nrg oncology
a randomized phase ii trial

This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network of NCTN organizations: the Alliance for Clinical Trials in Oncology; ECOG-ACRIN Cancer Research Group; and SWOG.
nrg oncology
coordinating center (04/29/2015)

NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19103 Study Team (20-DEC-2017)  
| Study Team (20-DEC-2017)                                                                                                                                                                                           |                                                                                                                                                                                                      |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Principal Investigator/Radiation Oncology Sue S. Yom, MD, PhD University of California, San Francisco 1600 Divisadero St., Suite H-1031 San Francisco, CA 94143 415-353-7175/FAX 415-353-9883 yoms@radonc.ucsf.edu | Medical Oncology Co-Chair Maura Gillison, MD, PhD University of Texas MD  Anderson Cancer Center 1515 Holcombe, Unit 432 Houston, Texas 77030 713-792-6363/FAX 713-792-1220 mgillison@mdanderson.org |
| Radiation Oncology Co-Chair U.S. Jimmy J. Caudell, MD, PhD Moffitt Cancer Center/Univ. of South Florida 12902 Magnolia Drive Tampa, FL 33612 813-745-3547/FAX 813-745-7231 Jimmy.Caudell@moffitt.org               | Medical Oncology Co-Chair Michael Gibson, MD, PhD  Vanderbilt-Ingram Cancer Center 2220 Pierce Avenue 777 Preston Research Building Nashville, TN 37232 615-936-8422 mike.gibson.1@vanderbilt.edu    |
| Radiation Oncology Co-Chair Canada John Waldron, MD Princess Margaret Hospital 610 University Avenue Toronto, ON M5G 2M9, Canada 416-946-6522/FAX 416-946-2111 John.Waldron@rmp.uhn.on.ca                          | Medical Physics Co-Chair Ping Xia, PhD Cleveland Clinic 9500 Euclid Avenue Cleveland, OH 44195 216-444-1938/FAX 216-444-8934 xiap@ccf.org                                                            |
| Study Team continued on next page.                                                                                                                                                                                 |                                                                                                                                                                                                      |
nrg oncology nrg-hn002 a randomized
coordinating center (04/29/2015)

| Study Team Continued (20-DEC-2017)                                                                                                                                                                                            |                                                                                                                                                                                                                                                                        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Translational Science Co-Chair Christine Chung, MD Moffitt Cancer Center 12902 USF Magnolia Drive Tampa, FL 33612 813-745-4673/FAX 813-449-8210  Christine.Chung@Moffitt.Org                                                  | Quality of Life Co-Chair Minh Tam Truong, MD Boston Medical Center 830 Harrison Ave., Moakley Bldg LL 238 Boston, MA 02118 617-638-7070/FAX 617-638-7037 Minh-Tam.Truong@bmc.org                                                                                       |
| Pathology Co-Chair Christina Kong, MD Stanford University 300 Pasteur Dr., Room L235 Stanford, CA 94305 650-723-9016/FAX 650-725-6902 ckong@stanford.edu                                                                      | Imaging Co-Chair Min Yao, MD  University Hospitals Cleveland 11100 Euclid Avenue Cleveland, OH 44106 Phone/Fax numbers Min.Yao@UHhospitals.org                                                                                                                         |
| Pathology Co-Chair Richard Jordan, DDS, PhD NRG Oncology Biospecimen Bank 2340 Sutter Street, Rm S341 San Francisco, CA 94115 415-476-7864/FAX 415-476-5271 richard.jordan@ucsf.edu                                           | Imaging Co-Chair Rathan Subramaniam, MD, PhD, MPH University of Texas Southwestern Medical  Center Division of Nuclear Medicine and Molecular  Imaging 5323 Harry Hines Boulevard Dallas, TX 75039 214-648-7770/FAX 214-648-7785 rathan.subramaniam@UTsouthwestern.edu |
| Swallowing Outcomes Co-Chair Jan S. Lewin, PhD University of Texas M.D. Anderson Cancer  Center; Speech/Language Pathology Unit 1445, P. O. Box 301402 Houston, TX 77030 713-745-2309/FAX: 713-794-4662 jlewin@mdanderson.org | Senior Statistician Jonathan Harris, MS NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19103 215-574-3202/FAX 215-928-0153 harrisj@nrgoncology.org                                                                                                       |
nrg oncology
coordinating center (04/29/2015)

NRG-HN002 A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE,
NON-SMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED
OROPHARYNGEAL CANCER  
| Study Team Continued (20-DEC-2017)                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                               |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Clincal Data Coordinators Vanita Patel, MS and  Janelle Robinson  NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19103  215-574-3170 (Patel) 215-717-0837 (Robinson) FAX: 215-940-8830 patelv@nrgoncology.org  robinsonj@nrgoncology.org | RT Technical Details (Section 5.2)  Nancy Linnemann, BS, RT(R)(T) and Marsha Radden, R.T.(R)(T) NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19103 215-717-0853 (Linnemann) 215-717-2757 (Radden)  nlinnemann@acr.org  mradden@acr.org Protocol Administrator Karen McClellan, MSW NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19103 215-717-0851 mcclellank@nrgoncology.org |  
Head and Neck Cancer Committee Chair: Quynh-Thu Le, MD, FACR, FASTRO  
| Protocol Agent   |            |       |        |             |
|------------------|------------|-------|--------|-------------|
| Agent            | Supply     | NSC # | IND #  | IND Sponsor |
| Cisplatin        | Commercial | N/A   | Exempt | N/A         |  
Participating Sites U.S. Canada Approved International Member Sites  
| Document History Version Date   | Broadcast Date    |                  |
|---------------------------------|-------------------|------------------|
| Amendment 3                     | December 20, 2017 | N/A              |
| Closure with Amendment 2        | May 24, 2016      | February 7, 2017 |
| Amendment 2                     | May 24, 2016      | June 20, 2016    |
| Amendment 1                     | April 29, 2015    | June 22, 2015    |  
Activation September 25, 2014 October 27, 2014  
This protocol was designed and developed by NRG Oncology. It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by NRG Oncology nor does NRG Oncology assume any responsibility for unauthorized use of this protocol.  
NRG-HN002 A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE,
NON-SMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED
OROPHARYNGEAL CANCER  
| CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (20- DEC-2017)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                    |                                                                                                                                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| To submit site registration                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | For patient enrollments:                                                                                                                                                                                                           | Submit study data                                                                                                                                                    |
| documents: Regulatory documentation  must be submitted to the  CTSU via the Regulatory  Submission Portal.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Please refer to the patient  enrolment sections of the  protocol for instructions in  using the Oncology Patient  Enrollment Network (OPEN) which can be accessed at  https://www.ctsu.org/OPEN_S YSTEM/ or  https://OPEN.ctsu.org | Data collection for this study  will be done exclusively  through Medidata Rave.  Please see the data  submission section of the  protocol for further  instructions |
| Regulatory Submission  Portal: (Sign in at  www.ctsu.org, and  select the Regulatory  Submission sub-tab under  the Regulatory tab.)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Do not submit study data or  forms to CTSU Data  Operations. Do not copy the  CTSU on data submissions.                                                                                                                            |                                                                                                                                                                      |
| Contact the CTSU Help Desk  with any OPEN-related  questions at  ctsucontact@westat.com                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                    |                                                                                                                                                                      |
| Institutions with patients  waiting that are unable to use  the Portal should alert the  CTSU Regulatory Office  immediately at 1-866-651- 2878 to receive further  instruction and support. Contact the CTSU  Regulatory Help Desk at 1- 866-651-2878 for regulatory  assistance. The most current version of the study protocol and all supporting documents must be  downloaded from the protocol-specific Web page of the CTSU Member Web site located at  https://www.ctsu.org. Access to the CTSU members' web site is managed through the Cancer  Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration  system and requires user log on with CTEP-IAM username and password.  For clinical questions (i.e. patient eligibility or treatment-related): Contact the Study PI of  the Lead Protocol Organization. |                                                                                                                                                                                                                                    |                                                                                                                                                                      |  
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) contact the CTSU Help Desk by phone or e-mail:
CTSU General Information Line - 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be triaged to the appropriate CTSU representative. For detailed information on the regulatory and monitoring procedures for CTSU sites please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members' web site https://www.ctsu.org > education and resources tab > CTSU Operations Information >CTSU Regulatory and Monitoring Policy The CTSU Website is located at https://www.ctsu.org.
nrg oncology
table of contents

| SCHEMA 9 1. OBJECTIVES 10 1.1 Primary Objective 10 1.2 Secondary Objectives 10 2. BACKGROUND 10 2.1 Rationale for Arm 1: Modestly Reduced Radiation Dose with Concurrent  Chemotherapy (60 Gy/30 fractions/6 weeks, with weekly cisplatin at  40/mg/m2 ) 12 2.2 Rationale for Arm 1 Radiosensitizer Regimen: Weekly Cisplatin at 40  mg/m2 16 2.3 Rationale for Arm 2: Modestly Accelerated Reduced Dose Radiation  Therapy (60 Gy/30 fractions/5 weeks) 17 2.4 Measuring Patient-Reported Outcomes (PROs) and Quality of Life (QOL) 20 2.5 FDG-PET/CT Imaging as a Predictive Imaging Marker for Locoregional  Control and Progression-Free Survival 29 2.6 Circulating HPV DNA as a Potential Marker for Relapse 33 2.7 PI3K Pathway Activation and Its Associated Genomic Profile as  Prognostic Biomarkers of HPV Related Oropharyngeal Cancer 34 3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 35 3.1 Patient Selection Guidelines 35 3.2 Eligibility Criteria 36 3.3 Ineligibility Criteria 38 4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW UP 39 5. TREATMENT PLAN/REGIMEN DESCRIPTION 45 5.1 Chemotherapy 45 5.2 Radiation Therapy 46 5.3 Surgery 62 5.4 Imaging 63 5.5 General Concomitant Medication and Supportive Care Guidelines 63 5.6 Duration of Therapy 64 5.7 Measurement of Response/Progression 64 6. TREATMENT MODIFICATIONS/MANAGEMENT 65 6.1 Chemotherapy Dose Modifications 65 7. ADVERSE EVENTS REPORTING REQUIREMENTS 67 7.1 Adverse Events (AE) 67 7.2 Serious Adverse Events (SAEs) 67 7.3 Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 68 7.4 CTEP-AERS Expedited Reporting Requirements 68   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 8. REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 71 8.1 Investigator Registration Requirements 72 8.2 Site Registration Requirements Error! Bookmark not defined. 8.3 RT-Specific Pre-registration Requirements 75 8.4 Patient Enrollment 77 9. DRUG INFORMATION 78 9.1 Investigational Study Agent 78 9.2 Commercial Agent: Cisplatin 78 10. BIOMARKER, CORRELATIVE, AND SPECIAL studies 78 10.1 Biomarkers 78 10.2 Quality of Life 83 10.3 FDG-PET/CT Imaging 87 10.4 Determining the Extent of Dysphagia using the Modified Barium Swallow 89 11. MODALITY REVIEWS 90 11.1 Radiation Therapy Quality Assurance Reviews 90 11.2 Drug Quality Assurance Reviews 90 12. DATA AND RECORDS 90 12.1 Data Management/Collection 90 12.2 Summary of Data Submission 91 12.3 Digital Data Submission Requirements 94 12.4 Global Reporting/Monitoring 94 13. STATISTICAL CONSIDERATIONS 94 13.1 Study Design 94 13.2 Study Endpoints 95 13.3 Primary Objectives Study Design 95 13.4 Study Monitoring of Primary Objectives 96 13.5 Accrual Considerations 97 13.6 Secondary/Correlative Elements 97 13.7 Gender/Ethnicity/Race Distribution 104 REFERENCES 105 APPENDIX I: DENTAL TOOTH COUNT AND DENTAL MANAGEMENT 118 APPENDIX II: Instructions and Forms for the Modified Barium Swallow (MBS) Substudy ...123   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
nrg oncology
table of contents

NRG-HN002 A RANDOMIZED PHASE II TRIAL FOR PATIENTS WITH p16 POSITIVE, NONSMOKING ASSOCIATED, LOCOREGIONALLY ADVANCED
OROPHARYNGEAL CANCER  
  
*Patients must have positive immunohistochemical staining for p16, as confirmed by the NRG Oncology Biospecimen Bank, prior to randomization.
nrg oncology
1. objectives 1.1 primary objective

To select the arm(s) achieving a 2-year progression-free survival rate of ≥ 85% without unacceptable swallowing toxicity at 1 year 1.2 Secondary Objectives **(5/24/16)**
To determine patterns of failure (locoregional relapse versus distant) and survival
(overall and progression-free) at 6 months and 2 years; To determine acute toxicity profiles at the end of radiation therapy and at 1 and 6 months; To determine late toxicity profiles at 1 and 2 years; To determine patient-reported swallowing outcomes at 6 months and 1 and 2 years; To determine the predictive value of 12-14 week, post-treatment FDG-PET/CT for locoregional control and PFS at 2 years; To determine the predictive value of blood and tissue biomarkers for disease outcomes at 2 years; To determine swallowing recovery per videofluoroscopy imaging at 2 years.
nrg oncology
2. background

The current standard of concurrent chemoradiation therapy produces excellent disease-free survival (DFS) and overall survival (OS) rates in oropharyngeal cancer. The cooperative groups, NRG Oncology and GORTEC, both have established the standard of care for stage III or IV oropharyngeal cancer to be a combination of 70 Gy of radiation therapy with concurrent platinum-based chemotherapy (Ang 2010, Bourhis 2012). However, these approaches also are associated with a high level of short- and long-term toxicities. One estimation is that the short-term toxicity burden, or T-score, stemming from definitive-intent radiation therapy can be increased by as much as 300% with the addition of the current standard of concurrent platinum-based chemotherapy (Trotti 2007). Long-term toxicities are likewise increased with intensive chemoradiation therapy (Machtay 2008). In human papilloma virus (HPV) positive oropharyngeal cancer patients, whose cancer-related outcomes often are excellent with a high probability of long-term survival, both short- and long-term toxicities are a growing concern among experienced head and neck oncologists. The philosophy of "de-escalation" or "de-intensification" has become an active topic of discussion in both academic and community head and neck treatment centers (Sturgis 2012). Furthermore, emerging data on dramatically improved outcomes in select populations of oropharyngeal cancer patients have called into question the global applicability and necessity of these standard chemoradiation paradigms. Oncogenic strains of HPV are associated with over 70% of oropharyngeal carcinomas (Chaturvedi 2011). Patients who develop HPVassociated oropharyngeal cancer are more likely to be younger, free of competing or limiting medical comorbidities, and have a lesser history of smoking. While the ultimate impact of long-term toxicities is complex and difficult to gauge, the HPV positive population has a higher likelihood of a better outcome subsequent to therapy at a younger age, thus making the conditional relevance of late toxicities and quality-of-life outcomes a more compelling issue. Furthermore, the sensitivity of advanced-stage HPV positive oropharyngeal cancer to both chemotherapy and radiation indicates that in some cases, the standard approach may result in over-treatment. For these reasons, the head and neck cancer community has voiced concerns about continued intensification of the chemoradiation approach, which may have value in other poor-risk head and neck cancer sites but which may constitute unnecessary additional treatment for good-prognosis HPV positive oropharyngeal cancer patients (Quon 2013). The cyclin-dependent kinase inhibitor, p16, is overexpressed as a byproduct of HPV infection, via inactivation of the retinoblastoma protein (pRb) by HPV oncoprotein E7. In orpharyngeal cancers, p16 is an immunohistochemical biomarker that is strongly indicative of HPV-related etiology and has been associated with a positive clinical prognosis. p16 is now used as a biomarker of improved prognosis enabling selection for clinical trials and has become a stratification factor for all NRG Oncology head and neck cancer trials that include oropharyngeal cancer patients. A recent analysis of RTOG 0129 separated the prognosis for advanced-stage oropharyngeal cancer patients into distinct groups based on HPV status and smoking history. The presence of oncogenic HPV DNA and the presence of p16 in primary tumors showed a high level of agreement. The HPV positive group with a history of ≤10 pack years of smoking had significantly improved outcomes on all fronts and was labeled to be at "low risk" for death. The 3-year rates of overall survival were 93.0% (95% CI, 88.397.7) in the low-risk group; 70.8% (95% CI, 60.7-80.8) in the intermediate-risk group; and 46.2% (95% CI, 34.7-57.7) in the high-risk group (Ang 2010). Similarly, the Princess Margaret Hospital published a retrospective review of their clinical experience with oropharyngeal cancer and identified a similar group called "low risk"; these patients were p16 positive, had ≤10 pack-year history of smoking, and were staged ≤ T3 and ≤ N2c. For these patients, the 3-year locoregional control rate was 95% (95% Cl, 91-97) and the 3-year distant control rate was 93% (95% Cl, 89-95). Based on very small numbers of patients, there was a suggestion of a lower distant control rate among minimal smokers with N2c nodal stage who did not receive concurrent chemotherapy. Importantly, there were no significant differences seen as a function of T stage in this group (O'Sullivan 2013). For p16 positive oropharyngeal cancer patients with ≤10 pack-year history of smoking, staged T1-2 N1-N2b M0 or T3 N0-N2b M0, NRG Oncology has recorded excellent 2-year PFS results. For this "low risk" population in RTOG 0129, the 2-year PFS is estimated at 85.3% (95%CI, 76.4-94.1) and locoregional recurrence/progression as a first event is estimated at 8.2% (95%CI, 1.3-15.1) with competing events consisting of 3.3% experiencing distant metastasis or death as the first event. In RTOG 0522, the 2-year PFS is estimated at 90.8% (95%CI, 83.7-97.8) and locoregional recurrence/progression as a first event is estimated at 4.6% (95%CI, 0-9.8), with competing events consisting of 4.6% experiencing distant metastasis or death as the first event (Zhang, personal communication, 2013). Therefore, this proposal seeks to define treatment paradigms for a newly emerging disease entity, in which high PFS rates are routinely achieved, corresponding to very low rates of locoregional failure. The emerging "low-risk" oropharyngeal cancer classification offers an opportunity to develop appropriate therapeutic paradigms for what is a recently identified and distinct subtype of HPV positive oropharyngeal cancer. It is worth noting that stage III/IV patients with stage T1N1-N3 and T2N1 disease were not eligible for RTOG 0129 or RTOG 0522, but the proposed eligibility for this trial allows all stage III/IV patients with ≤ T3 and ≤ N2b; thus, the PFS projections used in the proposed trial design are conservative, as our projections are estimated from previous trials that excluded the lowest-stage patients who will be included in this trial.
nrg oncology
2.1 rationale for arm 1

Chemotherapy (60 Gy/30 fractions/6 weeks, with weekly cisplatin at 40/mg/m2)
In the modern era, intensity-modulated radiation therapy (IMRT) given as a singlemodality treatment appears to produce high rates of locoregional control for the majority of low-volume oropharyngeal cancers. For example, RTOG 0022 was a prospective phase II feasibility trial designed to define standards for the use of IMRT in a multiinstitutional setting. The trial was designed for an oropharyngeal cancer population with a low to intermediate burden of disease; specific inclusion criteria allowed T1-2 N0-N1 M0 oropharyngeal cancers (AJCC group stages I-III). The protocol specified a prescribed dose to the high-dose planning target volume of 66 Gy at 2.2 Gy/fraction in 30 fractions delivered over 6 weeks. Subclinical PTVs simultaneously received 54-60 Gy at 1.8-2.0 Gy/fraction. Sixty-nine patients were accrued from 14 participating institutions. With a median follow up of 2.8 years, the 2-year locoregional failure rate was 9% (95% Cl, 2.115.9), the DFS was 82% (95% Cl, 72.7-91.2), and the OS was 95.5% (95% CI, 90.6100.0). Notably, all cases of locoregional failure, metastasis, or second primary cancer occurred among patients identifiable as current or former smokers (54% of all enrolled), and no such events were seen among reported nonsmokers (defined as < 5 packs per lifetime, with a prevalence of 34% in this study) (Eisbruch 2010). Similarly, single-institution retrospective reviews indicate that the contemporary population of HPV-positive oropharyngeal cancer patients has retained excellent outcomes when treated with radiation therapy alone. These studies suffer from negative selection bias, in that many patients included in modern radiation-alone series were not considered appropriate candidates for the administration of concomitant chemotherapy and likely had other important competing risks for death. For example, a small retrospective series of 21 patients with HPV positive oropharyngeal cancer treated to a median dose of 70 Gy with a variety of techniques found 3-year overall survival, locoregional control, and distant metastasis-free survival rates of 82%, 88%, and 88%. Both instances of locoregional failure were associated with T4 primary oropharyngeal tumors. Among the 18 HPV-positive never-smokers, 3-year overall survival and locoregional control rates were 100% (Chen 2013). A larger series from Princess Margaret Hospital included 148 patients treated with radiation therapy alone for p16 positive oropharyngeal cancers. A variety of conventional and altered fractionation radiation schemas were used, with total doses ranging from 60 to 64 to 70 Gy over 4 to 7 weeks given in either daily or twice-daily schedules. Among all 148 HPV positive oropharyngeal cancer patients, the 3-year overall survival, cause-specific survival, local control and regional control rates were 81%, 88%, 93%, and 94%. Patients with HPV positive oropharyngeal cancer who had a ≤ 10 pack-year history of smoking (n = 37) had 3-year OS, CSS, LC, and RC rates of 86%, 92%, 95% and 97%, with distant control rates of 92%. It was noted that there were important selection biases characterizing this series: 20% of all 96 HPV+ oropharyngeal cancer patients who received RT alone in this series were elderly (over 70 years of age) and of those having an age under 70 years, 39% were deemed medically unsuitable for concurrent chemoradiation therapy (O'Sullivan 2012). Given the promising results obtained with a variety of single-modality radiation therapy approaches, this arm tests the proposition that in combination with a systemic radiosensitizer, the standard doses of a highly effective, conventionally fractionated radiation therapy course may be modestly reduced. Radiobiological investigations indicate that the contribution of concurrent chemotherapy across a variety of chemoradiation trials may be considered equivalent to approximately 8.0-9.0 Gy10 of biologic effective dose (BED) (Lee 2009). One interesting study used the biologic effective dose equivalents from RTOG 90-03 to compare the gains achieved in that trial using altered fractionation against those of 14 prospective trials utilizing chemoradiotherapy. The mean additional BED contribution from concurrent chemotherapy may be at least 8.8 Gy10, or the equivalent of 3.6 fractions of 2 Gy translated back into total dose prescribed in standard fractionation (Kasibhatla 2007; Fowler 2008). Thus, if an effective concurrent radiosensitizer is given, the risks of reducing the radiation dose may be mitigated. Hence, Arm 1 in comparison to Arm 2 provides the opportunity to investigate whether systemic radiosensitization provides any advantage over a radiation-alone altered fractionation approach. Furthermore, for these HPV positive oropharyngeal cancer patients, single institutions, small informal collaborations (2-3 centers), and one formal cooperative group trial have begun to explore "de-escalation" of radiation therapy dose in combination with a variety of concurrent systemic therapies. The earliest results have been reported by ECOG, which completed accrual to E1308, a phase II study in HPV/p16 positive, stage III-IVA oropharyngeal cancer patients examining the effect of a triple-agent induction regimen of paclitaxel, cisplatin, and cetuximab for 3 cycles followed by radiation therapy combined with weekly concurrent cetuximab. The radiation dose was prescribed at 69.3 Gy in 33 fractions after a clinical assessment of partial response or stable disease, versus a deescalation of the dose to 54 Gy in 27 fractions for patients achieving a complete clinical response. For uninvolved nodes, the elective radiation dose was 51.3 Gy in 27 fractions. The primary endpoint was a 2-year PFS rate of ≥ 85%. Ninety patients were accrued, of whom 80 patients were evaluable; of these, 62 patients (78%, exceeding an expected rate of 69%) achieved complete clinical response and were treated on the reduced-dose radiation arm to 54 Gy. At a median follow up of 16.2 months, the preliminary result for 1-year PFS (n=62) in the low-dose arm was 91% (95% CI, 80-96). One-year PFS for the 15 patients treated to standard radiation dose was estimated at 87% (B. Burtness, personal communication). The ECOG trial used induction chemotherapy, which this trial does not. In addition, the doses used in the ECOG trial do not correspond to the proposed dose for this arm of 60 Gy. However, the ECOG trial is important in that a detailed breakdown of the patient subsets in the ECOG reduced dose radiation arm lends further prospectively obtained data to support the retrospective evidence forming the basis of the eligibility criteria proposed for this trial. In E1308, for patients with T1-T3 stage, the 1-year PFS was 92% (95% CI, 80-97) whereas for T4, the result was 86% (95% CI, 33-98). In patients with N0-N2b stage, the 1-year PFS was 92% (95% CI, 78-97) whereas for N2c, it was 88% (95% CI, 61-97). For patients with ≤ 10 pack-years of smoking, the 1-year PFS was 97% (95% CI, 83-99.6) whereas for patients with more smoking history, the result was 84% (95% CI, 57-94). Recently confirmatory 2-year PFS results were issued in preliminary form, reporting 96% PFS for patients with <10 pack-year history and T1-3 N0-N2b stage who were treated on the low-dose arm (Cmelak 2014). For this reason, the early results of E1308 support the hypothesis that our trial's proposed selection criteria are likely to identify a group of patients able to achieve excellent PFS with reduced-intensity treatment approaches. Several small prospective trials are now accruing using various combinations of reductions in radiation therapy dose, substitutions of systemic therapy for radiation therapy, and/or novel combinations of systemic and radiation therapy in an attempt to maintain high locoregional control rates with reduced toxicity (Trotti and Yom, unpublished data summary, 2013; see table below). It should be noted that many of these trials were designed prior to the release of preliminary data at ASCO 2012 from 2 important clinical trials. These 2 trials, DeCIDE and PARADIGM, were phase III trials testing the benefit of adding induction chemotherapy to a standard chemoradiation platform; neither demonstrated any additional benefits in either locoregional control or OS (Cohen 2012; Haddad 2012). In the PARADIGM trial, patients with stage III/IV squamous cell carcinomas of the oral cavity, oropharynx, larynx, or hypopharynx were eligible, but 55% of those enrolled had oropharyngeal cancer. By the time of the early closure of the PARADIGM trial due to slow accrual, 145 patients had been randomized to either induction docetaxel/cisplatin/5FU chemotherapy followed by radiation concurrent with either carboplatin or docetaxel, versus upfront cisplatin-radiation. All patients had radiation given to 70 Gy in 2 Gy fractions. At a median follow up of 49 months, the 3-year overall survival was 73% in the arm consisting of induction chemotherapy followed by chemoradiotherapy, versus 78% in the chemoradiotherapy group. No advantage was seen with the use of induction chemotherapy for patients with oropharyngeal cancer or in the subgroups with advanced nodal stages of N2b/N2c or N3 (Haddad 2013). No further large-scale, head-to-head trials of induction chemotherapy followed by concurrent chemoradiation versus concurrent chemoradiation are known to have been planned at this time. As both the DeCIDE and PARADIGM trials included a large majority of oropharyngeal cancer patients, further exploration of induction chemotherapy for this disease site has been deferred until the emergence of clearer indications for its application or until the mature results of E1308 are available.  
| Current Phase II Protocols for HPV Positive Oropharyngeal Cancer Patients   |                                                                                 |                                                                                                                                              |           |                                        |            |          |
|-----------------------------------------------------------------------------|---------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|-----------|----------------------------------------|------------|----------|
| Institution                                                                 | Systemic                                                                        | Dose to Gross                                                                                                                                | Target    | Activation                             | Planned    | Primary  |
| Name                                                                        | Agent                                                                           | Disease                                                                                                                                      | Accrual   | Date                                   | Closure    | Endpoint |
| Univ. North  Carolina,  Chapel Hill                                         | 60 Gy                                                                           | 40                                                                                                                                           | November  | January                                | Pathologic |          |
| 2011                                                                        | 2016                                                                            | response at 3  months                                                                                                                        |           |                                        |            |          |
| John  Hopkins  Univ.                                                        | Concurrent  cisplatin 30  mg/m2 weekly Concurrent  Cisplatin 40  mg/m2 weekly   | 63 Gy to  pharyngeal  constrictors,  larynx, parotids,  mandible, and  masticatory  muscles +8 mm  expansion, 70  Gy to remainder  of PTV 60 | January   | February                               | Localregional            |          |
| 2010                                                                        | 2015                                                                            | control ≥  80%, late  toxicity at 2  years                                                                                                   |           |                                        |            |          |
| Long Island  Jewish  Hosp.                                                  | Induction TPF  x 3, then +/- concurrent  chemotherapy                           | Responders: 70  Gy; non-responders:  70 Gy (with  concurrent  chemotherapy)                                                                  | 50        | August                                 | January    |          |
| 2010                                                                        | 2013; no  results  reported                                                     | Response at 3  months                                                                                                                        |           |                                        |            |          |
| Dana Farber  Cancer  Institute                                              | 50                                                                              | September                                                                                                                                    | September | Localregional                                        |            |          |
| 2010                                                                        | 2015                                                                            | control at 2  and 5 years                                                                                                                    |           |                                        |            |          |
| ECOG 1308                                                                   | Induction TPcetuximab x 3,  then  concurrent  chemotherapy Induction TPF  x 3, then  concurrent  chemotherapy                                                                                 | Responders  receive "reduced  dose" Responders: 54  Gy; nonresponders: 70  Gy  90                                                                                                                                              | March     | Closed                                 |            |          |
| 2010                                                                        | August  2011; early results  reported                                           | PFS at 2  years in 54  Gy group                                                                                                              |           |                                        |            |          |
| Memorial  Sloan  Kettering                                                  | Feasibility of  18F-MISO  PET to detect  hypoxia, 3- month neck  control ≥  80% |                                                                                                                                              |           |                                        |            |          |
| Univ. of  California,  Davis                                                | "standard  chemotherapy " (concurrent  regimens)                                | 70 Gy to  primary, 60 Gy  to nodes  followed by neck  dissection 100  HPV+,  50 HPV                                                                                                                                              | June 2004 | June 2013;  no final results  reported |            |          |
| Induction  carboplatinpaclitaxel x 2,  then  concurrent  paclitaxel                                                                             | Complete  response: 54 Gy;  non-responders:  60 Gy  50                          | October                                                                                                                                      | October   | PFS at 2                               |            |          |
| 2012                                                                        | 2014                                                                            | years                                                                                                                                        |           |                                        |            |          |  
In support of reduced total radiation doses for HPV-associated malignancy, additional consideration can be given to the experience of locally advanced cervical and anal squamous cell carcinomas, both entities etiologically related to oncogenic HPV strains in a manner similar to "low risk" HPV positive oropharyngeal squamous cell carcinoma. Anal and cervical squamous cell carcinomas share a standard treatment of radiation or chemoradiation, frequently cisplatin-based. Typical goals of protocol-based radiotherapy treatments for these cancer types are to achieve a radiation dose equivalent to gross disease of approximately 54-60 Gy in conventional fractionation, in combination with systemic radiosensitizing chemotherapy (Ajani 2008). For cervical cancer, weekly cisplatin chemotherapy at 40 mg/m2 is established as a highly effective concurrent platform that shows activity in concert with radiation therapy (Lanciano 2005, Kim 2008) and weekly cisplatin, due to its lesser toxicities, has for the most part replaced 5- FU-based regimens. While dosing to cervical cancers may incorporate brachytherapy implant to achieve the aforementioned dose goals, anal cancers are exclusively treated with external beam radiation therapy. For the earliest stages of anal cancer, a minimum dose of 45 Gy is given, but doses of 50.4-55.8 Gy are commonly recommended for bulky disease. Even for the most advanced cases of anal cancer, doses of 55.8-59.4 Gy are generally prescribed (Poggi 2010). Therefore, there is precedent among other HPV associated cancers to be treated to lower radiotherapy doses than typically used in the head and neck cancer community. Reduced-total dose radiation therapy is expected to diminish both acute and long-term toxicity and if similar survival outcomes are preserved, these efforts will rapidly redefine the landscape of oropharyngeal cancer clinical investigations. Therefore, in order to remain at the forefront of clinical research initiatives in HPV-associated oropharyngeal cancer, the study investigators propose that these principles of "deescalation" be incorporated into clinical investigations.  
2.2 Rationale for Arm 1 **Radiosensitizer Regimen: Weekly Cisplatin at 40 mg/m**2 Cisplatin is an established, effective radiosensitizing agent in head and neck cancer therapy. Cisplatin has been established as the concurrent systemic treatment of choice in multiple head and neck cancer protocols (Adelstein 2008). It also is the preferred systemic agent of choice in the NCCN guidelines. However, bolus cisplatin doses at 100 mg/m2have been of a subject of concern due to the known toxicities, particularly in terms of emetogenesis, renal impairment, blood counts, and ototoxicity. NRG Oncology head and neck cancer trials have traditionally employed 2-3 cycles of bolus cisplatin given every 21 days. For example, RTOG 0129 used cisplatin given for 3 cycles at 100 mg/m2, whereas RTOG 0522 used a similar regimen but reduced the number of cisplatin cycles to 2. RTOG 1016 uses 2 bolus cycles of cisplatin. Weekly cisplatin has been investigated as an alternative to cisplatin cycles given at 100 mg/m2 with a lower overall toxicity profile. For nasopharyngeal cancer, where the burden of toxicity from systemic chemotherapy administration is particularly high, weekly cisplatin at 40 mg/m2is well-established in practice as a concurrent radiosensitizing drug and has demonstrated a survival advantage over radiotherapy alone, while producing lower toxicities than the standard schedule (Chan 2002; Chen 2008; Qi 2011). In head and neck cancer more generally, a French randomized trial showed that patients treated with radiation plus weekly cisplatin at a fixed weekly dose of 50 mg (roughly equivalent to 30 mg/m2/week) had superior outcomes compared to those receiving radiation alone (Bachaud 1996). Another positive randomized trial combined cisplatin, 6 mg/m2/day (equivalent to 30 mg/m2 per week) with radiation versus radiation alone (Jeremic 2004). However, an older ECOG trial (Quon 2011) used 20 mg/m2/week of cisplatin; the reduced efficacy seen in this study may be attributable to the lower cumulative dose achieved. A review of combined modality trials indicated that cisplatin schedules delivering a cumulative dose of about 200 mg/m2concomitantly during radiation were associated with positive outcomes (Ang 2004); this principle may explain the radiosensitizing efficacy seen with cisplatin doses fractionated in a multitude of ways (daily dosing, weekly dosing, fractionated over a couple of days to a week for each cycle). Based on these various lines of evidence, weekly cisplatin at a dose of 40 mg/m2per week is used as a concurrent regimen in NRG Oncology trial designs going forward in nasopharyngeal cancer (NRG-HN001) and high-risk postoperative head and neck cancer (RTOG 1216).  
For the purposes of this trial, we are therefore choosing weekly cisplatin administration at 40 mg/m2, in order to maintain excellent cancer control and further reduce toxicity in this arm of the phase II trial and to be consistent with the emerging generation of NRG Oncology trials using weekly cisplatin.
nrg oncology
2.3 rationale for arm 2

In major head and neck cancer trials over the past decade, modestly accelerated radiation therapy has been shown to be tolerable, even in the context of concurrent systemic therapy delivery. For example, RTOG 0129 tested a randomization to either a standard versus concomitant boost radiation therapy regimen in combination with cisplatin for 3 versus 2 cycles, respectively; while no advantage was seen from the radiotherapy acceleration, a reduction in systemic radiosensitizer was shown to be possible with accelerated fractionation (Ang 2010). As a result, subsequent head and neck cancer trials, RTOG 0522 and RTOG 1016, have utilized a standard arm consisting of a modestly accelerated regimen of 70 Gy over 6 weeks delivered with 2 cycles of cisplatin. In both of these trials, patients were treated with 6 fractions of radiation therapy per week, utilizing a minimum 6-hour interfraction interval to assure normal tissue repair between fractions. Thus, a modest acceleration of the radiation regimen has been accepted as a feature of treatment for patients enrolled on NRG Oncology trials over the past decade. Radiation alone is already considered a standard treatment option for all patients with low and low-intermediate stages of oropharyngeal cancer. For T1-2, N0 oropharyngeal cancers, the NCCN guidelines support a treatment plan of radiation therapy alone to doses of 66-74 Gy, given in mildly accelerated or conventional fractionation at the standard evidence level of 2A. The addition of systemic radiosensitizer is only considered for T2N1M0 cancers and set at a lower evidence level of 2B. One should note that these treatment recommendations were found to be effective and installed as standard treatment recommendations in an era when HPV status was not known to be a critical prognostic factor and thus, these are considered to be standard recommendations independent of a patient's HPV status. The University of Texas - M.D. Anderson Cancer Center has frequently utilized 66 Gy in 30 fractions over 6 weeks as a standard treatment for "small primary" (T1-T2) oropharyngeal cancers; patients who receive concurrent chemoradiation are typically prescribed approximately 70 Gy. Recently, information was shared from the MD Anderson institutional database with the study investigators. For 214 patients with stage T1-T2 oropharyngeal cancer with any degree of nodal involvement (i.e. AJCC stage IIIIVB) who had ≤ 10 pack-year history of smoking and who were treated with radiation therapy alone, the 2-year locoregional control rate was 95.3% and the OS rate was 90.2%. For 109 patients with these same characteristics treated with radiation therapy and some form of concurrent systemic therapy (with or without induction chemotherapy), the 2year locoregional control and OS rates were 92.7% and 91.8% (Garden, personal communication, 2012). While there were undoubtedly strong selection biases in assigning patients to radiation therapy alone versus concurrent chemoradiotherapy, these results lend additional support to the hypothesis that the use of systemic radiosensitizer may not be necessary to achieve excellent results in low-risk HPV positive oropharyngeal cancer patients. For this trial, there is interest in pursuing radiation therapy alone as a viable treatment option to offer to selected "low risk" oropharyngeal cancer patients. Thus, the proposed arm is designed to explore a further modest de-escalation using radiation therapy alone, without the addition of a systemic radiosensitizer. This fractionation schema would be given in a manner similar to those delivered in previous NRG Oncology trials, in which 6 fractions would be delivered each week in order to produce a modest acceleration of the treatment course. These recent head and neck cancer trials have successfully delivered 70 Gy in this modestly accelerated manner at 6 fractions per week, in conjunction with systemic cisplatin chemotherapy; and in one arm of RTOG 0522, this modest acceleration was accompanied by not only concurrent cisplatin but concurrent cetuximab administration. Therefore, it is expected that modestly accelerated radiation therapy alone given in this way to a total dose of 60 Gy should be very well tolerated. Substantial total dose reduction has been previously implemented in Europe using altered fractionation schemas without apparent losses in locoregional control. For example, from 1966-1975, one prospectively randomized study including 734 patients with laryngeal and hypopharyngeal cancers demonstrated that a total dose reduction of 18-22% could be achieved using combinations of shortened treatment time and hypofractionation with no differences in laryngectomy-free survival or OS at 10-year follow up (Wiernik 1990). In the early 1990s, the Medical Research Council ran a multicenter trial involving 11 centers and 918 patients in which patients with head and neck cancer from stages II-IVB were randomized to either 66 Gy in 33 fractions given over 6.5 weeks or a regimen of 54 Gy in 36 fractions given at 1.5 Gy/fraction 3 times daily over 12 consecutive days (CHART). At a follow-up time of over 6 years, no differences were seen between the 2 arms in locoregional control, disease-free interval, freedom from metastasis, or survival, and 10year follow up likewise showed no difference in survival endpoints (Dische 1997; Saunders 2010). Thus, the principle of using accelerated schedule to decrease the total radiation dose has been clinically validated as effective. However, late toxicities have been a concern in such aggressively shortened treatment courses, and most investigators favor a more moderate approach to treatment acceleration. Most recently, NRG Oncology has adopted an acceleration schema modeled after that undertaken in the Danish Head and Neck Cancer Study Group (DAHANCA) using 6 fractions of standard radiation given per week. In the DAHANCA 6&7 randomized trial, 1476 patients with stage I-IV squamous cell carcinomas of the oral cavity, pharynx, or larynx receiving the hypoxic radiosensitizer nimorazole were assigned to either 5 or 6 fractions per week, to a total radiotherapy dose of 66-68 Gy in 33-34 fractions (except for T1 larynx cancer which was assigned to a lower dose). This trial showed improved 5-year locoregional control and DFS, with only transient acute morbidity related to the acceleration (Overgaard 2003). No significant differences were seen in late endpoints at a median follow-up time of over 4 years (Mortensen 2012). A
report on this trial analyzing the effect of p16 expression found improvements in locoregional control, disease-specific survival, and OS associated with p16 positivity, as well improvements in locoregional control and disease-specific survival from accelerated radiation therapy among both p16 positive and p16 negative tumor groups. Among p16 positive patients, the hazard ratios for the 6 fractions per week regimen as compared to the standard were 0.73 [0.59-0.92] and 0.43 [0.22-0.82]) for 5-year disease-specific survival and OS, respectively (Lassen 2011). The conclusion of the authors was that the use of a moderately accelerated radiotherapy regimen in this context specifically was advantageous for HPV/p16 positive head and neck squamous carcinoma. Clinically-based precedent exists for reduced-total dose radiation at 60 Gy delivered over a period of 5 weeks. In the Princess Margaret Hospital's series of 449 oropharyngeal cancer patients treated with radiation therapy alone using a variety of schedules ranging from 60-70 Gy over 4-7 weeks, the most commonly used schedule was 60 Gy in 25 fractions given at 2.4 Gy per fraction over 5 weeks. Of note, among 148 p16 positive oropharyngeal cancer patients in this series, 41% had T3-T4 tumors and 87% had stage grouping of III-IVB. Patients with p16 positive oropharyngeal cancer who had a ≤ 10 pack-year history of smoking (n = 37) had 3-year overall survival, cause-specific survival, local control, and regional control rates of 86%, 92%, 95% and 97%, with distant control rates of 92% (O'Sullivan 2012). Despite these excellent overall results, there were negative predictive factors identified among the p16 positive patients; T4 stage was an adverse predictor for cause-specific survival, and 13/24 patients with p16 positive N3 disease died. These findings, similar to those consistently seen in other retrospective and prospective series, further confirm the decision to exclude these patients with a very high burden of disease from de-intensified approaches. On this basis, for patients where excellent outcomes are most likely using reduced-dose approaches, the study investigators have chosen a schedule of 6 fractions per week based on its efficacy at producing improvements in tumor control, specifically in p16 positive patients (based on evidence from the DAHANCA experience), without intensifying the late effects of treatment. It is hypothesized that shortening of the total treatment time to 5 weeks, similar to the treatment package time used in the Canadian experience, will compensate for a modest reduction of the total dose. In summary, modestly accelerated radiation therapy using an IMRT technique has been shown to be feasible, safe, and able to be properly delivered within single institutions and the national clinical trial setting as an effective single modality treatment for "low-risk" oropharyngeal cancer. In this highly selected, good-prognosis population, DFS and OS results with modestly accelerated IMRT alone appear to be comparable to those achieved with chemoradiation therapy. Thus, Arm 2 offers a validated, de-escalated treatment for selected "low-risk" oropharyngeal cancer patients. As assistance in assessing the proposed efficacy of these regimens, we have provided a table of relative biologic effective dose (BED) differences between common standard schemas and this trial's proposed arms, which are spread over a fairly small range of values (John Murnane, personal communication, 2013).  
| Fractionation                                                                                                                                                                | Acute BED              | Late BED               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|------------------------|
| 70 Gy in 35 fx in 7 weeks +                                                                                                                                                  | 84.0 Gy10 + additional | 116.7 Gy3 + additional |
| cisplatin                                                                                                                                                                    | cisplatin effects      | cisplatin effects      |
| 66 Gy in 30 fx in 6 weeks (RTOG  0022)                                                                                                                                       | 80.5 Gy10              | 114.4 Gy3              |
| 60 Gy in 25 fx in 5 weeks (Princess  Margaret accelerated schedule)                                                                                                          | 74.4 Gy10              | 108 Gy3                |
| ARM 1: 60 Gy in 30 fx in 6 weeks                                                                                                                                             | 72 Gy10 + additional   | 100 Gy3 + additional   |
| + cisplatin                                                                                                                                                                  | cisplatin effects      | cisplatin effects      |
| ARM 2: 60 Gy in 30 fx in 5 weeks                                                                                                                                             | 75.2 Gy10              | 100 Gy3                |
| *The tumoricidal acute effect of Arm 2 is expected to be similar to that of the Canadian  experience but with less late effect BED as compared to hypofractionated regimens. |                        |                        |
nrg oncology
2.4 measuring patient-reported outcomes (pros)

The purpose of collecting PRO/QOL data in this phase II study is to evaluate the potential reduction in the burden of toxicity from the patient's perspective as compared between 2 different methods of treatment de-intensification, either using reduced-dose radiation with weekly cisplatin, or modestly accelerated, reduced-dose radiation alone. These findings will inform the selection of the least toxic arm from the patient's perspective with respect to achieving a better swallowing related QOL outcome, while maintaining at least 85% PFS. The hypothesis is that among the 2 approaches in this trial, swallowingrelated QOL will be superior in the radiation-alone arm compared to the chemoradiation arm at 1 year. The specific aim is to determine patient reported long-term swallowing outcomes (≥ 6 months to 2 years) in p16 positive oropharyngeal carcinoma patients treated with a reduced total dose radiation therapy approach +/- concurrent chemotherapy. Participation in the PRO component of the MD Anderson Dysphagia Inventory-Head and Neck (MDADI-HN) instrument is mandatory in this study. To complete the MDADI, the patient must comprehend verbal English or one of the validated written translated versions of the MDADI. All protocol-eligible patients will be asked to participate in the additional, optional PRO component of this study which is comprised by the University of Washington QOL questionnaire. In order to participate in this PRO assessment, patients must be able to comprehend verbal English. The selection of the primary PRO instrument (MDADI) has been limited to maintain a primary focus on the evaluation of late dysphagia (defined as ≥ 6 months to 2 years).  
Sample size will adjust for patients at Canadian centers who are unable to complete the MDADI in English (estimated at 12% based on prior enrollment to NRG Oncology head and neck cancer trials). Patients who are blind or illiterate may have questions and responses read verbatim by the investigator or research associate; non-validated translation of instruments is not allowed. To assess swallowing function, the MDADI (see Section 11.2 for details of this assessment) will be administered in each arm prior to the start of treatment (baseline), at completion of radiation therapy, and then at 6, 12 and 24 months from the end of radiation. We also will compare patient-reported swallowing outcome to objective clinical measures using CTCAE, v. 4 clinician-reported toxicity and documented gastrostomy tube retention rates at each follow-up visit. Additionally, baseline performance status and co-morbidities will be collected by chart extraction for patients in each treatment arm using the Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) and the Charlson Comorbidity Index (CCI). The MDADI constitutes the primary tool being used for this assessment; the PSS-HN, CTCAE, v. 4 graded toxicities, and CCI are exploratory, secondary tools.
nrg oncology
the mdadi as primary pro/qol

The MDADI has been validated in head and neck cancer patients in a single institution series (Chen 2001). Reliability (internal consistency reliability) was established with the overall Cronbach α coefficient = 0.96, suggesting that each item of the MDADI addresses the same concept. Stability was tested with test and retest reliability coefficients of the subscales ranging from 0.69-0.88 (global, 0.69; emotional, 0.88; functional, 0.88 and physical, 0.86). Spearman correlation coefficients between MDADI and Short Form 36 (SF-36) demonstrated construct validity. The MDADI also was able to detect differences in groups of patients with head and neck cancer who were expected to be functioning at different levels and also by head and neck site and pathological findings (Chen 2001). MDADI scores also discriminate clinically meaningful differences in swallowing performance among aspirators and non-aspirators, gastrostomy dependent, and gastrostomy-free patients, and various levels of oral intake (Hutcheson 2015). To be considered an acceptable arm in this trial, the MDADI results for the "superior" arm must be clinically acceptable (mean total MDADI score at 1 year ≥ 60). It is expected that this baseline of clinical acceptability should be met by one or both arms, but the ability to meet this basic criterion has been set as a required part of the primary endpoint for this trial. Furthermore, to compare between arms, the primary QOL endpoint will measure the mean individual change in total MDADI score at 1 year from baseline in each arm. One of the arms will be deemed inferior to the other only if there is a mean change score of ≥ 5 points from baseline for that arm and there is a ≥ 5 point difference between the 2 arms that is statistically significant. The minimum important difference (MID) is defined as the smallest difference in score in the domain of interest that patients perceive as important, that would lead to consider a change in the patient's management (King 2011). The MID for the MDADI has not been previously published; however, an important methodological proposal is that the MID should be within 5 to 10% of the instrument range (Ringash 2007). Since the MDADI score ranges from 0-100, a change of 5% (5 points) in the score is considered meaningful. Secondary analyses will evaluate the percentage of patients in each arm with poor swallowing QOL, defined as an individual patient MDADI score of ≤ 60 at 1 year. Secondary analyses also will evaluate poor swallowing QOL based on the subscale scores of the MDADI inventory, particularly the physical and functional subscales at 1 year. Oropharyngeal dysphagia after chemoradiation or radiation alone can have a significant impact on QOL. Multiple factors are thought to contribute to the severity of oropharyngeal dysphagia, including multimodality therapy (surgery, radiation, chemotherapy), total radiation dose, and dosimetry to organs at risk (OARs), including the larynx, oral cavity, and pharyngeal constrictors (Eisbruch 2002, Eisbruch 2011, Caudell 2010), as well as intrinsic patient radiosensitivity and susceptibility to late fibrosis. These factors will be addressed in this trial by the reduction of radiation dose, with improvements in dosimetric outcomes, as well as by the removal of chemotherapy from 1 arm. Therefore, this trial has high potential to improve post-treatment dysphagia and as a result, patient-reported swallowing related QOL.
nrg oncology
correlation of mdadi to measures

Bhide, et al. (2009) assessed dose volume histogram (DVH) data for superior, middle, and inferior constrictors in 37 head and neck cancer patients undergoing IMRT and correlated these to NRG Oncology-graded dysphagia at 1 year and MDADI scores in patients undergoing induction chemotherapy followed by high-dose cisplatin chemoradiation. While this study did not find a statistically a significant correlation between pharyngeal constrictor dose and objective measurements of dysphagia and MDADI parameters, only 1 time point was measured at 1 year post-treatment, and baseline pre-treatment QOL assessments were not obtained. Lack of correlation may have been due to small patient numbers and the possible confounding effects of induction chemotherapy and high dose cisplatin. In the patients treated with a primary chemoradiation approach, Bhide, et al. reported a 1-year median MDADI total score of 74 (range, 24-100), global 4/5 or 80, PT of 27 (range, 4-40) or 67.5, ET of 23 (range, 830) or 76.7, and FT of 20 (range, 5-25) or 80 (latter when scored out of 100). It also was noted that there was a significant correlation between observer-rated, RTOG graded dysphagia and all the MDADI parameters. Hence, MDADI was a valid endpoint to measure swallowing toxicity from the patient's perspective. Levendag, et al. (2007) also studied the relationship between pharyngeal constrictor dose, observer-reported dysphagia, and patient-reported swallowing QOL using the MDADI, in an oropharyngeal cancer population treated with chemoradiation using both IMRT and 3DCRT. A crosssectional survey was taken at a mean follow up of 18 months; the QOL response rate was 88%. When these authors compared chart-reviewed dysphagia rates corresponding to NRG Oncology grade 3 and 4 dysphagia (in 23% of patients) to MDADI scores, a total MDADI score of ≤ 50 was found in 26%, and a significant correlation was found between observer-rated grade 3 and 4 dysphagia and MDADI total score.
nrg oncology
use of mdadi to determine

treated with surgery, limited baseline and longitudinal data for the MDADI exist to define an acceptable level of swallowing QOL outcome in patients treated with either surgery or chemoradiation therapy. In a cross-sectional study of patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) (Gillespie 2004), the MDADI-HN was administered to patients at least 12 months after treatment. Patients receiving primary chemoradiation for oropharyngeal primary tumors demonstrated significantly better scores on the emotional (p=0.03) and functional (p=0.02) subscales of the MDADI than patients receiving surgery and post-operative radiation. However, in this study, surgical techniques varied including more extensive surgery with some patients receiving wide excision with reconstruction involving skin graft, radial forearm free flap, or levator scapular flap. Mean subscale MDADI scores for the group receiving surgery with postoperative radiation ranged from 52.5 to 62.5, while the primary chemoradiation group was 64.5 to 86.4. In more recent surgical series, with emerging endoscopic transoral surgery approaches, improved swallowing outcomes have been observed. Data from prospective single institutional series (Sinclair 2011) suggest that patients undergoing transoral robotic surgery (TORS) for T1 and T2 oropharyngeal squamous cell carcinomas have an initial decrease in mean scores on the MDADI-HN in the immediate postoperative period when compared to baseline pre-operative scores, although increasing improvement was observed over time. Additionally, global and physical subscales were most affected in the immediate post-operative period with recovery of scores observed at last follow up. Factors which predicted poorer physical MDADI outcomes included nodal status (p=0.049), less than 12 months follow up (p=0.01), and pre-operative physical scores of < 100 (p=0.01). Similar trajectories have been shown in nonsurgically treated cohorts (Roe 2014, Schwartz 2012, Hutcheson 2014).
nrg oncology
expected qol outcomes using the

Since the Gillespie study (2004) describes a fairly wide range of mean subscale MDADI
scores for patients receiving primary chemoradiation from 64.5 to 86.4 from the preIMRT era, it is important to prospectively collect PRO swallowing data at baseline and interval follow up in this study of modestly reduced radiation therapy dose in the modern IMRT era.  
Swallowing PROs previously have not been studied in a prospective, randomized, multiinstitutional setting to evaluate the benefit from the patient's perspective of treatment deintensification using a primary radiation approach.  
In the proposed study, since there will be 1 radiation-alone arm, and the other concurrent chemoradiation arm will be using weekly cisplatin, putative dosimetric and treatmentspecific factors may be more closely examined with regards to dysphagia outcome using serial measurements of swallowing-related toxicity and PROs before and after treatment and with and without the potential confounding effects of high-dose chemotherapy. Based on the studies by Gillespie (2004), Chen (2001) and Bhide (2009), it is expected that with a primary radiation approach that expected scores would approximate mean total MDADI ≥ 70 and global ≥ 80, with subscales for PT ≥ 65, ET ≥ 75, FT ≥ 80 when scored out of 100. Rationale for including a General QOL Instrument, the University of Washington QOL Questionnaire, for this Trial Oncologists now accept the quality of survival, in addition to the length of survival as an important clinical endpoint in trial design for patients with locally advanced cancers. While clinician-reported toxicity is able to detect adverse clinical events, PROs are paramount in this regard because they directly measure the patient's perception of symptom burden from the treatment of the disease and its impact on QOL without bias from the clinician. As the treatment for HPV positive oropharyngeal carcinoma evolves, a high rate of acute and late normal tissue complications from definitive radiation-based treatment may no longer be considered acceptable, if alternatives evolve to produce similar rates of cure but improved QOL. In a study of 177 patients with head and neck cancer, using the University of Washington QOL Questionnaire (UW-QoLv.4), data suggests that QOL and long-term swallowing outcome in the HPV positive oropharyngeal carcinoma population are significantly better compared to the HPV negative population at baseline and at 6 months to 1 year after treatment (Maxwell 2013). Moreover, since HPV positive oropharyngeal carcinoma patients are expected to have superior baseline QOL, with few co-morbidities compared to the HPV negative population, such patients may be less likely to accept additional acute or long-term toxicities, which generally have been associated with definitive head and neck radiotherapy even in the IMRT era. In this study we also will explore other exploratory QOL outcomes in this population receiving dose de-escalated radiotherapy with regards to the patient's perception of pain, their appearance, activity, recreation, chewing, speech, shoulder, taste, saliva function, mood and anxiety using the UWQoLv.4 at the same time points, in addition to the primary QOL endpoint of swallowing.  
Such items are quite applicable to this group of patients, who are relatively highperforming and have concerns beyond (but also including) dysphagia. Other, more general instruments were considered in choosing UWQoLv. 4 and were judged to contain excessive overlap with the MDADI and, moreover, to cover too many items resulting in excessive burden given the exploratory nature of this instrument in the novel setting of reduced dose radiation therapy . Adding the UW-QoLv.4 is justified, since this treatment paradigm essentially represents a new disease entity entailing a novel treatment paradigm, and there is no pre-existing data on the nature of outcomes in such patients receiving 60 Gy. The targeted patient group is a potentially more favorable group both in terms of oncologic and long term QOL outcomes, and having these additional data from the UW-QoLv.4 may aid decisions about next research steps, particularly if no significant differences in dysphagia are found in either arm. As such, both the primary and exploratory QOL data from this trial will inform which of the 2 arms may proceed to a future phase III randomized trial comparing our paradigm to other treatment de-intensification approaches such as surgery or standard dose chemoradiation.  
Employment/Work Status and Return to Work after Radiotherapy An exploratory objective will be to determine the impact of radiotherapy de-escalation on the patient's work status before and after treatment. In a study of 85 patients in head and neck cancer survivors in the Netherlands (Verdonck-de Leeuw 2010), it was found that the median time to return to work was 6 months (range 0-24 months), while 71% patients returned to work within 6 months. The hypothesis is that dose de-escalation of radiotherapy will lead to decreased acute and late toxicities resulting in earlier return to the work and improved retention in the work force compared to conventional dose radiotherapy with or without chemotherapy. Multiple QOL factors may affect the ability of the patient to return to work including anxiety, oral dysfunction including xerostomia, trismus, sticky saliva, problems with dentition, appetite, and social eating. Descriptive statistics will be used to assess work status before and after treatment. Work status will be tested for associations with concurrent chemotherapy use, age, gender, marital status, education level, tumor factors, and health-related QOL using the UW-QoLv.4. Work status in head and neck radiotherapy is currently being evaluated in depth in RTOG 1016 using a detailed PRO instrument. In HN002, a very limited number of questions completed by the investigator and/or research associate will be integrated into the demographic evaluation of the patient before and after radiotherapy to assess baseline employment/work status and return to work status after treatment. These questions are not completed by patients and will not add to their burden.
nrg oncology
optional online completion of qol

Missing data are a significant problem, particularly for QOL assessments. Unlike data for traditional endpoints, such as survival, QOL data can never be obtained retrospectively if it is not provided by the patient at the appropriate time point. This limits researchers' ability to accurately perform QOL statistical analyses and negatively impacts the clinical relevance of this effort. Typically, QOL forms are filled out in hardcopy (paper). To provide a more convenient method of completing QOL assessments, NRG Oncology is working with VisionTree Software, Inc., San Diego, CA. VisionTree offers patients on this study the option of completing their QOL forms online from any location that has a computer with Internet access, including the patient's home, and provides reminders to patients to complete the assessments. VisionTree has developed a tool, VisionTree Optimal Care (VTOC), a HIPAA-secure, user friendly, web-based software system (Gorgulho 2005; Gorgulho 2007; Pedroso 2006). The VTOC tool contains a web-based system for global patient and trial administration access, which allows improved compliance and accuracy of data collection, validation, and reporting. It is compliant with the Title 21, Code of Federal Regulations, Part 11 statistical process control system and provides a mobile solution for clinical trials. QOL data are collected with Microsoft Excel and PDF export of reports. VTOC also has mobile messaging and e-mail reminders. Surveys can be "pushed" to patients for completion at timed intervals (see http://www.visiontree.com for details). This technology allows consenting patients on this study to fill out their QOL forms online from any location and to receive e-mail reminders to complete assessments. Email reminders also can be sent to research associates (RAs) at the appropriate institutions to remind them that a QOL time point window is about to close so that a patient can be contacted to fill out QOL information on time, before it becomes "missing data". In a pilot RTOG study (RTOG 0828), the compliance rate of patients completing QOL assessments at 6 months significantly improved using electronic technology. Based on this pilot data, NRG Oncology is offering VisionTree as an option in other studies, including this one. Patients preferring to complete hardcopy QOL assessments can do so. For this trial, the baseline QOL forms must be completed in hardcopy at the time of enrollment. To complete subsequent QOL forms online, patients will be asked for an email address that they consent to use so that e-mail reminders may be sent to them. The patient's e-mail address also will be used for password-protected access to VTOC. Patients who are interested in participating but do not yet have an e-mail address can obtain one for free from a number of sources (e.g. Yahoo!, Hotmail, or AOL). Patients will receive a login card (either printed or sent via e-mail) with which to log in using the secure, web-based VTOC portal. VTOC meets all HIPAA guidelines and is encrypted (via 128-bit SSL) for the security, privacy, and confidentiality of QOL information. It is similar to the secure login commonly used when performing online banking. The login card can then be kept and maintained by the patient. The patient's e-mail address only will be used by NRG Oncology for this purpose. Patients will be sent e-mail reminders to complete QOL forms. A typical e-mail reminder would read: "Your Quality of Life forms for the study, NRG-HN001, are now due. Please go to http://www.optimalcare.com, use your secure login, and complete the online forms. If any questions make you feel uncomfortable, you may skip those questions and not give an answer. If you have any questions, please e-mail or call your research associate at [insert RA e-mail address] or [insert RA telephone number]. Thank you for participating in this study." The reminders will be created by NRG Oncology and placed into a study template that will be sent to patients at customized intervals (at the time points when QOL forms are due). The first reminder will be sent at the beginning of the "window" to complete a QOL form, with a second reminder halfway through the window period if the QOL forms are not yet completed at that time point. A maximum of 3 reminders will be sent for each of the 4 QOL time points (following the baseline QOL forms, which are completed in hardcopy). After a patient has completed all forms in the VTOC portal, a dialogue box will appear that says "Thank you for completing your Quality of Life forms," and the patient will no longer receive any remaining notices for that time point. The site RA or study administrator will be informed through the VTOC "At-A-Glance" form management system when QOL forms have been completed.
nrg oncology
rationale for including modified barium

The purpose of the MBS component of this trial is to determine the long-term safety and efficiency profile of pharyngeal swallowing function two years after de-escalated therapy in patients with low-risk oropharyngeal squamous cell carcinoma (OPSCC). Participating sites are given the option to participate in this NCI NCI Biomarker, Imaging and Quality of Life Studies Funding Program (BIQSFP) -funded component of the study; MBS studies are not required for all sites to participate in the main part of the study. Videofluoroscopic swallowing evaluation (also known as the modified barium swallow [MBS] study) remains the gold-standard method to measure pathophysiology of swallowing dysfunction. MBS is widely utilized in clinical practice to measure safety and efficiency of pharyngeal bolus transport. MBS data are complementary to patientreported outcome (PRO) data. Patients' perception of swallowing abilities are influenced by a host of factors including physical swallowing dysfunction after nonsurgical therapy (eg, radiation-associated dysphagia and stricture) alongside other confounding toxicities of therapy that make eating a less pleasant experience (eg, thick mucus, dysgeusia, xerostomia). As such, PROs can over or under-report the true level of physical impairment. MBS offers the specificity of detecting aspiration (perceived or silent) along with physical effects of therapy on swallowing biomechanics free of these competing toxicities that elevate an individual's perception of swallow dysfunction but do not carry the same risk of secondary pneumonia. Much of our knowledge of aspiration and physiologic swallowing impairment comes from single-institution organ preservation trials that aggregate functional outcomes from HNSCC at multiple sites and report aspiration rates up to 40% in unselected post-radiated HNSCC cohorts, and in up to 80% of symptomatic patients (Eisbruch 2002, Eisbruch 2011, Logemann 2006, Caudell 2009, Hutcheson 2012, Hutcheson 2014). These data, based on findings from MBS studies, confirm that when swallowing physiology is disrupted after head and neck radiotherapy, patients have high rates of aspiration, much of which is undetected by patient report because of diminished sensory awareness. Silent aspiration has been reported in excess of 50% of patients who aspirate (Eisbruch 2002, Hutcheson 2012). Data specific to patients with oropharyngeal primary tumors are limited but suggest still a high burden of dysphagia using traditionally prescribed doses around 70 Gy. Using prospective MBS (baseline through 2 years), Eisbruch and colleagues (2011) reported 31% of OPSCC patients with elevated occurrences of aspiration relative to baseline ≥1 year after treatment, and 22% 3-year risk of aspiration pneumonia in a trial of chemotherapy and IMRT (70 Gy in 35 fractions, with weekly carboplatin AUC of 1 and paclitaxel 30 mg/m2) that was designed to protect dysphagia-organs-at-risk using dose constraints. MBS-detected aspiration significantly predicted pneumonia in this trial (p=0.017, Se 80%, Sp 60%), and silent aspiration was evident on MBS studies in 63% of patients who developed pneumonia. Pharyngeal residue on MBS studies also was significantly predictive of pneumonia after chemotherapy and IMRT (p<0.01 ) (Eisbruch 2011, Hunter 2013). Using split-field IMRT (70-72 Gy/35 fractions), >6-month aspiration rates of 8% and 10% were detected in oropharyngeal cancer patients enrolled in two single-arm phase II instititutional trials of induction chemotherapy and adaptive IMRT, respectively, at U.T.-MD Anderson Cancer Center, per prospective MBS analysis baseline through 2 years (Hutcheson 2014, Schwartz 2012). These results offer compelling support for the radiographic examination of swallowing outcomes to measure swallowing safety and efficiency as health-related endpoints cannot be fully detailed by PROs. Thus, we propose to evaluate swallowing using MBS studies at baseline and at 2 years after the end of radiotherapy as a secondary measure of functional outcomes in this trial. This will be the first prospective MBS-driven swallowing outcomes assessment after de-escalated radiotherapy in low-risk OPSCC. As the radiotherapy effect on swallowing would be expected to be lessened as compared to the traditional treatment at 70 Gy or more, this data will provide a clearer assessment of the impact of the addition of concurrent chemotherapy to a radiotherapy platform. The data will not only be important as a functional comparison of OPSCC patients treated with and without chemotherapy but will supply baseline values needed for future trial design The optimal time point for MBS is contigent on the study question. Two MBS time points (baseline and at 2 years after end RT) were selected for the current trial in order to prioritize the understanding of baseline-adjusted, long-term swallowing recovery after de-escalated therapy. There is only limited data to date that delineates swallowing function beyond 1 year after radiotherapy. Single-institution HNSCC trials that have incorporated prospective MBS have examined MBS data at multiple intervals (typically baseline, 3-6-months, 12-months, and at 24-months after end of radiotherapy) to model trajectories of swallowing impairment. Trajectories suggest a nadir in MBS-detected swallowing function on early post-RT MBS (<6-month intervals) with partial recovery of function by 12-months and incremental improvement thereafter to 24 months. That is, most recovery of swallowing function will occur in the first year, and dysphagia events after that point can be taken to reflect chronic dysfunction that will likely persist lifelong. By 2 years, MBS analysis reflects the "new normal" swallow and the new baseline by which to benchmark any progressive functional deterioration in long-term survivorship. Progressive or late deterioriation of swallow function is possible (ie, late-radiation associated dysphagia or "late-RAD"), but emerging data suggest a much longer latency to de novo late-RAD well beyond 5 years (median latency: 8 years) making it unrealistic to attempt to capture these late events in the MBS arm of the current trial (Hutcheson 10/2015). Two-year MBS-detected swallow recovery outcomes must be obtained to set the foundation to evaluate late events in follow-up studies. The proposed MBS centralized scoring method for MBS studies is the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST). With DIGEST, two MBS outcomes will be rated: 1) penetration/aspiration (ie, "swallow safety"), and 2) pharyngeal residue (ie, "swallow efficiency"). These domains were selected as universal items reported in swallowing practice that have been shown to significantly predict pneumonia in patients with oropharyngeal cancers. Laryngeal penetration and aspiration represent impairments in airway protection or swallow safety, whereas pharyngeal residue represents impairment in bolus clearance or swallow efficiency. Factor analyses have established these as valid constructs of pharyngeal dysphagia in patients with head and neck cancer (Frowen 2008). Ratings of aspiration and penetration are highly reliable (intraclass correlation coefficient: 0.80- 1.0) (Stoeckli 2003, Frowen 2008). Intraclass correlation coefficients for inter- and intra-rater reliability on the Penetration-Aspiration Scale were 0.96 and 0.95-0.97, respectively (Rosenbek 1996). Pharyngeal residue also is reliably measured as an ordinal rating (weighted kappa: 0.73 interrater, 0.85 intrarater ) (Dyer 2008). A cutpoint of 50% residue is widely used to represent a significant impairment in bolus transit
(Eisenhuber 2002, Martin-Harris 2008, Ryu 2012). Furthermore, discriminant analyses of two-dimensional area measures suggested a threshold value of 55% residue correlates with qualitative ratings of moderate/severe residue by expert clinicians (Dyer 2008). Safety and efficiency profiles of the pharyngeal swallow using ordinal-scaled penetration/aspiration and residue scores from MBS have been mapped to the CTCAE taxonomy in a validation study that is currently concluding at U.T. MD Anderson - the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST). DIGEST ratings will be assigned to each MBS to provide a CTCAE-compatible summary grade to the pharyngeal swallow: grade 1 "mild", grade 2 "moderate", grade 3 "severe", and grade 4 "life threatening" pharyngeal dysphagia.
nrg oncology
2.5 fdg-pet/ct imaging as a

The purpose of studying FDG-PET/CT in the context of HN002 is to determine the predictive value of 12-14 week post therapy FDG-PET/CT for locoregional control and 2-year PFS. Patients and investigators are given the option to participate in this component of the study although PET/CT scans are not required to participate in the parent study, HN002. The sensitivity and specificity of post-treatment FDG-PET/CT depend on the time interval between the completion of therapy and FDG-PET/CT. In a study of 26 patients, Goerres, et al. (2004) observed a sensitivity and specificity of 91% and 93%, respectively, for PET/CT scans performed as early as 6 weeks after chemoradiotherapy. However, other studies have not been able to reproduce these data (Porceddu 2005, Yao 2005) and instead suggest that PET/CT after chemoradiotherapy should not be performed before 10-12 weeks after the end of radiation treatment. By that time, most of the post-treatment inflammatory changes will have subsided, reducing the number of potentially false-positive interpretations. In general, the rate of false-positive cases declines with the interval between the end of therapy and PET/CT imaging (Lonneux 2000). The optimal timing of the first response assessment FDG-PET/CT after definitive (chemo) radiation is not precisely known, but an interval of at least 12 weeks has generally been recommended to balance the drawbacks of imaging too early versus too late. In rare cases, early detection of residual/recurrent disease is central to successful surgical salvage if appropriate, while a demonstration of a clinical and radiographic complete response obviates the need for further unnecessary and potentially morbid interventions. A recent meta-analysis involving 51 studies and 2335 patients (Gupta 2011) estimated the sensitivity and specificity of post-treatment FDGPET/CT at 91.9% and 86.9% for primary tumor and 90.4% and 94.3% for neck nodes, respectively, when the PET/CT was performed > 12 weeks after completion of concurrent chemoradiation therapy. Therefore, in this study, the FDG-PET/CT should be obtained at 12-14 weeks post-treatment. A reliable imaging modality to predict long-term locoregional control can serve as a surrogate imaging biomarker to judge the effectiveness of the investigational treatment.  
Residual structural abnormalities seen on anatomic imaging such as CT or MRI after definitive radiotherapy may not harbor viable cancer cells (Ware 2004). FDG-PET/CT is a functional imaging assessment that detects glucose metabolism of the tissue, and it is highly sensitive in the detection of viable cancer cells due to the high metabolic rate in these cells. Several single-institution retrospective studies have shown that a negative post-radiotherapy PET/CT was highly predictive of long-term locoregional control in locally advanced head and neck cancer after chemoradiation. Yao, et al. (2009) from the University of Iowa reported 188 patients with FDG-PET/CT obtained at a median of 15 weeks after radiotherapy. Of 151 patients with a negative FDG-PET/CT at the primary site, only 2 developed locally recurrent disease, with a negative predictive value of 98.7%. Of 171 patients who had a negative PET/CT in the cervical lymphatic region, only 2 were falsely negative, with a negative predictive value of 99%. Ryan, et al. (2005)
summarized the experience from Stanford University in 103 patients with 118 posttreatment PET/CTs. PET/CT results were correlated with surgical pathology and clinical outcomes, and the negative predictive value of PET was 98%. In a prospective study of 98 patients by investigators from MD Anderson Cancer Center (Moeller 2010), using a post-radiation maximum standardized uptake value (SUVmax) of 6.0 of the primary tumor as a cut-off, the investigators reported that the negative predictive value of FDG-PET/CT for disease-specific survival was 92%. In this study, they reported that there was no additional prognostic information of FDG-PET/CT in low-risk patients, i.e. HPV positive oropharyngeal cancer patients. However, this was assessed under conditions of standard regimens of chemoradiation. In addition, this study was under powered due to a low number of events. In this trial, 2 de-intensified regimens are being tested in p16 positive oropharyngeal cancer patients, and the predictive value of 12-14 week post therapy FDGPET/CT for 2-year PFS is unknown when treatment intensity is reduced. Therefore, the assessment of PET/CT in this setting is novel and important. Currently, FDG-PET/CT is commonly used for staging and assessment of treatment response in head and neck cancer. The Centers for Medicare and Medicaid services and most third party payers in USA provide reimbursement for a pre-treatment and a posttreatment FDG-PET/CT in head and neck cancer patients scheduled to receive definitiveintent radiotherapy. While PET/CT has become very accepted, practice patterns among head and neck cancer treatment centers vary somewhat in their use of PET/CT. Therefore, obtaining a pretreatment PET/CT and a 12-14 week post therapy PET/CT is highly recommended but not required, and for this study, obtaining PET/CT is left to the discretion of the clinician, as dictated per local clinical practice, and participation in the PET/CT assessment study is highly recommended but optional on the part of the patient and the investigator. Because of the frequent use of PET/CT in local centers, it is of interest to the study investigators to document the performance of PET/CT under "real-world" conditions. This approach may increase the future generalizability of any findings. Furthermore, based on the experience of RTOG 0522, a requirement for scanner accreditation would pose a concerning barrier to participation and produce an unacceptably low sample size. Therefore, a study-specific accreditation of PET/CT scanners of the participating institutions will not be required for participation in the PET/CT sub-study, although information will be requested on the facility where the PET/CT scans were performed.  
Because the PET/CT images will be centrally reviewed and scored on a qualitative basis, the impact of variations in the imaging technique should be substantially lessened.  
Regarding PET/CT technique, the study investigators recommend that the standard-ofcare guidelines from the National Cancer Institute and ACRIN Imaging Standards for PET should be followed as closely as possible (Shankar 2006). To provide a platform for standardizing interpretations of the PET/CT scans, the study investigators have developed a reader-based scoring system to minimize the effect of varying acquisition techniques. This ordinal scoring system (see below) will identify those patients who have complete metabolic response and those who did not have complete metabolic response, retrospectively. All of the post-treatment PET/CT images will be centrally reviewed at the end of the recruitment period and correlated with the clinical treatment outcomes. The proposed centralized scoring system was modified from the well-validated and clinically most useful five-point scoring system for mid-therapy and post-therapy assessment for lymphoma (Deauville criteria). This scoring system has been previously validated as a collapsed three-point categorization (negative for tumor, indeterminate, positive for tumor) for head and neck FDG-PET/CT scans performed between 4 and 24 months after therapy completion (Paidpally 2013). The scoring system successfully predicted outcome in these patients and added value to the clinical assessment at the time of the scans. In addition, the five-point scoring system has been recently validated in head and neck FDG-PET/CT scans performed between five weeks and 6 months after therapy completion in 214 head and neck squamous cell carcinoma patients. There was 90%, 97.2%, 94.9% and 91.3% agreement between the readers for overall, left neck, right neck and primary tumor site response scores, respectively. The corresponding Kappa coefficients for inter-reader agreement were k=0.70 (p<0.0001), k=0.81 (p<0.0001), k= 0.69 (p<0.0001), and k=0.67 (p<0.0001), respectively. The accuracy of the scoring system against a 6 month clinical follow up as the reference standard is excellent with ROC area under the curve 0.98 (95% CI 0.97-0.99; P < 0.001). Cox regression analysis showed a significant difference in overall survival between the patients who had a score between 1-3 (negative for tumor) and those who had a score 4 or 5 (positive for tumor) (log-rank, P<0.0001 with a hazard ratio of 0.056 [95% CI 0.022-0.138] (Subramanian, personal communication, 2014; Marcus 2014). Proposed Harmonization of FDG-PET/CT Ordinal Scoring and Classification of Results The tumor response evaluation will be carried out using a 5-point ordinal scale ranging from Definite Complete Response (score 1) to Definite Residual Disease (score 5). Diffuse uptake is defined as homogeneous FDG uptake, with smooth tapering borders. Focal uptake is characterized by an abrupt drop-off of FDG activity at the boundaries of the active area.  
Score 1: Definite complete metabolic response: The FDG uptake in the primary tumor or nodal sites is less than the background blood pool FDG uptake.  
Score 2: Likely complete metabolic response: The FDG uptake in the primary tumor or nodal sites is greater than the background blood pool uptake but it is equal to or less than the liver FDG uptake.  
Score 3: Likely inflammatory: There is diffuse FDG uptake in the primary tumor or nodal sites. This diffuse FDG uptake is greater than the liver FDG uptake and likely related to post-radiation inflammation.  
Score 4: Likely residual metabolic disease: There is focal FDG uptake in the primary or nodal sites. The focal FDG uptake is greater than the liver FDG uptake.  
Score 5: Definite residual metabolic disease: There is intense focal FDG uptake in the primary tumor or nodal sites. This focal FDG uptake is greater than the liver FDG uptake.
Definitions of 'Positive,' 'Negative' and 'Indeterminate' FDG Uptake and PET/CT Results A score of 1 or 2 will be interpreted as 'Negative,' a score of 3 as 'Indeterminate,' and a score of 4 or 5 as 'Positive.' A 'Negative' result at the primary or nodal sites is defined as equal or less FDG uptake than the blood pool and liver FDG uptake. Uptake for the local blood pool reference value will be measured from the carotid or the aortic arch. The 'Indeterminate' result is defined as diffuse FDG uptake in the treatment field with intensity of the uptake greater than the liver FDG uptake. A 'Positive' result is defined as focal uptake visually greater than the background and at a higher level than the activity seen in the liver. Sites that are interested in participating are encouraged to explain this component of the study to patients and obtained consent from all patients. All pre and post therapy FDGPET/CT images for patients enrolled in this optional component will be collected. The first 3 studies from each site will be centrally reviewed as a 'live read' within 3 working days of submission of scans to IROC Imaging, to establish a training and quality assurance process that will validate the local interpretation using the 5-point scoring system. All positive and indeterminate post-therapy scans also will be centrally reviewed as 'live reads' within 3 working days of submission of the scans to IROC Imaging. It is important to note that local sites will decide the post-therapy management and may incorporate the information from FDG-PET/CT into decision making according to these guidelines. However, determination of PFS events will require pathologic confirmation from biopsy or surgery; and an indeterminate or positive reading on FDG-PET/CT in itself will not be considered to affect the primary endpoint unless pathologic confirmation of persistent/residual cancer is obtained. Any FDG-PET/CT scan that merits an indeterminate or positive read must be followed by a mandated, short-term follow up (either focused clinical examination or another imaging study within 4 weeks).
nrg oncology
2.6 circulating hpv dna as

Circulating HPV DNA was detected in the blood of mouse-bearing xenografts harboring HPV positive tumors (SCC90 & Hela cells) but not in HPV negative tumors (MiaPaCa2 and SAS cells) using a PCR-based approach with either the L1 G5+/6+ primer or HPV16/18 subtype specific nested E6/E7 primers. A quantitative PCR approach using qPCR E6/7 primers was able to quantify plasma HPV DNA in 40 patients with HPV positive oropharyngeal cancer (OPC), 24 patients with HPV negative head and neck cancer (HNC), and 10 non-cancer volunteers. This approach detected circulating HPV DNA in 65% of pretreatment plasma samples from HPV positive OPC patients. None of the HPV negative HNC or non-cancer controls had detectable HPV DNA. In addition, pre-treatment plasma HPV DNA copy number correlated significantly with nodal metabolic tumor volume (assessed on FDG-PET/CT). Serial measurements in 14 patients found a rapid decline in HPV DNA, which became undetectable at completion of the chemoradiation treatment course. In 3 patients, HPV DNA had risen to a discernible level at the time of metastasis (Cao 2012). One drawback about the traditional qPCR approach is its low sensitivity and the requirement of large amount of DNA. Recently, Newman, et al. have published on the use of "Cancer Personalized Profiling by Deep Sequencing" (Capp-Seq) as an ultrasensitive method to quantify circulating tumor (ct) DNA with broad coverage in patients with locally advanced non-small cell lung cancer (NSCLC) (Newman 2014). Capp-Seq has been shown to outperform existing methods with a mean background level of 0.0007% and a detection limit of 0.025% for SNV and < 0.01% for rearrangement. It can detect mutant or viral DNA in picograms of DNA due to its low background and high sensitivity. The researchers also showed that the ctDNA levels were highly correlated with the tumor volumes and that it could distinguish between residual disease and treatment related imaging changes in these patients. Moreover, measurement of ctDNA allowed for earlier response assessment in NSCLC than radiographic approaches. We are currently validating the Capp-Seq approach on HPV+ HNSCC using our samples, and the results are encouraging. Based on this, we would like to determine whether the levels of HPV ctDNA as measured by Capp-Seq reflects tumor burden in patients treated on this trial and whether serial measurements can be used to track response and identify patients at high risk of relapse after treatment de-intensification therapy. Hypothesis 1: To determine whether that HPV DNA levels as measured by the Capp-Seq platform correlates with the tumor volume (GTV) in HPV positive OPC. As mentioned above, tumor ctDNA as measured by this platform significantly correlated with the tumor volume in NSCLC. Similarly, we found that plasma HPV DNA copy number as measured by traditional qPCR approach significantly correlated with nodal classification and nodal metabolic tumor volume in patients with HPV+ oropharyngeal carcinoma. We hypothesize that Capp-Seq is more sensitive and HPV ctDNA measurements by Capp-Seq will be a better reflection of tumor burden than DNA copy from qPCR. Since all patients will undergo pre-treatment simulation with recorded GTV and have pre-treatment plasma collection, it should be straightforward to extract DNA and measure HPV DNA by Capp-Seq and qPCR and correlate with GTV. Hypothesis 2: To determine whether the rate of HPV DNA declines during therapy by Capp-Seq and whether the measured level at the completion of radiotherapy correlates with the rate of relapse in treated patients. Serial circulating HPV DNA was measured in 14 patients with qPCR during therapy and in all of these patients, HPV DNA declined during treatment and became undetectable after treatment. In this small study, the investigators were not able to distinguish the pattern of relapse based on these 14 patients (4 with relapse and 10 without). However, with such a small sample size and the poor sensitivity of the qPCR method, it was difficult to distinguish those with a very low detectable versus an undetectable level. In contrast, Capp-Seq was able to track the NSCLC response to chemotherapy or radiation in a few patients evaluated. We hypothesize that the Capp-Seq approach will be superior to the traditional qPCR approach in detecting very low levels of HPV DNA in the blood after completion of radiation therapy, and those with detectable levels by Capp-Seq are more likely to have persistent disease or relapse after treatment. To address this hypothesis, this study proposes to measure HPV DNA by both qPCR and Capp-Seq pretherapy, mid-way into the course of treatment (after 20 Gy) and within 2 weeks of completion of all therapy. We will quantify the rate of HPV DNA decline measured in a short window after the first 20 Gy. The specific hypothesis that the rate of initial decline after the first 20 Gy and/or the post-treatment level reflects tumor response to therapy and can be used to predict for tumor persistence and relapse in these patients.
nrg oncology
2.7 pi3k pathway activation and

Recent genomic studies using next-generation sequencing (NGS) technology have shown that HPV related oropharynx cancer is genetically distinct compared to HPV unrelated oropharynx cancer (Agrawal 2011; Stransky 2011). In addition, a 182-cancer gene targeted analysis showed that HPV related oropharyngeal cancer has a particularly high prevalence of the phosphotidylinositol-3-kinase (PI3K) pathway aberration through activating mutation and increased gene copy number of the PI3K catalytic subunit, PIK3CA, and PTEN loss of function, the negative regulator of PI3K (Lechner 2013). The PI3K pathway is a well-known oncogenic pathway in numerous cancers and is activated by several receptor tyrosine kinases including epidermal growth factor receptor (EGFR), a key pathway in HNSCC. Activation of PI3K initiates a signal transduction cascade that promotes cancer cell growth, survival, and metabolism through several important downstream mediators, including Akt and mTOR complex 1 (mTORC1). Akt is the serine–threonine kinase that is directly activated in the response to PI3K and serves as a major mediator within the PI3K pathway. Further downstream of Akt is the mTORC1, which is not only under control of PI3K–Akt signaling, but also integrates many cellular inputs from hypoxia to growth factor stimulation and stress response. In addition, PTEN loss is commonly seen in HNSCC resulting in uncontrolled activation of PI3K (Okami 1998). However, these aberrations generally are not the only abnormal oncogenic pathway but co-exist with other cancer related genes within an individual oropharyngeal cancer. Therefore, evaluation of PI3K pathway aberrations as prognostic biomarkers within the genetic contexts of other cancer gene mutations such as TP53 mutation is extremely important. In this proposal, the plan is to investigate mutations and copy number changes in genes within the PI3K pathway (PIK3CA and PTEN) and 180 additional cancer related genes using NGS. Improved understanding of this pathway in a specific genetic context also may lead to development of novel therapies and/or predictive biomarkers to improve the clinical outcomes of HPV related oropharyngeal cancer patients. Hypothesis 1: Activation of the PI3K pathway by PIK3CA activating mutation or copy number gain or PTEN loss of function mutation or copy number loss is associated with increased rates of locoregional failure in patients with HPV related oropharyngeal cancer. Hypothesis 2: Co-existence of PI3K pathway activation and TP53 mutation (or additional oncogene mutations such as KRAS mutation) will improve the prognostic potential of PI3K pathway activation.
nrg oncology
3. patient selection eligibility and

permitted. For questions concerning eligibility, please contact the Biostatistical/Data Management Center (via the contact list on the NRG web site). For radiation therapy-related eligibility questions, please contact IROC Philadelphia RT (via the contact list on the NRG web site).  
3.1 Patient Selection **Guidelines**
Although the guidelines provided below are not inclusion/exclusion criteria, investigators should consider these factors when selecting patients for this trial. Investigators also should consider all other relevant factors (medical and non-medical), as well as the risks and benefits of the study therapy, when deciding if a patient is an appropriate candidate for this trial.  
3.1.1 Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.  
3.1.2 Women of childbearing potential and men who are sexually active should be willing and able to use medically acceptable forms of contraception throughout the treatment phase of the trial and until at least 60 days following the last study treatment.  
3.1.3 Submission of H&E and p16 slides to the NRG Oncology Biospecimen Bank for confirmation of positive immunohistochemical staining for p16 is required for all patients. Investigators should check with their site Pathology department regarding release of biospecimens before approaching patients about participation in the trial. (See
nrg oncology
3.2 eligibility criteria (5/24/16) a

3.2.1 Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage).  
3.2.2 Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-therapeutic nodal excisions.  
3.2.3 Immunohistochemical staining for p16 must be performed on tissue, and this tissue must be submitted for central review. Fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue if formalin-fixed paraffin-embedded cell block material is available for p16 immunohistochemistry. FNA specimens prepared with adequate p16 testing in this manner are acceptable to submit for central review. If the p16 preparation is not adequate, additional specimens will be required to establish p16 status. Centers are encouraged to contact the pathology chairs for clarification.  
3.2.4 Clinical stage T1-T2, N1-N2b or T3, N0-N2b (AJCC, 7th ed.) including no distant metastases based on the following diagnostic workup:
General history and physical examination within 56 days prior to registration; Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 70 days prior to registration; One of the following combinations of imaging is required within 56 days 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 a PET/CT performed for the purposes of radiation planning may serve as both staging and planning tools.  
3.2.5 Patients must provide their personal smoking history prior to registration. The lifetime cumulative history cannot exceed 10 pack-years. The following formula is used to calculate the pack-years during the periods of smoking in the patient's life; the cumulative total of the number of pack-years during each period of active smoking is the lifetime cumulative history. Number of pack-years = [Frequency of smoking (number of cigarettes per day) × duration of cigarette smoking (years)] / 20 Note: Twenty cigarettes is considered equivalent to one pack. The effect of non-cigarette tobacco products on the survival of patients with p16-positive oropharyngeal cancers is undefined. While there are reportedly increased risks of head and neck cancer associated with sustained heavy cigar and pipe use (Wyss 2013), such sustained use of non-cigarette products is unusual and does not appear to convey added risk with synchronous cigarette smoking. Cigar and pipe tobacco consumption is therefore not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation.  
There is no clear scientific evidence regarding the role of chewing tobacco-containing products in this disease, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators are discouraged from enrolling patients with a history of very sustained use (such as several years or more) of noncigarette tobacco products alone.  
3.2.6 Zubrod Performance Status of 0-1 within 56 days prior to registration; 3.2.7 Age ≥ 18; 3.2.8 The trial is open to both genders; 3.2.9 Adequate hematologic function within 14 days prior to registration, defined as follows:
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.  
3.2.10 Adequate renal function within 14 days prior to registration, defined as follows:
Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula:
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ccr male = [(140 -

CCr female = 0.85 x (CrCl male)
3.2.11 Adequate hepatic function within 14 days prior to registration defined as follows:
Bilirubin < 2 mg/dl; AST or ALT < 3 x the upper limit of normal.  
3.2.12 Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential; 3.2.13 Patients who are HIV positive but have no prior AIDS-defining illness and have CD4 cells of at least 350/mm3 are eligible. HIV-positive patients must not have multi-drug resistant HIV infection or other concurrent AIDS-defining conditions. Patients must not be sero-positive for Hepatitis B (Hepatitis B surface antigen positive or antihepatitis B core antigen positive) or sero-positive for Hepatitis C (anti-Hepatitis C
antibody positive). However, patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B).  
3.2.14 The patient must provide study-specific informed consent prior to study entry, including consent for mandatory submission of tissue for required, central p16 review.  
3.2.15 Patients who speak English (or read one of the languages for which a translation is available (see Section 10.2) must consent to complete the mandatory dysphagia-related patient reported instrument (MDADI). If the patient cannot understand spoken English and reads only languages not available in the MDADI translations, the patient can still participate in the trial, as this has been factored into the trial statistics. For all other patients, the MDADI is mandatory as it is included in the primary endpoint to be studied.
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step 2 randomization

3.2.16 p16 positive by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review; (see Section 10.1 for details).
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3.3 ineligibility criteria (5/24/16) patients

3.3.1 Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16 positive, or histologies of adenosquamous, verrucous, or spindle cell carcinomas; 3.3.2 Carcinoma of the neck of unknown primary site origin (even if p16 positive);
3.3.3 Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat plane; 3.3.4 Supraclavicular nodes, defined as nodes visualized on the same axial imaging slice as the clavicle; 3.3.5 Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles; 3.3.6 Gross total excision of both primary and nodal disease with curative intent; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease. In other words, to participate in this protocol, the patient must have clinically or radiographically evident gross disease for which disease response can be assessed.  
3.3.7 Patients with simultaneous primary cancers or separate bilateral primary tumor sites are excluded with the exception of patients with bilateral tonsil cancers; 3.3.8 Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible);
3.3.9 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; 3.3.10 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; 3.3.11 Severe, active co-morbidity defined as follows:
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol other than those requested in Section 3.2.10.  
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition with immune compromise greater than that noted in Section 3.1.13; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.  
3.3.12 Pregnancy; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.  
3.3.13 Prior allergic reaction to cisplatin.
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4. requirements for study entry

| PRE-TREATMENT ASSESSMENTS                                                                                                                                                                                                                                                                               |                                                            |                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|------------------------------------|
| Assessments                                                                                                                                                                                                                                                                                             | Prior to Registration-Step 1  Registration (calendar days) | Prior to Treatment (calendar days) |
| History/physical with height                                                                                                                                                                                                                                                                            | 56                                                         |                                    |
| & weight  Fiberoptic exam with  laryngopharyngoscopy (see  note below)                                                                                                                                                                                                                                  | 70                                                         |                                    |
| Imaging: (see note below)  CT with contrast of neck  and CT of chest +/- contrast;  Or MRI with contrast of  neck and CT of chest +/- contrast;  Or CT with contrast of  neck and PET/CT of neck  and chest +/- contrast;  Or MRI with contrast of  neck and PET/CT of neck  and chest +/- contrast | 56                                                         |                                    |  
| Patient's smoking history                                            | X                            |
|----------------------------------------------------------------------|------------------------------|
| Zubrod Performance Status                                            | 56                           |
| CBC/differential                                                     | 14                           |
| Bilirubin, AST or ALT                                                | 14                           |
| Serum creatinine or creatinine                                       | 14                           |
| clearance Serum pregnancy test, if                                   | 14                           |
| applicable Na, K, Cl, glucose, Ca, Mg,                               | 28                           |
| and albumin (see note below) Dental assessment (see note             | 28                           |
| below) Audiogram                                                     | 112 (16 weeks)               |
| Swallowing assessment (see                                           | 28                           |
| note below) MDADI                                                    | Required: 28                 |
| PSS-HN, CCI, Work Status                                             | Required                     |
| EKG                                                                  | Recommended for Arm 1        |
| patients: 70 days (10 weeks)                                         |                              |
| Whole body PET/CT (see                                               | Recommended: 70 days (10     |
| note below)                                                          | weeks)                       |
| Nutritional evaluation (see                                          | Recommended: 28              |
| note below) QOL: UW-QoL, if patient                                  | Prior to start of protocolspecific treatment                              |
| consents Biospecimen Collection for  Central Review and for  Banking | See Section 10.1 for details |
| Modified Barium Swallow, if                                          | Prior to start of protocolspecific treatment                              |
| patient consents                                                     |                              |  
Notes for Pre-Treatment Assessments (table above)
The fiberoptic exam with laryngopharyngoscopy can be done by the treating surgeon, medical oncologist, or radiation oncologist with experience in endoscopic examinations of cancer patients.  
Patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive corrective magnesium supplementation but should continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g. magnesium oxide) at the investigator's discretion.  
The protocol-specific dental assessment is by a physician or designee (such as a physician's assistant, nurse or nurse practitioner, or a dentist/hygienist) to assess number of teeth and overall dental health with management; see guidelines at www.ctsu.org on the NRG-HN002 protocol page.  
The protocol-specific swallowing assessment is a single question completed by the physician and/or research associate to describe the consistencies of foodstuff that the patient is able to swallow.  
The MDADI is a required PRO (if the patient can comprehend spoken English or read one of the validated language translations) and it is completed by the patient.  
The EKG is recommended for Arm 1 patients (RT + cisplatin).  
"Whole body" PET/CT may be limited to neck and chest. Note: Diagnostic quality CT
scan of neck with contrast and/or PET/CT performed for radiation planning may serve as both staging and planning tools. Centers that wish to participate in the PET/CT correlative study component should refer to guidelines for submitting these images and their associated data (see Section 10.3).  
Nutritional evaluation to include the physician's evaluation for placement of prophylactic gastrostomy or other type of feeding tube; note: The decision to place a feeding tube should be individualized and is not mandated. Investigators 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, dietician counseling, 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). It is highly recommended as part of the standard of care that all patients, but particularly those who require feeding tubes, be provided with professional swallowing evaluations and counseling before, during, and after treatment.  
Quality of Life:
Patients are **required** to complete the MDADI at pre-treatment as this assessment is needed for the primary objective of the trial.  
Patients who consent to participate in the optional QOL study will complete the UWQoL.  
The Performance Status Scale for Head and Neck (PSS-HN), Charlson Comorbidity Index (CCI), and Work Status questions are required and are completed by the investigator and/or research associate.  
Patients who consent to participate in the quality of life (QOL) component of this study have the option of completing QOL forms online from any location, including home, via VisionTree Optimal Care (VTOC). Patients without e-mail or Internet access are still able to participate in the QOL component of the study by completing hardcopy (paper) forms. Indeed, at any time, any patient may choose to fill out their QOL form using the hardcopy form.  
If the patient wishes to complete QOL assessments online, the patient must have an email address that they consent to use for this purpose. Patients' e-mail addresses are necessary so that e-mail reminders may be sent to them to remind them to fill out QOL forms that are due. The patient's e-mail address also will be used for passwordprotected access to VTOC. Patients who are interested in participating but do not yet have an e-mail address can obtain one for free from a number of sources (e.g.,Yahoo!,
Hotmail, or AOL). Note: The site RA is responsible for setting up the patient's account on VTOC. The RA may do so by logging on the VTOC portal at the following link https://rtog.optimalcare.com - medical team. RA login information will be provided by VTOC after the patient is randomized to the study. The patient's VTOC account must be set up within 14 days after randomization.  
| Assessments                 | Weekly during Treatment                                    | As Clinically Indicated   |
|-----------------------------|------------------------------------------------------------|---------------------------|
| Brief history               | X                                                          | X                         |
| Physical examination        | X                                                          | X                         |
| Zubrod Performance Status   | X                                                          |                           |
| CBC/differential            | Arm 1: Weekly                                              |                           |
| Arm 2: At Weeks 3 and 5     |                                                            |                           |
| Serum creatinine or         | Arm 1: Weekly                                              |                           |
| creatinine clearance        | Arm 2: At Weeks 3 and 5                                    |                           |
| Na, K, Cl, glucose, Ca, Mg, | Arm 1: Weekly                                              |                           |
| and albumin                 | Arm 2: At Weeks 3 and 5                                    |                           |
| Bilirubin, AST or ALT       | At Weeks 3 and 5                                           |                           |
| Whole body PET/CT           | X                                                          |                           |
| CT or MRI or PET/CT of      | X                                                          |                           |
| neck, with contrast Biopsy  | If suspicion of tumor  recurrence                          |                           |
| Adverse Event Evaluation    | X                                                          | X                         |
| QOL: MDADI                  | Mandatory at completion of radiation                       |                           |
| QOL: UW-Qol                 | For patients who consent: At completion of radiation       |                           |
| QOL: PSS-HN, Work Status    | Required: Completed by the investigator and/or research    |                           |
| questions                   | associate at completion of radiation                       |                           |
| Biospecimen Collection for  | For patients who consent: After at least 20 Gy RT has been |                           |
| Banking                     | given but before 28 Gy RT has been given                   |                           |
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assessments during treatment (5/24/16)

| Assessments                                                                                                                                                                    | At 1 Month Posttreatment                                                                                                                     | q3 mos. from end  of RT for 2 yrs; q6  mos. for 3 yrs;  then annually   | As Clinically  Indicated   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|----------------------------|
| Brief history, physical  examination, and laryngopharyngoscopy                                                                                                                 | X                                                                                                                   | X                                                                       |                            |
| Zubrod Performance Status                                                                                                                                                      | X                                                                                                                   | X                                                                       |                            |
| CBC/differential                                                                                                                                                               | X                                                                                                                   |                                                                         |                            |
| Na, K, Cl, glucose, Ca, Mg,                                                                                                                                                    | X                                                                                                                   |                                                                         |                            |
| and albumin Total bilirubin; AST or ALT                                                                                                                                        | X                                                                                                                   |                                                                         |                            |
| Optional imaging study, if  patient consents: FDGPET/CT (see note below)                                                                                                                                                                                | 12-14 weeks posttherapy                                                                                                                     |                                                                         |                            |
| Chest CT or PET/CT                                                                                                                                                             | At 6 mos post-RT,  then annually for 2  years                                                                       | After 3 years, as                                                       |                            |
| clinically indicated                                                                                                                                                           |                                                                                                                     |                                                                         |                            |
| CT or MRI of the neck with                                                                                                                                                     | Initial post                                                                                                                     |                                                                         |                            |
| treatment scan at 3                                                                                                                                                            |                                                                                                                     |                                                                         |                            |
| contrast                                                                                                                                                                       | months is required;  recommended at  other time points if  disease progression  is suspected by  treating physician |                                                                         |                            |
| PET/CT of neck                                                                                                                                                                 | Initial post                                                                                                                     |                                                                         |                            |
| treatment scan at 3  months is  recommended; may  be substituted for  CT or MRI only if  the CT component  is performed with  contrast as a  diagnostic quality  imaging study |                                                                                                                     |                                                                         |                            |  
| Biopsy                       | If suspicion of                                                                                                |    |    |
|------------------------------|----------------------------------------------------------------------------------------------------------------|----|----|
| tumor recurrence             |                                                                                                                |    |    |
| Adverse Event Evaluation     | X                                                                                                              | X  | X  |
| Nutrition/Feeding Tube       | X                                                                                                              |    |    |
| Evaluation Dental Assessment | At 12, 24, 60, and  120 mos. from end  of treatment                                                            |    |    |
| QOL: MDADI                   | Mandatory at 6, 12, and 24 months from end of radiation                                                        |    |    |
| QOL: UW-Qol                  | For patients who consent: At 6, 12, and 24 mos. from end of  radiation                                         |    |    |
| QOL: PSS-HN                  | Required: Completed by the investigator and/or research associate  at 6, 12, and 24 mos. from end of radiation |    |    |
| QOL: Work Status             | Required: Completed by the investigator and/or research associate                                              |    |    |
| questions                    | at 6, 12, and 24 mos. from end of radiation                                                                    |    |    |
| Biospecimen Collection for   | For patients who consent: No earlier than 2 weeks and up to 1                                                  |    |    |
| Banking                      | month after the completion of treatment                                                                        |    |    |
| Modified Barium Swallow,     | 24 months +/- 3 months from end of radiation                                                                   |    |    |
| if patient consents          |                                                                                                                |    |    |  
Notes for Assessments in Follow Up (table above)
A brief history & 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.  
The initial post-radiation imaging evaluation at 3 months after the completion of radiotherapy is required. The imaging can be contrast-enhanced CT of the neck, MRI of the neck with contrast, PET/CT of the head and neck with contrast and including diagnostic quality imaging of the neck, or "whole body" PET/CT (minimum neck and chest) with contrast and including diagnostic quality imaging of the neck based on the preference of the treating clinician. Centers that wish to participate in the PET/CT
correlative study component should refer to guidelines for submitting these images and associated data (see Section 10.3).  
Radiographic imaging (CT, MRI, or PET/CT as appropriate) at follow-up 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 5.7).  
Chest imaging: A chest CT +/- contrast or a PET/CT including the chest is required once per year for a total of 3 image sets, then may be performed as clinically indicated.  
Optional imaging study: A post-therapy FDG-PET/CT scan is highly recommended at 12-14 weeks post-therapy for assessment of response to therapy. If the patient consents to participate, the site is required to submit the patient's post-treatment PET/CT scan; see Section 10.3 for details.  
Biopsy of any lesion(s) suspicious for tumor recurrence is recommended as clinically indicated.
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5. treatment plan/regimen description intensity-modulated

may be used to treat the low neck, if it is the institution's practice. For IMRT planning, margin expansions will be set at 0.5 cm from GTV to the high dose CTVs. Sites will have the option to use an additional 0.3 or 0.5 cm to the PTV, depending on the frequency of IGRT. If PTV margins of 0.3 cm are used, daily IGRT usage is required, and IGRT credentialing is required. If using 0.5 cm PTV margins, a minimum of weekly IGRT is required and imaging alignment must be approved by the attending physician on the first day of treatment and weekly thereafter. IGRT credentialing is not required for 0.5 cm PTV margin expansion.
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5.1 chemotherapy (5/24/16) protocol treatment

Dose should be based on actual body weight. Treatment may be administered before or after radiotherapy. The first cisplatin infusion should be started within 24 hours before or after the first scheduled radiation therapy administration. No concurrent cisplatin will be administered after the final week of radiation, but the final dose of cisplatin may be administered following the last dose of radiation if it is administered within the same calendar week. **Cisplatin should be administered on**
Mondays or Tuesdays to maximize overlap of daily radiation with cisplatin exposure. Administration on Wednesday prior to that day's radiation dose is acceptable but not preferred. Investigators should strive to administer cisplatin on the same day each week but variance of 1 day is acceptable for vacations, holidays, etc. If radiation treatments are held for toxicity, cisplatin dosing should also be held. If cisplatin is held for toxicity, then the dose will not be made up.  
5.1.2 Low-dose Cisplatin Concurrent with Radiation Administration Guidelines High dose cisplatin is highly emetogenic. While this protocol is using more frequent dosing of cisplatin that is considered moderately emetogenic, investigators should be prepared to use aggressive prophylactic antiemetics and hydration. Many institutions will have standard guidelines for the administration of cisplatin at the doses used in this study. For purposes of this protocol, individual investigators **may use these local guidelines**
for cisplatin administration. One possible approach is outlined below. These guidelines may need to be modified based on local guidelines and patient related factors (e.g. the substitution of normal saline in diabetic patients). Similarly, the anti-emetic regimen is to be determined by the local investigator, although one possible approach is outlined below.  
*Low-dose Cisplatin anti-emetic administration guidelines*: 5-HT3 antagonists and decadron should be given (e.g. ondansetron 16 mg PO prior to cisplatin and 8 mg PO up to 3 times daily on days 2 and 3 following cisplatin weekly and dexamethasone x 3 days starting prior to the cisplatin dose weekly, 12 mg on day 1 and 8 mg on days 2 and 3 each week OR palonosetron 0.25 mgs IV and decadron 12 mgs prior to cisplatin. Use of other anti-nausea meds such as aprepitant, metoclopramide, or prochlorperazine is left to the discretion of the investigator.  
*Low-dose Cisplatin pre-hydration guidelines*: Pre-hydration with 1 liter D5 ½ NS and 40 meq KCL/ liter x 1 liter prior to cisplatin should be given. Mannitol 12.5 gm IV immediately prior to cisplatin may be given. Use of mannitol is left to the discretion of the investigator.  
*Low-dose Cisplatin administration*: Standard administration is cisplatin, 40 mg/m2 over 30-60 minutes IV in 250 cc NS. Infusion rate not to exceed 2 mgs per min. See Section 6.0 for dose modifications. See above discussion on scheduling and number of doses concurrent with radiation.  
*Low-dose Cisplatin post-hydration guidelines*: Following the end of the cisplatin administration, an additional liter of D5½ NS with 10 meq KCL/L, 8 meq MgSO4/L, and 25 g mannitol should be infused over 2 hours. On the second and third day following cisplatin, patient should be encouraged to take at least 2 liters of fluid per day orally. Patients unable to orally self-hydrate should be considered for additional IV hydration on these days with NS. The amount of pre- and post-hydration is left to the discretion of the investigator.
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5.2 radiation therapy (5/24/16) protocol

All patients will receive 60 Gy delivered in 30 fractions of 2 Gy. Full details of radiation dose prescriptions are provided in Section 5.2.7. Unilateral radiation will be permitted in selected patients; see Section 5.2.4.  
5.2.1 Treatment Technology All patients will be managed with IMRT delivered with megavoltage photons. A matched AP or AP-PA field with larynx block may be utilized to manage the low neck as described in Section 5.2.4. All institutions must be credentialed for IMRT if not already done. Treatment verification is required and required frequency of IGRT depends on the use of PTV margins (see Section 5 and 5.2.13).  
5.2.2 Immobilization and Simulation Patients will be treated supine and must have a secure head and neck immobilization (e.g. aquaplast mask) made prior to the treatment planning CT scan. The treatment planning CT scan should be performed with IV contrast unless contraindicated, obtained in the immobilization device and in the treatment position with a slice thickness of 3 mm or less.  
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow-up A diagnostic CT or MRI for structure delineation is recommended. These may be fused to the planning CT scans to facilitate target and structure definition. When available FDG PET/CT images may also be fused to the planning CT data set.  
5.2.4 Definition of Target Volumes and Margins All specified target volumes and organs-at-risk (OAR) will be contoured on the planning CT scan data sets and named according to the nomenclature described below. For the purposes of contouring, MRI and PET images, if available and clinically indicated, may be fused with the planning CT data set. Target volumes and OARs will be labeled according to published guidelines (Santanam 2012).
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gross tumor volume (gtv)

The GTV represents clinically or radiographically grossly involved regions of primary tumor or involved nodes designated GTVp_6000 and GTVn_6000 respectively. These volumes are defined based on physical exam and review of available imaging. FDG-PET may assist in GTV identification but specific GTV border delineation should not rely exclusively on PET signal given the known variable association between gross tumor extent and PET signal cutoff. For purposes of dose evaluation GTVp and GTVn will be labeled GTVp_6000 and GTVn_6000.
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post-biopsy gtv

Patients undergoing gross total excision of both primary and gross nodal disease with curative intent are not eligible for this study (see Section 3.3.6). Patients undergoing diagnostic procedures at the primary site, such as simple/diagnostic tonsillectomy or excisional biopsy, are eligible but are not considered to have had an oncologically therapeutic surgical procedure even in the absence of clinically or radiologically appreciable gross residual disease at the primary site. As such, these patients require full radiation dose (60 Gy) to be delivered to a volume immediately adjacent to the tissues removed at the time of the biopsy. For purposes of planning, this volume will be labeled GTVp and it should be defined relative to the extent of disease prior to removal. This GTVp may be defined by fusion of pre-biopsy imaging studies (CT, MRI) with the planning CT data set. The gross primary tumor on the pre-biopsy imaging may be projected on the planning CT and defined as the intersection with the residual tissues. If there is not such an intersection or the residual tissues lie in a different anatomic orientation post-biopsy, the GTVp may be defined as a 5 mm expansion into the residual tissues circumferential to the area of the biopsy. In the event that pre-biopsy imaging is not available the GTVp must be defined relative to the clinical exam of the biopsy site and normal anatomic landmarks. For instance, in the specific case of tonsillectomy the GTVp will include, at a minimum, the tonsillar bed to include anterior and posterior tonsillar pillars up to the level of the soft palate and inferiorly to the pharyngoepiglottic fold; the GTVp should be expanded superiorly or inferiorly if the pre-biopsy tumor extended past these landmarks. A CTV_6000 and CTV_5400 are then defined for this GTVp according to methods defined below.
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nodal definitions

Grossly Positive Nodes (GTVn_6000) are defined as those greater than 1.5 cm in long axis and/or > 1 cm in short axis, a cluster of 3 or more borderline size nodes, radiographic evidence of extracapsular extension (ECE), or a node of any size with evidence of necrosis. Smaller nodes may be determined to be gross disease objects depending on clinical suspicion (based on proximity to the primary site or other involved nodes) or demonstration of significant uptake of FDG on PET scanning.  
Extracapsular extension (ECE): is defined as radiographic evidence of irregular borders and/or perinodal fat stranding, invasion of adjacent structures, or both. Any areas of potential involvement should be included within the GTV. Clinicians are highly encouraged to request radiologist review if the determination is unclear.  
Matted Nodes: Three or more abutting nodes with loss of the intervening fat planes. Patients with matted nodes should not participate in this trial (see exclusion criteria, Section 3.3).
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clinical target volume (ctv)

CTVs are defined and contoured in relation to the targets they are intended to encompass and the dose they are intended to receive. For gross targets (GTVs), the CTVs are defined by 3D isotropic expansions that should then be limited by potential barriers to tumor spread such as air cavities, external contours and bony or fascial planes through which tumor spread is not possible or apparent. Similarly CTVs may be expanded beyond the limits defined in this protocol in order to cover areas deemed at risk of tumor extension (e.g. neck musculature invaded by nodal disease, or pterygoid regions of infratemporal fossa in superiorly extending tonsilar cancers). For nodal regions of potential microscopic involvement CTVs are defined according to normal anatomic landmarks (Gregoire 2014).
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ctv6000 primary tumor and involved

A CTV_6000 will be defined for primary tumor and involved nodes as a 0.5 cm isotropic expansion of the GTVs defined for these structures. When defined for nodes, the CTV_6000 should be suffixed as CTVn_6000 to distinguish this from the primary, CTVp_6000, for the purposes of plan evaluation. CTV_6000 is the sum of CTVp_6000 and CTVn_6000.
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ctv5400 high-risk subclinical sites

High-risk subclinical sites are defined as: i) areas of potential subclinical tumor infiltration beyond the primary site CTVp_6000 and ii) the first echelon node levels to the primary site irrespective of gross nodal involvement and all node levels containing gross nodes. In the event of a node excision (≤ 4 per protocol) that occurred at time of diagnosis, the node levels that contained grossly involved adenopathy should be included in CTV_5400, even if there is no residual post excision adenopathy. A CTV_5400 will be defined for these sites and include the following:
i) 1.0 cm isotropic expansion of GTVp_6000 , which is an 0.5cm expansion on the CTVp_6000.  
ii) 1 st echelon node levels based on standard anatomic definitions. In most cases 1st echelon would be ipsilateral level II, but in cases of midline primary site involvement this should include bilateral level II. In cases with soft palate or posterior pharyngeal wall involvement this should include the  
lateral retropharyngeal lymph nodes.  
iii) All node levels containing a CTVn_6000 that has been assigned to involved nodes (all grossly involved nodal levels).  
iv) Other high-risk subclinical sites may include nodes < 1cm not thought to harbor gross disease yet thought to be at risk of containing more than subclinical disease based on their location relative to the primary site. In such cases of clinical concern that do not meet the above criteria, a 0.5cm expansion on these nodes can be added to the CTV_5400 at the discretion of the treating clinician.  
**CTV_4800: Node Levels at Risk of Microscopic Spread**
A CTV_4800 will be defined to treat node levels without evidence of gross disease yet at risk of microscopic spread and not contained in CTV_5400. These levels are defined anatomically according to published Intergroup consensus guidelines (Gregoire 2014). The levels to be treated will depend on the site and extent of the primary tumor and any grossly involved lymph nodes and are indicated in Table 5.2.4A.  
CTV_4400: **Low Neck Nodes at Risk of Microscopic Spread**
For patients with no low neck nodal involvement, a matched AP or AP-PA field with larynx block may be utilized to manage the low neck. Under this scenario, CTV_4800 will not include the low neck, but rather CTV_4400 will be defined by contouring the prescription iso-dose line of the AP or AP-PA field. For centers that use IMRT for the low neck, the low neck nodes at risk of microscopic spread will be included CTV_4800.  
| CTV_4800*                                                                                                                         | Ipsilateral Neck                                                                                       | Contralateral Neck**   |       |       |
|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|------------------------|-------|-------|
| N0-1 (in level II -                                                                                                               |                                                                                                       | Ib (for primary oral   |       |       |
| IV)                                                                                                                               | cavity extension),                                                                                     |                        |       |       |
|                                                                                                                                  | II-IV                                                                                                  |                        |       |       |
|                                                                                                                                  | RP ( lateral  retropharyngeal LN)  for primary extension  to posterior pharyngeal  wall or soft palate |                       | II-IV |       |
|                                                                                                                                  | RP (lateral  retropharyngeal LN)  for primary extension  to posterior  pharyngeal wall or  soft palate |                        |       |       |
| N2a-b                                                                                                                             |                                                                                                       | Ib,II,III,IV,V,RP      |      | II-IV |
|                                                                                                                                  | RP (lateral  retropharyngeal LN)  for primary extension  to posterior  pharyngeal wall or  soft palate |                        |       |       |
| *Applies to neck levels not included in CTV_5400. ** The contralateral neck may be omitted according to guidelines defined below. |                                                                                                        |                        |       |       |
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contralateral neck

It is recognized that the evidence as to the efficacy and safety of a unilateral neck radiotherapy approach within specific patient groups is largely retrospective, yet increasingly compelling evidence has led some centers to consider unilateral radiotherapy standard practice for selected patients while others continue to treat in a bilateral fashion. Unfortunately, the data for patients with selected N2b or lateralized tongue base cancers is less well defined in the literature than that for N0-N2a tonsillar cancer, and additionally, substantial disparities in opinions remain related to the effect of extracapsular extension (Vergeer 2010; Yeung 2012, Geropantas 2013, Lynch 2013). It also can be difficult to define the number of involved nodes, since it may vary depending on whether the site uses CT, MRI or PET/CT for initial staging. Based on these considerations, the study team has concluded that the use of unilateral radiation techniques should remain optional, in deference to the established practice and clinical judgment of the enrolling investigator, but have defined 3 groups of patients with respect to neck irradiation.  
Unilateral radiotherapy is recommended (see guidelines below) if it is the institution's established practice, if the primary tumor originates in the tonsil, and is well-lateralized, with less than 1 cm of involvement of the soft palate or base of tongue, no posterior pharyngeal wall involvement, and with minimal nodal disease burden (N0-N2a) as assessed by clinical exam and staging radiology studies. For patients who share these characteristics but have N2b nodal disease confined to ipsilateral level 2 of the neck, unilateral radiotherapy is optional. Due to the imperative to maintain high PFS for this trial and the lack of prospectively collected data on this controversial subject, for patients with characteristics that fall outside these categorizations, bilateral treatment is required.  
Groups of Patients with Regard to Unilateral or Bilateral Neck Irradiation Group 1: Unilateral treatment is recommended. T1 to T3 tonsil primaries with < 1cm clinical or radiographic extension into tongue base and/or palate, no posterior pharyngeal wall extension, N0-N2a (no ECE)
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group 2 unilateral treatment is

T1 to T3 tonsil primaries with < 1cm clinical or radiographic extension into tongue base and/or palate, no posterior pharyngeal wall extension, N2b (no ECE) with involved adenopathy confined to ipsilateral level 2 of the neck
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group 3 bilateral treatment is

Tongue base, palate or posterior pharyngeal wall primaries or tonsil primaries with >1cm soft palate and/or tongue base extension or any posterior pharyngeal wall extension; patients with any ECE or with involved adenopathy outside of ipsilateral level 2 of the neck Prior to individual patient randomization, oncologists will declare their intention to treat unilaterally or bilaterally, which will serve as a stratification factor (Unilateral vs. Bilateral) ensuring balance between the 2 study arms. Exploratory analyses adjusted for unilateral vs. bilateral radiotherapy will be conducted when the results are available.  
**Management of the Low Neck (levels III, IV, V)**
Treatment of the uninvolved low neck may be achieved with a single IMRT plan encompassing the whole neck along with the primary site. Alternatively the low neck may be treated with AP or AP-PA fields, with a midline block to shield larynx and spinal cord, junctioned isocentrically with the IMRT volumes at the plane of the isocenter. This may only be done in cases without gross nodes in the low neck and if the match is >1 cm clear of gross nodal disease and primary site superiorly. The dose for the low neck volumes managed with this technique will be 2 Gy per fraction prescribed to 3 cm depth to a total dose of 44 Gy in 22 once daily fractions.  
Table 5.2.4B: Clinical Target Volume Nomenclature and Description.  
All volumes are to be treated using IMRT in 30 fractions except CTV_4400 in 22 fractions given to the low neck when applicable. **Note**: All structures marked as Required in the table below must be contoured, and labeled as listed under "Standard Name" for digital RT data submission. All structures marked as **Required if applicable**
must be contoured and labeled as listed under "Standard Name" for digital data submission IF they are applicable to the patient's plan. Resubmission of data is necessary when labeling of structures does not conform to the DICOM Standard Name listed.  
| Standard Name           | Description                                       | Detailed Specification                                                                                                                                                                                                         |
|-------------------------|---------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| GTVp_6000               | GTV to receive 60 Gy at the primary site Required | Equivalent to GTVp as defined  above                                                                                                                                                                                           |
| GTVn_6000               | GTV to receive 60 Gy at  involved nodes Required  | Equivalent to GTVn as defined  above                                                                                                                                                                                           |
| CTVp_6000               | CTV to receive 60 Gy at the primary site Required | 0.5 cm isotropic expansion of  GTVp_6000 limited by potential  anatomic barriers to tumor spread  such as air cavities, external  contours and bony or fascial planes  through which tumor spread is not  possible or apparent |
| CTVn_6000               | CTV to receive 60 Gy at  involved nodes Required  | 0.5 cm isotropic expansion of  GTVn_6000 limited by potential  anatomic barriers to tumor spread  such as air cavities, external  contours and bony or fascial planes  through which tumor spread is not  possible or apparent |
| CTV_6000                | CTV to receive 60Gy                               | Sum of CTVp_6000 and                                                                                                                                                                                                           |
| Required                | CTVn_6000                                         |                                                                                                                                                                                                                                |
| CTV_5400                | CTV to receive 54 Gy at                           | i) 1.0 cm expansion of                                                                                                                                                                                                         |
| high risk volume at the | GTVp_6000, which is an 0.5cm                      |                                                                                                                                                                                                                                |  
| primary site and applicable  node levels Required   | expansion on the CTVp_6000 ii) First echelon nodes (unilateral or  bilateral) iii) node levels containing involved  nodes iv) 0.5 cm expansion on nodes < 1  cm thought to be at risk of  containing more than subclinical  disease.   |                                                                                                                                                                                                                                               |
|-----------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CTV_4800                                            | CTV to receive 48 Gy to  right and/or left neck  regions at risk of  microscopic disease Required if applicable                                                                                                                        | Defined anatomically according to  consensus guidelines (Gregoire  2014). The levels to be treated will  depend in the site and extent of the  primary tumor and any grossly  involved lymph nodes. See table 5.2.4A for specifics            |
| CTV_4400                                            | CTV to receive 44Gy to low  neck regions at risk of  microscopic disease Required if applicable                                                                                                                                        | Option for lower neck volumes  (levels III, IV,V) treated with non  IMRT techniques and midline  sparing junctioned >1cm clear of  gross disease, defined as prescription isodose line of the AP  or AP-PA field used to treat these  volumes |
| See Table 5.2.6 for corresponding PTV descriptions. |                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                               |  
5.2.5 Definition of Organs at Risk  
Note: All structures marked as **Required** in the table below must be labeled as listed  
under "Standard Name" for digital RT data submission. Resubmission of data is necessary when labeling of structures does not conform to the DICOM Standard Name listed.  
Table 5.2.5: Organ at Risk Nomenclature  
For detailed descriptions see below.  
OAR Standard Name Description SpinalCord Spinal cord  
Required  
SpinalCord_05 PRV = 5 mm expansion on  
spinal cord Required  
BrainStem Brain stem  
Required  
BrainStem_03 PRV= 3 mm expansion on  
brainstem Required  
Lips Lips  
| Required       |                                                       |
|----------------|-------------------------------------------------------|
| OralCavity     | Oral cavity Required                                  |
| Parotid_R      | Right parotid gland Required                          |
| Parotid_L      | Left parotid gland Required                           |
| Submandibula_R | Right submandibular gland Required, if applicable     |
| Submandibula_L | Left submandibular gland Required, if applicable      |
| Pharynx        | Non-treated pharynx Required                          |
| Esophagus_Up   | Cervical esophagus Required                           |
| Larynx         | Larynx Required                                       |
| Mandible       | Mandible Required                                     |
| NonPTV         | Unspecified tissue, External  minus all PTVs Required |
| External       | External border of the  patient  Required             |  
**Spinal Cord**: The cord begins at the cranial-cervical junction (ie, the top of the C1 vertebral body). Superior to this is brainstem and inferior to this is cord. The spinal cord must be contoured at least 1 cm below the lowest extent of the neck PTVs. 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 as: SpinalCord_05 = cord + 5 mm in each dimension.  
**Brain Stem**: 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 as: BrainStem_03 = brainstem + 3 mm in each dimension.  
**Lips**: The definition of lips is self-explanatory.  
**Oral Cavity**: The oral cavity will be defined as a composite structure posterior to lips consisting of the anterior ½ to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and superiorly the palate, and inferiorly to the plane containing the tip of the mandible.  
**Parotid Glands**: Parotid glands will be defined in their entirety (superficial and deep lobes) based on the treatment planning CT scan.  
**Submandibular Glands**: Submandibular glands will be defined in their entirety based on treatment planning CT scans.  
**Pharynx**: This will be defined as the pharyngeal wall plus adjacent constrictor muscles deemed not to require treatment (external to PTVs). This extends from the superior constrictor region (level of the inferior pterygoid plates) to the cricopharyngeal inlet (level of the posterior cricoid cartilage).  
**Esophagus**: This will be defined as the cervical (upper) esophagus, a tubular structure that starts at the bottom of pharynx (cricopharyngeal inlet) and extends to the thoracic inlet.  
**Larynx**: This will be defined as the glottic and supraglottic larynx, including the tip of the epiglottis, the aryepiglottic folds, arytenoids, false cords, and true cords, bounded by the thyroid cartilage laterally, anteriorly including the anterior edge of the pre-epiglottic fat, and posteriorly bounded by the anterior edge of the pharyngeal wall or the posterior edge of the arytenoid and/or cricoid cartilage.  
**Mandible**: This includes the entire bony structure of the mandible from TMJ through the symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and PTVs.  
**Unspecified Tissue Outside the Targets (NonPTV)**: This will be defined as tissue located between the skull base and thoracic inlet external to all PTVs and defined normal stuctures within the external contour of the patient.  
5.2.6 Planning Target Volumes All CTVs will have associated PTVs which represent the volumes to which radiation dose will be prescribed, delivered and evaluated. The PTVs are isotropic expansions of the CTVs to account for internal motion and residual set-up error.
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ptvs are defined as either

The simple isotropic expansion of CTVs to create PTVs will result in dosimetric challenges in 2 instances:
i. when the CTV expansion results in a PTV that overlaps a critical OAR or its PRV, hence dose delivered to this PTV will exceed the acceptable dose limits for the OAR;
ii. and when the CTV expansion results in PTVs extending beyond the patient external contour, making PTV dose calculation and evaluation unreliable.  
The PTVs may be modified in the following situations: 1) When a PTV overlaps a critical OAR (spinal cord and/or brainstem) and its associated PRV, the PTV should be modified to exclude the PRV so as to limit the dose delivered to the PRV within constraints defined in table 5.2.10.  
2) The PTVs should be constrained 5 mm within the external contour. For situations where gross disease is external to the external contour (disease at or through the skin surface), the use of 5 mm tissue equivalent material (bolus) is required, and no PTV constraint should be used underneath the bolus.
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table 5.2.6 planning target volume

All to be treated in 30 fractions except PTV_4400 in 22 fractions. For CTV descriptions see Table 5.2.4B. **Note**: All structures marked as **Required** in the table below must be contoured and labeled as listed under "Standard Name" for digital RT data submission. All structures marked as Required if applicable must be contoured and labeled as listed under "Standard Name" for digital data submission IF they are applicable to the patient's plan. Resubmission of data is necessary when labeling of structures does not conform to the DICOM Standard Name listed.  
| Standard Name                            | Description                                                                    | Detailed Description          |
|------------------------------------------|--------------------------------------------------------------------------------|-------------------------------|
| PTVp_6000                                | PTV to receive 60Gy at the  primary site Required                              | 3-5mm expansion of  CTVp_6000 |
| PTVn_6000                                | PTV to receive 60 Gy at  involved nodes Required                               | 3-5mm expansion of  CTVn_6000 |
| PTV_6000                                 | PTV to receive 60 Gy                                                           | Sum of PTVp_6000 and          |
| Required                                 | PTVn_6000                                                                      |                               |
| PTV_5400                                 | PTV to receive 54 Gy at the  primary site and applicable  node levels Required | 3-5mm expansion of  CTV_5400  |
| PTV_4800                                 | PTV to receive 48 Gy in neck                                                   | 3-5mm expansion of            |
| Required if applicable                   | CTV_4800                                                                       |                               |
| PTV_4400                                 | PTV to receive 44 Gy at  lower neck (non IMRT) Required if applicable          | CTV_4400*                     |
| *No expansion from CTV_4400 to PTV_4400. |                                                                                |                               |  
5.2.7 Dose Prescription The prescribed radiotherapy dose to gross disease for all patients will be 60 Gy delivered in 30 fractions of 2 Gy. For Arm 1, radiotherapy will be delivered once daily, 5 fractions per week Monday to Friday for 30 consecutive treatment days (6 weeks), with weekly concurrent cisplatin at 40 mg/m2.  
For Arm 2, the radiotherapy will be delivered alone (without the addition of chemotherapy) in an accelerated schedule over 5 weeks, which requires delivery of 6 fractions per week. The sixth fraction can be delivered either on a Saturday or as a second daily fraction, with at least a 6 hour interfraction interval if 2 fractions are given on one of the weekdays. Target volumes will be similar in both arms and for both, the primary tumor and involved nodes will receive 60 Gy (2 Gy per fraction for 30 fractions), high-risk subclinical sites will receive 54 Gy (1.8 Gy per fraction for 30 fractions) and nodal regions at risk of microscopic spread will receive 48 Gy (1.6 Gy per fraction for 30 fractions). If the low neck is treated with non-IMRT technique, 44 Gy (in 22 fractions) will be prescribed to a point of 3 cm depth. Unilateral radiation will be permitted in selected patients; see Section 5.2.4. Doses prescribed are indicated in Table 5.2.7 below. All PTVs are to be treated concurrently within a single IMRT plan of 30 fractions. If the low neck is treated with non-IMRT techniques to 44 Gy in 22 fractions once daily fractions will commence simultaneously and be delivered concurrently with the IMRT plan.  
| Table 5.2.7: Doses Prescribed to PTVs   |           |           |                          |                             |
|-----------------------------------------|-----------|-----------|--------------------------|-----------------------------|
| Target                                  | Dose (Gy) | Fraction  | # of                     | Dose                        |
| Standard Name                           | Size (Gy) | fractions | specification  technique |                             |
| PTV_6000                                | 60        | 2.0       | 30                       | Covering ≥ 95% of  PTV_6000 |
| PTV_5400                                | 54        | 1.8       | 30                       | Covering ≥ 95% of  PTV_5400 |
| PTV_4800                                | 48        | 1.6       | 30                       | Covering ≥ 95% of  PTV_4800 |
| PTV_4400                                | 44        | 2.0       | 22                       | 100% at 3 cm                |
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5.2.8 treatment planning priorities and

Doses are prescribed to PTVs as outlined in Table 5.2.7. The treatment goal is that 95% of the volume of all PTVs must receive the prescribed dose with a minimum dose (defined as dose to 99% of PTVs) greater than 93% of the prescription dose and a maximum dose (defined as dose encompassing 0.03 cc of the PTV) less than 110-115% of the highest prescription dose. It is recognized that portions of PTVs close to the skin or critical PRVs (spinal cord and brainstem) may receive significantly less than the prescription doses. This is acceptable in these regions as long as cold spots within these PTVs do not exist within the GTV. In cases of PTVs close to skin, tissue equivalent bolus must be utilized to ensure adequate dose. It is also recognized that PTVs abutting or enclosing higher dose PTVs will have regions of maximum dose that may exceed their prescribed dose in order to achieve acceptable minimal doses to the higher dose PTVs which are considered a higher priority target.
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prioritization for imrt planning

1. Spinal Cord 2. Brainstem 3. PTV_6000 4. PTV_5400 5. PTV_4800 and PTV_4400 6. a. Parotid gland contralateral to primary tumor site b. Larynx 7. a. Pharynx b. Contralateral submandibular 8. a. Oral Cavity b. Lips c. Esophagus 9. a. Parotid gland ipsilateral to primary tumor site b. Mandible 10. Unspecified tissue outside the targets 5.2.9 Doses to Normal Structure Dose limitations to normal stuctures are described below. For the critical structures of spinal cord and brainstem these are mandatory. For other structures recommended limits are provided, but the doses delivered should always be as low as reasonably achievable without compromising doses to PTVs.  
**Spinal Cord**: The PRV for spinal cord (SpinalCord_05) should not exceed 48 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 PRV for brainstem (BrainStem_03) 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 BrainStem_03 should be given less priority than the SpinalCord_05, but more than the 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 <
32 Gy for the 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 but efforts should be made to reduce this further if possible without compromising dose to PTVs.  
**Contralateral submandibular gland**: If contralateral level Ib is not a target, aim to reduce mean contralateral submandibular gland to < 39 Gy.  
**Pharynx:** Reduce the dose as much as possible. Some recommended (but not mandatory) treatment goals include: 1) No more than 33% of the Pharynx exceeds 50 Gy; 2) Mean dose < 40 Gy; 3) No more than 15% of the Pharynx exceeds 60 Gy.  
**Esophagus**: Reduce the dose as much as possible; recommended (but not mandatory) treatment goal: mean dose < 30 Gy.  
**Larynx**: Reduce the dose as much as possible. The larynx mean dose is recommended to be ≤ 35 Gy if whole-neck IMRT is used.  
**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 < 63 Gy.  
Unspecified Tissue Outside the Targets **(NonPTV)**: No more than 1cc of unspecified tissue outside the targets can receive ≥ 63Gy .  
5.2.10 Dose Compliance Criteria **(4/29/15)**
The compliance criteria listed in Table 5.2.10 will be used to evaluate each case. The Per Protocol and Variation Acceptable categories are both considered to be acceptable. The Per Protocol cases can be viewed as ideal plans, and the Variation Acceptable category can include more challenging plans that do not fall at or near the ideal results. A final category, called Deviation Unacceptable, results when cases do not meet the requirements for either Per Protocol or Variation Acceptable. Plans falling in this category are considered to be suboptimal and additional treatment planning optimization is recommended to avoid protocol deviation.  
| Table 5.2.10: Planning Target Volume and Critical OAR Constraints and  Compliance Criteria Name of  Dosimetric  Per Protocol Variation  Structure parameter* Dose (Gy) Acceptable PTV_6000 D95%*(Gy) D99%(Gy) Dmax**(Gy) 60 > 60 and ≤ 63 ≥ 55.8 ≥ 54 ≤ 66 ≤ 69 CTV_6000 V60 Gy (%) ≥ 99 % 95 to 99 % PTV_5400 D95%*(Gy) ≥ 54 ≥ 51.3 D99%(Gy) ≥ 50.2 ≥ 48  CTV_5400 V54 Gy (%) ≥99 % 95 to 99 % PTV_4800 D95%*(Gy) ≥ 48  ≥ 44 D99%(Gy) ≥ 44.6  ≥ 43.2 CTV_4800 V48 Gy (%) 99 % 95 to 99 % SpinalCord_05 Dmax**(Gy) ≤48 ≤50 Spinal Cord Dmax**(Gy) ≤45 ≤48 BrainStem_03 Dmax**(Gy) ≤ 50 ≤52 A Deviation Unacceptable will be scored when the Variation Acceptable limits are  not met.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
*D95%(Gy) = dose to 95% of volume
**Dmax = maximum dose to 0.03 cc of the volume  
| Structure                                         | Recommended dose acceptance criteria   |
|---------------------------------------------------|----------------------------------------|
| Parotid                                           | Mean dose to one parotid ≤ 26 Gy       |
| Larynx                                            | Mean dose ≤ 35 Gy                      |
| Pharynx                                           | Mean dose ≤ 40 Gy                      |
| Submandibula_R  Or Submandibula_L (contralateral) | Mean Dose ≤ 39 Gy                      |
| OralCavity (excluding PTV's)                      | Mean dose ≤ 32 Gy                      |
| Esophagus_Up                                      | Mean dose ≤ 30 Gy                      |
| NonPTV                                            | D1cc < 63 Gy                           |
| Mandible                                          | D0.03cc < 63 Gy                        |
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5.2.11 delivery compliance criteria

Protocol treatment must begin within 14 days of randomization. Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for the treatment break(s). Treatment breaks, if necessary, should not exceed 3 treatment days at a time and 5 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. Given the importance of timeliness of treatment delivery in this study, it is strongly recommended that patients receive twice-daily treatments with a minimum 6-hour interfraction interval to compensate for missed days including holidays and those for toxicity or illness once sufficiently recovered with the goal of keeping the overall treatment time within the limits defined in Table 5.2.11.  
| Per Protocol                          | Variation    | Deviation   |                                                                  |
|---------------------------------------|--------------|-------------|------------------------------------------------------------------|
| Acceptable                            | Unacceptable |             |                                                                  |
| Overall Treatment  time Six week arm  | <45 days     | 46-50 days  | >50 days without a  medically  appropriate  indication for delay |
| Overall Treatment  time Five week arm | <37 days     | 38-42 days  | >42 days without a  medically  appropriate  indication for delay |
| Interruptions (without                | 0-2 days     | 2-4 days    | >4 days                                                          |
| medical indication)                   |              |             |                                                                  |
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5.2.12 dose calculations

The primary data set for dose calculation is CT. In the case in which contrast is present during the treatment planning CT, the density of the contrast should be overridden to a representative background electron density. The dose grid size should be ≤ 3 mm in all directions, which means that the CT slice thickness should be ≤ 3 mm. Dose calculation algorithms have been credentialed by IROC Houston. To find whether your commercial treatment planning system has been credentialed by IROC Houston, please see the list from the following website: (http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20- %20algorithm%20list%20updated.pdf).
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any other dose calculation algorithms

If using PTV margins of 0.5 cm, a minimum of weekly IGRT will be required, and the imaging alignment must be approved by the attending physician on the first day of treatment and weekly thereafter. IGRT credentialing is not required for 0.5 cm PTV margin expansion.  
IGRT may be achieved using any one of more of the following techniques:
Orthogonal kilovoltage (KV) images, e.g. ExacTrac; Linear-accelerator mounted kV and MV conebeam CT images; Linear-accelerator mounted MV CT images (e.g., Tomotherapy);
Other mechanism, after discussion with the Radiation Oncology Co-Chair and/or Medical Physics Co-chair.  
The institution's procedure to register the treatment day imaging dataset with the reference dataset should comply with the following recommendations: Region-of-interest (ROI) or "clip box" for fusion should be set to encompass the high dose PTV and adjacent spinal cord; If the 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 surgical clips and 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, reimaging 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.