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management of radiation dose to

NRG Oncology is concerned about the estimated doses given from IGRT, and is committed to limiting the imaging dose when IGRT is used in any of its protocols. This can be accomplished by avoiding the use of this technology to make small changes in patient positioning that are within the stated PTV margins. The imaging dose to the patient may become significant if repeated studies are done for patients with severe set up problems (e.g. requiring frequent corrections that are larger than the PTV margins). It is recommended that patients demonstrating severe set up problems during the first week of treatment be moved to a treatment with larger margins.  
5.2.14 Replanning In cases of weight loss > 10% or substantial shrinkage of lymphadenopathy during therapy, it is recommended that the immobilization mask be adjusted or re-made in order to preserve adequate immobilization, and that a repeated simulation CT be performed to assess the dose distributions in the current anatomy. Whether or not a new IMRT plan will be generated is at the discretion of the treating physician. If a new plan is made, the targets should be the same as those used for the initial plan and not adjusted in cases of disease regression, except to respect clear anatomic barriers such as skin or fascial or muscle planes initially uninvolved by disease. The new CT dataset should be used for IGRT image registration when the patient's shape changes significantly.  
5.2.15 Radiation Therapy Adverse Events **(5/24/16)**
Grade 3-4 (CTCAE, v. 4) therapy-induced mucositis and/or dysphagia, which are enhanced by cisplatin, are expected to develop in about two thirds of patients. Nutritional evaluation prior to the initiation of therapy to decide on the use of a prophylactic gastrostomy (PEG) tube placement is recommended, but in the absence of significant pretreatment dysphagia and associated weight loss of < 10% body weight the insertion of a prophylactic PEG is not recommended. If done the placement of a feeding tube should be recorded, as should proportion of use of a feeding tube during and after treatment (e.g. greater than or less than 50% of nutrition by tube). Other common radiation adverse events include: fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient ear discomfort, dysgeusia, and skin erythema and desquamation within the treatment fields. Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much less common radiation adverse events include: mandibular osteoradionecrosis (< 5% incidence with attention to the dental recommendations provided in Appendix I, "Dental Assessment and Management Document), and cervical myelopathy (< 1% with restriction of spinal cord dose to ≤ 45 Gy).  
5.3 **Surgery**
Surgery is expected to play only a limited role in the favorable risk HPV-associated cancers included in this study. Locoregional progression is expected in <10% of patients. The role of neck dissection has been declining in recent years, in part due to a high rate of negative specimens when planned neck dissections are performed in cancers of the oropharynx.
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5.3.1 post-treatment imaging/timing

While centers are allowed to follow their institutional policies in conducting earlier posttreatment imaging evaluations, the major initial post-radiation imaging evaluation for the purposes of this study is required at 12-14 weeks after the completion of radiotherapy with diagnostic quality, contrast-enhanced CT or MRI of the neck. PET/CT may be conducted in this timeframe as well, based on the preference of treating clinicians, but does not substitute for the mandatory anatomic imaging. The required diagnostic CT may be performed as part of the integrated PET/CT but only if the CT is considered diagnostic quality and is contrast enhanced. PET/CT may facilitate pre-and post-treatment evaluation of metabolic response and the need for post-treatment neck dissection. Centers that are participating in the PET/CT correlative study component should refer to section 10.3 for guidelines on submitting the PET/CT images. If physical examination and imaging suggest residual disease at the primary site, a biopsy will be performed to confirm residual disease; otherwise, patients will undergo serial follow up. Annual chest imaging is required to a maximum of 3 annual imaging sets and thereafter should be performed based on clinical judgment.  
5.3.2 Post-Treatment Surgical Salvage of Residual Disease Treatment of residual disease at the primary site will be determined by the treating clinicians and the clinical situation, and surgical resection, re-irradiation, chemotherapy, or palliative care will be done. If the primary site is cleared of residual disease yet residual disease at the cervical nodal basin is strongly suggested by imaging/clinical evaluation, then selective neck dissection will be performed unless a cytologic sampling (biopsy) of the node is negative. Post-treatment "planned" neck dissection will be defined as being performed for residual disease and within 20 weeks (140 days) of completion of radiotherapy. Positive neck specimens removed within 140 days will be considered part of the initial treatment plan and not considered as failures of initial management; positive specimens upon neck dissection beyond 140 days will be considered regional failures. Note that this is relaxed from the traditional definition of 105 days (15 weeks) in order to permit resolution of HPV-associated adenopathy, which is commonly cystic and may have a somewhat slower regression rate. Such post-treatment consolidation neck dissections will encompass only the areas (typically only levels 2 and 3) initially involved in the side of the neck in question. The extent of neck dissections performed for nodal recurrence, nodal progression, or salvage of disease at the primary ultimately will be determined by the treating surgeon. In the case of negative PET/CT in patients who did not achieve clinical or CT/MRI-based radiological nodal CR, a minimum of careful clinical examination is required at 3 months, and further imaging is highly recommended, such as follow-up imaging every 3-4 months for at least 24 months, as well as careful recording of the clinical dimensions of the residual abnormality.  
5.4 **Imaging**
See Section 10.3 for details of the optional FDG-PET/CT correlative study.
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5.5 general concomitant medication and

All supportive therapy for optimal medical care will be given during the study period at the discretion of the attending physician(s) within the parameters of the protocol and documented on each site's source documents as concomitant medication. These may include analgesics, antiemetics, topical mouth rinses, skin creams/ointments, etc. In general, HIV-positive patients who are on a stable Highly Active Anti-Retroviral Therapy (HAART) regimen should continue HAART while receiving chemotherapy. However, for patients who are newly diagnosed with HIV but with laboratory parameters meeting the eligibility criteria, it is preferable to defer initiation of HAART until after chemotherapy is completed. HAART regimens containing zidovudine and stavudine should be avoided during chemotherapy due to concerns for overlapping toxicity with chemotherapy. In addition, the protease inhibitor atazanavir (RayatazTM) can cause a physiologically unimportant hyper-hyperbilirubinemia; however, in the setting of chemotherapy, some experts suggest switching that drug for another equally effective one. If HAART is withheld during chemotherapy, it should be resumed promptly after conclusion of the last cycle of chemotherapy.  
5.5.2 Prohibited Therapies The use of amifostine or palifermin as a radioprotectant is not allowed. The use of granulocyte colony stimulating factor or erythropoietin is not allowed. Transfusion is to be performed at the discretion of the treating physician. Any exceptions must be approved by the Principal Investigator, Dr. Yom, or the Medical Oncology Co-Chairs, Drs. Gillison and Gibson.  
5.5.3 Participation in Other Trials Patients may not participate in other clinical trials that are intended to treat the diagnosed oropharyngeal cancer or intended to reduce toxicity of therapy.  
5.6 **Duration of Therapy**
In the absence of treatment delays due to adverse event(s), treatment may continue as specified in the above treatment modality sections or until one of the following criteria applies: Disease progression, Intercurrent illness that prevents further administration of treatment, Unacceptable adverse event(s), Patient decides to withdraw from the study, or General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.
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5.7 measurement of response/progression response

Response and confirmation of local (primary site) or regional (neck) "tumor clearance" are not endpoints in this study. Clinical or radiographic evidence of progressive local-regional disease beyond 20 weeks should be documented in the clinical record and ideally confirmed by local or regional biopsy, neck dissection, or salvage surgery. CT or MRI (of head and neck region, with Chest CT), or PET/CT (including chest anatomy) may be used as radiographic evaluation of overall cancer status. The primary, neck and chest portions of the scans should be evaluated and reported separately. The CT portion of a PET/CT may serve as sufficient radiographic evaluation of the chest. If CT or MRI is used for evaluation of the head and neck region, CT of chest will be needed to rule out distant disease or second primaries at the designated evaluation intervals.
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local or regional progression

Local (primary site) or regional (neck) progression is defined as clinical or radiographic evidence of progressive disease at the primary site or neck. The location of progressive disease should be separately distinguished (local vs. neck) to document the precise pattern of failure if possible. Progression of local or regional disease should be confirmed by biopsy when possible but may be clinically assessed and documented in the clinical record at the judgment of the treating clinicians. Suspicion of disease progression exclusively on the basis of indeterminate or positive PET/CT scan must be pathologically confirmed.  
Distant Metastasis Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where possible. A solitary, spiculated lung mass/nodule is considered a second primary neoplasm unless proven otherwise.  
Second Primary Neoplasm Tumor reappearing with the initial and immediate adjoining anatomical region of the primary will be considered local recurrence. Multiple lung nodules/masses are considered distant metastases from the index cancer unless proven otherwise.  
6. TREATMENT MODIFICATIONS/MANAGEMENT (5/24/16) 6.1 Chemotherapy Dose Modifications **(20-DEC-2017)**
Note: If adverse events prevent the administration of chemotherapy, the patient may continue to receive radiation therapy.  
6.1.1 Cisplatin Dose Modifications During Concurrent Radiation Note: Substitution of carboplatin for cisplatin during adverse events is NOT allowed.
Patients will be examined and graded for subjective/objective evidence of developing toxicity weekly according to CTCAE, v. 4 while receiving concurrent cisplatin with radiotherapy. Treatment interruptions are allowed if there is symptomatic mucositis or skin reaction that, in the judgment of the clinician, warrants a break. For chemotherapy-attributable AEs requiring a break in treatment, resumption of concurrent cisplatin may begin when AEs have recovered to the levels specified below. Chemotherapy should be discontinued in the event of more than 2 events requiring dose reduction (e.g. if grade 3 or greater nonhematologic or hematologic event occurs at the reduced dose of cisplatin, at 23 mg/m2/week.  
If an AE does not resolve to the levels specified in the sections below prior to the calendar week of the last radiation treatment (See Section 5.1 for details concerning parameters for timing of last allowable concurrent cisplatin dose), then chemotherapy should be discontinued. There will be no dose re-escalation for concurrent cisplatin. Chemotherapy dosage modifications are based upon lab values obtained prior to cisplatin and interim non-hematologic toxicities during the week prior to a particular cisplatin dose. The dose modifications for cisplatin (below) are intended to be permanent (i.e., if the patient's dose is reduced to dose level -1, it remains at the reduced dose level).  
6.1.2 Cisplatin Dose Modifications for Hematologic Adverse Events during Concurrent Radiation  
| Starting Dose   | Dose Level -1   | Dose Level -2   |
|-----------------|-----------------|-----------------|
| 40 mg/m2        | 30 mg/m2        | 23 mg/m2        |  
Chemotherapy must not be administered until the ANC is ≥ 1,000 mm3and platelets are ≥ 75,000 mm3. If not, delay 7 days. Cisplatin should be held every week until the above ANC and platelet parameters are met. Dose reductions when cisplatin is resumed after delay for low ANC or platelets will be as follows, based upon counts at time cisplatin was held.  
| ANC                                                                               | Platelets   | Reduction   |                |
|-----------------------------------------------------------------------------------|-------------|-------------|----------------|
| < 1000 mm3                                                                        | or          | < 75,000    | One dose level |
| Note: Hematologic growth factors for neutropenia or anemia are not allowed during |             |             |                |  
Neutropenic Fever: Grade 3 (CTCAE, v 4) neutropenic fever (ANC < 1000/mm3 with a single temperature of > 38.3 degrees C [101 degrees F] or a sustained temperature of ≥ 38 degrees C [100.4 degrees F] for more than 1 hour) is an expected potential complication of concurrent chemotherapy and radiotherapy or chemotherapy alone. If neutropenic fever is noted, the chemotherapy dose reduction will be determined by the weekly blood counts. See above.
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6.1.3 cisplatin dose modifications for

Renal Adverse Events: Dose will be modified based on the serum creatinine prior to each cisplatin dose. If the serum creatinine is ≤ 1.5 mg/dL, creatinine clearance is not necessary for treatment with full dose. If the serum creatinine is > 1.5 mg/dL, a creatinine clearance should be obtained by urine collection or nomogram calculation (valid only if serum creatinine is not changing rapidly). Cisplatin must not be administered until creatinine is ≤ **1.5 or creatinine clearance ≥**
50. Once the creatinine has met the above parameters, cisplatin may be restarted with the below modifications based on the creatinine at the time the cisplatin was held: In general, cisplatin should be held for weekly intervals (rather than restarting cisplatin later in the same week that a dose limiting AE is seen).  
| Cisplatin dose modifications for creatinine during concurrent radiation   |                           |       |                |
|---------------------------------------------------------------------------|---------------------------|-------|----------------|
| Creatinine (mg/dL)                                                        | Creatinine                |       |                |
| clearance, measured  or calculated ml/min                                 | Cisplatin dose  reduction |       |                |
| ≤ 1.5                                                                     | or                        | ≥ 50  | No change      |
| > 1.5                                                                     | and                       | 40-49 | One dose level |
| < 40                                                                      | Hold drug                 |       |                |  
Neurologic (neuropathy) Adverse Events:  
| Grade (CTCAE, v. 4)   | Dose Reduction   |
|-----------------------|------------------|
| 0-1                   | None             |
| 2                     | One dose level   |
| 3-4                   | Hold drug        |  
Ototoxicity: Should patients develop clinical evidence of ototoxicity, further audiometric evaluation is required. A neurologic deficit should be distinguished from a conductive loss from obstruction of the Eustachian tube leading to a middle ear effusion. Because no AE scale, including the CTCAE, v. 4, has been validated in terms of correlation with clinically relevant hearing loss, there are no protocol mandates requiring dose reduction for audiogram-determined sensorineural hearing loss without an analogous clinical high grade ( > grade 2) hearing loss. However, for clinical grade 3 or higher hearing loss, cisplatin should be held and for grade 2 clinical hearing loss, one dose level reduction should be implemented. All Other Non-Hematologic Adverse Events Attributable to Cisplatin during Concurrent Radiation: For all other non-hematologic adverse events in which toxicity is ≥ grade 2 (CTCAE v. 4), investigators are advised to evaluate and manage correctable issues promptly to prevent worsening of toxicity. For these events in which toxicity is ≥ grade 3, investigators should hold cisplatin, with weekly re-evaluation until AE grade falls to 0-1, then restart cisplatin at one lower dose level. Note: Grade 3 mucositis is commonly experienced by head and neck cancer patients; the investigator generally would not hold the cisplatin dosing in this case, unless there is unusual concern for progression to grade 4 mucositis.
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7. adverse events reporting requirements

This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP web site at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via r the CTEP web site (https://eappsctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613)
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to NRG Oncology at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once Internet connectivity is restored, an AE report submitted by phone must be entered electronically into CTEP-AERS.  
7.1 **Adverse Events (AE)**
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting Requirements. ; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]
7.2 **Serious Adverse Events (SAEs)**
Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in section 7.2 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-AERS
notification are defined in the expedited reporting table in section 7.2. **Contact the**
CTEP-AERS Help Desk if assistance is required.  
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in any of the following outcomes:
Death; A life-threatening adverse drug experience; Inpatient hospitalization or prolongation of existing hospitalization; A persistent or significant disability/incapacity; A congenital anomaly/birth defect; Important medical events that may not result in death, be life threatening, or require hospitalization may be considered an SAE, when, based upon medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definition.  
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner.
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7.3 acute myeloid leukemia (aml)

AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system within 30 days of AML/MDS diagnosis. Secondary Malignancy A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia
[AML])
Myelodysplastic syndrome (MDS)
Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
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second malignancy

A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified.  
7.4 **CTEP-AERS Expedited Reporting Requirements (4/29/15)**
All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology requirements for expedited adverse event reporting. CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the NRG Oncology Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once Internet connectivity is restored, an AE report submitted by phone must be entered electronically into CTEP-AERS.  
CTEP-AERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification is electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 24-hour notification must be followed by an CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 hour CTEP-AERS notification are defined in the expedited reporting table below.  
Supporting source document is not mandatory. However, if the CTEP-AERS report indicates in the *Additional Information* section that source documentation will be provided, then it is expected. If supporting source documentation accompanies an CTEP-AERS report, include the protocol number, patient ID number, and CTEPAERS ticket number on each page, and fax supporting documentation the NRG
Oncology dedicated SAE FAX, 215-717-0990.  
A serious adverse event that meets expedited reporting criteria outlined in the following table but is assessed by the CTEP-AERS as "expedited reporting NOT required" must still be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the "NOT Required" assessment; the CTEP-AERS allows submission of all reports regardless of the results of the assessment.  
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the table below. **Important:** All AEs reported via CTEP-AERS also must be reported on the AE section of the appropriate case report form (see Section 13.2). Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse  
 Events that Occur on Studies under a Commercial Agent **within 30 Days of the Last**
Administration of the Commercial Agent. **1, 2**
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fda reporting requirements for serious

NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
ALL **SERIOUS** adverse events that meet the above criteria **MUST** be immediately reported to the NCI via CTEPAERS within the timeframes detailed in the table below.  
| Grade 1          | Grade 2            | Grade 3          | Grade 4 & 5   |            |
|------------------|--------------------|------------------|---------------|------------|
| Hospitalization  | Timeframes         | Timeframes       | Timeframes    | Timeframes |
| Resulting in     |                    |                  |               |            |
| Hospitalization  | 10 Calendar Days   |                  |               |            |
| ≥ 24 hrs         | 24-Hour 5 Calendar |                  |               |            |
| Not resulting in | Days               |                  |               |            |
| Hospitalization  | Not required       | 10 Calendar Days |               |            |
| ≥ 24 hrs         |                    |                  |               |            |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
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expedited ae reporting timelines are

o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.  
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
  
  
  
All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for:
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse events 2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period.  
Effective Date: May 5, 2011 Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting  
 Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent: The following are protocol specific exceptions to expedited reporting via CTEP-AERS. Report the following AEs in an expedited manner only if they exceed the grade in parentheses next to the AE: nausea (grade 3), vomiting (grade 3), diarrhea (grade 3), dehydration (grade 3), lymphocyte count decreased (grade 4), and mucositis (grade 3). Routine adverse event reporting on the case report form fulfills safety reporting requirements for these events at the aforementioned grades.
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8. registration study entry and

Access requirements for OPEN, Medidata Rave, and TRIAD: Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and Access Management (IAM) account.  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all individuals contributing to NCI-sponsored trials to register and to renew their registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their annual registration using CTEP's web-based Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation requirements per registration type are outlined in the table below.  
| Documentation Required   | IVR   | NPIVR   | AP   | A   |
|--------------------------|-------|---------|------|-----|
| FDA Form 1572            |      |        |      |     |  
| Documentation Required                                                       | IVR   | NPIVR   | AP   | A   |
|------------------------------------------------------------------------------|-------|---------|------|-----|
| Financial Disclosure Form                                                    |      |        |     |     |
| NCI Biosketch (education, training, employment,  license, and certification) |      |        |     |     |
| HSP/GCP training                                                             |      |        |     |     |
| Agent Shipment Form (if applicable)                                          |      |         |      |     |
| CV (optional)                                                                |      |        |     |     |  
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the following:
Added to a site roster Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN
Act as the site-protocol PI on the IRB approval Additional information can be found on the CTEP website https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR *Help Desk* by email at < RCRHelpDesk@nih.gov >.  
8.1 CTSU Registration Procedures (20-DEC-2017)
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
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irb approval

Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be approved to enroll patients. Assignment of site registration status in the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria including but not limited to the following:
An active Federal Wide Assurance (FWA) number An active roster affiliation with the Lead Network or a participating organization A valid IRB approval Compliance with all protocol specific requirements.  
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria:
Active registration status The IRB number of the site IRB of record listed on their Form FDA 1572 An active status on a participating roster at the registering site. Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are not required to submit separate IRB approval documentation to the CTSU Regulatory Office for initial, continuing or amendment review. For sites using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally. The CIRB's approval of the SSW is then communicated to the CTSU Regulatory Office. In order for the SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRB-approved institutions aligned with the Signatory Institution are participating in the study.
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downloading site registration documents

Site registration forms may be downloaded from the NRG-HN002 protocol page located on the CTSU members' web site.  
Go to https://www.ctsu.org and log in to the members' area using your CTEPIAM username and password Click on the Protocols tab in the upper left of your screen Either enter the protocol \# in the search field at the top of the protocol tree, or Click on the By Lead Organization folder to expand Click on the NRG Oncology link to expand, then select trial protocol \# Click on LPO Documents, select the Site Registration documents link, and download and complete the forms provided.  
Requirements for NRG-HN002 site registration:
IRB Approval Letter (for sites not participating via the NCI CIRB; local IRB
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted)
IRB/REB Approved Informed Consent (English and native language versions*)
*Note: Institutions must provide certification/verification of IRB/REB consent translation to NRG Headquarters (described below).  
IRB/REB registration number renewal information as appropriate.  
CTSU RT Facilities Inventory Form NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy component must participate in the Radiological Physics Center (RPC) monitoring program. If this form has been previously submitted to CTSU it does not need to be resubmitted unless updates have occurred at the RT facility.
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8.2 submitting regulatory documents (20-dec-2017)

Submit completed forms along with a copy of your IRB Approval and Informed Consent to the CTSU Regulatory Office via the Regulatory Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org (members' area)  Regulatory Tab Regulatory Submission When applicable, original documents should be mailed to:
CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA 19103 )
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and support.**8.2.1** Checking Your Site's Registration Status Check the status of your site's registration packets by querying the RSS site registration status page of the members' section of the CTSU web site.  
Go to https://www.ctsu.org and log in to the members' area using your CTEPIAM username and password Click on the Regulatory tab Click on the Site Registration tab Enter your 5-character CTEP Institution Code and click on Go Note: The status given only reflects compliance with IRB documentation and institutional compliance with protocol-specific requirements outlined by the Lead Network. It does not reflect compliance with protocol requirements for individuals participating on the protocol or the enrolling investigator's status with the NCI or their affiliated networks.
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non-english speaking canadian and international

*Translation of documents is critical. The institution is responsible for all translation costs. All regulatory documents, including the IRB/REB approved consent, must be provided in English and in the native language. Certification of the translation is optimal but due to the prohibitive costs involved NRG will accept, at a minimum, a verified translation. A verified translation consists of the actual REB approved consent document in English and in the native language, along with a cover letter on organizational/letterhead stationery that includes the professional title, credentials, and signature of the translator as well as signed documentation of the review and verification of the translation by a neutral third party. The professional title and credentials of the neutral third party translator must be specified as well.  
8.2.2 Pre-Registration Requirements FOR CANADIAN INSTITUTIONS
In addition to the requirements above, Canadian institutions must also complete the following documents to the CTSU Regulatory Office via the Regulatory Submission Portal:
Health Canada's Therapeutic Products Directorates' Clinical Trial Site Information Form; Qualified Investigator Undertaking Form; Research Ethics Board Attestation Form; Attestation memo for participation in FDG-PET/CT imaging.  
8.2.3 Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS
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for institutions that do not

International sites must submit an LOI to NRG Headquarters to receive approval to participate in this trial. (For more details, see http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx.
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for institutions that have an

For detailed information on the specific technology requirement required for this study, please refer to the table below and utilize the web link provided for detailed instructions. The check marks under the treatment modality columns indicate whether that specific credentialing requirement is required for this study. Specific credentialing components may require you to work with various QA centers; however, Imaging and Radiation Oncology Core (IROC) Houston will notify your institution when all credentialing requirements have been met and the institution is RT credentialed to enter patients onto this study.  
| Web Link for Procedures and Instructions:  http://irochouston.mdanderson.org                                                                                                                                                    |                          |                                                                                                                                                                                                                                                                   |
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| RT                                                                                                                                                                                                                              |                          |                                                                                                                                                                                                                                                                   |
| Credentialing  Requirements                                                                                                                                                                                                     | Treatment  Modality IMRT | Key Information                                                                                                                                                                                                                                                   |
| The IROC Houston electronic facility questionnaire (FQ) should  be completed or updated with the most recent information about  your institution. To access this FQ, email  irochouston@mdanderson.org to receive your FQ link. |                          |                                                                                                                                                                                                                                                                   |
| Facility                                                                                                                                                                                                                        |                          |                                                                                                                                                                                                                                                                   |
| Questionnaire                                                                                                                                                                                                                   | X                        | To determine whether your institution needs to complete any  further credentialing requirements, please complete the  "Credentialing Status Inquiry Form" found under credentialing  on the IROC Houston QA Center web site  (http://irochouston.mdanderson.org). |
| Knowledge  Assessment                                                                                                                                                                                                           | N/A                      |                                                                                                                                                                                                                                                                   |
| Benchmark  Cases                                                                                                                                                                                                                | N/A                      |                                                                                                                                                                                                                                                                   |
| Credentialing  Status Inquiry                                                                                                                                                                                                   | X                        |                                                                                                                                                                                                                                                                   |
| Form                                                                                                                                                                                                                            |                          |                                                                                                                                                                                                                                                                   |  
| An IMRT H&N phantom study provided by the IROC QA  Center Houston must be successfully completed. Instructions for  requesting and irradiating the phantom are found on the IROC  Houston web site (http://irochouston.mdanderson.org). Tomotherapy and Cyberknife treatment delivery modalities  must be credentialed individually.   |                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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| Phantom  Irradiation                                                                                                                                                                                                                                                                                                                   | X                                                                                                                         | The institution must submit a sample of verification images  showing their ability to reproducibly register daily IGRT  information with a planning CT dataset (i.e. the GTV falls  within the CT simulation defined PTV). The patient ("as if  patient") used for this study must have a target (or mock target)  in the H&N region. The information submitted must include 2  IGRT datasets (from 2 treatment fractions) for a single patient.  This information with a spreadsheet (the spreadsheet is available  on the IROC Houston web site:  http://irochouston.mdanderson.org. |
| Pre-Treatment  Review                                                                                                                                                                                                                                                                                                                  | N/A                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| IGRT                                                                                                                                                                                                                                                                                                                                   |                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Verification                                                                                                                                                                                                                                                                                                                           | X                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Study                                                                                                                                                                                                                                                                                                                                  |                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Institution                                                                                                                                                                                                                                                                                                                            | IROC Houston will notify the institution and NRG Headquarters  that all desired credentialing requirements have been met. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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8.3.1 digital rt data submission

TRIAD is the image exchange application used by the NRG. TRIAD provides sites participating in NRG clinical trials a secure method to transmit DICOM RT and other objects. TRIAD anonymizes and validates the images as they are transferred.
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triad access requirements

Site physics staff who will submit images through TRIAD will need to be registered with The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and Access Management (IAM) account. Please refer to the beginning of Section 4 for instructions on how to request a CTEP-IAM account.  
To submit images, the site physics user must have been assigned the 'TRIAD site user' role on the relevant Group or CTSU roster. NRG users should contact your site Lead RA to be added to your site roster. Users from other cooperative groups should follow their procedures for assignment of roster roles.  
RAs are able to submit standard of care imaging through the same method.
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triad installations

When a user applies for a CTEP-IAM account with proper user role, he/she will need to have the TRIAD application installed on his/her workstation to be able to submit images. TRIAD installation documentation can be found on the NRG website Core Lab **tab.** This process can be done in parallel to obtaining your CTEP-IAM account username and password. If you have any questions regarding this information, please send an e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org.  
8.4 Patient Enrollment Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have been met, and the study site is listed as 'approved' in the CTSU RSS. Patients must have signed and dated all applicable consents and authorization forms.  
8.4.1 Oncology Patient Enrollment Network (OPEN)
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). OPEN is a web-based registration system available on a 24/7 basis. All site staff (NRG and CTSU Sites) will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient position in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members' web site https://www.ctsu.org. Prior to accessing OPEN site staff should verify the following:
All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the registration forms provided on the group or CTSU web site as a tool to verify eligibility.  
All patients have signed an appropriate consent form and HIPAA
authorization form (if applicable).  
Access requirements for OPEN:
See beginning of Section 4 for information on obtaining a CTEP-IAM account. To perform registrations, the site user must have been assigned the 'Registrar' role on the relevant Group or CTSU roster.  
To perform registrations on protocols for which you are a member of the NRG,
you must have an equivalent 'Registrar' role on the NRG roster. Role assignments are handled through the Groups in which you are a member.  
To perform registrations to trials accessed via the CTSU mechanism (i.e., nonLead Group registrations) you must have the role of Registrar on the CTSU roster.  
Site and/or Data Administrators can manage CTSU roster roles via the new Site Roles maintenance feature under RSS on the CTSU members' web site. This will allow them to assign staff the "Registrar" role.  
The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the OPEN tab located on the CTSU members' web site at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. In the event that the OPEN system is not accessible, participating sites can contact NRG web support for assistance with web registration: websupport@acr.org or call the NRG Registration Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax in the eligibility checklist and will need the registering individual's e-mail address and/or return fax number. This information is required to assure that mechanisms usually triggered by the OPEN web registration system (e.g. drug shipment and confirmation of registration) will occur.
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9. drug information 9.1 investigational

Not applicable for this study.  
9.2 **Commercial Agent: Cisplatin**
Adverse Events: Sites must refer to the package insert for detailed pharmacologic and safety information.
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9.2.1 availability/supply

Please see Section 5.1 for administration instructions. Please refer to the current FDAapproved package insert provided with each drug and the site-specific pharmacy for toxicity information and instructions for drug preparation, handling, and storage.
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10. biomarker correlative and special

Institutions must screen patients, whose tumors must be p16 positive by immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Then the institution must submit one H&E slide and one p16 IHC slide to the NRG Oncology Biospecimen Bank for central review prior to randomization (see the table below). **Note**: A rigorous laboratory accreditation process similar to the U.S. CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable. Central review will be conducted with rapid turnaround (1-2 business days from receipt of the slides) coordinated by Dr. Richard Jordan at the NRG Oncology Biospecimen Bank. Specifics of type and source of p16 antibody and testing method will be requested (although not required) at the time of specimen submission. Every effort should be made to obtain and submit this information at the time of specimen transmission, in order to ensure the fastest possible resolution should there be any questions about staining technique.  
Note: Due to potential delays in customs, Canadian sites will be permitted to submit an Aperio digital image of the H&E and p16 stained slide for remote central review by Dr. Jordan. Prior approval for this must be obtained from the NRG Biospecimen Bank. In cases in which Dr. Jordan determines that the image quality or staining is inadequate, the site will be required to send the original slides to the Biospecimen Bank directly. H&E stained slides will be used to confirm presence of tumor in the sample and to aid in assay interpretation. Interpretation of each p16 immunostained slide will be performed using the H-score method described by Jordan, et al. (2012) that has been validated as a reliable, reproducible, and accurate method to score p16 in squamous cell carcinoma of the head and neck. The primary reviewer will be the Pathology Co-Chair, Richard Jordan, DDS, PhD, with secondary analysis by the Pathology Co-Chair, Christina Kong, MD. p16 IHC will be scored as evaluable if strong and diffuse positivity was observed in the tissue mounted on each slide. The highest intensity of p16 staining present in the tumor will be scored on an ordinal score of 0-3, relative to the intensity of the positive (score 3) and negative (score 0). The percent of tumor staining at the highest intensity also will be estimated within 5% increments. The H score is derived from the cross product of the intensity score (0 to 3), and the percent of tumor staining at the highest intensity (0100%). An optimal H-score cut-point of 60 on a scale of 0-300 yields an average sensitivity of 91.6% and specificity of 90.4% for HR-HPV oncogene expression and thus an H-score cut-point of 60 indicates that a tumor with diffuse low-intensity nuclear and cytoplasmic p16 staining in the majority of the tumor is a true positive (Jordan 2012).  
High agreement on inter-rater interpretation has been reported (Schlecht 2011, Thavaraj 2011), indicating the familiarity of pathologists with interpretation of IHC assays. Similarly, comparable assay performance for p16 to that observed here has also been previously reported (Schlecht 2011, Thavaraj 2011). The most common p16 monoclonal antibody in use is E6H4 (CINtec). Other acceptable p16 antibody types include 16P04 and JC8. If a different p16 antibody is used, discussion with the Pathology Co-Chairs is strongly encouraged. In cases in which a major discrepancy arises between the primary evaluator and the central reviewer (Dr. Jordan), the p16 stained slide and the associated probe and testing specifics will be sent to a secondary central reviewer, Dr. C. Kong at Stanford University, to resolve the disagreement. If p16 staining cannot be established as positive through the central review process, the patient is not considered eligible.  
Ship all biospecimens for central review and banking for this trial to:
NRG Oncology Biospecimen Bank—San Francisco 2340 Sutter Street, Room S341 (Box 1800) University of California San Francisco San Francisco, CA 94115 415-476-7864; NRGBB@ucsf.edu See the tables below for mandatory and optional specimen collection. See further details of specimen **collection/processing/shipping on the RTOG/NRG** Oncology web site, http://www.rtog.org/LinkClick.aspx?fileticket=1SFlEVxSui4%3d&tabid=281.  
Mandatory: Specimen Collection for Central p16 Confirmation The specimens are being collected for confirmation by central review (see Section 10). Institutions must screen patients, who must be p16 positive by immunohistochemistry in order to be eligible for the trial.  
Required Forms: ST form and pathology reports with accession number and p16 staining result; any other personal health information (PHI) should be redacted.  
Shipping costs: Submitting site pays cost of shipping. Results: Dr. Richard Jordan, NRG Oncology Biospecimen Bank, or Dr. Christina Kong, Pathology Co-Chair, will report to NRG Oncology.  
Residual Material: p16 slides will be retained unless return is requested by the submitting site.  
| NRG Oncology Biospecimen Bank;NRGBB@ucsf.edu; 415-476-7864/FAX 415-476- 5271 Specimen Type Collection Time  Collection  Points Information and  Requirements Shipping One H&E slide One p16 stained  IHC slide Pre-Treatment Enrolling institution,  using a CLIA certified  laboratory, screens  patient with p16 testing  by IHC (must be  positive). Then  Biospecimen Bank  does central review  prior to randomization. Slides shipped  ambient   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Optional Study \#1: Circulating HPV DNA as a Potential Marker for Relapse Patients must be offered the opportunity to consent to optional specimen collection. If the patient consents to participate, the site is required to submit the patient's specimens as specified in the protocol. Sites are not permitted to delete the specimen component from the protocol or from the sample consent.  
Specimens are being collected to determine whether a novel method for detecting tumorderived DNA is superior to qPCR in the detection of circulating HPV DNA in the blood
(see Section 2.6 for further details).  
Required Form: ST form Biospecimen Kits: Available from the NRG Oncology Biospecimen Bank Shipping days: Monday-Wednesday (U.S. sites); Monday-Tuesday (Canada and Non-North American).  
Shipping costs: Return labels are provided for frozen biospecimens only.  
| NRG Oncology Biospecimen Bank;NRGBB@ucsf.edu; 415-476-7864/FAX 415-476- 5271 Specimen Type Collection Time  Collection  Points Information and  Requirements Shipping Plasma: 5-10 mL of  anticoagulated  whole blood from two EDTA tubes #1 and #2 (purple/  lavender top) and  centrifuge 1) Pre-treatment; 2) During the  treatment, obtained after  20Gy RT but  before 28 Gy; 3) No earlier than 2  weeks and up to  1 month after the  completion of  treatment  Frozen plasma  samples containing  1 mL per aliquot in  1 mL cryovials (5- 10) Plasma sent frozen  on dry ice via  overnight carrierNeed plasma from  two tubes   |
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optional study #2 pi3k pathway

Patients must be offered the opportunity to consent to optional specimen collection. If the patient consents to participate, the site is required to submit the patient's specimens as specified in the protocol. Sites are not permitted to delete the specimen component from the protocol or from the sample consent.  
| the protocol or from the sample consent. Specimens are being collected to study the PI3K pathway (see Section 2.7 for further  details).  Required Forms: ST form and pathology reports to confirm the diagnosis  Biospecimen Kits: Available from the NRG Oncology Biospecimen Bank.  Shipping days: Frozen specimens: Monday-Wednesday (U.S. sites); MondayTuesday (Canada and Non-North American). FFPE: No restriction.  Shipping costs: Return labels are provided for frozen biospecimens only. For questions, contact: NRG Oncology Biospecimen Bank 415-476-7864/FAX 415-476-5271 NRGBB@ucsf.edu Specimen Type Collection Time  Collection  Points Information and  Requirements Shipping Representative H&E  stained slides of the  primary tumor Pre-treatment H&E stained slide (can be the same  one submitted for  central review) Slide shipped  ambient A corresponding paraffin-embedded  tissue block or 2 mm punch block of  the primary tumor  taken before  initiation of  treatment Pre-treatment Paraffin-embedded  tissue block or  punch block (with  punch block H&E).  If site is unable to  provide the block or  punch, then 10  unstained tumor  slides (cut at 5  micron) is an  acceptable  alternative Block or unstained  slides shipped  ambient (ship with a  cold pack during hot  weather) Whole blood for  DNA: 5-10 mL of  anticoagulated  whole blood in  EDTA tube #3 Pre-treatment; note:  If site missed this  collection time point  they may collect  whole blood for  Frozen whole blood  samples containing  1 ml per aliquot in  1ml cryovials (3-5) Whole blood sent  frozen on dry ice via  overnight carrier   |
|---|  
| (purple/lavender   | DNA at a later time                       |
|--------------------|-------------------------------------------|
| top) and mix       | point but must note  this on the ST Form. |  
10.2 Quality of Life **(5/24/16)**
Completion of the MD Anderson Dysphagia Inventory-Head and Neck (MDADI-HN)is mandatory, as the MDADI is being used to assess the primary objective of the trial.  
Patients who speak English (or read one of the languages for which a translation is available; see below) are required to complete the MDADI assessments. If the patient does not understand spoken English and only reads languages not available in the validated MDADI translations, the patient can still participate in the trial, as this has been factored into the trial statistics; however, reasons for not completing this required component should be clearly documented. Patients must be offered the opportunity to consent to the optional quality of life component. If the patient consents to participate, the site is required to administer the University of Washington Quality of Life Questionnaire, version 4 (UW-QoLv.4) at baseline, completion of radiation therapy, and at 6, 12 and 24 months from the end of radiation. Sites are not permitted to delete the quality of life component from the protocol or from the sample consent. Optional Online Completion of QOL Assessments Patients who consent to participate in the quality of life (QOL) component of this study have the option of completing QOL forms online from any location, including home, via VisionTree Optimal Care (VTOC). The baseline QOL forms must be completed in hardcopy at the time of enrollment, but all subsequent QOL forms can be completed by the patient online. Patients without e-mail or Internet access can participate in the QOL component of the study by completing hardcopy (paper) forms. Indeed, at any time, any patient may choose to fill out their QOL form using the hardcopy form. The QOL forms completed via VTOC are identical to the hardcopy forms; this technology does not add to or change the QOL assessments in this study. Following completion of baseline QOL forms, if the patient wishes to complete any of the subsequent QOL assessments online, the patient must have an e-mail address that they consent to use for this purpose. Patients' e-mail addresses are necessary so that email reminders may be sent to them to remind them to fill out QOL forms that are due.  
The patient's e-mail address also will be used for password-protected access to VisionTree Optimal Care (VTOC), Patients who are interested in participating but do not yet have an e-mail address can obtain one for free from a number of sources (e.g.,Yahoo!, Hotmail, or AOL). VTOC will send patients e-mail reminders to complete QOL forms. The first reminder will be sent at the beginning of the window for completion of the form, with a second reminder sent halfway through the window, if the form has not yet been completed. A maximum of 3 reminders will be sent for each of the 4 QOL assessment time points
(subsequent to the baseline assessments). After the patient has completed all forms, a dialogue box will appear thanking the patient for completing the QOL form(s), and the patient will no longer receive reminders for that time point. Site Research Associates (RAs) will receive training in the use of VTOC via NRG
Oncology webinars and educational sessions. Note: The site RA is responsible for setting up the patient's account on VTOC. The RA may do so by logging on the VTOC portal at the following link https://rtog.optimalcare.com - medical team. RA login information will be provided by VTOC after the patient is randomized to the study. The patient's VTOC account must be set up within 14 days after randomization. The RA or study administrator will be informed via the VTOC "At a Glance" form management system when QOL forms have been completed or when the window for a particular form has closed. If the site RA receives a notice that forms have not been completed, she or he will contact the patient to remind the patient to fill out the QOL form or inquire why the forms have not been completed. The RA will complete the cover page for each form that was not completed (either via VTOC or in hardcopy) and will submit the cover page (see Section 12). The Performance Status Scale for Head and Neck Cancer (PSS-HN and the Work Status questions will be completed by the investigator and/or research associate at the following time points: at baseline, at completion of radiation therapy, and at 6, 12 and 24 months from the end of radiation. The Charlson Comorbidity Index (CCI) will be completed by the investigator and/or research associate at baseline only. The MD Anderson Dysphagia Inventory-Head and Neck (MDADI-HN) The MDADI will be the primary tool to assess swallowing-related QOL. The MDADI is a 20-item PRO instrument, scored on a scale from 1 to 5 (lowest to highest), consisting of global, emotional, functional, and physical subscales. The questionnaire can be completed by the patient in 5-10 minutes and is available in English, Spanish, Brazilian, and Portugese. The MDADI is the first validated self-administered questionnaire designed to measure the impact of dysphagia on the health-related QOL (HRQOL) of patients with head and neck cancer. Scores range from 0 (extremely low functioning) to 100 (high functioning). The score is further divided into a global score question, six emotional quotient questions (score range 6–30), five functional quotient questions (score range 5–25) and eight physical quotient questions (score range 8–40). The University of Washington Quality of Life Questionnaire, version 4 (UW-QoLv.4) The UW-Qolv.4 will be used as a secondary tool to assess general QOL. Hassan and Weymuller of the University of Washington, Seattle, developed the University of Washington Quality of Life Questionnaire and first published in 1993 (Hassan). It has been validated and widely used since. This questionnaire was designed specifically to address problems incurred by head and neck cancer patients. The first scale consists of 20 questions on head and neck cancer symptoms that generate scores for 4 domains or dimensions of quality of life; communication, eating, pain, and emotional well-being. Global symptoms, disability attributable to head and neck cancer, and response to treatment also are assessed (Terrell 1998). It is a validated instrument that is available in English. In the original UW-QoLv.4 relevant domains were identified: Eating (6 items),
Communication (4 items), Pain (4 items), and Emotion (6 items). Each had an internal consistency (Cronbach α value) of greater than 0.80. Construct validity was demonstrated by moderate correlations with SF-12 Physical and Mental component scores (r=0.430.60). Test-retest reliability for each domain demonstrated strong reliability between the 2 time points. Correlations were strong for each individual question, ranging from 0.53 to 0.93 (Terrell 1997). The questionnaire was tested on 75 head and neck cancer patients and was compared to 2 established tools, the Karnofsky Performance Scale (KPS) and the Sickness Impact Profile (SIP), for validity, acceptability, reliability, and responsiveness. The scores of the UW-QoLv.4 correlated well with the KPS and Sickness Impact Profile, indicating validity. The test-retest reliability coefficient was 0.95 (Hassan 1993). Normative data have previously been published (Lin 2003, Terrell 1997).  
The UW-QoLv. 4 has undergone several improvements. Version 3 included 10 domainspecific questions focusing on physical symptoms, physical functioning, and social function. Specifically, the items address pain, appearance, activity level, recreation, swallowing, chewing, speech, shoulder function, taste, and saliva production. The most current version, Version 4, includes 2 additional questions about emotional function; the 2 specific questions address depression and anxiety (Weymuller 2001, Roges 2002). In addition to domain-specific items, both versions also include 4 generic QOL questions:
What is your overall quality of life ('Global QOL')?;
What is your *health-related* quality of life ("Global HR-QOL")?  
How has your health-related quality of life changed ("Transitional HRQOL",
"Incremental HR-QOL")?  
Free text response to describe quality of life ("Open-ended QOL"). Patients have used this question as an opportunity to describe their QOL in their own words or in drawings.  
The additional items of mood and anxiety have been tested against the Center for Epidemiology Studies Depression Scale (CES-D) and the Hospital Anxiety Depression Scale (HADS). The UW-QOLv.4 mood correlated with the scores and "case-ness" categories of the HADS depression and CES-D scales, whereas the UW-QOLv.4 anxiety correlated with the scores and "case-ness" of the HADS anxiety. Questions on mood and anxiety can help identify significant psychological morbidity, taking a score of less than 75 for UW-QOLv.4 mood and less than 70 for UW-QOLv.4 anxiety (Rogers 2006). Scoring of the UW-QoLv.4 can be found at http://depts.washington.edu/otoweb/research/head_neck_cancer/uw_qol_scoring_instruct ions.pdf. Each of the domain-specific items is scored from 0 (worst QOL) to 100 (best QOL). The 'composite' score is created by averaging the scores from the 10 (version 3) or 12 (version 4) items. The 4 generic questions in the composite scoring are not included, because they represent different constructs. It is recommended that the questions on global QOL, global HR-QOL and transitional HR-QOL items be used independently as they provide different and useful perspectives from the composite score. Scoring of individual domain items range from 0 (worst QOL) to 100 (best QOL) for each item.  
Intermediate scores depend on the number of responses to each question: On 3 point items, scores are 0, 50, and 100. On 4 point items, scores are 0, 33, 67, and 100. On 5 point items, scores of 0, 25, 50, 75, and 100. For clarity, the scoring sheets list specific scores for each item response. The scoring sheet should not be used as the questionnaire.
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the performance status scale for

The PSS-HN will be an exploratory tool to compare clinician ratings of swallowing function between arms. The PSS-HN is a clinician-rated instrument consisting of 3 subscales: normalcy of diet, public eating, and understandability of speech. The PSS-HN has been psychometrically validated (List 1990) and recommended by the National Comprehensive Cancer Network for measurement of swallowing and speech performance in patients with head and neck cancer. The tool is used in an unstructured interview format. It is not a PRO; hence, investigators or research associates can complete it quickly without adding to patient burden.
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charlson comorbidity index (cci)

Classically, head and neck cancer patients have a high burden of comorbidity, related in part to risk behaviors of smoking and alcohol use. In the HPV positive population, preexisting comorbidities are expected to be lower compared to the HPV negative head and neck cancer population. The CCI (Charlson 1987) will be collected by chart extraction once at baseline to characterize the study cohort and assess comparability between the treatment arms. It is not a PRO; hence, it can be completed by investigators or research associates without adding to patient burden.  
Employment/Work Status and Return to Work after Radiotherapy An exploratory objective will be to determine the impact of radiotherapy de-escalation in HPV positive oropharyngeal cancer on the patient's work status before and after treatment. Descriptive statistics will be used to assess work status before and after treatment. Work status will be tested for associations with concurrent chemotherapy use, age, gender, marital status, education level, tumor factors and health related quality of life using the UW-QoLv.4. The following questions regarding work status will be completed by the investigator and/or research associate on a case report form. At Baseline and Follow Up Q1. Which if the following best describes the patient's current work status? (Select all that apply) 1 Currently working in at least one FULL time job 2 Currently working in at least one PART time job 3 Not working outside of the home 4 Student, full-time 5 Student, part-time 6 Not employed 7 On disability 8 On sick leave 9 Retired 10 Other, please specify_________________________________________________ 11 Don't know Q2. How many hours a week does the patient work? ____ hours Q3. Which of the following best describes the patient's primary income? 1 Salaried annual 2 Wages hourly 3 Self employed 4 Other specify _ Method of payment (for health care received) 1. Private insurance 2. Medicare 3. Medicare and Private Insurance 4. Medicaid 5. Medicaid and Medicare 6. Military or Veterans sponsored 7. Self-Pay (No Insurance) 8. No means of payment 9. Unknown
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10.3 fdg-pet/ct imaging (5/24/16)

Patients must be offered the opportunity to consent to the optional FDG-PET/CT imaging. If the patient consents to participate, the site is required to submit the patient's post-treatment PET/CT scan and associated information, as specified in Section 10.3.3. Sites are not permitted to delete the imaging component from the protocol; however, it is acceptable for sites in Canada to remove the optional PET/CT scan from the sample consent if the site does not plan to participate in this component. A post-therapy FDG-PET/CT scan is highly recommended at 12-14 weeks post-therapy for assessment of response to therapy (see Section 2.5 for rationale and hypothesis). This scan is required for the patient to participate in this substudy. If the patient's pre-therapy FDG-PET/CT scan is available, institutions are highly encouraged to submit this scan as well (see Section 10.3.3 below for details of submission).  
10.3.1 Recommended FDG-PET/CT Imaging Sequence and Details Serum glucose must be measured (ideally within 1 hour of FDG administration).  
If the serum glucose concentration is found to be > 200 mg/dL, the study should be rescheduled. The referring physician or primary physician will be contacted to optimize blood glucose control.  
It is recommended that the PET/CT scan begin 60 minutes +/- 10 minutes after FDG
injection.  
It is recommended that patients be imaged from the orbits through the upper thigh.  
A dedicated head and neck imaging acquisition (orbits to upper thorax) with the patient's arms down is recommended given the higher sensitivity of this exam. The remainder of the body is to be scanned with the patient's arms raised over the patient's head. If patients cannot tolerate these positions for the PET/CT scan, investigators can use different patient positioning.  
A low-dose CT scan is required for attenuation correction and anatomical localization of findings in the PET scan.  
The acquisition parameters for the dedicated head and neck CT, low-dose CT scan must be approximately as follows: kV = 120; effective mAs = 90-150 (patient dependent, auto current modification acceptable); gantry rotation time < 0.5 sec; maximum reconstructed slice width = 2.5 mm (overlap acceptable); standard reconstruction algorithm, maximum reconstruction diameter = 30 cm; and without iodinated contrast.  
The acquisition parameters for the low-dose CT scan for attenuation correction must be approximately as follows: kV = 120; effective mAs = 30–80 (patient dependent, auto current modification acceptable); gantry rotation time < 0.5 sec; maximum reconstructed width = 3–5 mm without overlap; standard reconstruction algorithm, minimum reconstruction diameter = outer arm to outer arm; and without iodinated contrast.  
The axial field of view of the CT scan for attenuation correction will range from the mid thighs to the base of the skull. Arm positioning will be the same as for the PET scan (see above).  
The CT scan will be performed during the patient's normal breathing. No respiratory gating is needed.  
After the CT scan, a PET scan covering the same axial field of view will be performed. This scan will start at the upper thighs. The number of bed positions and the acquisition time per bed position will be scanner specific. Typical parameters are 6 bed positions and an acquisition of 2 to 5 minutes per bed position. The dedicated head and neck PET/CT will typically follow the body exam. Two bed positions will often suffice for orbits to upper thorax (top of aortic arch), and acquisitions must be at a minimum of 6 minutes per bed position and be reconstructed into a 30 cm field of view (FOV) with a 256 x 256 matrix.  
Additional diagnostic-quality CT of the neck may be performed with contrast if needed to fulfill requirements for anatomic post-treatment imaging.  
10.3.2 FDG-PET/CT Image Reconstruction The PET/CT data will be corrected for dead time, scatter, randoms, and attenuation using standard algorithms provided by the scanner manufacturers. For the dedicated head and neck views, a post-filter with a full-width at half maximum (FWHM) in the range of 5 mm is recommended.  
10.3.3 Submission of FDG-PET/CT Image and Site Read Following the completion of PET/CT imaging at the site, the institution will submit images in DICOM format via TRIAD to IROC Imaging; see Section 8.3.1 for details regarding TRIAD.  
Institutions must submit a case report form (CRF) for each PET/CT image in which a site reader characterizes the patient's therapy response using the 5-point scale outlined in Section 2.5 (i.e. the local site read).  
10.3.4 FDG-PET/CT Central Image Evaluation Rapid review process: For the first 3 patient cases with post-treatment PET/CT
imaging submitted by an enrolling center, these images will be evaluated with central rapid review by the Imaging Co-Chairs to ensure consistency in the application of the scoring system and provide feedback to the local site, if advisable. Subsequently, central rapid review only will be conducted based on CRFs indicating an indeterminate or positive read by the local site.  
For study purposes, PET/CT images will be retroactively interpreted by an NRG
Oncology Imaging Core Panel (NRGICP) of expert PET/CT readers who will have no involvement or knowledge of the participant's clinical care and who will be blinded to the participant's diagnosis, local PET/CT scan results, and clinical history. No NRGICP readers can be site investigators at the site producing the PET/CT scans and local site reads (characterization of patient response). NRGICP readers will be shown a group of 10 cases for training purposes. Feedback on each of these training cases will be provided prior to reading the HN002 patients' PET/CT scans.  
NRGICP readers will be provided with a case report form (CRF) that details—in a standardized manner—basic patient demographics that include age, gender, height, and weight. Readers will be instructed to characterize the therapy response using the 5-point scale outlined in Section 2.5.  
Each PET/CT scan will be evaluated independently by 3 NRGICP PET/CT readers.
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10.4 determining the extent of

10.4.1. Long-term swallowing outcomes will be measured at selected sites using modified barium swallow (MBS) studies according to the assessment schedule in Section 4 (baseline and 24 months ± 3 months after the end of radiotherapy) and the instructions provided in the Modified Barium Swallow Study Form. Participating institutions must complete the the MBS Credentialing Checklist prior to enrolling patients on this substudy and must follow the instructions for the MBS and submission of the MBS video in Appendix II. Facilities unable to participate in the MBS assessments may still enroll patients on the main study, NRG-HN002, without participating in the swallowing evaluations.
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11. modality reviews 11.1 radiation

The Principal Investigator, Sue S. Yom, MD, PhD, and the Radiation Oncology CoChairs, Jimmy J. Caudell, MD, PhD, and John Waldron, MD, will perform RT Quality Assurance Reviews after cases enrolled have been received at IROC Philadelphia RT. The RTQA reviews will be ongoing, and will be facilitated by IROC Philadelphia RT. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of radiotherapy treatment data as specified in Section 12.2. The scoring mechanism is: Per Protocol, Variation Acceptable, and Deviation Unacceptable.  
11.2 **Drug Quality Assurance Reviews**
The Medical Oncology Co-Chairs, Maura Gillison, MD, PhD, and Michael Gibson, MD,
will perform a Chemotherapy Assurance Review of all patients who receive or are to receive chemotherapy in this trial. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of chemotherapy treatment data as specified in Section 13. The scoring mechanism is: Per Protocol/Acceptable Variation, Unacceptable Deviation, and Not Evaluable. A report is sent to each institution once per year to notify the institution about compliance for each case reviewed in that year. Drs. Gillison and Gibson will perform a Quality Assurance Review after NRG Headquarters has received complete data for the first 20 cases enrolled. Drs. Gillison and Gibson will perform the next review after NRG Headquarters has received complete data for the next 20 cases enrolled. The final cases will be reviewed within 3 months after this study has reached the target accrual or as soon as NRG Headquarters has received complete data for all cases enrolled, whichever occurs first.
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12. data and records (5/24/16)

12.1 Data Management/Collection **(20-DEC-2017)**
Data collection for this study will be done exclusively through Medidata Rave®. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles in RSS (Regulatory Support System). To access Rave via iMedidata, the site user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave.  
Each person responsible for data entry must be on the NRG roster in order to receive access to Medidata Rave®. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata (iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Once an account is activated, eLearning modules will be available for Rave RDC instructions. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be listed in the upper right pane of the iMedidata screen. Users that have not previously activated their iMedidata/Rave accounts also will receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.  
12.2 **Summary of Data Submission**
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during the trial using Medidata Rave®. Additionally, certain adverse events must be reported in an expedited manner for more timely monitoring of patient safety and care. See Section 7.0 for information about expedited and routine reporting. For reporting of secondary cancers or other report forms available in Rave: Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is required.  
| Folder                                                                            | Form/Item                                        |                                                          |
|-----------------------------------------------------------------------------------|--------------------------------------------------|----------------------------------------------------------|
| Registration via the OPEN System                                                  |                                                 | Subject Enrollment Form                                  |
|                                                                                  | Step Information                                 |                                                          |
|                                                                                  | Treatment Assignment Form                        |                                                          |
|                                                                                  | Demography                                       |                                                          |
|                                                                                  | Eligibility Checklist Form                       |                                                          |
|                                                                                  | Eligibility Checklist 2 Form                     |                                                          |
| p 16 CRF                                                                          |                                                 | p 16 CRF- to be completed prior to Step II  registration |
| Baseline                                                                          |                                                 | Work Up                                                  |
|                                                                                  | Lab Results Baseline                             |                                                          |
|                                                                                  | Patient History Form (formerly known as  the A5) |                                                          |
|                                                                                  | Protocol Specified AE Form                       |                                                          |
|                                                                                  | MDADI Coversheet                                 |                                                          |
|                                                                                  | MDADI- if questionnaire completed = 'yes'        |                                                          |
| Enrollment When pushed into RAVE there  will be 5 forms representing registration |                                                  |                                                          |  
Summary of Data Submission  
|                                                                                                                                                                                                                                                                                               | CCI                                                                    |                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|-----------------------------------------------------|
|                                                                                                                                                                                                                                                                                               | PSS-HN Coversheet                                                      |                                                     |
|                                                                                                                                                                                                                                                                                               | PSS-HN- if questionnaire completed = 'yes'                             |                                                     |
|                                                                                                                                                                                                                                                                                               | Work Status                                                            |                                                     |
| RT Upload                                                                                                                                                                                                                                                                                      |                                                                       | Digital Data-(Refer to section 12.3)                |
| End of RT                                                                                                                                                                                                                                                                                      |                                                                       | RT Administration                                   |
|                                                                                                                                                                                                                                                                                               | RT Treatment-if was radiation therapy  given = 'yes'                   |                                                     |
|                                                                                                                                                                                                                                                                                               | Protocol Specific RT Form-if was  radiation therapy given = 'yes'      |                                                     |
|                                                                                                                                                                                                                                                                                               | Cisplatin (Arm 1 only)                                                 |                                                     |
|                                                                                                                                                                                                                                                                                               | Supportive Care                                                        |                                                     |
|                                                                                                                                                                                                                                                                                               | Hospitalization                                                        |                                                     |
|                                                                                                                                                                                                                                                                                               | Follow-up Head and Neck                                                |                                                     |
|                                                                                                                                                                                                                                                                                               | Protocol Specified AE Form                                             |                                                     |
|                                                                                                                                                                                                                                                                                               | Other Adverse Event Forms– if new or continuing adverse events = 'yes' |                                                     |
|                                                                                                                                                                                                                                                                                               | MDADI Coversheet                                                       |                                                     |
|                                                                                                                                                                                                                                                                                               | MDADI- if questionnaire completed =  'yes'                             |                                                     |
|                                                                                                                                                                                                                                                                                               | PSS-HN Coversheet                                                      |                                                     |
|                                                                                                                                                                                                                                                                                               | PSS-HN- if questionnaire completed =  'yes'                            |                                                     |
|                                                                                                                                                                                                                                                                                               | Work Status                                                            |                                                     |
| Concurrent Labs                                                                                                                                                                                                                                                                                |                                                                       | Lab Units Pre-Rx, week 1-6 (During Treatment  Labs) |
|                                                                                                                                                                                                                                                                                               | Lab Results Follow Up (During Treatment Labs)                          |                                                     |
| MONTH 1 (Post RT) Arm 1 & 2                                                                                                                                                                                                                                                                    |                                                                       | Patient Contacted                                   |
|                                                                                                                                                                                                                                                                                               | Follow-up- if Patient able to be Contacted ='yes'                      |                                                     |
|                                                                                                                                                                                                                                                                                               | Follow-up Head and Neck -if Patient able to be  Contacted ='yes'       |                                                     |
|                                                                                                                                                                                                                                                                                               | Disease Assessment- if Documented clinical  assessment = 'yes'         |                                                     |
|                                                                                                                                                                                                                                                                                               | New Primary Cancer- If New Primary  Cancer= 'yes'                      |                                                     |
|                                                                                                                                                                                                                                                                                               | Non-Protocol Treatment- if non-protocol  cancer therapy= 'yes'         |                                                     |
|                                                                                                                                                                                                                                                                                               | Protocol Specified AE Form- if Patient able to  be Contacted ='yes'    |                                                     |
|                                                                                                                                                                                                                                                                                               | Other Adverse Events– if new or continuing adverse events = 'yes'      |                                                     |
|                                                                                                                                                                                                                                                                                               | Primary Cause of Death- - if Patient's Vital Status = 'dead'           |                                                     |
|                                                                                                                                                                                                                                                                                               | Salvage surgery- if salvage surgery= 'yes'                             |                                                     |
| MONTH 3 (Post RT) Arm 1 & 2 MONTH 6 (Post RT) Arm 1 & 2 MONTH 9 (Post RT) Arm 1 & 2 MONTH 12 (Post RT) Arm 1 & 2 MONTH 15 (Post RT) Arm 1 & 2 MONTH 18 (Post RT) Arm 1 & 2 MONTH 21 (Post RT) Arm 1 & 2 MONTH 24 (Post RT) Arm 1 & 2 MONTH 30 (Post RT) Arm 1 & 2 MONTH 36 (Post RT) Arm 1 & 2 |                                                                        |                                                     |  
| MONTH 42 (Post RT) Arm 1 & 2                                                                                                                                                                                                                                           |                                                                                                                                                                    | MDADI Coversheet*                                                                                             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                       | MDADI- if questionnaire completed = 'yes'*                                                                                                                          |                                                                                                               |
|                                                                                                                                                                                                                                                                       | PSS-HN Coversheet*                                                                                                                                                  |                                                                                                               |
|                                                                                                                                                                                                                                                                       | PSS-HN- If questionnaire completed = 'yes'*                                                                                                                         |                                                                                                               |
|                                                                                                                                                                                                                                                                       | Work Status*                                                                                                                                                        |                                                                                                               |
| MONTH 48 (Post RT) Arm 1 & 2 MONTH 54 (Post RT) Arm 1 & 2 MONTH 60 (Post RT) Arm 1 & 2 Year 6-15 Arm 1 & 2                                                                                                                                                             | * These quality of life forms will appear in  Month 6 (Post RT), Month 12 (Post RT) and  Month 24 (Post RT)                                                         |                                                                                                               |
| Source Documentation Upload                                                                                                                                                                                                                                            |                                                                                                                                                                    | Source Documentation Upload- used by site in  the event that source documentation needs to be  uploaded to HQ |
| FDG-PET/CT Imaging Image submission forms will appear  in the following folders if the patient  has consented to the Optional  Imaging Study. (Note: Institutions  will submit images in DICOM  format via TRIAD to IROC  Imaging, refer to section 8.4.1.)  Baseline |                                                                                                                                                                    | Scan submission                                                                                               |
|                                                                                                                                                                                                                                                                       | SOC imaging form                                                                                                                                                    |                                                                                                               |
|                                                                                                                                                                                                                                                                       | Site Interpretation of PET/CT *                                                                                                                                     |                                                                                                               |
| * This form only appears if the Scan submission form is  submitted and 'Was the Site Interpretation form completed' was answered as YES.                                                                                                                               |                                                                                                                                                                     |                                                                                                               |
|                                                                                                                                                                                                                                                                       | Month 3 (Post RT) Arm 1 &  2                                                                                                                                        |                                                                                                               |
| Quality of Life Coversheets will  appear in the following folders if the  patient has consented to the Quality  of Life Component: UW-QOL  Baseline                                                                                                                   |                                                                                                                                                                    | UW QOL Coversheet                                                                                             |
|                                                                                                                                                                                                                                                                       | UW-QOL* *These quality of life forms only appear if the  corresponding cover page is submitted and 'Was  the patient questionnaire completed' was  answered as YES. |                                                                                                               |
|                                                                                                                                                                                                                                                                       | Completion of RT                                                                                                                                                    |                                                                                                               |
|                                                                                                                                                                                                                                                                       | 6 months from end of RT                                                                                                                                             |                                                                                                               |
|                                                                                                                                                                                                                                                                       | 12 months from end of RT                                                                                                                                            |                                                                                                               |
|                                                                                                                                                                                                                                                                       | 24 months from end of RT                                                                                                                                            |                                                                                                               |
|                                                                                                                                                                                                                                                                       |                                                                                                                                                                     |                                                                                                               |
| MBS CRF will appear in the  following folders if the patient has  consented to the modified barium  swallowing study:                                                                                                                                                  |                                                                                                                                                                    | MBS                                                                                                           |  
Baseline  
  
Month 24
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12.3 digital data submission requirements

| Submit Digital RT Data via TRIAD; see Section 8.3.1 for TRIAD account                 | Due           |
|---------------------------------------------------------------------------------------|---------------|
| access and installation instructions. Item Arm 1 and Arm 2 DICOM Items DICOM CT Image | Within 1      |
| DICOM Structure                                                                       | week of start |
| DICOM Dose                                                                            | of RT         |
| DICOM RT Plan                                                                         |               |
| All required structures must be labeled per the tables in Section 5.2 HN002 DVH Analysis Worksheet to be submitted via TRIAD with RT Digital  Data listed above is located on the CTSU web site, www.ctsu.org, on the NRGHN002 protocol page. Upon submission of the digital data via TRIAD, complete an online Digital  Data Submission Information Form (DDSI): https://www.irocqa.org/Resources/TRIAD-for-RT-QA NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES  WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED.                                                                                       |               |  
12.4 **Global Reporting/Monitoring**
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31, and October 31.
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13. statistical considerations 13.1 study

Patients will be stratified by radiotherapy planning (Unilateral vs. Bilateral), based on the investigator's decision to place the patient into one of the two groups described in Section 5.2 and the investigator's pre-randomization declaration of the type of treatment that will be used (Unilateral vs. Bilateral).  
13.1.2 Randomization Patients will be randomized to each arm using a randomized permuted blocked design.  
13.1.3 Total Accrual 296 patients
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13.2 study endpoints

13.2.1 Primary Endpoint Progression-free survival (PFS) at 2 years 13.2.2 Secondary Endpoints Local-regional failure at 6 months and 2 years; Distant metastasis at 6 months and 2 years; Overall survival at 6 months and 2 years; Acute toxicities (≥ grade 3, CTCAE, v. 4) at the end of radiation therapy and at 1 and 6 months; Late toxicities at (≥ grade 3, CTCAE, v. 4) 1 and 2 years; Patient-reported swallowing outcomes at 6 months and 1 and 2 years; Post-treatment FDG-PET/CT;
Translational research.
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13.3 primary objectives study design

For patients with p16 positive, locoregionally advanced oropharyngeal cancer who have a smoking history of ≤10 pack-years, a program of reduced-dose radiation therapy (given either in combination with concurrent radiosensitizing cisplatin or in modestly accelerated fractionation) will achieve a 2-year progression-free survival (PFS) rate of ≥ 85%, without unacceptable swallowing toxicity.  
13.3.2 Definitions of Primary Endpoints and How These Will Be Analyzed Progression free survival is defined as from time of randomization to local- regional failure, distant metastasis, or deaths due to any causes. PFS rates will be estimated for all treatment arms using the Kaplan-Meier method (1958). One sample binomial test will be used to test the 2-year PFS for each arm. Multivariate analysis will be performed using the Cox proportional hazards model.  
13.3.3 Sample Size and Power Calculations:
The estimated 2-year PFS for this population is 91% based on the eligible population of patients on the 2 arms of 0522 (N=65 available patients) at this time. If the 2-year PFS is less than 85%, we will consider it unacceptable. So, the null hypothesis for this study is: Neither arm achieves a 2-year progression-free survival (PFS) rate of ≥ 85%. The alternative hypothesis is: One or both arms result in a 2-year progression-free survival (PFS) rate of > 91%. With one-sided type I error rate of 10% and 80% power, we would need 140 analyzable patients per arm. All head and neck cancer trials must account for post-randomization attrition. In RTOG 1016, patients were not randomized for the following reasons: 5.3% not p16 positive; 5.2% patient refusal; 1.2% physician preference; 0.4% disease progression; 0.4% failure to submit tissue assay; and 2.5% for other reasons. In addition, 3.5% of patients were determined ineligible after randomization and 0.5% were randomized but did not receive any protocol therapy. For this trial, since p16 is tested prior to registration, we anticipate lower loss due to lack of tissue or improper p16 determination, since that should be better controlled through central review prior to randomization. p16 positive patients may be preference-sensitive about the arm to which they are randomized. Thus, we estimate there will be 5% loss of patients due to the reasons of "not p16 positive" and "patient refusal" pre-randomization in this study. The stated sample size for NRG-HN002 must be adequate to provide an analyzable cohort of 280 patients. Assuming 5% loss post-randomization, we must enroll 296 patients to be randomized. We project a total pre-randomization loss of 10% for potential withdrawal of consent related to physician or patient refusal, not p16 positive, or progression of disease, failure to submit tissue assay, and other reasons, so we expect to enroll 328 patients to get the required number of patients to be randomized. The rationale for the <85% unacceptable rate for 2-year PFS is as follows: The estimated 2-year PFS for this group of selected patients with p16 positive tumors is 91%, based on estimates derived from patients in RTOG 0522. If we set an unacceptable rate of 88% (3% difference from the expected outcome), the trial would require 500 analyzable patients per arm (1000 analyzable patients total) to conduct this phase II study. This was deemed less feasible based on the required number of patients and cost. If we set an unacceptable rate of 86% (5% difference from the expected outcome), then the trial would require 200 analyzable patients per arm (400 analyzable patients total). The number of patients required is more feasible but is still quite large for a 3-arm phase II study, in order to achieve only a 1% difference from 85%. If we set an unacceptable rate of 85% (6% difference from the expected outcome), then the trial would require 140 analyzable patients per arm (280 analyzable patients total). At this time, based on the projected rate of accrual, this was considered the most feasible scenario to accomplish in a reasonable timeframe and forms the basis of the current proposal.
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13.4 study monitoring of primary

At 6 months, the estimated PFS for the eligible group of patients from RTOG 0522 is 94%. With 95% two-sided confidence and a lower limit of 85% PFS, we plan to enroll 40 analyzable patients for each arm to be followed for 6 months. After these patients have been enrolled and followed for 6 months, the interim analysis will take place. The stopping rule corresponds to a number of 6 or more progressions within the first 40 patients at 6 months of follow up. The interim analysis time will be 1.56 years from the start of the study (6 months for site IRB approval, 0.56 years for accrual, 6-month follow up). If 1 arm has more than specified number of progressions, then we will suspend the arm and a panel review will be called to decide on next steps, including closing accrual to the arm. The trial will continue to accrue during that 6 month observation period, after 40 patients/arm have been enrolled, until adequate follow up is obtained for interim analysis. With the 2-arm design, the expected number of PFS events serving as a cut off among the 140 analyzable patients is 15 or fewer events on each arm to reject the null hypothesis and the cut off number of events for the interim analysis is 6 among the 40 analyzable patients. Monitoring of Study Progress for Quality of Life NRG Oncology will prepare reports twice a year to follow compliance with required quality of life data collection. Data that is missing will be requested from enrolling institutions at each reporting time point. Further corrective action may be taken by the Study Chairs if an institution is noted to have >30% non-compliance with quality of life data collection. Routine Interim Analysis to Monitor Study Progress Interim reports will be prepared twice each year until the final analysis has been accepted for presentation or publication. These reports will contain information about the accrual rate, pretreatment characteristics of patients accrued, and the frequency and severity of adverse events.
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interim analysis for the dmc

The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a year with respect to patient accrual and morbidity. The DMC also will review the study on an "as needed" basis.  
13.5 Accrual Considerations 13.5.1 Accrual Rate The accrual rate is estimated to be 15 patients per month.  
13.5.2 Accrual Goal The total sample size is 296 patients.  
13.5.3 Study Duration Trial accrual is projected to take 1.94 years. Allowing 6 months for site IRB approval and 2 years of follow up, the trial is estimated to take a total of 4.5 years.  
13.5.4 Estimated Duration for Completion of Primary Endpoint:
Trial accrual is projected to take 1.94 years. Allowing 6 months for site IRB approval and 2 years of follow up, the trial is estimated to take a total of 4.5 years.
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13.6 secondary/correlative elements

13.6.1 How Secondary Endpoints Will Be Analyzed For the secondary endpoints listed in Section 13.2.2, OS rates will be estimated using the Kaplan-Meier method (1958) and the failure rates for the experimental treatment will be compared against the control using a log rank test. The cumulative incidence method will be used to estimate locoregional and distant failure rates and the failure rates for the experimental treatment will be compared against the control using a failure specific log rank test. Failure for local-regional failure and distant metastasis endpoints is as follows:  
First event Local-regional  
failure  
Distant metastasis  
None Censored Censored Local-regional progression or recurrence Failure Competing risk Distant metastasis Competing risk Failure Death due to study cancer or unknown Failure Competing risk  
| causes Death due to any other reason                                                           | Competing risk   | Competing risk   |
|------------------------------------------------------------------------------------------------|------------------|------------------|
| Salvage surgery of primary with tumor                                                          | Failure          | Competing risk   |
| present/unknown Salvage neck dissection with tumor present/unknown, > 20 weeks from end of  RT | Failure          | Competing risk   |  
Multivariate analysis will be performed using the Cox proportional hazards model. Rates of Adverse Events (≥ grade 3, CTCAE, v. 4) for acute and late toxicities will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test between the 2 treatment arms.  
13.6.2 Quality of Life (QOL)
The primary QOL endpoint will measure the mean individual change in total MDADI score at 1 year from baseline with the goal of detecting a ≥ 5 point difference between the 2 arms. In the table below, we have outlined our decision making process of interpreting the phase II data with regards to PFS and QOL in order to proceed to a future phase III trial. PFS will be the primary decision making endpoint, with QOL using the comparison of mean change in MDADI score in each arm from baseline to inform the subsequent choice of one or more arms to proceed to a phase III trial. If a PFS of ≥ 85% is not reached for any of the arms, regardless of the QOL outcome, none of the therapy regimens will move forward to a phase III study. If 1 or both of the arms reach ≥ 85% PFS, the swallowing-related QOL endpoint of 1 year mean total MDADI score must be clinically acceptable of ≥ 60, in order to move forward into a phase III trial. That is, if the MDADI results for an arm are not clinically acceptable (mean total MDADI score at 1 year < 60), then that arm will not proceed to phase III testing, regardless of PFS results.  
| Long-term Swallowing-Related  QOL                                                             |                                                                                                                                                                                                                                               |
|-----------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PFS                                                                                           | Decision Algorithm                                                                                                                                                                                                                            |
| (MDADI at 1 year)                                                                             | The arm meeting the PFS cutoff  with acceptable swallowing  outcome, measured by mean  total MDADI results of ≥ 60 at  1 year, proceeds to phase III;  will be compared to other  approaches, such as primary  surgery or 70 Gy + concomitant |
| Arm selected on the basis of PFS,  and without unacceptable  dysphagia as measured by  MDADI. |                                                                                                                                                                                                                                               |
| Only one arm achieves ≥  85% PFS                                                              | MDADI results for the "superior"  arm must be clinically acceptable  (mean total MDADI score at 1                                                                                                                                             |  
| year ≥ 60)                                                                                    | cisplatin chemotherapy The arm with statistically  superior PFS and acceptable  swallowing outcome, measured  by mean total MDADI of ≥ 60 at 1 year, results proceeds to  phase III; will be compared to  other approaches, such as  primary surgery or 70 Gy +  concomitant cisplatin  chemotherapy   |
|-----------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Arm selected on the basis of PFS,  and without unacceptable  dysphagia as measured by  MDADI. |                                                                                                                                                                                                                                                                                                        |
| Two arms achieve ≥ 85%  PFS; one statistically  superior  MDADI results for the "superior"  arm must be clinically acceptable  (mean total MDADI score at 1  year ≥ 60) One arm is deemed "inferior" only  if (1) its MDADI mean change  score from baseline to 1 year  shows a statistically significantly  difference from the other arm; (2)  a between-arms difference of at  least 5 points is observed; and (3)  the "inferior" arm shows a withingroup decline of 5 points or more  from baseline and MDADI results  are clinically acceptable for the  "superior" arm (mean total  MDADI score at 1 year ≥ 60) The arm with "superior" QOL  proceeds to phase III; will be  compared to other approaches,  such as primary surgery or 70  Gy + concomitant cisplatin  chemotherapy Two arms achieve ≥ 85%  PFS; statistically not  different Any conditions other than those  described in the row above (e.g.  no difference in harm is  demonstrated between arms), and  Both arms move to phase III* MDADI results are clinically  acceptable for both arms (mean  total MDADI score at 1 year ≥ 60) Two arms achieve ≥ 85%  PFS; statistically not  different                                                                                               |                                                                                                                                                                                                                                                                                                        |
| *If PFS and QOL are both acceptable and comparable, and neither arm has MDADI results that    |                                                                                                                                                                                                                                                                                                        |  
*If PFS and QOL are both acceptable and comparable, and neither arm has MDADI results that can be deemed "inferior" or "clinically unacceptable," then both arms may move forward for further testing in a phase II or III trial.  
If PFS goals are met by both arms, and the MDADI results are stable or improved in one or both arms, then decision making will proceed as follows. If the MDADI data shows:  
Stability or improvement in 1 arm at 1 year from baseline, and the other arm shows a within-group decline of 5 points or more from baseline, then the arm which shows stability or improvement will proceed to a phase III.
Stability or improvement in 1 arm at 1 year from baseline, and the other arm shows a within-group decline of less than 5 points from baseline, and there is at least a 5 point difference between arms which is statistically different, the better arm will proceed to a phase III.  
Stability or improvement in 1 arm at 1 year from baseline, and the other arm shows a within-group decline of less than 5 points from baseline, and there is less than a 5 point difference between arms or the difference between arms is not statistically different, both arms will proceed to a phase III.  
Improvement or stability in both arms, with or without a statistical difference, then both will be considered for a phase III study.  
The table below shows statistical power for detecting potential PFS differences between 2 arms. For example, if the 2 arms have 2-year PFS of 85% and 92.5%, based on a twosided log rank test (hypothesis generating) with a type I error rate of 0.1/0.2 and 140 analyzable patients in each arm, we will have 84%/91% power.  
| 85%   | 87.5%   | 90%     | 92.5%   | 95%      | 97.5%    |
|-------|---------|---------|---------|----------|----------|
| 85%   | 20%/32% | 51%/65% | 84%/91% | 98%/99%  | >99%/99% |
| 87.5% | 22%/27% | 57%/56% | 90%/84% | >99%/99% |          |
| 90%   | 25%/38% | 67%/79% | 96%/98% |          |          |
| 92.5% | 31%/44% | 82%/90% |         |          |          |
| 95%   | 43%/58% |         |         |          |          |  
With an effect size of 0.333, an expected mean change in individual MDADI score between the 2 arms of ≥ 5 (and SD estimated to be between 15 [Gillespie 2004]) at 1 year from completion of radiation, and a two-sided, two-sample independent t-test (hypothesis generating) with alphas of 0.2, the table below shows statistical power for various rates of attrition (including 12% from French-speaking Canadian sites); for example, we will have 80% power to detect a 5 point difference for MDADI scores between 2 arms. If PFS is better for one arm but not significant, then this difference between the arms in the mean change in MDADI scores will be used to select the best arm for phase III.  
| Effect size = 0.333   |     |
|-----------------------|-----|
| All cases (n=280)     | 93% |
| 40% attrition (n=168) | 80% |
| 50% attrition (n=140) | 75% |  
The mean summary score of the MDADI, PSS-HN, and CCI and the MDADI subscales including the physical, functional, and emotional domains will be determined. The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean score and mean change from baseline will be compared between the arms using a two-sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. Mean change from baseline will be tested using an omnibus F test followed by individual comparisons of change scores at different time points within each treatment group. The same analysis will be conducted for between group comparisons at each time point. Overall trends for the MDADI scores and subscale scores could be modeled using the general linear mixedeffect model. This model will be used to compare the differences of scores over time between the 2 arms and to compute least squares mean and SEs, including clinical variables and treatment by visit interaction terms. The model also allows for adjustments using stratification variables (unilateral vs. bilateral radiotherapy) and other covariates of interest. The use of general linear mixed modeling allows flexibility in analyzing data with missing responses. To handle poor compliance and missing data, efforts will be made to minimize attrition due to avoidable factors. To assess the missing data mechanism, we will compare possible differences between patients who dropped out of the study against those who remained in the study with respect to imbalance factors such as treatment, baseline scores, clinical, and demographic data. We will undertake sensitivity analyses to investigate reasons for missingness (e.g. by drop-out), considering various factors as mentioned earlier. A logistic regression model will be used to summarize number of missing data and to test if the dropout process is missing completely at random (MCAR). Analysis of complete cases and cases with multiple imputations for missing observations (before death or progression) will be done to check robustness of the main results. Correlation between MDADI and dysphagia as well as other variables will be calculated using Spearman's correlation coefficient and the corresponding p values will be reported. Correlation between categorical measures will be summarized by odds ratios, chi square tests, and associated measures. Adjusted correlation may be derived from ANCOVA models or derived directly using nonparametric ANOVA models if normality assumption is violated. If comparison to historical control is needed, a one-sample t test will be utilized. Binary endpoints will be compared using Fisher's exact test.  
13.6.3 FDG-PET/CT Imaging as a Predictive Imaging Marker for Locoregional Control and Progression-Free Survival Primary endpoint: Determine the Negative Predictive Value (NPV) of FDG-PET/CT, performed at 12-14 weeks post-therapy, for locoregionally advanced oropharyngeal cancer treated with (chemo) radiation therapy for PFS at 2 years. Of the 280 evaluable patients, we anticipate that 140-180 (approximately one half to two thirds) of them will undergo 12-14 weeks post-therapy PET/CT. We assume that approximately 75-80% of total available FDG-PET/CT scans will be negative, 11-12% positive, and 8-14% indeterminate. NPV is then the proportion of PET-negative patients that remain progression-free at 2 years. The power is calculated to reject the null hypothesis of <90% and an alternative hypothesis of 95% using a one-sided binomial test at a significance level of 0.10. With a total of 140 available scans, which indicates 105-112 PET-negative patients, the statistical power is 76-77% and if the total number of scans is 180 and 135-144 PETnegative patients, we will have 83-85% power to reject the null hypothesis regarding the negative predictive value.  
13.6.4 HPV DNA As a Potential Marker for Relapse For Hypothesis 1, with a two-sided type error rate of 5% and based on chi-squared test for proportions, we have greater than 99% power to detect HPV DNA detection rate of 65% and 95% between the 2 groups (n=140 in each arm). The rate of detection for each group will be summarized based on binomial distributions and a 95%CI will be provided. For Hypothesis 2, correlation between HPV DNA copy number and the nodal metabolic volume (nMTV) will be calculated using Spearman's correlation coefficient and R2, and the corresponding 95%CI will be provided. For Hypothesis 3, first, with a two-sided type error rate of 5% and based on paired t test for means, we have 99% power to detect HPV DNA rate decline of 0.375 (effect size) within each arm (n=140). The HPV DNA rate for each group will be summarized using means and standard deviations. For Hypothesis 3, second, assuming 5%, 6%, 7%, 8% LRF for two-year PFS of 91%, 89%, 87% and 85%, the following tables show statistical power for detecting various hazard ratios. For example, if the variance for HPV DNA is 15 and the two-year PFS is 89%, then we will have 80% power to detect a hazard ratio of 1.20 with 3 arms combined. Univariable and multivariable cause specific analysis will be performed using the Cox proportional hazards model for rate of relapse. Potential covariates evaluated for the multivariate models would be treatment, age, Zubrod performance status, T-stage, Nstage, smoking history, other risk behaviors.  
| Hazard Ratio   |      |      |      |      |      |
|----------------|------|------|------|------|------|
| 1.01           | 1.05 | 1.10 | 1.15 | 1.20 |      |
| 5              | 0.03 | 0.06 | 0.12 | 0.21 | 0.33 |
| 10             | 0.03 | 0.08 | 0.20 | 0.37 | 0.57 |
| 15             | 0.03 | 0.10 | 0.28 | 0.52 | 0.75 |
| 20             | 0.03 | 0.12 | 0.35 | 0.64 | 0.86 |
| 25             | 0.03 | 0.14 | 0.42 | 0.74 | 0.92 |
| Variance       |      |      |      |      |      |  
Statistical power to detect various hazard ratios, continuous variable, 2 arms combined 2year PFS 91%, 14 locoregional failure events, 2-sided 0.05 Statistical power to detect various hazard ratios, continuous variable, 2 arms combined **2-year PFS 89%, 17 locoregional failure events, 2-sided 0.05**  
| Hazard Ratio   |      |      |      |      |      |
|----------------|------|------|------|------|------|
| 1.01           | 1.05 | 1.10 | 1.15 | 1.20 |      |
| 5              | 0.03 | 0.06 | 0.13 | 0.25 | 0.39 |
| 10             | 0.03 | 0.09 | 0.23 | 0.44 | 0.66 |
| 15             | 0.03 | 0.11 | 0.33 | 0.60 | 0.82 |
| Variance       |      |      |      |      |      |  
Hazard Ratio  
1.01 1.05 1.10 1.15 1.20  
20 0.03 0.14 0.41 0.73 0.91  
25 0.03 0.17 0.50 0.82 0.96  
| Variance   |
|------------|  
Statistical power to detect various hazard ratios, continuous variable, 2 arms combined **2-year PFS 87%, 20 locoregional failure events, 2-sided 0.05**  
Hazard Ratio  
1.01 1.05 1.10 1.15 1.20  
5 0.03 0.07 0.15 0.28 0.44 10 0.03 0.10 0.27 0.50 0.73 15 0.03 0.13 0.37 0.67 0.88 20 0.03 0.16 0.47 0.79 0.95 25 0.04 0.19 0.56 0.87 0.98  
Statistical power to detect various hazard ratios, continuous variable, 2 arms  
combined **2-year PFS 85%, 22 locoregional failure events, 2-sided 0.05**
nrg oncology
pi3k pathway activation and its

The predictive and prognostic potential for these proposed biomarkers may become scientifically obsolete or the assay technology may evolve over time, making the technology outlined in the current protocol obsolete when the study is finished. As such, no marker assays will be reviewed on the collected specimens other than those required for patient selection (i.e. p16 immunohistochemistry). When sufficient information is available from the parent study, a full correlative study protocol for the marker studies detailing the scientific hypothesis, research plan, assay methods for each biomarker, and a complete statistical section (with adequate power justification and analysis plan) will be submitted and subjected to CTEP review in accordance with the National Clinical Trials Network (NCTN) policies.  
13.6.5 Determining the Extent of Long-Term Dysphagia Using MBS **(5/24/16)**
Primary endpoint: Determine the risk of grade ≥3 MBS-detected dysphagia 2-years after de-escalated IMRT.  
| Hazard Ratio   |      |      |      |      |      |
|----------------|------|------|------|------|------|
| 1.01           | 1.05 | 1.10 | 1.15 | 1.20 |      |
| 5              | 0.03 | 0.07 | 0.15 | 0.28 | 0.44 |
| 10             | 0.03 | 0.10 | 0.27 | 0.50 | 0.73 |
| 15             | 0.03 | 0.13 | 0.37 | 0.67 | 0.88 |
| 20             | 0.03 | 0.16 | 0.47 | 0.79 | 0.95 |
| 25             | 0.04 | 0.19 | 0.56 | 0.87 | 0.98 |
| Variance       |      |      |      |      |      |  
| Hazard Ratio   |      |      |      |      |      |
|----------------|------|------|------|------|------|
| Variance       | 1.01 | 1.05 | 1.10 | 1.15 | 1.20 |
| 5              | 0.03 | 0.07 | 0.16 | 0.31 | 0.48 |
| 10             | 0.03 | 0.10 | 0.29 | 0.54 | 0.77 |
| 15             | 0.03 | 0.14 | 0.40 | 0.71 | 0.91 |
| 20             | 0.03 | 0.17 | 0.51 | 0.83 | 0.96 |
| 25             | 0.04 | 0.20 | 0.60 | 0.90 | 0.98 |  
Of the 90 evaluable patients, we anticipate that 63-72 (approximately 20-30% attrition) will complete the 2 year MBS. We expect <20% of patients will have DIGEST grade ≥3 (severe) MBS-detected dysphagia at 2 years. No life threatening dysphagia (DIGEST grade 4) is expected. Exploratory analyses of MBS arm will include:
Concordance/discordance of perceived dysphagia (per PRO instrument –
MDADI) with MBS detected dysphagia (per DIGEST)
Develop predictive model for DIGEST grade ≥3 MBS detected dysphagia 2 years after de-escalated radiotherapy per age, tumor characteristics, treatment parameters (including use of concurrent chemotherapy), early toxicity profiles (clinician and provider graded)
nrg oncology
13.7 gender/ethnicity/race distribution

| Gender                                    |         |       |       |
|-------------------------------------------|---------|-------|-------|
| Ethnic Category                           | Females | Males | Total |
| Hispanic or Latino                        | 1       | 9     | 10    |
| Not Hispanic or Latino                    | 28      | 258   | 286   |
| Ethnic Category: Total of all subjects    | 29      | 267   | 296   |
| Gender                                    |         |       |       |
| Racial Category                           | Females | Males | Total |
| American Indian or Alaskan Native         | 0       | 1     | 1     |
| Asian                                     | 1       | 0     | 1     |
| Black or African American                 | 2       | 12    | 14    |
| Native Hawaiian or other Pacific Islander | 0       | 1     | 1     |
| White                                     | 26      | 253   | 279   |
| Racial Category: Total of all subjects    | 29      | 267   | 296   |
nrg oncology
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appendix i dental tooth count
dental tooth count diagram

Use the diagram below as a guide to count the number of native teeth in place, not including full or partial dentures or bridges. The exact location of teeth does not need to be recorded, only the total number of native teeth in place (attached to bone in mandible or maxilla) on the day of evaluation. This exam should be completed by a physician or designee, such as a physician's assistant, nurse or nurse practitioner, or a dentist/hygienist.  
Date of evaluation: Total number of native teeth in place (0-32):
appendix i (continued) dental effects
dental tooth count diagram

0 Normal: Edentulous, with no gingival disease; native teeth in place with gingiva in excellent condition.  
1 Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated.  
2 Moderate/fair dental health: moderate periodontal inflammation; deep periodontal cleaning indicated; 6 or more restorations indicated; less than full mouth extractions indicated.  
3 Severe changes in dental health: widespread periodontal disease with extensive procedure/surgery indicated; full mouth extractions indicated.  
4 Life-threatening dental condition: extensive abscess, extensive soft issue or bone infection, sepsis; urgent intervention indicated.
appendix i (continued) management of
dental tooth count diagram

Goals for a dental care program include: 1. To reduce incidence of bone necrosis. 2. To reduce incidence of irradiation caries. 3. To allow proper fitting of dentures following treatment. Pre-irradiation Care and Procedures The patients may be grouped into four groups in accordance with the problems they present prior to irradiation.  
Group 1: Includes edentulous patients. They may require surgical removal of any symptomatic cysts, infected retained root tips, or alveolar hyperplasia. These patients require hygiene instruction and precautionary instruction about trauma with premature use of a prosthesis.  
Group 2: Includes those with poor dental hygiene, including those patients whose teeth are beyond repair by ordinary dental procedure, those with generalized oral sepsis, those with generalized periodontal disease, and those with chronic periapical abscesses or granulomas. Procedures performed on this group include removal of all remaining teeth prior to irradiation with primary closure and surgical preparation of the alveolar ridges to laterally support a prosthesis. There should be antibiotic coverage during the healing stage and adequate time prior to the start of radiation therapy. These patients need complete hygiene instruction and precautionary instruction about premature use of a prosthesis.  
Group 3: Includes those in whom dental condition is fair, including those patients whose teeth are restored, ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions are not in proximity to the pulp, and no more than 20 restorable carious lesions are present. X-ray examinations show at least 1/2 of the bone still present around root surfaces. These patients require removal of any teeth that are nonsalvageable in accordance with the above and restorations of the remaining teeth as required. The patients are instructed for dental prophylaxis and the patients utilize custom-made fluoride carriers.  
Group 4: Includes those in whom dental hygiene is good. This includes patients who do not have severe malocclusion in whom few carious lesions are present. Carious lesions are not in close proximity to the pulp and are correctable by conventional methods. These patients require periodontal evaluation and dental prophylaxis training, restorations as needed, no extractions prior to radiation therapy, and fitting for custom carriers.
appendix i (continued) management of
appendix i (continued) management of

If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that closure at the extraction site is possible. All loose spicules and sharp projections must be removed. The approximation of the gingival tissue must be such that the closure is neither too loose nor too tight. At least 10 days are required for adequate healing prior to initiation of therapy.
appendix i (continued) management of
causative factors

The major causative factors appear to be the reduction of the amount of saliva and secondarily, reduced pH in the mouth. This occurs following high dose radiation to the major salivary glands using parallel opposed fields. The decay process usually occurs in the first year following radiation therapy. It tends to occur more quickly in teeth which have a large amount of root cementum exposed to those teeth with large amounts of plaque formation present. Doses of radiation in excess of 20 Gy to salivary tissue place the teeth at risk.
appendix i (continued) management of
preventive program

The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible to the decay process. This is accomplished by a combination of increasing fluoride concentration on the tooth surface and by the effect of fluoride on the plaque and flora that are present in the oral cavity. Adequate results are obtained by: 1) cleansing the teeth thoroughly, followed by a good home care dental prophylaxis program, 2) construction of fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution to the gingiva and tooth surfaces. Fluoride carriers are made individually with the use of casts. Material used for making a mouth guard is "Sta-Guard" plastic used in conjunction with vacutrole unit produced by Jelrus Technical Products, Corp., both of which are available through local dental supply. This material is molded to the cast impression and allowed to harden. A fluoride solution prepared at the M.D. Anderson Hospital is now available from the Emerson Laboratories, Inc., Dallas, Texas 75221. It has been used to coat the plastic carrier for use in the mouth. The patients are instructed to cleanse their teeth prior to placement of the carrier. It is then worn in place for 5 minutes each day. The patients are instructed to rinse their mouths thoroughly following the use of the carrier. This will be continued for an indefinite period of time. Close follow-up is necessary.
appendix i (continued) management of
results

In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 patients shows that the incidence of necrosis of the jaw was reduced to approximately 21% compared to 37% prior to initiation of the study. Groups 3 and 4 patients randomized with and without fluoride treatment showed reduction in radiation carries from 67% to 34% among Group 3 patients, and from 65% to 22% among Group 4 patients.
appendix i (continued) management of
failure to control decay

Management of failure to control radiation decay includes silver fillings with continued use of fluoride treatments. If the decay process is sufficiently advanced that a filling will no longer stay in place, these teeth are merely smoothed so that there will be no sharp, irritating edges. The mere existence of such a decayed tooth is not necessarily reason for extraction, for it must be remembered that extraction could lead to complications such as bone necrosis. Pulp exposure resulting from the decay process can usually be handled by use of antibiotics and/or root-canal therapy.
appendix i (continued) management of
hypersensitivity of teeth

Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished amounts of saliva. This has been shown to be reduced in incidence with the fluoride treatments. Should this problem become manifest, increasing the fluoride treatment to 10 to 15 minutes 3 times a day is recommended.
appendix i (continued) management of
infections

Infections occurring in patients under or after radiation therapy are best managed conservatively with good oral hygiene, irrigation and flushing procedures, and systemic antibiotics.
appendix i (continued) management of
bone necrosis

The patients receiving radiation therapy to a high dose to the head and neck region have increased susceptibility to bone necrosis for several reasons including: impairment of normal metabolism, increased susceptibility to infection and severely limited repair process. Bone necrosis occurs most often after dental or oral surgery in patients who have been previously radiated. Conservative management should be tried first, though in more aggressive lesions a more radical approach may ultimately be necessary.
appendix i (continued) management of
appendix ii instructions and forms

Prior to enrolling patients to this substudy, sites must complete the NRG-HN002 MBS Credentialing Checklist (see below). The institution will e-mail the completed form to Martha Portwood, MPH, mportwood@mdanderson and will receive a letter of instruction confirming that the site is approved to enroll patients in the substudy. Institutions should allow adequate processing time (10-14 days) before enrolling the first patient on this substudy. Facilities must use a standardized contrast medium (Varibar® thin liquid and pudding contrast, Bracco Diagnostics, Inc. Princeton, NJ, or comparable in Canadian centers) and digitally record MBS studies (30 frames/second, although a minimum of 15 frames/second is acceptable if this is made clear at the time of credentialing). DIGEST grades will be assigned by the site Speech-Language Pathologist conducting the MBS study and reported by research staff on the Modified Barium Swallow Study Form as: 0 "normal", 1 "mild", 2 "moderate", 3 "severe", or 4 "life threatening". Participating sites are required to perform MBS studies as specified on the Modified Barium Swallow Study Form (below) and then upload the MBS video to the TRIAD (Transfer of Images and Data) application, as specified below, for central review and scoring. The percent of patients with scores of 0, 1, 2, 3, and 4 dysphagia per MBS will be compared at baseline and 24 months (+/- 3 months) from end of radiation. Questions related to conduct of MBS studies can be directed to: Martha Portwood, MPH University of Texas MD Anderson Cancer Center Phone: 713-792-6364 E-mail: mportwood@mdanderson.org Kate Hutcheson, PhD University of Texas MD Anderson Cancer Center Phone: 713-792-6513 Email: karnold@mdanderson.org Jan S. Lewin, PhD University of Texas MD Anderson Cancer Center Phone: 713-792-5309 Email: jlewin@mdanderson.org
appendix i (continued) management of
appendix ii (continued) instructions for

1) Download and install TRIAD 4 via https://triadinstall.acr.org/triadclient/  
 2) Launch TRIAD, click the dropdown to select Clinical Trials (NCI Oncology). Login using your CTEP ID and password (see Section 8 for access requirements for OPEN, Medidata Rave, and TRIAD).  
3) To begin file submission:  
  
A. Select the HN002 Trial from the *Trial* dropdown.  
B. Select your Hospital from the *Site* dropdown. C. Once these options are selected, select *Import Folder* (to select a group of video files), or *Import Files* (to import an individual video file).
appendix ii (continued)
instructions for submission of mbs

4) Your selected file(s) will appear in the preview screen for review. Select *Move to*  
  
Submission Queue to move your files to the submission queue.  
5) To complete, enter subject information (Subject ID, Time Point ID, Time Point  
  
Description, Submission Type, etc.), then select *Submit*.
appendix ii (continued) instructions and
modified barium swallow (mbs) credentialing

This checklist must be completed by the institution before patients can be enrolled to the MBS substudy of NRG-HN002. 1. Please provide the following data specific to your site regarding conduct of modified barium swallow (MBS) studies to evaluate swallowing disorders.  
a) Number of speech/language pathologists at your institution who perform MBS
studies:_________
b) Average number of MBS studies conducted at your institution each week:_________ c) Average number of MBS studies conducted on patients who have head and neck cancer each week:__________
2. Are your MBS videos recorded digitally at a minimum frame rate of 30 frames/second
(i.e., accurate to 0.01 time code imprints)?
YES NO If no, specify frame rate used at your facility (note: 15 to 30 permitted): _____________  
3. Do you use the Kay Pentax Digital Swallowing Workstation? (this is NOT mandatory for participation)
YES NO If no, specify the recording system used:_____________________________________
appendix ii (continued) instructions and
modified barium swallow (mbs) credentialing

4. Do you use Varibar contrast agents specified in this substudy, including Varibar Thin Liquid and Varibar Pudding? YES NO If no, specify the standardized contrast medium used:____________________________
5. If no, can you access Varibar contrast agents for MBS studies conducted for this substudy? YES NO
Signature of Institution Speech/Language Pathologist_________________________________ Printed Name of Speech/Language Pathologist______________________________________ Institution Name______________________________________________________________ Site NRG number/CTEP ID Number______________________________________________
appendix ii (continued)
modified barium swallow (mbs) credentialing

Instructions and Forms for the Modified Barium Swallow (MBS) Substudy Institution Contact Person______________________________________________________ Institution Contact Person's phone and fax numbers__________________________________ Institution Contact Person's e-mail address_________________________________________ Name and e-mail address of person uploading MBS video E-mail the completed checklist to Martha Portwood, MPH, at mportwood@mdanderson.org. After review and approval of the form by the Swallowing Outcomes Co-Chair, Jan S. Lewin, PhD, the CRA will receive a letter of instruction confirming that the site is approved to enroll patients in this substudy.  
APPENDIX II (Continued)