eligibility checklist -step 2 (10/17/13)
5.5 regulatory pre-registration requirements (6/3/14)

Prior to the recruitment of a patient for this study, investigators must be registered members of a lead protocol organization. Each investigator must have an NCI investigator number and must maintain an "active" investigator registration status through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms are available on the CTSU registered member web site http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. For questions, please contact the CTEP Investigator Registration Help Desk by e-mail at pmbregpend@ctep.nci.nih.gov. The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored clinical trials).Associates will use the CTEP-IAM application to register (both initial registration and annual re-registration) with CTEP and to obtain a user account. Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator Registration Procedures above for information on registering with CTEP as an Investigator, which must be completed before a CTEP-IAM account can be requested.) An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications, including the CTSU members' web site. Additional information can be found on the CTEP web site at http://ctep.cancer.gov/branches/pmb/associate_registration.htm. For questions, please contact the CTEP Associate Registration Help Desk by email at ctepreghelp@ctep.nci.nih.gov . Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll patients. Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU member web site by entering credentials at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically load to RSS.  
Site registration forms may be downloaded from the RTOG 1016 protocol page located on the CTSU members' web site. Go to https://www.ctsu.org and log in to the members' area using your CTEP-IAM username and password Click on the Protocols tab in the upper left of your screen Click on the (state organization type e.g. P2C, CITN, NCTN Groupname) link to expand, then select trial protocol, RTOG 1016 Click on the Site Registration Documents link Requirements for RTOG 1016 site registration:
CTSU IRB Certification (for sites not participating via the NCI CIRB);
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI CIRB);
CTSU RT Facilities Inventory Form (if applicable);
IRB/REB approval letter IRB/REB approved consent (English and native language versions*)
*Note: Institutions must provide certification of consent translation to NRG Oncology IRB/REB assurance number renewal information, as appropriate
Non-English Speaking Canadian and Non-North American Institutions:
*Translation of documents is critical. The institution is responsible for all translation costs. All regulatory documents, including the IRB/REB approved consent, must be provided in English and in the native language. Certification of the translation is optimal but due to the prohibitive costs involved NRG Oncology will accept, at a minimum, a verified translation. A verified translation consists of the actual REB approved consent document in English and in the native language, along with a cover letter on organizational/letterhead stationery that includes the professional title, credentials, and signature of the translator as well as signed documentation of the review and verification of the translation by a neutral third party. The professional title and credentials of the neutral third party translator must be specified as well.  
Submit completed forms along with a copy of your IRB Approval and Informed Consent to the CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA 19103 Phone: 1-866-651-2878 Fax: 215-569-0206 E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) Check the status of your site's registration packets by querying the RSS site registration status page of the members' section of the CTSU web site. (Note: Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.)
Go to https://www.ctsu.org and log in to the members' area using your CTEP-IAM
username and password Click on the Regulatory tab at the top of your screen Click on the Site Registration tab Enter your 5-character CTEP Institution Code and click on Go
eligibility checklist -step 2 (10/17/13)
5.5.2 pre-registration requirements for canadian

to the requirements above, Canadian institutions must electronically complete (versus hand write) a Study Agent Shipment Form (SASF) available on the NRG Oncology/RTOG web site, www.rtog.org, under protocol-specific materials/Canadian resources. Canadian institutions must fax the SASF to the CTSU Regulatory Office (Fax 215-569-0206) as soon as the individual responsible for the study agent has been identified Prior to clinical trial commencement, Canadian institutions must complete and fax (215-5690206) or e-mail (CTSURegulatory@ctsu.coccg.org) the following forms to the CTSU Regulatory Office Health Canada's Therapeutic Products Directorates:
Clinical Trial Site Information Form Qualified Investigator Undertaking Form Research Ethics Board Attestation Form 5.5.3 Pre-Registration Requirements FOR NON-CANADIAN INTERNATIONAL INSTITUTIONS
*For institutions that do not have an approved LOI for this protocol:*
International sites must receive written approval of submitted LOI forms from NRG Oncology prior to submitting documents to their local ethics committee for approval. See http://www.rtog.org/pdf_forms.html?members/forms=Intl_LOI_Form.doc
*For institutions that have an approved LOI for this protocol:*
All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling patients to this study.
eligibility checklist -step 2 (10/17/13)
5.6 registration for use of

Prior to registration of the institution's first case, participating institutions must register into the CASI system for access to computer software and hardware (iPAD) for administration of the following: 1) the mandatory smoking survey for all participants; the optional QOL Patient-Reported Outcomes assessments (QOL component closed 2/28/13);
2) the optional head and neck cancer risk factor survey; 3) and the optional baseline demographic Work Status Questionnaire. Note: Institutions must have site IRB approval and have completed all pre-registration requirements before registering into the CASI system. Guidelines for registering into the CASI system and getting a clinical research associate (CRA) user account are available on the NRG Oncology/RTOG web site, www.rtog.org, on the 1016 protocol page, under "Miscellaneous". When the CRA user account is established, an "iPAD and CASI Survey User Manual", which provides detailed instructions, will be automatically be e-mailed to the institution. Institutions should e-mail questions or requests for further information to RTOG1016@osumc.edu 5.6.2 Access to Institution's Local WiFi Network Prior to registration of the institution's first case, participating institutions should gain access or confirm access to their local WiFi network. Sites will need the name of their local network, user name and password for the local network, and an IT contact at the institution who will assist with setting up network access on the iPAD.  
5.7 Registration 5.7.1 Two Step Registration **(6/3/14)**
All patients must consent to submission of tissue to the NRG Oncology Biospecimen Bank for p16 analysis.  
Institutions must complete the Eligibility Checklist at Step 1 registration.  
The patient must complete the smoking history survey on the iPAD following Step 1 registration.  
The patient has the option of completing the entire head and neck risk factor survey via the computer-assisted self-interview (CASI) following Step 1 registration.  
The patient has the option of completing the baseline demographic Work Status Questionnaire on the iPAD following Step 1 registration.  
Institutions will submit the patient's tissue to the Biospecimen Resource using the case number obtained from Step 1 registration (see Section 10.2 for details of submission).  
The results of the p16 analysis are expected in approximately 5 business days, and NRG
Oncology will inform sites by e-mail of the completion of the HPV analysis. At this point, institutions must complete Step 2 registration, and the patient can be randomized.  
5.7.2 OPEN Registration Instructions **(6/3/14)**
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have been met, and the study site is listed as 'approved' in the CTSU RSS. Patients must have signed and dated all applicable consents and authorization forms. All site staff will use OPEN to enroll patients to this study. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members' web site, https://www.ctsu.org.  
Prior to accessing OPEN site staff should verify the following:
All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the registration forms provided on the group or CTSU web site as a tool to verify eligibility.  
All patients have signed an appropriate consent form and HIPPA authorization form (if applicable).  
Access requirements for OPEN:
See Section 5.0 for obtaining a CTEP-IAM account. To perform registrations, the site user must have been assigned the 'Registrar' role on the relevant Group or CTSU roster.  
To perform registrations on protocols for which you are a member of NRG Oncology, you must have an equivalent 'Registrar' role on the NRG Oncology roster. Role assignments are handled through the Groups in which you are a member.  
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead Group registrations) you must have the role of Registrar on the CTSU roster. Site and/or Data Administrators can manage CTSU roster roles via the new Site Roles maintenance feature under RSS on the CTSU members' web site. This will allow them to assign staff the "Registrar" role.  
The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records.  
Further instructional information is provided on the CTSU members' web site OPEN tab or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-8235923 or ctsucontact@westat.com.  
In the event that the OPEN system is not accessible, participating sites can contact web support for assistance with web registration: websupport@acr.org or call the Registration Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax in the eligibility checklist and will need the registering individual's e-mail address and/or return fax number. This information is required to assure that mechanisms usually triggered by the OPEN web registration system (e.g. drug shipment and confirmation of registration) will occur.
eligibility checklist -step 2 (10/17/13)
6.0 radiation therapy (10/17/13)

Note: This trial is not utilizing the services of the ITC for dosimetry digital treatment data submission. See Section 5.4 for information on installing TRIAD for submission of digital RT data prior to enrolling patients. NOTE: FOR THIS STUDY, IMRT IS MANDATORY. Use of IGRT and IGRT credentialing is MANDATORY when using PTV margins < 5 mm.  
Protocol treatment must begin within 2 weeks after Step 2 registration.  
6.1 Dose Specifications (6/25/13)
It is recognized that the total doses to subclinical sites have crept higher over the last decade as dosepainting simultaneous integrated boost (SIB) techniques have evolved. In this trial, dose will be slightly reduced to low risk subclinical sites (50-52.5 Gy IMRT or 44 Gy low neck anterior field) in an effort to effect a potentially modest impact in late toxicity to soft tissue and bone. IMRT will be delivered in 35 fractions over 6 weeks, 6 fractions weekly (typically, with 2 fractions one day per week at least 6 hours apart) in one plan (SIB). Concomitant boost using separate IMRT plans is not allowed. Missed treatments due to holidays or logistic reasons can be compensated for by delivering an additional BID treatment during the week, OR treating on the Saturday or Sunday of that week, OR adding to the end of treatment. 6.1.1 The primary tumor and involved nodes (CTV1) will typically consist of a 0.5-1.5 cm expansion of the gross tumor volume (GTV) to cover potential local invasion and will be prescribed 2 Gy/fraction, total 70 Gy (see Section 6.1.3 for details of prescription for PTV1). High-risk sub-clinical disease sites, which include possible local subclinical infiltration at the primary site (primary site CTV2) and first echelon nodes, which are not clinically or radiographically involved (nodal CTV2), should be expanded by 3-5 mm to create PTV2. PTV2 should receive 1.6 Gy/fraction to a total dose of 56 Gy. (This dose assumes an alpha/beta ratio of 10 Gy for tumor and 0.7 Gy loss for each day of extending treatment time beyond the time required to deliver the dose at 2 Gy/fraction; 56/1.6 over 6 weeks would result in BED2 of approximately 52 Gy). Lower-risk targets (PTV3) (such as neck nodal levels which are not first echelon nodes and are not adjacent to levels containing grossly involved nodes) will be prescribed 50-52.5 Gy (at 1.431.5 Gy/fraction, BED2 = approximately 40-45 Gy).  
6.1.2 Treatment of the low neck: see details in Section 6.5.1. If the low neck is treated, the preferred technique is to treat with isocentric matching AP or AP-PA fields with larynx block, matched to the IMRT portals just above the arytenoids. The dose will be 2 Gy per fraction prescribed to 3 cm depth to a total dose of 44 Gy in 22 daily fractions. Whole-neck IMRT is allowed. Involved low neck nodes will receive total 60 Gy in 30 fractions. This can be achieved by either boosting the low neck field with an additional 16 Gy in 8 fractions, by an AP or AP-PA fields, or by planning the whole neck using IMRT. In cases of gross involvement of the vallecula or low neck, whole-neck IMRT should be considered. Whole-neck IMRT may also be considered if level VI is considered to be at risk due to gross involvement of level IV nodes.  
6.1.3 All plans must be normalized such that 95% of the volume of the PTV1 is covered with prescription dose of 70 Gy. Additionally:
At 1 cc PTV1 volume on the DVH curve, the dose should not be > 110% of the prescribed dose.  
At a volume of 0.03 cc within the PTV1 volume on the DVH curve, the dose should not be
< 95% of the prescribed dose.  
For any volume of tissue outside the PTVs that has a size of 1 cc, the dose should not be
> 74 Gy.
eligibility checklist -step 2 (10/17/13)
6.2 technical factors

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 for previous NRG Oncology trials is acceptable.  
6.2.2 Image Guidance for IGRT When Using Reduced Margins (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 helical conebeam CT images; Linear-accelerator mounted MV CT images (e.g., Tomotherapy);
Other mechanism, after discussion with the Co-Principal Investigator, Andy Trotti, MD,
and the Medical Physics Co-chair, Søren Bentzen, PhD.  
The institution's procedure for registering daily treatment imaging datasets with a 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. However, the use of numerous repeat IGRT studies should be avoided (see next section).
eligibility checklist -step 2 (10/17/13)
management of radiation dose to

Estimates of patient doses per imaging study for various imaging systems vary considerably.  
The doses are in the range of 1 mGy for Cyberknife's and BrainLab's ExacTrac planar kVsystems. The doses from helical MV CT scan on a tomotherapy unit were estimated to be in the range of 1 to 3 cGy for head and neck studies, similar to doses reported for kV cone beam CT on the Elekta Synergy machine. The doses for MV cone beam CT are in the range of 10 cGy for a pelvis study to 6 cGy for a head and neck study. Thus, the doses for 3D
imaging systems are in the range from 1 to 6 cGy for head and neck imaging and can contribute from 0.5 to 3% to the daily dose of 2.0 Gy. These dose estimates apply to a single imaging procedure, and the 2 cGy dose is used as a typical fraction size for comparison purposes within the treated region. It is important to point out that the imaging dose typically covers parts of the patient's anatomy that are outside the high-dose region that is treated therapeutically, and that it is sometimes necessary to repeat the procedure a number of times during, before, or after a single fraction delivery. The imaging dose to nearby critical structures may become significant when repeated IGRT procedures are performed 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 Treatment Planning/Target Volumes (6/25/13)
6.4.1 Definition of Target Volumes: See Section 6.1.1.  
*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 if it is judged clinically that the skin is at risk but is generally not recommended.  
PTV expansion w**ithout** credentialing for daily IGRT: For those institutions that are not using daily IGRT (see Section 6.2.2) specifically for margin reduction, the minimum CTV-to-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-toPTV expansion (without IGRT) should not exceed 10 mm.  
PTV expansion with credentialing for daily IGRT: For those institutions that are using daily IGRT (see Section 6.2.2) for margin reduction, the minimum CTV-to-PTV expansion is 3.0 mm (a larger expansion may be necessary for a target volume subject to significant intrafraction variability, such as the non-immobilized oral tongue).In general, the CTV-to-PTV
expansion (with IGRT) should not exceed 5 mm.  
6.4.2 Definition of Normal Tissues/Organs at Risk (OARs): NOTE: Only the parts of the normal tissues/organs at risk outside the PTVs will be considered for dose optimization purposes.  
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 self explanatory. 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.  
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan.  
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).  
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): 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.  
*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.  
6.4.3 In cases of weight loss > 10% or significant shrinkage of lymphadenopathy during therapy, it is recommended that the immobilization mask will be adjusted or re-made in order to preserve adequate immobilization, and that a repeated simulation CT be performed to assess the dose distributions in the current anatomy. Whether or not a new IMRT plan will be generated is at the discretion of the treating physician. If a new plan is made, the targets should be the same as those used for the initial plan. The new CT dataset should be used for IGRT image registration when the patient's shape changes significantly.  
6.5 Treatment Planning and Delivery 6.5.1 Management of the Low Neck/Supraclavicular Region (Match versus No Match) It is recognized that comprehensive head and neck irradiation incorporating IMRT can be done in several ways, any of which is permitted for this study. Patient-specific QA measurements are required for all IMRT treatments. When a field "match" technique is used for treating the lower neck, patient-specific measurements should include a verification of the dose coverage in the gap region for each patient 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. Matching 2 IMRT plans is allowed.  
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.  
6.5.2 IMRT Dose Prescription to PTVs See Sections 6.1 and 6.4 for definitions of CTVs and PTVs and their prescribed doses. The goal is for 95% of the PTV70 to receive ≥ 2 Gy with a minimum dose (cold spot) of no less than 66.5 Gy. It is recognized that portions of the PTV70 close to the skin may receive significantly less than 66.5 Gy. This is acceptable as long as cold spots within PTV1 do not exist at a depth deeper than 8 mm beneath the skin (see Section 6.8, compliance criteria).
For planning prioritization and priorities in dose coverage, in the final plan, PTV1 will be the highest priority target structure. PTV2 and PTV3, if applicable, will be ranked in the IMRT planning as lower priority than PTV1m although usually at a higher priority than normal structures other than spinal cord and brain stem.  
6.5.3 Doses to Normal Structures **(6/28/12)**
Spinal Cord: The PRVcord (as defined in Section 6.4) should not exceed ≤ 50 Gy to any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the spinal cord PRV should be given the highest priority.  
Brainstem: The PRVbrainstem (as defined in Section 6.4) 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.  
*Oral Cavity:* Reduce the dose as much as possible. The mean dose should be < 30 Gy for the non-involved oral cavity. Efforts should also be made to avoid hot spots (> 60 Gy) within the non-involved oral cavity.  
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. Taking into account new data suggesting monotonous improvement in saliva as dose is reduced, without a threshold (Dijkema 2010), the objective will be to reduce the mean doses to both parotid glands as much as possible.  
Contralateral submandibular gland: If contralateral level I is not a target, aim to reduce mean contralateral submandibular gland to < 39 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. Some recommended (but treatment goals include: Mean dose < 30 Gy.  
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. The glottic larynx mean dose is recommended to be <20 Gy. If whole-neck IMRT is used, , underdosage of PTV2/PTV3 adjacent to the glottic larynx will be limited to <10% receiving < 95%
prescribed dose (this under-dosage is similar to that caused by the laryngeal block inserted in the split-field IMRT; Webster 2009).  
Mandible: Reduce the dose as much as possible. 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: No more than 1cc of unspecified tissue outside the targets can receive 74 Gy or more.  
6.5.4 Prioritization for IMRT Planning 1. Spinal Cord 2. Brainstem 3. PTV1 4. PTV2(if applicable) 5. PTV3 (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
eligibility checklist -step 2 (10/17/13)
6.6 critical structures (7/16/14)

Note: All required structures must be labeled as listed in the table below for digital RT data submission. Resubmission of data may be required if labeling of structures does not conform to
eligibility checklist -step 2 (10/17/13)
the standard dicom name listed.

The following table outlines the naming of the various normal and critical structures for submission to TRIAD.  
Standard Name Description GTV Primary tumor and involved nodes  
Required  
CTV_7000 Primary tumor and involved nodes  
Required  
PTV_7000 CTV to PTV expansion should be 5 mm minimal margin  
without IGRT; 3 mm minimal margin with Daily IGRT  
49 RTOG 1016, Version Date: 2/23/16  
| Required      |                                                                                                                                          |
|---------------|------------------------------------------------------------------------------------------------------------------------------------------|
| CTV_5600      | First Echelon nodal regions  Required when applicable                                                                                    |
| PTV_5600      | CTV to PTV expansion should be 5 mm minimal margin  without IGRT; 3 mm minimal margin with Daily IGRT  Required when applicable          |
| CTV_5000      | Lower risk nodal regions  Required when applicable                                                                                       |
| PTV_5000      | CTV to PTV expansion should be 5 mm minimal margin  without IGRT; 3 mm minimal margin with Daily IGRT  Required when applicable          |
| CTV_5250      | Lower risk nodal regions  Required when applicable                                                                                       |
| PTV_5250      | CTV to PTV expansion should be 5 mm minimal margin  without IGRT; 3 mm minimal margin with Daily IGRT  Required when applicable          |
| 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  Optional                                                                                                                    |
| Lips          | Lips  Optional                                                                                                                           |
| Mandible      | Mandible  Optional                                                                                                                       |
| Pharynx       | Uninvolved posterior pharyngeal wall plus adjacent constrictor  muscles; should not include PTVs  Optional                               |
| Esophagus     | Cervical Esophagus  Optional                                                                                                             |
| Larynx        | Glottic/Supraglottic Larynx  Optional                                                                                                    |
| External      | External border of patient used to define Unspecified Tissue  Required                                                                   |
| PTV_7000_8mm  | Minimum dose(cold spot within PTV1 not including portion of  PTV near (<8mm) skin) defined for a point that is 0.03cc in  size  Required |
| NonPTV_7000   | Maximum dose (hot spot > 1cc outside the PTVs)  Required                                                                                 |
| 6.7           | Documentation Requirements for IMRT Approach (10/17/13)                                                                                  |  
6.7 Documentation Requirements for IMRT Approach (10/17/13)
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; 6.8 Compliance Criteria (6/28/12)
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 5 treatment days at a time and 10 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 2 treatment days for reasons other than toxicity/illness will be considered a protocol deviation.  
All treatment plans are to be normalized to provide exactly 95% volume coverage of the PTV1 with 70 Gy.  
| Per Protocol                                                                                                                                        | Variation                                                                                   | Deviation                                                            |                                                                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|----------------------------------------------------------------------|------------------------------------------------------------------------|
| Acceptable                                                                                                                                          | Unacceptable                                                                                |                                                                      |                                                                        |
| Total RT dose to PTV1 (to 95%                                                                                                                       | 70 Gy                                                                                       | None                                                                 | None                                                                   |
| of the PTV)  Minimum dose ("cold spot"  within PTV1, not including  portion of PTV near (<8 mm)  skin) defined for a point that is  0.03 cc in size | 66.5 Gy (equals 95% of                                                                      | < 66.5 but > 63 Gy                                                   | ≤ 63 Gy                                                                |
| prescribed dose)                                                                                                                                    |                                                                                             |                                                                      |                                                                        |
| Maximum dose ("hot spot" >                                                                                                                          | ≤ 77 Gy                                                                                     | > 77 but ≤ 82 Gy                                                     | > 82 Gy                                                                |
| 1cc) within PTV1  Maximum dose ("hot spot" >                                                                                                        | < 74 Gy                                                                                     | 74-77 Gy                                                             | > 77 Gy                                                                |
| 1cc outside the PTVs)  Total dose to PTV2 (to 95% of                                                                                                | 56 Gy                                                                                       | ≥ 45 but < 56 Gy                                                     | < 45 Gy                                                                |
| the PTV)  Total dose to PTV3 (to 95% of                                                                                                             | 50-52.5 Gy                                                                                  | ≥ 40 but < 50 Gy                                                     | < 40 Gy                                                                |
| the PTV)  Total RT dose to spinal cord                                                                                                              | ≤ 50 Gy                                                                                     | ≥ 50 but ≤ 52 Gy                                                     | > 52 Gy                                                                |
| PRV (0.03 cc)  Definition of Spinal cord PRV                                                                                                        | Based on case review by Co-Principal Investigator, Dr. Trotti or other  designated reviewer |                                                                      |                                                                        |
| Overall RT treatment time                                                                                                                           | < 45 days                                                                                   | 46-50 days (without  a medically  appropriate  indication for delay) | > 50 days  (without a  medically  appropriate  indication for  delay). |
| Non-Medically Indicated                                                                                                                             | 0-2                                                                                         | 2-4                                                                  | > 4                                                                    |
| Treatment Interruptions                                                                                                                             |                                                                                             |                                                                      |                                                                        |
eligibility checklist -step 2 (10/17/13)
6.9 r.t. quality assurance reviews

The Co-Principal Investigator, Andy Trotti, MD, the Radiation Oncology Co-Chairs, Avraham Eisbruch, MD, and Paul Harari, MD, and the designated Radiation Oncology reviewers, Min Yao, MD, and James Caudell, MD, will perform RT Quality Assurance Reviews. These reviews will be ongoing. RT Quality Assurance reviews will be facilitated by IROC Philadelphia.  
Use of H&N IMRT (and associated QA) was begun in 2005 in RTOG 0522, as an optional technique. At the close of the accrual phase, approximately 90% of cases enrolled on 0522 (> 800 patients) were treated with IMRT. Oropharynx cases comprised 70% of the study population. IMRT has been a standard of care in the U.S. beginning in 2005 and is now widely used in practice. Analysis of the contouring scores and dose plans from RTOG 0522 will be performed in 2011, after completion of final reviews and reporting of the primary trial analysis. RTOG 1016-specific educational materials regarding contouring and treatment planning of tonsil and base of tongue cases will be offered at NRG Oncology semi-annual meetings and online.
eligibility checklist -step 2 (10/17/13)
6.10 radiation therapy adverse events

Grade 3-4 (CTCAE, v. 4) therapy-induced mucositis and/or dysphagia, which are enhanced by cisplatin, are expected to develop in about two thirds of patients. Nutritional evaluation prior to the initiation of therapy for a prophylactic gastrostomy (PEG) tube placement is highly recommended. Placement of a feeding tube should be recorded, 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).
eligibility checklist -step 2 (10/17/13)
6.11 radiation therapy adverse event

7.1 Treatment 7.1.1 Arm 1: Cisplatin with Concurrent Radiation Therapy (RT) **(12/4/12)**
Patients will receive cisplatin, 100 mg/m2, administered intravenously on days 1 and 22 of the treatment course (Note: cisplatin given within 24 hours of days 1 and 22 due to holidays, for example, is acceptable). Weekends count as days. Use the actual body weight for all patients. There should be no dose modifications because of obesity.  
Cisplatin can be given either before or after the radiation therapy fraction that is given on the same day. If radiation is held for more than 2 days (for any reason), cisplatin may be held as well until radiation resumes.  
High dose cisplatin is a highly emetogenic regimen with significant incidence of delayed nausea and vomiting. Institutional guidelines for highly emetogenic regimens should be followed. In the absence of such guidelines:
For acute nausea and vomiting, premedication should include a 5-HT3 antagonist, such as granisetron 1 mg iv; ondansetron, up to 16 mg iv; or palonosetron, 0.25 mg iv; plus a corticosteroid, such as dexamethasone, up to 20 mg iv. Palonosetron has a longer half life (40h) than the first generation 5HT3 antagonists.  
Breakthrough nausea and vomiting should be managed at the discretion of the medical oncologist or radiation oncologist. Delayed nausea and vomiting (greater than 24 hours after chemotherapy administration) may be managed by the addition of aprepitant concurrently or with metoclopramide and dexamethasone. Potential delayed nausea regimens include:
1. The NK-1 antagonist, aprepitant (125 mg p.o.), may be added for prevention of delayed emesis on the day of cisplatin administration and for two consecutive days thereafter (80, 80), with a corticosteroid, such as dexamethasone on days 1-4. Fosaprepitant 115 mg iv may be substituted for the aprepitant 125 mg on day 1. Dexamethasone should be reduced on day 1 to 12 mg and delivered at up to 8 mg total daily for the 3 days following cisplatin administration. A 5HT3 antagonist (e.g. granisetron, ondansetron) may be also given for the 3 days following cisplatin administration, only if palonosetron was not given prior to chemotherapy.  
2. Delayed emesis also may be managed by the addition of dexamethasone 8 mg bid x 2 days, followed by dexamethasone 4mg bid x 2 days, beginning on the day after chemotherapy; and oral metoclopramide 0.5 mg/kg (usually 20-40 mg) qid x 2-4 days. A 5HT3 antagonist (e.g. granisetron, ondansetron) may also be given for up to 3 days after cisplatin administration, only if palonosetron was not given prior to chemotherapy.  
Patients must receive vigorous hydration and diuresis. A suggested regimen is prehydration with a 1 liter of D5N S over 2-4 hours and mannitol, 12.5g iv bolus immediately prior to cisplatin. Then cisplatin, 100 mg/m2, in 500-1000 ml NS is administered over 1-2 hours followed by an additional 1 to 1.5 liters of fluid. Any pre-existing dehydration must be corrected prior to cisplatin administration. Should extravasation occur, the treating physician should follow institutional guidelines for management.  
Overnight hospitalization for hydration after cisplatin should be considered if it is allowed by the patient's insurance company. Additional iv hydration and BUN/creatinine check also should be considered, if necessary, later in the week after cisplatin administration, in order to address any dehydration or severe fluid/electrolyte imbalance.  
7.1.2 Arm 2: Cetuximab with Concurrent Radiation Therapy (RT) **(12/4/12)**
Cetuximab Initial Dose (prior to RT): Patients on Arm 2 will receive an initial dose of cetuximab, 400 mg/m2, intravenously (iv) over 120 minutes. No radiation will be given this day, and the 400 mg/m2 initial dose of cetuximab will precede the first 250 mg/m2 dose of cetuximab and the first radiation treatment by at least 5, but no more than 7, 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.  
Use the actual body weight, even if the BSA is > 2.0. The cetuximab dose always will be calculated using the actual body weight.  
Cetuximab Weeks 2-8 (concurrent with RT and for 1 week after RT): Patients on Arm 2 will receive cetuximab, 250 mg/m2, intravenously (iv) 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 for a total of 6 doses concurrent with radiation therapy and for one additional dose after RT completed. Note: Patients receive a total of 8 doses of cetuximab over 8 weeks, including the initial loading dose, 6 doses concurrent with radiation therapy, and 1 additional dose postcompletion of radiation therapy. If a dose of cetuximab is omitted, it will not be made up or added to the end of treatment. The omitted dose and the reason for the omission should be recorded in the site's source documentation.  
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 iv 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 iv. 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 Section 7.5.4 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 7.5.4 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
eligibility checklist -step 2 (10/17/13)
7.2 cisplatin (for arm 1

Refer to the package insert for detailed pharmacologic and safety information 7.2.1 Formulation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH range will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in aqueous solution, each ml containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to adjust pH.  
7.2.2 Mechanism of Action: The dominant mode of action of cisplatin appears to be inhibition of the incorporation of DNA precursors, although protein and RNA synthesis are also inhibited. Although this drug seems to act as an alkylating agent, there are data to indicate that its mode and sites of action are different from those of nitrogen mustard and the standard alkylating agents.  
7.2.3 Administration: Cisplatin will be given as a bolus, infused over 1-2 hours along with appropriate hydration and anti-emetics.  
7.2.4 Storage and Stability: Reconstituted solution of cisplatin is stable for 20 hours when stored at 27°C and should be protected from light if not used within 6 hours. The vials and injection should not be refrigerated. Cisplatin has been shown to react with aluminum needles, producing a black precipitate within 30 minutes.  
7.2.5 Adverse Events: Human toxicity includes nausea, vomiting, renal toxicity (with an elevation of BUN and creatinine and impairment of endogenous creatinine clearance, as well as renal tubular damage, which appears to be transient), ototoxicity (with hearing loss that initially is in the high-frequency range, as well as tinnitus), and hyperuricemia. Much more severe and prolonged toxicity has been observed in patients with abnormal or obstructed urinary excretory tracts. Myelosuppression, often with delayed erythrosuppression, is expected.  
7.2.6 Supply: Cisplatin is commercially available. The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption.
eligibility checklist -step 2 (10/17/13)
non-canadian international institutions

Please refer to your LOI Approval Notification. Your institution will be responsible for acquiring any drug noted in the protocol as commercially available and not provided for the study. Before drug can be provided your institution must comply with all pre-registration requirements and certifications and provide all necessary documentation listed in your LOI Approval Notification document.
eligibility checklist -step 2 (10/17/13)
7.3 cetuximab (for arm 2

Refer to package insert for detailed pharmacologic and safety information. Note the black box warning for cardiopulmonary arrest in patients receiving radiation therapy in combination with cetuximab. 7.3.1 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.  
7.3.2 Safety Precautions Appropriate mask, protective clothing, eye protection, gloves and Class II vertical-laminarairflow safety cabinets are recommended during preparation and handling.  
7.3.3 Preparation and Administration Cetuximab must not be administered as an iv 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 (10/17/13)
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. (6/25/13) Following the cetuximab infusion, a one-hour observation period is required.  
7.3.4 Adverse Events **(6/25/13)**
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 7.5 for details.
eligibility checklist -step 2 (10/17/13)
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.  
7.3.5 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.  
7.3.6 (2/23/16) Supply Commercially available in the U.S. and provided free of charge to Canadian sites by Eli Lilly and Company or its local affiliate.
eligibility checklist -step 2 (10/17/13)
canadian institutions

Cetuximab will be distributed by a vendor, Biologics, Inc., under contract to NRG Oncology.  
Biologics will place the cetuximab in a Biologics logo box for easy identification at the site.  
Biologics will ship a patient-specific supply of cetuximab with enough quantity to complete protocol treatment for a 200-pound individual (43 vials) once the site has registered the patient. Since doses are dependent on the patient's BSA, sites can obtain additional perpatient supply for individuals over 200 pounds by contacting Biologics.  
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), which is available on the NRG Oncology/RTOG web site (www.rtog.org, under protocol-specific materials/Canadian resources) Canadian institutions must fax the SASF to the CTSU Regulatory Office (Fax 215-569-0206) as soon as the individual responsible for the study agent has been identified.  
Biologics will ship the order "same day" for all orders received before 4 p.m. EST, Monday through Thursday via FedEx International Priority. Orders received after 4 p.m. EST, Monday through Thursday and any time on Friday will be processed and shipped the next business morning.  
Drug deliveries are restricted during weekends and holidays. Biologics 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. Sites should plan ahead to accommodate patients being treated during restricted times. Upon notification of a new patient enrollment, Biologics will place an outbound call to the site contact to confirm that the site's shipment is being processed. Biologics' distribution team will monitor packages throughout the duration of transit via the FedEx web site and FedEx OneCall Solution (live support). Real-time monitoring enables Biologics to mitigate potential delivery delays. At the completion of the trial, unused supplies of cetuximab will be destroyed at the site according to the institution's policy for drug destruction. Sites should complete the drug destruction form located on the NRG Oncology/RTOG website www.rtog.org (under protocol-specific materials/Canadian resources) and send the form to Biologics (see contact information below).
eligibility checklist -step 2 (10/17/13)
questions about supply and delivery

Clinical Research Services Biologics, Inc.  
120 Weston Oaks Court Cary, NC 27513-2256
(800) 693-4906/(919) 459-4990
eligibility checklist -step 2 (10/17/13)
fax (919) 256-0794 elee@biologicsinc.com or

Non-Canadian International Institutions Please refer to your LOI Approval Notification. Your institution will be responsible for acquiring any drug noted in the protocol as commercially available and not provided for the study. Before drug can be provided your institution must comply with all pre-registration requirements and certifications and provide all necessary documentation listed in your LOI
Approval Notification document.  
7.4 Dose Modifications for Cisplatin (7/16/14)
7.4.1 Neutropenia: If on the day of scheduled treatment with cisplatin the absolute neutrophil count
(ANC) is < 1200/mm3, hold the second chemotherapy treatment but not the radiation until ANC ≥ 1200/mm3, then treat at 100% dose.
Neutropenic fever (i.e. ANC <1000/mm3 with a single temperature of > 38.3 degrees C [101 degrees F] or a sustained temperature of ≥ 38 degrees C [100.4 degrees F] for more than 1 hour) will require a 25% dose reduction of the second cisplatin dose.  
7.4.2 Thrombocytopenia: If on the day of scheduled treatment with cisplatin the platelet count is
< 75,000/mm3, hold the second chemotherapy treatment but not the radiation until platelets are ≥ 75,000/mm3, then treat at 100% dose.  
Thrombocytopenia that results in bleeding will require a 25% dose reduction of the second cisplatin dose.  
7.4.3 Neurotoxicity: If grade 2 neurotoxicity developed, hold cisplatin (but continue RT) until toxicity improves to < grade 1, then reduce the second cisplatin dose to 80 mg/m2.  
If any signs of grade 3 or greater neurotoxicity occur, discontinue cisplatin, but continue RT.  
7.4.4 Renal Adverse Events: Cisplatin dose should be based on the serum creatinine or creatinine clearance immediately prior to the second cisplatin dose using the following guidelines:
Note: If creatinine is > 1.5 mg/dl, creatinine clearance must be calculated (Cockcroft-Gault) in order to make dose adjustment. If the calculated clearance is 50 mL/min or above, a 24-hour urine collection is not needed, but if the calculation is less than 50 mL/min, a 24-hour urine collection is mandated, and the cisplatin dose will be determined as follows:  
Serum Creatinine Creatinine Clearance Cisplatin Dose  
≤ 1.5 mg/dl or > 50 ml/min 100 mg/m2  
> 1.5 mg/dl and 40-50 ml/min 50 mg/m2  
> 1.5 mg/dl and < 40 ml/min Hold drug*  
*Cisplatin should be held (but the RT continued) and the creatinine measured weekly, until it is < 1.5 mg/dl or the creatinine clearance is > 50 ml/min, and then the second dose of cisplatin  
should be given at the reduced dose of 50 mg/m2.  
7.4.5 Nausea and Vomiting: Maximum supportive therapy will be given, and cisplatin will be continued at full dose for ≤ grade 2 nausea and vomiting. For grade 3 nausea and vomiting refractory to supportive therapy, cisplatin will be held until recovery to < grade 2. No dose reductions will be made.  
7.4.6 Mucositis: Significant mucositis (grade 3-4, CTCAE, v. 4) is expected from radiation and cisplatin and should not be a reason for a treatment break, unless it significantly interferes with fluid intake or nutrition. Aggressive supportive care is encouraged.  
7.4.7 Ototoxicity: For clinical hearing loss not requiring a hearing aid, reduce cisplatin to 50 mg/m2.  
For hearing loss requiring a hearing aid, discontinue cisplatin. For grade 2-3 tinnitus (CTCAE, v. 4) at the time of retreatment, hold cisplatin until improvement to grade 1 or less and then reduce the 2nd dose of cisplatin to 50 mg/m2. If tinnitus does not improve to grade 1 or less by the last day of radiation therapy, discontinue cisplatin.
eligibility checklist -step 2 (10/17/13)
7.5 dose modifications for cetuximab

| Starting Dose                                                                    | Dose Level –1       | Dose Level –2       |                     |
|----------------------------------------------------------------------------------|---------------------|---------------------|---------------------|
| Cetuximab                                                                        | 400 mg/m2  (week 1  |                     |                     |
| only)                                                                            |                     |                     |                     |
| Cetuximab                                                                        | 250 mg/m2  (weekly) | 200 mg/m2  (weekly) | 150 mg/m2  (weekly) |
| Note: If a weight change of ≥ 10% occurs, the cetuximab dose should be adjusted. |                     |                     |                     |  
| 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                                                                                                                                               |                                                                   |
| Other Non-hematologic  Adverse Events b, c Grade 3- 4, if possibly related to  cetuximab, or likely to be exacerbated by  continuation of cetuximab, e.g. diarrhea,  except for weight loss or mucositis | Hold drug until < grade 3, then resume at 1 dose  level reduction |
| Any grade 1-2                                                                                                                                                                                            | Maintain dose levels                                              |
| a Dose levels are relative to the previous dose. Dose reductions of cetuximab below the –2 dose                                                                                                          |                                                                   |  
An audiogram is strongly recommended when there is any report of significant change in hearing and/or an increase in tinnitus.  
7.4.8 For any other grade 3-4 non-hematologic adverse events possibly related to cisplatin, hold cisplatin until toxicities have recovered to grade 1 or less.  
7.4.9. If the second dose of cisplatin is delayed more than 21 days because of hematologic, neurologic, renal, or other adverse events, that dose will be omitted. If a weight change of ≥ 10% occurs, the second cisplatin dose should be adjusted.  
7.5.2 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.  
aDose levels are relative to the previous dose. Dose reductions of cetuximab below the –2 dose level will not be allowed. If a dose reduction below the -2 dose is mandated by the toxicity grade, cetuximab will be permanently discontinued. 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 ;
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).  
7.5.3 Cetuximab Dose Modifications for Non-Hematologic Adverse Events (12/4/12)
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,  v. 4  Grade                                                                                                                    | Serum Magnesium  mg/dL mmol/L   | Guidelines for management   | Action                                                                                                                                                                                                                     |                                                                            |
|----------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|-----------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|
| Consider replacement with IV  magnesium sulfate 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                                                                                                                                              |                                                                            |
| 3                                                                                                                                      | < 0.9 - 0.7                     | < 0.4 - 0.3                 | As above for grades 1 and 2                                                                                                                                                                                                | Hold cetuximab until  recovery to < grade 2,  then reduce by 1 dose  level |
| 4                                                                                                                                      | < 0.7                           | < 0.3                       | As above for grades 1 and 2                                                                                                                                                                                                |                                                                            |  
7.5.4 Cetuximab Infusion Reaction Management (6/28/12)  
| 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. 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, slow the infusion rate for cetuximab  by 50% when the drug is restarted 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                                              | NO FURTHER STUDY DRUG THERAPY. 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.  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  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 > grade 2 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-Chair should be contacted immediately to discuss and grade the reaction.  
7.5.5 Cetuximab Special Instructions **(6/25/13)**
Weekly cetuximab will continue if radiation therapy is being held. 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. If adverse events prevent the administration of cetuximab, the subject may continue to receive radiation therapy. If a dose of cetuximab is omitted, it will not be made up or added to the end of treatment. The omitted dose and the reason for the omission should be recorded in the site's source documentation.  
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.  
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 (10/17/13)
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 either the "outside of the radiation field" or the "inside of the radiation field" definitions below), cetuximab treatment adjustments should be made according to the Cetuximab Dose Modification table that follows. 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 or localized                                                                                                            | Intense or widespread                                                                                                                                                                                                                                | Intense or  widespread and  interfering with ADL                                                                                                                                                                               | -  |
| Rash/acneiform*                                                                                                                                                                                                                         | Papules and/or  pustules covering  <10% BSA, which  may or may not be  associated with  symptoms of  pruritus or  tenderness | Papules and/or  pustules  covering any %  BSA, which may  or may not be  associated  with symptoms  of pruritus or  tenderness and  are associated  with extensive  superinfection  with IV  antibiotics  indicated; life  threatening  consequences |                                                                                                                                                                                                                                |    |
| Paronychia*                                                                                                                                                                                                                             | Nail fold edema or  erythema;  disruption of the  cuticle                                                                    | Papules and/or  pustules covering 10- 30% BSA, which may  or may not be  associated with  symptoms of pruritus or  tenderness; associated  with psychosocial  impact; limiting  instrumental ADLI                                                    | Papules and/or  pustules covering  >30% BSA, which  may or may not be  associated with  symptoms of pruritus  or tenderness;  limiting self care ADL;  associated with local  superinfection with  oral antibiotics  indicated |    |
| Localized intervention  indicated; oral  intervention indicated  (e.g., antibiotic,  antifungal, antiviral);  nail fold edema or  erythema with pain;  associated with  discharge or nail plate  separation; limiting  instrumental ADL | Surgical intervention  or IV antibiotics  indicated; limiting self  care ADL                                                 | -                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                |    |
| *Onset of grade 3 will require modification. See the table below, "Cetuximab Dose Modification Guidelines for  Dermatologic Changes".                                                                                                   |                                                                                                                              |                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                |    |  
*Onset of grade 3 will require modification. See the table below, "Cetuximab Dose Modification Guidelines for Dermatologic Changes".  
Rash Occurring **Inside** the Radiation Field: Acute radiation dermatitis may be exacerbated by cetuximab or chemotherapy. The severity of such rash should be graded using CTCAE, v. 4 criteria for radiation dermatitis (table below).  
| 1                                                                 | 2                                                                                                   | 3                                                                                                       | 4                                                                                                                                                          |
|-------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Radiation recall  reaction  (dermatologic);  Dermatitis radiation | Faint erythema or                                                                                   | Moderate to brisk                                                                                       |                                                                                                                                                            |
| dry desquamation                                                  | erythema; patchy  moist desquamation,  mostly confined to  skin folds and  creases; moderate  edema | Moist desquamation  other than skin folds  and creases;  bleeding induced by  minor trauma or  abrasion | Life-threatening  consequences;  skin necrosis or  ulceration of full  thickness dermis;  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 ≤ Grade 2 | Resume at 250 mg/m2                   |
| weeks                                                                                                                          |                       |                          |                                       |
|                                                                                                                                | No Improvement;       | Discontinue cetuximab    |                                       |
| remains grade 3                                                                                                                |                       |                          |                                       |
| 2nd occurrence                                                                                                                 | Delay infusion 1 to 2 | Improvement to ≤         | Resume at Dose Level -1  (200 mg/m2 ) |
| weeks                                                                                                                          | Grade 2               |                          |                                       |
|                                                                                                                                | No Improvement;       | Discontinue cetuximab    |                                       |
| remains grade 3                                                                                                                |                       |                          |                                       |
| 3rd occurrence                                                                                                                 | Delay infusion 1 to 2 | Improvement to ≤         | Resume at Dose Level -2               |
| weeks                                                                                                                          | Grade 2               | (150 mg/m2 )             |                                       |
|                                                                                                                                | No Improvement;       | Discontinue cetuximab    |                                       |
| remains grade 3                                                                                                                |                       |                          |                                       |
| 4th occurrence                                                                                                                 | Discontinue cetuximab |                          |                                       |
eligibility checklist -step 2 (10/17/13)
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.  
7.6 Modality Review (6/3/14)
The Co-Principal Investigator, Maura Gillison, MD, PhD and the Medical Oncology Co-Chair, David Adelstein, MD, will perform a Chemotherapy Assurance Review of all patients who receive or are to receive chemotherapy in this trial. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of chemotherapy treatment data as specified in Section 12.1.  
The scoring mechanism is: Per Protocol, Acceptable Variation, Unacceptable Deviation, and Not Evaluable. A report is sent to each institution once per year to notify the institution about compliance for each case reviewed in that year.  
The Co-Principal Investigator, Dr. Gillison and the Medical Oncology Co-Chair, Dr. Adelstein will perform a Quality Assurance Review after complete data for the first 20 cases enrolled has been received at IROC Philadelphia. Drs. Gillison and Adelstein 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.  
7.7 Adverse Events (3/26/14)
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be reported via the CTEP-AERS (Adverse Event Expedited Reporting System) application accessed via the CTEP web site (https://eapps-ctep.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 CTEPAERS.  
7.7.1 Adverse Events (AEs) (3/26/14)
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. February 29, 2012; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]
7.7.2 Serious Adverse Events (SAEs) - Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in section 7.8 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-AERS notification are defined in the expedited reporting table in Section 7.8. **Contact the CTEP-AERS Help Desk if assistance is required.**  
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in any of the following outcomes:
Death; A life-threatening adverse drug experience; Inpatient hospitalization or prolongation of existing hospitalization; A persistent or significant disability/incapacity; A congenital anomaly/birth defect; Important medical events that may not result in death, be life threatening, or require hospitalization may be considered an SAE, when, based upon medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definition.
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner.  
7.7.3 Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) **(6/25/13)**
AML or MDS that is diagnosed during or subsequent to treatment in patients on NCI/CTEPsponsored clinical trials must be reported via the CTEP-AERS **within 30 days of AML/MDS**
diagnosis.
eligibility checklist -step 2 (10/17/13)
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.
eligibility checklist -step 2 (10/17/13)
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.
eligibility checklist -step 2 (10/17/13)
7.8 ctep-aers expedited reporting requirements

All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the Adverse Event Reporting System, accessed via the CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613.  
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology requirements for expedited adverse event reporting.  
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway.  
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the NRG
Oncology Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report submitted by phone must be entered electronically into CTEPAERS.  
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 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 (10/17/13)
fda reporting requirements for serious

NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
| ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI  via CTEP-AERS within the timeframes detailed in the table below. Grade 1  Grade 2  Grade 3  Hospitalizatio Grade 4 & 5  Timeframes  Timeframes  Timeframes  n Timeframes  Resulting in  Hospitalization  10 Calendar Days  ≥ 24 hrs 24-Hour 5 Calendar  Not resulting in Days  Hospitalization  Not required 10 Calendar Days  ≥ 24 hrs NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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  
Expedited AE reporting timelines are defined as:  
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 the 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.
eligibility checklist -step 2 (10/17/13)
(7/16/14) additional instructions or exceptions

following AEs in an expedited manner only if they exceed the grade in parentheses next to the AE: lymphocyte count decrease (grade 4), nausea (grade 3), vomiting (grade 3), diarrhea (grade 3), dehydration (grade 3), and mucositis (grade 3). Routine adverse event reporting on the case report form fulfills safety reporting requirements for these events at the aforementioned grades.
eligibility checklist -step 2 (10/17/13)
8.0 surgery

Surgery is expected to play only a limited role in favorable risk HPV-associated cancers. Locoregional progression is expected in <10% of patients. The role of neck dissection has been declining in recent years, in part due to higher response rates with use of concurrent chemotherapy and a high rate of negative specimens when planned neck dissections are performed in cancers of the oropharynx. In fact, this may be a reflection of the growing proportion of HPV-associated cancers (29% of oropharynx cases in RTOG 90-03; 60% in RTOG 0129).
eligibility checklist -step 2 (10/17/13)
8.1 post-treatment imaging/timing

The initial post-radiation imaging evaluation will be performed at 12 weeks after the completion of radiotherapy with contrast-enhanced CT, MRI, and/or PET/CT based on the preference of treating clinicians. PET/CT is preferred to facilitate pre-and post-treatment evaluation of metabolic response and the need for post-treatment neck dissection. If physical examination and imaging suggest residual disease at the primary site, a biopsy will be performed to confirm residual disease; otherwise, patients will undergo serial follow up.
eligibility checklist -step 2 (10/17/13)
8.2 post-treatment surgical salvage of

Treatment of residual disease at the primary site will be determined by the treating clinicians and the clinical situation, and surgical resection, re-irradiation, chemotherapy, or palliative care will be done. If the primary site is cleared of residual disease yet residual disease at the cervical nodal basin is suggested by imaging/clinical evaluation, then selective neck dissection will be performed unless a cytologic sampling of the node is negative. Post-treatment "planned" neck dissection will be defined as being performed for residual disease and within 20 weeks (140 days) of completion of radiotherapy. Positive neck specimens removed within 140 days will be considered part of the initial treatment plan and not considered as failures of initial management; positive specimens upon neck dissection beyond 140 days will be considered regional failures. Note that this is relaxed from the traditional definition of 105 days (15 weeks) in order to permit resolution of HPV-associated adenopathy, which is commonly cystic and has a somewhat slower regression rate. Such post-treatment consolidation neck dissections will encompass only the areas (typically only levels 2 and 3) initially involved in the side of the neck in question. The extent of neck dissections performed for nodal recurrence, nodal progression, or salvage of disease at the primary will be determined by the treating surgeon. In the case of negative PET in patients who did not achieve clinical or CT/MRI-based radiological nodal CR, follow-up PET scans are recommended every 3-4 months for 24 months, then every 6 months for years 3-5, as well as careful recording of the clinical dimensions of the residual abnormality.
eligibility checklist -step 2 (10/17/13)
9.0 other therapy 9.1 permitted

9.1.1 All supportive therapy for optimal medical care will be given during the study period at the discretion of the attending physician(s) within the parameters of the protocol and documented on each site's source documents as concomitant medication. These may include analgesics, antiemetics, topical mouth rinses, skin creams/ointments, etc.  
9.1.2 In general, HIV-positive patients who are on a stable HAART regimen should continue HAART
while receiving chemotherapy. However, for patients who are newly diagnosed with HIV, it is preferable to defer initiation of HAART until after chemotherapy is completed. HAART regimens containing zidovudine and stavudine should be avoided during chemotherapy due to concerns for overlapping toxicity with chemotherapy. In addition, the protease inhibitor atazanavir
(RayatazTM) can cause a physiologically unimportant hyper-hyperbilirubinemia; however, in the setting of chemotherapy, some experts suggest switching that drug for another equally effective one. If HAART is withheld during chemotherapy, it should be resumed promptly after conclusion of the last cycle of chemotherapy.  
9.2 Non-permitted Supportive Therapy 9.2.1 The use of amifostine as a radioprotector is not allowed. The use of granulocyte colonystimulating factor or erythropoietin is not allowed. Any exceptions must be approved by the Principal Investigators, Dr. Trotti or Dr. Gillison, or the Medical Oncology Co-Chair, Dr.  
Adelstein. Transfusion is to be performed at the discretion of the treating physician.
eligibility checklist -step 2 (10/17/13)
10.0 tissue/specimen submission (6/3/14)

NOTE: Patients must be offered the opportunity to participate in the correlative components of the study, such as tissue/specimen submission. If the patient consents to participate in the specimen component of the study, the site is required to submit the patient's specimens as specified in Section 10.0 of the protocol. **Note**: Sites are not permitted to delete the tissue/specimen component from the protocol or from the sample consent.  
10.1 Tissue/Specimen Submission 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 Oncoloyg encourages participants in protocol studies to consent to the banking of their tissue. The NRG Oncoloyg 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. The NRG Oncology Biospecimen Bank also collects tissue for central review of pathology. Central review of tissue can be for eligibility and/or analysis.  
In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the purpose of p16 testing (mandatory) at the Innovation Center at The Ohio State University (OSU) and for banking and translational research (highly recommended).
eligibility checklist -step 2 (10/17/13)
10.2 specimen collection for central

The H & E slide and the formalin-fixed, paraffin-embedded tissue block, punch biopsy, or section taken from a biopsy must be submitted to the NRG Oncology Biospecimen Bank in San Francisco to facilitate central p16 analysis within 1 week of study entry. Cytopathology smears are inadequate for p16 determination and thus, are not acceptable for central review. Paraffin-embedded cytopathology (cell block) may be evaluable depending on the cellularity of the specimen, but tissue is preferred. The NRG Oncology Biospecimen Bank will ship the unstained sections to the Innovation Center CLIA lab at The Ohio State University (OSU) for p16 determination within 2 business days of receipt of the specimens at the Biospecimen Resource (based upon ongoing experience with RTOG 0920). The Innovation Center at OSU will report the tumor p16 status to NRG Oncoloyg within 2 business days of receipt. The total time from receipt of samples to reporting of p16 results is therefore anticipated to be approximately 5 business days. NRG Oncology will inform sites by e-mail of the results of the HPV determination. Note: Regardless of smoking history, all oropharynx cancers of eligible stage should be considered for study enrollment and evaluated for tumor p16 status. Fifty percent of HPV-positive patients enrolled in a prior RTOG study had a history of tobacco smoking. Investigators are therefore encouraged to evaluate all oropharynx cancer patients for trial eligibility. The use of mandatory central p16 testing is not intended to discourage institutional p16 testing. However, current data suggest that p16 testing has not been standardized at a national level, resulting in up to 30% discordance between local and central testing. Therefore, central confirmation of p16 is required for randomization.
eligibility checklist -step 2 (10/17/13)
the following material must be

One H & E and two 5 micron unstained slides cut onto positively charged slides AND two 2 mm cores of the block taken with a punch tool is acceptable. The unstained slides should be cut before punching the cores from the block. A specimen plug kit can be requested from the NRG Oncology Biospecimen Bank (see Appendix V for instructions). OR
If the site will not release the block or allow punches to be taken, then the H & E AND a minimum of 10 five micron unstained slides cut onto positive charged (adherent) slides is an acceptable substitute.  
10.2.3 A Pathology Report documenting that the submitted block, core, or slides contain 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.  
10.2.3 A Specimen Transmittal (ST) Form stating that the tissue is being submitted for Central Review.  
The Form must include the NRG Oncology protocol number and the patient's case number.  
10.2.4 Central Review will be performed for every case at the NRG Oncology Biospecimen Bank for adequacy of tumor tissue.  
10.2.5 Tumor p16 expression will be evaluated in a CLIA certified laboratory at the Innovation Center of The Ohio State University by means of immunohistochemical analysis with a mouse monoclonal antibody (MTM Laboratories, Westborough, MA) visualized with use of an autostainer (Discovery XT, Ventana, Tucson, AZ) and a secondary detection kit (iVIEW DAB Detection Kit, Ventana) by standard protocol. Positive p16 expression will be defined as a strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells.
eligibility checklist -step 2 (10/17/13)
10.3 specimen collection for tissue

For patients who have consented to participate in the tissue/blood component of the study (See Appendix I).] The overall objective of collecting specimens for translational research is to prospectively establish a repository of both risk factor profiles and biospecimens from patients enrolled in RTOG 1016 to facilitate future hypothesis generated research.  
See Appendix V for detailed collection instructions, including information pertaining to collection kits. Note: Kits can be requested from the NRG Oncology Biospecimen Bank, RTOG@ucsf.edu, and include a pre-paid shipping label for shipment of frozen biospecimens. 10.3.1 Tumor Tissue Tissue for banking will be taken from the tumor tissue block for central review (see Section 10.2.2).  
10.3.2 Serum, Plasma, and Whole Blood Collection Serum, plasma, and whole blood will be collected pre-treatment. In addition, plasma and serum will be collected at the 3- and 6-month follow-up visits. If a site misses the pre-treatment collection time point, they may collect the whole blood specimen at any time during treatment or at follow up.  
The following materials must be provided to the NRG Oncology Biospecimen Bank: A
Specimen Transmittal (ST) Form documenting the date of collection, time point of collection of the biospecimen; the NRG Oncology protocol number, the patient's case number, and method and time point of storage (for example, stored at -80° C for 3 days) must be included.  
10.3.3 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 (ST) Form the storage conditions used and time stored.  
10.3.4 Specimen Collection Summary (6/28/12)  
| Specimens for Central Review (Mandatory) and                                                                                                      |                                                                                                                                             |                                                                                      |                                                                      |
|---------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|----------------------------------------------------------------------|
| Tissue Banking/ Translational Research (Highly Recommended)                                                                                       |                                                                                                                                             |                                                                                      |                                                                      |
| Specimens taken from                                                                                                                              | Collected when:                                                                                                                             | Submitted as:                                                                        | Shipped:                                                             |
| patient:                                                                                                                                          |                                                                                                                                             |                                                                                      |                                                                      |
| Mandatory representative  H&E stained slides of the  primary tumor for central  review (and banking if the  patient consents)                     | Pre-treatment                                                                                                                               | Mandatory H&E stained                                                                | Slide shipped ambient                                                |
| slide                                                                                                                                             |                                                                                                                                             |                                                                                      |                                                                      |
| Mandatory: A paraffinembedded tissue block of  the primary tumor taken  before initiation of treatment  OR two 5 micron slides  AND two 2 mm diameter  core of tissue, punched  from the tissue block with a  punch tool for central review  (and banking if the patient  consents)                                                                                                                                                   | Pre-treatment                                                                                                                               | Mandatory paraffinembedded tissue block  or punch biopsy  Note: 10 unstained  slides are permitted  ONLY if site is not able  to submit a block or  provide a punch.                                                                                      | Block or punch (or  unstained slides) shipped  ambient               |
| SERUM: 5-10 mL of whole  blood in 1 red-top tube and  centrifuge for banking if the  patient consents                                             | Pre-treatment and at 3-  and 6-month follow-up  visits                                                                                      | Frozen serum samples  containing 0.5 mL per  aliquot in 1 mL cryovials  (5 to 10)    | Serum sent frozen on dry  ice via overnight carrier  (Mon-Wed)       |
| PLASMA: 5-10 mL of  anticoagulated whole blood  in EDTA tube #1  (purple/lavender top) and  centrifuge for banking if the  patient consents       | Pre-treatment and at 3-  and 6-month follow-up  visits                                                                                      | Frozen plasma samples  containing 0.5 mL per  aliquot in 1 mL cryovials  (5 to 10)   | Plasma sent frozen on dry  ice via overnight carrier  (Mon-Wed)      |
| DNA: 5-10 mL of  anticoagulated whole blood  in purple/lavender EDTA  tube #2 (purple/lavender  top) and mix for banking if  the patient consents | Pre-treatment; Note: if site  missed this collection, the  site may collect whole  blood at any other time  during treatment or follow  up. | Frozen whole blood  samples containing 1 ml  per aliquot in 1 mL  cryovials (3 to 5) | Whole blood sent frozen  on dry ice via overnight  carrier (Mon-Wed) |
| 10.3.5                                                                                                                                            | Submit materials for Tissue Banking, Central Review, Translational Research as follows:                                                     |                                                                                      |                                                                      |  
U. S. Postal Service Mailing Address: For Non-urgent/Non-frozen Specimens Only NRG Oncology Biospecimen Bank University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): For Urgent FFPE and Frozen Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341San Francisco, CA 94115 Questions: 415-476-7864/FAX 415-476-5271; RTOG@ucsf.edu 10.4 Reimbursement (6/3/14)
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per the requirements/methods specified by the 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.  
10.5 Confidentiality/Storage
(See the Patient Tissue Consent Frequently Asked Questions, http://www.rtog.org/biospecimen/tissuefaq.html for further details.) 10.5.1 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.  
10.5.2 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 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.
eligibility checklist -step 2 (10/17/13)
11.0 patient assessments 11.1 study

11.2.1 One of the following combinations of imaging is required within 8 weeks prior to registration:
a) A CT scan of the neck (with contrast) and a chest CT scan (with or without contrast); b) or an MRI of the neck (with contrast) and a chest CT scan (with or without contrast); c) or a CT scan of neck (with contrast) and a PET/CT of neck and chest (with or without contrast);
d) Or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with or without contrast);
Note: A CT scan of neck and/or PET/CT performed for radiation planning and read by a radiologist may serve as both staging and planning tools.  
11.2.2 Evaluation by a nutritionist and/or swallowing therapist is highly recommended within 2 weeks prior to the start of treatment and should include evaluation for placement of prophylactic gastrostomy or other type of feeding tube. The decision to place a feeding tube should be individualized and may consider a number of factors including: prior weight loss, current nutritional status, size and location of the primary tumor (impacting high dose target volume), availability of feeding tube placement services, availability of speech and swallowing specialists, and social support. Feeding tubes may be placed after start of treatment at the discretion of the clinical team. If a tube is placed, the site will document on the appropriate case report form (see Section 12.1) if the tube was placed prophylactically (as a preventative measure) or therapeutically (because of nutritional compromise or other clinical indications).  
11.2.3 Patients who are HIV positive but have no prior AIDS-defining illness and have CD4 cells of at least 350/mm3 are eligible. Institutions must perform a CD4 count for patients with known HIV
infection prior to Step 1 registration to determine eligibility.
eligibility checklist -step 2 (10/17/13)
11.3 evaluation during radiotherapy

11.3.1 A brief history & physical by a Radiation Oncologist and/or Medical Oncologist must be done
eligibility checklist -step 2 (10/17/13)
weekly.

11.3.2 Biopsy of any lesion(s) suspicious for tumor recurrence is recommended.
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11.4 evaluation in follow up

11.4.1 A brief history & a physical examination by a Radiation or Medical Oncologist or an ENT or Head & Neck Surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure), must be done at 1 and 3 months from the end of radiation treatment, then every 3 months through year 2, every 6 months for 3 years, then annually.  
Radiographic imaging (CT, MRI, or PET as appropriate) at these time points is highly recommended if disease progression is suspected by the treating physician. If performed, radiographic imaging to evaluate the patient for both local-regional recurrence and distant metastases is highly recommended (see Section 11.5.1).  
11.4.2 Chest imaging: A chest CT or a PET/CT of chest **is required once per year** for a total of 5 image sets.  
11.4.3 Biopsy of any lesion(s) suspicious for tumor recurrence is recommended as clinically indicated.  
11.4.4 The initial post-radiation imaging evaluation at 3 months after the completion of radiotherapy is highly recommended to assess response but is not required. The imaging can be contrastenhanced CT, MRI, or PET/CT of the head and neck or "whole body" PET/CT (minimum neck and chest) based on the preference of the treating clinician.
eligibility checklist -step 2 (10/17/13)
11.5 measurement of response/progression 11.5.1

Response and confirmation of local (primary site) or regional (neck) "tumor clearance" are not endpoints in this study. Clinical or radiographic evidence of progressive local-regional disease beyond 20 weeks should be documented in the clinical record and ideally confirmed by local or regional biopsy, neck dissection, or salvage surgery. CT or MRI (of head and neck region, with CXR or Chest CT), or PET/CT (including chest anatomy) may be used as radiographic evaluation of overall cancer status. The primary, neck and chest portions of the scans should be evaluated and reported separately. The CT portion of a PET/CT may serve as sufficient radiographic evaluation of the chest. If CT or MRI is used for evaluation of the head and neck region, CXR or CT of chest will be needed to rule out distant disease or second primaries at the designated evaluation intervals as outlined above in Section 11.4.  
11.5.2 Local or Regional Progression Local (primary site) or regional (neck) progression is defined as clinical or radiographic evidence of progressive disease at the primary site or neck. The location of progressive disease should be separately distinguished (local vs. neck) to document the precise pattern of failure if possible. Progression of local or regional disease should be confirmed by biopsy when possible but may be clinically assessed and documented in the clinical record at the judgment of the treating clinicians.  
11.5.3 Distant Metastasis Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where possible. A solitary, spiculated lung mass/nodule is considered a second primary neoplasm unless proven otherwise.  
11.5.4 Second Primary Neoplasm Tumor reappearing with the initial and immediate adjoining anatomical region of the primary will be considered local recurrence. Multiple lung nodules/masses are considered distant metastases from the index cancer unless proven otherwise.  
11.6 Criteria for Discontinuation of Protocol Treatment (6/25/13)
Unacceptable toxicity; see Sections 7.4 and 7.5 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 Sections 7.4 and/or 7.5.  
If protocol treatment is discontinued, follow up and data collection will continue as specified in the protocol.
eligibility checklist -step 2 (10/17/13)
11.7 quality of life and

Work Status Questionnaire and baseline BRASS; see Sections 11.7.5 and 11.7.6 below). **Note:** For patients already enrolled on the QOL component, sites must submit follow-up QOL as specified in Section 12.1.  
To minimize selection bias, all patients must be offered the opportunity to participate in the correlative components of the study, such as quality of life assessment. If the patient consents to participate in the quality of life (QOL) component of the study, sites are required to administer the baseline QOL and functional assessments prior to the start of protocol treatment.  
After 400 consecutive patients have been enrolled into the optional QOL component, this component will close. However, all patients should continue to be offered participation in the baseline head and neck risk factor survey.  
The assessments below (with the exception of the Head and Neck Risk Factor Survey [Section 11.7.6])
will be completed at the following time points: pre-treatment (baseline), end of treatment, and at 3, 6, and 12 months from the end of treatment. Target windows for data collection will be: 1) for end of treatment should be collected within 2 weeks of the last day of radiation therapy; 2) at 3 and 6 months should be collected within +/- 2 weeks of these time-points; and 3) at 12 months within +/- 4 weeks of this timepoint. However, if not possible, data should still be collected outside of these windows and analysis will account for the timing of data collection. The Head and Neck Risk Factor Survey will be administered once, at baseline. All QOL/functional assessments, the PRO-CTCAE H&N, and the head and neck cancer risk factor surveys listed below will be collected from patients at clinic visits via iPAD computers or an online CASI
system (Guidelines for registering into the CASI system are available on the RTOG web site, www.rtog.org, on the 1016 protocol page, under "Miscellaneous"). To complete electronic questionnaires, site research personnel who have been trained to use the CASI iPAD and/or online systems should remain available to patients to assist them if necessary. Versions of the surveys are available on the RTOG web site for submission to site's IRBs. 11.7.1 The EORTC QLQ-C30 The EORTC QLQ-C30, v. 3.0 is a 30-item self-reporting questionnaire grouped into 5 functional subscales (role, physical, cognitive, emotional, and social functioning). In addition, there are 3 multi-item symptom scales (fatigue, pain, and nausea and vomiting), questions concerning common symptoms in cancer patients, and 2 questions assessing overall quality of life. It has been translated and validated in 81 languages. The patient can complete the QLQ-C30 in approximately 7 minutes. Sites can check the web site for the specific languages available: http://groups.eortc.be/qol/translations.htm 11.7.2 The EORTC QLQ-H&N35 The Head and Neck module of the EORT QLQ-C30 is a 35-item self-reporting questionnaire that the patient can complete in approximately 7 minutes. The patient answers questions about head and neck pain, swallowing, saliva, eating, and social interactions. The QLQ-H&N35 has been translated and validated in over 20 languages. Sites can check the web site for the specific languages available: http://groups.eortc.be/qol/translations.htm 11.7.3 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 EQ-5D has been translated into multiple languages; these translations are available from the EuroQol web site at http://www.euroqol.org/. 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 QOL cover page.  
11.7.4 PRO-CTCAE H&N
PRO-CTCAE is a new outcome measure recently developed by the NCI designed to capture the patient's self-report of adverse events (Hay 2010). A subset of items drawn the PROCTCAE system have been aggregated into a head and neck specific tool for use in this trial
(PRO-CTAE H&N). The PRO-CTCAE H& N measure tailored for use in this study consists of 25 items that evaluate the presence and/or severity of a range of symptoms, as well as the degree to which the symptom/toxicity interferes with usual function. Individuals respond to the questionnaire items using a 5-point Likert scale, and the PRO-CTCAE H&N requires approximately 10 minutes to complete. In most circumstances, the patient will complete the QOL and PRO-CTCAE-H&N tools prior to the clinical encounter, thus most likely facilitating responses to the clinical team on the same information. At this time, PRO-CTCAE is available only in English. PRO-CTCAE is designed to be completed by the patient without assistance from research staff similar to other quality of life measures.  
11.7.5 Work Status Questionnaire H&N
The Work Status Questionnaire H&N is a study-specific survey designed to be completed by the patient without assistance from clinical or research staff, if the patient chooses to complete it on the iPAD at baseline. . This is a new survey tool, adapted from previous studies, and was customized specifically for RTOG 1016. It is available only in English at this time and can be completed in less than 5 minutes.  
11.7.6 The Behavioral Risk Assessment Survey System (BRASS)
The Behavioral Risk Assessment Survey System (BRASS) is a computer-assisted selfinterview (CASI) head and neck risk factor survey. The domains covered by the survey include demographic profiles, alcohol use, tobacco use, marijuana use, sexual behavior, family history of cancer, oral hygiene, and diet. The entire survey is anticipated to take the patient approximately 20 minutes or less to complete using CASI methods. Institutions also can download a copy of the BRASS for site IRB review on the NRG Oncology/RTOG web site, next to the protocol. Because of the sensitive nature of the data, data are completely de-identified, will not be assessable to clinical staff, and will be protected by a Certificate of Confidentiality from the National Institutes of Health. Patients enrolled to this trial already will have completed a short version of the tobacco-related section of the BRASS survey regarding smoking history, required for stratification (see Section 3.1.10). Depending on the patient's smoking history, these questions can be completed in 1-5 minutes. Additional questions regarding the other domains will be collected via BRASS if the patient chooses to complete these on the iPAD at baseline..  
11.7.7 Hearing Handicap Inventory for Adults (HHIA-S)
The Hearing Handicap Inventory for Adults screening version (HHIA-S) is a 10-item selfreporting questionnaire designed to measure patients' reactions to their hearing loss. There are social/situational and emotional subscales (5 items each) that assess self-perceived hearing handicap in various daily listening situations. The patient can complete the questionnaire in approximately 2 minutes.
eligibility checklist -step 2 (10/17/13)
12.0 data collection data should

Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be used (first-last). Last names with apostrophes will be identified by the first letter of the last name.  
12.1 Summary of Data Submission (2/23/16)  
Item Due BRASS Tobacco: Smoking history **(PQ)** Demographic Work Status Questionnaire **(FQ)**  
Within 1 week of step 1 registration  
Within 2 weeks of study entry Demographic Form **(A5)** Initial Evaluation Form **(I1)** HIV Status **(I3)** Pathology Report **(P1)** Slides/Blocks **(P2)**
Baseline QOL **(SA)** (includes QLQ-C30; QLQH&N35; PRO-CTCAE; HHIA-S)
EQ-5D **(HP)** QOL Cover Page **(CP)** BRASS: Optional survey **(PF)** Note: The baseline PQ, FQ, SA, CP, and PF will be completed on the iPAD.  
Follow-up QOL **(SB)** (includes QLQ-C30; QLQH&N35; PRO-CTCAE; Work Status Questionnaire; HHIA-S)* EQ-5D **(HP)***
At end of treatment, and at 3, 6, and 12 mos. from end of treatment QOL Cover Page **(CP)*** Note: If the institution is not provided with an iPAD for the follow-up survey, a hardcopy of the SB and CP will be completed. Treatment Form **(TF)** At end of treatment Surgery Form **(S1)** Operative Note **(S2)** Surgical Pathology Reports **(S5)**
For patients who have surgery for the cancer under study: Within 2 weeks of surgery Short-term Follow-up Form **(F0)** At 1 and 3 mos. from end of treatment, then q3 mos. through year 2 Long-term Follow-up Form **(F1)** q6 mos. for 3 yrs; then annually
***Note** The QOL documents listed above should be submitted per the schedule provided in Appendix I for all patients who consented to participate in the QOL component prior to its closure on 2/28/13. Baseline forms (shaded) are no longer necessary.
eligibility checklist -step 2 (10/17/13)
preliminary dosimetry information

Digital Data Submission Within 1 week of start of RT
Digital data submission includes the following:
CT data, critical normal structures, all GTV, CTV, and PTV
contours Digital beam geometry for beam sets Doses for sets of concurrently treated beams Digital DVH data for all required critical normal structures, GTV,
CTV, and PTVs for total dose plan All required structures **MUST** be labeled per the table in Section 6.6.  
All Digital RT Data must be in DICOM format.  
RTOG 1016 Datasheet, located on the NRG Oncology/RTOG web site at http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?  
study=1016 is to be submitted via TRIAD with RT Digital Data listed above Due within 1 week of start of RT
Upon submission of the digital data via TRIAD, complete an online DigitalData Submission Information (DDSI) located in the Forms section on the NRG Oncology/RTOG web site at http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1 016 Note: All simulation and portal films and/or digital film images will be kept by the institution and only submitted if requested. Radiotherapy Form **(T1) via web** Daily Treatment Record (T5) [copy to HQ only]
Final Dosimetry Information Due within 1 week of RT
end 12.2.1 TRIAD **(10/17/13)**
See Section 5.4 for account access and installation instructions.
eligibility checklist -step 2 (10/17/13)
13.0 statistical considerations 13.1 primary

| 13.2   | Secondary Endpoints (6/28/12)  13.2.1 Progression-free survival;  13.2.2 Local-regional failure;  13.2.3 Distant metastasis;  13.2.4 Second primary cancers;  13.2.5 Pattern of failure;  13.3.6 Early deaths;  13.2.7 Acute toxicities (CTCAE, v. 4) and overall toxicity burden at end of treatment and at 1, 3, and 6  months from end of treatment;  13.2.8 Late toxicities (CTCAE, v. 4) at 1, 2, and 5+ years;  13.2.9 Feeding tube rate at 1 year;  13.2.10 Quality of life: EORTC QLQ-C30 and EORTC QLQ-H&N35, including swallowing domains, at  baseline, end of treatment, 3, 6, and 12, months;  13.2.11 PRO-CTCAE-H&N at baseline, end of treatment, and at 3, 6, and 12 months from end of  treatment;  13.2.12 Health utility: EQ-5D at baseline, end of treatment, and 3, 6, and 12 months from end of  treatment;  13.2.13 Work Status Questionnaire at baseline, end of treatment, and 3, 6, and 12 months from end of  treatment;  13.2.14 Dental Status at baseline and 12, 24, 60, and 120 months from end of treatment;  13.2.15 Hearing quality of life outcomes as measured by the HHIA-S at baseline, end of treatment, and  at 3, 6, and 12 months from the end of treatment;  13.2.16 Behavioral Risk Assessment Survey System (BRASS) at baseline only;  13.2.17 Translational research analysis.   |
|--------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
13.3 Randomization and Stratification Patients will be randomized to 1 of 2 treatment arms. Additionally, patients will be stratified according to T stage (T1-2 vs. T3-4); N stage (N0-2a vs. N2b-3); Zubrod performance (0 vs. 1); and Smoking history (≤ 10 pack-years vs. > 10 pack-years).  
13.4 Sample Size The primary objective is to compare the overall survival between the control arm and the experimental arm. The null hypothesis is a hazard ratio greater than 1.4; the alternative hypothesis is a hazard ratio of 1. For the RTOG 0129 p16 + patients, the overall death rate for the first 4 years were 5.6%, 5.9%, 5.8%, and 3.5%, respectively. With 43% of living patients censored during 5th year, the estimated yearly death rate was 10.0%. For the RTOG 90-03 p16 + patients, the 4-year survival rate was 53.2%, and the 10-year survival rate was 31.5%. Assuming an exponential failure rate between those time points, the resulting yearly death rate post-4 years would be 8.4%. For planning purposes, a different exponential death rate is assumed for the first 4 years and after 4 years for the control arm. The yearly death rate of 5.3% for the first 4 years will be assumed and 10% yearly death after 4 years will be evaluated. A group sequential design with 3 interim analyses based on Haybittle's boundary will be used. The significance level for a one-sided test, the statistical power, and the noninferiority hazard ratio were set at 0.05, 0.80, and 1.4, respectively. A total of 600 analyzable patients are targeted. Adjusting by approximately 15% to allow for ineligibility, lack of data (e.g. no follow up post-study entry), the total sample size required is 706 patients. The total number of events required is 219 deaths. So, to reject the null hypothesis of inferiority, we would need to observe a hazard ratio of approximately 1.12 or better by assuming log rank test divided by total information (proportional to the total number of expected deaths) of the study approximate the observed hazard ratio. From the latest data from RTOG 0522 (2/22/13), overall death rates for p16+ patients (N=235) are 8.2%, 3.33%, 3%, 3% and 3% for the first 5 years for the 2 arms combined. We used data from both arms because the survival curves are similar and failure rate estimates are more reliable. This also is confirmed by the 5-year survival on the control arm of 0522 after multiple imputations of p16 and pack years (Ang 2013). At this time, the combined (blinded) failure rate from 1016 is not reliable due to the short median follow up of 0.467 years. Since the observed death rates in RTOG 0522 and in the current trial are lower than those in RTOG 0129, which was used for the initial design, the resulting trial time to completion will be at least 5 years longer than originally projected. Additionally, we have observed a higher than 10% ineligibility rate due to reasons described below. Thus, we propose to increase the sample size in order to finish the study within the timeframe outlined in the original design and to guarantee statistical power for the primary comparison. A group sequential design with 3 interim analyses based on Haybittle's boundary will be used. The significance level for a one-sided test, the statistical power, and the noninferiority hazard ratio were set at 0.05, 0.80, and 1.45, respectively. A total of 800 analyzable patients are needed. Allowing for 4% of patients to be retrospectively declared ineligible after randomization, the targeted accrual is 834 patients. Adjusting by approximately 20% to allow for ineligibility (In RTOG 1016, patients were not randomized for the following reasons: 5.3% not p16-positive; 5.2% patient refusal; 1.2% physician preference; 0.4% disease progression; 0.4% failure to submit tissue assay; and 2.5% for other reasons. In addition, 3.5% of patients were determined ineligible after randomization and 0.5% were randomized but did not receive any protocol therapy), it is estimated that we will need a total sample size of 1000 patients to obtain 800 analyzable patients, but if the rate of ineligibility is lower, the total number of patients required would be less than 1000. The total number of events required is 180 deaths. So, to reject the null hypothesis of inferiority, we would need to observe a hazard ratio of approximately 1.13 or smaller by assuming log rank test divided by total information (proportional to the total number of expected deaths) of the study approximate the observed hazard ratio. According to this design, the OS difference between the 2 arms at 5 years is 7.6% as compared to 9% in the original design (73.4% vs. 81%), and the total study duration will be 8.15 years. Note: Participation of HIV-positive individuals who meet the eligibility criteria is encouraged. However, the required sample size of 706 is based on the total number of HIV uninfected individuals enrolled into the study. The experience of the HIV-positive individuals will be analyzed and reported separately. The cohort of HIV+ patients will be assessed in a preliminary observational manner to gain insight into the feasibility of enrolling and treating this population on randomized phase III trials in the NCI-sponsored Cooperative Group Program. This effort is aimed at expanding access to cancer clinical trials for HIV infected persons who are healthy form the point of view of their HIV disease but who have cancer and are otherwise eligible for investigational cancer investigational therapeutics. The treatment analysis will be intent to treat and restricted only to eligible patients and may possibly exceed 600 patients. A yearly accrual rate of 180 patients is projected after the study is opened 6 months. With that accrual rate, the final definitive treatment for this component would occur 8.5 years after study is initially opened. If the alternative hypothesis of noninferiority is accepted based on the proposed analyses, a test of superiority also will be conducted if the cetuximab arm is shown to be more effective than the control arm. With the 600 analyzable patients and a one-sided type I error of 0.05, there will be 80% power to detect a 30% reduction of hazard rate based on intention to treat analysis.  
(10/17/13) The treatment analysis will be intent to treat and restricted only to eligible patients and may possibly exceed 800 patients. With the current accrual rate, if the alternative hypothesis of noninferiority is accepted based on the proposed analyses, a test of superiority also will be conducted if the cetuximab arm is shown to be more effective than the control arm. With the 800 analyzable patients and a one-sided type I error of 0.05, there will be 80% power to detect a 30% reduction of hazard rate based on intention to treat analysis; this requires 2 more years of follow up and 195 deaths.  
Death due to toxicity or within 30 days of completing radiation was not reported in the Bonner study (it is assumed in the current study that there will be no toxic deaths from cetuximab). In the RTOG 0522, the oropharynx cohort (N=278), 6 patients (2.2%), died from toxicity or within 30 days of completing treatment
(2 patients died of treatment-related causes and 4 additional patients died within 30 days of treatment from other causes). There is 55% and 99% power to detect a difference of 2% or 5% (0 vs. 2% or 5%) between the arms with a two sided type I error rate of 5%. (10/17/13) Death due to toxicity or within 30 days of completing radiation was not reported in the Bonner study (it is assumed in the current study that there will be no toxic deaths from cetuximab). In the RTOG 0522, in the oropharynx cohort (N=278), 6 patients (2.2%), died from toxicity or within 30 days of completing treatment (2 patients died of treatment-related causes and 4 additional patients died within 30 days of treatment from other causes). There is 81% and 99% power to detect a difference of 2% or 5% (0 vs. 2% or 5%) between the arms with a two sided type I error rate of 5%. Based on comparative review of adverse events data, detectable reductions are anticipated in 9 specific acute effects items in which cetuximab is expected to carry significantly lower (> 50% relative reduction)
acute toxicity with a one-sided alpha of 0.05: (auditory < 10 versus 28%, power=0.99); bone marrowleukopenia/anemia (5% versus 71%, power=0.99), grade 3+ dysphagia (26% versus 61%, power=0.99),
grade 3+ nausea (2% versus 12%, power=0.99), vomiting (3% versus 8%, power=0.81), peripheral sensory (0% versus 6%, power=0.09), pain (28% versus 71%, power=0.99), renal (0% versus 7%, power=0.99), and fatigue (4% versus 10%, power=0.87). (10/17/13) Based on comparative review of adverse events data, detectable reductions are anticipated in 9 specific acute effects items in which cetuximab is expected to carry significantly lower (> 50% relative reduction) acute toxicity with a one-sided alpha of 0.05 and 800 patients: (auditory < 10 versus 28%, power>0.99); bone marrow-leukopenia/anemia (5% versus 71%, power>0.99), grade 3+ dysphagia (26% versus 61%, power>0.99), grade 3+ nausea (2% versus 12%, power>0.99), vomiting (3% versus 8%, power=0.91), peripheral sensory (0% versus 6%, power>0.99), pain (28% versus 71%, power>0.99), renal (0% versus 7%, power>0.99), and fatigue (4% versus 10%, power=0.94). As described in Section 1.5.7, we expect to detect a between arm T score difference of 200 for overall acute toxicity burden. The following table shows statistical power with a two-sided type I error rate of 0.05 and different standard deviations for two sample independent t test.  
| SD    | 1000   | 800   | 600   | 400   |
|-------|--------|-------|-------|-------|
| Power | 68%    | 86%   | 98%   | 99%   |  
(10/17/13) As described in Section 1.5.7, we expect to detect a between arm T score difference of 200 for overall acute toxicity burden. The following table shows statistical power with 800 patients, a two-sided type I error rate of 0.05 and different standard deviations for two sample independent t test.  
| SD    | 1000   | 800   | 600   | 400   |
|-------|--------|-------|-------|-------|
| Power | 80%    | 94%   | >99%  | >99%  |  
Late toxicity was not reported by the Bonner study. Detectable relative reductions of ≥ 50% are anticipated in 4 specific late effects items with a one-sided alpha of 0.05 and 270 patients from each arm:
auditory (27% versus 13.5%, power=0.98), hemoglobin (15% versus 7.5%, power=0.80), pain (35%
versus 17.5%, power=0.99), and peripheral sensory neuropathy (11% versus 5.5%, power=0.70).  
(10/17/13) Late toxicity was not reported by the Bonner study. Detectable relative reductions of ≥ 50%
are anticipated in 4 specific late effects items with a one-sided alpha of 0.05 and 360 patients from each arm: auditory (27% versus 13.5%, power>0.99), hemoglobin (15% versus 7.5%, power=0.92), pain (35%
versus 17.5%, power>0.99), and peripheral sensory neuropathy (11% versus 5.5%, power=0.82).  
(10/17/13) We anticipate feeding tube rates in the cetuximab arm will be the same or better than in the cisplatin arm of RTOG 1016. Assuming 28% vs. 18% at 1 year and a one-sided alpha of 0.05, we have 92% power to detect this difference with 360 patients on each arm available for this analysis at 1 year.  
13.4.1 Feasibility The exact enrollment mix of T-N stages, smoking history, and accrual rates cannot be precisely projected. A sensitivity analysis seen below explores 3 scenarios in which patient accrual and the number of events (deaths) may be 10%, 33%, or 50% lower than projected from historical estimates. This indicates that even under worse-case conditions, the accrual time changes somewhat (4.35, 5.88, and 7.79 years), but time to analysis will not be more than 8.7, 8.8, and 8.97 years. This analysis strongly supports the feasibility and likelihood of completing enrollment and analysis within a relatively narrow timeframe. In the following table, yearly accrual and hazard rates are reduced by 10%, 33%, and 50% with the same analyzable number of patients. The accrual is then adjusted by 15% (to approximately 700) to account for ineligibility, lack of data (e.g. no follow up post-study entry), and non-compliance. Study durations are derived to achieve same survival difference at 5 year.  
|         | Yearly   | Accrual   | Study    | Total      | Sample Size   |
|---------|----------|-----------|----------|------------|---------------|
| Accrual | Duration | Duration  | Analyses | Analyzable |               |
| 10%     | 162      | 4.35      | 8.7      | 4          | 600           |
| 33%     | 120      | 5.88      | 8.8      | 4          | 600           |
| 50%     | 90       | 7.79      | 8.97     | 4          | 600           |  
13.4.2 Definitions of Failure The following table shows how each first event will be counted for progression-free survival, local-regional failure, and distant metastasis. 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 overall survival, death from any cause will be considered a failure. All failure times will be measured from randomization to the date of failure, competing risk, or last follow-up.  
| ProgressionFree Survival                                                                                 | Local-Regional   | Distant        |                |
|---------------------------------------------------------------------------------|------------------|----------------|----------------|
| First event                                                                     | Failure          | Metastasis     |                |
| None                                                                            | Censored         | Censored       | Censored       |
| Local-regional progression or recurrence                                        | Failure          | Failure        | Competing risk |
| Distant metastasis                                                              | Failure          | Competing risk | Failure        |
| Death due to study cancer or from  unknown causes                               | Failure          | Failure        | Competing risk |
| Death to due any other reason                                                   | Failure          | Competing risk | Competing risk |
| Salvage surgery of primary with tumor  present/unknown                          | Failure          | Failure        | Competing risk |
| Salvage neck dissection with tumor  present/unknown, > 20 weeks from end  of RT | Failure          | Failure        | Competing risk |  
13.5 Analysis Plan 13.5.1 Routine Interim Analysis to Monitor Study Progress Interim reports will be prepared twice each year until the final analysis has been accepted for presentation or publication. 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.  
13.5.2 Interim Analysis to Monitor Progression-Free Survival (PFS)
We plan to monitor futility of the difference between the control arm and the experimental arm with respect to PFS on a yearly basis during first 4 years of the trial starting from year 2. Additional analyses can be added if necessary. The purpose is to detect a significantly worse PFS for the experimental arm as compared to the control arm and if found, the patient accrual to the trial would be discontinued. The statistical monitoring boundary will be based on testing the alternative hypothesis of hazard ratio of 1.0 at a one-sided alpha level of 0.001, as recommended by Freidlin and Korn (2002). The NRG Oncology Data Monitoring Committee
(DMC) will review the results of these analyses.  
(10/17/13) We plan to monitor futility for the difference between the control arm and the experimental arm with respect to PFS on a yearly basis during the accrual phase of the trial starting from year 2. Additional analyses can be added if necessary. After the trial is reopened for sample size increase, the futility analysis will be based on the primary endpoint, overall survival, when about 20% of the total required deaths are observed. The purpose is to detect a significantly worse PFS and/or OS for the experimental arm as compared to the control arm and if found, then patient accrual to the trial would be discontinued. The statistical monitoring boundary will be based on testing the alternative hypothesis of hazard ratio of 1.0 at a onesided alpha level of 0.001, as recommended by Freidlin and Korn (2002). The NRG Oncology Data Monitoring Committee (DMC) will review the results of these analyses.  
13.5.3 Analysis for Reporting the Treatment Results **(2/23/16)**
The analysis reporting the treatment results will be carried out after 180 failures have been observed, unless the criteria for early stopping are met. 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 6.1.  
The difference in overall survival (OS) distributions between the control arm and the experimental arm will be tested using the one-sided log-rank test at the significance level of 0.0494 for noninferiority, given that the 3 interim analyses are carried out and show no statistical significance. If the number of interim analysis is other than 3, then the significance level will be adjusted accordingly.  
13.5.4 Interim Analysis for Data Monitoring Committee 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. The significance testing of efficacy will be performed at a designated time as outlined below and the results reported to the NRG Oncology DMC with a recommendation for possible early reporting. As further long-term survival information from RTOG 0129 and RTOG 0522 regarding P16 positive patients becomes available (HPV analysis of 0522 expected in 2012),
the study design assumptions will be re-evaluated. If the death rate is much lower than the projected rate or if the observed difference of survival is less than projected, the implication of this decreased rate, survival difference and accrual will be assessed in terms of when the projected final (definitive) treatment analysis will be performed. If the timing of that analysis is lengthened by more than a year, increasing the sample size will be explored.  
(10/17/13) Overall survival monitoring for both efficacy and futility will be performed when there are 45 OS events (25% information), 90 OS events (50% information, around 1 year from completion of accrual), 135 OS events (75% information, around 2.4 years from completion of accrual) and 180 OS events as required for the final analysis are reported. A Haybittle-Peto boundary will be utilized for efficacy monitoring. For futility, the statistical monitoring boundary will be based on testing the alternative hypothesis at a one-sided alpha of 0.005, as recommended by Freidlin and Korn (2002). If judged to be necessary, futility analysis also can be performed in between the above planned interim analyses using the same rule. For efficacy, the statistical monitoring boundary will be based on testing the null hypothesis at one-sided alpha level of 0.001.  
13.5.5 Interim Analysis for Special Reporting **(2/23/16)**
The reporting paradigm developed at CTEP specifically for noninferiority trials (if all 9 conditions and other requirements are met as in Korn 2005) may be used in order to keep the oncology community apprised of trial outcomes. There may be a release of limited and specific survival and the toxicity data for presentation at a major cancer meeting such as ASCO, and the first outcome publication will utilize at least 2-year minimum follow up after all the patients have been enrolled (ideally >50% of the total required deaths). The survival and the toxicity results will be reported without any statistical significance values, and a detailed reporting plan will be developed and needs to be approved by the DMC prior to the first report of results.  
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and October 31.  
13.5.6 Final Analysis **(2/23/16)**
The PFS and OS rates will be estimated for both treatment arms using the Kaplan-Meier method (1958). Their distributions will be compared between treatment arms with a one-sided log rank test (Mantel 1966). The confidence interval approach will be used for the final analysis; if the upper 95% bound is below 1.45 with 180 deaths, then the radiation plus cetuximab arm is noninferior to concurrent chemoradiation arm. If the upper 95% bound is above 1.45, then radiation plus cetuximab is inferior. The cumulative incidence method will be used to estimate local-regional failure rates, distant metastasis, and second primary tumor rates, and the failure rates for the experimental treatment will be compared against the control using a failure-specific log-rank test. Multivariate analysis will be performed using the Cox proportional hazards model. An overall toxicity analysis will be done 2 ways: 1) The first method will be based upon only adverse events (AEs) attributed by investigator to be definitely, probably, or possibly related (if relationship is missing, it will be considered related) to protocol treatment; 2) The second method will be based upon all reported AEs regardless of attribution. Rates of specific acute toxicity profiles and late toxicity profiles will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test between the 2 treatment arms. Overall acute toxicity burden scores will be compared using two sample t test.
eligibility checklist -step 2 (10/17/13)
13.6 statistical considerations for translational

We consider below the sample size and power for objectives 2 and 3 (see Section 1.7.1) noted above. In this analysis, variables of interest from objective 2 would be considered as selfreported behaviors, e.g. smoking status. For objective 3, variables of interest would include presence or absence of a biomarker in the tumor. Given that submission of tumor samples will be required for patient eligibility, it is projected that 100% of randomized patients will be analyzable for tumor marker evaluation (for high priority analyses), giving a total of 800 analyzable patients or 400 per arm. For dichotomized variables, the statistical power can be calculated by the method of Schoenfeld (1981). The table below shows statistical power to detect hazard ratios of 1.25, 1.50, 1.75, 2.00, 2.25, and 2.50 for prevalence rates of 10%, or 20%, or 30%, etc., for overall survival (arms combined) and overall survival (single arm). Progression-free survival (not shown) has more events and thus more statistical power than overall survival. Statistical power will be the same if prevalence rate is 1-prevalence. The significance level was set at 0.05. As seen in the table, there will be > 80% power (given prevalence of >20% of the factor of interest in the study population) to detect a hazard ratio of 1.75 or greater for two arms combined or a hazard ratio of 2.5 or greater for one arm only. Given the large hazard ratios reported for EGFR, Cyclin D1, etc., noted in the literature as potential modifiers of outcomes in HPV-positive patients (see table below), we will have sufficient statistical power to detect the expected hazard ratios. For example, for Bcl-2, with hazard ratio 4.0 and 40% of patients over-expressed, the statistical power is >99%.  
| Potential Biomarkers of Disease Outcome Among HPV-Positive Patients Reported in the Literature  Factor % HPV-positive  Outcome  Hazard Ratio  95% CI  with factor  measure  univariate  EGFR 78 Local-regional failure 6.6 2.1-40.0  Cyclin D1 27 Local-regional failure 3.5 1.9-7.2  P21 63 Disease-specific survival 0.4 NR  Bcl-2 40 Overall survival 4.0 1.2-13.6  P53 40 Disease-specific survival 1.7 NR  16q loss 29 Overall survival NR NR   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Prevalence  
Hazard Ratio 1.25 1.5 1.75 2 2.25 2.5  
0.1 0.14 0.37 0.61 0.79 0.90 0.95 0.2 0.22 0.58 0.85 0.96 0.99 0.99 0.3 0.27 0.70 0.93 0.98 0.99 0.99  
0.4 0.31 0.75 0.95 0.99 0.99 0.99  
0.5 0.32 0.77 0.96 0.99 0.99 0.99  
Statistical Power to Detect Various Hazard Ratios (OS, One Arm, 90 Events)  
Prevalence Hazard Ratio  
1.25 1.5 1.75 2 2.25 2.5  
0.1 0.09 0.21 0.35 0.50 0.63 0.74  
0.2 0.13 0.33 0.56 0.74 0.86 0.93  
0.3 0.16 0.42 0.68 0.85 0.94 0.97 0.4 0.17 0.46 0.73 0.89 0.96 0.98 0.5 0.18 0.48 0.75 0.90 0.97 0.99  
13.6.2 Analysis Plan Recursive partitioning analysis (RPA) is a mathematical technique that tests the association of variables with a specific outcome (e.g., overall survival). It is used to segregate groups of patients who have similar outcomes. Relying solely on Kaplan-Meier estimates and the log-rank test, RPA requires absolutely no knowledge of the biological behavior of a disease. Instead, mathematical cut points divide the database into multiple samples. The cut points (also known as splits) can be then combined based on clinical decisions, sample size, or statistical significance. The terminal branches then represent homogeneous groupings. All patients belong to one, and only one, group. The patients will be initially divided into two subgroups based upon previously defined (or hypothesized) cut points one or more tumor markers, and these two groups will be referred to as favorable and unfavorable risk groups. In univariate analysis, the log-rank test will be used to test for PFS and OS differences between the favorable and unfavorable risk groups; a failure-specific log-rank test will be used for LRF. Univariable and multivariable analysis will be performed using the Cox proportional hazards model for OS and PFS. Potential covariates evaluated for the multivariate models would be assigned treatment, age, Zubrod performance status, T-stage, N-stage, primary site, smoking history, other risk behaviors, as well as tumor markers. It is entirely possible that factors shown to be prognostic in other published series may not be found prognostic here. Then the tumor marker or combination of markers (or combination of behavioral risk factors) will be added to the model to test for significance.  
In addition, exploratory analysis will be performed to determine if there is any outcome difference between the marker risk group and treatment arm. A Cox regression model will be used with the following covariates: 1) assigned treatment; 2) marker status; and 3) assigned treatment by marker status interaction. The covariate for interaction will provide an estimate as to whether the treatment effect is similar for the marker + and the marker - patients.  
The analysis of one individual marker will include only patients with that marker. However, the analysis of two or more markers will include all patients with at least one determination of the multiple tumor makers. The assumption is made that the other tumor maker values are missing completely at random. The missing tumor values will be imputed 10 times, and the average value along with the pooled standard error associated with the parameter estimates for each tumor marker in the Cox model analysis will be reported. The tumor marker study population will be compared with the patients without a value for that tumor marker to determine if there are any differences with respect to distribution of baseline variables or outcome.  
13.7 Statistical Considerations for Quality of Life (6/25/13)
The focus of the quality of life (QOL) analysis is the change of QOL score as measured by the EORTC QLQ at 6 months from baseline and patterns of scores over time points and the change of score of the EORTC swallowing domain at 2 years from baseline with data from first 400 patients. Overall, the mean summary score of the EORTC QLQ-C30 and QLQH&N35 and the subscales including the swallowing domain will be determined. The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean change from baseline will be compared between the arms using a two sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. Mean change from baseline will be tested using an omnibus F test followed by individual comparisons of change scores at different time points within each treatment group. The same analysis will be conducted for between group comparisons at each time point. The primary QOL outcome for the study will be a comparison between arms of the EORTC QLQ change score from baseline to 6 months and the change score of the swallowing domain from baseline to 2 years. In addition to comparing the change scores at end of treatment, 3, 6, and 12 months from end of treatment to baseline, overall trends in the EORTC QLQ and subscale scores will be modeled using the general linear mixed-effect model. This model will be used to compare the differences of scores over time between the 2 arms and to compute least squares mean and SEs, including clinical variables and treatment by visit interaction terms. The model also allows for adjustments using stratification variables and other covariates of interest. The use of general linear mixed modeling allows flexibility in analyzing data with missing responses. For quality of life endpoints, based on results from 175 patients enrolled on RTOG 0522 and Ringash (2004), the mean change score is approximately half of the standard deviation. Also, from the results of Osoba (1998) and Curran (2007), we expect a meaningful between group change from baseline of 10 points on the EORTC QLQ (approximately half of the standard deviation as observed in Curran 2007) for a one-sided test with alpha of 0.05 and 90% power, we will need 140 analyzable patients for the 2 arms. Based on prior trials in head and neck cancers, the attrition rate is 35% at 6 months, we expect 216 patients will need to be recruited for the evaluation at 6 months. Even if the change from baseline were as small as 0.375 of the standard deviation, it would be detectable in the planned trial; we would need 246 analyzable and 398 total patients at 6 months with 90% statistical power and one sided alpha of 0.05. With these sample sizes for the above two design effect sizes, if the compliance rate is 55% at two years, we will have 85% and 85% power with one side alpha of 0.05 for both overall QOL and the swallowing domain. To handle poor compliance and missing data, efforts will be made to minimize attrition due to avoidable factors. To assess missing data mechanism, we will compare possible differences between patients who dropped out of the study against those who remained in the study with respect to imbalance factors such as treatment, baseline scores, clinical and demographic data. We will undertake sensitivity analyses to investigate reasons for missingness (e.g., by drop-out), considering various factors as mentioned earlier.  
A logistic regression model will be used to summarize number of missing data and to test if the dropout process is missing completely at random (MCAR). Analysis of complete cases and cases with multiple imputations for missing observations (before death or progression) will be done to check robustness of the main results. A pattern mixed model or selection model may be used to assess treatment effect to see if it is dropout dependent. The EORTC QLQ non-worsened vs. worsened for the arms will be compared using Fisher's exact test for each time point and modeled using a longitudinal model for binary outcomes based on the general estimating equation (GEE) approach.
eligibility checklist -step 2 (10/17/13)
13.8 gender and minorities (10/17/13)

|                                           | Gender   |       |       |
|-------------------------------------------|----------|-------|-------|
| Ethnic Category                           | Females  | Males | Total |
| Hispanic or Latino                        | 0        | 20    | 20    |
| Not Hispanic or Latino                    | 120      | 694   | 814   |
| Ethnic Category: Total of all subjects    | 120      | 714   | 834   |
|                                           | Gender   |       |       |
| Racial Category                           | Females  | Males | Total |
| American Indian or Alaskan Native         | 0        | 12    | 12    |
| Asian                                     | 3        | 3     | 6     |
| Black or African American                 | 0        | 54    | 54    |
| Native Hawaiian or other Pacific Islander | 0        | 0     | 0     |
| White                                     | 117      | 645   | 762   |
| Racial Category: Total of all subjects    | 120      | 714   | 834   |