eligibility checklist - step 2
protocol treatment must begin within

6.1 Dose Specifications for both **Arms**
The prescribed radiotherapy dose will be 60 Gy in 2 Gy once-daily fraction size (total of 30 fractions). Radiotherapy should begin on a Monday, Tuesday or Wednesday. The daily dose of 2 Gy will be prescribed such that 95% of the PTV60 volume receives at least 60 Gy. As described in Section 6.4, PTV56 and PTV66 also may be defined. The spinal cord dose may not exceed 48 Gy to any volume larger than 0.03 cc.  
6.2 Technical Factors (13-NOV-2017)
6.2.1 *Treatment Planning/Delivery*: Megavoltage energy photon beam irradiation is required. Any treatment planning and delivery system that has been credentialed for head and neck IMRT by the IROC Houston is acceptable.  
6.2.2 Image Guidance for IGRT (see *Section 5.2.2)*: Daily image guidance of IMRT may be achieved using any one or more of the following techniques:
- Orthogonal kilovoltage (KV) images, e.g. ExacTrac;
- Linear-accelerator mounted kV and MV conebeam CT images;
- Linear-accelerator mounted MV CT images (e.g., Tomotherapy); - Other mechanism, after discussion with the Study Chair and Medical Physics Co-chair.  
The institution's procedure to register treatment day imaging dataset with the reference dataset should comply with the following recommendations:
- Region-of-Interest (ROI) or "clip box" for fusion should be set to encompass the high dose PTV and adjacent spinal cord; if the supraclavicular region is a part of the target volume the ROI should extend to the C6 level;
- If the fusion software allows the user to create an irregular ROI (e.g., ExacTrac),
treatment room objects seen on in-room X-rays should be excluded from the registration;
- Both manual (e.g., based on bony anatomy) and automatic (e.g., based on mutual information) types of registration can be used; the result of the fusion must be visually checked for the alignment of the bony anatomy, such as vertebral bodies and applicable soft tissue structures (e.g., optic nerves and/or optic chiasm).  
Following the registration, the translational and (if the appropriate technology is available)
rotational corrections should be applied to the treatment couch. If all the variances are less than 2.5 mm (this typically corresponds to one half of the usual PRV margin), the treatment can proceed without correction (however, the physician/team may elect to perform adjustments even for a variance < 2.5 mm). If one or more corrections are 2.5-5 mm, adjustment is necessary prior to treatment; however, re-imaging is not mandatory. If one or more of the corrections are larger than 5 mm, the imaging must be repeated in addition to performing table/positioning adjustments.  
CTV60 also will include the ipsilateral pathologically positive hemineck (if both sides of the neck are proven pathologically positive, CTV60 will include both sides). This generally means encompassing nodal levels 2a, 3, and 4 for all cases. Nodal levels 1, 2b, 5a, and 5b are included in CTV60 in selected circumstances. For example, level 1 must be included for oral cavity cancer but is not mandatory for larynx cancer. Level 5a must be included for oropharynx cancer but is not mandatory for larynx cancer. For questions, contact the Principal Investigator, Dr. Machtay, or one of the Radiation Oncology Co-Chairs, Drs. Thorstad, Nguyen-Tan, and Quon. CTV56: This will include all other regions felt to be at risk for harboring microscopic cancer that do not meet the criteria for CTV60. For example, this would apply to the contralateral hemineck being irradiated electively for base of tongue cancer. This volume should not approach the skin < 5 mm. This volume will receive approximately 1.85 Gy per day.  
CTV66 **Optional**: This may be defined at the discretion of the treating radiation oncologist.  
This would include a region or regions felt to be at especially high risk for recurrence (e.g.,
an area of very close margin of resection). **Note**: This area will be receiving a daily fraction size of 2.2 Gy and thus, the volume of CTV66 should be kept **as small aspossible**.  
Planning Target Volumes (PTVs): In general, the PTV should not go outside of the skin surface; if it does exceed the skin surface, the application of bolus material over this portion of the PTV may be considered but is generally not recommended. It is also allowable to define two PTV's for a given CTV: 1) PTV Planning, which extends beyond the skin surface and is used for planning treatment segments; and 2) PTV Evaluation, which does not reach the skin surface within 2 mm and is used for evaluation of the dose volume histogram to determine if treatment goals have been met.
eligibility checklist - step 2
ptv expansion without daily igrt

For those institutions that are not using daily IGRT (see Section 6.2.2), the minimum CTVto-PTV expansion should be 5 mm (a larger expansion may be necessary for a target volume subject to significant inter-fraction variability such as the tongue). In general, the CTV-to-PTV expansion (without IGRT) should not exceed 10 mm.
eligibility checklist - step 2
ptv expansion with daily igrt

For those institutions that are using daily IGRT (see Section 6.2.2), the minimum CTV-toPTV expansion is 2.5 mm (a larger expansion may be necessary for a target volume subject to significant intra-fraction variability, such as the non-immobilized oral tongue).In general, the CTV-to-PRV expansion (with IGRT) should not exceed 5 mm.  
6.4.2 Definition of Normal Tissues/Organs at Risk (OARs)
Management of Radiation Dose to the Patient from IGRT
Radiation doses from IGRT are small enough dose contributions that if there is only one imaging study done per treatment session, the dose does not need to be incorporated into treatment planning and is not expected to have any clinical relevance to the patient. However, 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 of more than 5 mm). It is recommended that patients demonstrating severe set up problems during the first week of treatment be moved to a treatment with larger margins.  
6.3 Localization, Simulation, and Immobilization 6.3.1 Patients must have an immobilization device (e.g., aquaplast mask) made prior to treatment planning CT scan.  
6.3.2 The treatment planning CT scan should be performed with IV contrast so that the major vessels of the neck are easily visualized. The treatment planning CT scan must be performed with the immobilization device and in the treatment position. Slice thickness should be 0.3 cm.  
6.4 Target and Normal Tissue Volume Definitions **(13-NOV-2017)**
6.4.1 Definition of Target *Volumes* CTV60: This volume will receive 2 Gy per day. CTV60 will include the primary tumor bed (based on preoperative imaging, preoperative physical exam/endoscopy, operative findings, pathologic findings) plus region(s) of grossly involved lymphadenopathy. This volume may approach the skin but should not approach < 2mm. It is recognized that after surgery, there can be considerable distortion of normal anatomy. If possible, map preoperative GTV(s) onto the postoperative radiation therapy planning CT scan, and add appropriate margins for microscopic spread (1.5-2 cm).  
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 vertebral body). Superior to this is brainstem and inferior to this is cord. The inferior border of the spinal cord is at approximately T3-4 (i.e., just below the lowest slice level that has PTV on it). The spinal cord shall be defined based on the treatment planning CT scan. In addition, however, a Planning Risk Volume (PRV) spinal cord shall be defined. The PRVcord = cord + 5 mm in each dimension. This is irrespective of whether or not IGRT is used.  
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction where it meets the spinal cord. For the purposes of this study, the superior most portion of the brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall be defined based on the treatment planning CT scan. In addition, however, a Planning Risk Volume (PRV) brainstem shall be defined. The PRVbrainstem = brainstem + 3 mm in each dimension.  
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to keep the lip dose much lower than the oral cavity dose. The definition of lips is selfexplanatory. For non-oral cavity cancers, the oral cavity will be defined as a composite structure consisting of the anterior ½ to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and palate. For oral cavity cancers, the oral cavity will be defined as the subset of this composite structure that does not overlap with PTV.  
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan.  
Parotid gland volume will not include any portion of any of the CTVs, although they can overlap the PTVs. OARpharynx: This will be defined as the "uninvolved" posterior pharyngeal wall plus adjacent constrictor muscles. This extends from the superior constrictor region (the inferior pterygoid plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level). This should not overlap the PTVs. Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of OARpharynx and extends to the thoracic inlet.  
Glottic/Supraglottic Larynx (GSL): Obviously, for patients who have had a total laryngectomy, this structure is not applicable. This will be defined as a "triangular prism shaped" volume that begins just inferior to the hyoid bone and extends to the cricoid cartilage inferiorly and extends from the anterior commissure to include the arytenoids. This includes the infrahyoid but not suprahyoid epiglottis.  
Mandible: This includes the entire boney structure of the mandible from TMJ through the symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and PTVs.  
Unspecified Tissue Outside the Targets: This will be defined as tissue located between the skull base and thoracic inlet that is not included in either the target volumes or the normal tissues described above.  
6.5 Treatment Planning and Delivery 6.5.1 Management of the Low Neck/Supraclavicular Region (Match vs. No Match)
It is recognized that comprehensive head and neck irradiation incorporating IMRT can be done in 1 of 2 ways, either of which is permitted for this study.  
1. Match: The upper cervical lymphatics and primary tumor bed are treated with IMRT. The lower cervical lymphatics and supraclavicular region are treated with a single AP (or occasionally APPA for larger patients with posterior neck at high risk) non-IMRT technique. The latter non-IMRT field(s) is matched to the upper neck IMRT fields. This technique requires comprehensive mid-line spinal cord blocking in the lower neck fields. This technique also allows for a simultaneous blocking of portions of the larynx, hypopharynx, and cervical esophagus in the lower neck fields. In general, this technique is appropriate for irradiation of cancers of the oral cavity or oropharynx.  
2. No Match: The entire clinical target volume (CTV) [upper and lower neck and primary tumor bed] is irradiated with IMRT. There is no match line between upper and lower portions of the
regions at risk. In this technique, limiting radiotherapy dose to organs at risk (OARs), e.g.,
the cervical esophagus, is entirely achieved by inverse treatment planning via IMRT algorithms. This technique in general is appropriate for irradiation of cancers of the larynx and/or oral/pharyngeal cancers that involve the hypopharynx.  
6.5.2 Dose to Supraclavicular Nodal Region Regardless of whether technique 1 (Match) or technique 2 (No Match) is used, the dose to the supraclavicular nodal region may be limited to 50 Gy if level 4 nodes were dissected and found to be negative or in the case of oral cavity cancer with level 3 nodes dissected and found to be negative.  
6.5.3 IMRT Dose Prescription to PTVs See Section 6.4.1 for definitions of CTVs and PTVs. As described in Section 6.1, prescribed radiotherapy dose will be 60 Gy in 2 Gy once-daily fraction size. For inverse planning IMRT, the goal is for 95% of the PTV60 to receive ≥ 2 Gy with a minimum dose (cold spot) of no less than 56 Gy. It is recognized that portions of the PTV60 close to the skin may receive significantly less than 56 Gy. This is acceptable as long as cold spots within PTV60 do not exist at a depth deeper than 8 mm beneath the skin (see Section 6.8, compliance criteria). For prioritization, PTV60 will be the highest priority target structure. PTV66 and PTV56, if applicable, will be ranked in the IMRT planning as lower priority than PTV60 although higher priority than normal structures other than spinal cord and brain stem.  
6.5.4 IMRT Dose Constraints to Normal Structures Spinal Cord: The PRVcord (as defined in Section 6.4.2.) should not exceed 48 Gy to any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV
should not exceed 50 Gy to any volume in excess of 0.01 cc. In treatment planning, the spinal cord PRV should be given the highest priority. Brainstem: The PRVbrainstem (as defined in Section 6.4.2.) should not exceed 52 Gy to any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the PRVbrainstem should be given less priority than the PRVcord but more priority than the other critical structures listed below.  
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. For nonoral cavity cancers, the maximum dose will be < 30 Gy. For oral cavity cancers, the maximum dose will be < 50 Gy. Oral Cavity: Reduce the dose as much as possible. For non-oral cavity cancers, the mean dose should be < 30 Gy. For oral cavity cancers, the mean dose should be < 50 Gy. Efforts should be made to avoid hot spots (> 60 Gy) within the oral cavity, particularly for non-oral cavity cancers. Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The treatment planning goal will be for this individual parotid gland to receive a mean dose of < 26 Gy. Additional planning goals may include: 1) At least 50% of one parotid will receive <
30 Gy; and/or 2) At least 20 cc of parotid tissue (from the combination of both glands) will receive < 20 Gy. OARpharynx: Reduce the dose as much as possible. Some recommended (but not mandatory) treatment goals include: 1) No more than 33% of the OARpharynx exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the OARpharynx exceeds 60 Gy.  
Cervical Esophagus: Reduce the dose as much as possible. For oral or oropharyngeal cancer, some recommended (but not mandatory) treatment goals include: 1) No more than 33% of the esophagus exceeds 45 Gy; 2) Mean dose < 35 Gy; 3) No more than 15% of the esophagus exceeds 54 Gy. For larynx cancer, higher doses are expected and permitted.  
Some recommended doses (but not mandatory) treatment goals include: 1) No more than 33% of the esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the esophagus exceeds 60 Gy. Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. In patients with resected oral or oropharyngeal carcinoma, it is recommended that the dose to the larynx should be kept < 45 Gy whenever feasible.  
Mandible: Reduce the dose as much as possible. It is recognized that particularly for oral cavity cancers, significant portions of the mandible will overlap the CTVs and/or PTVs; however, hot spots within the mandible should be avoided. It is recommended that maximum dose within the mandible be < 66 Gy.  
Unspecified Tissue Outside the Targets: For the typical case in which there is no CTV66, no more than 5% of unspecified tissue can receive greater than 58 Gy and no more than 1% or 1cc of unspecified tissue can receive 64 Gy or more. When a boost is used to increase the dose to high risk regions to as much as 66 Gy, these numbers can be increased. In this case, no more than 5% of the unspecified dose should exceed the level of the boost dose, and no more than 1% or 1 cc should exceed the boost dose value plus 10%.  
6.5.5 Prioritization for IMRT Planning 1. Spinal Cord 2. Brainstem 3. PTV60 4. PTV56 (if applicable)
5. PTV66 (if applicable)
6. a. OARpharynx b. Parotid gland contralateral to primary tumor site 7. a. GSL
b. Esophagus 8. a. Lips b. Oral Cavity 9. a. Parotid gland ipsilateral to primary tumor site b. Mandible 10. Unspecified tissue outside the targets 6.6 Critical Structures **(25-JAN-2016)**
Note: All structures marked "required" in the table below must be contoured and submitted for review. Resubmission of data may be required if labeling of structures does not conform to the standard DICOM name as listed.  
The following table outlines the naming of the various normal and critical structures for submission to TRIAD.  
| Standard Name   | Description                                                                                                         |
|-----------------|---------------------------------------------------------------------------------------------------------------------|
| CTV_6000        | Primary Tumor Bed plus  involved nodes. Required                                                                    |
| CTV_5600        | At risk regions Required when applicable                                                                            |
| CTV_6600        | Optional higher dose region;  should be kept small as  possible. Required when applicable                           |
| PTV_6000        | CTV-PTV 5 mm margin without  IGRT; 2.5 mm with Daily IGRT. Required PTV_6000, not including portion                 |
| PTV_6000-08     | of PTV_6000 near (<8 mm) skin Required                                                                              |
| PTV_5600        | CTV-PTV 5 mm margin without  IGRT; 2.5 mm with Daily IGRT. Required when applicable PTV_5600, not including portion |  
| PTV_5600-08   | of PTV_5600 near (<8 mm) skin Required when applicable                                                                                             |
|---------------|----------------------------------------------------------------------------------------------------------------------------------------------------|
| PTV_6600      | CTV-PTV 5 mm margin without  IGRT; 2.5 mm with Daily IGRT. Required when applicable PTV_6600, not including portion  of PTV_6600 near (<8 mm) skin |
| PTV_6600-08   | Required when applicable                                                                                                                           |
| NonPTV6000    | External minus PTV_6000 Required                                                                                                                   |
| SpinalCord    | Spinal Cord Required                                                                                                                               |
| SpinalCord_05 | Planning risk Volume of 5 mm Required                                                                                                              |
| BrainStem     | Brain Stem Required                                                                                                                                |
| BrainStem_03  | Planning Risk Volume of 3 mm Required                                                                                                              |
| Parotid_L     | Left Parotid Required                                                                                                                              |
| Parotid_R     | Right Parotid Required                                                                                                                             |
| OralCavity    | Oral Cavity Required                                                                                                                               |
| Lips          | Lips Required                                                                                                                                      |
| Mandible      | Mandible Required                                                                                                                                  |
| Pharynx       | Uninvolved posterior pharyngeal  wall plus adjacent constrictor  muscles; should not include  PTVs Required                                        |
| Esophagus_Up  | Cervical Esophagus Required                                                                                                                        |
| LarynxGSL     | Glottic/Supraglottic larynx Required                                                                                                               |
| External      | External border of patient used  to define Unspecified Tissue. Required                                                                            |  
6.7 Documentation Requirements for IMRT Treatment Approach **(13-NOV-2017)**
- Pre-treatment Radiation therapy planning CT scan;
- If IGRT is not used, then orthogonal images that localize the isocenter placement of IMRT
are required. This information should be archived by the submitting institution, so it can be made available for possible future review; 6.7.1 Additional Documentation Requirements for IGRT Treatment *Approach* If an IGRT treatment approach is utilized, the following documentation is required:
- IGRT images obtained on the first day of treatment;
- One IGRT image data set per week of treatment; Note: Sites should retain all daily images. Any or all of the institution's daily images may be subject to **auditing.**
- Spreadsheet that includes data on daily pre-treatment variances based on analysis of daily IGRT. See CTSU website (https://www.ctsu.org) for the spreadsheet.  
6.8 Compliance Criteria **(03-NOV-2014)**
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for the treatment break(s). Treatment breaks, if necessary, ideally should not exceed five treatment days at a time and ten treatment days total. Treatment breaks should be allowed only for resolution of severe acute toxicity and/or for intercurrent illness and not for social or logistical reasons. Any treatment break(s) exceeding two treatment days for reasons other than toxicity/illness will be considered a protocol deviation.  
| toxicity/illness will be considered a protocol deviation. Per Protocol     | Minor Variation                      | Major Variation                                                       |                                                                          |          |          |         |
|----------------------------------------------------------------------------|--------------------------------------|-----------------------------------------------------------------------|--------------------------------------------------------------------------|----------|----------|---------|
| Total RT dose to PTV_6000 (to                                              | 60-64 Gy                             | 58-60 or 64-66                                                        | <58 or > 66 Gy                                                           |          |          |         |
| Gy                                                                         |                                      |                                                                       |                                                                          |          |          |         |
| 95%) of PTV_6000) Minimum dose ("cold                                      | spot"                                |                                                                       |                                                                          |          |          |         |
| within PTV_6000, not including  portion of PTV_6000 near (<8  mm) skin)    | 56-60 Gy                             | 54-56 Gy                                                              | < 54 Gy                                                                  |          |          |         |
| Maximum                                                                    | dose                                 | ("hot                                                                 | spot")                                                                   | < 70 Gy  | 70-72 Gy | > 72 Gy |
| within PTV_6000* Maximum dose                                              | ("hot                                | spot"                                                                 | < 66 Gy                                                                  | 66-70 Gy | > 70 Gy  |         |
| outside of PTV_6000) Total RT dose to PTV_5600 (to                         | 56-60                                | 54-56 or 60-62                                                        | <54 or >62                                                               |          |          |         |
| 95%) of PTV_5600) Minimum dose ("cold                                      | spot"                                |                                                                       |                                                                          |          |          |         |
| within PTV_5600, not including  portion of PTV near (<8 mm)  skin)         | 52-56                                | 50-52                                                                 | <50                                                                      |          |          |         |
| Total RT dose to PTV_6600 (to                                              | 66-70                                | 64-66 or 70-72                                                        | <64 or >72                                                               |          |          |         |
| 95%) of PTV_6600) Minimum dose ("cold                                      | spot"                                |                                                                       |                                                                          |          |          |         |
| within PTV_6600, not including  portion of PTV near (<8 mm)  skin)         | 62-66                                | 60-62                                                                 | <60                                                                      |          |          |         |
| Definition of CTV_6000                                                     | Based on case review by study chair  |                                                                       |                                                                          |          |          |         |
| Definition of PTV_6000                                                     | Based on case review by study chair. |                                                                       |                                                                          |          |          |         |
| Total RT dose to                                                           | < 48 Gy                              | 48-50 Gy                                                              | > 50 Gy                                                                  |          |          |         |
| SpinalCord_05(0.03 cc) Total RT dose to                                    | < 50 Gy                              | 50-52 Gy                                                              | > 52 Gy                                                                  |          |          |         |
| SpinalCord_05(0.01 cc) Definition of SpinalCord_05                         | Based on case review by study chair  |                                                                       |                                                                          |          |          |         |
| Overall RT treatment time                                                  | < 45 days                            | 46-50 days (without  a medically  appropriate  indication for delay). | > 50 days  (without a  medically  appropriat  e  indication  for delay). |          |          |         |
| Non-Medically Indicated                                                    | 0-2                                  | 2-4                                                                   | >4                                                                       |          |          |         |
| Treatment Interruptions                                                    |                                      |                                                                       |                                                                          |          |          |         |
| *Not including the region of PTV60 that falls within PTV66 (if applicable) |                                      |                                                                       |                                                                          |          |          |         |  
6.9 R.T. Quality Assurance Reviews **(07-APR-2014)**
The Principal Investigator/Radiation Oncology Chair, Mitchell Machtay, MD, and the Radiation Oncology Co-Chairs, Wade Thorstad, MD, and Phuc Felix Nguyen-Tân, MD, will perform RT
Quality Assurance Reviews. These reviews will be ongoing. RT Quality Assurance reviews will be facilitated by IROC Philadelphia.
eligibility checklist - step 2
6.10 radiation therapy adverse events

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for AE reporting. CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Grade 3 therapy-induced mucositis and/or dysphagia are expected to develop in about one third to one half of patients. Nutritional evaluation prior to the initiation of therapy for a prophylactic gastrostomy (PEG) tube placement is highly recommended. Placement of a feeding tube should be recorded on the appropriate case report form (see Section 12.1), as should 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 IV), and cervical myelopathy (<
1% with restriction of spinal cord dose to ≤ 45 Gy).  
6.11 Radiation Adverse Event **Reporting**
See CTEP-AERS Expedited Reporting Requirements in Sections 7.5 and 7.6.
eligibility checklist - step 2
7.0 drug therapy (07-apr-2014) protocol

7.1 Arm 2 Treatment (03-NOV-2014)
7.1.1 Cetuximab Initial Dose (Prior to RT): Patients on Arm 2 will receive an initial dose of cetuximab, 400 mg/m2, intravenously (i.v.) over 120 minutes. No chemotherapy or radiation will be given this day, and the 400 mg/m2initial dose of cetuximab will precede the first 250 mg/m2 dose of cetuximab and the first radiation treatment by at least 5 days (the day of the loading dose is not included in these 5 days). The infusion rate of cetuximab must never exceed 5 mL/min.  
Cetuximab weeks 2-7 (concurrent with RT): Patients on Arm 2 will receive cetuximab, 250 mg/m2, intravenously (i.v.) over 60 minutes on a weekly schedule. The infusion rate of cetuximab must never exceed 5 mL/min. Cetuximab will be given once a week on Monday or Tuesday before or after radiation therapy for a total of 6 doses.  
Cetuximab weeks 8-11 (post-completion of RT): Patients on Arm 2 will receive cetuximab, 250 mg/m2, intravenously (*i.v.*) over 60 minutes, on a weekly schedule after the completion of radiation therapy, for a total of 4 additional doses. The infusion rate of cetuximab must never exceed 5 mL/min. For these 4 additional doses, cetuximab should be given once a week for a total of 4 doses. There should be at least 5 days between two consecutive doses. Note: Patients receive a total of 11 doses of cetuximab over 11 weeks, including the initial loading dose, 6 maintenance doses concurrent with radiation therapy, and 4 additional maintenance doses post-completion of radiation therapy. In cases of delay in the completion of radiation therapy, then the concurrent doses of cetuximab may continue beyond week 7 without dose interruption until radiation therapy is completed, and then be followed by weekly infusion of the remaining doses of cetuximab postradiation therapy. The total of number of cetuximab doses should remain as 11 and should not exceed 11. For example, if a patient receives the initial cetuximab loading dose, plus 7 maintenance doses concurrent with radiation therapy, then 3 additional maintenances doses post-completion of radiation therapy should be given.  
CAUTION: Infusion reactions may occur during or following cetuximab administration.  
Most infusion reactions occur with the first infusion of cetuximab, but some patients' first infusion reactions have been reported following subsequent doses (a severe reaction occurred in one patient following the 8th dose). The infusion reaction may occur during the infusion or be delayed until any time after the infusion. All patients will be premedicated with diphenhydramine hydrochloride, 50 mg, (or an equivalent antihistamine) by *i.v.* 30-60 minutes prior to the first dose of cetuximab in an effort to prevent an infusion reaction. At the discretion of the treating physician, dexamethasone, 20 mg, and an H2 blocker also may be administered i.v. Premedications are recommended prior to subsequent doses, but at the Investigator's discretion, the dose of diphenhydramine or dexamethasone may be reduced.  
The medical staff must closely observe patients for treatment-related adverse events, especially infusion reactions (see Sections 1.4 and 1.5 for details and Section 7.3.4 for management) during the cetuximab infusion and during a post-infusion observation hour. For the initial cetuximab infusion, vital signs (blood pressure, heart rate, respiratory rate, and temperature) should be monitored prior to the administration of cetuximab, a half hour into the infusion, at the completion of the infusion, and 60 minutes post the infusion in an area with resuscitation equipment and other agents (epinephrine, prednisone equivalents, etc.) available.  
A nurse must be present in the immediate treatment area throughout the infusion and observation period. A physician must be in close proximity to the patient treatment area. In the event that a patient experiences an infusion reaction, see Section 7.3.4 for proper management.  
For subsequent infusions, vital signs should be taken pre- and post-infusion; however, it is recommended that the patient be observed for 1 hour post infusion. For the duration that patients are on study therapy, adverse event monitoring will be done continuously. Patients will be evaluated for adverse events at each visit and are to be instructed to call their physician to report any clinically significant adverse events between visits. **Patients should be instructed**
to report any delayed reactions to the investigator immediately.  
7.2 Cetuximab (IND Exempt) **(08-MAR-2018)**
Refer to package insert and investigator brochure for additional information. Note the black box warning for cardiopulmonary arrest in patients receiving radiation therapy in combination with cetuximab.  
7.2.1 *Formulation* Cetuximab is an anti-EGFR receptor humanized chimeric monoclonal antibody. Cetuximab is expressed in SP2/0 myeloma cell line, grown in large scale cell culture bioreactors, and purified to a high level purity using several purification steps including protein A chromatography, ion exchange chromatography, low pH treatment, and nanofiltration. Cetuximab is not known to be a vesicant.  
7.2.2 Safety *Precautions* Appropriate mask, protective clothing, eye protection, gloves and Class II vertical-laminarairflow safety cabinets are recommended during preparation and handling.  
7.2.3 Preparation and *Administration* Cetuximab must not be administered as an *i.v.* push or bolus. Cetuximab must be administered with the use of a low protein binding 0.22-micrometer in-line filter. Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at a concentration of 2 mg/mL in phosphate buffered saline. The solution should be clear and colorless and may contain a small amount of easily visible white amorphous cetuximab particulates. **DO NOT SHAKE OR DILUTE.**
Cetuximab can be administered via infusion pump or syringe pump.  
Infusion Pump:
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate needle
(a vented spike or other appropriate transfer device may be used).  
2. Fill cetuximab into a sterile evacuated container or bag such as glass containers, polyolefin bags (e.g., Baxter Intravia), ethylene vinyl acetate bags (e.g., Baxter Clintec), DEHP plasticized PVC bags (e.g., Abbott Lifecare), or PVC bags.  
3. Repeat procedure until the calculated volume has been put in to the container. Use a new needle for each vial.  
4. Administration must be through a low protein binding 0.22-micrometer in-line filter
(placed as proximal to the patient as practical).  
5. Affix the infusion line and prime it with cetuximab before starting the infusion.  
6. Maximum infusion rate should not exceed 5 mL/min.  
7. Use 0.9% saline solution to flush line at the end of infusion.
eligibility checklist - step 2
syringe pump

1. Draw up the volume of a vial using a sterile syringe attached to an appropriate needle
(a vented spike may be used).  
2. Place the syringe into the syringe driver of a syringe pump and set the rate. 3. Administration must be through a low protein binding 0.22-micrometer in-line filter rated for syringe pump use (placed as proximal to the patient as practical).  
4. Connect up the infusion line and start the infusion after priming the line with cetuximab. 5. Repeat procedure until the calculated volume has been infused.  
6. Use a new needle and filter for each vial.  
7. Maximum infusion rate should not exceed 5 mL/min.  
8. Use 0.9% saline solution to flush line at the end of infusion.  
Cetuximab should be piggybacked to the patient's infusion line.  
Following the cetuximab infusion, a one-hour observation period is required.  
7.2.4 Adverse *Events* Cetuximab may be associated with significant toxicities, most commonly fatigue, skin rash/folliculitis and paronychia, and gastrointestinal effects, nausea and diarrhea.  
Hypomagnesia is common. Of greatest concern is the potential for an allergic reaction, possibly anaphylaxis; see Section 7.3 for details.
eligibility checklist - step 2
other adverse events

- Blood and lymphatic system: Anemia;
- Ear and labyrinth disorders: External ear inflammation, tinnitus;
- Eye disorders: Conjunctivitis, dry eye, uvelitis, watering eyes;
- Gastrointestinal disorders: Diarrhea, nausea, abdominal pain, cheilitis, constipation, dry mouth, dyspepsia, oral mucositis, vomiting;
- General disorders and administration site conditions: Fatigue, fever, chills, edema limbs, flu-like symptoms, infustion-related reaction, non-cardiac chest pain;
- Metabolism and nutritional disorders: Anorexia, dehydration, hypocalcemia, hypomagnesemia;
- Musculoskeletal and connective tissue disorders: arthralgia, back pain, myalgia;
- Nervous system disorders: Headache, syncope;
- Respiratory, thoracic, and mediastinal disorders: Allergic rhinitis, bronchospasm, cough, dyspnea, hoarseness, and rarely, pneumonitis and non-cardiogenic pulmonary edema;
- Skin and subcutaneous tissue disorders: dry skin, rash acneiform, rash maculo-papular, alopecia, nail loss, photosensitivity, pruritus, purpura, skin ulceration, urticaria, and rarely, Palmar-plantar erythrodysesthesia syndrome;
- Vascular disorders: hypotension, thromboembolic event.  
Note: Cetuximab in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
7.2.5 Storage *Requirements/Stability* Store vials under refrigeration at 2 C to 8 C (36 F to 46 F). **DO NOT FREEZE.** Increased particulate formation may occur at temperatures at or below 0C. This product contains no preservatives. Preparations of cetuximab in infusion containers are chemically and physically stable for up to 12 hours at 2 C to 8 C (36 F to 46 F) and up to 8 hours at controlled room temperature (20 C to 25 C; 68 F to 77 F). Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2 to 8 C. Discard any unused portion of the vial.  
7.2.6 *Supply* Eli Lilly and Company (Eli Lilly) or its local affiliate will supply cetuximab free of charge to patients on study in the United States and Canada. The product is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous cetuximab particulates. Each single-use 50-mL vial contains 100 mg of cetuximab at a concentration of 2 mg/mL and is formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42mg/mL sodium phosphate monobasic monohydrate, and Water for injection, USP.  
7.2.7 Drug Ordering and *Accountability* Eli Lilly and Company (Eli Lilly) or its local affiliate will supply cetuximab free of charge to patients on study in the United States and Canada. In the U.S., the drug will be distributed by a vendor, Biologics/McKesson., under contract to NRG Oncology. Please see shipping timelines in the section below. In Canada, the drug will be distributed by Eli Lilly Canada.  
U.S. and Canadian Institutions All pre-registration requirements must be met before calling to register the first case.  
Institutions must electronically complete (versus hand write) a Study Agent Shipment Form (SASF) available on the CTSU website. U.S. and Canadian institutions must fax the SASF to the CTSU Regulatory Office via the Regulatory Submission Portalas soon as the individual responsible for the study agent has been identified. This must be done prior to registration of the institution's first case. Biologics/McKesson will ship a patient-specific supply of cetuximab with enough quantity to complete protocol treatment for a 200-pound individual (58 vials) once the site has randomized the patient. Since doses are dependent on the patient's BSA, sites can obtain additional perpatient supply for individuals over 200 pound by contacting Biologics/McKesson. It is possible that sites will have more than one cetuximab clinical study ongoing at the same time. It is imperative that only product designated for RTOG 0920 be utilized for this study. RTOG 0920 product must be segregated from other investigational or marketed product. Cetuximab will be placed in a temperature controlled cooler with 3 pounds of gel packs. U.S. shipments will be sent via FedEx for Priority Overnight delivery for orders received 4 p.m. EST, Monday through Thursday. Orders received after 4 p.m. EST Monday through Thursday will be processed and shipped next business morning**. For Canadian sites, Eli Lilly Canada will** ship the drug. Sites should allow 10 business days to receive **drug**. Drug deliveries are restricted during weekends and holidays. **Biologics/McKesson observes**
the following holidays: New Year's Day, Memorial Day, July 4th, Labor Day, Thanksgiving Day and the Friday following Thanksgiving Day, Christmas Eve, and Christmas Day.  
Eli Lilly Canada observes the following holidays. Sites should plan ahead to accommodate patients being treated during restricted times.  
| Event                           | Date                |
|---------------------------------|---------------------|
| New Year's Day                  | January 1, Friday   |
| Family Day                      | February 15, Monday |
| Good Friday                     | March 25, Friday    |
| Victoria Day                    | May 23, Monday      |
| Canada Day                      | July 1, Friday      |
| Eli Lilly Canada office closure | July 4, Monday      |
| Civic Holiday                   | August 1, Monday    |
| Labour Day                      | September 5, Monday |
| Thanksgiving                    | October 10, Monday  |
| Christmas Day                   | December 25, Sunday |
| Boxing Day                      | December 26, Monday |
| Eli Lilly Canada office closure | December 30, Friday |  
Inside each shipping container will be a disposable electronic unit (TagAlert™) to ensure the product has remained at the appropriate temperature during shipping. This unit will be attached to an information card. The LCD display will show OK (indicating no alarm has been triggered)
or a black bar and the number(s) 1-4 (indicating an alarm/alarms have been triggered). Should an alarm be triggered, follow the instructions on the attached information card. Display results should be recorded on the packing list. For questions regarding drug requisitioning, contact Biologics/McKesson.  
Upon notification of a new patient enrollment in the U.S., Biologics/McKesson will place an outbound call to the site contact to confirm that the site's shipment is being processed. Biologics/McKesson distribution team will monitor packages throughout the duration of transit via the FedEx web site and FedEx One Call Solution (live support). Real-time monitoring enables Biologics/McKesson to mitigate potential delivery delays.  
Questions about supply and delivery should be directed to:
eligibility checklist - step 2
mckesson specialty health

Clinical Research Services 845 Regent Boulevard, Suite 100B
Irving, TX 75093 Email: clinicalresearchservices@mckesson.com Phone: Toll Free 800-693-4906 Fax: 919-256-0794
eligibility checklist - step 2
non-canadian international institutions

Please refer to your LOI Approval Notification.  
7.2.8 Handling and Dispensing of Investigational *Product* Investigational product should be stored in a secure area according to local regulations. It is the responsibility of the Investigator to ensure that investigational product is only dispensed to study patients. The investigational product must be dispensed only from official study sites by authorized personnel according to local regulations.  
7.2.9 Drug *Destruction* Opened vials must be disposed of at the site as chemotherapy or biohazardous waste, provided documented procedures for destruction are in place. At the completion of the study, all unused drugs will be destroyed at the site according to the institution's policy for drug destruction. It is the responsibility of the Investigator to ensure that a current record of investigational product disposition is maintained at each study site where investigational product is inventoried and disposed, including dates and quantities. If approved procedures for destruction are not in place and/or for questions regarding cetuximab destruction, please contact Biologics/McKesson at 800-693-4906.  
7.3 Dose Modifications **(23-JAN-2013)**
7.3.1 Cetuximab Dose *Levels*  
| Study Agent                                                                      | Starting Dose            | Dose Level –1   | Dose Level –2      |
|----------------------------------------------------------------------------------|--------------------------|-----------------|--------------------|
| Cetuximab                                                                        | 400 mg/m2 (week 1  only) |                 |                    |
| Cetuximab                                                                        | 250 mg/m2 (weekly)       | 200 mg/m2       | 150 mg/m2 (weekly) |
| (weekly)                                                                         |                          |                 |                    |
| Note: If a weight change of ≥ 10% occurs, the cetuximab dose should be adjusted. |                          |                 |                    |  
7.3.2 Cetuximab Dose Modifications for Hematologic Adverse *Events* Cetuximab will not be dose reduced or held for hematologic adverse events, such as neutropenia, neutropenic fever, or thrombocytopenia.  
7.3.3 Cetuximab Dose Modifications for Non-Hematologic Adverse *Events*  
| Toxicity Grade                                                                                                                                                              | Cetuximab Dose a                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| (CTCAE, v. 4) Renal-Calculated  Creatinine Clearance ≥ 50 mL/min                                                                                                            | Maintain dose levels                                              |
| < 50 mL/min                                                                                                                                                                 | Maintain dose levels                                              |
| Fatigue (Asthenia) ≥ Grade 3                                                                                                                                                | Maintain dose levels                                              |
| Nausea/Vomiting ≤ Grade 2 with maximal  medical management ≥ Grade 3 with maximal  medical management                                                                       | Maintain dose levels                                              |
| Hold drug until ≤ grade 2, then resume at same  dose level or reduce by 1 dose level                                                                                        |                                                                   |
| Other non-hematologic Adverse Events b, c Grade 4 (In the RT field, or possibly related  to cetuximab, or likely to be exacerbated by  continuation of cetuximab)           | Hold drug until ≤ grade 3, then resume at 1 dose  level reduction |
| Grades 2-4 (out of RT field that does not  reverse to Grade 1 at time of treatment, or  unrelated to cetuximab, or unlikely to be exacerbated by continuation of cetuximab) | Maintain dose levels                                              |
| For grade 4 out of RT field toxicity, drug shouldbe  held until < grade 3 and then resumed at thesame  level or reduced by 1 dose level                                     |                                                                   |  
aDose levels are relative to the previous dose. Dose reductions of cetuximab below the –2 dose level will not be allowed. In any case of cetuximab treatment delay, there will be no re-loading infusion, and all subsequent treatment will be at the assigned dose level.  
bWith the exception of infusion reaction or acne-like rash (rash/desquamation);
cFor depressed K or Mg, administer replacement therapy. Chemotherapy should continue at the discretion of the treating physician. (see table below for management of hypomagnesemia).
eligibility checklist - step 2
hypomagnesemia

Electrolyte repletion, principally magnesium, was necessary in some patients treated with cetuximab and in severe cases, intravenous replacement was required. The time to resolution of electrolyte abnormalities is not well known, hence monitoring during and after cetuximab treatment is recommended:  
| CTCAE,     | Serum Magnesium                                                                                                                         |                             |                                                                                                                                                                                                                         |                                                                                                          |
|------------|-----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|
| mg/dL      | mmol/L                                                                                                                                  | Guidelines for management   | Action                                                                                                                                                                                                                  |                                                                                                          |
| v. 4 Grade | Consider replacement with IV  magnesium sulphate 2-5 g in  normal saline or D5W. Infusion  schedule based on institutional  guidelines. | Maintain dose and  schedule |                                                                                                                                                                                                                         |                                                                                                          |
| 1          | < LLN - 1.2                                                                                                                             | < LLN - 0.5                 | As above for grade 1 and consider  prophylactic weekly infusion of  magnesium and/or oral  magnesium supplementation (e.g.  magnesium oxide) if grade 2 of  higher hypomagnesemia persists. Maintain dose and  schedule |                                                                                                          |
| 2          | < 1.2 - 0.9                                                                                                                             | < 0.5 - 0.4                 | Hold cetuximab until  recovery to < grade 2,  then resume at same dose  level or reduce by 1 dose  level                                                                                                                |                                                                                                          |
| 3          | < 0.9 - 0.7                                                                                                                             | < 0.4 - 0.3                 | As above for grades 1 and 2                                                                                                                                                                                             | Hold cetuximab until  recovery to < grade 2,  then resume at same dose  level or reduce by 1 dose  level |
| 4          | < 0.7                                                                                                                                   | < 0.3                       | As above for grades 1 and 2                                                                                                                                                                                             |                                                                                                          |  
| 7.3.4                                                                                                                                                                                                                                                                                                                          | Cetuximab Infusion Reaction Management                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CTCAE, v. 4                                                                                                                                                                                                                                                                                                                    | Treatment Guidelinesa                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Adverse Event Grade Grade 1: Mild transient reaction;  infusion interruption not  indicated; intervention not  indicated                                                                                                                                                                                                       | For mild infusion reactions manifesting only as delayed drug fever, consider  administering prophylactic antihistamine medications for subsequent doses.  Maintain the cetuximab dose, but slow the infusion rate by 50%.  Acetaminophen or a non-steroidal anti-inflammatory drug (NSAID) may be  administered prior to subsequent cetuximab infusions, if not otherwise  contraindicated in subjects.                                                                           |
| Grade 2: Therapy or infusion  interruption indicated but  responds promptly to  symptomatic treatment (e.g.,  antihistamines, NSAIDS,  narcotics, IV fluids);  prophylactic medications  indicated for ≤ 24 hrs                                                                                                                | For moderate infusion reactions manifesting only as delayed drug fever, slow  the infusion rate for cetuximab by 50% and consider administering  antihistamine medications and/or steroidal medications. Maintain the cetuximab  dose. Acetaminophen or a non-steroidal anti-inflammatory drug (NSAID) may  be administered prior to subsequent cetuximab infusions, if not otherwise  contraindicated in subjects.                                                               |
| Grade 3: Prolonged (e.g., not rapidly  responsive to symptomatic  medication and/or brief  interruption of infusion);  recurrence of symptoms following  initial improvement;  hospitalization indicated for  clinical sequelae                                                                                                | Severe infusion reactions require immediate interruption of cetuximab  infusion and permanent discontinuation from further treatment with  cetuximab. Appropriate medical therapy including epinephrine, corticosteroids,  diphenhydramine, bronchodilators, and oxygen should be available for use in  the treatment of such reactions. Subjects should be carefully observed until  the complete resolution of all signs and symptoms.                                          |
| Grade 4: Life-threatening  consequences; urgent  intervention indicated                                                                                                                                                                                                                                                        | NO FURTHER STUDY DRUG THERAPY. Life threatening infusion reactions  require immediate interruption of cetuximab infusion and permanent  discontinuation from further treatment with cetuximab. Appropriate  medical therapy including epinephrine, corticosteroids, diphenhydramine,  bronchodilators, and oxygen should be available for use in the treatment of such reactions. Subjects should be carefully observed until the complete  resolution of all signs and symptoms. |
| a Study Therapy Retreatment Following Infusion Reactions: Once a cetuximab infusion rate has been  decreased due to an infusion reaction, it will remain decreased for all subsequent infusions. If the subject has  a second infusion reaction with the slower infusion rate, the infusion should be stopped, and the subject |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |  
a**Study Therapy Retreatment Following Infusion Reactions: Once a cetuximab infusion rate has been**
decreased due to an infusion reaction, it will remain decreased for all subsequent infusions. If the subject has a second infusion reaction with the slower infusion rate, the infusion should be stopped, and the subject should receive no further cetuximab treatment. If a subject experiences a Grade 3 or 4 infusion reaction at any time, the subject should receive no further cetuximab treatment. If there is any question as to whether an observed reaction is an infusion reaction of Grades 1-4, the Study Chair or Medical Oncology Co-Chairs should be contacted immediately to discuss and grade the reaction.  
7.3.5 *Cetuximab Special Instructions* If cetuximab is omitted for more than four consecutive infusions for adverse events due to cetuximab, or for an intercurrent illness (e.g., infection) requiring interruption of therapy, the subject should be discontinued from further cetuximab therapy. Cetuximab doses held due to toxicity should not be made up. If a cetuximab dose is missed for reasons unrelated to drug toxicity, then the missed dose may be made up at the discretion of the investigator, at the next appropriate time point according to Section 7.1.1. If adverse events prevent the administration of cetuximab, the subject may continue to receive radiation therapy.  
Management of Cetuximab Infusion Reactions Severe or life threatening (grade 3 or 4) infusion reactions require the immediate interruption of cetuximab therapy and permanent discontinuation from further treatment. Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen should be available for use in the treatment of such reactions. Patients should be carefully observed until the complete resolution of all signs and symptoms. In clinical trials, mild to moderate infusion reactions were managed by slowing the infusion rate of cetuximab and by continued use of antihistamine pre-medications (e.g.,
diphenhydramine) in subsequent doses. If the patient experiences a mild or moderate
(grade 1 or 2) infusion reaction, the infusion rate should be permanently reduced by 50%.  
For grade 1 or 2 reactions manifesting only as delayed drug fever, see below.  
Cetuximab should be immediately and permanently discontinued in patients who experience severe (grade 3 or 4) infusion reactions. Treatment of Isolated Drug Fever In the event of isolated drug fever, the investigator must use clinical judgment to determine if the fever is related to the study drug or to an infectious etiology.  
If a patient experiences isolated drug fever, for the next dose, pre-treat with acetaminophen or non-steroidal anti-inflammatory agent (investigator discretion), repeat antipyretic dose 6 and 12 hours after cetuximab infusion. The infusion rate will remain unchanged for future doses.  
If a patient experiences recurrent isolated drug fever following pre-medication and postdosing with an appropriate antipyretic, the infusion rate for subsequent dosing should be 50% of previous rate. If fever recurs following infusion rate change, the investigator should assess the patient's level of discomfort with the event and use clinical judgment to determine if the patient should receive further cetuximab.
eligibility checklist - step 2
cetuximab-related rash manifestations

Rash associated with EGFR-inhibitors is a relatively new dermatologic condition. It appears to be "acneiform" but it is NOT considered a form of acne; rather, it is a form of folliculitis. Skin changes may be manifested in a number of ways: erythema; follicle based papules, which may ulcerate; pain; itching; cosmetic disturbance; and/or nail disorders. The rash may become infected and transform into cellulitis.  
➢ *Grading of Cetuximab-induced Rash* According to physician judgment, if a patient experiences grade 3 rash (according to any of the terms below), cetuximab treatment adjustments should be made according to the Cetuximab Dose Modification table below. In patients with mild and moderate skin adverse events, cetuximab should continue without adjustment.  
NOTE: Rash intensity (i.e., the size and number of papules or the level of discomfort and extent of erythema) may be an important consideration. However, the absolute number of lesions, **without associated physical discomfort**, does not necessarily constitute a basis for a dose reduction or delay. Rash considered "intolerable" (because of pain, itching, or appearance) or that has failed to respond to symptomatic management may be considered grade 3 and thus prompt dose reduction or delay of cetuximab. **The clinical judgment of the treating physician is critical to grading**
and will ultimately dictate dose **modification.**
➢ Acute Skin *Changes*
- Rash Occurring **Outside** of the Radiation Field: Should be graded using the following CTCAE, v. 4 terms. A rash complicated by secondary infection or cellulitis should be graded per additional CTCAE terms.  
| 1                                                                                                                                     | 2                                                                                                         | 3                         | 4                        |                |
|---------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|---------------------------|--------------------------|----------------|
| Pruritus*                                                                                                                             | Mild of localized                                                                                         | Intense or widespread     | Intense or widespread    | -              |
| and interfering with ADL                                                                                                              |                                                                                                           |                           |                          |                |
| Rash/acneiform*                                                                                                                       | Papules and/or                                                                                            | Papules and/or pustules   | Papules and/or pustules  | Papules and/or |
| pustules covering                                                                                                                     | covering 10-30% BSA,                                                                                      | covering >30% BSA,        | pustules                 |                |
| <10% BSA, which                                                                                                                       | which may or may not be                                                                                   | which may or may not      | covering any %           |                |
| may or may not be                                                                                                                     | associated with symptoms                                                                                  | be associated with        | BSA, which may           |                |
| associated with                                                                                                                       | of pruritus or                                                                                            | symptoms of pruritus or   | or may not be            |                |
| symptoms of pruritus                                                                                                                  | tenderness; associated                                                                                    | tenderness; limiting self | associated               |                |
| or tenderness                                                                                                                         | with psychosocial impact;                                                                                 | care ADL; associated      | with symptoms of         |                |
| limiting                                                                                                                              | with local superinfection                                                                                 | pruritus or               |                          |                |
| instrumental ADLI                                                                                                                     | with oral antibiotics                                                                                     | tenderness and            |                          |                |
| indicated                                                                                                                             | are associated with extensive superinfection with IV antibiotics indicated; life threatening consequences |                           |                          |                |
| Paronychia*                                                                                                                           | Nail fold edema or                                                                                        | Localized intervention    | Surgical intervention or | -              |
| erythema; disruption                                                                                                                  | indicated; oral intervention                                                                              | IV antibiotics indicated; |                          |                |
| of the cuticle                                                                                                                        | indicated (e.g., antibiotic,                                                                              | limiting self             |                          |                |
| antifungal, antiviral);                                                                                                               | care ADL                                                                                                  |                           |                          |                |
| nail fold edema or erythema with pain; associated with discharge or nail plate separation; limiting instrumental ADL                  |                                                                                                           |                           |                          |                |
| *Onset of grade 3 will require modification. See the table below, "Cetuximab Dose Modification Guidelines for  Dermatologic Changes". |                                                                                                           |                           |                          |                |  
| 1                    | 2                                                             | 3                      | 4                     |                  |
|----------------------|---------------------------------------------------------------|------------------------|-----------------------|------------------|
| Radiation recall     | Faint erythema or                                             | Moderate to brisk      | Moist desquamation    | Life-threatening |
| reaction             | dry desquamation                                              | erythema; patchy moist | other than skin folds | consequences;    |
| (dermatologic);      | desquamation, mostly                                          | and creases; bleeding  | skin necrosis or      |                  |
| Dermatitis radiation | confined to skin folds                                        | induced by minor       | ulceration of full    |                  |
| −                    | and creases; moderate                                         | trauma or abrasion     | thickness dermis;     |                  |
| edema                | spontaneous bleeding from involved site; skin graft indicated |                        |                       |                  |  
➢ *Late Skin Changes* A potential late change of interest is consequential scarring/pock marking **in or out of the radiation field**. This may be reported by using the MedDRA code, "Skin and subcutaneous tissue disorders - Other, specify", with the following protocol-specific grading scale as guidance:
- Grade 1: Mild (seen only on close inspection) - Grade 2: Moderate (scarring, intervention or cosmetic coverage/intervention indicated)
- Grade 3: Severe (significant disfigurement, deep scarring, or ulceration) - Grade 4: Deep cratering/scarring, skin necrosis, or disabling  
| Cetuximab Dose Modification Guidelines for Dermatologic Changes (≥ Grade 3) Cetuximab Outcome Cetuximab Dose  Modification   |                          |                  |                          |
|------------------------------------------------------------------------------------------------------------------------------|--------------------------|------------------|--------------------------|
| 1st occurrence                                                                                                               | Delay infusion 1 to 2    | Improvement to ≤ | Continue at 250 mg/m2    |
| weeks                                                                                                                        | Grade 2                  |                  |                          |
| No Improvement;                                                                                                              | Discontinue cetuximab    |                  |                          |
| remains grade 3                                                                                                              | Reduce dose to 200 mg/m2 |                  |                          |
| 2nd occurrence                                                                                                               | Delay infusion 1 to 2    | Improvement to ≤ |                          |
| weeks                                                                                                                        | Grade 2                  |                  |                          |
| No Improvement;                                                                                                              | Discontinue cetuximab    |                  |                          |
| remains grade 3                                                                                                              |                          |                  |                          |
| 3rd occurrence                                                                                                               | Delay infusion 1 to 2    | Improvement to ≤ | Reduce dose to 150 mg/m2 |
| weeks                                                                                                                        | Grade 2                  |                  |                          |
| No Improvement;                                                                                                              | Discontinue cetuximab    |                  |                          |
| remains grade 3                                                                                                              |                          |                  |                          |
| 4th occurrence                                                                                                               | Discontinue cetuximab    |                  |                          |  
Drug Related Rash Management Patients developing dermatologic adverse events while receiving cetuximab should be monitored for the development of inflammatory or infectious sequelae, and appropriate treatment of these symptoms initiated. Below are suggestions for managing cetuximabinduced rash*:
- **Antibiotics**: The benefit of routine antibiotics in uncomplicated (uninfected) rash is unclear. Some clinicians have used oral minocycline (Minocin), mupirocin
(Bactroban), or topical clindamycin (Cleocin). Rash complicated by cellulitis should be treated with appropriate antibiotics based on clinical judgment or microbial sensitivity analysis.  
- **Antihistamines**: Benadryl or Atarax may be helpful to control itching.  
- **Topical Steroids**: The benefit of topical steroids is unclear. - **Retinoids**: No data to support use. Use is not advised.  
- **Benzoyl peroxide**: Should NOT be used--may aggravate rash. - **Makeup**: Rash can be covered with makeup; this should not make it worse (use a dermatologist-approved cover-up, e.g., Dermablend, or any other type of foundation). Remove makeup with a skin-friendly liquid cleanser, e.g., Neutrogena, Dove, or Ivory Skin Cleansing Liqui-Gel.  
- **Moisturizers**: Use emollients to prevent and alleviate the skin dryness, e.g.,
Neutrogena Norwegian Formula Hand Cream or Vaseline Intensive Care Advanced Healing Lotion.  
- **Sunlight**: It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving cetuximab as sunlight can exacerbate any skin reactions that may occur.  
- **Over-the-counter medications**: Over-the-counter acne vulgaris medications (e.g.,
benzoyl peroxide) are not advised. This rash is not like acne vulgaris and these treatments could make it worse.  
*Adapted from Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-associated rash: Future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. *The Oncologist*. 10:345–356, 2005.  
7.4 **Modality Review (07-APR-2014)**
The Medical Oncology Co-Chair, Lillian L. Siu, MD, will perform a Systemic Therapy Assurance Review of all patients who receive or are to receive cetuximab 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 12.1. The scoring mechanism is: Per Protocol, Not Per Protocol, 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.  
The Medical Oncology Co-Chair, Dr. Siu, will perform a Quality Assurance Review after complete data for the first 20 cases enrolled has been received at IROC Philadelphia. Dr. Siu will perform the next review after complete data for the next 20 cases enrolled has been received at IROC
Philadelphia. The final cases will be reviewed within 3 months after this study has reached the target accrual or as soon as complete data for all cases enrolled has been received at IROC Philadelphia, whichever occurs first.  
7.5 Adverse Events **(26-JAN-2018)**
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for AE reporting.  
CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 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 either 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 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.  
7.5.1 Adverse Events **(AEs)**
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].  
7.5.2 **Serious Adverse Events (SAEs) —** Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in section 7.6 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-AERS notification are defined in the expedited reporting table in section 7.6. 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 drug experience, 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.
eligibility checklist - step 2
7.5.3 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.  
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.  
7.6 CTEP-AERS Expedited Reporting Requirements **(25-JAN-2016)**
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 System, accessed via the CTEP web site, https://eappsctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613.  
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG
Oncology's 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 a 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 a 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 a CTEP-AERS report, include the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and fax supporting documentation to 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 12.1). As of 2/1/16, NRG Oncology will submit all SAEs to Eli Lilly Global Patient Safety, FAX 866-644-1697 or 317-453-3402.
eligibility checklist - step 2
late phase 2 and phase

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 lifefunctions 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 Days |                  |               |            |
| Not resulting in  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
eligibility checklist - step 2
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.  
NOTE: Deaths clearly due to progressive disease should NOT be reported via CTEP-AERS but rather should be reported via routine reporting methods (e.g., CDUS and/or CTMS).
eligibility checklist - step 2
8.0 surgery (23-jan-2013) 8.1 intermediate

Patients must have been found to have an "intermediate" risk of recurrence (see Section 3.1.3) after having undergone gross total surgical resection with curative intent of the primary tumor of the oral cavity, oropharynx, or larynx (excluding lip, nasopharynx, or sinuses) within 7 weeks of registration. Patients with a positive margin by intraoperative frozen section during any part of the primary tumor resection are eligible for this study, provided that a subsequent negative margin supercedes this initially positive margin. Only patients with positive margins on final pathology would be excluded from this study.  
Concurrent neck dissection should be performed with patients initially staged cN1 and above. However, for cN0 patients, selective neck dissection may or may not be required.  
The following should be reported on the Operative Note **(S2)**:
- Documentation of whether a transoral versus "open" transcervical approach was used in assessing the primary tumor;
- Documentation of how the neck was managed: excisional biopsy, superselective, standard selective neck, or modified radical;
- Documentation of whether robotics or laser microsurgery was used for visualization of the primary tumor during surgery.  
8.2 Surgical Quality Assurance **Reviews**
The Surgical Oncology Co-Chair, Dr. Holsinger, will perform a modified Quality Assurance Review after complete data for the first 50 cases enrolled has been received at NRG Oncology. This quality assurance review will specifically examine the issues related to eligibility and the presence of intermediate risk of recurrence (see Section 3.1.3). No S1 case report form is required for this study.  
Dr. Holsinger will perform the next review after complete data for the next 50 cases enrolled has been received at NRG Oncology. The final cases will be reviewed within 3 months after this study has reached the target accrual or as soon as complete data for all cases enrolled has been received at NRG Oncology, whichever occurs first.
eligibility checklist - step 2
9.0 other therapy 9.1 permitted

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, anti-emetics, topical mouth rinses, skin creams/ointments, etc. The use of amifostine as a radioprotector is not allowed. The use of granulocyte colony-stimulating factor or erythropoietin is not allowed. Any exceptions must be approved by the Principal Investigator, Dr. Machtay, or Medical Oncology Co-Chair, Dr. Siu.
eligibility checklist - step 2
10.0 tissue/specimen submission (07-apr-2014) 10.1

The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved through careful block storage and processing. NRG Oncology encourages participants in protocol studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank provides tissue specimens to investigators for translational research studies. Translational research studies integrate the newest research findings into current protocols to investigate important biologic questions. **Note**: The NRG Oncology Biospecimen Bank will provide collection kits and instructions at no charge for the submission of specimens in this protocol.  
In this study, it is required that tissue will be submitted to the NRG Oncology Biospecimen Bank for the purpose of EGFR analysis and HPV assay for oropharyngeal carcinomas. In addition, it is highly recommended (but optional) that fresh and archival tissues and blood be submitted for banking for future translational research. The NRG Oncology Biospecimen Bank provides tissue specimens to investigators for approved studies. Translational research studies integrate the newest research findings into current protocols to investigate important biologic questions.
eligibility checklist - step 2
10.2 tissue collection for egfr

Tissue from a biopsy or surgical specimen will be obtained, formalin fixed, and paraffin embedded in tissue blocks. Institutions must ship tissue blocks from patients to the NRG
Biospecimen Bank by overnight courier. Prepaid Federal Express Labels can be requested from the Biospecimen Bank for this purpose (see Section 10.5 for contact information). Upon determination that the specimen is adequate, 2 unstained sections will be sent to the Pathology Co-Chair, Dr. Adel El-Naggar, for quantitative analysis of EGFR by immunohistochemistry. EGFR
analysis results are expected in approximately 7-8 business days. The specific hypothesis is that the relative improvement in disease-free survival (DFS) will be similar for patients with high
(defined as ≥ 80% of cells staining positive for EGFR) or low (defined as < 80% of cells staining positive) EGFR expression. However, the absolute values for DFS will be significantly greater for patients with low EGFR expression. Physicians or institutions can request the patient's EGFR level from NRG Oncology (215-574-3154 or 215-574-3170) after the patient has completed study treatment.  
Institutions that are unable to submit a tissue block for the required EGFR analysis (and for patients with oropharyngeal carcinoma, the required HPV analysis) may instead take 6 unstained sections from the block then obtain three 3 mm core punches of the block and re-imbed the core punches into a recipient paraffin for submission. Institutions can request an FFPE specimen plug kit (**see Appendix V**) from the NRG Oncology Biospecimen Bank free of charge for this purpose:
415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu If an institution is uncomfortable with obtaining the unstained sections and punches and wants to retain the tissue block, the site can send the entire block to the NRG Biospecimen Bank, and the Bank will obtain the unstained sections and the core punches from the block and return the remaining block to the site. Please indicate this request (to obtain the sections, perform the core punch procedure, and return the block) on the submission form. **Note**: For oropharyngeal carcinoma patients, there is a 10-day turnaround needed for HPV assays, so institutions should send the block by overnight courier to the Biospecimen Bank as soon as possible with their request.  
The following material must be provided to the NRG Biospecimen Bank for EGFR expression:
10.2.1 Representative H & E stained slides (slides can be duplicate cut stained H&E; does not have to be diagnostic slide).  
10.2.2 Corresponding Tissue Block (the block must match the H&E diagnostic slide)
- A Pathology Report documenting that the submitted block contains tumor; the report must include the NRG Oncology protocol number and patient's case number. The patient's name and/or other identifying information should be removed from the report. The surgical pathology numbers and information must NOT be removed from the report.  
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the submitted material is reviewed and is not tumor, the site may be assessed a protocol violation.  
- A copy of the gross description of the tumor must accompany the specimen in order to evaluate the closest margin and distance.  
- A Specimen Transmittal (ST) Form stating that the tissue is being submitted for central review. Sites can access the form (no password required) at http://www.rtog.org/members/forms/list.html (under "Pathology"). The form must include the NRG Oncology protocol number and the patient's case number. If the patient is also enrolled on other NRG Oncology trials, this should be indicated on the form.  
- EGFR analysis will be performed for every case by the Pathology Co-Chair, Adel ElNaggar.
eligibility checklist - step 2
10.3 tissue collection for hpv

For patients with oropharyngeal carcinoma, the NRG Oncology Biospecimen Bank will process 4 unstained sections from the tissue block (submitted for EGFR analysis) and will send the sections to Dr. Adel El-Naggar who will determine HPV status by p16 immunohistochemistry within 7-10 business days. Specific hypotheses include: 1) HPV negative patients will have greater absolute benefit from the addition of cetuximab compared to HPV positive patients because HPV positive patients have an extremely good prognosis and the addition of cetuximab in the postoperative adjuvant setting may not add more benefit to RT alone; 2) HPV positivity will associate with low EGFR expression because the HPV positive tumors may not be driven by EGFR but by viral oncogene E6/E7 causing the loss of p53 and Rb; 3) EGFRvIII will associate with HPV negativity and treatment failure due to ligand-independent constitutive activation of the receptor, escaping the effects of cetuximab. Physicians or institutions can request the patient's HPV status from NRG Oncology (215-574-3154 or 215-574-3170) after the patient has completed study treatment.  
10.4 Specimen Collection for Tissue Banking and Translational Research: Highly Recommended (But Optional) **(13-NOV-2017)**
Patients must be offered the opportunity to participate in the tissue/specimen collection for banking and translational research. If the patient consents to participate in this component, the site is required to submit the patient's specimens as specified below. **Note**: Sites are not permitted to delete the tissue/specimen component from the protocol or from the sample consent form.
eligibility checklist - step 2
10.4.1 peripheral blood plasma serum

alone OR radiation + cetuximab) (see Appendix I). The following materials need to be provided to the NRG Oncology Biospecimen Bank: A
Specimen Transmittal Form documenting the date of collection of the biospecimen; the NRG
Oncology protocol number, the patient's case number, time point of study, and method of storage (for example, stored at -80° C) must be included.  
A blood collection kit can be obtained free of charge from the Biospecimen Bank. See Appendix VI for detailed collection instructions, including information pertaining to the blood collection kit. Note: The kit includes a shipping label. Storage Conditions Store frozen specimens at –80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:
- Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
OR:
- Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out Monday-Wednesday only Canada: Monday-Tuesday).  
OR:
- Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only Canada: Monday-Tuesday).  
Please indicate on Specimen Transmittal Form the storage conditions used and time stored.  
10.4.2 *Translational Research: TP53 Mutations and EGFR Intron* 1 A recent study by Poeta, et al. (2007) has shown that patients with *TP53* mutations have poor overall survival and time to disease progression compared to patients with *TP53* wild type after surgical resection. We will determine the *TP53* mutation status in this study to validate the association and to further the effort of clinical implementation of this assay and stratification of risks based on biology of the tumors. There is evidence that the length of the repeats in EGFR Intron 1 may be prognostic and predictive of outcomes after standard of care and EGFR inhibitor treatments (Press 2008; Liu 2003; Han 2007). We will examine the CA dinucleotide repeats in EGFR intron 1 and associations with poor overall survival and time to disease progression. By studying a diverse NRG Oncology patient population of mixed sex and race, the prognostic and predictive nature of this polymorphic variant can be further defined and validated. In addition, we will determine whole genome-wide single nucleotide polymorphism (SNP) in these patients using Affymetrix SNP chips to associate other polymorphic variants with response and toxicities as exploratory studies.  
10.4.3 Summary of Specimens for Tissue Banking and Translational *Research*  
| Specimens taken from patient:                                                                                                                                                                                                                                                                                                                       | Submitted as:                                                                          | Shipped:                                                                                                                                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|
| One H&E stained slide of the                                                                                                                                                                                                                                                                                                                        | H&E stained slide: Must match                                                          |                                                                                                                                                 |
| primary tumor                                                                                                                                                                                                                                                                                                                                       | block or unstained slides  submitted                                                   | Slide shipped ambient to  NRGBB-SF                                                                                                              |
| Formalin-fixed paraffin embedded                                                                                                                                                                                                                                                                                                                    | Tissue block. If a block is not                                                        |                                                                                                                                                 |
| tumors                                                                                                                                                                                                                                                                                                                                              | available then 10 unstained slides  (5 micron cut onto positively  charged slides)     | Blocks/slides sent ambient                                                                                                                      |
| SERUM: 5-10 mL of whole blood in 1                                                                                                                                                                                                                                                                                                                  | Frozen serum samples containing                                                        |                                                                                                                                                 |
| red-top tube and centrifuge                                                                                                                                                                                                                                                                                                                         | minimum of 0.5 mL per aliquot in 1  mL cryovials (five)                                | Serum sent frozen on dry  ice via overnight carrier to  NRGBB-SF in batch  shipments                                                            |
| PLASMA: 5-10 mL of anticoagulated  whole blood collected in EDTA tube#1  (purple/lavender top) and centrifuge                                                                                                                                                                                                                                       | Frozen plasma samples containing a 0.5 mL per aliquot in 1 mL cryovials  (five to ten) | Plasma sent frozen on dry ice  via overnight carrier Whole blood sent frozen on  dry ice via overnight carrier to  NRGBB-SF in batch  shipments |
| Note: Blood for research should be collected prior to the start of treatment (radiation therapy  alone OR radiation + cetuximab) (see Appendix I). Whole blood for DNA: 5-10 mL of  anticoagulated whole blood in  EDTA tube #2 (purple/lavender top) and mix Frozen whole blood samples  containing 1-2 mL per aliquot in 12  mL cryovials (three) |                                                                                        |                                                                                                                                                 |  
10.5 Submission of materials for Tissue Banking and Translational Research **(13-NOV-2017)**
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology Biospecimen Bank—San Francisco University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): For Frozen Specimens NRG Oncology Biospecimen Bank—San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 Questions: 415-476-7864/FAX 415-476-5271; **NRGBB@ucsf.edu**
10.6 Reimbursement **(03-NOV-2014)**
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per the requirements/methods specified by the new National Clinical Trials Network (NCTN) Program. This information will be made available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) portal system.  
10.7 Confidentiality/Storage **(05-OCT-2011)**
(See the Patient Tissue Consent Frequently Asked Questions, http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspxfor further details.)
10.7.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient's case number only. The NRG Oncology Biospecimen Bank database only includes the following information: the number of specimens received, the date the specimens were received, documentation of material sent to a qualified investigator, type of material sent, and  
the date the specimens were sent to the investigator. No clinical information is kept in the database.  
10.7.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for central review will be retained until the study is terminated. Specimens for the translational research component of this protocol will be retained until the specimen is consumed/exhausted or study is terminated, unless the patient has consented to storage for future studies. If at any time the patient withdraws consent to store and use specimens, the material will be returned to the institution that submitted it.
11.0 PATIENT **ASSESSMENTS**
11.1 **Study Parameters (06-DEC-2010)**: See Appendix I for a summary of assessments and time frames.  
11.1.1 Gross total resection/surgical pathology must be completed within 7 weeks prior to registration.  
11.1.2 A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be done within 8 weeks prior to registration.  
11.1.3 An examination by an ENT or Head & Neck Surgeon must be done within 8 weeks prior to registration. A laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is recommended but not required.  
11.2 Evaluation During Radiotherapy **(08-MAR-2018)**
11.2.1 A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be done weekly.  
11.2.2 Arm 2 patients must have Na, K, Cl, glucose, Ca, Mg, and albumin testing every 3 weeks during radiation therapy, every 3 weeks after radiation therapy is completed, and during maintenance cetuximab infusion (weeks 8-11, and then every 3 weeks after the last dose of cetuximab, for a total of 9 weeks (weeks 12-20).  
11.2.3 Biopsy of any lesion(s) suspicious for tumor recurrence is urged.  
11.2.4 Arm 2 patients should have serum creatinine or creatinine clearance, AST or ALT, and bilirubin every 3 weeks after radiation therapy is completed, and during maintenance cetuximab infusion (weeks 8-11).  
11.3 Evaluation in Follow Up (07-APR-2014)
11.3.1 A general history and physical by one of the following: a Radiation Oncologist, Medical Oncologist, an ENT, or a Head and Neck Surgeon must be done at 1 and 3 months post-XRT,
then q3 months for 2 years, every 6 months for 3 years, then annually. A
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is recommended at these time points but is not required.  
11.3.2 Chest imaging (at minimum a chest x-ray or chest CT or CT/PET of chest) is required once per year for a total of 5 image sets.  
11.3.3 Biopsy of any lesion(s) suspicious for tumor recurrence is urged.  
11.4 Outcomes Criteria 11.4.1 No evidence of disease (NED): All patients must have not measurable tumor following surgery.  
11.4.2 Local-Regional Relapse: Recurrent cancer in the tumor bed and/or neck not clearly attributable to a second primary neoplasm; both imaging and biopsy confirmation are strongly recommended. LRR will be further subdivided into three subcategories:
In-Field Local-Regional Relapse Review of the imaging of the local-regional relapse and the patient's previous IMRT
treatment data reveals that the "epicenter" of the local-regional relapse is within CTV60 and received an estimated dose of at least 50 Gy.
eligibility checklist - step 2
marginal local-regional relapse

Review of the imaging of the local-regional relapse and the patient's previous IMRT
treatment data reveals that the "epicenter" of the local-regional relapse was "near" CTV60. This is defined as an estimated dose to this region that is between 20 and 50 Gy.
eligibility checklist - step 2
out-of-field local-regional relapse

Review of the imaging of the local-regional relapse and the patient's previous IMRT treatment data reveals that the "epicenter" of the local-regional relapse was not near CTV60 or CTV56 and received an estimated dose < 20 Gy. An example would be recurrence in the retropharyngeal nodal space for a patient with oral cavity cancer.  
11.4.3 Distant Relapse: Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where possible. A solitary lung mass/nodule should be considered a second primary upper aerodigestive neoplasm unless proven otherwise. If there is any question  
whether or not a malignancy is a recurrence of the original primary cancer versus a new primary, contact the Principal Investigator, Dr. Machtay.  
11.4 4 Second Primary Neoplasm: All second primary neoplasms will be biopsy proven with documentation of specific histology. Modified rigorous criteria for a second primary (below)
have been adapted from the definition by Warren and Gates (1932). Localized non-melanoma skin cancers are not considered new primary tumors.  
- A distinct lesion separated from the primary tumor site by > 2 cm of normal epithelium;
- A new cancer with different histology; - Any cancer, regardless of head and neck mucosal subsite, occurring 5 or more years after initial treatment;
- In the lung, new primary tumors, if squamous cell cancer, must have histologic findings of dysplasia or CIS.  
11.4.5 Second Primary Upper Aerodigestive Neoplasm: The emergence of a new, invasive malignancy in the upper aerodigestive tract as a second primary should be documented. These neoplasms include lung cancer, esophageal cancer (including GE junction cancer), or 2nd primary head and neck cancer that is clearly remote from the index cancer (e.g., pyriform sinus cancer developing in a patient whose original diagnosis was tongue cancer). If there is any question whether or not a malignancy is a recurrence of the original primary cancer versus a new primary, contact the Principal Investigator, Dr. Machtay.  
11.5 Quality of Life and Functional Assessments **(25-JAN-2016)**
The assessments will be completed prior to the start of treatment (baseline) and at 3, 12, and 24 months from the end of RT.  
11.5.1 *The Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N)* is a multidimensional, patient-self report quality of life (QOL) instrument specifically designed and validated for use with head and neck patients. The patient can complete the assessment in 510 minutes. The site research nurse or CRA is encouraged to be sensitive to each patient's demeanor. If patients appear particularly uncomfortable answering a question, they will be informed that they can skip that question. Similarly, interviewers will give patients a short break if the patient appears fatigued or otherwise in need of a few minutes break.  
11.5.2 *The Performance Status Scale for Head and Neck Cancer (PSS-HN)* consists of assessment of three functional areas (subscales): Normalcy of Diet, Eating in Public, and Understandability of Speech. The site research nurse or clinical research associate (CRA) will administer the PSSHN. Interviewers are encouraged to be sensitive to each patient's demeanor. If patients appear particularly uncomfortable answering a question, they will be informed that they can skip that question. Similarly, interviewers will give patients a short break if the patient appears fatigued or otherwise in need of a few minutes break. The interviewer rates the patient on each scale based on the patient's responses to targeted questions. The PSS-HN takes approximately 5 minutes to complete.  
11.5.3 *The EuroQol (EQ-5D)* has been frequently used in cooperative group studies as a general QOL
measure and for cost-utility analysis It is a two-part questionnaire that the patient can complete in approximately 5 minutes. The site research nurse or CRA should encourage the patient not to skip questions on the EQ-5D or take breaks during the completion of this questionnaire, as this will invalidate the assessment. If this occurs, sites will document it on the HP case report form.  
11.5.4 *The University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS)* consists of 15 items covering four major domains of oral health-related quality of life: physical functioning, personal/psychological functioning, social functioning, and pain/discomfort issues. The patient can respond to the 15 items in the scale in approximately 5 minutes. The Scale is only available in English.  
11.5.5 *The Dermatology Life Quality Index (DLQI)* consists of 10 items and covers 6 domains including symptoms and feelings (e.g., felt itchy, sore, painful, embarrassed), daily activities, leisure, work and school, personal relationships, and treatment. Response categories include
"not at all," "a little," "a lot," and "very much," with corresponding scores of 0, 1, 2, and 3 respectively; the response "not relevant" (and unanswered items) are scored as "0".Items A total score is calculated by summing the score of all items, resulting in a maximum score of 30 and a minimum score of 0. Scale scores are calculated for each domain. Higher scores indicate poorer HRQL (i.e., more impairment). The patient can complete the DLQI in approximately 5 minutes.  
11.5.6 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.  
If the patient wishes to complete 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 e-mail 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).  
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. 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. 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. 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 to NRG Oncology (see Section 12.1).  
11.6 Criteria for Discontinuation of Protocol Treatment **(23-JAN-2013)**
- Unacceptable toxicity; see Sections 6.9 and 7.3 for further information.  
- Progression of disease; - Development of a 2nd primary upper aerodigestive tract malignancy (e.g., lung cancer, esophagus cancer, 2nd primary head and neck cancer);
- A delay in protocol treatment, as specified in Section 7.3.  
If protocol treatment is discontinued, follow up and data collection will continue as specified in the protocol.
eligibility checklist - step 2
12.0 data collection (11-may-2023) data

Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be used (first-last). Last names with apostrophes will be identified by the first letter of the last name.
eligibility checklist - step 2
12.1 summary of data submission

Within 2 weeks of study entry  
Item Due  
Demographic Form **(A5)** Initial Evaluation Form **(I1)***  
Operative Note **(S2)** Surgical Pathology Report **(S5)** Pathology Report [biopsy report] **(P1)** Slides/Blocks **(P2)**  
Functional Assessment of Cancer Therapy-H &N  
[FACT] **(FA)**  
Performance Status Scale for H & N Cancer [PSSHN] **(QP)**  
EuroQol [EQ-5D] **(HP)**  
University of Michigan Xerostomia-Related Quality  
of Life Scale [XeQOLS] **(L4)**  
Dermatology Life Quality Index [DLQI] **(DL)** Treatment Form (TF)* **Arm 2**: At the completion or discontinuation of  
cetuximab  
Initial Follow-up Form **(F0)*** Within 1 week of end of RT [FACT] **(FA)** [PSS-HN] **(QP)** [EQ-5D] **(HP)** [XeQOLS] **(L4)** [DLQI] **(DL)**  
Note: QOL forms completed online will be stored on the VisionTree, Inc. web site and transferred to NRG Oncology.  
Follow-up Form **(F1)*** From completion of RT, q3 months for 2 years, q6  
months for 3 years, then annually; also at death  
QOL Forms Cover Sheets Within 1 month of the QOL form being due (Note:  
Completed only if the patient did not complete a specific QOL form or if the patient completed a hardcopy of the form.  
| months for 3 years, then annually; also at death At 3, 12, and 24 months from the end of RT   |
|-----------------------------------------------------------------------------------------------|  
| Note: QOL forms completed online will be stored  on the VisionTree, Inc. web site and transferred to  NRG Oncology.   |
|-----------------------------------------------------------------------------------------------------------------------|
eligibility checklist - step 2
12.2 summary of dosimetry digital

Preliminary Dosimetry Information (DD)
Item Due  
| Within 1 week of  start of RT   |
|---------------------------------|  
Digital data submission includes the following:
- DICOM CT Image
- DICOM Structure
- DICOM Dose
- DICOM RT Plan
- All required structures **MUST** be labeled per the table in Section 6.6.  
- Submit via TRIAD with the digital data listed above.  
Upon submission of the digital data via TRIAD, complete a Digital Data Submission Information form (DDSI) located at www.irocqa.org/Resources/TRIAD-for-RT-QA
IGRT Submission via TRIAD (see Section 6.7.1 for details) Within 1 week of IGRT images obtained on first day of treatment **(IG)** One IGRT image data set per week of treatment **(IG)** IGRT Data Collection Spreadsheet on daily variances (SG)
RT end NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES
WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED.  
Final Dosimetry **Information** Within 1 week of Radiotherapy Form **(T1) via web**
Daily Treatment Record **(T5) [copy to HQ only]**
RT end
eligibility checklist - step 2
13.0 statistical considerations (23-jan-2013)

13.1 Primary **Endpoint**
Overall survival (OS)
13.2 Secondary **Endpoints**
- CTCAE, v. 4 adverse events: dysphagia, dry mouth, and skin and their relationships with patientreported outcomes at 3 months; - CTCAE, v. 4 adverse events: dysphagia, dry mouth, and skin and their relationships with patientreported outcomes at 12 and 24 months;
- Other CTCAE, v. 4 acute ( 90 days from start of RT) adverse events; - Other CTCAE, v. 4 late (> 90 days from start of RT) adverse events; - Disease-free survival (DFS).  
13.3 Tertiary Endpoints (Exploratory) **(06-DEC-2010)**
- Local-regional control;
- Quality of life as measured by Functional Assessment of Cancer Therapy-Head & Neck (FACTHN) at baseline and 3, 12, and 24 months from end of RT;
- Xerostomia as measured by University of Michigan Xerostomia-Related Quality of Life Scale
(XeQOLS) at baseline and 3, 12, and 24 months from end of RT;
- Swallowing as measured by the normalcy of diet subscale in Performance Status Scale for Head and Neck Cancer (PSS-HN) at baseline and 3, 12, and 24 months from end of RT;
- Quality of life measured as measured by the EuroQol (EQ-5D) at baseline and 3, 12 and 24 months from end of RT;
- Skin toxicity as measured by the Dermatology Life Quality Index (DLQI) at baseline and 3, 12, and 24 months from end of RT.
eligibility checklist - step 2
13.4 background and sample size

13.4.1 Background and Sample Size Determination for Cetuximab Question The target study population for this trial includes, but is not limited to, all patients that would have been eligible for either the RTOG 9501 or the EORTC 22931 trials, except for patients with positive margins and/or extracapsular extension (ECE). The subset of patients with positive margins and/or ECE did exceedingly poor in terms of efficacy outcomes and is excluded from this trial. The primary hypothesis is that the addition of cetuximab to postoperative radiation therapy (RT) will improve overall survival (OS) when compared to RT alone. A secondary endpoint includes a comparison of disease-free survival (DFS) and a tertiary (exploratory endpoint includes a comparison of local-regional control (LRC). The survival experience for patients who did not have either positive margins or ECE and were treated with postoperative RT on the RTOG 9501 and EORTC 22931 trials will be used as an estimate for the control arm. In RTOG 9501, there were 94 such patients; 45 of those patients have died. Their estimated yearly hazard rate based on a 3-year Kaplan-Meier (1958) survival estimate was 0.1697 with a 95% confidence interval (CI) [0.1183, 0.2304]. In EORTC 22931, there were 56 such patients; 23 of those patients have died. Their estimated yearly hazard rate based on a 3-year Kaplan-Meier survival estimate was 0.1654 (0.1002, 0.2466). For planning purposes, the survival rate for the control arm will be assumed to follow an exponential distribution with a yearly hazard rate for OS of 0.1697. The results from the completed Bonner phase III trial show that there was a 26% reduction in the risk of death rate when cetuximab was given before and concurrently with RT without cisplatin (Bonner 2006). Therefore, this study will test for a similar effect for cetuximab when given in conjunction with postoperative RT in reducing the death rate. The statistical software EaST for group sequential design was used for calculating the sample size with the Haybittle-Peto boundary for efficacy where the 3 interim significance levels were set at 0.005; then the significance level 0.0183 for the final analysis was derived in order to preserve a 0.025 significance level for the entire study. Futility will be tested using the lower boundary based on testing the alternative hypothesis at 0.005 level and because it was shown to have very little effect on the type I error, there will be no adjustment made to the sample size (Freidlin 2002).  
Three hundred seven-two deaths will be required to detect a 26% reduction in the death rate with 80% statistical power using a 1-sided test at the 0.025 significance level with 3 interim tests. Six hundred thirty-four patients accrued over 6.6 years will be required. Adjusting by approximately 10% to allow for ineligibility and lack of data, **the total sample size required** will be 700 patients. The maximum study duration, including follow-up requirements, under the above constraints is 9.6 years, if the 3-year survival rate for the control arm is 60.1%.  
In addition, a subset analysis using only HPV negative (HPV-) patients will compare the treatment arms. Patients with an oropharyngeal primary site who are either HPV positive (HPV+) or have unknown HPV status will be excluded in this analysis. Patients with a primary site other than oropharyngeal will be assumed to be HPV- because of the exceedingly low reported prevalence rate of HPV. It is estimated from RTOG 9501 and the EORTC trials that 35% of patients will be entered on RTOG 0920 with an oropharyngeal primary. In the completed ECOG trial, 23991, prospectively evaluating HPV status, 61% of the patients with an oropharyngeal primary were HPV+, and in the completed trial, RTOG 0129, the preliminary results from a retrospective review of HPV status in 122 oropharyngeal patients show a 63%
incidence of HPV+ patients (Pajak 2008). The assumption will be made for analyses that all patients with non-oropharyngeal primaries are HPV negative (HPV-). In light of these data, it is projected that 20% of the RTOG 0920 study population will be HPV+. Restricted to the 508 (=
0.80 * 634) HPV- patients, there will be 80% statistical power to detect a 28% reduction in the OS failure rate using a 1-sided test at the 0.025 significance level, assuming that the trial is not reported earlier. This subset analysis will be done when there are 294 deaths among the HPVpatients. If the hazard rate for the control arm is approximately the same for HPV- patients as it is for all patients, 294 deaths are projected to occur for the subset analysis, approximately at the same time as the 372 deaths have occurred for the final treatment analysis of the entire population. However, the hazard rate for HPV- patients is expected to be higher and thus, the subset analysis certainly can be performed at the same time as the "definitive" protocol treatment analysis.  
13.4.2 Background and Statistical Power Determination for Evaluating the Addition of IGRT to IMRT
The yearly failure rate for the endpoint LRC in patients who did not have either positive margins or ECE and were treated with postoperative RT on the RTOG 9501 trial will be used as an estimate for the patients treated with IMRT but without IGRT (Table 1 below). For planning purposes, the following assumptions will be made to simplify the calculations:
1. The use of IMRT would not appreciably change the LRC rates observed in RTOG 9501 with RT;
2. The addition of cetuximab to postoperative RT will not appreciably change the LRC
rates; 3. The yearly LRC failure rates in Table 1 will be used.  
| Table 1: Estimated Yearly Local-Regional Failure Rates   |                                |                             |
|----------------------------------------------------------|--------------------------------|-----------------------------|
| Year                                                     | Projected RTOG 0920 IMRT Alone | Observed RTOG 9501 RT Alone |
| 1                                                        | 13.5%                          | 13.0%                       |
| 2                                                        | 13.5%                          | 13.4%                       |
| 3                                                        | 4.0%                           | 4.7%                        |
| 4                                                        | 4.0%                           | 3.5%                        |
| 5+                                                       | 0.1%                           | 0.0%                        |  
Currently, there are only a limited number of academic and community institutions using IGRT.  
During this study, the number of institutions using IGRT is expected to increase as the technology becomes more readily available on modern Linacs. Although it is projected now that 40% of patients will have received IMRT + IGRT, 3 other various percentages (30, 50, and 60%) also will be evaluated. Reductions of 25% and 30% in the LRC failure rate with the additional of IGRT will be evaluated. The significance level for a two-sided test was set at 0.05.  
The monthly accrual rate, its duration, and the follow-up interval from the sample size derivation for the cetuximab question were used. The statistical power for each scenario was derived by using the Lakatos method (1986).  
Table 2: Statistical Power Associated with Evaluating the Addition of IGRT  
| Percentage of patients  treated with IMRT and IGRT   | 30% reduction   |      |
|------------------------------------------------------|-----------------|------|
| in local-regional failure rate  with IMRT and IGRT   |                 |      |
| 30%                                                  | 0.37            | 0.51 |
| 25% reduction                                        |                 |      |
| in local-regional failure rate  with IMRT and IGRT   |                 |      |
| 40%                                                  | 0.43            | 0.58 |
| 50%                                                  | 0.45            | 0.61 |
| 60%                                                  | 0.44            | 0.60 |  
As seen in Table 2, the statistical power is quite low for all scenarios. Given the results from the Bonner trial (2006), we do expect that cetuximab will reduce the local-regional failure rate; therefore, the statistical power will even be lower. Therefore, the impact of IGRT only will be estimated and reported with its 95% confidence interval. Furthermore, the estimate for IGRT effect will be derived from a Cox model with pathologic T-stage, performance score, and protocol treatment as covariates. These variables were selected to adjust for possible imbalance, since patients were not randomized between IMRT and IMRT+IGRT, This result will be viewed as hypothesis generating, not as definitively testing the addition of IGRT.  
13.4.3 Background for Evaluating Local Regional Control in IMRT (without IGRT) Treated Patients Since the intergroup postoperative randomized trial, RTOG 95-01, completed accrual in 2000, radiation planning and delivery has evolved. It is generally accepted that intensity modulated radiation therapy (IMRT) will minimize late toxicity (especially xerostomia) [Kam 2007; Pow 2006]. It has been assumed that IMRT will not "significantly" reduce the local-regional control
(LRC) rates, but presently, there are no randomized studies available that definitively have tested this hypothesis. It should be noted that there are no published results from uncontrolled series to suggest that IMRT may compromise LRC rates. With the current widespread use of IMRT in the treatment of head and neck cancer, it would not be possible to launch a definitive randomized trial to test this question. For example, in the recently completed randomized trial for locally advanced head and neck cancer, RTOG 0522, 85% of patients are treated with IMRT. The assumption that IMRT will not seriously compromise LRC rates will be assessed twice against the RTOG 95-01 LRC rates using the cohort of patients treated with IMRT alone in RTOG 0920. The first assessment will occur after these patients have been potentially followed for 1 year and the second time after potential follow up for 2 years. In RTOG 95-01, 86% [95% confidence interval 79-93] and 78% (70-87) LRC rates were observed at 1 and 2 years, respectively in the 93 patients treated with external beam irradiation only and that would have been eligible for RTOG 0920 (table below). Based upon these rates, it is projected that the 1- and the 2-year LRC rates would be 90% and 80% in RTOG 0920. An absolute decrease of 10% or more in either yearly estimated rate is considered unacceptable and would call into question the assumption about IMRT not adversely affecting LRC. If such a decrease is observed at either special analysis, the patient accrual to 0920 will be suspended. The NRG
Oncology Data Monitoring Committee will review the results from the analysis and make a recommendation about the study's future disposition (e.g., discontinuation of further patient entries) to the NRG Oncology Group Co-Chair who, in turn, will act upon that recommendation.  
A particular concern is that the RTOG 0920 patients may be more elderly and possibly sicker than the RTOG 95-01 patients. The RTOG 95-01 trial had more stringent eligibility criteria because the patients could be randomized to receive concurrent chemotherapy with radiation therapy. Assuming that the true LRC rate at 2 years is 80% with external beam irradiation, the 2-sided 95% confidence interval (assuming a binominal distribution) around it would have 70% as its lower limit with 64 evaluable patients. That sample size would result in 2-sided 99%
confidence interval around an assumed true LRC rate at one year of 90% with 80% as its lower limit. The 2 interim analyses will be performed once the data are mature enough for the first 70 patients assigned to the radiation alone arm and for whom the participating institution does not elect to treat with IGRT added to IMRT. The additional 6 patients entered beyond the required 64 guards against loss to follow up and retrospective ineligibility. The timing of these analyses depends not only on the patient accrual rate but also on the percentage of patients treated without IGRT added to IMRT. With a projected patient accrual rate of 108 patients per year, 54 would be randomized to receive RT alone. If 80% of these patients initially entered are treated with IMRT but not with IGRT, the 2 special interim analyses are projected to occur at 3 and 4 years from the time the study opens to patient accrual. If that percentage is 70% instead of 80%, it will take an additional 6 months. These time intervals take into account the period of time to accrue the required 70 patients, the designated risk period for local-regional failure (one and two years), and an additional 6 months for data collection and analysis.
eligibility checklist - step 2
rtog 95-01 local-regional control patients

| Year   | Estimate   | 95% CI (%)   | Cumulative   | At Risk   |
|--------|------------|--------------|--------------|-----------|
| (%)    | Failures   |              |              |           |
| 0      | 100.0      | --           | 0            | 93        |
| 1      | 86.0       | 78.9, 93.1   | 13           | 71        |
| 2      | 78.4       | 69.9, 86.8   | 20           | 58        |
| 3      | 76.2       | 67.4, 84.9   | 22           | 49        |
| Total  | 22         |              |              |           |  
RT only arm 13.4.4 Background and Statistical Power Determination for Evaluating Various Tumor Markers EGFR Expression Levels The specific hypothesis is that the relative improvement in OS will be similar for patients with high EGFR expression (defined as ≥ 80% of cells staining positive for EGFR) or low EGFR
expression (defined as < 80% of cells staining positive). However, the absolute values for OS will be significantly greater for patients with low EGFR expression.  
Although baseline EGFR expression is a stratification variable for treatment assignment, all patients may not have it available for analysis. The protocol has strict time constraints to start postoperative RT. Since it is entirely possible that the initially submitted pathologic material maybe inadequate to determine HPV status and/or EGFR level within that time period, the patients will be classified as not evaluable for treatment randomization. However, every attempt will be made to appropriately classify these patients with respect to these 2 variables for tumor marker analysis. It is conservatively projected that the baseline EGFR expression will be available on 90% of the patients. The hypotheses will be tested with a Cox regression model with 3 covariates: 1) assigned treatment; 2) baseline EGFR expression; and 3) treatment by EGFR expression interaction. The covariate for baseline EGFR expression tests whether the patients with low EGFR have better OS while the covariate for interaction tests whether the treatment effect is similar within each EGFR subgroup. For planning purposes, it is assumed that patient accrual will not be discontinued in the trial or that trial is not reported early because of highly significant results. So at the time of final treatment analyses, there will be at least 335 deaths (= 0.90 * 372 events) observed in all patients and 247 deaths ( = 0.90 * 274 events) in HPV- patients. It is projected that 40% to 60% of patients will be in the low EGFR group.  
The equation described by Schoenfeld (1981) was used to calculate statistical power:
Number of failures = (z 1- α/2 + z 1- β)
2/ (ln HR)2 w (1 - w), where z 1- α/2 = normal deviate for the significance level z 1- β = normal deviate for the statistical power HR = hazard ratio comparing favorable risk group (low EGFR values) to unfavorable risk group (high EGFR values)
w = prevalence rate of risk group Table 3 below provides the statistical power to detect hazard ratios for OS of 1.50, 1.75, and 2.00 for prevalence rates of 40% or 50% or 60% in all patients and in HPV- patients. As seen in the table, there will be good power to detect a hazard ratio of 1.50 or greater. In fact, there is 80% statistical power to detect ratio of at least 1.4 in both patient groups. The statistical power for DFS would be higher since its failure rate would be higher than death rate; thus resulting in more events.  
| All patients (335 deaths)   | HPV- patients(247 deaths)   |      |      |      |      |      |
|-----------------------------|-----------------------------|------|------|------|------|------|
| Hazard Ratio                | Hazard Ratio                |      |      |      |      |      |
| Prevalence                  | 1.50                        | 1.75 | 2.00 | 1.50 | 1.75 | 2.00 |
| 40% (or                     | 0.95                        | 0.99 | 0.99 | 0.87 | 0.99 | 0.99 |
| 60%) 50%                    | 0.95                        | 0.99 | 0.99 | 0.88 | 0.99 | 0.99 |  
In order to properly test the hypothesis that the treatment effect on OS is the same within each EGFR subgroup, a minimum relative 20% difference would have to be ruled out with 90% statistical power. Using the method of Peterson and George (1993), that would require over 3,000 cases under the following assumptions:
1. The patients are equally divided by EGFR subgroup and treatment assignment; 2. The high EGFR subgroup failed 1.5 times faster than low EGFR subgroup; 3. 86 (= 0.90 * 96) analyzable patients accrued per year for 6.6 years, and all patients were followed potentially for 3.0 years.  
Modifying any of these assumptions will not substantially decrease the number of cases because of the small difference to detect. The estimate for interaction along with its 95% confidence will be reported. The closer this estimate is to 1, the more support is for the hypothesis that the treatment effect is the same within each EGFR subgroup.
eligibility checklist - step 2
hpv positivity and negativity the

1. HPV negative patients will have greater absolute benefit from the addition of cetuximab compared to HPV positive patients; 2. HPV positivity will associate with low EGFR expression because the HPV positive tumors may not be driven by EGFR but by viral oncogene E6/E7, causing the loss of p53 and Rb; 3. EGFRvIII will associate with HPV negativity and treatment failure due to ligandindependent constitutive activation of the receptor, escaping the effects of cetuximab.  
Hypothesis 1:
Although HPV status is a stratification variable for treatment assignment, all patients may not have it available for analysis. Since it is entirely possible that the initially submitted pathologic material may be inadequate to determine HPV status and/or EGFR level, patients will be classified as not evaluable for treatment randomization. However, every attempt will be made to appropriately classify these patients with respect to these 2 variables for tumor marker analysis. It is conservatively projected that the HPV expression will be available on 90% of the patients. The hypothesis will be tested with a Cox regression model with the following covariates: 1) treatment, 2) HPV status, and 3) treatment by HPV status interaction. The covariate for interaction tests whether the treatment effect is similar for the HPV+ and the HPV - patients. For planning purposes, it is assumed that the patient accrual will not be discontinued in the trial or that trial is not reported early because of highly significant results. At the time of final treatment analyses, there will be at least 335 deaths (= 0.90 * 372 events) observed in all patients. It is projected that 20% of patients will be HPV+. Using the method of Peterson and George (1993), an effect size of 50% or greater for this interaction can be detected with 80% statistical power under the following assumptions:
1. The patients are equally divided by treatment assignment within each HPV status; 2. The HPV- subgroup failed 1.5 times faster than the HPV+ subgroup; 3. The hazard ratio associated with smallest treatment effect ranges between 0.85 and 1.00; 4. 86 (=0.90 * 96) patients accrued per year for 6.6 years, and all patients were followed potentially for 3.0 years.  
Modifying any of these assumptions will not substantially change the effect because only 20% of the patients are projected to be HPV+. The estimate for the treatment by HPV status interaction with its 95% confidence will be reported. A smaller effect for DFS would be detected, since its failure rate would be higher than the death rate; thus resulting in more events. Hypothesis 2: Although both baseline EGFR level and HPV status are stratification variables for treatment assignment, all patients may not have these data available for analysis. Since it is entirely possible that the initially submitted pathologic material may be inadequate to determine HPV
status and/or EGFR level, patients will be classified as not evaluable for treatment randomization. However, every attempt will be made to appropriately classify these patients with respect to these 2 variables for tumor marker analysis. It is conservatively projected that the HPV expression will be available on 90% of the patients. It is projected that 20% of patients will be HPV+. There are no definitive data available to estimate the percentage of the HPV+ patients with low EGFR values; however, a published study showed 65% of p16
(surrogate of HPV status) positive tumors had low EGFR expression (Reimers 2007). With a projected sample size of 112 HPV+ patients and 457 HPV- patients and 80% statistical power, the detectable difference in the rate of patients with low EGFR values between these 2 subgroups would be approximately 0.15.
eligibility checklist - step 2
hypothesis 3

Although both baseline EGFR level and HPV status are stratification variables for treatment assignment, all patients may not have these data available for analysis. Since it is entirely possible that the initially submitted pathologic material may be inadequate to determine HPV
status and/or EGFR level, the patients will be classified as not evaluable for treatment randomization. However, every attempt will be made to appropriately classify these patients with respect to these 2 variables for tumor marker analysis. It is conservatively projected that both the HPV status and EGFR expression will be available on 90% of the patients. However, EGFRvIII may not be determined in all patients because of limited tissue available. For planning proposes, it is projected that 90% of patients with both HPV status and baseline EGFR expression also will have a EGFRvIII value and that 20% of these patients will be HPV+. There are no data available to estimate the percentage of the HPVpatients with EGFRvIII present. With a projected sample size of 101 HPV+ patients and 411 HPV- patients and 80% statistical power, the detectable difference in the rate of patients with EGFRvIII present between these 2 subgroups will be approximately 0.16. EGFR Ligand Expression Levels The specific hypothesis is that patients with high values of EGFR ligand expressions (defined as the 4th quartile) will have better OS and DFS than patients with low values (defined as the 1-3rd quartile).  
For planning purposes, it is assumed that EGFR ligand expression can be determined in 75% of the patients and that patient accrual will not be discontinued in the trial or that trial is not reported early because of highly significant results. At the time of final treatment analyses, there will be at least 279 (= 0.75 * 372) deaths (events) observed in all patients and 220 ( = 0.75 * 294 ) deaths (events) in HPV- patients. It is projected that 25% of patients will be in the group with high EGFR ligand expression. The equation described by Schoenfeld (1981) was used to calculate statistical power: Hazard ratio in this instance compares favorable risk group (high expressions) to unfavorable risk group (low expressions) and prevalence rate is for favorable risk group. Table 4 below provides the statistical power to detect hazard ratios for OS of 1.50, 1.75, and 2.00 in all patients and in HPV- patients. As seen in the table, there will be good power to detect a hazard ratio of 1.50 or greater in both patient groups. If DFS was used instead of OS, there would be more failures at time of the analysis and thus, more statistical power.  
Hence, there is 99% statistical power to detect a ratio of ≥ 2.00, reported by Khambata-Ford
(2007) for DFS in recurrent/metastatic colon patients.  
| All patients (279 events)   | HPV- patients (220 events)   |      |      |      |      |
|-----------------------------|------------------------------|------|------|------|------|
| Hazard Ratio                | Hazard Ratio                 |      |      |      |      |
| 1.50                        | 1.75                         | 2.00 | 1.50 | 1.75 | 2.00 |
| 0.83                        | 0.98                         | 0.99 | 0.74 | 0.94 | 0.99 |
eligibility checklist - step 2
table 4 statistical power for

Evaluation of TP53 Mutations The specific hypothesis is that the patients with *TP53* mutations will have poorer OS and DFS than patients with wild-type *TP53* mutations.  
For planning purposes, the following assumptions will be made:
1. *TP53* mutation status can be determined in 75% of the patients; 2. 50% of patients will have *TP53* mutations; 3. Mutations will be distributed as follows: functionally non-disruptive=33% and functionally disruptive=20%. Thus, approximately 50% of all patients are projected to have no *TP53* mutations; 4. Patient accrual will not be discontinued in the trial or that trial is not reported early because of highly significant results; 5. Since the comparison will be made between patients with *TP53* mutations and patients with wild-type *TP53*, there will be at least 140 (= 372 * 0.75) deaths
(events) observed in these 2 patient groups at the time of final treatment analyses; 6. After assessing the *TP53* mutational status, the mutations will be categorized into functionally non-disruptive and disruptive mutations for a subset analysis to further investigate the clinical effects of the mutations.
The equation described by Schoenfeld (1981) was used to calculate statistical power:
Hazard ratio in this instance compares unfavorable risk group (*TP53* mutation) to unfavorable risk group (wild-type *TP53*). The prevalence rate of favorable risk group was set at 0.50 but also prevalence rates of 0.40 and 0.60 will be evaluated. Table 5 below shows statistical power to detect hazard ratios for OS of 1.50, 1.75, and 2.00 for prevalence rates of 40% or 50% or 60% in all patients. As seen in the table, there will be excellent statistical power (> 90%) to detect a hazard ratio of ≥ 1.50, and 80% statistical power to detect a ratio of at least 1.4 in all patients. The statistical power for DFS would be higher since its failure rate would be higher than the death rate; thus resulting in more events.  
| All patients (279 deaths) Hazard Ratio   |      |      |      |
|------------------------------------------|------|------|------|
| Prevalence of pts with  wild type TP53   | 1.50 | 1.75 | 2.00 |
| 40%                                      | 0.91 | 0.99 | 0.99 |
| 50%                                      | 0.92 | 0.99 | 0.99 |
| 60%                                      | 0.91 | 0.99 | 0.99 |  
Table 5: Statistical Power for All Patients with 2-Sided 5% Alpha Evaluation of Polymorphic Variants in CA Dinucleotide Repeats in EGFR Intron 1 The specific hypothesis is that short CA dinucleotide repeats in EGFR intron 1 will be associated with poor OS and DFS.  
For planning purposes, it is assumed that dinucleotide repeats in EGFR intron 1 can be determined in 75% of the patients and that patient accrual will not be discontinued in the trial or that trial is not reported early because of highly significant results. It is projected that 25%
of the study population will be female and < 5% will be Asian. At the time of final treatment analyses, there will be at least 279 (= 0.75 * 372) deaths (events) observed in all patients and 80 (= 0.25 * 0.75 * 294 ) deaths (events) in female patients. The equation described by Schoenfeld (1981) was used to calculate statistical power:
Hazard ratio in this instance compares favorable risk group (short CA dinucleotide repeats in EGFR intron 1) to unfavorable risk group (long CA dinucleotide repeats in EGFR intron 1) and the prevalence rate is for the favorable risk group. Table 6 below shows statistical power to detect hazard ratios for OS of 1.50, 1.75, and 2.00 for prevalence rates of 40% or 50% or 60% in all patients and in only female patients. As seen in the table, there will be excellent statistical power (> 90%) to detect a hazard ratio of 1.50 or greater and 80% statistical power to detect ratio of at least 1.4 in all patients. However, there is only adequate statistical power (> 80%) to detect large ratio in the female patients. The statistical power for DFS would be higher since its failure rate will be higher than death rate; thus resulting in more events.  
| All Patients (279 deaths)   | Female Patients (80 deaths)   |      |      |      |      |      |
|-----------------------------|-------------------------------|------|------|------|------|------|
| Hazard Ratio                | Hazard Ratio                  |      |      |      |      |      |
| Prevalence                  | 1.50                          | 1.75 | 2.00 | 1.50 | 1.75 | 2.00 |
| 40% (or 60%)                | 0.91                          | 0.99 | 0.99 | 0.42 | 0.68 | 0.85 |
| 50%                         | 0.92                          | 0.99 | 0.99 | 0.44 | 0.70 | 0.87 |  
13.4.5 Background and Statistical Power Determination for Evaluating Factors Associated with LongTerm, Post-Radiotherapy Adverse Events and Patient-Reported Outcomes (PROs)
In this trial, long-term adverse events will be graded using CTCAE, v. 4, with particular attention to dysphagia, dry mouth , and skin toxicity (rash: acneiform; rash: maculo-papular; and pruritus). However, it is recognized that CTCAE (physician graded) does not always reflect the patient experience and quality of life (QOL). Therefore, patient-reported outcomes (PROs) will be studied with head and neck specific instruments, including: the Performance Status Scale for Head and Neck Cancer (PSS-HN), the Functional Assessment of Cancer Therapy-Head &
Neck (FACT-H&N), the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS), the Dermatology Life Quality Index (DLQI), and a cost-utility analysis will be done using the EuroQol (EQ-5D). Data will be collected at the baseline and at 3, 12, and 24 months from the start of treatment.  
Hypothesis 1: The primary question of interest is whether the addition of cetuximab to postoperative radiation therapy (RT) at 12-month assessment results in poorer PROs. In the Bonner study with  
The following 5 hypotheses will be examined:
1. PROs will be similar in the 2 arms (i.e., the use of cetuximab does not result in decreased QOL);
2. Patients treated with IMRT + IGRT will have improved XeQOLS scores compared with patients treated with IMRT;
3. Clinician-rated functional assessment of dysphagia (CTCAE, v. 4 dysphagia) is at least moderately correlated (r ≥ 0.20) with its PRO assessment (the Normalcy of Diet component of the PSS-HN);
4. Clinician-rated functional assessment of xerostomia (CTCAE, v. 4 dry mouth) is at least moderately correlated (r ≥ 0.20) with its PRO assessment (the XeQOLS);
5. Clinician-rated skin toxicity (CTCAE, v. 4 rash: acneiform; rash: maculo-papular; and pruritus) is at least moderately correlated (r ≥ 0.20) with its PRO assessment (the DLQI);
6. The EQ-5D is highly correlated (r ≥ 0.50) with FACT-H&N, XeQOLS, the PSS-HN, and DLQI.
patients who received definitive RT, the addition of cetuximab did not adversely affect QOL.  
The effect of the addition of cetuximab at 3 months from start of RT also will beevaluated.  
In this trial, the participation in the QOL component of the study is optional for patients. In the past, RTOG has not evaluated QOL in any postoperative RT trial; therefore, the projected percentage of patients with PRO/QOL data for the 12-month assessment will be based on the ongoing phase III trial, RTOG 0522, testing the addition of cetuximab to chemoradiation. RTOG 0522 uses the same PRO/QOL instruments, with the exception of the University of Michigan 15-item Xerostomia Related Quality of Life Scale (XeQOLS). In the first 78 patients entered into RTOG 0522 with potentially 12-month follow up, approximately 50% had both the baseline and the 12-month assessment; therefore, it is projected that half of the patients entered onto RTOG 0920 will have both assessments (158 patients per arm). Hypothesis 1 will be tested using the following 3 endpoints:
A. University of Michigan 15-item Xerostomia Related Quality of Life Scale *(XeQOLS)*
The endpoint for the XeQOLS will be differences between arms in the mean XeQOLS score for the baseline and the 12-month assessment. Only patients alive at 10 months with baseline (XeQOLS) scores will initially be included in this analysis. With 158 patients per arm and an effect size of 0.32 or higher, where the effect size is
=
1 −  2  
, where  *is the common s* tan dard *deviation*, under assumption of normal distribution, there is 80% statistical power to detect this effect.  
B. *Normalcy of Diet Subscale in the Performance Status Scale for Head and Neck Cancer*
(PSS-HN)
For the PSS-HN scale, the frequency of patients with scores of ≤ 50 (considered to be impaired swallowing or speech) on each of the 3 subscales (Normalcy of Diet; Eating in Public; and Understandability of Speech) will be estimated along with its 95% confidence interval for each treatment regimen at 12 months from start of treatment. These frequencies will be compared between the 2 treatments using the z-statistic for testing binomial proportions. Only patients alive at 10 months with baseline diet subscale scores will be included in this analysis. There are no data available to estimate the percentage of the patients on the postoperative RT arm with impaired swallowing or speech at 12 months in this study population. With projected sample size of 158 patients per arm and 80% statistical power, the detectable difference would be approximately 0.16 between the treatment arms.  
C. Functional Assessment of Cancer Therapy-Head & Neck *(FACT-H&N)* The primary patient-reported endpoint for the FACT-H&N will be differences between arms in the mean FACT-H&N score for the baseline and the 12-month assessment. Only patients alive at 10 months with baseline FACT-H&N scores will be included in this analysis. With 158 patients per arm and an effect size of 0.32 or higher, where the effect  
```
size is  =
1 −  2

, where  is the common s tan dard deviation, there is 80% statistical
power to detect this effect.

```
eligibility checklist - step 2
hypothesis 2

The ideal way to determine whether patients treated with IMRT + IGRT will have improved Xerostomia Related Quality of Life Scale (XeQOLS) scores would be in a study in which patients are randomly assigned to IMRT +/- IGRT. This randomization would not be possible because many NRG Oncology institutions do not have IGRT capabilities or because some radiation devices with IGRT capabilities cannot be utilized without IGRT. As the proposed study is written, the treating institution decides on a patient-by-patient basis whether or not IGRT will be utilized. An exploratory analysis will be performed looking at this question. The analysis will be done with multivariate regression models to correct for potential prognostic factors, including protocol cetuximab treatment, tumor site, stage, patient age, pretreatment performance status, and type and extent of surgery performed prior to IMRT. The number of patients available for analysis will be for the same as for the protocol treatment evaluation described above. It is expected that the number of institutions with IGRT capabilities will steadily increase over the time in which the study is active and by the time the study is complete, most institutions will have IGRT capabilities. The same 12-month PRO/QOL endpoints will be analyzed in a similar fashion for the treatment comparison. The statistical power associated with the evaluation of the 12-month PRO/QOL endpoints was generated under the assumption that 40% (i.e., 126) of 316 patients will have received IMRT + IGRT, and 60% (i.e., 190) will receive IMRT without IGRT. The primary patient-reported endpoint for the XeQOLS and FACT-H&N respectively will be differences between arms in their respective mean score for the baseline and the 12-month assessment.  
Only surviving patients at 10 months with their baseline scores will initially be included in this analysis. With 126 patients treated with IMRT + IGRT, 190 patients treated with IMRT without IGRT and an effect size of 0.33 or higher, where the effect size is
=
1 −  2  
, where  *is the common s* tan dard *deviation*, under assumption of normal distribution, there is 80% statistical power to detect this effect. For the PSS-HN diet subscale, the frequency of patients with scores of ≤ 50 (considered to be impaired swallowing) will be compared between IMRT +/- IGRT using the z-statistic for testing binomial proportions. Only surviving patients at 10 months with baseline diet subscale scores will be included in this analysis. There are no data available to estimate the percentage of the patients on postoperative RT arm with impaired swallowing at 12 months in this study population. With projected sample size of 126 IMRT+ IGRT patients and 190 IMRT without IGRT patients and 80% statistical power, the detectable difference would be approximately 0.17.  
Hypotheses 3-5: Patients with a PRO data collection form received within 2 months of the 12-month assessment will be included in the analyses of these hypotheses, as long as they had a clinical assessment of dry mouth, dysphagia, and skin toxicity (rashacneiform; rashmaculo-papular; and pruritus)
during that study timeframe. It is projected that there will be approximately 300 such patients.
eligibility checklist - step 2
hypothesis 6

Patients with an EQ-5D data form received within 2 months of the 12-month assessment will be included in the analyses of this hypothesis, as long as they had at least one of the other PRO data forms (FACT-H&N, XeQOLS, the PSS-HN, and DLQI) completed during that study timeframe. It is projected that there will be approximately 300 such patients.  
13.5 Patient **Accrual**
The study design is based on a 79-month accrual period with an average of approximately 9.0 patient entries per month. However, during the first 6 months following activation, little accrual is anticipated while the trial is approved by institutional IRBs. It is projected that 11 patients in total will be entered during study months 1-6 (none in months 1-3; 3 patients in the 4th month; and 4 patients in months 5-6), and then the average monthly accrual rate after study month 6 will be 9.5 patients. If the total accrual during months 13 through 18 of the study is ≤ 20% of the targeted accrual (≤ 11 cases in total), then the protocol will be discontinued per NCI-CTEP accrual guidelines for phase III studies. If the total accrual is between 21-49%, then the protocol will continue to accrue subject to approval of the NRG Oncology Data Monitoring Committee (DMC)
and NCI-CTEP. If continued, the study has to accrue at least 50% of targeted accrual (≥ 15 cases in total) during months 22 through 24 in order to remain open beyond 2 years.  
13.6 Randomization **(23-FEB-2012)**
Patients will be stratified by 4 variables: Pretreatment EFGR level (high [≥ 80% of cells staining positive for EGFR] vs. low [< 80% of cells staining positive for EGFR] vs. EGFR not evaluable);
Primary Site (Oral cavity, Larynx, Oropharynx HPV positive, Oropharynx HPV negative, Oropharynx HPV not evaluable); use of IGRT (no vs. yes), and clinical stage (T1-3 vs. T4a). To avoid possible bias in randomization of patients to the study, the patient's HPV status will not be provided to the patient's physician or institution until the patient has completed study treatment. The treatment allocation scheme described by Zelen (1974) will be used because it balances patient factors other than institution. The protocol has strict time constraints to start postoperative RT.  
13.7 Analysis Plan **(11-MAY-2023)**
13.7.1 Statistical *Methods* This study will be analyzed using all eligible patients with follow up based on the treatment arm to which they were randomized, regardless if they started the assigned treatment. In addition, a second efficacy comparison will be performed as a sensitivity analysis for the primary endpoint of survival using all patients entered on RTOG 0920 by their randomized treatment assignment.  
The Spearman method will be used to calculate the correlation coefficients with their associated 95% confidence levels.  
DFS and OS rates will be estimated using the Kaplan-Meier method (1958). The distributions of the OS and DFS will be compared between treatment arms with a one-sided, stratified log rank test (Mantel 1966). The patients will be stratified by EGFR level (high vs. low vs. not evaluable)
and primary site/HPV status (oropharyngeal HPV positive vs. oropharyngeal HPV negative/oral cavity/larynx vs. oropharyngeal HPV not evaluable). Since the use of IGRT is not projected to significantly affect overall survival, it was not included as a stratification variable for the cetuximab efficacy analysis. This minimizes the number of cells for the log rank test. Since protocol treatment has to start within 2 weeks of protocol registration, it is expected that some of patients will not have an EGFR level and/or HPV status available at the time of randomization because the tissue submission was inadequate; these patients will be randomized as not evaluable. Most of these patients subsequently will have the unknown value for the stratification variable determined. However, values of the stratification variables at the time of randomization will be used for both OS and DFS endpoints in primary/secondary efficacy analysis. It is very possible that some stratification cells defined by oropharyngeal HPV
positive patients or oropharyngeal HPV undetermined patients may have less than 20 patients. In those situations, the oropharyngeal HPV undetermined patients will be considered HPV positive and the cells combined accordingly. Sensitivity analysis also will be performed, restricting it to patients with known values for both stratification variables that are either before or after randomization.  
Local-regional progressions in head and neck cancer trial mostly occur during the first two years and so death or distant metastasis without LRP can greatly influence the treatment effect, the associated p-value, and hence the interpretation of the trial. Therefore, localregional control will be analyzed the following two ways:  
1. Cumulative incidence curves comparing the treatment arms where LRP is considered as a failure and death or distant metastasis without LRP as a competing risk (Kalbfleisch 1980). The distributions of this failure pattern will be compared between treatment arms with the failure-specific log rank test (Prentice 1978).  
2. Cumulative incidence curves comparing the treatment arms where death or distant metastasis with LRP is considered as a failure and LRP as a competing risk
(Kalbfleisch 1980). The distributions of this failure pattern will be compared between treatment arms with the failure-specific log rank test (Prentice 1978).
The results from two approaches in this exploratory analysis for objectives (Sections 2.3.1 and 2.3.2) will be reported. Approach 1 will provide an estimate the efficacy for new treatment (cetuximab) and new radiation technique (IGRT) respectively and will be interpreted supporting their use if the associated p-value is less than p < 0.10 and if approach 2 does not show for patients treated with cetuximab or IGRT an increase in death rate without LRP progression especially during the first two years. All failure times will be measured from the date of treatment randomization to the date of failure, competing risk, or last follow up. Table 7 shows how each first event will be counted for LRC and DFS. Anything not explicitly in the table (e.g., second primary tumor) is not considered an event, and the patient will continue to be followed for failure. For OS, death from any cause will be considered a failure.  
| Local-Regional                               | Local-Regional   | Disease-free   |          |
|----------------------------------------------|------------------|----------------|----------|
| First Event                                  | Control (1)      | Control (2)    | Survival |
| None                                         | Censored         | Censored       | Censored |
| Local-regional progression or                | Failure          | Competing risk | Failure  |
| recurrence Distant metastasis                | Competing risk   | Failure        | Failure  |
| Death due to study cancer or from  Failure   | Competing risk   | Failure        |          |
| unknown causes Death due to any other reason | Competing risk   | Failure        | Failure  |  
Table 7: Definition of Failure for LRC and DFS
For the endpoints in Sections 13.1.2.1, 13.1.2.2, and 13.1.2.3, only adverse events (AEs) assessed to be definitely, probably, or possibly related (if relationship is missing, it will be assumed to be definitely, probably, or possibly) to protocol treatment will be considered. The rates of ≥ grade 3 acute and late AEs (specifically, dry mouth, dysphagia, skin, and all) 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 groups. A 2-sided van Elteren's test with α = 0.05 will be used to test whether the distribution of the Functional Assessment of Cancer Therapy-Head & Neck [FACT-H&N] and University of Michigan Xerostomia-Related Quality of Life Scale [XeQOLS] at 3, 12, and 24 months from start of RT scores is the same in the treatment arms. Van Elteren's test is an extension of the stratified Wilcoxon rank-sum test. It will be obtained from the generalized Cochran-MantelHaenszel (CMH) test for mean difference using the standardized midranks (also known the modified ridit scores) [Stokes 1995].  
13.7.2 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. In general, these reports will contain information about the accrual rate with projected completion date for the accrual phase, exclusion rates and reasons, pretreatment characteristics of patients accrued, compliance rate of treatment delivered with respect to the protocol prescription, and the frequency and severity of adverse events. 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. After this study has been opened 1.5 years, the study design assumptions made about percentage of HPV+ oropharyngeal patients entered on 0920 will be checked semiannually. If the observed frequency of HPV+ patients is greater by at least 10% than the projected frequency of 20%, the implication of this increased frequency will be assessed in terms of when the projected final (definitive) treatment analysis will be performed. If timing of that analysis is lengthened by more than a year, a recommendation of increasing the sample size will be explored.  
13.7.3 Significance Testing for Early Termination and *Reporting* Three interim treatment comparisons will be performed when the following are observed: 25%
(93 deaths), 50% (186 deaths), and 75% (279 deaths) of the 372 required number of deaths. Only the primary endpoint of survival will be tested in the interim analysis. The efficacy will be tested using Haybittle-Peto boundaries of 0.005 for interim tests and 0.0183 for final analysis to preserve an overall alpha level of 0.025 for the study. The futility will be tested using the lower boundary based on testing the alternative hypothesis at 0.005 level. The results will be reported to the NRG Oncology DMC with the treatment blinded.  
| Interim Test   | Number of Events   | p-value for Efficacy   | p-value for Futility   |
|----------------|--------------------|------------------------|------------------------|
| 1              | 93                 |  0.005                | < 0.005                |
| 2              | 186                |  0.005                | < 0.005                |
| 3              | 279                | ≤ 0.005                | < 0.005                |
| Final          | 372                |  0.0183               | N/A                    |
| Analysis       |                    |                        |                        |  
At each planned interim analysis, the results from the test for assessing treatment efficacy and futility will be reported to the NRG Oncology DMC. The responsible statistician may recommend early reporting of the results and/or stopping accrual (if applicable) of the trial if the treatment effect, with respect to OS, is highly significant or if it is not likely to be; that is, if the pvalue is less than the nominal value specified in a sequential design for either efficacy or futility.  
Before making such a recommendation, the accrual rate, treatment compliance, safety of the treatments, and the importance of the study also are taken into consideration with the p-value. The DMC will then make a recommendation about the trial to the NRG Oncology Group Chair.  
13.7.4 *First Special Interim Analysis of Local Regional Control (LRC) in IMRT Treated Patients* The interim analysis will be performed on the first 70 patients assigned to the radiation alone arm and for whom the participating institution does not elect to treat with IMRT and IGRT. It will occur after these 70 patients have been potentially followed for 1 year. The 1-year rate for LRC will be computed, and if it is less than 80%, the patient accrual to 0920 will be suspended. The NRG Oncology Data Monitoring Committee will review the results from the analysis as soon as possible and make a recommendation about the study's future disposition (e.g., discontinuation of further patient entries) to the NRG Oncology Group Chair who, in turn, will act upon that recommendation. The analysis will include pretreatment characteristics of this patient cohort.  
13.7.5 Second Interim Analysis of Local Regional Control (LRC) in IMRT Treated *Patients* The interim analysis will be performed on the first 70 patients assigned to the radiation alone arm and for whom the participating institution does not elect to treat with IMRT and IGRT It will occur after these 70 patients have been potentially followed for 2 years. The 2-year rate for LRC will be computed, and if it is less than 70%, the patient accrual to 0920 will be suspended.  
The NRG Oncology Data Monitoring Committee will review the results from the analysis as soon as possible and make a recommendation about the study's future disposition (e.g.,
discontinuation of further patient entries) to the NRG Oncology Group Chair who, in turn, will act upon that recommendation. The analysis will include pretreatment characteristics of this patient cohort.  
13.7.6 Analysis for Reporting the Initial Cetuximab Treatment Results *First* The analysis reporting these treatment results will be carried out as described in Section 13.7.7. Only eligible patients with both on-study and follow-up information will be included in the primary treatment analysis. The usual components of this analysis are:
- Tabulation of all cases entered and any excluded from analysis with reasons for exclusion;
- Patient accrual rate; - Institutional accrual; - Distribution of important baseline prognostic variables;
- Frequency and severity of adverse events;
- Observed results with respect to the endpoints described in Section 13.1.  
The difference in OS between the control arm and the experimental arm will be tested using the stratified one-side log-rank test at the significance level of 0.0183 given that the 3 interim analyses are carried out and show no statistical significance. The stratification will be done by EGFR level (high vs. low vs. not evaluable) and primary site/HPV status (oropharyngeal HPV
positive vs. oropharyngeal HPV negative/oral cavity/larynx vs. not evaluable) [See Section 13.5.1]. The differences in DFS times between the treatment arms will be tested with the onesided, stratified log rank test as described above at the 0.025 significance level given no interim analysis. Differences in LRC will be tested as described in Section 13.5.1. A subset analysis using only HPV- patients will compare the protocol treatment arms with respect to the primary and all the secondary endpoints (Section 13.2.1). In addition, subset analyses using patients treated with each radiation technique (IMRT alone vs. IMRT+ IGRT)
will compare the protocol treatment arms with respect to the secondary endpoints of adverse events (Sections 13.1.2.1-13.1.2.3).  
13.7.7 *Time-Driven Definitive Analysis:*
The statistical analysis plan changes were done in accordance with the NCI Policy for Major Design Amendments for Ongoing Randomized Clinical Trials. The specifics for the changes were performed by a statistician independent from the trial. Due to a lower than expected event rate for the primary endpoint, overall survival (OS), throughout the trial (the trial will not reach the third interim analysis for possibly three more years), the primary endpoint analysis will be performed with the number of OS events reported through June 1, 2023 (or completion of this amendment, whichever is later). The proposed date allows for a minimum of 5 years of potential follow-up on all randomized patients. The primary endpoint analysis will use a one-sided alpha of 0.0183 as specified in the initial design (see first paragraph in Section 13.7.2). The original study design called for randomization of 634 patients
(increased to 700 to allow for ineligibility and dropouts), which was projected to yield 372 events, providing 80% power to detect a hazard ratio (HR) of 0.74, based on a one-sided, three interim analyses, and stratified logrank test at the overall 0.025 alpha level.  
Analysis of OS in the control arm using data as of 3/15/2023 yields estimated 5- and 10-year survival rates of 69% and 57%, respectively, with a total of 95 observed events (deaths) among 287 patients. The number of observed events in years 5, 6, 7, 8, and 9 post-randomization was 10, 1, 1, 3, 3, and 3, respectively. With an additional 3 months of follow-up received to June 1, we therefore expect to see only about 1-2 additional deaths in the control arm, and thus assume there will be 97 control deaths and 97*.74=72 experimental arm deaths, or 169, by this time.  
Projected # of OS events in  
both arms by 6/1/2023  
HR Power  
(1-sided alpha of 0.0183)  
169 0.74 45%  
169 0.71 55%  
169 0.68 66% 169 0.64 79%  
Thus, there will be 45% power to detect the original assumed HR of 0.74. With 79% power, a true HR of 0.64 can be detected. Note that this revised analysis plan was developed independent of any information from accruing data other than the current control group event  
rate.  
The table below gives the power to detect an HR of 0.74 based on 169 events, as well as the HR that can be detected with 169 events at powers of 55%, 66%, and 79%.  
13.7.8 Analysis for Reporting the Results with Addition of IGRT to *IMRT*
The analysis of RT delivery technique (IMRT vs. IMRT with IGRT) will be done at same time as the initial cetuximab treatment analysis. Its results probably will be considered exploratory since the patients were randomized to the RT delivery technique. They will be reported separately from the cetuximab results. Only eligible patients who started IMRT and with follow-up information will be included in this analysis. The components of this analysis are:
- Tabulation of all cases entered and any excluded from analysis with reasons for exclusion by RT techniques;
- Distribution of important baseline prognostic variables and protocol treatment assignment by RT techniques;
- Frequency and severity of adverse events by RT techniques.  
The estimate for IGRT effect on LRC will be derived from a Cox model with other factors added to correct for possible serious imbalance in their distributions between the techniques. The estimate for IGRT effect on the XeQOLS and the FACT respectively will be derived from multivariate regression models with other factors added to correct for possible serious imbalance in their distributions between the two treatment technique patient groups. These imbalances are possible since patients are not randomized between IMRT and IMRT+ IGRT.  
The other factors include cetuximab treatment, tumor site, stage, patient age, pretreatment performance status, and type and extent of surgery performed prior to IMRT, These results will be viewed as hypothesis generating, not as definitively testing the addition of IGRT.  
13.7.9 Analysis for Reporting PRO *Data* The analysis for hypotheses 1 and 3-6 in Section 13.2.4 will be done following the analyses of cetuximab treatment and the RT delivery techniques. The analysis of hypothesis 2 will be done as part of RT delivery technique analysis (Section 13.5.5) The results from these analyses will be considered exploratory, since the patient's participation was strictly voluntary for each PRO
assessment. The results probably will be reported separately from the cetuximab treatment results. Only eligible patients with follow-up information will be included in these analyses.  
13.7.10 Analysis for Reporting Tumor *Markers* The analysis for the hypotheses for various tumor markers in Section 13.2.3 will be done following the analyses of cetuximab treatment and the RT delivery techniques. The results will be reported separately. Only eligible patients with both on-study and follow-up information will be included in these analyses.
13.8 Gender and **Minorities**
Men and women of all races and ethnic groups are eligible for this study.  
In conformance with the National Institutes of Health Revitalization Act of 1993 with regard to inclusion of women and minorities in clinical research, we have considered the possible interactions (treatment by race and treatment by gender). The study was designed under the assumption of the same results between the gender and among the races. Based on accrual to RTOG's previous protocol, RTOG 0234, we project that 78% of patients enrolled on this study will be male, 90% white, and 4% Hispanic. The following table provides the projected number of patients in each race, ethnicity, and gender group.  
| Projected Distribution of Gender and Minorities Gender   |         |       |       |
|----------------------------------------------------------|---------|-------|-------|
| Ethnic Category                                          | Females | Males | Total |
| Hispanic or Latino                                       | 4       | 15    | 19    |
| Not Hispanic or Latino                                   | 172     | 509   | 681   |
| Ethnic Category: Total of all subjects                   | 176     | 524   | 700   |
| Racial Category American Indian or Alaskan Native        | 0       | 3     | 3     |
| Asian                                                    | 3       | 7     | 10    |
| Black or African American                                | 3       | 30    | 33    |
| Native Hawaiian or other Pacific Islander                | 0       | 0     | 0     |
| White                                                    | 170     | 484   | 654   |
| Racial Category: Total of all subjects                   | 176     | 524   | 700   |
eligibility checklist - step 2
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eligibility checklist - step 2
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