eligibility checklist - step 2
references (continued) (05-oct-2011)

Fortin A, Allard J, Albert M, Roy J. Outcome of patients treated with cobalt and 6 MV in head and neck cancers. *Head Neck*. 23:181-8, 2001. PMID: 11428447 Fox PC, Busch KA, Baum BJ. Subjective reports of xerostomia and objective measures of salivary gland performance. *J Amer Dent Assoc*. 115(4): 581-4, 1987. PMID: 3477595 Freidlin B, Korn EL. A comment on futility monitoring. *Controlled Clin Trials*. 23: 355-366, 2002. PMID: 12161079 Friedlander P, Caruana S, Singh B, et al. Functional status after primary surgical therapy for squamous cell carcinoma of the base of tongue. *Head Neck*. 24:111–4, 2002. PMID: 11891940 Gillison ML, D'Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J
Natl Cancer Inst. 100(6):407-20, 2008. Epub 2008 Mar 11. PMID: 18334711 Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. *J Natl Cancer Inst*. 92:709-20, 2000. PMID: 10793107 Goodwin WJ Jr. Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means? *Laryngoscope*. (3 Pt 2 Suppl 93):1-18, 2000. PMID:
10714711 Gorgulho A, De Salles A, Mattozo C, et al. Definition of a Treatment Modality by the Patients Using a DecisionMaking Software. Poster presented at: Annual Meeting of the American Association of Neurological Surgeons; April 18-20, 2005; San Francisco, CA.  
Gorgulho A, De Salles A, Mattozo C, et al. VisionTree Software - Stereotactic Radiation vs. Conventional Surgery. Paper presented at: Annual Meeting of the International Stereotactic Radiosurgery Society; June 2327, 2007; San Francisco, CA. Han, SW, Jeon YK, Lee KH, et al. Intron 1 CA dinucleotide repeat polymorphism and mutations of epidermal growth factor receptor and gefitinib responsiveness in non-small-cell lung cancer. *Pharmacogenet Genomics*.  
17(5):313-9, 2007. PMID: 17429313 Hanna E, Sherman A, Cash D, et al. Quality of Life for patients following total laryngectomy vs.  
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15262766 Harari PM. Personal communication. ASTRO 2008 submission.  
Harari, PM, Harris J, Kies M, et al. Phase II randomized trial of surgery followed by chemoradiation plus cetuximab for high-risk squamous cell carcinoma of the head and neck (RTOG 0234). Int J Radiat Oncol Biol Phys. 69(3): S13, 2007. Henson BS, Inglehart MR, Eisbruch A, Ship JA. Preserved salivary output and xerostomia-related quality of life in head and neck cancer patients receiving parotid-sparing radiotherapy. *Oral Oncol.* 37(1):84-93, 2001.  
PMID: 11120488 Hertrampf K, Wenz HJ, Lehmann KM, Lorenz W, Koller M. Quality of life of patients with maxillofacial defects after treatment for malignancy. *Int J Prosthodont.* 17: 657–652004. PMID: 15686093 Hinerman RW, Mendenhall WM, Morris CG, et al. Postoperative irradiation for squamous cell carcinoma of the oral cavity: 35-year experience. *Head Neck*. 26(11): 984-94, 2004. PMID: 15459927
eligibility checklist - step 2
references (continued)

Hinerman RW, Morris CG, Amdur RJ, et al. Surgery and postoperative radiotherapy for squamous cell carcinoma of the larynx and pharynx. *Am J Clin Oncol*. 29(6): 613-21, 2006. PMID: 17149000 Hong TS, Tome WA, Chappell RJ, et al. The impact of daily setup variations on head and neck intensity modulated radiation therapy. *Int J Radiat Oncol Biol Phys*. 61(3):779-8, 2006. PMID: 15708257 Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. Translating the science of quality of life into practice: What do dermatology life quality index scores mean? *J Invest Dermatol*. 125(4):659-64, 2005. PMID: 16185263 Jensen K, Jensen AB, Grau C. The relationship between observer-based toxicity scoring and patient assessed symptom severity after treatment for head and neck cancer. A correlative cross sectional study of the DAHANCA toxicity scoring system and the EORTC quality of life questionnaire. *Radiatiother and Oncol.*
78:298-305, 2006. PMID: 16524633 Kalbfleisch JD, Prentice, RL. *The Statistical Analysis of Failure Time Data*. New York: John Wiley and Sons; 1980.  
Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. *J Clin Oncol.* 25(31):4873-9, 2007.  
PMID: 17971582 Kaplan, E. and P. Meier, Nonparameteric estimation from incomplete observations. *J Amer Stat Assoc.* 53:
457-481, 1958.  
Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. *J Clin* Oncol. 25(22): 3230-7, 2007. PMID: 17664471 Lakatos, E. Sample size determination in clinical trials with time-dependent rates of losses and noncompliance. *Controlled Clin Trials*. 7:189-199, 1986. PMID: 3802834 Langendijk JA, Slotman BJ, van der Waal I, Doornaert P, Berkof J, Leemans CR. Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy. *Cancer*. 104(7): 1408-17, 2005. PMID: 16130134 Laramore GE, Scott CB, al-Sarraf M, et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report on Intergroup Study 0034. *Int J Radiat Oncol Biol Phys*. 23(4):705-13, 1992.  
PMID 1618662 Lavaf A, Genden E, Packer S, Kao J. Adjuvant radiotherapy (RT) improves overall survival (OS) for node positive head and neck squamous cell carcinoma (HNSCC). Proc Am Soc Clin Oncol (ASCO). *J Clin Oncol.* 25 (18S), 2007. Abstract 6087. PMID: 18076014 Lennox RD, Leahy MJ. Validation of the Dermatology Life Quality Index as an outcome measure for urticariarelated quality of life. *Ann Allergy Asthma Immunol.* 93(2):142-6, 2004. PMID: 15328673 Lewis V, Finlay AY. 10 years experience of the Dermatology Life Quality Index (DLQI). J Investig Dermatol Symp Proc. 9(2):169-80, 2004. Review. No abstract available. PMID: 15083785 List M, Ritter-Sterr C, Baker T, et al. Longitudinal assessment of quality of life in laryngeal cancer patients. Head Neck. 18:1–10, 1996. PMID: 8774916 List MA, D'Antonio LL, Cella DF, et al. The performance status scale for head and neck cancer patients and the functional assessment of cancer therapy-head and neck scale: A study of utility and validity. *Cancer*. 77: 2294-301, 1996. PMID: 8635098
eligibility checklist - step 2
references (continued) (05-oct-2011)

List MA, Siston A, Haraf D, et al. Quality of life and performance in advanced head and neck cancer (HNC: Comparison between paclitaxel-based (P-CT/XRT) and cisplatin-based (C-CT/XRT) concomitant chemoradiotherapy: A prospective examination. *J Clin Oncol.* 17: 1020-8, 1999. PMID: 10071297.  
Liu W, Innocenti F, Chen P, et al. Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. *Clin Cancer Res*. 2003 Mar;9(3):1009-12.PMID: 12631599 Logemann JA, Pauloski BR, Rademaker AW, et al. Swallowing disorders in the first year post-radiation and chemoradiation. *Head & Neck*. 30: 148-158, 2008. PMID: 17786992 Manning MA, Wu Q, Cardinale RM, et al. The effect of setup uncertainty on normal tissue sparing with IMRT
for head and neck cancer. *Int J Radiat Oncol Biol Phys*. 51:1400-9, 2001. PMID: 11728701 Mantel, N., Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Reports. 50: 163-170, 1966. PMID: 5910392 Mellin H. Human papillomavirus (HPV) DNA in tonsillar cancer: Clinical correlates, risk of relapse, and survival. *Int J Cancer.* 89:300-304, 2000. PMID: 10861508 Meyer TK, Kuhn JC, Campbell BH, Marbella AM, Myers KB, Layde PM. Speech intelligibility and quality of life in head and neck cancer survivors. *Laryngoscope*. 114:1977–81, 2004. PMID: 15510026 Michiels S, et al. Surrogate endpoints for overall survival (OS) in head and neck squamous cell carcinoma (HNSCC) using individual data of 23,737 Patients. *J Clin Oncol*. 25: Abstract 6035, 2007. Milas L, Fang FM, Mason KA, Valdecanas D, Hunter N, Koto M, Ang KK. Importance of maintenance therapy in C225-induced enhancement of tumor control by fractionated radiation. *Int J Radiat Oncol Biol Phys*.  
67(2):568-72, 2007. PMID: 17236972 Moore GJ, Parsons JT, Mendenhall MD. Quality of life outcomes after primary radiotherapy for squamous cell carcinoma of the base of tongue. *Int J Radiation Biol Phys*. 36:351–4, 1996. PMID: 8892459 Murphy BA, Ridner S, Wells N, Dietrich M. Quality of life research in head and neck cancer: A review of the current state of the science. *Crit Reviews Oncol/Hemat*. 62:251–267, 2007. PMID: 17408963 Nguyen NP, Frank C, Moltz CC, et al. Impact of dysphagia on quality of life after treatment of head and neck cancer. *Int J Radiation Biol Phys*. 61:772–8, 2005. PMID: 15708256 Pajak TF. Personal communication, 2008.  
Pedroso A, De Salles A, Mattozo C, et al. Decision Support Software Use For Patients: Immediate and Post Evaluation. Paper presented at: Annual Meeting of the Congress of Neurological Surgeons; April 28-29, 2006; Los Angeles, CA.  
Peterson B, George SL. Sample size requirements and length of study for testing interaction in a 1 x k factorial design when time-to-failure is the outcome. *Controlled Clinical Trials*. 511-522, 1993. PMID: 8119066 Pfreundner L, Willner J, Marx A, et al. The influence of the radicality of resection and dose of postoperative radiation therapy on local control and survival in carcinomas of the upper aerodigestive tract. Int J Radiat Oncol Biol Phys. 47(5): 1287-97, 2000. PMID: 10889383 Poeta ML, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. *NEJM*. 357:2552-2561, 2007. PMID: 18094376
eligibility checklist - step 2
references (continued)

Pow EH, Kwong DL, McMillan AS, Wong MC, Sham JS, Leung LH, Leung WK. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial. *Int J Radiat Oncol Biol Phys*. 66(4): 981-91, 2006. PMID: 17145528)
Prentice RL, Kalbfleisch JD, Peterson AV, Flournoy N, Farewell VT, Breslow NE. The analysis of failure times in the presence of competing risks. Biometrics. 34: 541-554, 1978.  
Press OA, Zhang W, Gordon MA. Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer. *Cancer Res*. 68(8): 3037-42, 2008. PMID: 18413774 Racadot S, Mercier M, Dussart S, et al. Randomized clinical trial of post-operative radiotherapy versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement. Radiother Oncol. 2008 Jan 24 [Epub ahead of print]. PMID 18222010 Reimers N, Kaspar HU, Weissenborn SJ, et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. *Int J Cancer.*120(8):1731-8, 2007. PMID: 17236202 Ringstrom E, Peters E, Hasegawa M, Posner M, Liu M, Kelsey KT. Human Papillomavirus Type 16 and Squamous Cell Carcinoma of the Head and Neck. *Clin Cancer Res.* 8:3187-92, 2002. PMID: 12374687 Rosenthal DI, Machtay M, Chalian AA, et al. Importance of the treatment package time in surgery and postoperative radiotherapy for squamous cell carcinoma of the head and neck. *Head Neck*. 24(2): 115-26, 2002. PMID: 11891941 Sanguineti G, Richetti A, Bignardi M, et al. Accelerated versus conventional fractionated postoperative radiotherapy for advanced head and neck cancer: results of a multicenter Phase III study. *Int J Radiat Oncol* Biol Phys. 61: 762-71, 2005. PMID: 15708255 Sarna L, Swann S, Langer C, et al. Clinically meaningful differences in patient-reported outcomes with amifostine in combination with chemoradiation for locally advanced non-small-cell lung cancer: An analysis of RTOG 9801. *Int J Radiat Oncol Biol Phys*. May 21 2008. [Epub ahead of print]. PMID: 18501528 Schoenfeld D. The asymptotic properties of nonparametric tests for comparing survival distributions.  
Biometrika. 68: 316-319, 1981. Schwartz S, Yueh B, Mcdougall J, Daling J, Schwartz S. Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. *Otol Head Neck Surg*. 125:1-9, 2001. PMID: 11458206 Shikiar R, Harding G, Leahy M, Lennox RD. Minimal important difference (MID) of the Dermatology Life Quality Index (DLQI): Results from patients with chronic idiopathic urticaria. *Health Qual Life Outcomes*. May 20;3:36, 2005. PMID: 15907211 Stokes M, Davis C, Koch G. *Categorical Data Analysis Using the SAS System*. Cary, NC: SAS Institute; 1995. the general measure. *J Clin Oncol.* 11(3): p. 570-9, 1993. PMID: 844533 Thilman C, Nill S, Tucking T, et al. Correction of patient positioning errors based on in-line cone beam CTs: clinical implementation and first experiences. *Radiat Oncol*. 1(1):16, 2006. PMID: 16723023 Tome WA, Meeks SL, McNutt TR, et al. Optically guided intensity modulated radiotherapy. *Radiother Oncol*.  
61:33-44, 2001. PMID: 11578726 Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: A systematic literature review. Radiother Oncol. 66: 253-62, 2003. PMID: 12742264  
Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. *J Clin Oncol*.; 25: 2171-7, 2007. PMID: 17538161 Vermorken JB Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. NEJM. 359: 1116-27, 2008. PMID: 18784101. Warren S, Gates O. Multiple primary malignant tumors: A survey of the literature and statistical study. Am J
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Zelen, M., The randomization and stratification of patients to clinical trials (MI \#7506064). *J Chronic Dis*. 27:
365-375, 1974. PMID: 4612056
eligibility checklist - step 2
appendix i study parameter table

| Assessments                                                                               | Within 8 wks prior to                         | Within 4 wks prior to   | Within 2 wks prior to   |
|-------------------------------------------------------------------------------------------|-----------------------------------------------|-------------------------|-------------------------|
| registration                                                                              | registration                                  | registration            |                         |
| General H&P by Rad Onc                                                                    | X*                                            |                         |                         |
| and/or Med Onc ENT/Surgeon's exam                                                         | X*                                            |                         |                         |
| CT with contrast, or CT/PET,                                                              | Recommended within 4 weeks prior to treatment |                         |                         |
| and/or MRI of H & N Chest x-ray (or chest CT or                                           | X                                             |                         |                         |
| CT/PET) Pathology Assessment (Gross  total resection within 7 wks  prior to registration) | X*                                            |                         |                         |
| Performance status                                                                        | X                                             |                         |                         |
| CBC w/ diff & AGC                                                                         | X                                             |                         |                         |
| Bilirubin, AST or ALT                                                                     | X                                             |                         |                         |
| Serum creatinine or creatinine                                                            | X                                             |                         |                         |
| clearance Na, K, Cl, glucose, Ca, Mg,                                                     | X                                             |                         |                         |
| albumin Serum pregnancy test (if                                                          | X                                             |                         |                         |
| applicable) Dental eval                                                                   | Within 3 months prior to start of treatment   |                         |                         |
| Assessment of swallowing                                                                  | Within 2 weeks prior to treatment             |                         |                         |
| function Eval for G-tube placement                                                        | Recommended within 4 weeks prior to treatment |                         |                         |
| EKG                                                                                       | Recommended within 8 weeks prior to treatment |                         |                         |
| QOL/Functional Assessments:  FACT-H&N; PSS-HN; EQ-5D;  XeQOLS; DLQI                       | Prior to treatment (Baseline)                 |                         |                         |
eligibility checklist - step 2
appendix i study parameter table

| Assessments                                      | Weekly                            | Every 3 wks   | As clinically indicated   |
|--------------------------------------------------|-----------------------------------|---------------|---------------------------|
| General H&P by Rad Onc                           | X*                                |               |                           |
| and/or Med Onc CT with contrast, or CT/PET,      | X                                 |               |                           |
| and/or MRI of H & N Chest x-ray (or chest CT or  | X                                 |               |                           |
| CT/PET) Biopsy                                   | If suspicion of tumor  recurrence |               |                           |
| Performance status                               | X                                 |               |                           |
| CBC w/ diff & AGC                                | Prior to start of  treatment      |               |                           |
| Bilirubin, AST or ALT                            | X                                 |               |                           |
| Serum creatinine or                              | X                                 |               |                           |
| creatinine clearance Na, K, Cl, glucose, Ca, Mg, | X*                                |               |                           |
| albumin Adverse event eval                       | X                                 |               |                           |
| Blood for research-if patient                    | Prior to start of                 |               |                           |
| consents                                         | treatment                         |               |                           |
eligibility checklist - step 2
appendix i study parameter table

| Both Arms: At 1 mo.                                                  | Both Arms:                                                                |                                     |
|----------------------------------------------------------------------|---------------------------------------------------------------------------|-------------------------------------|
| post-XRT                                                             | q3 mos. post-XRT,  then q3 mos. x 2 yrs,  q6 mos. x 3 yrs, then  annually | Both Arms: As  clinically indicated |
| General H&P by Rad Onc  and/or Med Onc                               | See Section 11.3 for details of assessments                               |                                     |
| ENT/Surgeon's exam CT with contrast, or CT/PET,                      | As clinically indicated                                                   | After 5 years, as                   |
| and/or MRI of H & N                                                  | clinically indicated                                                      |                                     |
| Chest x-ray (or chest CT or                                          | X*                                                                        |                                     |
| CT/PET) Biopsy                                                       | If suspicion of tumor recurrence                                          |                                     |
| Performance status                                                   | X                                                                         | X                                   |
| CBC w/ diff & AGC                                                    | X                                                                         | X                                   |
| Bilirubin, AST or ALT                                                | X*                                                                        |                                     |
| Serum creatinine or                                                  | See Section 11.2 for details of assessments                               |                                     |
| creatinine clearance Na, K, Cl, glucose, Ca, Mg,                     | See Section 11.2 for details of assessments                               |                                     |
| albumin Assessment of swallowing                                     | X                                                                         | X                                   |
| function Adverse event eval                                          | X                                                                         | X                                   |
| QOL/Functional  Assessments: FACT-H&N;  PSS-HN; EQ-5D; XeQOLS;  DLQI | At 3, 12, and 24 months from the end of radiation treatment               |                                     |  
0 Fully active, able to carry on all predisease activities without **restriction**  
1 **Restricted in physically strenuous activity but ambulatory and able to carry**
work of a light or sedentary nature. For example, light housework, office work
2 **Ambulatory and capable of all self-care but unable to carry out any work**
activities. Up and about more than 50% of waking **hours**
3 Capable of only limited self-care, confined to bed or chair 50% or more of waking **hours**
4 Completely disabled. Cannot carry on self-care. Totally confined to bed or 5 Death
eligibility checklist - step 2
staging-primary tumor (t)

TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ
eligibility checklist - step 2
lip and oral cavity

| TX                    | Primary tumor cannot be assessed                                                                                         |
|-----------------------|--------------------------------------------------------------------------------------------------------------------------|
| T0                    | No evidence of primary tumor                                                                                             |
| Tis                   | Carcinoma in situ                                                                                                        |
| T1                    | Tumor 2 cm or less in greatest dimension                                                                                 |
| T2                    | Tumor more than 2 cm but not more than 4 cm in greatest dimension                                                        |
| T3                    | Tumor more than 4 cm in greatest dimension                                                                               |
| T4 (lip)              | Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face  (i.e., chin or nose)      |
| T4a (oral             | Tumor invades adjacent structures (e.g., through cortical bone, into deep [extrinsic] muscle of                          |
| cavity)               | tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of  face                       |
| T4b                   | Tumor invades masticator space, pterygoid plates or skull base and/or encases internal  carotid artery                   |
| PHARYNX Oropharynx T1 | Tumor 2 cm or less in greatest dimension                                                                                 |
| T2                    | Tumor more than 2 cm but not more than 4 cm in greatest dimension                                                        |
| T3                    | Tumor more than 4 cm in greatest dimension                                                                               |
| T4a                   | Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate, or  mandible.                  |
| T4b                   | Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base  or encases carotid artery. |
eligibility checklist - step 2
appendix iii (continued)

| LARYNX Supraglottis T1   | Tumor limited to one subsite of supraglottis with normal vocal cord mobility                                                                                                                                                      |
|--------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| T2                       | Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region  outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform  sinus) without fixation of the larynx. |
| T3                       | Tumor limited to larynx with vocal cord fixation and/or invades any of the following:  postcricoid area, pre-epiglottic tissues, paraglottic space, and/or minor thyroid cartilage  erosion (e.g., inner cortex).                 |
| T4a                      | Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g.,  trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles,  thyroid, or esophagus).             |
| T4b                      | Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.                                                                                                                                      |
| Glottis T1               | Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal  mobility                                                                                                                           |
| T1a                      | Tumor limited to one vocal cord                                                                                                                                                                                                   |
| T1b                      | Tumor involves both vocal cords                                                                                                                                                                                                   |
| T2                       | Tumor extends to supraglottis and/or subglottis, or with impaired vocal cord mobility                                                                                                                                             |
| T3                       | Tumor limited to the larynx with vocal cord fixation, and/or invades paraglottic space, and/or  minor thyroid cartilage erosion (e.g., inner cortex).                                                                             |
| T4a                      | Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g.,  trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles,  thyroid, or esophagus).                 |
| T4b                      | Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.                                                                                                                                      |
| Subglottis T1            | Tumor limited to the subglottis                                                                                                                                                                                                   |
| T2                       | Tumor extends to vocal cord(s) with normal or impaired mobility                                                                                                                                                                   |
| T3                       | Tumor limited to larynx with vocal cord fixation                                                                                                                                                                                  |
| T4a                      | Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g.,  trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles,  thyroid, or esophagus).                 |
| T4b                      | Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.                                                                                                                                      |
eligibility checklist - step 2
appendix iii (continued) regional lymph

| NX   | Regional lymph nodes cannot be assessed                                                                                                                                                                                                                                      |
|------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| N0   | No regional lymph node metastasis                                                                                                                                                                                                                                            |
| N1   | Metastasis in a single ipsilateral node, 3 cm or less in greatest dimension                                                                                                                                                                                                  |
| N2   | Metastasis in a single ipsilateral node, more than 3 cm, but not more than 6 cm in greatest  dimension, or in multiple ipsilateral lymph nodes, none greater than 6 cm in greatest  dimension, or bilateral or contralateral nodes, none more than 6 cm in greatestdimension |
| N2a  | Metastasis in a single ipsilateral node more than 3 cm, but not more than 6 cm in greatest  dimension                                                                                                                                                                        |
| N2b  | Metastasis in multiple ipsilateral nodes, none more than 6 cm in greatest dimension                                                                                                                                                                                          |
| N2c  | Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest  dimension                                                                                                                                                                             |
| N3   | Metastases in a lymph node, more than 6 cm in greatest dimension                                                                                                                                                                                                             |
eligibility checklist - step 2
distant metastasis (m)

MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis  
| STAGE GROUPING Excluding Nasopharynx Stage 0 Tis, N0, M0 Stage I T1, N0, M0 Stage II T2, N0, M0 Stage III T3, N0, M0 T1-3, N1, M0 Stage IVA T4a, N0-2, M0  Any T, N2, M0 Stage IVB T4b, Any N, MO  Any T, N3, M0 Stage IVC Any T, Any N, M1   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Dental Care for Irradiated Patients Goals for a dental care program include: 1. To reduce incidence of bone necrosis.  
2. To reduce incidence of irradiation caries. 3. To allow proper fitting of dentures following treatment.
Pre-irradiation Care and Procedures The patients may be grouped into four groups in accordance with the problems they present prior to irradiation.
eligibility checklist - step 2
group 1

Includes edentulous patients. They may require surgical removal of any symptomatic cysts, infected retained root tips, or alveolar hyperplasia. These patients require hygiene instruction and precautionary instruction about trauma with premature use of a prosthesis.
eligibility checklist - step 2
group 2

Includes those with poor dental hygiene, including those patients whose teeth are beyond repair by ordinary dental procedure, those with generalized oral sepsis, those with generalized periodontal disease, and those with chronic periapical abscesses or granulomas.  
Procedures performed on this group include removal of all remaining teeth prior to irradiation with primary closure and surgical preparation of the alveolar ridges to laterally support a prosthesis. There should be antibiotic coverage during the healing stage and adequate time prior to the start of radiation therapy. These patients need complete hygiene instruction and precautionary instruction about premature use of a prosthesis.
eligibility checklist - step 2
group 3

Includes those in whom dental condition is fair, including those patients whose teeth are restored, ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions are not in proximity to the pulp, and no more than 20 restorable carious lesions are present. X-ray examinations show at least 1/2 of the bone still present around root surfaces. These patients require removal of any teeth that are non-salvageable in accordance with the above and restorations of the remaining teeth as required. The patients are instructed for dental prophylaxis and the patients utilize custom-made fluoride carriers.
eligibility checklist - step 2
group 4

Includes those in whom dental hygiene is good. This includes patients who do not have severe malocclusion in whom few carious lesions are present. Carious lesions are not in close proximity to the pulp and are correctable by conventional methods. These patients require periodontal evaluation and dental prophylaxis training, restorations as needed, no extractions prior to radiation therapy, and fitting for custom carriers.
eligibility checklist - step 2
extraction of teeth

If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that closure at the extraction site is possible. All loose spicules and sharp projections must be removed. The approximation of the gingival tissue must be such that the closure is neither too loose nor too tight. At least 10 days are required for adequate healing prior to initiation of therapy.
eligibility checklist - step 2
causative factors

The major causative factors appear to be the reduction of the amount of saliva and secondarily, reduced pH in the mouth. This occurs following high dose radiation to the major salivary glands using parallel opposed fields. The decay process usually occurs in the first year following radiation therapy. It tends to occur more quickly in teeth which have a large amount of root cementum exposed to those teeth with large amounts of plaque formation present. Doses of radiation in excess of 20 Gy to salivary tissue place the teeth at risk.
eligibility checklist - step 2
preventive program

The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible to the decay process. This is accomplished by a combination of increasing fluoride concentration on the tooth surface and by the effect of fluoride on the plaque and flora that are present in the oral cavity. Adequate results are obtained by:
1) cleansing the teeth thoroughly, followed by a good home care dental prophylaxis program, 2) construction of
eligibility checklist - step 2
appendix iv (continued)

fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution to the gingiva and tooth surfaces. Fluoride carriers are made individually with the use of casts. Material used for making a mouth guard is "Sta-Guard" plastic used in conjunction with vacutrole unit produced by Jelrus Technical Products, Corp., both of which are available through local dental supply. This material is molded to the cast impression and allowed to harden. A fluoride solution prepared at the M.D. Anderson Hospital is now available from the Emerson Laboratories, Inc., Dallas, Texas 75221. It has been used to coat the plastic carrier for use in the mouth. The patients are instructed to cleanse their teeth prior to placement of the carrier. It is then worn in place for 5 minutes each day. The patients are instructed to rinse their mouths thoroughly following the use of the carrier. This will be continued for an indefinite period of time. Close follow-up is necessary.
eligibility checklist - step 2
results

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

Management of failure to control radiation decay includes silver fillings with continued use of fluoride treatments.  
If the decay process is sufficiently advanced that a filling will no longer stay in place, these teeth are merely smoothed so that there will be no sharp, irritating edges. The mere existence of such a decayed tooth is not necessarily reason for extraction, for it must be remembered that extraction could lead to complications such as bone necrosis.  
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics and/or root-canal therapy.
eligibility checklist - step 2
hypersensitivity of teeth

Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished amounts of saliva.  
This has been shown to be reduced in incidence with the fluoride treatments. Should this problem become manifest, increasing the fluoride treatment to 10 to 15 minutes 3 times a day is recommended. Infections Infections occurring in patients under or after radiation therapy are best managed conservatively with good oral hygiene, irrigation and flushing procedures, and systemic antibiotics.
eligibility checklist - step 2
bone necrosis

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

This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen Bank.  
 The plug kit contains a shipping tube and a punch tool.  
Step 1  
  
If the block is stored cold, allow it to equilibrate for 30 minutes at room temperature. Place the punch tool on the paraffin block over the selected tumor area. (Ask a pathologist to select area with tumor.) Push the punch into the paraffin block. Twist the punch tool once around to separate the plug from the block. Then pull the punch tool out of the block. The punch should be filled with tissue sample.  
  
Label the punch tool with the proper specimen ID and Block ID.  
DON'T remove specimen from the punch.  
Use a separate punch tool for every specimen. Call or e-mail us if  
  
you have any questions or need additional specimen plug kits.  
Site that have the capacity to embed the blocks may do so. They should submit a fresh H&E from the punch block.
Step 3 Once punch tool is labeled, place in shipping tube and mail to address below. Please do not mix specimens in the same tube.  
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID.  
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please send the entire block to the NRG Oncology Biospecimen Bank- San Francisco and we will sample a plug from the block and return the remaining block to your facility. Please indicate on the ST form the request to perform the plug procedure and return of the block. Include a return request form with a return airbill Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the NRG Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.edu **or call 415-476-7864/Fax 415-476-5271.**
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology Biospecimen Bank—San Francisco University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): For Frozen Specimens or Trackable shipments NRG Oncology Biospecimen Bank—San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 APPENDIX VI: NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (13-NOV-2017)
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as specified by the protocol):
Kit contents: (Note: Sites are responsible for providing blood draw tubes):
- Thirty (30) 1 ml cryovials for plasma and serum - all time points
- Three (3) 2 ml cryovials for whole blood
- Biohazard bags (7) and Absorbent shipping material (7)
- One Styrofoam container (inner) and Cardboard shipping (outer) box per case
- UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers
- Specimen Transmittal (ST) Form and Kit Instructions
appendix v nrg oncology ffpe
preparation and processing of serum

❑ Label five1ml cryovials for the serum collected. Label them with the study and case number, collection date, time point, and clearly mark cryovials "serum".  
Process:
1. Allow one red top tube to clot for 30 minutes at room temperature.  
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the ST Form.  
3. Aliquot a minimum of 0.5 ml serum into each of the five as many cryovials as are necessary for the serum collected labeled with study and case numbers, collection date, protocol time-point collected (e.g. pretreatment, post-treatment), and clearly mark specimen as "serum".  
4. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90 C, and store frozen until ready to ship. See below for storage conditions.  
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions.  
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the ST Form.
appendix v nrg oncology ffpe
(b) plasma (if requested) purple

❑ Label five1ml cryovials for the plasma collected. Label them with the study and case number, collection date, and time point, and clearly mark cryovials "plasma".  
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA.  
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, keep specimen on ice until centrifuging is performed.  
4. Carefully pipette and aliquot a minimum of 0.5 ml plasma into each of the five cryovials as necessary for the plasma collected labeled with study and case numbers, collection date, time point collected and clearly mark specimen as "plasma". Avoid pipetting up the buffy coat layer.  
5. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90C.  
6. Store frozen plasma until ready to ship on dry ice. 7. See below for storage conditions.  
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the ST Form.  
(continued on next page)  
  
BLOOD COLLECTION KIT INSTRUCTIONS (continued)
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube \#2 (one 5 ml or 10 ml **tube)**
❑ Label three1ml cryovials as necessary for the whole blood collected..Label them with the study and case number, collection date, and time point, and clearly mark cryovials "blood".  
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be mixed for 5 minutes on a mixer at room temperature.  
2. Carefully pipette and aliquot 1.0-2.0ml blood into three 2mlcryovials as necessary for the blood collected labeled with study and case numbers, collection date, time point collected and clearly mark specimen as "blood".  
3. Place cryovials into biohazard bag and freeze tubes upright immediately at -70 to -80 Celsius.  
4. Store blood samples frozen until ready to batch ship on dry ice. 5. See below for storage conditions.
appendix v nrg oncology ffpe
please make sure that every

Freezing and Storage:
Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen.  
❑ Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,
- Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
- Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
- Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
❑ Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored.  
Shipping/Mailing:
❑ Ship specimens on Dry Ice overnight **Monday-Wednesday (Monday-Tuesday from Canada)** to prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
❑ Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
❑ Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods together) in absorbent shipping material and place each specimen type in a separate biohazard bag. Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the *tubes.*
❑ Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box.  
(continued on next page)
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued)  
❑ Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the *tubes.*
❑ For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail NRGBB@ucsf.edu or call (415)476-7864.
appendix v nrg oncology ffpe
shipping address

Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology Biospecimen Bank—San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu