much variation as possible for each outcome before it is tested. It is entirely possible that factors shown to be prognostic in other published series may not be found prognostic here.  
If high-dimensional data, such as two-color Microarray data, are generated from blood/urinebased proteomic and genomic data, the following guideline could be applied for the data preprocessing. A careful examination of array images of each gene's spots on the array images will be carried out to find the spots affected by experiment artifacts. This is a general guideline for the statistical consideration for the two-color Microarray data analysis.  
We will not include genes whose intensity is less than 100116-117 n both green and red intensities.  
Local background hybridization signals will be subtracted from the intensities. Let Rj be the background-adjusted fluorescence intensity for the cancer or benign sample and Gj be the background-adjusted fluorescence intensity for the reference sample for gene j on a particular array. The gene expression ratio is computed as Rj /Gj and undergoes normalization and transformation to the log-2 scale. Normalization will be applied to remove systematic differences due to extraneous factors such as array effects, global dye effects, print tip effects, etc. Simple normalization methods such as global median centering116 will be considered as well as more complex methods such as print tip-specific corrections and intensity-based normalization methods such as lowess smoothing118if diagnostic plots (e.g., M vs A plots119) suggest they are needed.  
These log-transformed, normalized gene expression ratios are used as the basic data in subsequent analyses. If one of the two intensities in a spot is less than 100, that intensity will be set to 100. Genes with greater than 20% of spots missing intensities will be removed from the analysis. For remaining genes, individual missing log ratio values will be imputed using the knearest neighbors approach, with k = 10.  
120 The high-dimensional data from patients who yield both pre- and post-treatment tissue specimens will be used to see the gene expression difference. Let m be the number of genes that will be tested. Let diij be the gene expression difference between pre- and post- treatment for patient i and gene j on a treatment arm. Denote the mean difference between pre- and post- treatment gene expression for gene j as Dj
. A test will be conducted to test the following null (H0
) and alternative (HA
) hypotheses for each gene:
H0
: Dj = 0 vs. HA
: Dj
≠ 0 We will control the false discovery proportion when a test for a gene is called significant. A paired t-test will be used to calculate the unadjusted univariate p-value for each gene. We will identify all genes with adjusted p-values121 ≤ 0.05 as being differentially expressed between pre- and posttreatment to be 95% confident that the false discovery proportion is no more than 10%.
arm 1 pbrt alone pbrt
13.5.6 analysis for endpoints related

We will use seven instruments to assess quality of life (QOL): the Expanded Prostate Cancer Index (EPIC), EPIC Sexual Medications/Devices Supplement (Utilization of Sexual Meds/Devices), the 25-item version of the Hopkins Symptom Checklist (HSCL-25), the EuroQol (EQ-5D), Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test, parts A & B, and the Controlled Oral Word Association Test (COWAT). Protocol eligible patients will be included in the QOL analysis only if they agree to participate in the QOL portion of this study. All the QOL
instruments (EPIC, Utilization of Sexual Meds/Devices, HSCL-25, EQ-5D, HVLT-R, Trail Making Test, parts A & B, and COWAT) will be collected on all cases participating in the trial. To minimize missing QOL data, we have included detailed instructions for collection of QOL and what to do if the patient misses a scheduled assessment, and RTOG provides individualized patient calendars available to Investigators and Research Associates 24/7 on the NRG Oncology/RTOG
web site.  
We will describe the distributions of QOL data collection patterns over all collection points in each treatment arm. Longitudinal data analysis, specifically the general linear mixed-effect model122 will be performed to describe the change trend of the EPIC, Utilization of Sexual Meds/Devices, HVLT-R, Trail Making Test parts A & B, COWAT, HSCL-25, and EQ-5D scores over time across the three treatments. The primary objective in HRQOL analysis is to determine the QOL
differences. The response will be the change of measurement from baseline for each measurement. The model will include the baseline and stratification variables (SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage).  
The EPIC and HSCL-25 will be collected at pretreatment (baseline), the end of RT, and at 1 year and 5 years after therapy starts. Patient self-assessment of symptoms will be performed using four primary EPIC domains: urinary, bowel, sexual, and hormonal symptoms. The data about the use of erectile aids from Utilization of Sexual Meds/Devices will be reported along with question 17-b in the EPIC. The HSCL-25 has 25 items and is scored by a four point Likert scale (1-not at all, 2-a little, 3-quite a bit, and 4-extremely). A higher score means a worse mood or depression.  
The HVLT-R, Trail Making Test, parts A & B, and COWAT will be collected at pretreatment
(baseline), the end of RT, and at 1 year after the therapy starts. There are three immediate recall responses, one delayed recall response, and one delayed recognition response in the HVLT-R.  
The response is the number of words the patient can recall out of 12 words for recall responses and the difference of the listed words correctly and incorrectly recalled for recognition response.  
The response from Trail Making Test, parts A & B is the time takes to finish each test less than 3 and 5 minutes, respectively. There are three responses for the COWAT, and each response is the number of words starting with a provided letter of the alphabet that the patient can produce in one minute. The EQ-5D will be collected at pretreatment (baseline), at 1 year and 5 years after therapy starts. The EQ-5D is a two-part self-assessment questionnaire. The first part consists of 5 items covering 5 dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a three point Likert scale (1-no problems, 2moderate problems, and 3-extreme problems). There are 243 (=35) health states. The second part is a visual analog scale (VAS) valuing the current health state measured by 100 point scale with 10 point interval (0-worst imaginable health state, 100-best imaginable health state). The QOL Co-Chair, Dr. Bruner, will review and specify the VAS score for each case. We will transform the 5-item index score and VAS score into a utility score between 0 (Worst health state) and 1
(Best health state) for comparative purposes.  
We hypothesize that the measurements from EPIC, HVLT-R, Trail Making Test, parts A & B, and COWAT will be worse in the arms with NC-STAD than in the PBRT arm. We also hypothesize that measurements from HSCL-25 will be lower in the arms with NC-STAD than in the PBRT arm.  
For all QOL analyses, we will conduct two comparisons between the two treatment arms (Arm 1 vs. Arm 2 and Arm 1 vs. Arm 3) with a two-sided test. The significance level α for the pair-wise comparison will be adjusted by the Bonferroni method123to α =0.05/2 to maintain the overall significance level of α =0.05. To address the non-ignorable missing data caused by censoring survival time, the data analysis also will include patients who have not died. The required sample size per treatment arm when we use 1 domain is 64 with 80% statistical power and 86 with 90% statistical power, respectively, based on an effect size of 0.5 according to the EPIC web site.  
124 The required sample size per treatment arm when we use 4 domains is 91 with 80% statistical power and 116 with 90% statistical power, respectively, based on an effect size of 0.5. Therefore, there will be sufficient statistical power to detect a difference of 0.5 in four domain scores of HRQOL measurements in the EPIC instrument among the treatment arms.  
Because the participation rate in QOL assessments will be less than 100%, the expected sample size for the QOL analysis must be adjusted according to the participation rate. Table 11 shows adjusted sample sizes for a range of participation rates. Considering the possible low response rate, 200 cases per arm are required. Accrual for the QOL studies will be limited to 200 cases per randomization arm.  
| Table 11: Adjusted sample size* per treatment with four domains in EPIC RESPONSE RATE 80% POWER 90% POWER 100% 91 116 90% 102 129 80% 114 145 70% 130 166 60% 152 194 *The sample size is calculated by dividing the sample size at 100% by participation rate   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
To examine trade-offs between the survival time and QOL, we will combine them for each patient into two single measurements: Quality Adjusted Life Year (QALY) and Quality Adjusted FFP Year (QAFFPY). If (and only if) the primary endpoint hypothesis is substantiated, we will conduct a cost-utility analysis. The cost-utility analysis will not be done until after the primary endpoint results are published. QALY and QAFFPY are defined by the weighted sum of different time episodes added up to a total quality-adjusted survival time and a total quality-adjusted FFP time, respectively. These health state-based methods of quality-adjusted survival analysis are known as Q-TwiST,79 the quality-adjusted time without symptoms and toxicity method.
arm 1 pbrt alone pbrt
q-twist = i=1k qi si

where qi is the quality (the utility coefficient) of health state i, si is the duration spent in each health state, and k is the number of health states. We will use Glasziou's multiple health-state (Q-TwiST)
models125to use the repeated measures of EQ-5D. Because Glasziou's method incorporates longitudinal QOL data into an analysis of quality-adjusted survival, the health-stated model must be constructed on the following assumptions:
A1) QOL is independent from treatment.  
A2) A health state is independent from previous states. A3) Proportionality of quality-adjusted duration and duration of the actual state of a health state.  
Assumption A1 can be checked by plotting QOL over time according to treatment, and the t-test can be used to compare the mean QOL scores of each treatment arm. Assumption A2 can be checked by comparing the QOL for patient groups in a given health state where the groups are defined by duration of previous health state experience using a regression model. Suitable checks for assumption A3 at minimum would be a simple plot. If data does not support these assumptions, we will use a method which uses the longitudinal QOL data directly.  
The Medicare reimbursement in dollars/QALY and the Medicare reimbursement in dollars/QAFFPY will be calculated as a function of the monetary cost per relative value of each health state and its duration. Cost-utility will be analyzed at two time points: at 1 year and 5 years post-therapy. We will use the five-item utility score in EQ-5D for the cost-utility analysis. We will use the z-test to test the hypothesis that the cost-utility in the two treatment arms (Arm 1 vs. Arm 2 and Arm 1 vs. Arm 3) is the same with significance level of 0.05/2=0.025 and a two-sided test.  
We will compare the cost-utility using the Medicare reimbursement in dollars/QALY and the Medicare reimbursement in dollars/QAFFPY between the two treatment arms after adjusting for the baseline and stratification variables.  
We will evaluate the cost-utility of the treatment arm in terms of the primary outcome and will also compare the cost-utility among the three treatment arms. The cost-utility analysis will only include patients whose care are reimbursed under the federal Medicare payment system but will exclude those in Medicare HMOs as well as those under alternative federal coverage (including Medicaid, DOD, and the VA) as well as those covered by private payers or other payment systems. Costutility will be analyzed for planned publication at two time-points: looking at initial treatment costs and quality of life at 1 year post-therapy and at 5 years post-therapy. The cost-utility analysis will not be done until after the primary endpoint results are published. We will use the 5-item utility score in EQ-5D for the cost-utility analysis and the Medicare costs defined as in Section 1.6.3.  
The Medicare cost in dollars/QALY will be calculated as a function of the monetary cost per relative value of each health state and its duration. We will use Analysis of Variance (ANOVA) to compare the cost-utility among the three treatment arms at a significance level of 0.05. If there is a statistically significant difference, a Z-test will be used to compare it between each combination of two treatment arms (Arm 1 vs. Arm 2 and Arm 1 vs. Arm 3, and Arm 2 and Arm 3) after adjusting for the baseline and stratification factors with a significance level of 0.05/3=0.017 and a two-sided test. A multivariate regression model will be used to model the association between serum levels of beta-amyloid (Abeta) and measures of the HVLT-R, Trail Making Test, parts A & B, COWAT, and HSCL-25, respectively. The model will include at least the baseline and stratification factors (SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage) as covariates. To inspect the missing data mechanism, we will use at least a graphical method. A missing completely at random (MCAR) mechanism exists when missing values are randomly distributed across all observations. A missing at random (MAR) mechanism exists when values are not randomly distributed across all observations, rather than one or more sub-samples. If the cause of missing data is MCAR, listwise deletion (complete case analysis) will be done. If the MAR
assumption is supported by the data, then an imputation method such as multiple imputation will be applied to impute missing data. If the MAR assumption is not supported by the data, then adjusting for covariates (such as the baseline QOL score) might reduce the conditional association between outcomes and missing values. If missing data patterns look similar when stratified by such covariate(s), then an analysis that adjusts for such covariate(s) will be conducted and an imputation method such as multiple imputation will be applied. If approximate conditional independence cannot be obtained with any set of covariates, then MNAR (missing not at random) must be addressed by an explicit model for the missing data mechanism126 and then an imputation method such as multiple imputation will be applied. All results from the imputed analysis using the multiple imputation will be compared to the complete case analysis results to assess any potential biases. We will conduct a sensitivity analysis using various assumptions on the missing data to determine what impact missing data and imputation methods have on the study conclusions. Imputation methods when prescribed by validated instrument developers will be employed first. Additional methods or methods used when none are described for a given instrument may include: worst-case scenario (in which missing data are assumed to be unfavorable for those on the experimental treatment and favorable of those in the control group);
use of the mean response for individual patients who withdrew from the trial from either all or similar (matched) patients remaining in the trial; last observation carried forward (LOCF) [using the last observation as the final observation]; or linear mixed-effects models, to obtain separate estimates for the QOL outcome within strata based on missing data patterns.126-127 RTOG
recognizes that all options are subject to bias and analysis of more than one method for consistency across methods is prudent.  
13.5.7 Group Sequential Testing for Early Termination and Reporting of Efficacy and Futility **(1/8/09)**
A group sequential test with three planned interim analyses and a final analysis will be performed.  
The interim analysis will be carried out when the cumulative accrual (patients whose follow-up is at least 5 years from the randomization date) are met. For each interim analysis, one efficacy and two futility tests will be carried out. At each planned interim analysis, the p-value from the Z-test statistics, eq.1, for the difference between the two FFP rates assessing treatment efficacy or futility with respect to the primary endpoint will be compared to the nominal significance level. The significance level of 0.001, which is similar to the Haybittle-Peto test104-105, was chosen for efficacy testing. For the futility testing boundary, we will use a less aggressive boundary, Rule C in Freidlin and Korn.  
106 We will first compare Arm 3 with Arm 2 and choose the arm that has the higher FFP rate (if they are the same, Arm 2 will be chosen). Let p1, p2, and p3 equal the rate of 5-year FFP of Arm 1, Arm 2 and Arm 3, respectively. If Arm 2 is better than Arm 3 (p2 ≥ p3), then we compare Arm 2 with Arm 1. The following hypothesis is tested. H02: p2≤ p1 vs. HA2: p2 > p1 If H02 is rejected (p-value ≤ 0.001), then we conclude that the 5-year FFP of Arm 2 is better than Arm 1. We report that Arm 2 is better than arm 1 and stop accrual to arm 1 if applicable. If H02 is not rejected (p-value > 0.001), then we continue following the trial and proceed to the next interim analysis without any results reporting.  
With respect to interim evaluation of Arm 2 vs. Arm 3, if H02 is rejected, then the following hypothesis is tested.  
H03: p2≤ p3 vs. HA3: p2 > p3 If H03 is rejected (p-value < 0.001), then Arm 2 is declared best and the complete trial results (superior arm identified) are reported. If H03 is not rejected (p-value > 0.001), then we continue following the trial to the next interim analysis to evaluate Arm 2 vs. Arm 3.  
If Arm 3 is better than Arm 2 (p2 < p3), then we compare Arm 3 with Arm 1. The following hypothesis is tested.  
H04: p3 ≤ p1 vs. HA4: p3 > p1 If H04 is rejected (p-value ≤ 0.001), then we conclude that the 5-year FFP of Arm 3 is better than Arm 1. We report that Arm 3 is better than arm 1 and stop accrual to arm 1 if applicable. If H04 is not rejected (p-value > 0.001), then we continue following the trial and proceed to the next interim analysis without any results reporting.  
With respect to interim evaluation of Arm 2 vs. Arm 3, if H04 is rejected, then the following hypothesis is tested. H05: p3≤ p2 vs. HA5: p3 > p2 If H05 is rejected (p-value < 0.001), then Arm 3 is declared best and the complete trial results
(superior arm identified) are reported. If H05 is not rejected (p-value > 0.001), then we continue following the trial to the next interim analysis to evaluate Arm 2 vs. Arm 3. Note that if H02 [H04] is rejected but H03 [H05] is not rejected, the trial will continue in order to further evaluate the relative efficacy of arms 2 and 3. A recommendation from the DMC will be sought regarding whether to continue follow-up in Arm 1 and the process for informing arm 1 patients of the findings.  
For futility testing, we compare Arm 3 vs. Arm 1 and Arm 2 vs. Arm 1 if applicable. The following hypotheses are tested.  
H01: p1 ≥ p2 vs. HA1: p1 < p2 and H03: p1 ≥ p3 vs. HA3: p1 < p3 The alternative hypotheses, HA1 (p1 = p2 + 0.1) and HA3 (p1 = p3 + 0.1) will be tested at 0.001 level (the futility nominal significance level). If the computed p-value is less than 0.001 then we will consider stopping the trial in favor of H01 or H03 and report the results. If we stop the trial for futility, then we will conclude that the 5-year FFP of Arm 1 will be better than Arm 2 or Arm 3 and continue the trial for the other two remaining arms. Otherwise, we will continue the trial.  
| Table 12: The Schedule for the Planned Interim Analysis Information  Estimated  Cumulative  Time Analysis Time* Accrual in the  Three Arms** 0.25 7 years 397 0.50 9 years 794 0.75 11 years 1191 1.0 13 years 1587   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| * Time to the interim analysis from the first patient entry without considering ineligibility  or lack-of-data rate                                                                                                   |  
Based on the results of each interim analysis, the following action will be taken and the responsible statistician will recommend to the DMC that the randomization be discontinued, if applicable, and the study be considered for early publication. Before making such a recommendation, the accrual rate, treatment compliance, safety of the treatments, and the importance of the study are taken into consideration along with the p-value. The DMC will then make a recommendation about the trial to the appropriate NRG Oncology Leadership as needed.  
13.6 **Interim Report to Monitor the Study Progress**
Interim reports with descriptive statistics will be prepared twice per year until the initial paper reporting the treatment results has been submitted. In general, the interim reports will contain information about the patient accrual rate with a projected completion date for the accrual phase, compliance rate of treatment delivery with the distributions of important prognostic baseline variables, and the frequencies and severity of the adverse event by treatment arm. The interim reports will not contain the results of the treatment comparisons with respect to the primary endpoint and secondary endpoints. This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and October 31.  
13.7 Reporting the Initial Treatment Analysis **(1/8/09)**
The analysis reporting the treatment results will be carried out after the criteria for early stopping/reporting are met. Three interim comparisons and one final analysis will be performed for efficacy and futility of the experimental treatment will be carried out as described in Section 13.5.7. The Z-test statistics for the difference between the two rates with the standard errors estimated by Greenwood's method, eq. (1), will be used with an overall significance level of 0.025.  
It will include tabulation of all cases entered and those excluded from the analyses; the distribution of the important prognostic baseline variables; safety treatments; treatment compliance; and observed results with respect to the primary and secondary endpoints will be shown. All eligible patients randomized will be included in the comparison and will be grouped by assigned treatment in the analysis (intent-to-treat analysis). In addition, exploratory analyses of treatment comparisons of the primary and secondary survival endpoints will be tested using the Cox proportional hazard model114that includes treatment arms, the stratification factors (SV
involvement, prostatectomy Gleason score, pre-radiation PSA level, and pathology stage), age, and race (as appropriate).  
13.8 **Gender and Minorities**
In conformance with the National Institute of Health (NIH) Revitalization Act of 1993 with regard to inclusion of women and minorities in clinical research, Participation rates of men will be examined in the interim analyses. Based on the accrual statistics from RTOG 94-08, we project that 81% of the men in the study are White, 15% are Black or African American, 3% are Hispanic, 0.5% are Asian, 0.3% are Pacific Islander and 0.2% are American Indian or Alaskan Native. The following table lists the projected accrual by race/ethnicity.  
| Projected Distribution of Gender and Minorities Gender   |         |       |       |
|----------------------------------------------------------|---------|-------|-------|
| Ethnic Category                                          | Females | Males | Total |
| Hispanic or Latino                                       | N/A     | 53    | 53    |
| Not Hispanic or Latino                                   | N/A     | 1711  | 1711  |
| Ethnic Category: Total of all subjects                   | N/A     | 1764  | 1764  |
| Gender                                                   |         |       |       |
| Racial Category                                          | Females | Males | Total |
| American Indian or Alaskan Native                        | N/A     | 6     | 6     |
| Asian                                                    | N/A     | 9     | 9     |
| Black or African American                                | N/A     | 251   | 251   |
| Native Hawaiian or other Pacific Islander                | N/A     | 4     | 4     |
| White                                                    | N/A     | 1494  | 1494  |
| Racial Category: Total of all subjects                   | N/A     | 1764  | 1764  |
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appendix i (19-feb-2019)
references (1/8/09)

| STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS                                                                    |                       |                 |                 |               |                  |
|---------------------------------------------------------------------------------------------------------------------|-----------------------|-----------------|-----------------|---------------|------------------|
| Assessments (May be  required for  eligibility)                                                                     | 120 days prior        | 90 days prior   | 60 days prior   | 45 days prior | 30 days prior to |
| to registration                                                                                                     | to registration       | to registration | to registration | registration  |                  |
| Prostate biopsy  with Gleason  score                                                                                | Prostatectomy Gleason |                 |                 |               |                  |
| History/physical                                                                                                    | X                     |                 |                 |               |                  |
| Digital rectal                                                                                                      | X                     |                 |                 |               |                  |
| exam Performance                                                                                                    | X                     |                 |                 |               |                  |
| status CT or MRI of                                                                                                 | X                     |                 |                 |               |                  |
| pelvis* Bone Scan*                                                                                                  | X                     |                 |                 |               |                  |
| CBC w/ diff                                                                                                         | X                     |                 |                 |               |                  |
| AST or ALT                                                                                                          | X                     |                 |                 |               |                  |
| PSA *                                                                                                               | X                     |                 |                 |               |                  |
| Testosterone                                                                                                        | X                     |                 |                 |               |                  |
| Alk phos                                                                                                            | Recommended           |                 |                 |               |                  |
| CT-sim                                                                                                              | X                     |                 |                 |               |                  |
| Urethrogram or                                                                                                      | Recommended           |                 |                 |               |                  |
| MRI-sim Tissue for                                                                                                  | If patient consents   |                 |                 |               |                  |
| banking Blood Plasma  Serum† , urine for  banking                                                                   | If patient consents   |                 |                 |               |                  |
| AUA SI                                                                                                              | X                     |                 |                 |               |                  |
| *And as needed based on reporting requirements. † Includes serum for beta-amyloid testing. -Continued on next page- |                       |                 |                 |               |                  |  
| Assessments                                                                                                         | During Treatment   |                 |
|---------------------------------------------------------------------------------------------------------------------|--------------------|-----------------|
| Arms 2 & 3: Within 2 wks prior                                                                                      | Weekly during      | During 6th week |
| to start of RT                                                                                                      | RT                 | of RT           |
| History/physical                                                                                                    | X                  |                 |
| Performance status                                                                                                  | X                  |                 |
| CBC w/ diff                                                                                                         | X                  | X               |
| AST or ALT                                                                                                          | X                  | X               |
| PSA *                                                                                                               | X                  |                 |
| Testosterone                                                                                                        | X                  | X               |
| Blood, Plasma, serum† , urine for                                                                                   | X                  |                 |
| banking AUA SI                                                                                                      | X                  | X               |
| Adverse event evaluation*                                                                                           | X                  |                 |
| *And as needed based on reporting requirements. † Includes serum for beta-amyloid testing. -Continued on next page- |                    |                 |
appendix i study parameter table
references (1/8/09)

| STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW-UP                                                                                                                                                               |                       |                                        |      |                |        |          |     |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|----------------------------------------|------|----------------|--------|----------|-----|----|
| Assessments                                                                                                                                                                                                   | Follow up After RT    | Longterm  Follow  up                                        |      |                |        |          |     |    |
| 1.5 mo                                                                                                                                                                                                        | 3 mo                  | 6 mo                                   | 9 mo | 12  mo (yr1)   | q 6 mo | Annually | As  |    |
| thereafter                                                                                                                                                                                                               | thereafter            | indicated in  Sections  11.2 and  11.3 |      |                |        |          |     |    |
| History/physical                                                                                                                                                                                              | X                     | X                                      | X    | X              | X      | X        |     |    |
| Performance                                                                                                                                                                                                   | X                     | X                                      | X    | X              | X      |          |     |    |
| status                                                                                                                                                                                                        | q 3  mos.  for 1  yr. | q 6  mos.  for 6  yrs.                 |      |                |        |          |     |    |
| CT or MRI of                                                                                                                                                                                                  | X                     |                                        |      |                |        |          |     |    |
| pelvis* Bone Scan*                                                                                                                                                                                            | X                     |                                        |      |                |        |          |     |    |
| Digital rectal                                                                                                                                                                                                | X                     | X                                      | X    | X              | X      | X        |     |    |
| exam CBC w/ diff                                                                                                                                                                                              | X                     | X                                      |      |                |        |          |     |    |
| AST or ALT                                                                                                                                                                                                    | X*                    | X*                                     | X    |                |        |          |     |    |
| PSA *                                                                                                                                                                                                         | X                     | X**                                    | X**  | X**            | X**    | X**      | X** | X  |
| Testosterone                                                                                                                                                                                                  | X                     | X                                      | X    | X              | X      | X        | X   |    |
| Urine for                                                                                                                                                                                                     | Year 5                |                                        |      |                |        |          |     |    |
| banking Serum† ,  plasma, for  banking                                                                                                                                                                        | X                     | X                                      | X    | Years 2- 6 yrs |        |          |     |    |
| AUA SI                                                                                                                                                                                                        | X                     | X                                      | X    | X              | X      |          |     |    |
| EPIC, HSCL25, EQ-5D, Document use  of sexual  meds/devices^                                                                                                                                                                                                               | X                     | Year 5                                 |      |                |        |          |     |    |
| HVLT-R, Trail  making A & B,  COWAT^                                                                                                                                                                          | x                     | Year 5                                 |      |                |        |          |     |    |
| Adverse event                                                                                                                                                                                                 | X                     | X                                      | X    | X              | X      | X        |     |    |
| eval* *And as needed based on reporting requirements. ** If the PSA is ≤ 0.1 ng/mL, PSA will be drawn every 3 months from the completion of radiotherapy for  two years, and at 6-month intervals thereafter. |                       |                                        |      |                |        |          |     |    |
appendix i study parameter table
appendix i study parameter table

*And as needed based on reporting requirements.  
** If the PSA is ≤ 0.1 ng/mL, PSA will be drawn every 3 months from the completion of radiotherapy for two years, and at 6-month intervals thereafter.  
If PSA post-radiotherapy is ≥ 0.2 ng/mL, then continue at 3-month intervals (See Section 11.3.2).  
† Includes serum for beta-amyloid testing.  
^ Completion of QOL assessments in follow up are for patients who provided consent for the QOL
portion of the study prior to QOL closure.
appendix i study parameter table
appendix ii (10/22/09) zubrod performance

0 Fully active, able to carry on all predisease activities without restriction  
1 Restricted in physically strenuous activity but ambulatory and able to carry work of a light or sedentary nature. For example, light housework, office work
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited self-care, confined to bed or chair 50% or more of waking hours 4 Completely disabled. Cannot carry on self-care. Totally confined to bed 5 Death
appendix iii ajcc staging system
definition of tnm primary tumor

TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Clinically inapparent tumor neither palpable nor visible by imaging T1a Tumor incidental histologic finding in 5% or less of tissue resected T1b Tumor incidental histologic finding in more than 5% of tissue resected T1c Tumor identified by needle biopsy (e.g., because of elevated PSA)
T2 Tumor confined with prostate* T2a Tumor involves one-half of one lobe or less T2b Tumor involves more than one-half of one lobe but not both lobes T2c Tumor involves both lobes T3 Tumor extends through prostate capsule**
T3a Extracapsular extension (unilateral or bilateral)
T3b Tumor involves the seminal vesicle(s)
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles and/or pelvic wall
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c.  
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.
appendix iii ajcc staging system
regional lymph nodes (n) (1/8/09)

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in regional lymph node(s) Pathologic pNX Regional nodes not sampled pN0 No positive regional nodes pN1 Metastases in regional node(s)
appendix iii ajcc staging system
primary tumor pathologic (pt) pt2

pT2a Unilateral, involving one-half of one lobe or less pT2b Unilateral, involving more than one-half of one lobe but not both lobes pT2c Bilateral disease pT3 Extraprostatic extension pT3a Extraprostatic extension**
pT3b Seminal vesicle invasion pT4 Invasion of bladder, rectum
*Note: There is no pathologic T1 classification.  
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease). ***Note: The type of prostatectomy (radical retropubic, perineal, robotic) should be recorded.
appendix iii ajcc staging system
appendix iii (continued) ajcc staging

Distant Metastasis **(M)*** MX Presence of distant metastasis cannot be assessed (not evaluated by any modality)  
M0 No distant metastasis  
M1 Distant metastasis  
M1a Nonregional lymph node(s) M1b Bone(s)  
M1c Other site(s) with or without bone disease  
*Note: When more than one site of metastasis is present, the most advanced category is used; pM1c is most advanced.  
| G1   | Well-differentiated (slight anaplasia [Gleason 2-4])                          |
|------|-------------------------------------------------------------------------------|
| G2   | Moderately differentiated (moderate anaplasia [Gleason 5-6])                  |
| G3-4 | Poorly undifferentiated or undifferentiated (marked anaplasia [Gleason 7-10]) |  
| Stage I   | T1a   | N0   | M0    | G1       |
|-----------|-------|------|-------|----------|
| Stage II  | T1a   | N0   | M0    | G2, G3-4 |
| T1b       | N0    | M0   | Any G |          |
| T1c       | N0    | M0   | Any G |          |
| T1        | N0    | N0   | Any G |          |
| T2        | N0    | M0   | Any G |          |
| Stage III | T3    | N0   | M0    | Any G    |
| Stage IV  | T4    | N0   | M0    | Any G    |
| Any T     | N1    | M0   | Any G |          |
| Any T     | Any N | M1   | Any G |          |  
APPENDICES FOR NRG ONCOLOGY **BIOSPECIMEN COLLECTION**
Blood Collection Kit Instructions Urine Collection Kit Instructions Shipping Instructions:
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only NRG Oncology Biospecimen Bank- San Francisco University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): **For Frozen or Trackable Specimens**
NRG Oncology Biospecimen Bank- San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 Include all NRG Oncology paperwork in pocket of biohazard bag.  
Check that the Specimen Transmittal Form has the consent boxes checked off.  
Check that all samples are labeled with the NRG Oncology study and case number, and include date of collection as well as collection time point (e.g., pretreatment, post-treatment).
appendix iii ajcc staging system
ffpe specimens

o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the container. If you can hear the slides shaking it is likely that they will break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap blocks with bubble wrap. Place padding in top of container so that if you shake the container the blocks are not shaking. If you can hear the slides shaking it is likely that they will break during shipping.  
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). Do NOT ship on Dry Ice.
appendix iii ajcc staging system
frozen specimens

o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and clearly identified.  
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs).  
There should be plenty of dry ice under and above the specimens. If the volume of specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any Styrofoam box can be used, as long as it is big enough.  
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent thawing due to delivery delays.  
Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -80 C until ready to ship.  
For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271.  
BLOOD COLLECTION KIT AND INSTRUCTIONS
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood *(as* specified by the protocol):
Kit contents: **Sites will have to provide their own blood draw tubes**
- Fifteen (15) 1 ml cryovials for first time point, Ten (10) 1 ml cryovials for subsequent timepoints
- Biohazard bags (3) and Absorbent shipping material (3)
- 1 Styrofoam container (inner) and Cardboard shipping (outer) box
- UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers - Specimen Transmittal Form and Kit Instructions
appendix iii ajcc staging system
preparation and processing of serum

Label Five (5) 1ml cryovials for the serum collected. Label them with the NRG Oncology study and case number, collection date, time, and time point, and clearly mark cryovials "serum".  
Process:
1. Allow one red top tube to clot for 30 minutes at room temperature.  
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the STF.  
3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected into five cryovials labeled with NRG Oncology study and case numbers, collection date/time, protocol timepoint collected (e.g. pretreatment, post-treatment), and clearly mark specimen as "serum".  
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen until ready to ship. See below for storage conditions.  
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions.  
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED **and include collection time point on the**
Specimen Transmittal Form.
appendix iii ajcc staging system
(b) plasma (if requested) purple

Label Five (5) 1ml cryovials for the plasma collected. Label them with the NRG Oncology study and case number, collection date, time, and time point, and clearly mark cryovials "plasma".  
Process:
1. After collection of blood into a purple top tube,, invert tube(s) multiple times to ensure adequate mixing of EDTA.  
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the STF..  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, keep specimen on ice until centrifuging is performed.  
4. Carefully pipette and aliquot 0.5 ml plasma for the plasma collected into five cryovials labeled with NRG
Oncology study and case numbers, collection date/time, time point collected and clearly mark specimen as "plasma". Avoid pipetting up the buffy coat layer.  
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C.  
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions.
appendix iv
blood collection kit instructions (continued)

Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected..Label them with the NRG
Oncology study and case number, collection date/time, and time point, and clearly mark cryovials "blood".  
Process:
1. After collection of blood into a purple top tube, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be mixed for 5 minutes on a mixer at room temperature.  
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials (3-5) as are necessary for the blood collected labeled with NRG Oncology study and case numbers, collection date/time, time point collected and clearly mark specimen as "blood".  
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius.  
4. Store blood samples frozen until ready to ship on dry ice. 5. See below for storage conditions.
appendix iv
please make sure that every

Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen.  
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,
- Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
- Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
- Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
Please indicate on Specimen Transmittal Form the storage conditions used and time stored.  
Shipping/Mailing:
Ship specimens on Dry Ice overnight Monday-Wednesday **(Monday-Tuesday from Canada)** to prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods together) in absorbent shipping material and place each specimen type in a separate biohazard bag.  
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box. (continued on next page)
BLOOD COLLECTION KIT INSTRUCTIONS (continued)  
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that there is enough room for plenty of dry ice. *Add padding to avoid the dry ice from breaking the tubes.*
**For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail**
NRGBB @ucsf.edu **or call (415)476-7864.**
appendix iv
shipping address

Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology Biospecimen Bank- San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 For questions, call 415-476-7864 or e-mail: NRGBB @ucsf.edu
appendix iv (continued) urine collection
kit contents

- One (1) Sterile Urine collection cup - one-two 15 ml polypropylene centrifuge tubes
- Two 7 ml disposable pipettes - Biohazard bags
- Absorbent paper towel - Parafilm for sealing outside of tubes
appendix iv (continued) urine collection
preparation and processing of urine

- A clean catch urine specimen will be collected. To collect the specimen, use the following instructions:
o Males should wipe clean the head of the penis and females need to wipe between the labia with soapy water/cleansing wipes to remove any contaminants.  
o After urinating a small amount into the toilet bowl to clear the urethra of contaminants, collect a sample of urine in the collection cup.  
o After 10-25 mL urine has been collected, remove the container from the urine stream without stopping the flow of urine.  
o Finish voiding the bladder into the toilet bowl.  
- Aliquot 5-10 mls of Urine one-two 15 ml polypropylene centrifuge tubes (disposable pipets are provided in the kit). Do not fill with more than 10 mls to avoid cracking of tubes due to expansion during freezing. Replace the cap and tighten on the tubes. Make sure the cap is not cross-threaded or placed on incorrectly or leaking will occur.  
- Use parafilm to seal the cap around the outside rim of the urine tube to prevent leakage.  
- Discard remaining Urine and collection cup.  
- Clearly label the specimen with the NRG Oncology study and case number, collection date and time, time point of collection, and clearly mark specimens as "urine". Labels can fall off at cold temperatures so label the tube with a sharpie first before using a label, or don't use a sticky label.  
- Wrap Urine Tubes with absorbent material (paper towels) and place into biohazard bag and seal the bag.  
Freeze and store Urine samples in a -20C or -80C freezer until ready to ship.
appendix iv (continued) urine collection
storage and shipping freezing and

Urine specimens may be sent in batches or with other frozen biospecimens, if within 30-60 days of collection. Store at -20C or -80C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:
- Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
- Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out MondayWednesday only; Canada: Monday-Tuesday only).  
- Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
appendix iv (continued) urine collection
shipping/mailing

Ship specimens on Dry Ice overnight Monday-Wednesday **(Monday-Tuesday from Canada)** to prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum). Add padding to avoid the dry ice from breaking the tubes.  
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box.  
*Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that there is* enough room for plenty of dry ice. *Add padding to avoid the dry ice from breaking the tubes.*
Samples received thawed will be discarded, and a notification will be sent immediately to the Principal Investigator and Clinical Research Assistant of the submitting institution. The institution should send a subsequent sample, collected as close as possible to the original planned collection date.  
**For questions regarding ordering, collection, or shipping of a Urine Collection Kit, please e-mail**
NRGBB@ucsf.edu or call (415)476-7864 or fax (415) 476-5271.  
Shipping Address: FedEx/UPS/Courier address **(For all frozen samples)**
NRG Oncology Biospecimen Bank - San Francisco 2340 Sutter Street, Room S341, San Francisco, CA 94115 Contact Phone: (415) 476-7864
appendix iv (continued) urine collection
appendix v (12/10/13) rtog 0534

Prior to testing a patient, potential examiners must view the training video and take the post-test. Administrators that have previously been certified for RTOG 0525, 0614, or 0825 do not need to go through the training procedure again, but must fax the certification worksheet to Dr. Wefel, and indicate that they have previously been certified. Please note previous certification for RTOG 0212, 0214 and 0424 is not sufficient. Training, which takes 15-30 minutes, will involve review of the forms and instructions for the administration and scoring of the neurocognitive test battery (Hopkins Verbal Learning Test - Revised, Trail Making Test Parts A and B, and Controlled Oral Word Association Test) and discussion of study-specific logistics. The trainee will then complete a practice assessment for review. This assessment must be faxed to Dr. Wefel (see certification worksheet below), and he will review the results with the trainee. If the trainee demonstrates competency, he/she will be approved to administer the tests to study subjects as part of RTOG 0534. Dr. Wefel will fax his approval to the CTSU for documentation and to ensure that only certified examiners are testing subjects on RTOG 0534.  
Examiner Certification Worksheet This worksheet must be completed and signed by the person requesting certification and submitted to Dr. Wefel prior to the registration of patients to RTOG 0534.  
(Y) 1. Have you reviewed the Neuropsychological Test Instructions in Appendix VI of the 0534 protocol?  
(Y) 2. Have you been trained by Dr. Wefel at an RTOG meeting or by teleconference, watched the 0534 Neuropsychological Test Administration video, or previously been certified for RTOG 0525, 0614, or 0825 within the past 6 months?  
(Y) 3. Have you completed and submitted the post-test associated with the training video and a
"practice" neuropsychological assessment?  
(Y) 4. Have you contacted Dr. Wefel (See Section 11.9) for test translations and found that no translations are available for your institution?
Signature of test administrator Date (Person who read Appendix VI, completed a RTOG meeting training or teleconference *or watched video and* completed the "practice" Neuropsychological Assessment)
___
Printed name of test administrator Institution number/Name-NCI Code
appendix iv (continued) urine collection
telephone number of test administrator

If you have any questions regarding the certification, please contact Dr. Wefel. Once you have completed this form, please attach the Neuropsychological Assessment forms from the "practice" individual and the training video post test and and fax to:
Dr. Jeffrey S. Wefel; phone: 713.563.0514; FAX: **713.794.4999**; e-mail: jwefel@mdanderson.org For Dr. Wefel's Use Only (To fax to 215-569-0206, *CTSU)*
(Y/N) The above individual has been certified for administering the neurocognitive assessments for this study.  
Signature Date
appendix iv (continued) urine collection
appendix v (continued)

Testing: **General Information**
1. As noted above, copies of the test forms and summary sheets for the first case from each site must be faxed to Dr. Wefel for review.  
2. Testing should be completed in one session. Test instructions must be followed verbatim with every patient at every assessment visit.  
3. Tests should be administered in the following order to every patient and at each assessment visit: HVLTR Part A (Learning Trials); Trail Making Test Part A; Trail Making Test Part B; COWAT; HVLT-R Part B
(Delayed Recall); and the HVLT-R Part C (Delayed Recognition).  
4. Follow the instructions on the Forms Packet Index before submitting forms to RTOG.  
5. All test results are recorded on the Neurocognitive Evaluation Summary Form (CS), which is found in the Forms Packet. Study/case-specific labels must be applied to all forms.  
6. **Note**: Test results are not submitted to Dr. Wefel, nor to RTOG Headquarters (test results are recorded on forms and submitted). Sites should keep all original test records, and test results must remain on file at the institution as source documentation pending request for submission by RTOG or a Study Chair. In the event of questions, contact Dr. Wefel.  
7. Patients should not be given copies of their tests to avoid learning the material between test administrations.  
8. The HVLT-R and the COWAT have alternate forms or versions in order to reduce the effects of practice.  
See the test instructions below for the versions to be administered at pre-treatment and subsequent sessions. The forms should continue to be alternated in this order for the duration of the study. The forms packet will contain alternate versions of these neuropsychological tests.  
Before dismissing the patient, thank him/her for their cooperation. Remind the patient of their next appointment and that these tests will be repeated.  
In the event that a patient cannot complete a given test, please write the reason(s) on the test form AND the data summary form.  
Testing: Specific Instructions Note: Administer the tests in the following order to every patient at each assessment visit.
appendix iv (continued) urine collection
1. hopkins verbal learning test

This test has three parts and six alternate forms (only the first 4 forms will be used in this study):
Part A - **Free Recall:** Complete the three learning trials first Part B - **Delayed Recall:** Complete after Trail Making Tests and COWAT Part C - **Delayed Recognition:** Complete after Delayed Recall
appendix iv (continued) urine collection
2. trail making test [timed

Part A - **Sample**: Place the Sample A worksheet flat on the table, directly in front of the patient (the bottom of the worksheet should be approximately six inches from the edge of the table). Give the patient a black pen and say:
Examiner*: "On this page* (point) *are some numbers. Begin at number 1* (point to 1) and draw a line from 1 to 2 (point to 2), *2 to 3* (point to 3)*, 3 to 4* (point to 4), *and so on, in order, until you reach the end* **(point to**
the circle marked END). *Draw the lines as fast as you can. Ready, begin."*  
If the patient completes Sample A correctly, and in a manner demonstrating that s/he understands what to do, proceed immediately to Test A. If the patient makes a mistake on Sample A, point out the error and explain it.  
The following explanations of mistakes serve as illustrations:
- *This is where you start (point to number 1).*
- *You skipped this circle (point to the circle omitted).*
- You should *go from number 1 to 2, 2 to 3, and so on, until you reach the circle marked END.*
If it is clear that the patient intended to touch a circle but missed it, do not count it as an omission. Remind the patient, however, to be sure to touch the circles. If the patient still cannot complete Sample A, take his/her hand and guide him/her through the trail using the opposite end of the pen, lightly touching the worksheet to avoid making marks on he copy. Then say: Examiner*: "Remember, begin at number 1 (*point to 1*) and draw a line from 1 to 2 (*point to 2*), 2 to 3 (***point** to 3*), 3 to 4 (*point to 4) and so *on, in order, until you reach the circle marked END (*point*). Do not skip* around, but go from one number to the next in proper order. Remember to work as fast as you can.  
Ready, begin."
If the patient does not succeed, or it becomes evident that s/he cannot do the task, DISCONTINUE testing **and**
indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A correctly and appears to understand what to do, proceed immediately to Part A.  
Part A - **Test:** After the patient has completed Sample A, place the Part A test worksheet directly in front of the patient and say:
Examiner: "Good! Let's try the next one. On this page are numbers from 1 to 25. Do this the same way.  
Begin at number 1 (point*) and draw a line from 1 to 2 (*point to 2*), 2 to 3 (*point to 3*), 3 to 4 (*point to 4) and so on, in order, until you reach the circle marked END (point*). Do not skip around, but go from one* number to the next in proper order. Remember to work as fast as you can. Ready, begin."
- Start timing as soon as the instruction is given to "begin" Part B - **Sample:** Place the Sample B worksheet flat on the table, directly in front of the patient (the bottom of the worksheet should be approximately six inches from the edge of the table) and say: Examiner*: "On this page (*point*) are some numbers and letters. Begin at number 1 (*point to 1*) and draw a* line from 1 to A (point*), A to 2 (*point to 2*), 2 to B (*point to B*), B to 3 (*point to 3*), 3 to C (*point to C) and so on, in order, until you reach the end (point to the circle marked END). Remember, first you have a number
(point to 1*), then a letter (*point to A*), then a number (*point to 2), then a letter (point to B), and so on. Draw the lines as fast as you can. Ready, *begin."* If the patient completes Sample B correctly, and in a manner demonstrating that s/he understands what to do, proceed immediately to Part B. If the patient makes a mistake on Sample B, point out the error and explain it.  
The following explanations of mistakes serve as illustrations:
- *You started with the wrong circle. This is where you start (point to number 1)*
- *You skipped this circle (point to the circle omitted)* - *You should go from number 1 (*point*) to A (*point*), A to 2 (*point to 2*), 2 to B (*point to B), B to 3
(point to 3*) and so on, until you reach the circle marked END (***point**).  
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission. Remind the patient, however, to be sure to touch the circles. If the patient still cannot complete Sample B, take their hand and guide them through the trail using the opposite end of the pen, lightly touching the worksheet to avoid making marks on the copy. Then say:
Examiner*: "Now you try it. Remember, begin at number 1 (*point to 1*) and draw a line from 1 to A (***point to**
A*), A to 2 (*point to 2*), 2 to B (*point to B*), B to 3 (*point to 3*) and so on, in order, until you reach the circle* marked END (point*). Ready, begin."*
If the patient does not succeed or it becomes evident that s/he cannot do the task, DISCONTINUE testing **and**
indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A correctly and appears to understand what to do, proceed immediately to Part A.
appendix iv (continued) urine collection
part b - test

After the patient has completed Sample B, place the Part B Worksheet directly in front of the patient and say: Examiner*: "Good! Let's try the next one. On this page are both numbers and letters. Do this the same* way. Begin at number 1 (point*) and draw a line from 1 to A (*point to A*), A to 2 (*point to 2*), 2 to B (*point to B*), B to 3 (*point to 3*), 3 to C (*point to C*) and so on, in order, until you reach the circle marked END (***point**). Remember, first you have a number (point to 1*), then a letter (*point to A*), then a number (*point to 2*), then* a letter (point to B*), and so on. Do not skip around, but go from one circle to the next in the proper order.*
Draw the lines as fast as you can. Ready, begin."
- Start timing as soon as the instruction is given to "begin".  
- Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it to his/her attention immediately and have him/her proceed from the point the mistake occurred
- The patient must complete the test in **5 minutes** or less.  
- **DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED "END".**
- Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and seconds.  
- Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it to his/her attention immediately and have him/her proceed from the point the mistake occurred
- The patient must complete the test in **3 minutes** or less.  
- **DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED "END".**
- Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and seconds
- If the patient does not complete the test within **3 minutes** terminate the testing. The test can also be discontinued if the patient is extremely confused and is unable to perform the task. Collect the worksheet and complete the Trail Making Data Sheet indicating the reason the test was terminated and the last correct number reached on the test.  
- If the patient does not complete the test within **5 minutes** terminate the testing. The test can also be discontinued if the patient is extremely confused and is unable to perform the task. Collect the worksheet and complete the Trail Making Data Sheet indicating the reason the test was terminated and the last correct number or letter reached on the test.
appendix iv (continued) urine collection
4. hopkins verbal learning test

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ting the content of the AAAA
ting the content of the e and the state of the state of the s AAA
e and the second of the second the second of the second the second the second the AAA
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