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10.2 specimen collection for tissue

The following must be provided in order for the case to be evaluable for the NRG Oncology Biospecimen Bank:
10.2.1 One H&E stained slide of the tumor (this must be either the invasive portion of the tumor and/or the grade 3 DCIS portion if no invasive component;(slide can be a duplicate cut stained H&E; it does not have to be the diagnostic slide).  
- A corresponding paraffin-embedded tissue block (preferred) of the tumor or a 2 mm diameter core of tumor tissue punched from the tissue block containing the invasive tumor (or the grade 3 DCIS if no invasive tumor present) with a punch tool and submitted in a plastic tube labeled with the surgical pathology number and block ID. The block or punches must be submitted with the H&E from the same block.  
NOTE: A kit with the punch, tube, and instructions can be obtained free of charge from the Biospecimen Resource. Block or core must be clearly labeled with the pathology identification number and block ID that corresponds to the Pathology Report. NOTE: If sites are unable to submit a block or punch from the block then they may instead submit 1 H&E and 10-15 unstained slides from the tumor block. The unstained slides must be cut from the same block as the H&E and must be labeled with the pathology number and block ID.  
- If available, a corresponding paraffin-embedded tissue block (preferred) of normal breast tissue taken from adjacent to tumor (or a 2 mm diameter core of this tissue punched from the tissue block containing the normal with a punch tool and submitted in a plastic tube labeled with the surgical pathology number). **NOTE:** A kit with the punch, tube, and instructions can be obtained free of charge from the NRG Onoclogy Biospecimen Bank. Block or core must be clearly labeled with the pathology identification number and block ID that corresponds to the Pathology Report.  
NOTE: If sites are unable to submit a block or punch from the block then they may instead submit 1 H&E and 10-15 unstained slides from the normal tissue block. The unstained slides must be cut from the same block as the H&E and must be labeled with the pathology number and block ID
10.2.2 A Pathology Report documenting that the submitted block or core contains tumor. The report must include the NRG ONcology protocol number and patient's case number.  
The patient's name and/or other identifying information should be removed from the report. The surgical pathology numbers and information must NOT be removed from the report.  
10.2.3 A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG
Oncology Biospecimen Bank; if for translational research, this should be stated on the form. The form must include the NRG Oncology protocol number and patient's case number.  
Plasma and whole blood collection: For detailed processing and shipping instructions, see Appendix IV.  
10.2.4 Plasma and Whole Blood for Tissue Banking The following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen Transmittal Form documenting the date of collection of the biospecimen; the NRG Oncology protocol number, the patient's case number, time point of study, and method of storage, for example, stored at -80° C, must be included. The specimens to be provided are:
- 5-10 mL of anticoagulated whole blood in EDTA tube \#1 (purple/lavender top)
taken from patient and processed for collection of plasma. This sample is to be obtained only once prior to treatment. No additional samples are to be obtained during follow-up visits following treatment.  
- 5-10 mL of anticoagulated whole blood in EDTA tube \#2 (purple/lavender top)
taken from patient for collection of DNA. This sample is to be obtained once prior to treatment. However, if the site missed this collection time point, they may collect whole blood at any time point or during a follow-up visit. No additional samples are to be obtained.  
10.2.5 Storage Conditions Store frozen biospecimens at -80 C (-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: MondayTuesday).  
OR:
- Samples can be stored in plenty of dry ice for up to one week, replenishing daily
(ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
OR:
- Samples can be stored in liquid nitrogen vapor phase (ship out MondayWednesday only; Canada: Monday-Tuesday).
Please indicate on Specimen Transmittal Form the storage conditions used and time stored  
| 10.2.6                                                                                                                                                                        | Specimen Collection Summary Specimens for Tissue Banking/Translational Research   |                                                                                                                                                                   |                                                                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|
| Specimens taken from                                                                                                                                                          | Collected when:                                                                   | Submitted as:                                                                                                                                                     | Shipped:                                                       |
| patient:                                                                                                                                                                      |                                                                                   |                                                                                                                                                                   |                                                                |
| Representative H&E stained  slides of the primary tumor (this must be either the  invasive portion of the tumor  and/or the grade 3 DCIS  portion if no invasive  component). | Prior to protocol treatment                                                       | H&E stained slide                                                                                                                                                 | Slide shipped ambient                                          |
| Pre-treatment                                                                                                                                                                 |                                                                                   |                                                                                                                                                                   |                                                                |
| A corresponding paraffinembedded tissue block (preferred) of the primary  tumor taken before initiation  of treatment or a 2 mm  diameter core of tissue,  punched from the tissue  block with a punch tool                                                                                                                                                                               | Prior to protocol treatment                                                       | Paraffin-embedded  tissue block or punch  biopsy (must match the  H&E slide being  submitted)                                                                     | Block or punch shipped  ambient                                |
| Note: For sites unable to  submit the block or  punch then 10-15  unstained slides is an  acceptable substitute                                                               |                                                                                   |                                                                                                                                                                   |                                                                |
| If available: representative  H&E stained slides of  Normal tissue adjacent to  the tumor (>1cm from  lesion)                                                                 | Prior to protocol treatment                                                       | H&E stained slide                                                                                                                                                 | Slide shipped ambient                                          |
| Pre-treatment                                                                                                                                                                 |                                                                                   |                                                                                                                                                                   |                                                                |
| If available: A paraffinembedded tissue block of  adjacent normal tissue  (>1cm from lesion) taken  before initiation of treatment  or a 2 mm diameter core of  tissue, punched from the  tissue block with a punch tool                                                                                                                                                                               | Prior to protocol treatment                                                       | Paraffin-embedded  tissue block or punch  biopsy  Note: For sites unable to  submit the block or  punch then 10-15  unstained slides is an  acceptable substitute | Block or punch shipped  ambient                                |
| PLASMA: 5-10 mL of  anticoagulated whole blood in  EDTA                                                                                                                       | Prior to protocol treatment                                                       | Frozen plasma samples  containing 0.5 mL per  aliquot in 1 mL cryovials                                                                                           | Plasma sent frozen on dry  ice via overnight carrier (Mon-Wed) |  
| tube#1(purple/lavender top)                                                                                                 | (five to ten)                                                                                                                                                                                |                                                                                           |                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|----------------------------------------------------------------------|
| and centrifuge  Whole blood for DNA: 5-10  mL of anticoagulated whole  blood in EDTA tube #2  (purple/lavender top) and mix | Prior to protocol treatment.  (Note: If site missed this  collection time point they  may collect whole blood for  DNA at any time point or  follow up visit but must  note this on the ST). | Frozen whole blood  samples containing 1ml  per aliquot in 1 mL cryovials (three to five) | Whole blood sent frozen  on dry ice via overnight  carrier (Mon-Wed) |  
10.2.7 Submit materials for Tissue Banking and Translational Research as follows:
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u. s. postal service mailing

Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115
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questions 415-476- 7864/fax 415-476-5271 rtog@ucsf.edu

10.3 **Reimbursement** (4/4/14)
Please note that with the start of the new NCI National Clinical Trials Network (NCTN)
Program, NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per the requirements/methods specified by the new NCTN Program. This information will be made available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) portal system. OPEN will serve as the registration system for all patient enrollments onto NCI-sponsored NCTN trials, including this study, which will be transitioned into the new Program from the NCI-sponsored Cooperative Group Clinical Trials Program.  
10.4 **Confidentiality/Storage**
(See the Patient Tissue Consent Frequently Asked Questions, http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.asp x for further details.)
10.4.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient's case number only. The NRG Oncology Biospecimen Bank database only includes the following information: the number of specimens received, the date the specimens were received, documentation of material sent to a qualified investigator, type of material sent, and the date the specimens were sent to the investigator. No clinical information is kept in the database.  
10.4.2 Specimens for tissue banking will be stored for an indefinite period of time. Trial participants will be invited to donate specimens for tissue banking and to consent to store these indefinitely for future translational studies. If at any time the patient withdraws consent to store and use specimens, the material will be returned to the institution that submitted it.  
11.0 **PATIENT ASSESSMENTS** (5/6/2013)
11.1 **Study Parameters**
See Appendix I for a summary of assessments and time frames. Note: Clarifications of or exceptions to the study parameters are indicated in Appendix I with an asterisk (*) and are discussed below:
11.1.1 A breast assessment will be conducted weekly during radiation and at the last day of radiation. This assessment will include inspection of the breast being treated and toxicity assessment. Palpation of the breast during this assessment is optional at the discretion of the treating physician.  
11.1.2 A breast examination will be conducted within 28 days prior to study entry, at 1 month, at 6 months and subsequent interval visits where the history and physical examination is required. An examination is inspection and palpation of both breasts and toxicity assessment
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11.2 cosmetic and quality of

NOTE: Patients must be offered the opportunity **to participate in the correlative** components of the study, such as quality of life assessment. Breast Cancer Treatment Outcome Scale (BCTOS) - a 22-item measure of perceived aesthetic (e.g., breast shape) and functional status (e.g., pain, mobility) after breastconserving surgical treatment (BCT) and radiotherapy.  
This brief self-report instrument has high reliability and validity, and it has been used in a variety of previous studies on recovery from breast cancer treatment. These endpoints will be assessed at baseline prior to start of RT, end of radiation, 1 month and 6 months after radiation, and 1, 2 and 3 years after completion of radiation. This tool was also used and at these same time points to facilitate comparisons with the outcomes from RTOG 0413/NSABP B39. This tool includes items that focus specifically on radiotherapy-relevant symptoms (e.g., reports of skin problems, tenderness in the breast, hardness in the breast due to enhanced fibrosis, and pain).  
Physician reported cosmetic outcome has been consistently reported from prospective studies evaluating new methods for breast radiation. It is important to demonstrate that physician reported cosmetic outcomes are non-inferior with this novel method as well.  
Physician assessed cosmetic outcome will be assessed at baseline prior to start of RT
but after surgery, 1 year and 3 years using a 4 point scale (Harvard/ EORTC). This scale has been used in prior RTOG studies assessing PBI, and is currently used on the ongoing Phase III study (NSABP B-39/RTOG 0413) comparing standard fractionated WBI to PBI.  
11.2.1 Finally, digital images (photographs) will be taken of the treated and untreated breasts, again using RTOG-established protocol. For practical reasons, these digital images will only be taken at three points in time, at baseline (prior to the start of radiation but after surgery) and at the 1-year and 3-year (final) assessment points. Two digital images will be taken at each of these assessment points. One will be a close up of the treated breast alone, in order to provide detailed information regarding the treatment effects.  
The second digital image will be a straight frontal view of both breasts taken in either a standing or seated position with the patient's hands symmetrically placed on her hips, taking care to exclude her face and framing and focusing on both the treated and untreated breast to allow optimal comparison of the breasts for symmetry.
These photographs will then be uploaded as J-peg files @ https://silver1.phila.acr.org/clinical_rtog/pgsitetools.html. (See Appendix VII) These digital images will later be evaluated for cosmetic results by a panel of physicians using diagnostic criteria established in previous RTOG trials (e.g., degree of scarring, extent of pock marks and/or dimpling, degree of symmetry between the breasts, extent of changes to the skin). We think it is of interest and important to obtain multiple measures of cosmetic outcome, in order to assess the degree of correspondence between physician-generated and patient-generated outcomes. Prior research, taken together with data generated from previous NSABP trials, suggests that physician-generated ratings often underestimate the degree of dissatisfaction experienced and problems perceived by the patient. Our plan is to use the patient's self-report as our primary cosmetic endpoint.
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11.3 measurement of response not

11.4 **Criteria for Discontinuation of Protocol Treatment**
11.4.1 Progression of disease 11.4.2 A delay in protocol treatment, as specified in Section 6.0
If study therapy is stopped but she still allows the study doctor to follow her care, she should continue to be followed according to the study schedule. Follow up and data collection will continue as specified in the protocol.
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12.0 data collection data should

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.  
12.1 **Summary of Data Submission** (1/9/14)
Item Due Demographic Form **(A5)** Within 2 weeks of study entry Initial Evaluation Form **(I1)** Pathology Report **(P1)** Slides/Blocks **(P2)** See Section 10.0
Surgical Pathology Report (S5) Surgical Operative report (S2)
Within 2 weeks of study entry. Also at time of progression/relapse if applicable.  
Digital Images(Photographs)  
Photograph Submission Notification Form(T7)  
Baseline prior to RT but after surgery);1 and 3 years post RT completion  
(for patients registered prior to 1/9/14)  
  
  
Cosmesis Questionnaires: Patient Reported Cosmesis Questionnaire
(BQ) (*for patients registered prior to 1/9/14*)
Baseline prior to RT but after surgery);at the completion of RT; 1 and 6 months post RT completion; 1, 2 and 3 years post RT completion  
| Physician Reported Cosmesis Questionnaire      | Baseline (prior to RT start but after surgery);1                                                               |
|------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| (QP) (for patients registered prior to 1/9/14) | and 3 years post RT completion                                                                                 |
| Follow-up Form (F1)                            | At 1 and 6 months post RT; at 1 year post RT,  then annually. Also at progression /relapse  and death          |
| Comorbidities & Other Conditions Form (CF)     | Baseline (prior to study entry); at 6 months  post RT completion; at 1 year post RT  completion ,then annually |  
| Item                                                                                                                                                                                                                            | Due                                                                                                                                                                                      |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Preliminary Dosimetry Information (DD) Digital Data Submission - Treatment Plan submitted                                                                                                                                       | Within 1 week of start of RT                                                                                                                                                             |
| to TRIAD by Physicist Digital data submission includes the following: -                                                                                                                                                         | CT                                                                                                                                                                                       |
| data, critical normal structures, all GTV, CTV,  and PTV contours                                                                                                                                                               |                                                                                                                                                                                          |
| -                                                                                                                                                                                                                               | Digita                                                                                                                                                                                   |
| l beam geometry for initial and boost beam  sets                                                                                                                                                                                |                                                                                                                                                                                          |
| -                                                                                                                                                                                                                               | Dose                                                                                                                                                                                     |
| s for initial and boost sets of concurrently  treated beams                                                                                                                                                                     |                                                                                                                                                                                          |
| -                                                                                                                                                                                                                               | Digital DVH data for all required critical normal  structures, GTV, CTV, and PTVs for total dose  plan                                                                                   |
| -                                                                                                                                                                                                                               | All required structures MUST be labeled per  the table in Section 6.5.                                                                                                                   |
| -                                                                                                                                                                                                                               | The "RTOG 1005 Datasheet" is available in  the Forms section of the of the NRG  Oncology/RTOG web site,  http://www.rtog.org/ClinicalTrials/ProtocolTabl e/StudyDetails.aspx?study=1005. |
| Submit via TRIAD with the digital data listed above. Upon submission of the digital data via TRIAD,  complete an online digital data transmission form  (DT) located in the Forms section on the NRG  Oncology/RTOG web site at |                                                                                                                                                                                          |
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12.2 summary of dosimetry digital

| http://www.rtog.org/ClinicalTrials/ProtocolTable/Study Details.aspx?study=1005 Note: All simulation and portal films and/or digital film  images will be kept by the institution and only  submitted if requested. Final Dosimetry Information   | Within 1 week of RT end   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|
| Radiotherapy Form (T1) [copy to HQ] Daily Treatment Record (T5) [copy to HQ] Modified digital patient data as required through  consultation with Image-Guided Therapy QA Center                                                                 |                           |  
13.0 STATISTICAL CONSIDERATIONS
13.1 Study Endpoints 13.1.1 Primary Endpoint Local failure (failure: the first occurrence of a local-in breast failure)
13.1.2 Secondary Endpoints
- Overall survival (failure: death due to any cause); - Disease-free survival (failure: local-regional disease recurrence or distant metastases or second primary or death due to any cause);
- Distant disease-free survival (failure: distant metastases or second primary or death due to any cause);
- Adverse events related to treatment; - Changes in breast-related symptoms and side effects and cosmesis; - Correlation between dose-volume data and both adverse events and efficacy;
- Translational research of single nucleotide polymorphisms (SNPs) in TGFB1 and ATM genes.  
- Treatment costs
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13.2 study design (16-dec-2021) 13.2.1

Patients will be stratified before randomization with respect to age (< 50 vs. ≥ 50), chemotherapy use (no vs. yes),histologic grade (1, 2 vs. 3)and ER status (+ vs. –). The treatment allocation scheme described by Zelen (1974) will be used because it balances patient factors other than institution.  
13.2.2 Sample Size Derivation The sample size calculations are based on the primary hypothesis that the local failure rate in the hypofractionated arm (Arm 2) will not be significantly worse than in the standard treatment arm (Arm 1). The null hypothesis (H0) of this test is that the hazard rate of Arm 2 (2) is significantly worse than the hazard rate of Arm 1 (1). The alternative hypothesis (HA) is that the hazard rate of Arm 2 is not significantly worse than the hazard rate of Arm 1.  
H0:  ≥ 0 vs. HA:  < 0 where  = -ln ( 2/1 ) and 0 is a non-inferiority margin.  
The estimated rate of local recurrence at 5 years for the control arm of whole breast radiation with sequential boost for this trial is 6%. The justification based upon prospective trials is shown in Table 2 (in Section 1.7.4). Table 3 below shows the estimates for patient enrollment of high-risk subgroups. It is expected the percentage of high risk features to be significantly higher in this trial than previous hypofractionation trials from Canada (Whelan 2002) and the United Kingdom (START) because these groups are specifically targeted by this study's eligibility. The following patient enrollment is assumed: 65% N0, and 35% N1. The enrollment of node positive patients in the UK START A trial was 29% and START B trial 23%. It is assumed that approximately 50% of patients will be ≤ 50 years of age. In the UK START A 23% were age ≤ 50 and UK START B 21% age ≤ 50 years. In the Whelan study, 25% were ≤ 50 years of age. Because this protocol specifically is limiting eligibility to high risk patients, and excludes low-risk patients > 50 years, node negative patients will be disproportionately younger in order to be eligible, while node positive patients will be expected to have a more typical age distribution. It is assumed that 45% of patients will be grade 3.  
The enrollment of grade 3 patients on the UK START A was 28% and START B 23%, and 19% in the trial by Whelan et al. The percentage enrollment on the UK START trials of age < 50, grade 3 or node positive was 56% for trial A and 48% for trial B. It is also assumed that 60% of patients will be ER-positive, and 40% ER-negative. In the Whelan study, the enrollment of ER-negative patients was 27%.  
| Table 3: Patient Enrollment Estimates Cohort Protocol enrollment N0 65% N1 35% Age ≤ 50 50% Age > 50 50% Grade 3 45% ER negative 40%   |    |
|----------------------------------------------------------------------------------------------------------------------------------------|----|
| Neoadjuvant chemo                                                                                                                      | 5% |  
The protocol will specifically exclude the following patients which have a very low risk of 5-year local recurrence:
1) DCIS and age ≥ 50 years. 2) DCIS and age < 50 years and grade 1 or 2 3) Invasive breast cancer and ≥ 70 years old, T1, N0, ER/PR positive 4) Invasive breast cancer and ≥ 50 years old, T1, N0, Grade 1-2, ER/PR positive.  
Based on a control arm 5-year local failure rate of 6%, Table 4 below shows the noninferiority margin and corresponding sample sizes for 5-year local failure rates for the hypofractionated arm of 9 and 9.5%.  
Table 4: Sample Size Calculations  
| 5-Year                                |              |      |      |             |
|---------------------------------------|--------------|------|------|-------------|
| Control Arm  Local Failure  Rate      | 5-Year       |      |      |             |
| Experimental  Arm Local  Failure Rate | Hazard Ratio |      |      |             |
| (Hypo/Control)                        | Non              |      |      |             |
| Inferiority  Margin                   | Required     |      |      |             |
| Sample Size                           |              |      |      |             |
| Evaluable (Total)                     |              |      |      |             |
| 6%                                    | 9%           | 1.52 | 0.42 | 2150 (2312) |  
6% 9.5% 1.61 0.48 1900 (2044)  
The required sample size for the primary endpoint of local failure is based on the following conditions:
- Local- failure times are exponentially distributed with (at least approximately)
constant hazards in both treatment arms
- The control (standard) arm will have a 5-year local failure rate of 6% (yearly crude hazard of 0.01238)
- The experimental arm will have a 5-year local failure rate of no more than 9%
(yearly crude hazard of 0.01886)
- 0 = 0.42 (non-inferiority margin)
- Upper limit on hazard ratio (experiment/control) = 1.52
- One-sided test at  = 0.025
- Statistical power of 90% to conclude non-inferiority if HR = 1 - 4 years of accrual with 5 years of follow-up - Two interim significance tests and a final test are planned
With 90% statistical power to conclude non-inferiority if the HR = 1, a one-sided significance level of 0.025 and the parameters above, 2150 patients will be accrued uniformly over 4 years to reach the required 245 local failure events. Guarding against an ineligibility or lack-of-data rate of up to 7%, the final targeted accrual for this study will be 2312 patients.  
Given the impact of treatment crossovers on non-inferiority trials, the rate of treatment crossovers will be closely monitored. Table 5 shows the impact for 5% and 10% crossover rates. If the crossover rate falls between 5% and 10%, the RTOG will discuss with NCI the potential of amending the trial in order to adjust for this crossover so as to maintain the original study parameters. If the crossover rate reaches or exceeds 10%, RTOG will discuss with NCI the feasibility of continuing the trial. Table 5: Impact of Crossover  
| Crossover   | Adjusted 5-yr   | Adjusted 5-yr   | Type I Error       |                                                            |
|-------------|-----------------|-----------------|--------------------|------------------------------------------------------------|
| Rate        | Control Rate    | Hypo Rate       | (0.025 by  Design) | Increase in Accrual Time  to Maintain Original  Parameters |
| 5%          | 0.0615          | 0.0885          | 0.05               | 0.82 years                                                 |
| 10%         | 0.0631          | 0.0870          | 0.08               | 2.16 years                                                 |  
Redesign (2021)
The redesign was done in accordance with the NCI Policy for Major Design Amendments for Ongoing Randomized Clinical Trials and redesign specifics performed by a statistician independent from the trial. The statistical design and analysis plan is revised based on the following changes to the assumptions made in the original design, using the completed accrual. These adjustments will allow for timely reporting of the trial results, while maintaining statistical integrity and reflecting current knowledge of the observed local failure rate in the control arm.  
1) Change the upper limit on the hazard ratio and the corresponding non‐inferiority margin Based on the currently observed local failure rate in the control arm (Arm 1), the redesign is based on a 5‐year local failure rate of 1.59% (yearly hazard =
0.0032). Since this is much lower than the original estimate of 6%, the redesign for the non-inferiority primary endpoint hypothesis will use a larger hazard ratio (HR) upper limit of 2.12 (yearly hazard = 0.0068, corresponding to a non‐inferiority margin = 0.75), while maintaining a smaller absolute difference in 5‐year local failure rates. The 5‐year event rate for the experimental arm (Arm 2)
under the null hypothesis of inferiority would be no more than 3.33%, an absolute increase of 1.74% from the control arm, compared to the original design of no more than 9%, which was an absolute increase of 3%.  
2) Change the power and significance level to 80% and 0.05, respectively.  
The original sample size calculations were based on statistical power of 90% to conclude non‐inferiority if HR=1 and a one‐sided significance level of 0.025. The redesign is revising these to 80% and 0.05, respectively, to allow for more timely reporting so that the trial may maintain clinical relevancy.  
3) Omit the originally planned interim analyses.
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summary

Assuming a 5‐year local failure rate of 1.59% in Arm 1, an upper bound HR of 2.12 for the non-inferiority alternative hypothesis and using a 1‐sided significance level of 0.05, an analyzable sample size of at least 2150 patients will provide >80% power to conclude non‐inferiority if the HR is 1 when at least 46 IBR events are observed.  
If the alternative hypothesis of noninferiority is accepted based on the proposed analyses, a test of superiority also will be conducted to determine if the hypofractionated treatment (Arm 2) is superior to the standard treatment (Arm 1). With 2150 analyzable patients and a one-sided type I error of 0.05, there will be 71% power to detect a reduction in the 5-year local failure rate from 1.59% to 0.8% based on an intention to treat analysis.  
13.3 **Accrual**
Patient accrual is projected to be 45 cases per month, with a ramp-up period in the first 6 months. The expected monthly accrual in months 1 through 3 and months 4 through 6 following the study being broadcast to RTOG membership and placed on the CTSU
menu are 0 and 20, respectively. If the total accrual during months 13 through 18 of the study is ≤ 20% of the targeted accrual (< 55 cases in total), then the protocol will be discontinued per NCI-CTEP accrual guidelines for phase III studies. If the total accrual during months 13 through 18 is between 21% and 49% (55 to 133 cases), then the protocol will continue to accrue subjects and will be evaluated again at the end of month 24. If the accrual during months 22 through 24 is at least 50% of the targeted accrual (≥
68 cases in total), the NCI-CTEP accrual guidelines for phase III studies will have been met and the study will continue accrual; otherwise, the study will be discontinued.  
13.4 Analysis Plan (16-DEC-2021)
13.4.1 Statistical Methods Local failure time will be measured from the date of randomization to the date of first local failure or last follow-up. The primary hypothesis will be tested using the logrank test comparing the crude (i.e.  
cause-specific) hazard of local failure between treatment groups. The Cox proportional hazards regression model will be used to estimate the treatment hazard ratio and investigate additional factors that may be related to local failure. The cumulative probability of local failure in the presence of competing failure events will be estimated by the cumulative incidence method. (Kalbfleish 1980) The cumulative incidence distributions between the two arms will be compared using Gray's test (1988). We note that because competing failure types are not expected to differ between treatment arms, it is anticipated that results from comparing cause-specific hazards or cumulative incidence functions should yield similar inferential results.  
Overall survival, disease-free survival, and distant disease-free survival will be estimated by the Kaplan-Meier method (Kaplan 1958) and distributions between the two arms will be compared using the log-rank test (Mantel 1966).  
13.4.2 Interim Analysis to Monitor the Study Progress Interim reports with statistical analyses will be prepared twice per year until the initial treatment results have been presented/published. In general, the interim reports will contain the following information:
- patient accrual rate with a projected completion date (while the study is still accruing)
- total patients accrued
- distributions of important pretreatment and prognostic baseline variables - the frequencies and severity of adverse events by treatment arm - compliance rates of treatment delivery
The interim reports will not contain the results from the treatment comparisons with respect to the primary endpoint, overall survival, or any secondary endpoints, with the exception of reporting of adverse events. Additionally, the rate of treatment crossovers will be evaluated on a quarterly basis, until the last patient has completed treatment. If this rate exceeds 10%, the study will be evaluated for a potential sample size increase to adjust for the crossover effect.  
13.4.3 CDUS Reports 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.  
13.4.4 Data Monitoring Committee (DMC) Review To monitor the safety and efficacy of this study, it will be officially reviewed by the NRG
Oncology DMC twice a year in conjunction with the NRG Oncology semi-annual meeting and in between meetings as needed.  
13.4.5 Significance Testing for Early Termination and/or Reporting Primary Endpoint: Local Failure Two interim analyses will be performed when 33% and 67% of the local failure events have occurred, corresponding to 81 and 165 local failure events. At each look, if the experimental arm is significantly better than the standard arm (at p<0.001) then accrual will be stopped (if applicable) and the trial results will be reported with the conclusion that the hypo-fractionated WBI arm is non-inferior to the standard fractionated WBI arm with respect to local failure. For the study, a hazard ratio up to 1.52 (hypo/standard) will still result in a conclusion of non-inferiority. At the interim looks, if the lower bound of the 95% confidence interval for the hazard ratio (hypo/standard) is greater than 1.52, then accrual will be stopped (if applicable)
and the trial results will be reported, with the conclusion that the hypo-fractionated WBI arm is inferior to the standard fractionated WBI arm with respect to local failure.  
In addition to accrual, distributions of pretreatment characteristics, frequency and severity of adverse events, and compliance with protocol treatment, at the first RTOG DMC meeting following the required number of deaths for each planned interim analysis, blinded efficacy results will be reported to the NRG Oncology DMC.  
Analysis for Reporting the Initial Treatment Results The primary hypothesis of this study is that the local failure rate in the hypofractionated arm (Arm 2) will not be significantly worse than in the standard treatment arm (Arm 1). This major analysis will occur after at least 46 local failures have been observed. It will include:
- tabulation of all cases entered and those excluded from the analyses with the reasons for exclusion given
- distributions of important prognostic baseline variables - the frequencies and severity of adverse events by treatment arm - compliance rate of treatment delivery - observed results with respect to the primary and secondary endpoints All eligible patients randomized will be included in the comparison and will be grouped by assigned treatment in the analysis. The primary hypothesis of noninferiority will be tested using the logrank test statistic, comparing the cause-specific hazards, with a 1-sided significance level of 0.05. Additional analyses of treatment effect will be performed using the Cox proportional hazard model with the stratification factors included as fixed covariates, as well as any factors that show an imbalance between the arms. Where feasible, treatment comparisons with respect to the primary endpoint (local failure) will be compared within ethnic and racial categories.
nrg oncology rtog 1005 a
13.5 quality of life

13.5.1 Design The primary endpoint for the breast-related symptoms and side effects of the trial is self-reported cosmesis, using the BCTOS cosmesis scale (Stanton 2001). Patients that do and do not receive chemotherapy will be recruited and analyzed separately to address this cosmesis endpoint. The BCTOS will be collected at baseline, after informed consent has been obtained, end of radiation, 1 month and 6 months after radiation, and 1, 2 and 3 years after completion of radiation; with the primary endpoint focusing on mean change from baseline to 3 years. The goal is to establish that self - reported cosmesis results for the experimental arm are non-inferior to those of the control arm.  
Two-hundred and sixty-six evaluable patients provide 90% power, with a one-sided alpha of 0.025, to test the null hypothesis that the mean change in cosmesis score in the experimental arm will be at least 0.4 standard deviations worse than in the control arm. To answer this hypothesis separately in patients that do and do not receive chemotherapy and to allow for up to a 10% attrition rate for the 3-year assessment, 296 patients receiving chemotherapy and 296 patients not receiving chemotherapy will be recruited for the QoL substudy, for a total of 592 patients.  
Physician reported cosmesis will also be evaluated at baseline, and 1 & 3 years after completion of radiation, as well as photos being collected at the same time points.  
13.5.2 Analysis The t-test will be used for the primary QoL comparison of mean change in cosmesis score (baseline to 3 years), measured by BCTOS between the treatment arms. In addition to cosmesis, the pain and functional status subscales from the BCTOS will be compared, focusing on change from baseline to 1 year from the completion of radiation.  
The t-test will also be used to compare the treatment arms for these subscales. Within each of the chemotherapy and non-chemotherapy groups, 266 patients will provide 90% and 85% power to detect effect sizes of 0.4 and 0.37 respectively, with 1-sided alpha levels of 0.025, for these subscales.  
Secondary longitudinal analyses, using all of the time points collected, will be evaluated for the three subscales of the BCTOS.  
Using photographs collected at baseline, and 1 and 3 years after completion of radiation, cosmesis will be evaluated by an independent panel using the same scoring scale as reported by the physicians; and will be reported separately for chemotherapy and nonchemotherapy patients.  
13.5.3 Missing Quality of Life Data Processes such as e-mail alerts will be in place to prospectively remind sites about upcoming QoL assessments in order to help minimize the amount of missing data. The distributions of quality of life data collection patterns over all collection points in each treatment arm will be described. To inspect the missing data mechanism at least a graphical method will be used. 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, list wise 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 quality of life 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 mechanism (Donaldson 2005) 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.  
13.6 **Treatment Costs**
The shorter duration of accelerated WBI with concurrent boost can be expected to lead to lower costs for those procedures based on the time of a patient's treatment compared to standard WBI with sequential boost, but the type and intensity of procedures may differ between the two study arms. For example the distribution of treatment approaches, e.g. IMRT, 3DCRT, may differ between the study arms. Patients treated with hypofractionated WBI with concomitant boost may be more likely to receive IMRT than patients treated with standard WBI with sequential boost and the difference in approach could lead to higher treatment costs. A cost model will be developed for each study arm with each of the possible treatment approaches, and the procedures used in each approach. The model will use the actual distribution of type of treatment approach in each study arm and Medicare relative value units and conversion factors to estimate and compare treatment costs for each study arm and each type of treatment. The model will also include stratification and patient risk factors. The primary cost analysis will test whether hypofractionated WBI with concurrent boost is not higher in treatment cost than standard WBI with sequential boost.  
13.7 **Gender and Minorities**
Women of all races and ethnic groups are eligible for this study. In conformance with the national Institutes of Health (NIH) Revitalization Act of 1993 with regard to inclusion of women and minorities in clinical research, possible interactions between race/ethnicity and treatment have been considered. Based on NSABP B-39/RTOG 0413, it is projected that 3% of the patients will be of Hispanic or Latino ethnicity and 97% will not; racial distribution are projected to be 91% white, 6% black or African American, 2.5% Asian and
< 1% for both American Indian or Native Alaskan and Native Hawaiian or other pacific islander. The projected non-White and Hispanic/Latino accrual rates are too low for any meaningful treatment comparisons.  
The following table lists the projected accrual by gender, ethnic, and racial categories.  
| Gender                                    |         |       |       |
|-------------------------------------------|---------|-------|-------|
| Ethnic Category                           | Females | Males | Total |
| Hispanic or Latino                        | 58      | N/A   | 58    |
| Not Hispanic or Latino                    | 2254    | N/A   | 2254  |
| Ethnic Category: Total of all subjects    | 2312    | N/A   | 2312  |
| Gender                                    |         |       |       |
| Racial Category                           | Females | Males | Total |
| American Indian or Alaskan Native         | 2       | N/A   | 2     |
| Asian                                     | 58      | N/A   | 58    |
| Black or African American                 | 139     | N/A   | 139   |
| Native Hawaiian or other Pacific Islander | 9       | N/A   | 9     |
| White                                     | 2104    | N/A   | 2104  |
| Racial Category: Total of all subjects    | 2312    | N/A   | 2312  |
nrg oncology rtog 1005 a
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appendix i (5/6/13) study parameter

| Pre-Treatment Assessments                                            |                                          |                                        |                                        |
|----------------------------------------------------------------------|------------------------------------------|----------------------------------------|----------------------------------------|
| Assessments                                                          | Within 180 days prior                    | Within 90                              |                                        |
| to study entry*                                                      | days of                                  |                                        |                                        |
| diagnostic, biopsy of  the affected  breast  establishing  diagnosis | Within 50  days from study entry         | Within 28  days prior  to study  entry | Within 14  days prior  to study  entry |
| Last surgery  (breast/axilla)/ last  chemo                           | X                                        |                                        |                                        |
| History and  Physical, Zubrod  and weight  documentation             | X                                        |                                        |                                        |
| Breast Examination*                                                  | X                                        |                                        |                                        |
| Right and Left                                                       | X                                        |                                        |                                        |
| Mammogram CT scan of  ipsilateral breast for  treatment planning     | X*                                       |                                        |                                        |
| Performance status                                                   | X                                        |                                        |                                        |
| CBC w/ diff & ANC                                                    | X                                        |                                        |                                        |
| Chemistry panel                                                      | X                                        |                                        |                                        |
| Determination of  hormone receptor                                   | Prior to study entry. See section 3.1.11 |                                        |                                        |
| status Serum or urine pregnancy test (if  applicable)                | X                                        |                                        |                                        |
| Bone scan                                                            | X*                                       |                                        |                                        |
| CT of chest, ab, and                                                 | X*                                       |                                        |                                        |
| pelvis or PET/CT Negative postexcision  mammogram                                                                      | Recommended*                             |                                        |                                        |
| *See sections 4.0 and 11.1 for exceptions and details                |                                          |                                        |                                        |  
| Assessments During Treatment (1/9/14)                                                                                                                                                                    |                   |               |                |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|---------------|----------------|
| Assessments                                                                                                                                                                                              | Prior to Start of | Weekly During | Last Day of RT |
| RT                                                                                                                                                                                                       | RT                |               |                |
| History and Physical, Zubrod and                                                                                                                                                                         | X                 | X             |                |
| weight documentation Breast Assessment *                                                                                                                                                                 | X                 | X             |                |
| Performance status                                                                                                                                                                                       | X                 | X             |                |
| Adverse event evaluation                                                                                                                                                                                 | X                 | X             |                |
| Specimens for research-(if patient                                                                                                                                                                       | X                 |               |                |
| consents)  Cosmesis/QOLStudy (if patient  consents) (for patients registered prior to 1/9/14)                                                                                                            | X                 |               |                |
| NOTE: Non-chemotherapy Cosmesis subset  closed to accrual 3/8/13;chemotherapy  Cosmesis subset closed to accrual 1/9/14 - Doctor cosmetic assessment  (questionnaire and photos) - Patient questionnaire | X                 | X             |                |
| (BCTOS)                                                                                                                                                                                                  |                   |               |                |
| *See section 11.1 for details                                                                                                                                                                            |                   |               |                |  
| Follow-Up Assessments                                                                                                                                                                                    |                 |                           |                 |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|---------------------------|-----------------|
| Assessments                                                                                                                                                                                              | 1 Month After   | 6 Months After            | 1 Year After RT |
| RT Completion                                                                                                                                                                                            | RT Completion   | Completion  Then Annually |                 |
| History and Physical, Zubrod and                                                                                                                                                                         | X               | X                         | X               |
| weight documentation Breast Examination *                                                                                                                                                                | X               | X                         | X               |
| Bilateral or Right and Left                                                                                                                                                                              | X               |                           |                 |
| Mammography Ipsilateral Mammography of the                                                                                                                                                               | X               |                           |                 |
| treated breast Performance status                                                                                                                                                                        | X               | X                         | X               |
| Adverse event evaluation                                                                                                                                                                                 | X               | X                         | X               |
| Cosmesis/QOLStudy (if patient  consents) (for patients registered prior to 1/9/14)                                                                                                                       | X (and @ year 3 |                           |                 |
| NOTE: Non-chemotherapy Cosmesis subset  closed to accrual 3/8/13;chemotherapy  Cosmesis subset closed to accrual 1/9/14 - Doctor cosmetic assessment  (questionnaire and photos) - Patient questionnaire | X               | X                         | X (for 3 yrs)   |
| (BCTOS)                                                                                                                                                                                                  |                 |                           |                 |
| *See section 11.1 for details                                                                                                                                                                            |                 |                           |                 |
nrg oncology rtog 1005 a
appendix ii zubrod performance scale

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
appendix ii zubrod performance scale

AJCC STAGING SYSTEM
Edge, SB, ed. *AJCC Cancer Staging Manual*. 7th ed. New York, NY: Springer; 2010.
appendix iii
breast

| slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be  rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is  reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the  subscript "c" or "p" modifier to indicate whether the T classification was determined by clinical (physical  examination or radiologic) or pathologic measurements, respectively. In general, pathologic  determination should take precedence over clinical determination of T size. TX Primary tumor cannot be assessed T0 No evidence of primary tumor.  Tis Carcinoma in situ Tis (DCIS) Ductal carcinoma in situ Tis (LCIS) Lobular carcinoma in situ Tis (Paget's) Paget's disease of the nipple NOT associated with invasive carcinoma and/or carcinoma  in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the  breast parenchyma associated with Paget's disease are categorized based on the size  and characteristics of the parenchymal disease, although the presence of Paget's  disease should still be noted T1 Tumor ≤20 mm in greatest dimension T1mi Tumor ≤1 mm in greatest dimension T1a Tumor >1 mm but ≤5 mm in greatest dimension T1b Tumor >5 mm but ≤10 mm in greatest dimension T1c Tumor >10 mm but ≤20 mm in greatest dimension T2 Tumor >20 mm but ≤50 mm in greatest dimension T3 Tumor >50 mm in greatest dimension T4 Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or  skin nodules). Note: Invasion of the dermis alone does not qualify as T4 T4a Extension to the chest wall, not including only pectoralis muscle adherence/invasion T4b Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of  the skin, which do not meet the criteria for inflammatory carcinoma  T4c Both T4a and T4b T4d Inflammatory carcinoma (see "Rules for Classification") Note: Inflammatory carcinoma is restricted to cases with typical skin changes involving a third or more of the skin of the breast. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| NX   | Regional lymph nodes cannot be assessed (e.g., previously removed)                                                                                                                                  |
|------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| N0   | No regional lymph node metastases                                                                                                                                                                   |
| N1   | Metastases to movable ipsilateral level I, II axillary lymph node(s)                                                                                                                                |
| N2   | Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in  clinically detected* ipsilateral internal mammary nodes in the absence of clinically evident |  
| axillary lymph node metastases                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| N2a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to  other structures                                                                                                                                                                                                                                                                                                       |                                                                    |
| N2b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Metastases only in                                                                                                                                                                                                                                                                                                                                                                                                     | clinically detected* ipsilateral internal mammary nodes and in the |
| absence of clinically evident level I, II axillary lymph node metastases                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                    |
| N3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I,  II axillary lymph node involvement; or in clinically detected* ipsilateral internal mammary  lymph node(s) with clinically evident level I, II axillary lymph node metastases; or metastases  in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary  lymph node involvement |                                                                    |
| N3a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Metastases in ipsilateral infraclavicular lymph node(s)                                                                                                                                                                                                                                                                                                                                                                |                                                                    |
| N3b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)                                                                                                                                                                                                                                                                                                                                    |                                                                    |
| N3c                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Metastases in ipsilateral supraclavicular lymph node(s)                                                                                                                                                                                                                                                                                                                                                                |                                                                    |
| *Note: Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by  clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic  macrometastasis based on fine needle aspiration biopsy with cytologic examination. Confirmation of  clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f)  suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the  absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the  confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy, or sentinel lymph  node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in  conjunction with a pathologic T assignment. Regional Lymph Nodes Pathologic (pN)* pNX Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for  pathologic study) pN0 No regional lymph node metastasis identified histologically *Note: Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or  single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section. ITCs may be  detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are  excluded from the total positive node count for purposes of N classification but should be included in the total  number of nodes evaluated. pN0(i-) No regional lymph node metastases histologically, negative IHC pN0(i+) Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC  including ITC) pN0  No regional lymph node metastases histologically, negative molecular findings (RT-PCR) (mol-) pN0 Positive molecular findings (RT-PCR),** but no regional lymph node metastases detected by  histology or IHC (mol+) pN1 Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or in internal mammary  nodes with metastases detected by sentinel lymph node biopsy but not clinically detected*** pN1mi Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than  2.0 mm) pN1a Metastases in 1-3 axillary lymph nodes, at least one metastasis greater than 2.0 mm pN1b Metastases in internal mammary nodes with micrometastases or macrometastases detected  by sentinel lymph node biopsy but not clinically detected*** pN1c Metastases in 1-3 axillary lymph nodes and in internal mammary lymph nodes with  micrometastases or macrometastases detected by sentinel lymph node biopsy but not  clinically detected pN2 Metastases in 4-9 axillary lymph nodes; or in clinically detected**** internal mammary lymph  nodes in the absence of axillary lymph node metastases |                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                    |  
| pN2a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Metastases in 4-9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm)                                                                                                                                                                                                                                                                                                                                                                                                                 |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| pN2b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Metastases in clinically detected**** internal mammary lymph nodes in the absence of axillary lymph node metastases                                                                                                                                                                                                                                                                                                                                                                                     |
| pN3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph  nodes; or in clinically detected**** ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph  nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel  lymph node biopsy but not clinically detected***; or in ipsilateral supraclavicular lymph nodes |
| pN3a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Metastases in ten or more axillary lymph nodes (at least one tumor deposit greater than 2.0  mm); or metastases to the infraclavicular (level III axillary lymph) nodes                                                                                                                                                                                                                                                                                                                                 |
| pN3b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Metastases in clinically detected**** ipsilateral internal mammary lymph nodes in the  presence of one or more positive axillary lymph nodes; or in more than three axillary lymph  nodes and in internal mammary lymph nodes with micrometastases or macrometastases  detected by sentinel lymph node biopsy but not clinically detected***                                                                                                                                                            |
| pN3c                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Metastases in ipsilateral supraclavicular lymph nodes                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| *Notes: *Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy.  Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node  dissection is designated (sn) for "sentinel node," for example, pN0(sn). **RT-PCR: reverse transcriptase/polymerase chain reaction ***"Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy)  or not detected by clinical examination. ****"Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by  clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
appendix iii
distant metastasis (m)

M0 No clinical or radiographic evidence of distant metastases cM0(i+) No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases M1 Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm  
| Anatomic Stage/Prognostic Groups Stage 0   | Tis             | N0   | M0   |
|--------------------------------------------|-----------------|------|------|
| Stage IA                                   | T1*             | N0   | M0   |
| Stage IB                                   | T0 T1*          |      |      |
| Stage IIA                                  | T0 T1* T2       |      |      |
| Stage IIB                                  | T2 T3           |      |      |
| Stage IIIA                                 | T0 T1* T2 T3 T3 |      |      |
| Stage IIIB                                 | T4 T4 T4        |      |      |  
| N1mi                    | M0                |
|-------------------------|-------------------|
| N1mi                    | M0                |
| N1** N1** N0            | M0 M0 M0          |
| N1                      | M0                |
| N0                      | M0 M0 M0 M0 M0 M0 |
| N2 N2 N2 N1 N2 N0 N1 N2 | M0 M0 M0          |  
Stage IIIC Any T N3 M0 Stage IV Any T Any N M1
*Notes: *T1 includes T1mi. **T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB. M0 includes M0(i+).  
- The designation pM0 is not valid; any M0 should be clinical. - If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.  
- Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.  
- Post neoadjuvant therapy is designated with "yc" or "yp" prefix. Of note, no stage group is assigned if there is a complete pathologic response (CR) to neoadjuvant therapy, for example, y Appendices for NRG Oncology **Biospecimen Collection**
NRG Oncology FFPE Specimen Plug Kit Instructions NRG Oncology Blood Collection Kit Instructions Shipping Instructions:
US Postal Service Mailing Address: **For FFPE or Non-frozen Specimens Only** NRG Oncology **Biospecimen Bank** University of California San Francisco UCSF Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens NRG Oncology Biospecimen Bank 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 ST has the consent boxes checked off.  
❑ Check that all samples are labeled with NRG Oncology study and case number, and include date of collection as well as collection time point.  
❑ **FFPE Specimens:**
o Slides should be shipped in a plastic slide holder/ slide box. Place a small wad of padding in top of container If you can hear the slides shaking they are likely to 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 or gauze. Place padding in top of container so that if you shake the container the blocks are not shaking. If you can hear them shaking they might break during shipping.  
o Slides, Blocks or Plugs can be shipped ambient or with a cold pack either by USPS to the USPS address (94143) or by Courier to the Street Address (94115). Do NOT ship on Dry Ice.  
❑ **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. If possible keep serum, plasma, and whole blood submissions in separate bags.  
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 on dry ice 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 -80C until ready to ship.  
❑ For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank by email at: RTOG@ucsf.edu or (415)-476-7864 or fax (415)-476-5271.
appendix iv continued nrg oncology
distant metastasis (m)

This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology **Biospecimen**  
  
  
  
 Bank. The plug kit contains a shipping tube and a punch tool.  
Step 1 If the block is stored cold, allow it to equilibrate for 30 minutes at room temperature. Place the punch tool on the paraffin block over the selected tumor area. (Ask a pathologist to select area with tumor.) Push the punch into the paraffin block. Twist the punch tool once around to separate the plug from the block. Then pull the punch tool out of the block. The punch should be filled with tissue sample.  
Step 2 Label the punch tool with the proper specimen ID. DON'T remove specimen from the punch.  
Use a separate punch tool for every specimen. Call or e-mail us if you have any questions or need additional specimen plug kits. Step 3 Once punch tool is labeled, place in shipping tube and mail to address below. Please do not mix specimens in the same tube.  
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID.  
  
  
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block and return the remaining block to your facility. Please indicate on the submission form the request to perform the plug procedure and return of the block.  
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below: For Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the NRG Oncology Biospecimen Bank by email at: RTOG@ucsf.edu or call 415-476-7864
/FAX 476-5271; U.S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology Biospecimen Bank University of California San Francisco UCSF Box 1800 2340 Sutter Street, Room S341 San Francisco, CA **94143-1800**
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens or Trackable shipments NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115
appendix iv continued
nrg oncology blood collection kit

This Kit is for collection, processing, storage, and shipping of plasma and whole blood *(as specified by* the protocol):
Kit contents:
- One Purple Top EDTA tube for plasma (A)
- One Purple Top EDTA tube for Whole Blood
(B)
- Twenty (20) 1 ml cryovials
- Styrofoam container (inner)
- Cardboard shipping (outer) box
- Kit Instructions
- Specimen Transmittal Form
- Absorbent shipping material (3) - Biohazard bags (3)
- UN1845 DRY Ice Sticker - UN3373 Biological Substance Category B
Stickers
appendix iv continued
preparation and processing of plasma

❑ Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with the RTOG study and case number, collection date, time and time point, and clearly mark cryovials "plasma".  
Process:
1. After collection, 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 ST.  
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 into as many cryovials as are necessary for the plasma collected (5 to 10) labeled with RTOG 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 -70 to -90 C until ready to ship on dry ice.  
7. See below for storage conditions.
appendix iv continued
please make sure that every

❑ 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 clearly mark cryovials "blood".  
  
Process:
1. After collection, invert tube(s) multiple 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 as are necessary for the blood collected (3 to 5) 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 -70 to -90 C until ready to ship on dry ice.  
5. See below for storage conditions.
appendix iv continued
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 -20 C Freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only- Canada Mon-Tues).  
- 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 Mon-Tues).  
- OR:
- Samples can be stored in lid. nitrogen vapor phase (ship out Monday-Wednesday onlyCanada Mon-Tues).  
❑ Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
appendix iv continued
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 and tape to the outside top of the Styrofoam box.  
❑ Wrap frozen specimens of same type (i.e., all 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 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.  
❑ For questions regarding collection, shipping or to order a Blood Collection Kit, please Email RTOG@ucsf.edu or call (415)476-7864.
appendix iv continued
shipping address

Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology **Biospecimen Bank** University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 For questions, call 415-476- 7864 or e-mail: RTOG@ucsf.edu 77
appendix v (5/6/13) radiation therapy
1 contouring targets and organs

Contouring accurately and consistently is essential for case evaluation and the data comparison necessary to achieve the primary and secondary endpoints of this protocol. The structures to be contoured are the same in both arms 1 and 2.  
The targets to be contoured in every case are:
- Lumpectomy
- Lumpectomy clinical target volume (CTV) - Lumpectomy planning target volume (PTV)
- Lumpectomy planning target volume for evaluation (PTV-eval)
- Breast CTV
- Breast PTV
- Breast PTV-eval The following OAR will be contoured on all cases:
- Ipsilateral lung - Contralateral lung
- Heart
- Contralateral breast - Thyroid.  
2 Contouring Targets:
The targets to be contoured are listed in the protocol under section 6.4.2 are listed below with accompanying figures 1- 5.  
2.1 Lumpectomy Target Volumes 2.1.1 Lumpectomy: (Figure 1.) For this protocol the term "lumpectomy" will represent the surgical cavity from the breast conserving surgery. This is to replace the typical gross tumor volume designation (GTV) used in other disease sites or when the tumor is insitu. Contour using all available clinical and radiographic information including the excision cavity volume, architectural distortion, lumpectomy scar, seroma and/or extent of surgical clips (clips are strongly recommended). Patients without a clearly identifiable excision cavity are not eligible for protocol participation.  
2.1.2 Lumpectomy Clinical Target Volume (CTV): (Figure 1.) The Lumpectomy CTV
consists of the contoured Lumpectomy plus a 1 cm 3D expansion with the following 3 limitations: 1. limit the CTV posteriorly at anterior surface of the pectoralis major; 2. limit anterolaterally 5 mm from skin; and 3. should not cross midline. In general, the pectoralis muscles and/or serratus anterior muscles are excluded from the lumpectomy CTV unless clinically warranted by the patient's pathology.  
2.1.3 Lumpectomy Planning Target Volume (PTV): (Figure 2.) The lumpectomy PTV is a 7 mm expansion on the Lumpectomy CTV and excludes the heart. This is the structure used for beam aperture generation.  
2.1.4 Lumpectomy Planning Target Volume for evaluation (PTV_EVAL) (Figure 3.).  
This Lumpectomy PTV_EVAL is limited to exclude the portion of the PTV that extends outside the ipsilateral breast beyond skin or into the chest wall or thorax.  
The lumpectomy PTV-eval consists of the lumpectomy PTV excluding the first 5 mm of tissue under the skin (in order to remove most of the buildup region for the DVH analysis) and excluding the Lumpectomy PTV expansion beyond the posterior extent of breast tissue (chest wall, pectoralis muscles and lung) when pertinent. This Lumpectomy PTV_EVAL is the structure used for DVH constraints and analysis.  
  
  
  
2.2 Breast Target Volumes 2.2.1 Breast Clinical Target Volume (CTV): (figure 4.), Consists of and takes into account the clinical borders placed at the time of CT simulation, the apparent glandular and fatty breast tissue visualized by CT, consensus definitions of anatomical borders from the RTOG breast cancer atlas, and should include the Lumpectomy CTV. The breast CTV is limited anteriorly within 5 mm from the skin and posteriorly to the anterior surface of the pectoralis muscles, serratus anterior muscle/ chestwall, boney thorax and lung. In general, the pectoralis and serratous anterior muscles/chestwall are excluded from the breast CTV unless clinically warranted by the patient's pathology. RTOG anatomy consensus guidelines are available at:
(http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx)
2.2.2 Breast Planning Target Volume (PTV): (figure 4.): Consists of the Breast CTV
generated above plus a 7 mm 3D expansion (excluding heart and not to cross midline). This is the structure used for beam aperture generation.  
2.2.3 Breast Planning Target Evaluation for evaluation (PTV eval): (figure 5) This Breast PTV_EVAL is intended to exclude the portion of the breast PTV that extends outside the outside the patient or into the boney thorax and lungs. This Breast PTV_EVAL consists of the breast PTV limited to exclude the part anteriorly outside the patient and the first 5 mm of tissue under the skin (in order to remove most of the buildup region for the DVH analysis) and posteriorly is limited no deeper to the anterior surface of the ribs (excludes boney thorax and lung). This Breast PTV_EVAL is the structure used for DVH constraints and analysis.  
   
  
3 Organs at Risk (OAR)
The OAR to be contoured on all cases are the ipsilateral and contralateral lung, heart, thyroid and contralateral breast. 3.1 Ipsilateral and contralateral Lung: This may be contoured with auto-segmentation with manual verification.  
3.2 Heart: This is to be contoured on all cases- *not just the left sided ones*. The heart should be contoured beginning just inferior to the level in which the pulmonary trunk branches into the left and right pulmonary arteries (PA). Above the PA, none of the heart's 4 chambers are present. The heart should be contoured on every contiguous slice thereafter to its inferior most extent near the diaphragm. The following structures if identifiable should be excluded from the heart contour: esophagus, great vessels (ascending and descending aorta, inferior vena cava). One need not include pericardial fat, if present. Contouring along the pericardium itself, when visible, is appropriate.  
3.3 Thyroid: The thyroid is easily visible on a non-contrast CT due to its preferential absorption of Iodine, rendering it "brighter" or denser than the surrounding neck soft tissues. The left and right lobes fo the thyroid are somewhat triangular in shape and often do not converge anteriorly at mid-line. All "bright" thyroid tissue should be contoured.  
3.4 Contralateral Breast: Includes contralateral breast as defined by clinical markers And the apparent CT glandular breast tissue visualized by CT and consensus definitions of anatomical borders from the RTOG Breast Atlas. In general the borders are:
Posterior border: At the anterior surface of the pectoralis, serratous anterior muscles excluding chest wall, ribs, boney thorax and lung/heart; Medial border: The sternal-costal junction, Lateral border: Varies based on the size of the breast but typically is at the mid-axillary line and excludes the ipsilateral lattismus dorsi muscle. Cephald border: Should be similar to that of the ipsilateral breast CTV Caudal:border: Inframammary fold and should be similar to that of the ipsilateral breast CTV.  
Anterior border: Skin minus 5 mm to minimize inaccuracy of dose calculation at the skin surface. RTOG anatomy consensus guidelines are available at: (http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx)
appendix vi (5/6/13) dose volume
1 contouring targets and organs

All maximum doses should be defined in one dose calculation voxel, e.g., 3x3x3 mm3.  
The conformity index is an optional constraint, but must be recorded and reported on all cases  
| Breast PTV Eval  Breast  PTV eval Description   | Constraint                                                    | ARM II 40 Gy in 15  concurrent  boost to 48  Gy                   |          |              |         |
|-------------------------------------------------|---------------------------------------------------------------|-------------------------------------------------------------------|----------|--------------|---------|
| Goal                                            | Volume                                                        | Dose                                                              |          |              |         |
| Breast PTV  Eval  receiving  wholebreast dose                                                 | ARM I 50 Gy in 25 sequential  12-14 Gy  boost total  62-64 Gy | ARM I  42.7 in 16 sequential 12- 14 Gy boost  total 54.7-56.7  Gy |          |              |         |
| Per                                             | at least                                                      |                                                                   |          |              |         |
| Protocol                                        | 95% of the  breast PTV  Eval  receives                        | at least 95% of  whole breast  dose which is                      | 47.5 Gy  | 40.6 Gy      | 38 Gy   |
| Variation                                       | at least                                                      |                                                                   |          |              |         |
| Acceptable                                      | 90% of the  breast PTV  Eval  receives                        | at least 90% of  whole breast  dose which is                      | 45 Gy    | 38.4 Gy      | 36 Gy   |
| Breast PTV  Eval  receiving  boost dose         | Per                                                           | no more                                                           |          |              |         |
| Protocol                                        | than 30%  of the  breast PTV  Eval                            | exceeds 100%  of boost dose  which is                             | 62-64 Gy | 54.7-56.7 Gy | 48 Gy   |
| Variation                                       | no more                                                       |                                                                   |          |              |         |
| Acceptable                                      | than 35%  of the  breast PTV  Eval                            | exceeds 100%  of boost dose which is                              | 62-64 Gy | 54.7-56.7 Gy | 48 Gy   |
| Breast PTV  Eval  receiving  above the  wholebreast dose                                                 | Per                                                           | no more                                                           |          |              |         |
| Protocol                                        | than 50%  of the  breast PTV  Eval                            | exceeds 108%  of whole breast  dose which is                      | 54 Gy    | 46.1 Gy      | 43.2 Gy |
| Variation                                       | no more                                                       |                                                                   |          |              |         |
| Acceptable                                      | than 50%  of the of  the breast  PTV Eval                     | exceeds 112%  of whole breast  dose which is                      | 56 Gy    | 47.8 Gy      | 44.8 Gy |
| Breast PTV  Eval  maximum  dose                 | Per                                                           | does not                                                          |          |              |         |
| Protocol                                        | exceed 115%  of prescription  whole breast  dose which is     | 57.5 Gy                                                           | 49.1 Gy  | 46 Gy        |         |
| Variation                                       | does not                                                      |                                                                   |          |              |         |
| Acceptable                                      | exceed 120%  of prescription                                  | 60 Gy                                                             | 51.2 Gy  | 48 Gy        |         |  
| whole breast  dose which is                                                                                 |                            |              |
|-------------------------------------------------------------------------------------------------------------|----------------------------|--------------|
| Conformity  Index (Ratio  of volume  covered by  95%  prescription  isodose /  volume of  Breast PTV  Eval) | Per                        | no less than |
| Protocol                                                                                                    | 0.95 and no  more than 2.0 |              |
| Variation                                                                                                   | No less than               |              |
| Acceptable                                                                                                  | 0.85 and no  more than 2.5 |              |  
| Lumpectomy PTV Eval Lumpectomy                   | ARM I                                                             |                                                 |              |              |         |
|--------------------------------------------------|-------------------------------------------------------------------|-------------------------------------------------|--------------|--------------|---------|
| PTV Eval                                         | 50 Gy in 25                                                       |                                                 |              |              |         |
| Constraint                                       |                                                                   |                                                 |              |              |         |
| Description                                      | sequential  12-14 Gy  boost total  62-64 Gy                       | ARM II 40 Gy in 15  concurrent  boost to 48  Gy |              |              |         |
| Goal                                             | Volume                                                            | Dose                                            |              |              |         |
| Lumpectomy  PTV Eval  receiving  boost dose      | ARM I  42.7 in 16 sequential 12- 14 Gy boost  total 54.7-56.7  Gy |                                                 |              |              |         |
| Per                                              | at least                                                          |                                                 |              |              |         |
| Protocol                                         | 95% of  the  lumpecto my PTV  Eval  receives                      | at least 95% of boost dose which is             | 58.9-60.8 Gy | 52-53.9 Gy   | 45.6 Gy |
| Variation                                        | at least                                                          |                                                 |              |              |         |
| Acceptable                                       | 90% of  the  lumpecto my PTV  Eval  receives                      | at least 90% of  boost dose which is            | 55.8-57.6 Gy | 49.2-51 Gy   | 43.2 Gy |
| Lumpectomy PTV Eval  receiving  above boost dose | Per                                                               | no more                                         |              |              |         |
| Protocol                                         | than 5%  of the  lumpecto my PTV  Eval                            | exceeds 110%  of boost dose which is            | 68.2-70.4 Gy | 60.2-62.4 Gy | 52.8 Gy |
| Variation                                        | no more                                                           |                                                 |              |              |         |
| Acceptable                                       | than 10%  of the  lumpecto my PTV  Eval                           | exceeds 110%  of boost dose which is            | 68.2-70.4 Gy | 60.2-62.4 Gy | 52.8 Gy |
| Lumpectomy  PTV Eval  maximum  dose              | Per                                                               | does not                                        |              |              |         |
| Protocol                                         | exceed 115%  of boost dose which is                               | 71.3-73.6 Gy                                    | 62.9-65.2 Gy | 55.2 Gy      |         |
| Variation                                        | does not                                                          |                                                 |              |              |         |
| Acceptable                                       | exceed 120%  of boost dose which is                               | 74.4-76.8 Gy                                    | 65.6-68 Gy   | 57.6 Gy      |         |  
| Conformity  Index (Ratio  of volume  covered by  95%  prescription  isodose /  volume of  Lumpectomy  PTV Eval)   | Per                                                                                      | No less than                                                                             |         |         |
|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|---------|---------|
| Protocol                                                                                                          | 0.95 and no  more than 2.5                                                               |                                                                                          |         |         |
| Variation                                                                                                         | No less than                                                                             |                                                                                          |         |         |
| Acceptable                                                                                                        | 0.9 and no  more than 3                                                                  |                                                                                          |         |         |
| Normal Tissue Constraints Description                                                                             | Volume                                                                                   | ARM I                                                                                    | ARM II  |         |
| Heart dose constraint                                                                                             | Per                                                                                      | no more than 5% of the                                                                   |         |         |
| 1                                                                                                                 | Protocol                                                                                 | heart for left-sided  cancer 0% of the heart for  right-sided exceeds                    | 20 Gy   | 16 Gy   |
| Variation                                                                                                         | no more than 5% of the                                                                   |                                                                                          |         |         |
| Acceptable                                                                                                        | heart for left-sided  cancer 0% of the heart for  right-sided exceeds                    | 25 Gy                                                                                    | 20 Gy   |         |
| Description                                                                                                       | Volume                                                                                   | ARM I                                                                                    | ARM II  |         |
| Heart dose constraint                                                                                             | Per                                                                                      | no more than 30% of                                                                      |         |         |
| 2                                                                                                                 | Protocol                                                                                 | the heart for left-sided  cancer no more than 10% of  the heart for right-sided  exceeds | 10 Gy   | 8 Gy    |
| Variation                                                                                                         | no more than 35% of                                                                      |                                                                                          |         |         |
| Acceptable                                                                                                        | the heart for left-sided  cancer no more than 15% of  the heart for right-sided  exceeds | 10 Gy                                                                                    | 8 Gy    |         |
| Heart dose constraint                                                                                             | Per                                                                                      | Mean dose does not                                                                       | 400 cGy | 320 cGy |
| 3                                                                                                                 | Protocol                                                                                 | exceed                                                                                   |         |         |
| Variation                                                                                                         | Mean dose does not                                                                       | 500 cGy                                                                                  | 400 cGy |         |
| Acceptable                                                                                                        | exceed                                                                                   |                                                                                          |         |         |
| Ipsilateral lung dose                                                                                             | Per                                                                                      | no more than 15% of                                                                      |         |         |
| Protocol                                                                                                          | the ipsilateral lung exceeds                                                             | 20 Gy                                                                                    | 16 Gy   |         |
| Variation                                                                                                         | no more than 20% of                                                                      |                                                                                          |         |         |
| Acceptable                                                                                                        | the ipsilateral lung  exceeds                                                            | 20 Gy                                                                                    | 16 Gy   |         |
| Ipsilateral lung dose                                                                                             | Per                                                                                      | no more than 35% of                                                                      |         |         |
| constraint 1                                                                                                      | Protocol                                                                                 | the ipsilateral lung exceeds                                                             | 10 Gy   | 8 Gy    |
| Variation                                                                                                         | no more than 40% of                                                                      |                                                                                          |         |         |
| Acceptable                                                                                                        | the ipsilateral lung  exceeds                                                            | 10 Gy                                                                                    | 8 Gy    |         |
| Ipsilateral lung dose                                                                                             | Per                                                                                      | no more than 50% of                                                                      |         |         |
| constraint 2                                                                                                      | Protocol                                                                                 | the ipsilateral lung  exceeds                                                            | 5 Gy    | 4 Gy    |  
| Variation            | no more than 55% of                         |                                                                                                      |               |      |
|----------------------|---------------------------------------------|------------------------------------------------------------------------------------------------------|---------------|------|
| Acceptable           | the ipsilateral lung  exceeds               | 5 Gy                                                                                                 | 4 Gy          |      |
| Contralateral Lung   | Per                                         | no more than 10%                                                                                     | 5 Gy          | 4 Gy |
| Protocol             | exceeds                                     |                                                                                                      |               |      |
| Variation            | no more than 15%                            | 5 Gy                                                                                                 | 4 Gy          |      |
| Acceptable           | exceeds                                     |                                                                                                      |               |      |
| Contralateral Breast | Per                                         | Dmax does not exceed                                                                                 |               |      |
| Protocol             | / no more than 5%  exceeds                  | 310 / 186                                                                                            | 240 / 144 cGy |      |
| cGy                  |                                             |                                                                                                      |               |      |
| Variation            | Dmax does not exceed                        |                                                                                                      |               |      |
| Acceptable           | / no more than 5%  exceeds                  | 496 /                                                                                                | 384 / 240 cGy |      |
| 310cGy               |                                             |                                                                                                      |               |      |
| Thyroid              | Per                                         | Max point dose does                                                                                  |               |      |
| Protocol             | not exceed 2% of  prescribed dose which is  | 1.24-1.28  Gy for 62- 64 Gy  prescribed  dose or  1.09-1.13  Gy for  54.7-56.7  Gy  prescribed  dose | 0.96 Gy       |      |
| Variation            | Max point dose does                         |                                                                                                      |               |      |
| Acceptable           | not exceed 3% of  prescribed dose which  is | 1.86-1.92  Gy for 62- 64 Gy prescribed  dose or  1.64-1.7  Gy for  54.7-56.7  Gy  prescribed  dose   | 1.44 Gy       |      |
appendix vii (5/6/13) instructions for
1 contouring targets and organs

To submit cosmesis **photos:**
- **Make sure photos are available in a JPEG format on the computer that you are usingIdentify the photos as follows:**
Baseline photos-Single_B forTreated Breast view Both_B for Both Breasts view 1-year photos - Single_1 for Treated Breast view Both_2 for Both Breasts view 3-yearphotos- Single_3 for **Treated breast view Both_3 for Both Breasts view**
- Go **to http://www.rtog.org/**
- **Click on site tools link at the top of the page**
- Click on RTOG **Cosmesis Upload Tool** - **Click on RTOG 1005** - Log in using your personal ID **and Password** - **Complete the required fields and upload the photos**
- Please be sure to upload one photo of the treated breast and one photo showing **both**
breasts as instructed in Section 11.2.1 of the protocol