Phase II Trial Of Induction Chemotherapy Followed By Attenuated Chemoradiotherapy For Locally Advanced Head And Neck Squamous Cell Carcinoma Associated With Human Papillomavirus (HPV)
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: University of California, Davis

 
 PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY ATTENUATED 
CHEMORADIOTHERAPY FOR LOCALLY ADVANCED HEAD AND NECK SQUAMOUS 
CELL CARCINOMA ASSOCIATED WITH HUMAN PAPILLOMAVIRUS (HPV) 
 
NCT01716195 
 
Protocol CCRO022 
And 
Consent 
February 25 2014 
 

unmarked_02.25.14 
 
 
 
 
 
PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY ATTENUATED 
CHEMORADIOTHERAPY FOR LOCALLY ADVANCED HEAD AND NECK SQUAMOUS 
CELL CARCINOMA ASSOCIATED WITH HUMAN PAPILLOMAVIRUS (HPV) 
 
 
 
 
 
 
 
 
 
 
Protocol Number: 
CCRO022 
 
 
 
 
Study Chairs: 
 
UC Davis Principal Investigator 
Megan Daly, M.D. 
UC Davis Comprehensive Cancer Center 
Department of Radiation Oncology 
4501 X Street, Basement Level 
Sacramento, CA 95817 
Ph (916) 734-5428/Fax (916) 703-5069 
megan.daly@ucdmc.ucdavis.edu 
 
Medical Oncology 
Karen Kelly, M.D. 
Otolaryngology-Head/Neck Surgery 
D. Gregory Farwell, M.D. 
Pathology 
Regina Gandour-Edwards, M.D. 
Nuclear Medicine 
David K. Shelton, M.D. 
Medical Physics/Quality Assurance 
James A. Purdy, Ph.D. 
Translational Research 
Andrew K. Vaughan, Ph.D. 
Statistics 
Lihong Qi, Ph.D. 
 
Protocol Version Date: 
February 25, 2014  
 
(July 12, 2012: Original) 
 
(November 7, 2013) 
 
(December 12, 2013) 

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Page 2 of 57 
 
 
 
 
 
 
 
 
INDEX 
 
 
 
 
 
Schema 
 
Eligibility Checklist 
 
1.0 
Hypothesis/Objectives 
 
2.0 
Background 
 
3.0 
Eligibility Criteria 
 
4.0 
Additional Pretreatment Evaluations/Management 
 
5.0 
Drug Therapy 
 
6.0 
Radiation Therapy 
 
7.0 
Functional Imaging: FDG-PET/CT Imaging 
 
8.0 
Surgery 
 
9.0 
Other Therapy 
 
10.0 
Tissue/Specimen Submission 
 
11.0 
Patient Assessments 
 
12.0 
Statistical Considerations 
 
13.0 
Data Review and Management 
 
References 
 
Appendix I        - Performance Status Scoring 
Appendix II       - Staging System 
Appendix III      - Dental Management 
Appendix IV      - University of Washington Quality of Life Instrument 
Appendix V       - Functional Assessment of Cancer Therapy (FACT) 
Appendix VI      - Data Submission Schedule 

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Page 3 of 57 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schema 
 
 
 
 
 
 
Stage III/IV, M0 squamous cancer of oropharynx, hypopharynx or larynx 
(Positive Human Papillomavirus) 
 
 
 
 
 
 
Chemotherapy1 
(No response) 
(Partial/Complete Response) 
 
 
 
 
 
Radiation2 
Radiation3 
+ 
+ 
Weekly Paclitaxel4 
Weekly Paclitaxel4 
 
 
 
 
 
 
1Chemotherapy: Paclitaxel 175 mg/m2 and carboplatin AUC 6 x two cycles 
 
2Radiation: To begin at least 2 weeks after chemotherapy. The primary tumor and involved nodes 
will receive 2 Gy per fraction each day and subclinical disease sites will receive 1.6 Gy per 
fraction each day. The total doses will thus be 60 Gy and 48 Gy, respectively. 
 
3Radiation: To begin at least 2 weeks after chemotherapy. The primary tumor and involved nodes 
will receive 2 Gy per fraction each day and subclinical disease sites will receive 1.6 Gy per 
fraction each day. The total doses will thus be 54 Gy and 43 Gy, respectively. 
 
4Weekly paclitaxel: 30 mg/m2 weekly x 5 weeks. 

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ELIGIBILITY CHECKLIST 
(Page 1 of 2) 
 
 
 
  
(Y) 
1. Does the patient have pathologically (histologically or cytologically) proven 
(from primary lesion and/or lymph nodes) diagnosis of HPV-positive squamous 
cell carcinoma of the oropharynx, hypopharynx, larynx? 
 
  
(Y) 
2. Does the patient have clinical stage III or IV disease (T1-4, N1-3 or T3-4 any 
N M0)? 
 
  
(Y) 
3. Was a history/physical examination completed within 4 weeks prior to 
registration, including assessment of weight and weight loss in past 6 months? 
 
  
(Y) 
4. Was a Chest x-ray or Chest CT scan (or PET/CT) completed within 6 weeks 
prior to registration? 
 
  
(Y) 
5. Was a CT scan or MRI of the head and neck (of the primary tumor and neck 
nodes) and PET/CT scan completed within 6 weeks prior to registration? 
 
  
(Y) 
6. If a PET/CT was used (instead of a CT scan or MRI) was the CT component a 
high quality scan with contrast? 
 
  
(Y) 
7. Is the Zubrod 0-1? 
 
  
(Y) 
8. Is the patient at least 18 years of age? 
 
  
(Y) 
9. Were the following lab parameters confirmed within 4 weeks prior to study 
entry? 
 
 
Absolute neutrophil count (ANC) ≥ 1,800 cells/mm
3 
 
Platelets ≥ 100,000 cells/mm3
 
 
Hemoglobin ≥ 8.0 g/dl 
 
AST or ALT ≤ 2x the upper limit of normal 
 
Serum creatinine ≤ 1.5 mg/dl or institutional upper limit of normal 
 
Creatinine clearance (CC) ≥ 50 ml/min 
 
  
(Y/NA) 
10. For women of childbearing potential, was a pregnancy test completed within 
4 weeks of registration? 
 
  
(Y/NA) 
11. If a male participant or a woman of child bearing potential, is the patient 
agreeable to practice effective birth control throughout the treatment phase of the 
study (until at least 60 days following the last study treatment)? 
 
  
(Y/NA) 
12. Is there a history of prior invasive malignancy (other than non-melanomatous 
skin cancer)? 
 
  
(Y) If yes, has the patient been disease free for greater than three years? 
 
  
(N) 
13. Does the patient have simultaneous primaries or bilateral tumors? 
 
  
(N) 
14. Is the patient presenting with recurrent head and neck cancer? 
 
  
(N) 
15. Has the patient had prior systemic chemotherapy for the study cancer? 
(Continued on next page) 

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ELIGIBILITY CHECKLIST 
(Page 2 of 2) 
 
  
(N) 
16. Has the patient had prior radiotherapy to the region of study cancer that 
would result in overlap of radiation therapy fields? 
 
  
(N) 
17. Is the primary tumor site unknown, oral cavity, nasopharynx, sinuses, or 
salivary gland? 
 
  
(N) 
18. Has the patient had initial surgical treatment other than the diagnostic biopsy 
of the primary site or nodal sampling of neck disease? 
 
  
(N) 
19. Does the patient have any active symptoms of systemic lupus erythematosus 
or sceleroderma? 
 
  
(N) 
20. Does the patient have any of the severe comorbid conditions listed in Section 
3.2.8 that would exclude him/her from participation? 
 
 
 
The Eligibility Checklist must be completed in its entirety prior to registration. The completed, 
signed, and dated checklist used at study entry must be retained in the patient’s study file. 
 
 
Completed by   
 
Date   
 

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1.0 HYPOTHESIS AND OBJECTIVES 
1.1 Hypothesis 
Due to the exquisite radiosensitivity of human papillomavirus (HPV)-associated squamous cell 
carcinoma (HNSCC) of the head and neck, patients who present with this disease may be 
currently "over-treated" using traditional chemoradiotherapy regimens and can effectively be 
treated with de-intensified strategies which result in improved tolerability and enhanced quality of 
life without compromising disease control or overall survival. 
 
1.2 Objectives 
To determine the progression-free survival, toxicity, local-regional control, and overall survival 
among patients with HPV-positive HNSCC treated by induction chemotherapy followed by 
attenuated chemoradiotherapy. 
 
2.0 BACKGROUND 
Head and neck cancer, mostly of squamous cell origin, ranks sixth among the most common 
cancers, accounting for approximately 6% of all malignancies. Each year, more than 500,000 
new cases are diagnosed worldwide. For the 60% of patients presenting with locally advanced 
(stages III and IV) HNSCC, chemoradiotherapy has been established as a definitive treatment 
option through the publication of notable phase III trials (Brizel 1998; Adelstein 2003; Dennis 
2004; Bourhis 2012). However, opinions regarding the proper role and timing of chemotherapy 
remain divided, particularly with regard to which chemotherapy drugs to use and how to optimally 
integrate them with radiation therapy. Moreover, attention has focused on identifying the 
appropriate radiation dose given that the accepted standards have remained at the same level for 
more than 30 years. 
 
One of the most exciting developments in recent years is the recognition that not all HNSCC 
behave similarly from a biological standpoint. Prospective and retrospective data have shown 
that HPV-associated HNSCC, which comprises an increasing proportion of all HNSCC, 
represents a unique entity with distinct clinical and molecular characteristics (Braakhuis 2005, 
Licitra 2006; Gillison 2008; Weinberger 2006). While HPV-negative HNSCC is characterized by a 
multitude of genetic alterations involving deletions or methylation of tumor-suppressor genes 
and/or activation of tumor-promoting oncogenes, HPV-positive HNSCC is largely devoid of many 
of these genetic aberrations. This may be linked to the transforming potential of high-risk HPV 
(e.g. HPV-16), which through two viral oncoproteins, E6 and E7, inactivate two human tumor- 
suppressor proteins, p53 and pRb, respectively. Research is now showing that the distinct 
genetic profiles between HPV-positive and HPV-negative HNSCC underline not only differences 
related to the pathogenesis of this disease, but also differences with respect to prognosis and 
treatment response (Slebos 2006; Schlecht 2007; Klussman 2009). For instance, data has 
emerged that patients with HPV-positive HNSCC have a significantly improved prognosis, with at 
least half the risk of death from cancer, compared to their HPV-negative counterparts (Fakhry 
2008; Kong 2008; Kumar 2008; Settle 2009; Rischin 2010; Hong 2010). Additionally, evidence is 
accumulating that HPV-related HNSCC is exquisitely more sensitive to the effects of radiation 
therapy (Lindel 2001; Lassen 2009; Ang 2010; Fischer 2010). Indeed, pre-clinical and clinical 
studies have demonstrated differential rates of response to irradiation between HNSCC from 
HPV-positive and HPV-negative settings (Spanos 2009; Gupta 2009; Williams 2009). 
 
This recognition that HPV-positive HNSCC responds favorably to radiation therapy has prompted 
investigators to suggest that patients with these cancers might be “over-treated” and 
unnecessarily subjected to the toxicity of intensive chemoradiotherapy with excessively high 
radiation doses. While it has been proposed that treatment should be individualized for patients 
with HPV-related HNSCC, the specific recommendations on how to do so are non-existent. The 
proposed clinical trial, which will treat patients with HPV-positive HNSCC using radiation doses 
approximately 10-15% less than historically used, would be the first to individualize radiation for 
HNSCC based on the biological characteristics of the tumor. 

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2.1 Rationale for Induction Chemotherapy Followed by Concurrent Chemoradiotherapy as 
Definitive Treatment 
With the widespread implementation of concurrent chemoradiotherapy as primary therapy for 
locally advanced HNSCC, the historical pattern of disease failure seems to have been altered. 
Single-institution phase II trials (Adelstein 2006; Brockstein 2004) of aggressive 
chemoradiotherapy protocols have reported that distant metastasis has emerged as the most 
common cause of treatment failure, even among patients who have HPV-positive HNSCC 
(Maxwell 2010). These data have rekindled interest in the potential use of induction 
chemotherapy in conjunction with definitive concurrent treatment in an effort to further improve 
survival by decreasing distant metastases. 
 
Prospective trials (Machtay 2002; Kies 2010; Posner 2007; Vermorken 2007) have demonstrated 
encouraging outcomes using induction chemotherapy followed by concurrent chemoradiotherapy 
for locally advanced HNSCC. In previously untreated patients, overall response rates of 70% to 
90% and complete response rates of 30% to 60% have been reproducibly reported after 
combination chemotherapy regimens (Salama 2008). The impressive sensitivity to chemotherapy 
has suggested the possibility that this treatment modality might decrease distant metastasis and 
improve local-regional control, organ preservation, and overall survival. Notably, induction 
chemotherapy is included in National Comprehensive Cancer Network guidelines for the 
treatment of locally advanced HNSCC and its administration before concurrent 
chemoradiotherapy has become increasingly accepted as a means for effective eradication of 
systemic micrometastases. Although many of the earlier tested regimens included 5-flourouracil 
as a component of the induction regimen, in recent years, taxane-based chemotherapy has 
emerged as a preferred strategy in the induction setting for HNSCC due to its activity and 
improved tolerability. 
 
Investigators from Vanderbilt University (Cmelak 2007) reported on 44 patients with locally 
advanced HNSCC treated by 3 cycles of paclitaxel (175 mg/m2) and carboplatin (AUC, 6-7.5) 
every three weeks followed by concurrent chemoradiotherapy. The clinical response rate to 
induction chemotherapy was 89%, including a 51% complete response rate. The most common 
grade 3+ complication during induction chemotherapy was neutropenia which developed in 68% 
of the patients. The 2-year local control, progression-free survival, and overall survival were 82%, 
77%, and 71%, respectively. As importantly, no significant difference in progression-free survival 
or organ-preservation was noted between concurrent regimens using cisplatin/paclitaxel or 
carboplatin/paclitaxel. However, due to the improved toxicity profile with the latter regimen, this 
was adopted as more “practical for use in the community setting.” Investigators from the 
University of Chicago (Vokes 2003) also reported on 69 patients treated by induction 
chemotherapy with 6 cycles of weekly carboplatin (AUC, 2) and paclitaxel (135 mg/m2) followed 
by concurrent chemoradiotherapy. The overall response rate to induction chemotherapy was 
92%, with 35% of patients having a complete clinical response. The most common grade 3+ 
toxicity during the induction phase was neutropenia which developed in 18% of the population. 
 
Based on encouraging single-institutional data, the Eastern Cooperative Oncology Group 
(ECOG) conducted a prospective phase II trial (2399) in which 111 patients with stage III/IV 
HNSCC received 2 cycles of induction chemotherapy every 3 weeks with carboplatin (AUC, 6) 
and paclitaxel (175 mg/m2) followed by concurrent paclitaxel (30 mg/m2) weekly with radiation 
therapy to 70 Gy (Cmelak 2007). With a median follow-up of 37 months, the 2-year rates of 
organ preservation and overall survival were 81% and 76%, respectively, which compared 
favorably to historical controls among patients treated by upfront concurrent chemoradiotherapy. 
The clinical response rate was 65% after induction chemotherapy (including 82% for HPV- 
positive tumors). Furthermore, no patient progressed during the induction phase of treatment, 
and its use did not preclude subsequent delivery of concurrent chemoradiotherapy. These 
studies have shown induction chemotherapy followed by concurrent chemoradiotherapy is a 
promising approach which may enhance distant control and improve treatment tolerability while 
maintaining high rates of local-regional control. Consequently, it is now commonly accepted that 
a course of induction chemotherapy with carboplatin and paclitaxel is active and well-tolerated 

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without compromising the ability to administer subsequent intensive chemoradiotherapy. As a 
result of the published data in support of this strategy, the ECOG regimen is increasingly used 
both as protocol and non-protocol treatment for patients with stage III/IV head and neck cancer. 
 
Another increasingly recognized benefit of this approach is the ability of induction chemotherapy 
to help stratify patients to additional therapy. Since the tumor can be assessed in vivo, various 
investigators have shown that induction chemotherapy can serve as a predictive tool, allowing 
appropriate selection of the definitive management strategy. For instance, investigators from the 
University of Michigan recently reported a phase II trial of 66 patients with stage III/IV HNSCC in 
which one cycle of platinum-based induction chemotherapy was used to stratify subsequent local 
therapy. Responders to induction chemotherapy were subsequently selected for concurrent 
chemoradiotherapy and non-responders proceeded to surgery (Worden 2008). Although the 
limited size of the study made it difficult to draw definitive conclusions, the feasibility of this 
approach, particularly for patients with HPV-positive HNSCC (in which the rate of response to 
induction chemotherapy was 93%) was demonstrated. 
 
2.2 Toxicity of Concurrent Chemoradiotherapy 
Despite trials documenting a benefit to concurrent chemoradiotherapy in both the definitive and 
postoperative settings, it is important to note that this strategy (particularly with high dose 
cisplatin) significantly increases toxicity compared with radiation therapy alone (Trotti 2003; 
Bernier 2005; Garden 2008). In particular, acute mucositis and dysphagia are enhanced with the 
addition of concurrent chemotherapy. High dose cisplatin also causes constitutional and 
systemic toxicities that are well recognized and independent of the concomitant administration of 
radiation therapy. It is theoretically possible that these systemic toxicities might interfere with the 
ability of patients to tolerate and receive maximally effective dose intensity of radiation therapy in 
an uninterrupted fashion. For instance, the grade 3+ acute toxicity rate on RTOG 99-14, which all 
patients received radiation therapy with concurrent cisplatin was 79%, the most common of which 
were related to mucositis and esophagitis (Ang 2005). Similarly, in an analysis of late toxicity of 
patients treated on 3 chemoradiation trials using cisplatin for HNSCC by the RTOG, Machtay et al 
reported that 43% experienced grade 3+ late toxicity related to laryngeal and/or esophageal 
dysfunction (Machtay 2008). The toxicity of radiation therapy, in aggregate, has been shown to 
contribute to significant quality of life burden with respect to physical and psychosocial functioning 
(Langendijk 2008). These data suggests that concurrent chemoradiotherapy has eclipsed the 
limits of acceptable short- and long-term toxicity, and that attempts to reduce radiation dose in 
appropriately selected patients are warranted. 
 
Although taxane-based chemoradiotherapy regimens appear to improve toxicity, the rates of 
complications are nonetheless high. Suntharalingam et al reported that the rates of acute grade 
3 mucositis and dysphagia were 70% and 33%, respectively, among patients treated by 
concurrent carboplatin and paclitaxel at the University of Maryland (Suntharalingam 2000). 
Similarly, Cmelak et al reported grade 3+ acute mucositis in 47% of patients completing 
concurrent radiation with carboplatin and paclitaxel at Vanderbilt University (Cmelak 2007). For 
patients treated by radiation therapy with weekly paclixtaxel on ECOG 2399, 49% developed 
grade 3+ acute mucositis and 40% were G-tube dependent at end of treatment (Cmelak 2007). 
 
2.3 Role of HPV in Predicting and Modulating HNSCC Radiation Response 
Progress in the understanding of tumor biology has opened an exciting new era for research. 
Preclinical and correlative biomarker studies from various laboratories have so convincingly 
confirmed HPV status as the single most important predictor of radiation response that HPV 
staining is now routinely performed for prognostic purposes both in the community and in 
academic settings. Notably, when patients from the ECOG 2399 trial were examined by HPV 
status (Fakhry 20007), patients with HPV-positive tumors had significantly higher response rates 
after induction chemotherapy (82% versus 55%) and after chemoradiotherapy (84% vs. 57%). 
With a median follow-up of 39 months, patients with HPV-positive tumors had significantly 
improved 2-year overall survival (95% vs. 62%), progression-free survival (86% vs. 53%), and a 
64% lower risk of death compared to patients with HPV-negative tumors. Similarly, recent data 

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published from the Radiation Therapy Oncology Group (RTOG) confirmed a dramatic difference 
in 3-year rates of local-regional control (86% vs. 65%) and overall survival (82% vs. 57%) 
between 433 patients with HPV-positive and HPV-negative phenotypes treated prospectively by 
chemoradiotherapy (Ang 2010). Interestingly, the risk of distant metastasis for HPV-positive and 
HPV-negative tumors in patients receiving upfront concurrent chemoradiotherapy was observed 
to be similar, affecting 10% and 13% of patients, respectively. This observation further suggests 
that a sequential treatment strategy utilizing induction chemotherapy prior to chemoradiotherapy 
for patients with HPV-positive HNSCC may be particularly applicable. Table 1 outlines published 
data in the form of secondary analysis from prospective trials demonstrating the improved 
prognosis for patients with HPV-positive HNSCC. 
 
The mechanism of HPV-mediated radioresponse is currently unclear, and there are limited studies 
that have addressed this topic in the setting of head and neck cancer. The most direct 
explanation is that HPV infection and the subsequent degradation of the p53 and pRb proteins by 
the viral products E6 and E7 somehow renders the host tumor cell more susceptible to radiation- 
induced apoptosis. Both in vitro and in vivo studies, however, have demonstrated, quite 
paradoxically, that transfer of the E6/E7 genes or gene products into cells tends to increase 
radiation resistance, not decrease it as might be expected (Hampson 2001). Similarly, 
experiments designed to abrogate p53 function in head and neck cancer cells by other extrinsic 
means have not altered radiosensitivity, thereby suggesting that host cell characteristics, rather 
than the virus itself, mediates radiosensitivity (DeWeese 1997). Indeed, several recent studies 
have suggested that radiation therapy enhances the host immune response to viral antigens 
which are expressed on tumor (Rajjoub 2007; Wansom 2010). 
 
Regardless of the underlying mechanisms responsible for HPV-mediated radioresponse, 
preclinical work have confirmed the exquisite radiosensitivity of HPV-positive HNSCC. Gupta et 
al performed clonogenic survival assays of HPV-positive and HPV-negative cell-lines after 
exposure to various doses of radiation and showed that the former are characterized by markedly 
enhanced radiosensivity (Gupta 2009). Preliminary data from the University of California, Davis 
(Chen 2011), using a model system from axial imaging studies obtained serially during the course 
of radiation therapy to observe in vivo patterns of tumor response similarly showed that HPV- 
positive HNSCC tends to regress early during treatment, reaching a plateau by week 5-6, 
suggesting that radiation doses can possible be reduced (Figure 1). 
 
 
 
 
Table 1: Subset Analysis of Prospective Trials Demonstrating Improved Prognosis with 
HPV-positive HNSCC 
 
Author 
N 
Dose 
Induction 
Concurrent 
Outcomes 
Fakhry 
96 
70 Gy 
Carbo/paclitaxel x2 
Paclitaxel 
86% vs 53%, 2yr PFS, p=0.02 
Rischin 
172 70 Gy 
None 
CDDP +/- 
Tirapazamine 
87% vs 72%, 2yr PFS, p=0.01 
93% vs 86%, 2yr LRC, p=0.09 
Ang 
323 70-72 Gy 
None 
Cisplatin 
74% vs 43%, 3yr PFS, p<0.001 
86% vs 65%, 3yr LRC, p<0.001 
Lassen 
331 66-68 Gy 
None 
+/- Nimorazole 
61% vs 35%, 5yr LRC, p<0.001 
Lassen 
794 66-68 Gy 
None 
None 
78% vs 64%, 5yr PFS, p=0.001 
69% vs 57%, 5yr LRC, p=0.004 
Worden 
66 
70 Gy 
Carbo/CDDP+5FU x1 
Carbo/CDDP 
85% vs 37%, 3yr PFS, p=0.001 
 
Carbo: Carboplatin; CDDP: Cisplatin; 5FU, 5-fluorouracil; PFS, Progression-free survival; LRC: 
Local-regional control. 

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Figure 1: Regression in tumor volume (in cc) among 10 patients treated for HPV-positive 
HNSCC as determined using daily imaging (Chen 2011) 
 
 
2.4 Rationale for Paclitaxel and Radiation Therapy for HNSCC 
Given the toxicity of high dose cisplatin, attention has focused on the use of non-cisplatin 
radiosensitizers during radiation therapy as well as identifying patients at lower risk for failure who 
may potentially benefit from less aggressive chemoradiotherapy approaches. Paclitaxel, an 
inhibitor of depolymerization of microtubules, is a potent radiosensitizing agent in vitro and in vivo 
(Tisher 1992; Choy 1994). At our institution, it has become an important component of 
chemoradiotherapy for lung cancer (Lau 1997; Lau 1999) and esophageal cancer (Wang 2007). 
As a single agent, paclitaxel has moderate efficacy in head and neck cancer that a response rate 
as high as 50% has been reported (Grecula 2000). Given with radiation for head and neck 
cancer, promising results have also been reported for paclitaxel in multiple phase I and II trials. A 
summary of these trials published in the last 5 years is shown in Table 2. 
 
Table 2: Background Phase I/II Trials Supporting Use of Paclitaxel in Concurrent 
Chemoradiotherapy for HNSCC 
 
Investigators 
Schedule 
Dose (Gy) 
Response (%) 
Sunwoo, 2001 
120 mg/m2/120 hr x2 
70-72 
 
70 
Rosenthal,2001             10.5 mg/m2/day x7wks              70                                  58 
Feher, 2002                   45 mg/m2/wk, x8 wks                 66-70                             83 
Bucci, 2004                    40-120 mg/m2/96 hr x2              70-72                             60 
Wang, 2004                   30 mg/m2/wk x 7 wks                 68-70                             NR 
Pergolizzi, 2004             40 mg/m2/wk x 7 wks                 66-70                             NR 
Amrein, 2005                 60 mg/m2/wk x 6 wks                 70                                  91 
Jain, 2009                      20 mg/m2/wk x 6 wks                 66-70                             73 
Citrin, 2009                    105-120 mg/m2/96 hr x2            70-72                             NR 
NR: Not reported. 

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Based on the reports of these trials, the response of HNSCC to paclitaxel and radiation is 
comparable to that of cisplatin and radiation. A recently published a prospective study comparing 
low dose paclitaxel to cisplatin for 100 patients undergoing concurrent chemoradiotherapy for 
HNSCC reported no statistical significant differences In outcome (Jain, 2009). The MTD of 
paclitaxel given concurrently with radiation therapy is estimated to be 40-50 mg/m2/week for 7 
weeks. The dose-limiting toxicity for all of the above trials included mucositis and dermatitis, 
which were generally mild. At our institution, weekly paclitaxel, administered at 30-40 mg/m2 for 
5-6 weeks with concurrent radiation, has been used to treat HNSCC for patients in whom cisplatin 
is contraindicated. Retrospective analysis of over 100 patients treated in such a manner have 
demonstrated excellent rates of local-regional control, progression-free survival, and enhanced 
tolerability compared to patients receiving cisplatin-based chemoradiotherapy for locally 
advanced HNSCC (Chen 2011). 
 
2.5 Rationale for Attenuated Chemoradiotherapy for HPV-positive HNSCC 
Given that the dose-limiting toxicity from prior chemoradiotherapy trials have been mucosal and 
esophageal, reducing the radiation dose in selected patients with more favorable biology (e.g. 
HPV-positive tumors) is an attractive option. Numerous prospective and retrospective data have 
demonstrated consistent dose-response relationships predicting toxicity for organs involved in 
salivary production, swallowing, and mucosal integrity (Eisbruch 1999; Chao 2001, Feng 2007; 
Narayan 2008). For xerostomia, it has been long known that the ability to keep mean parotid 
dose below 26 Gy will significantly reduce the incidence of hyposalivation and preserve quality of 
life (Deasy 2010). Normal tissue complication probability models have observed that for every 1 
Gy in mean dose, the likelihood of xerostomia increases by approximately 5% at 1 year after 
radiation therapy (Dijkema 2008). An increasing amount of data is similarly showing that dose to 
anatomical structures thought to be responsible for swallowing is of critical importance in 
predicting acute and late toxicity from chemoradiotherapy (Eisbruch 2004). For instance, 
published data from the University of California Davis showed that minimizing dose to the 
constrictor muscles, cervical esophagus, and cricopharyngeal inlet may decrease the incidence of 
dysphagia, esophageal stricture, and gastrostomy-tube dependence (Chen 2009; Li 2009). 
Between 55 Gy and 70 Gy, a strong linear relationship was established between dose to the 
inferior constrictor muscles/cricopharyngeal inlet and the probability of late grade 3+ dysphagia 
as defined as gastrostomy-tube dependence (Figure 2). These data are consistent with published 
literature demonstrating that the threshold for radiation-induced long-term dysphagia likely exists 
at approximately 55 to 60 Gy, and dependent on dose-volume effects (Table 3). With respect to 
clinical mucositis, prospective data from the University of California Davis showed that limiting the 
maximum dose to the oral cavity to less than 40 Gy significantly reduced the 
incidence of acute mucositis during chemoradiotherapy (Narayan 2008). Notably none of the 
patients who received an oral cavity dose of less than 40 Gy developed grade 2+ mucositis 
compared to 50% of patients who received a dose of greater than 40 Gy (Figure 3). Additionally, 
it is increasingly recognized the limiting radiation dose to tissues such as the parotid gland, 
swallowing structures, and oral cavity translates into improved quality of life (Nguyen 2005; 
Langendijk 2008; Lin 2003). 
 
The recognition that patients with HPV-related HNSCC fare exceptionally well have led some 
investigators to suggest that treatment can be de-intensified, particularly with respect to radiation 
dose. The currently utilized doses in the primary and postoperative setting are 70 Gy and 60-66 
Gy, respectively. Indeed, both in vitro and in vivo studies have shown that HPV-positive HNSCC 
is exquisitely sensitive to the effects of radiation therapy. We hypothesize that by effectively 
reducing radiation to the normal structures of the head and neck, there will be a consequent 
reduction in side effects—particularly acute mucositis and esophagitis side effects—resulting in 
improved quality of life while maintaining high rates of disease control and overall survival. By 
potentially decreasing toxicity without lowering cure rates, de-intensification of radiation dose for 
HPV positive tumors has the potential to improve therapeutic ratio by decreasing toxicity while 
maintaining high rates of disease control. 

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Table 3: Dysphagia After High-Dose Radiation Therapy for HNSCC 
 
Author 
Incidence grade 3+ 
late 
Predictive factors 
Caudell 
22% 
Larynx, mean dose >41 Gy; V60 >24% 
Inferior PC V60< 12% 
Superior PC 
Middle PC 
Feng 
7% 
Chen 
30% 
Inferior PC V65 < 15% 
Cricopharyngeal inlet, Dmax <60 Gy 
Levendag 
23% 
Dirix 
8% 
Middle PC V50 
Lawson 
13% 
Esophageal inlet, V60<30% 
Schwartz 
10% 
Superior PC, V55< 80% 
Oral cavity, V30< 65% 
Teguh 
22% 
Superior PC, mean dose< 60 Gy 
Caglar 
37% 
Larynx, mean dose<48 Gy 
Inferior constrictor, mean dose<54 Gy 
Dornfeld 
33% 
False vocal cords, mean dose<50 Gy 
NR: Not reported; PC: Pharyngeal constrictor muscles. 
 
Figure 2:  Volume-response or dose-response relationship for the average probability of 
having prolonged GT dependence and (a) mean dose to the inferior constrictor muscles 
and (b) maximum dose to the cricopharyngeal inlet (Li 2009); GT = gastrostomy tube; IPC = 
inferior pharyngeal constrictors; CPI = cricopharyngeal inlet. The ೦ lines plot the mean risk; the - 
lines plot the estimated upper and lower limits of 95% confidence interval. The ♦ points depict the 
observed values. 
(a) 
(b) 
 

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Figure 3. Dose-response relationship between maximum point dose to the oral cavity and 
grade of clinically significant mucositis (Narayan 2007) 
 
 
 
2.6 Study Design 
This study is the first of its kind to select patients with HPV-positive HNSCC for attenuated 
therapy and may have important implications for individualization of care in the future. The 
regimen of carboplatin and paclitaxel was selected for the induction chemotherapy phase 
because of its ease of administration, improved toxicity profile, high rates of dose delivery, and 
excellent published results showing high response rates and overall survival. We chose to use 
induction chemotherapy primarily as a means to select HPV-positive HNSCC patients, who may 
benefit from significant radiation dose de-intensification in the concurrent chemoradiotherapy 
phase of treatment. The rationale for this risk-adapted approach to local therapy based on HPV 
status is to administer effective comprehensive treatment individualized at diagnosis and after 
assessment of response to induction chemotherapy (for patients with HPV-positive tumors), thus 
avoiding unnecessary and potentially toxic treatment, and hence optimizing the therapeutic ratio. 
 
2.6.1 Selection of the treatment arm for HPV-positive HNSCC 
The induction chemotherapy regimen was chosen based on studies from ECOG and Vanderbilt 
University, showing high rates of response to carboplatin and paclitaxel (Hainsworth 2002; 
Cmelak 2007). The radiation regimen has not been rigorously tested in a multi-institutional 
setting. However, investigators from the University of Chicago treated 64 patients with locally 
advanced HNSCC (HPV-status undetermined) to a reduced dose of 54 Gy to areas considered 
“high-risk” for microscopic disease after induction chemotherapy and reported that the reduction 
in radiation dose did not compromise survival or disease control compared to historical controls 
treated using higher radiation doses (Haraf 2003). More recently, retrospective data from the 
University of California, Davis, has shown that HPV-positive tumors have regressed in entirety as 
determined by clinical examination and axial imaging by 50 Gy of radiation. As such, for this trial, 
patients with and without a response to induction chemotherapy will receive doses of 54 and 60 
Gy, respectively, which represents a 23% and 14% reduction in radiation dose, respectively, 
compared to the standard of 70 Gy (Chen, in press). Since weekly administration of carboplatin 
and paclitaxel has historically been given concurrently with radiation after induction 
chemotherapy, we chose to administer these agents in the same fashion for this Phase I/II trial. 
The regimen used by ECOG 2399 will comprise the standard induction chemotherapy strategy 
and will serve as the basis for exploratory comparison analyses (Cmelak 2007). Since HPV has 
been increasingly shown to affect cellular response to radiation, this phase I/II trial tests the 
hypothesis that radiation dose de-intensification for HPV-positive patients with locally advanced 
(stage III and IV) HNSCC will decrease toxicity while maintaining progression-free survival. 

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2.7 Specific Aims 
2.7.1 Primary 
2.7.1.1 To determine the progression-free survival at 2 years in patients with HPV- 
positive HNSCC who receive induction chemotherapy followed by dose de-intensified 
chemoradiotherapy 
 
2.7.2 Secondary 
2.7.2.1 To determine the overall survival and local-regional control for patients with HPV- 
positive HNSCC who receive induction chemotherapy and dose de-intensified 
chemoradiotherapy 
2.7.2.2 To determine the incidence of acute grade 3+ mucosal and esophageal toxicity 
associated with attenuated concurrent chemoradiotherapy in patients with HPV-positive 
HNSCC 
2.7.2.3 To determine the incidence of late toxicity in patients with HPV-positive HNSCC 
who receive the dose de-intensified chemoradiotherapy 
2.7.2.4 To estimate the incidence of all toxicity (hematologic and non-hematologic) 
associated with protocol treatment for all patients on trial 
2.7.2.5 To estimate the response rate of HPV-positive to induction chemotherapy using 
carboplatin and paclitaxel 
2.7.2.6 To determine the effect of reduced radiation dose on short-term and long-term 
quality of life among patients treated by chemoradiotherapy. 
 
3.0 ELIGIBILITY CRITERIA 
3.1 Inclusion Criteria 
3.1.1  Pathologically (histologically or cytologically) proven (from primary lesion and/or 
lymph nodes) diagnosis of HPV-positive squamous cell carcinoma of the oropharynx, 
hypopharynx, or larynx. HPV-positivity will be defined as tumors that are p16-positive by 
immunohistochemistry. Numerous studies have demonstrated near 100% agreement 
between p16 and HPV for patients with squamous cell carcinomas. As such, the use of 
p16 has been accepted by large cooperative groups as an appropriate surrogate for HPV 
status, and testing for p16 has been routinely performed for all head and neck cancers at 
most centers since 2009. 
3.1.2 Clinical stage III or IV disease; Note: Patients with M1 tumors are not eligible. 
3.1.3 Appropriate stage for protocol entry, including no distant metastases, based upon the 
following minimum diagnostic workup: 
3.1.3.1 History/physical examination within 4 weeks prior to registration, including 
assessment of weight loss in past 6 months; 
3.1.3.2 Chest x-ray (or Chest CT scan or PET/CT scan) within 6 weeks prior to 
registration; see Section 8.0 for details of PET scans. 
3.1.3.3 CT scan or MRI of the head and neck (of the primary tumor and neck nodes) 
and PET/CT scan within 6 weeks prior to registration; see Section 8.0 for details of 
PET scans. 
3.1.4 Zubrod Performance Status 0-1 
3.1.5 Age > 18 
3.1.6 Adequate bone marrow function, defined as follows: 
3.1.6.1 Absolute neutrophil count (ANC) > 1,800 cells/mm
3 based upon 
CBC/differential obtained within 4 weeks prior to registration on study; 
3.1.6.2 Platelets > 100,000 cells/mm3 based upon CBC/differential obtained within 4 
weeks prior to registration on study; 
3.1.6.3 Hemoglobin (Hgb) > 8.0 g/dl based upon CBC/differential obtained within 4 
weeks prior to registration on study (Note: The use of transfusion or other 
intervention to achieve Hgb > 8.0 g/dl is acceptable). 
3.1.7 Adequate hepatic function, defined as follows: 
3.1.7.1 AST or ALT < 2x the upper limit of normal within 4 weeks prior to registration 
on study; 

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3.1.8 Adequate renal function, defined as follows: 
3.1.8.1 Serum creatinine ≤ 1.5 mg/dl or institutional upper limit of normal within 4 
weeks prior to registration 
3.1.8.2 Creatinine clearance (CC) ≥ 50 ml/min within 4 weeks prior to registration 
determined by 24-hour collection or estimated by Cockcroft-Gault formula: CrCl male 
= [(140 – age) x (weight in kg)] [(Serum Cr mg/dl) x (72)] CrCl female = 0.85 x (CrCl 
male) 
3.1.9 Pregnancy test within 4 weeks prior to registration for women of childbearing 
potential; 
3.1.10 Women of childbearing potential and male participants must agree to use a 
medically effective means of birth control throughout their participation in the treatment 
phase of the study (until at least 60 days following the last study treatment); 
3.1.11 Patient must sign study specific informed consent prior to study entry. 
 
3.2 Conditions for Patient Ineligibility 
3.2.1 Prior invasive malignancy (except non-melanomatous skin cancer) unless disease 
free for a minimum of 3 years; 
3.2.2 Patients with simultaneous primaries or bilateral tumors are excluded. 
3.2.3 Patients who present with a cervical lymph node metastasis of unknown primary 
origin; 
3.2.4 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a 
different cancer is allowable; 
3.2.5 Prior radiotherapy that would result in overlap of radiation therapy fields; 
3.2.6 Primary site of tumor of oral cavity, nasopharynx, nasal cavity, paranasal sinuses, or 
salivary glands; 
3.2.7 Recurrent head and neck cancer; 
3.2.8 Severe, active co-morbidity, defined as follows: 
3.2.8.1 Current uncontrolled cardiac disease; i.e., uncontrolled hypertension, 
unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled 
congestive heart failure, and cardiomyopathy with decreased ejection fraction; 
3.2.8.2 Congestive heart failure with left Ventricular Ejection Fraction < 20%; 
3.2.8.3 Transmural myocardial infarction within the last 6 months; 
3.2.8.4 Acute bacterial or fungal infection requiring intravenous antibiotics at 
registration; 
3.2.8.5 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory 
illness requiring hospitalization or precluding study therapy at the time of registration; 
3.2.8.6 Active lupus erythematosus or scleroderma with ongoing physical 
manifestations 
3.2.8.7 Any uncontrolled condition, which in the opinion of the investigator, would 
interfere in the safe and timely completion of study procedures; 
3.2.9 Pregnant or lactating women or women of childbearing potential and men who are 
sexually active and not willing/able to use medically acceptable forms of contraception; this 
exclusion is necessary because the treatment involved in this study may be significantly 
teratogenic. 
3.2.10 Prior allergic reaction to the study drug(s) involved in this protocol. 
 
4.0 ADDITIONAL PRETREATMENT EVALUATIONS/MANAGEMENT 
4.1 Additional Mandatory Pre-Treatment Evaluations/Interventions 
Not applicable for this study. 
 
4.2 Additional Recommended Pre-Treatment Evaluations/Interventions 
The following pre-treatment evaluations/interventions are not required but are recommended: 
4.2.1 Speech and swallow evaluation within 6 weeks prior to registration; 
4.2.2 Dental evaluation and, if applicable, prophylaxis within 16 weeks prior to initiation of 
chemoradiotherapy (see Appendix III); 
4.2.3 Serum albumin within 4 weeks prior to treatment; 

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4.2.4 Baseline audiogram within 12 weeks prior to registration; 
4.2.5 Nutritional evaluation for prophylactic gastrostomy (PEG) tube placement; 
4.2.6 Nutritional counseling to discuss optimal dietary needs during treatment 
 
 
5.0 DRUG THERAPY 
5.1  Rationale 
This study is the first of its kind to stratify HNSCC patients for treatment based on HPV status and 
may have important implications for individualization of care in the future. Based on the 
encouraging phase II data reviewed above, patients in this trial will undergo surgery or receive 
induction chemotherapy prior to chemoradiotherapy. The regimen of carboplatin and paclitaxel 
was selected for the induction chemotherapy phase because of its track record in the treatment of 
HNSCC and favorable toxicity profile. 
5.2 Induction Chemotherapy 
Two cycles of carboplatin/paclitaxel will be planned as induction chemotherapy for all patients 
5.2.1 Pre-medications for paclitaxel and carboplatin 
All patients should be premedicated with dexamethasone 10 mg IV, diphenhydramine 25 
mg IV, cimetidine 300 mg IV (or its equivalent) and ondansetron 8 mg IV, 60 minutes prior 
to paclitaxel infusion. 
5.2.2 Carboplatin and paclitaxel administration 
Paclitaxel 175 mg/m2 3 hour IV infusion, Carboplatin AUC = 6, 30 minute IV infusion 
repeated on day 22 
Note: Guidelines for Carboplatin Administration 
The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose 
level. The creatinine clearance will be calculated using a serum creatinine obtained within 
14 days prior to dosing. Carboplatin dose will be based on GFR (glomerular filtration rate) 
equivalent to creatinine clearance calculated according to the Cockroft-Gault Formula: 
 
CrCI = (140 - age) x actual body weight (kg)* 
72 x serum creatinine** 
*Multiply this number by 0.85 if the patient is female. 
**For serum creatinine of less than 1, use 1 for calculation. 
 
5.3  Concurrent Chemoradiotherapy with Paclitaxel 
5.3.1  Weekly paclitaxel infusion with radiation: At least 2 weeks after completion of induction 
chemotherapy, paclitaxel will be infused at a dose of 30 mg/m2 for over one hour weekly prior to 
the daily radiation for 5 total cycles. 
5.3.2 Pre-medications: As outlined in section 5.2.1, pre-medications will be used only for patients 
who have never been treated with paclitaxel or patients who experienced allergic reaction due to 
induction chemotherapy. Subsequent pre-medications can be deleted if a patient does not 
experience any allergic reaction after the first weekly paclitaxel. 
5.3.3 Safety monitoring: Weekly physical examination, CBC and basic chemistry panels are 
required. 
5.3.4  Weekly paclitaxel should not be given if radiation has been held on the day of scheduled 
paclitaxel administration. 
5.3.5 Patients who have evidence of progressive disease after 2 cycles of induction 
chemotherapy will be removed from the protocol and offered therapy at the discretion of the 
treating physician 
5.3.6  Day 1 of concurrent chemoradiotherapy must be a Monday or Tuesday 
 
5.4 Carboplatin 
5.4.1 Formulation: (see manufacturer prescribing information) 
5.4.2 Preparation: (see manufacturer prescribing information) 
5.4.3 Administration: 

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Carboplatin will be administered after paclitaxel as an IV infusion over 30 minutes. The dose will 
be calculated based on the patient’s actual body weight at each treatment visit and the AUC (area 
under curve) dosing. (see Section 5.2.2) 
5.4.4 Storage: (see manufacturer prescribing information) 
5.4.5 Adverse Events: 
• 
Hematologic: Myelosuppression 
• 
Gastrointestinal: Nausea and vomiting; hepatic toxicity; electrolyte imbalance; 
hypomagnesemia; hypercalcemia 
• 
Neurological: Peripheral neuropathy, ocular changes 
• 
Other: Ototoxicity, myalgia, fatigue, allergic reaction 
5.4.6 Supply: Carboplatin is commercially available. The use of drug(s) or combination of drugs in 
this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption. 
 
5.5 Paclitaxel (Taxol®) 
5.5.1 Formulation: (see manufacturer prescribing information) 
5.5.2 Preparation: (see manufacturer prescribing information) 
5.5.3 Administration: Paclitaxel, at the appropriate dose and dilution, will be given as a one-hour 
infusion. The paclitaxel is mixed in non-PVC containers and infused via polyolefin-lined 
nitroglycerin tubing or low absorption AVI i.v. administration with 0.22 micron in-line filter. 
Paclitaxel will be administered via an infusion control device (pump) using non-PVC tubing and 
connectors, such as the i.v. administration sets (polyethylene or polyolefin) which are used to 
infuse parenteral nitroglycerin. Nothing else is to be infused through the line through which 
paclitaxel is administered. 
5.5.4 Storage: (see manufacturer prescribing information) 
5.5.5 Adverse Effects: See Package Insert for complete listing. 
• 
Hematologic: Myelosuppression 
• 
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, 
pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis, increased liver 
function tests (SGOT, SGPT, bilirubin, alkaline phosphatase), hepatic failure, 
hepatic necrosis 
• 
Heart: Arrhythmias, heart block, ventricular tachycardia, myocardial infarction 
(MI), bradycardia, atrial arrhythmia, hypotension, hypertension, lightheadedness 
• 
Neurological: Sensory (taste), peripheral neuropathy, seizures, mood swings, 
hepatic encephalopathy, encephalopathy, sensation of flashing lights, blurred 
vision, scintillating scotoma 
• 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritus 
• 
Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, 
induration, tenderness, rarely ulceration), radiation recall reaction 
5.5.6 Supply: Paclitaxel is commercially available. The use of drug(s) or combination of drugs in 
this protocol meet the criteria described under Title 21 CFR 312.2(b) for IND exemption. 
 
5.6 Dose Modifications for Paclitaxel/Carboplatin- Induction Chemotherapy 
Note: All dose modifications will be based on the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 

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Toxicity NCI CTCAE 
Grade (CTCAE v4.0) 
Paclitaxel Dose At Start of 
Subsequent Cycle of Therapy
a 
Carboplatin Dose at Start of 
Subsequent Cycles of Therapy
b 
Neutropenia 
1 (1500-1999/mm3) 
Maintain dose level 
Maintain dose level 
2 (1000-1499/mm3) 
Reduce to 150 mg/m2 
Reduce to AUC 5 
3 (500-999/mm3) 
Reduce to 150 mg/m2 
Reduce to AUC 5 
4 (<500-999/mm3) 
Reduce to 150 mg/m2 
Reduce to AUC 5 
Neutropenic fever 
Reduce to 150 mg/m2 
Reduce to AUC 5 
Thrombocytopenia 
1 (LLN-75,000/mm
3) 
Maintain dose level 
Maintain dose level 
2 (50,000-74,999/mm3) 
Reduce to 150 mg/m2 
Reduce to AUC 5 
3 (25,000-49,999/mm3) 
Reduce to 150 mg/m2 
Reduce to AUC 5 
4 (<25,000/mm3) 
Reduce to 150 mg/m2 
Reduce to AUC 5 
Other Hematological 
toxicities 
There will be no dose modifications for changes in leucopenia or 
lymphopenia 
 
5.6.1  Hematologic (ANC, Platelets) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aFor induction chemotherapy, doses will be adjusted based on the worst toxicity observed during 
cycle 1. 
bTo receive the second cycle of chemotherapy, all patients must meet the following minimum 
criteria: WNC ≥ 3000/mm,3 ANC ≥ 1500/mm,3 and Platelets ≥ 100,000/ mm,3 to be drawn within 
5 days of delivery of cycle 2. Otherwise, hold the second cycle, repeat lab work weekly, and 
resume chemotherapy based on this table once criteria are satisfied. Failure to meet minimum 
criteria for 3 consecutive weeks will remove the patient from the study. 
 
5.6.2 Hepatic - Paclitaxel 
The following paclitaxel dose adjustments are based on SGOT/SGPT and bilirubin levels and 
(after the first cycle) should be obtained within 7 days prior to delivery of second cycle. 
 
SGOT or SGPT  
Bilirubin  
Paclitaxel  
 
 
Grade 0 - 1 
and 
Grade 0 - 2 
No change 
Grade 2 - 4 
or 
Grade 3 - 4 
HOLD* 
  
_ 
*If recovery of toxicity exceeds two weeks, discontinue carboplatin and paclitaxel. If recovery of 
toxicity occurs within two weeks (< Grade 2), resume treatment with paclitaxel 175 mg/m2. 
5.6.3 Neuropathy: Motor/Sensory - Carboplatin and Paclitaxel 
The following dose adjustments are based on the worst toxicity grade experience of neuropathy - 
motor/sensory of any preceding treatment cycle. 
Neuropathy - motor/sensory  
Carboplatin and Paclitaxel  
 
Grade 0 - 1 
No change 
Grade 2 - 3 
HOLD BOTH DRUGS (until resolution 
to ≤ Grade 1); If within 2 weeks, 
resume Paclitaxel at 175 mg/m2, 
Carboplatin AUC = 5 
Grade 4 
REMOVE PATIENT FROM PACLI- 
TAXEL AND CARBOPLATIN 
TREATMENT 
  
_ 

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5.6.4 Cardiac Toxicity - Carboplatin and Paclitaxel 
If a patient develops chest pain or arrhythmia during the infusion, the infusion should be stopped. 
Manage any arrhythmias according to standard practice. Patients who experience chest pain 
during paclitaxel infusion should not restart paclitaxel until a cardiac ischemic event has been 
ruled out. Patients will be removed from paclitaxel and carboplatin treatment in cases of 
symptomatic arrhythmias or AV block (except first degree) or other heart block. In case of first 
degree AV block, patient may continue paclitaxel infusion with continuous cardiac monitoring 
during the infusion, at the discretion of the treating physician. 
 
5.6.5 Hypersensitivity Reactions - Paclitaxel 
Caution: Patients who have a mild to moderate hypersensitivity reaction should be rechallenged, 
but careful attention to prophylaxis and bedside monitoring of vital signs is recommended. 
 
For moderate symptoms (e.g. moderate rash, flushing, mild dyspnea, chest discomfort), stop the 
infusion. Give intravenous diphenhydramine 25 mg and intravenous dexamethasone 10 mg. 
After recovery of symptoms, resume infusion at a low rate, 20 mg/hr for 15 minutes. If no further 
symptoms, resume at full dose rate until infusion is complete. If symptoms recur, stop infusion. 
The patient should receive no additional paclitaxel for that cycle, but may be retreated after 
discussion with the Study Coordinator. 
 
For severe life threatening symptoms (e.g. hypotension requiring pressor therapy,angioedema, 
respiratory distress requiring bronchodilator therapy, generalized urticaria), stop the infusion. 
Give intravenous diphenhydramine and dexamethasone as above. Add epinephrine or 
bronchodilators if indicated. If wheezing is present that is not responsive to administration of 0.35 
cc of nebulized salbutamol solution (or equivalent), epinephrine is recommended. The patient will 
be taken off paclitaxel treatment. 
 
5.6.6 Myalgia/Arthralgia 
Myalgia/arthralgia will be classified as mild (grade 1): muscle and joint aches; moderate (grade 
2): decreased function, decreased ability to perform daily tasks, but still functioning; or severe 
(grade 3): unable to function, confined to bed. Treatment for myalgia and arthralgias may include 
nonsteroidal anti-inflammatory medication (Toradol®, ibuprofen, etc.). If there is still no relief, 
narcotic pain medications may be used. Grade 3 toxicity, reasonably attributable to paclitaxel, will 
require a dose reduction of 25% following resolution to grade ≤ 1. No further dose reduction will 
be permitted, and no further paclitaxel will be given. 
 
5.6.7 For all other grade 3 or 4 non-hematological toxicity, please call the study PI. 
 
5.7 Dose Modifications for Paclitaxel - Concurrent Therapy 
Lab assessments will be repeated weekly during concurrent chemoradiotherapy and dose 
modification will be made according to the guidelines below at each time point. Doses that are 
missed during weekly schedule of concurrent radiation will not be made up but will be 
documented. 
5.7.1 
Hematologic Toxicity (table continued on next page) 
 
 
 
Toxicity NCI CTCAE 
Grade (CTCAE v4.0) 
Paclitaxel Dose At Start of 
Subsequent Cycle of Therapy
a 
Neutropenia 
1 (1500-1999/mm
3) 
Maintain dose level 
2 (1000-1499/mm3) 
Hold therapyb 
3 (500-999/mm3) 
Hold therapyb 

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Toxicity NCI CTCAE 
Grade (CTCAE v4.0) 
Paclitaxel Dose At Start of 
Subsequent Cycle of Therapy
a 
4 (<500-999/mm3) 
Hold therapyb 
Neutropenic fever 
Hold therapyb 
Thrombocytopenia 
1 (LLN-75,000/mm
3) 
Maintain dose level 
2 (50,000-74,999/mm3) 
Hold therapyb 
3 (25,000-49,999/mm3) 
Hold therapyb 
4 (<25,000/mm3) 
Hold therapyb 
Other Hematological 
toxicities 
There will be no dose 
modifications for changes in 
leucopenia or lymphopenia 
Worst Toxicity NCI 
CTCAE Grade (CTCAE 
v4.0)a,c 
Paclitaxel Dose At Start of 
Subsequent Cycles of 
Therapyb 
Neuropathy 
≤ Grade 1 
Maintain dose level 
Grade 2 
Hold therapy until Grade ≤ 1; 
restart at full dose 
Grade 3 
Discontinue therapy 
Other grade 3-4 non- 
hematological toxicities 
Hold treatment until ≤ Grade 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aFor concurrent therapy, paclitaxel doses will not be adjusted. 
bRepeat lab work weekly and resume chemotherapy based on this table. 
 
Radiation therapy will be held for grade 4 hematologic toxicities described in the table above. 
 
5.7.2 Non-Hematologic Toxicity During Concurrent Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aFor ≤ CTCAE Grade 2 non-hematologic toxicity not described above, excluding neuropathy, 
maintain dose level of all study. 
bFor concurrent therapy, paclitaxel doses will not be adjusted. 
cRadiation therapy should continue to be delivered for ≤ Grade 3 non-hematologic toxicities in or 
outside the radiation treatment field. Radiation therapy should be held for all Grade 4 non- 
hematologic toxicity in or outside the treatment field and resumed only when toxicity is ≤ Grade 2. 
 
5.7.3 If there is a decline in Zubrod performance status to ≥ 2 for greater than 2 weeks while 
under treatment, radiotherapy should be held with no further chemotherapy administered. Re- 
evaluate patient after one week for resumption of radiotherapy. 
 
6.0 RADIATION THERAPY 
Note: Radiotherapy must be delivered with intensity modulated radiation therapy (IMRT) 
techniques using image-guided radiation therapy (IGRT) (see 6.2 and 6.3 for technical details) 
 
6.1 Dose Specifications (See Section 6.4 for definition of target volumes) 
6.1.1 Definitive IMRT after Induction Chemotherapy 
6.1.1.1 For patients with a complete response (CR) or partial response (PR) after induction 
chemotherapy, IMRT will be delivered in 27 fractions over 5.5 weeks, with treatment daily, five 
days per week. The primary tumor and involved nodes (PTVHD) will receive 2 Gy per fractions 
and subclinical disease sites (PTVED) will receive 1.6 Gy per fraction. The total doses will thus 

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be 54 Gy and 43 Gy, respectively. When desired, PTVINT can receive 1.8 Gy per fractions to a 
total dose of 49 Gy. 
6.1.1.2 For patients with stable disease (SD) or progressive disease (PD) after induction 
chemotherapy, IMRT will be given in 30 fractions over 6 weeks, with treatment delivered daily, 
five days per week. The primary tumor and involved nodes (PTVHD) will receive 2 Gy per 
fractions and subclinical disease sites (PTVED) will receive 1.6 Gy per fraction. The total doses 
will thus be 60 Gy and 48 Gy, respectively. When desired, PTVINT can receive 1.8 Gy per 
fractions to a total dose of 54 Gy. 
6.1.1.3 The low neck or supraclavicular regions must be included in the IMRT plan using an 
extended-field technique. Because the doses used are below commonly accepted tolerance 
levels for the swallowing structures, use of an isocentric matching AP or AP/PA fields, with larynx 
block, matched to IMRT portals just above the arytenoids, is not allowed. 
6.1.2 Dose Prescription 
Choice of treatment plan used for each patient will be based on an analysis of the volumetric 
dose, including dose-volume histogram (DVH) analyses of the targets and critical normal 
structures. An “inverse” planning with computerized optimization should be used. The 
prescription dose is the isodose surface that encompasses at least 95% of the planning target 
volume (PTV) with no more than 20% of any PTVHD receiving ≥ 110% of the prescribed dose 
and no more than 1% of any PTVHD and PTVED receiving ≤ 93% of the prescribed dose. No 
more than 1% or 1 cc of the tissue outside the PTV should receive ≥ 110% of the prescribed dose 
to the PTVHD. The density corrected dose distributions shall be calculated and the dose 
prescription is to be based on a dose distribution corrected for heterogeneities. 
 
6.2 Technical Factors 
6.2.1 Photon beams of ≥ 4 MV are required. 
6.2.2 Treatment distance must be ≥ 80 cm SAD for isocentric techniques. 
6.2.3 IMRT: Megavoltage equipment capable of delivering intensity modulated beams using a 
step- and-shoot technique with a multi-leaf collimator or using dynamically moving leaves. 
Additionally, a binary multi-leaf collimator or rotational methods (e.g. Tomotherapy) can be used 
to modulate the beam. Other techniques, e.g. physical compensators, are acceptable as long as 
dose specifications and constraints are satisfied. 
 
6.3 Immobilization, Simulation, and Localization 
6.3.1 Immobilization 
Although a thermoplastic head mask may suffice for conformal radiotherapy, the use of a head 
and shoulder mask is recommended for better reproducibility. The use of a thermoplastic head 
and shoulder mask is mandatory for IMRT. The margins used for expansion of the CTVs to PTVs 
are discussed in Section 6.4.4. 
6.3.2 Planning CT scan 
A treatment planning CT scan is mandatory for defining target volumes (see Section 6.4). CT 
scan thickness should be at most 0.3 cm as is customary for IMRT. The treatment planning CT 
scan should be acquired with the patient in the same position and using the same immobilization 
device as for treatment. All tissues receiving irradiation should be included in the CT scan. It is 
recommended, but not required, that a simulation CT scan (with the patient immobilized in the 
treatment position) be obtained both prior to and after induction chemotherapy. The pre-induction 
immobilization apparatus can be used if it still fits and provides sufficient support. However, 
weight loss, alterations in neck mobility, changes in neck contours, and primary and nodal tumor 
responses could render pre-induction chemotherapy immobilization devices ineffective. In this 
instance, new immobilization devices should be created that approximate the head, chin, 
shoulder, and neck position of the initial devices as closely as possible. A new mask and new 
planning image will be required in some cases after induction chemotherapy because of changes 
in body weight, neck contours, and tumor volumes. 
6.3.3 Image-Guidance 
Image guidance is required for target localization and dose verification and may be achieved 
using any one of more of the following: 
• Orthogonal kilovoltage (KV) images, e.g. ExacTrac; 

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• Linear-accelerator mounted kV and MV conebeam CT images; 
• Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 
6.3.3.1 The 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 PTVHD and 
adjacent spinal cord; if the supraclavicular region is a part of the target volume, the ROI should 
extend to the C6 level; 
• If the fusion software allows the user to create an irregular ROI (e.g. ExacTrac), treatment room 
objects seen on in-room X-rays should be excluded from the registration; 
• Both manual (e.g. based on bony anatomy) and automatic (e.g. based on mutual information) 
types of registration can be used; the result of the fusion must be visually checked for the 
alignment of the bony anatomy, such as vertebral bodies and applicable 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 margin on critical structures), 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. 
6.3.3.2 Management of Radiation Dose to the Patient from IGRT 
Available peer reviewed literature estimates the patient dose within and outside of the target 
region when IGRT is used to correct positioning to vary considerably. This is the case when the 
same imaging hardware is used with x-ray technique and with different data gathering 
procedures. The dose variation is even greater when different imaging equipment is used. The 
estimated doses are in the range of 1 mGy for 2D systems such as the BrainLab’s ExacTrac 
system or either the Varian or Elekta kV systems used for orthogonal imaging. These doses are 
small compared with doses from MV portal imaging and kV or MV conebeam CT. The doses from 
helical MVCT scanning with a tomotherapy unit are estimated to be in range from 1 to 3 cGy for 
head and neck studies, similar to doses reported for kV cone-beam CT on Elekta Synergy 
machine. The doses for MV cone beam CT were reported to be in range from 10 cGy for a pelvis 
study to 6 cGy for a head and neck study. Thus, the doses for 3D imaging systems are in the 
range from 1 to 6 cGy for head and neck imaging and can contribute from 0.5 to 3% to the daily 
dose of 2.0 Gy. These doses apply each day when image guidance is used, and the numbers 
double and triple when extra imaging is needed to adjust positioning on a particular day. The 
imaging dose to the patient may become significant if repeated studies are done for patients with 
severe set up problems (e.g. requiring frequent corrections that are larger than the margins used 
to account for positional uncertainty). It is recommended that patients demonstrating severe set 
up problems during the first week of treatment be moved to a treatment with larger margins and 
taken off protocol. 
 
6.4 Treatment Planning/Target Volumes 
6.4.1 CT based treatment planning is mandatory for every patient and should be performed using 
the CT scan obtained after the induction chemotherapy cycle. Fusion of the pre-induction 
chemotherapy simulation images, when obtained, with the post-induction chemotherapy 
simulation CT is strongly encouraged. In these cases, the gross tumor volume (GTV) can be 
modified when a dramatic response would place the GTV within air or outside the patient's body 
such that the volume should be altered to fit within the patient's post-induction chemotherapy 
anatomy. 
6.4.2 Gross Tumor Volume (GTV) represents the region judged to contain gross primary tumor or 
involved node(s) based on clinical and endoscopic examinations, CT scan, and, when applicable, 
other imaging techniques. Grossly positive lymph nodes are defined as any lymph nodes > 1 cm 
or nodes with a necrotic center.  The pre-induction chemotherapy simulation CT scan will be 
used to define the GTV on the post-induction chemotherapy CT images. 

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6.4.3 Clinical Target Volume (CTV) for patients treated by induction chemotherapy is defined as 
the GTV plus areas considered at risk for containing microscopic disease delineated by the 
treating physician. CTVHD represents GTV plus a margin of generally 0.5 to 1 cm and CTVED 
represents GTV with a margin of about 2 cm and nodal regions to receive elective irradiation. 
When the tumor is infiltrative (endophytic) or when the border is ill defined, it might be desirable to 
deliver an intermediate dose (e.g., 49-54 Gy) to a volume (CTVINT) that is slightly larger than 
CTVHD. The CTV margins can be narrower when GTV is in the proximity of the spinal cord, 
brainstem, or critical normal tissues.  (The guidelines for CT based delineation of lymph node 
levels can be found at the RTOG web site:http://www.rtog.org/hnatlas/main.html). 
6.4.4 Planning Target Volume (PTVHD and PTVED) represents an additional margin around the 
CTV to compensate for the variability of treatment set up and internal organ motion. A minimum 
margin of 0.5 cm around the CTV is required in all directions to define each respective PTV if 
IGRT is performed on a less than daily basis. A 3 mm margin can be used in all directions as long 
as daily IGRT is implemented and the scans reviewed by the treating physician prior to the 
delivery of the subsequent fraction. 
 
 
6.5 Critical Structures 
6.5.1 Definition of Normal Tissues/Organs at Risk (OARs) 
6.5.1.1  Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 
vertebral body). Superior to this is brainstem and inferior to this is cord. The inferior border of the 
spinal cord should be below the lowest slice level that has PTV on it. The spinal cord shall be 
defined based on the treatment planning CT scan. In addition, however, a Planning Risk Volume 
(PRV) spinal cord shall be defined. The PRVcord = cord + 5 mm in each dimension. 
6.5.1.2  Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction 
where it meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall be 
defined based on the treatment planning CT scan. In addition, the PRVbrainstem = brainstem + 3 
mm in each dimension. 
6.5.1.3 Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is 
to keep the lip dose much lower than the oral cavity dose. The definition of lips is self- 
explanatory. The oral cavity will be defined as a composite structure consisting of the anterior ½ 
to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and palate. The oral cavity OAR should 
not overlap any PTV. 
6.5.1.4  Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan. 
The objective is to limit the mean dose to at least one gland to less than 24 Gy; alternatively at 
least 20 cc of the combined volume of both parotid glands to <20 Gy or at least 50% of one gland 
to <30 Gy. Both deep and superficial lobes of the parotid glands are contoured as one structure. 
6.5.1.5  Pharynx: This will be defined as the “uninvolved” posterior pharyngeal wall plus adjacent 
constrictor muscles. This extends from the superior constrictor region (the inferior pterygoid 
plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level). This should not overlap 
the PTVs. 
6.5.1.6 Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of 
OARpharynx and extends to the thoracic inlet. 
6.5.1.7 Glottic/Supraglottic Larynx (GSL): This will be defined as a “triangular prism shaped” 
volume that begins just inferior to the hyoid bone and extends to the cricoid cartilage inferiorly 
and extends from the anterior commissure to include the arytenoids. This includes the infrahyoid 
but not suprahyoid epiglottis. 
6.5.1.8  Mandible: This includes the entire bony structure of the mandible from TMJ through the 
symphysis. It is recognized that in many cases, this may overlap with CTVs and PTVs. 
6.5.1.9  Brachial plexus: Brachial plexus contouring can be delineated as outlined by Hall 2008. It 
comprises of linear structures of 5 mm thickness that extend from the neural foramina of C5 
through T1 to the small space between the anterior and middle scalene muscles. For CT slices 
where no neural foramen is present, one can contour only the space between the anterior and 
middle scalene muscles. If one follows the space between these muscles inferiorly; one will find 
the cords of the brachial plexus posterior to subclavian neurovascular bundle. They are the non- 

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enhanced structures posterior to the enhanced subclavian vein. These cords extent laterally 
along the axillary vein into the axilla. 
6.5.1.10  Cochlea: Contour for all cases. 
6.5.1.11  Brain: Contour the brain for all cases. 
6.5.1.12  Eyes: Contour the globes and lens for all cases. 
6.5.1.13 Optic Nerves and Chiasm: Contour for all cases. Care should be given to contour optic 
nerves through the optic canal in continuity with the chiasm. 
6.5.1.14  Unspecified Tissue Outside the Targets: This will be defined as tissue located between 
the skull base and thoracic inlet that is not included in either the target volumes or the normal 
tissues described above. 
6.5.2 Dose Constraints to Normal Structures 
6.5.2.1  Spinal Cord: The PRVcord (as defined in Section 6.5) should not exceed 45 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV should 
not exceed 48 Gy to any volume in excess of 0.01 cc. In treatment planning, the spinal cord PRV 
should be given the highest priority. 
6.5.2.2  Brainstem: The PRVcord (as defined in Section 6.5) should not exceed 48 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm) unless the skull base is 
included in CTVHD. When the skull base is treated, the PRVbrainstem (as defined in Section 6.5) 
should not exceed 52 Gy to any volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 
mm). In treatment planning, the PRVbrainstem should be given the same priority as the PRVcord. 
6.5.2.3 Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. 
6.5.2.4 Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 30 Gy if 
feasible. Efforts should be made to avoid hot spots (> 60 Gy) within the oral cavity. 
6.5.2.5  Parotid Glands: The goal is keep the mean dose to at least one parotid gland to < 24 Gy. 
Additional planning goals may include: 1) At least 50% of one parotid will receive < 30 Gy; and/or 
2) At least 20 cc of parotid tissue (from the combination of both glands) will receive < 20 Gy. 
6.5.2.6  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 10% of the pharynx exceeds 60 Gy. 
6.5.2.7 Cervical Esophagus: Reduce the dose as much as possible. Some recommended (but not 
mandatory) treatment goals include: 1) No more than 30% of the esophagus exceeds 45 Gy; 2) 
Mean dose < 35 Gy; 3) No more than 10% of the esophagus exceeds 54 Gy. 
6.5.2.8 Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. It is 
recommended that the dose to the larynx should be kept < 40 Gy whenever feasible. 
6.5.2.9  Mandible: Reduce the dose as much as possible. It is recognized that particularly for 
these cancers, portions of the mandible will overlap the CTVs and/or PTVs; however, hot spots 
within the mandible should be avoided. It is recommended that maximum dose within the 
mandible be < 64 Gy whenever possible. 
6.5.2.10  Brachial plexus: The maximum dose to the ipsilateral brachial plexus should be kept < 
60 Gy if there are no involved low neck nodes. If the low neck is involved, the maximum brachial 
plexus dose should be kept < 66 Gy. 
6.5.2.11  Cochlea: It is recommended to keep the ipsilateral cochlea maximum dose < 50 Gy. It is 
recognized that this will not be possible when it is required to include the temporal bone in the 
clinical target volume. 
6.5.2.12  Brain: It is recommended that the brain maximum dose should not exceed 60 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm) when the skull base is not 
included in the clinical target volume. It is recommended that the brain maximal dose should not 
exceed 66 Gy for all cases. 
6.5.2.13  Eyes: The maximum dose should not exceed 30 Gy. Particular attention should be given 
to keep the lens maximum dose < 25 Gy. 
6.5.2.14 Optic Nerves: The maximum dose should not exceed 54 Gy. 
6.5.2.15 Optic Chiasm: The maximum dose should not exceed 50 Gy. 
6.5.2.16  Unspecified Tissue Outside the Targets: <100% of the dose prescribed to the CTVHD. 
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6.5.3 Prioritization for IMRT Planning 
1. Spinal cord and brainstem 
2. PTVHD 
3. PTVED 
4. PTVID (if applicable) 
5. Chiasm 
6. Optic nerve 
7. Brain 
8. Eyes 
9. Parotid gland contralateral to primary tumor site 
10. Pharynx 
11. GSL 
12. Esophagus 
13. Lips 
14. Oral cavity 
15. Parotid gland ipsilateral to primary tumor site 
16. Mandible 
17. Lens 
18. Unspecified tissue outside the targets 
 
6.6 Documentation Requirements 
6.6.1 Orthogonal images that localize the isocenter are recommended on the first day of therapy. 
6.6.2 A minimum of weekly volumetric IGRT is required 
6.6.3 Daily IGRT imaging is strongly recommended. 
6.6.4 Isodose plans and DVHs of GTV, CTVs, and critical normal structures. 
 
6.7 Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Missed treatments due to holidays or logistic reasons can be 
compensated for by delivering additional BID treatments with a minimum inter-fraction 
interval of 6 hours or by treating on a Saturday or Sunday. 
 
Treatment breaks should be allowed only for resolution of severe acute toxicity and/or for inter- 
current illness and ideally, should not exceed 5 treatment days at a time and 10 treatment days in 
total. Any treatment break(s) exceeding two treatment days for reasons other than toxicity/illness 
will be considered a protocol deviation. 
 
6.8 Radiation Therapy Quality Assurance Reviews 
The Principal Investigator, Allen M. Chen, M.D. and the Medical Physics Co-Chair, James Purdy, 
Ph.D., will remotely perform RT Quality Assurance Review for the first 10 cases enrolled. 
 
7.0 ADVERSE EVENT REPORTING 
Adverse event reporting is a fundamental component of every clinical trial. 
 
7.1 Adverse Event Monitoring 
Subjects must be carefully monitored for adverse events. This monitoring includes clinical and 
laboratory tests. The study will utilize the NCI CTCAE 4.0 Common Terminology Criteria (CTC) 
for Adverse Events for toxicity and Adverse Event Reporting. A copy of the CTCAE version 4.0 
can also be downloaded from the CTEP home page (http://ctep.cancer.gov/reporting/ctc.html). 
Adverse events will be assessed each cycle, and the highest grade according to NCI-CTCAE 
Version 4.0 will be recorded. Adverse events should be assessed in terms of seriousness, 
severity, and relationship to the study treatment. 

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7.2 Adverse Event Definitions 
7.2.1 Adverse Events (AEs) 
Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite). 
 
7.2.2 Serious Adverse Events (SAEs) 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after that results in any of the following outcomes: 
• 
Results in death. 
• 
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. 
 
7.2.3 Intensity (Severity) of the Adverse Event 
The intensity or severity of adverse events should be graded according to the NCI-CTCAE 
version 4.0 criteria. 
 
7.2.4 Adverse Event Documentation 
All adverse events occurring after the subject has received the first dose of investigational 
treatment must be fully recorded in the subject’s case record form. Documentation must be 
supported by an entry in the subject’s file. Each event should be described in detail along with 
start and stop dates, severity, relationship to study treatment, action taken and outcome. 
 
7.3 Study Treatment Adverse Events 
 
Grade 3-4 therapy-induced mucositis and/or dysphagia, which are enhanced by palcitaxel, are 
expected to develop in about one-half of patients. Nutritional evaluation prior to the initiation of 
therapy for a prophylactic gastrostomy (PEG) tube placement is highly recommended. Placement 
of a feeding tube should be recorded, as should use of a feeding tube during and after treatment 
(e.g., greater than or less than 50% of nutrition by tube). Other common radiation adverse events 
include: fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient ear discomfort, 
dysgeusia, and skin erythema and desquamation within the treatment fields. A proportion of 
patients may require intravenous fluid support secondary to dehydration, and this should be 
documented. 
 
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much less 
common radiation adverse events include: mandibular osteoradionecrosis (< 5% incidence), and 
cervical myelopathy (< 1% with restriction of spinal cord dose to ≤ 45 Gy). 
 
Adverse events (AEs) may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures must be reported to Principal Investigator (or designee). 

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Reporting Forms: 
• 
SAE Report Form 
• 
Reporting to the FDA: US FDA MedWatch 3500A 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
Each serious adverse event must be followed up until resolution or stabilization, by submission of 
updated reports to the principal investigator Dr. Allen Chen. 
 
Reporting to the Institutional Review Board 
Both serious and non-serious adverse events will be reported in accordance with UCD IRB 
Administration and UCD Cancer Center Clinical Trial Support Unit (CTSU) policies. The UC 
Davis IRB can be reached at (916) 703-9151. 
 
7.4  Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and must permanently discontinue study treatment. 
All pregnancies and suspected pregnancies must be reported to Principal Investigator (or 
designee) immediately. The pregnancy must be followed for the final pregnancy outcome (ie, 
delivery, still birth, miscarriage). 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to Principal Investigator (or designee) immediately. Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
 
8.0 FUNCTIONAL IMAGING: FDG-PET/CT IMAGING 
A pre-treatment PET/CT scan is required for all patients on study and should be obtained prior to 
any treatment. A post-treatment FDG-PET/CT scan is also required 8-12 weeks after completion 
of treatment to assess for the possibility of residual disease. Note: If the CT portion of a PET/CT 
is done with contrast and a radiologist formally reviews and reports the findings on head and neck 
and thoracic regions, then there is no need to order additional diagnostic CT/MRI of the head and 
neck or chest x-rays or CT scan of the chest. 
8.1 PET Image and Scanner Compatibility Requirements 
All imaging must be conducted on a combined PET/CT scanner with full ring PET and four slice 
or greater multi-detector CT. The scanner should be operating in high-sensitivity 2D mode, if 
available. 3D mode is permissible for patients imaged on combined PET/CT scanners without a 
2D mode. 
8.2 Pre-FDG Injection: Patient Preparation 
Height and weight will be recorded before each PET scan. Patients will observe a four to six- 
hour fasting period prior to FDG injection. Patients with a history of medically controlled diabetes 
will be counseled to check serial blood sugars prior to each scan to ensure that values average 
below 200 mg/dL. For these patients, a blood sugar measurement will be performed after a six- 
hour fast to gauge fasting tolerance. Serum glucose concentration will be measured for all 
patients prior to scanning and must be less than 200 mg/dL to proceed to imaging. 
8.3 FDG Injection 
A dose of 10-20 mCi of 18FDG will be infused intravenously. As per best clinical practice, 
administration of 0.5 mg of alprazolam 5-15 minutes prior to FDG injection to relax the patient and 
to reduce neck 18FDG muscle uptake should be considered. The patient will lie quietly for at 
least 30 minutes, and scanning will begin 50-70 minutes following the FDG injection. 
8.4 PET Imaging 
Imaging must encompass the vertex of the head down through the entire pelvis. The 
recommended imaging protocol incorporates two discrete phases, and is as follows: During the 
first phase, head and neck scanning will be performed with full neck extension. The patient will 
initially be imaged with a 120 KeV/300 mA, 0.5-second detector rotation time (“high mA”) CT scan 
with intravenous contrast (100 cc contrast bolus administered at 1.5 cc/second, with a 50 second 
scan delay and with the scan started inferiorly, moving cranially), followed by a 120 KeV/80 mA, 
0.8-second detector rotation time (“low mA”) CT scan for PET attenuation correction, followed 

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lastly by PET scanning. Alternatively, an initial low mA CT scan may be performed for 
attenuation correction, followed by a high mA CT scan with intravenous contrast. Standard 
manufacturer recommendations for specific low and high mA CT scanning parameters can be 
substituted for those listed above. Two fields of view (approximately 15 cm) will be used for head 
and neck PET imaging. Patients then will be allowed to rest their necks for 1-2 minutes. For the 
second phase of imaging, the neck will be shifted into neutral position, and the remainder of the 
body will be surveyed per routine local institutional protocol with arms raised above the head to 
allow for optimal thoracic and upper abdominal imaging. At least four to five PET fields of view 
will be used for this phase. Images will be reconstructed via the filtering algorithm provided by 
the scanner manufacturer. 
8.5 Assessment at 8-12 Weeks Post-Treatment 
A post-treatment FDG-PET/CT scan is required 8-12 weeks after completion of treatment for all 
patients. The post-treatment PET/CT scan should be done on the same scanner, as specified 
above. It is anticipated that most patients with stage N2-3 disease at presentation and all with 
residual adenopathy will undergo neck dissection. Surgery should take place within 4 weeks of 
post-treatment FDG-PET/CT imaging. Bilateral neck dissection, if necessary, can take place in 
two stages. See Section 8.1 for details of surgery. 
8.6 Maximum Standardized Uptake Value (SUVmax) 
SUV normalized by specific injected dose and patient weight will be calculated using vendor- 
provided software. Maximum standardized uptake value (SUVmax) will be defined as ( tissue 
activity) (μ Ci/ml)/(injected dose (mCi)/(patient weight [kg]) within the voxel having the highest 
activity within a given region of interest (ROI). This will be determined for ROIs within the primary 
tumor and within the involved cervical node with highest FDG uptake. It is strongly recommended 
that an experienced head and neck radiologist assist with delineation of tumor volumes. Detection 
of primary and nodal disease by FDG-PET/CT will not be classified according to an FDG SUV 
threshold. Instead, malignancy will be qualitatively determined by FDG uptake greater than 
surrounding normal soft tissue within a CT-delineated anatomic (primary disease or nodal) 
abnormality. FDG-PET ROIs delineation will be generated on the PET/CT scanner workstation. 
Each ROI must encompass the entire FDG-avid lesion of interest, with boundaries guided by CT 
delineation. Maximum standardized uptake values (SUVmax) for primary tumor and nodal 
disease will be recorded for these manually generated ROIs. 
8.7 Functional Imaging Adverse Events 
There is a negligible risk of exposure to radiation from PET imaging. Less likely adverse events 
include potential bruising or bleeding and/or infection at the site of the injection of the tracer. 
Serious allergic reactions to the tracer are rare. 
 
9.0 SURGICAL THERAPY 
9.1 Salvage Neck Dissection after Chemoradiotherapy 
It is required that all patients be assessed 8-12 weeks post-treatment with CT scan or MRI. A 
post-treatment PET/CT scan is also required (see Section 8.5). Note: If the CT portion of a 
PET/CT is done with contrast and a radiologist formally reviews and reports the findings on head 
and neck and thoracic regions, then there is no need to order additional diagnostic CT/MRI of the 
head and neck or chest x-rays or CT scan of the chest. 
 
If the primary site is cleared of residual disease yet residual disease at the cervical nodal basin 
is suggested by imaging/clinical evaluation, then selective neck dissection will be performed unless 
a cytologic sampling of the node is negative. Post-treatment “planned” neck dissection will be 
defined as being performed for residual disease and within 20 weeks (140 days) of completion of 
radiotherapy. Positive neck specimens removed within 140 days will be considered part of the 
initial treatment plan and not considered as failures of initial management; positive specimens 
upon neck dissection beyond 140 days will be considered regional failures. Note that this is 
relaxed from the traditional definition of 105 days (15 weeks) in order to permit resolution of HPV- 
associated lymphadenopathy, which is commonly cystic and has a somewhat slower regression 
rate. Such post-treatment consolidation neck dissections will encompass only the areas (typically 
only levels 2 and 3) initially involved in the side of the neck in question. The extent of neck 
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primary will be determined by the treating surgeon. The status of the primary tumor should be 
assessed thoroughly at the beginning of the surgical procedure before undertaking nodal 
dissection. Presence of persistent disease at the primary site, confirmed by frozen section, will be 
considered a failure of protocol treatment. In the case of negative PET in patients who did not 
achieve clinical or CT/MRI-based radiological nodal CR, follow-up PET scans are recommended 
every 3-4 months for  24  months, then every 6 months for years 3-5, as well as careful recording 
of the clinical dimensions of the residual abnormality. 
 
For Patients Undergoing a Neck Dissection 
Cervical lymphadenectomy will encompass the original levels of lymph node involvement, which 
should be removed en bloc. Preservation of the accessory nerve, jugular vein, and sternomastoid 
muscle is encouraged if consistent with complete removal of all residual nodal disease; however, 
the extent of the neck dissection will be at the discretion of the surgeon. A selective neck 
dissection should be performed when feasible. At no time will synchronous bilateral radical neck 
dissections be performed. If bilateral radical neck dissections are necessary the neck procedure 
must be staged at an interval of 6 weeks between lymphadenectomies. 
 
The neck dissection specimens must be divided and oriented into discrete anatomic levels in the 
operating room by the supervising surgeon, and submitted for pathologic review in separate 
containers. Discrete groups of nodes that are matted or spaced too closely to be resolved as 
separate nodes under the microscope or by FDG-PET/CT (< 0.5 cm intervening distance) will be 
categorized as “nodal clusters.” These clusters will be considered equivalent to solitary nodes to 
allow for simpler and more accurate categorization of all sampled tissue. An attending pathologist 
should oversee evaluation of all neck dissection specimens. 
 
9.2 Surgical Removal (Salvage) of the Primary Tumor 
Directed biopsies at the site of the index lesions will not be performed in the absence of suspicion 
for relapse. Criteria for biopsy after chemoradiation include a persistent mucosal abnormality or 
imaging studies that are suspicious for persistent or recurrent disease at 8-9 weeks after 
completion of therapy. Options for salvage therapy will depend upon the clinical situation and are 
at the discretion of the treating physicians. Surgical removal (salvage resection) of the primary 
tumor will be performed, if possible, when biopsy-proven cancer remains more than three months 
after completion of therapy. The nature of the surgical resection will be dictated by the extent of 
tumor at the initial evaluation. The operation will be conducted using accepted criteria for primary 
surgical treatment of the cancer. 
 
Tissues for pathologic evaluation of margins should be taken from the patient (rather than the 
surgical specimen itself). However, the specimen itself should be marked at sites corresponding 
to the evaluated margins in order to assess sampling error in obtaining clear margins. If gross 
tumor remains or when no effort to remove tumor has been made, the patient will be considered 
to have "gross residual disease." In the absence of residual disease, if the cancer extends to 
within 5 mm of a surgical margin, the patient would be considered to have "close" margins. 
 
Questions about salvage surgery should be directed to the Co-Principal Investigator, Dr. Gregory 
Farwell. 
 
10.0 OTHER THERAPY 
10.1 Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication. The use of amifostine and pilocarpine 
is not allowed in light of the overlapping adverse event profile with paclitaxel and possible impact 
on the endpoints. 

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11.0 TISSUE/BLOOD/SPECIMEN SUBMISSION 
NOTE: Patients must be offered the opportunity to participate in the correlative components of 
the study, such as tissue/blood/specimen submission. 
 
11.1 Specimen   Collection   for   Tissue   Banking   and   Translational   Research 
(Highly Recommended) 
The overall objective of collecting specimens for translational research is to prospectively 
establish a repository of both risk factor profiles and biospecimens from patients to facilitate 
future hypothesis generated research. Translational research studies integrate the newest 
research findings into current protocols to investigate important biologic questions. Please 
contact the translational research co-principal investigator, Dr. Andrew Vaughan for additional 
questions. 
11.1.1 
Tumor Tissue 
Tissue for banking will be taken from the tumor tissue block for central review. The 
Radiation Oncology laboratories at the University of California Davis will acquire and maintains 
high quality specimens from this trial. Paraffin-embedded tissue blocks are preserved through 
careful block storage and processing per standard institutional protocols. These tissue 
specimens will be used by investigators for future translational research studies. 
11.1.2 
Serum, Plasma, and Whole Blood Collection 
Plasma, serum and whole blood will be collected pre-treatment as well as various periods during 
treatment (see 12.0). In addition, plasma and serum will be collected at the 3- and 6-month 
follow-up visits. If a site misses the pre-treatment collection time point, they may collect the 
whole blood specimen at any time during treatment or after follow-up. Recent data has 
suggested that plasma HPV DNA is released from HPV-positive tumors, and that circulating HPV 
DNA may be detectable and ultimately used to identify patients at high risk for progression (Cao 
2012). 
 
Two blood specimens will be collected from each patient prior to initiating protocol treatment (2 x 
10 ml, 1 purple top tube, 1 red top tube). Subsequent blood specimens (1 x 10 ml, purple top 
tube) should be collected weekly during radiation therapy and 3- and 6- months. 
 
Prior to therapy, and weekly during radiation, one blood specimen should be collected in a 10 ml 
purple-top (EDTA) tube, inverted several times, and placed on wet ice until centrifugation. The 
tube should be centrifuged as soon as possible at approximately 1,000-1,500 rpm for 10 minutes. 
Plasma should be removed and placed in 1 ml aliquots in labeled cryotubes. Buffy coat cells 
should be separately removed and placed in labeled cryotubes. All specimens must be labeled 
with protocol number, patient registration number, and date of specimen collection. All 
tubes are then to be frozen (snap frozen with liquid nitrogen if possible) and stored at -70°C. 
 
Prior to initiating protocol therapy, a second blood specimen should be collected in a 10 ml red- 
top tube, allowed to clot at room temperature for 30 minutes, and placed on wet ice until 
centrifugation. The tube should be centrifuged at 3000 rpm for 10 minutes. Serum should be 
removed and placed in 1 ml aliquots in labeled cryotubes. All specimens must be labeled with 
protocol number, patient registration number, and date of specimen collection. All tubes 
are then to be frozen (snap frozen with liquid nitrogen if possible) and stored at -70°C. 
 
 
11.2  Confidentiality/Storage 
11.2.1 Upon receipt, the specimen is labeled with the protocol number, the patient’s 
registration number, and date of specimen collection.  Encoded databases will  only  include the   
following information:  the  number  of  specimens  received,  the  date  the  specimens were  
received, documentation of material sent to a qualified investigator, type of material sent, and 
the date the specimens were collected. No clinical information is kept in the database. 
11.2.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens 
for central review will be retained until the study is terminated. Specimens for the translational 
research component of this protocol will be retained until the study is terminated, unless the 

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patient has consented to storage for future studies. If at any time the patient withdraws consent 
to store and use specimens, the material will be returned to the institution that submitted it. 
 
Shipping Instructions: All archival paraffin block or slide specimens should be sent at ambient 
temperature. Frozen specimens should be shipped on dry ice. These should be shipped by 
overnight courier Monday through Wednesday only, to the following address: 
 
Andrew Vaughan, Ph.D. 
Department of Radiation Oncology 
UC Davis Comprehensive Cancer Center 
4501 X Street, Sacramento, CA 95817 
Office Phone: 916-734-8726 
Laboratory Phone: 916-213-1810 
Fax: 916-703-5069 
 
The Federal Guidelines for Shipment are as follows (these periodically change, please check for 
the most current guidelines): 
1. The specimen must be wrapped in an absorbable material 
2. The specimen must then be placed in an AIRTIGHT container (resealable bag) 
3. Pack the resealable bag and specimen in a styrofoam shipping container 
4. Pack the styrofoam shipping container in a cardboard box 
5. The cardboard box should be labeled “UN3373 Biological Substance, Category B” “BIOHAZARD” 

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12.0 PATIENT ASSESSMENTS 
12.1.1 Study Parameters- Patients treated by Induction Chemotherapy followed by 
Concurrent Chemoradiotherapy 
 
Assessments 
During Treatment 
Follow Up 
Pre-study 
entry 
After each 
cycle ICT 
Weekly 
during CRT 
4 wks after 
CRT 
8 wks after 
CRT 
12 weeks 
after CRT 
Evaluations 
History/physical 
X 
X 
X 
X 
X 
X 
Zubrod, weight 
X 
X 
X 
X 
X 
X 
Protocol-specific AE 
evaluation 
X 
X 
X 
X 
X 
X 
Dental evaluation 
Y 
Audiogram 
Y 
Nutrition evaluation 
Y 
Imaging 
Chest x-ray or chest CT 
X 
CT/MRI of primary site 
X 
X 
PET/CT 
X 
P 
Labs 
CBC, Diff, platelets 
X 
X 
X 
X 
Mg, Ca, Na, K, Phos 
X 
X 
X 
X 
Creatinine, BUN 
X 
X 
X 
X 
LFTs 
X 
Serum albumin 
Y 
Pregnancy test 
Z 
QOL assessments 
FACT-H&N 
X 
X 
X 
UW-Qol 
X 
X 
X 
Tissue/Blood, for 
research if patient 
consents 
X 
X 
X 
 
X) Required 
Y) Not required, but highly recommended 
Z) For women of childbearing potential, within 4 weeks prior to registration 
P) Required; Can be obtained 8-12 weeks after completion of chemoradiotherapy 
 
After 12 weeks from the completion of protocol treatment, all patients will return for follow-up at 6, 
9 and 12 months. For year 2, all patients will be seen every 3 months then every 6 months for 
years 3-5. Additional imaging after 12 weeks will be optional and may be performed at the 
discretion of the treating physician. 
 
12.2 Evaluation during and post-treatment 
12.2.1 Protocol-Specific Adverse Event Evaluation 
In an effort to improve the capture and consistency of adverse event (AE) reporting, essential 
adverse events commonly associated with head and neck treatment are to be assessed at 
baseline, during treatment, and at follow up using CTCAE version 4.0. Additional AE terms and 
grading criteria can be accessed online at http://ctep.cancer.gov/reporting/ctc.html 
 
12.3. Criteria for Evaluation and Endpoint Definitions 
12.3.1 Measurable Disease: Unidimensionally measurable, with clearly defined margins on 
photograph, x-ray or scan. At least one diameter must be > 1 cm. Bone lesions are not included. 

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12.3.2 Malignant Lymph Nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be > 15 mm in short axis when assessed by CT scan. At baseline and in 
follow-up, only the short axis will be measured and followed.. 
12.3.3 Objective Status to be Recorded at Each Evaluation: When more than one measurable 
lesion is present at baseline all lesions up to a maximum of five lesions total representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
basline. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition, should be those that lend 
themselves to reproducible repeated measurements. 
12.3.3.1 Complete Response (CR): Complete disappearance of all measurable disease and 
target lesions In the absence of any new lesions. 
12.3.3.2 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
12.3.3.3 Stable Disease: Neither sufficient shrinkage to quality for PR nor sufficient increase to 
quality for progression, taking as reference the smallest sum diameters while on study. 
12.3.3.4 Progression: At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesion is also considered 
progression). 
12.3.5 Determination of Response after Induction Chemotherapy 
Evaluation of response to induction chemotherapy will be performed via physical examination 
(including direct endoscopic evaluation). Repeat biopsies are not recommended. Palpation of 
the neck to determine response of lymphadenopathy is also required. In cases where the treating 
physician is uncertain whether clinical complete response has occurred, a CT scan may be used, 
but this not required. A patient will be considered to have complete response to induction 
chemotherapy if there is no visible or palpable tumor. 
12.3.5 Tumor Clearance after Completion of Protocol Treatment 
A patient will be considered to have complete response if there is no measurable or palpable 
tumor either on clinical or radiographic (CT scan or MRI) examination. The PET portion of a 
PET/CT scan is investigational and therefore should not be used in determining a patient’s 
response to treatment for purposes of evaluating efficacy endpoints, such as progression-free 
survival. If the CT portion of a PET/CT is done with contrast and a radiologist formally reviews 
and reports the findings on head and neck and thoracic regions, then there is no need to order 
additional diagnostic CT/MRI of the head and neck or chest x-rays or CT scan of the chest. The 
primary tumor and regional nodes will be evaluated and reported separately. 
12.3.6 Local or Regional Relapse 
Relapse is defined as reappearance of tumor after complete response. Relapse should be 
confirmed by biopsy. 
12.3.7 Local or Regional Progression 
Progression is defined as an estimated increase in the size of the tumor (product of the 
perpendicular diameters of the two largest dimensions) of greater than 20%, taking as reference 
the smallest value of all previous measurements or appearance of new areas of malignant 
disease. In addition to the relative increase of 20, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
12.3.8 Distant Metastasis 
Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where 
possible. A solitary, spiculated lung mass/nodule is considered a second primary neoplasm 
unless proven otherwise. 
12.3.9 Progression-free Survival 
This endpoint will be defined from date of registration to date of first documentation of 
progression and/or distant metastasis, or death due to any cause. Patients last known to be alive 
without report of progression will be censored at date of last contact. 

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12.3.10 Second Primary Neoplasm 
Tumor reappearing with the initial and immediate adjoining anatomical region of the primary will 
be considered local recurrence. Multiple lung nodules/masses are considered distant metastases 
from the index cancer unless proven otherwise. 
 
12.3.11 Discontinuation of Protocol Treatment 
Protocol treatment may be discontinued for any of the following reasons: 
• Progression of disease; 
• Unacceptable adverse events [at the discretion of the treating physician(s)]; 
• Patient refusal. 
If protocol treatment is discontinued, follow up and data collection will continue as specified. 
12.3.12 Discontinuation of Follow-Up Assessments 
Follow-up assessments may be discontinued for either of the following reasons: 
• Patient refusal; 
• Patient’s withdrawal of consent; Data for these patients will not be used for analysis. 
Otherwise, patients will be followed at least every 3 months during the first year after completion 
of protocol treatment; at least every 6 months during the second and third year after completion of 
protocol treatment; and yearly thereafter 
12.4 Quality of Life Assessments 
12.4.1 Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N) is a 
multidimensional, QOL instrument specifically designed and valid for use with HNSCC patients 
that the patient can complete in 5-10 minutes. The site research nurse or clinical research 
associate (CRA) is encouraged to be sensitive to each patient's demeanor. If patients appear 
particularly uncomfortable answering a question, they will be informed that they can skip that 
question. Similarly, interviewers will give patients a short break if the patient appears fatigued or 
otherwise in need of a few minutes break. 
12.4.2 The UWQol (UWQol) instrument is a questionnaire that the patient can complete in 
approximately 5 minutes. self-administered scale consisting of 15 questions assessing nine 
domains including pain, physical appearance, activity, recreation, employment, chewing, 
swallowing, speech, shoulder function, and overall QOL. The site research nurse or CRA should 
encourage the patient not to skip questions on the UWQol or take breaks during the completion of 
this questionnaire, as this will invalidate assessment. 
 
13.0 STATISTICAL CONSIDERATIONS 
This is a one-arm phase II trial designed to assess treatment efficacy in terms of 2-year 
progression free survival. A two-stage Simon design (Simon, 1989) was adopted, which will 
permit early stopping of the trial if there is strong evidence that the study regimen is inactive or is 
effective enough to warrant further investigation in a phase III trial. 
13.1 Primary Endpoint 
The primary endpoint of the study is 2-year progression-free survival, and failure is defined as 
disease progression or death. The primary objective of the study is to determine the treatment 
efficacy evaluated using the 2-year progression-free survival rate. The 2-year progression-free 
survival rate is the proportion of efficacy-evaluable patients progression-free 2 years from 
registration. This will be defined based on the total number of efficacy-evaluable patients on study 
without documentation of disease progression from registration divided by the total number of 
efficacy-evaluable patients enrolled. All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for 2-year progression-free survival. 
 
13.2 Patient Accrual and Study Duration 
We plan to enroll 50 patients into the study. Based on accrual history in this disease, we anticipate 
accruing approximately 20 eligible patients per year (about 2 patients per month). We will follow 
up all patients closely and do not expect any patients to drop out of the trial except for death, so 
censoring due to other reasons would be unlikely. We expect to complete the accrual in 
2.5 years and will follow up the last enrolled patient for additional 2 years to allow all patients to 
become evaluable for the primary endpoint. We expect to carry out the interim analysis 
approximately at 3 years when the initial stage of accrual is met and these patients become 

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evaluable for the primary endpoint. Since the proposed dose de-intensified regimen is expected 
to have relatively low toxicity, we will not stop enrolling patients during this period unless high 
incidence of adverse events occurs. The final analysis will start toward the end of year 5. 
 
 
13.3 Primary Objective and Study Design 
13.3.1 Study Design 
The primary objective of the study is to determine the treatment efficacy evaluated using the 2- 
year progression-free survival rate and to decide whether induction chemotherapy followed by 
dose de-intensified chemoradiotherapy is worth further investigation in a phase III trial. A two- 
stage Simon design (Simon 1989) was adopted to study the 2-year progression-free survival rate 
in patients with HPV-positive HNSCC who receive this regimen. We will consider a 2-year 
progression-free survival rate of 72% or lower as ineffective for the proposed dose de-intensified 
therapy in this population, and a 2-year progression-free survival rate of 86% or higher would 
warrant further subsequent studies. The following two-stage Simon design (Simon 1989) was 
employed using 50 patients to test the null hypothesis that the true 2-year progression-free 
survival rate is at most 72%. 
 
Stage 1: Consider the first 25 enrolled patients in the study. If 19 or fewer of the first 25 evaluable 
patients enrolled are progression-free at 2 years, then the study will be terminated and the 
regimen would be considered inactive in this patient population. If 22 or more of the first 25 
evaluable patients enrolled are progression-free at 2 years, then the trial will be stopped and 
accept the alternative hypothesis that the true 2-year progression-free survival rate is 86% or 
higher. Otherwise, the trial would continue to the second stage. 
 
Stage 2: Consider the additional 25 patients in the study. If 40 or fewer of the first 50 evaluable 
patients enrolled are progression-free at 2 years, then we accept that the dose de-intensified 
therapy is ineffective in this population and not worth further investigation. If 41 or more patients 
are progression-free at 2 years, then we will further study the regimen in a phase III trial. 
 
13.3.2 Power Consideration 
With 50 patients, given the true 2-year progression-free survival rate is 72%, the probability of 
ending the trial during stage 1 is 79.3%; given the true 2-year progression-free survival rate is 
86%, the probability of ending the trial in Stage 1 is 66%. The overall significance level is about 
9% and the power is 81%. Assuming the significance level is at most 10%, if the true 2-year 
progression-free survival rates are78%, 81%, 85% and 87%, the probabilities of declaring that 
this regimen warrants further studies (i.e. statistical power) are 32%, 52%, 78%, 0.61, and 0.89, 
respectively. 
 
 
13.3.3 Other Considerations 
Adverse events, duration of response, overall survival, and the pace of accrual as well as other 
scientific discoveries or changes in standard of care will be taken into account in any decision to 
terminate this study earlier than designed. 
 
13.4 Analysis Plan 
13.4.1 Primary Endpoint 
All patients meeting the eligibility criteria who have signed a consent form and begun treatment 
will be considered evaluable for estimation of the 2-year progression-free survival rate. Those 
who die within 2 years will be considered to have had disease progression unless documented 
evidence clearly indicates no progression has occurred. In the event that such evidence is 
obtained, or in the case of major treatment violation, the patients’ response data will be 
considered censored at the date the patient is withdrawn from treatment. However, based on our 
previous experience, we expect such cases are unlikely and we will be able to evaluate all 
patients for their 2-year progression-free survival. The true 2-year progression-free survival rate 
will be estimated by the proportion of efficacy-evaluable patients on study without documentation 

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of disease progression or death 2 years from registration. A 95% confidence interval (CI) for the 
true progression-free survival rate will be constructed using the Duffy-Santner approach (Duffy 
1987). However, Kaplan-Meier methodology (Kaplan 1958) will be used to estimate the final 2- 
year progression-free survival rate and its 95% CI in case there are censored patients. 
 
13.4.2 Secondary Endpoints 
• 
Overall survival 
• 
Local-regional control 
• 
Mucosal and esophageal toxicity (Rates of ≥ grade 3, clinical exam) 
• 
Other toxicity (Rates of ≥ grade 3) 
• 
Protocol treatment delivery 
• 
Death during or within 30 days of discontinuation of protocol treatment 
• 
Quality of life as assessed by FACT-H&N and UWQol 
 
Overall survival will be defined as the time from registration to death. Time to event distributions 
will be estimated using the Kaplan-Meier method (Kaplan 1958). The 2-year rates of local- 
regional control will be calculated along with 95% CI for HPV-positive patients receiving the dose 
de-intensified therapy. We will also compare it with the rate from historical controls (93%, Rischin 
2010) using a one-sided Z-test. Rates and 95% CIs of grade 3+ mucosal and esophageal toxicity, 
late toxicity, other toxicities, protocol treatment delivery (PTD) and death during or within 30 days 
of discontinuation of protocol treatment will be calculated for the patients receiving the dose de- 
intensified therapy. Measures of quality of life as assessed by FACT-H&N and UWQol will be 
obtained. Continuous variables will be summarized using the mean (s.d.) or median (range). 
Frequency tables will be used to summarize categorical variables. The distribution of time-to- 
event endpoints will be estimated using the method of Kaplan and Meier (Kaplan 1958). 
 
We will also obtain descriptive statistics for quality of life measurements, using mean and 
standard deviation for continuous measures and frequency tables for categorical measures. 
 
13.4.3 Over Accrual 
If more than the target number of patients are accrued, the additional patients will not be used to 
evaluate the stopping rule or used in any decision making process; however, they will be included 
in final point estimates and confidence intervals as they were accrued in the final stage. 
 
13.4.4 Monitoring 
The principal investigator and the study statistician will review the study periodically (at least 
semi-annually) to identify accrual, adverse events, and any endpoint problems that might be 
developing. This study will also be monitored by the UC Davis Data and Safety Monitoring Board 
(DSMB) at least annually, or more frequently as warranted. 
 
This protocol is also subject to the UC Davis Cancer Center’s (UCDCC) Data and Safety 
Monitoring Plan. The UCDCC is committed to pursuing high-quality patient-oriented clinical 
research and has established mechanisms to ensure both scientific rigor and patient safety in the 
conduct of clinical research studies. The UCDCC relies on a multi-tiered committee system that 
reviews and monitors all cancer clinical trials and ensures the safety of its participants, in 
compliance with institutional and federal requirements on adverse event (AE) reporting, 
verification of data accuracy, and adherence to protocol eligibility requirements, treatment 
guidelines, and related matters. The Scientific Review Committee (SRC) assumes overall 
oversight of cancer studies, with assistance and input from two independent, but interacting, 
committees: the Quality Assurance Committee and the Data and Safety Monitoring Committee. A 
multi-level review system strengthens the ability of the UCDCC to fulfill its mission in conducting 
high quality clinical cancer research. 
 
As per University of California Davis Cancer Center (UCDCC) Clinical Trials Support Unit (CTSU) 
SOP AM 506: Protocol Specific Meetings, the principal investigator (PI), clinical research 
coordinator, and the clinical research nurse meet at least monthly for ongoing study information, 

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to discuss patient data and adverse events and to determine if dose escalation is warranted, 
when applicable. 
 
According to the UCDCC Data and Safety Monitoring Plan, any new serious adverse events 
related to the drugs being used on this trial are reviewed monthly by the UCDCC Data and Safety 
Monitoring Committee and any applicable changes to the study are recommended to the PI, if 
necessary. 
 
The UCDCC SRC determines if a UCDCC Data and Safety Monitoring Board (DSMB) is required. 
If required, the Data and Safety Monitoring Committee will appoint a DSMB. The DSMB is 
responsible for reviewing study accrual logs, adverse event information and dose escalation 
meeting minutes (where applicable) to ensure subject safety and compliance with protocol 
defined guidelines. 
 
 
13.4.5 Adverse Events Stopping Rule 
If 20 or more of the first 25 patients (80% of all patients after 25 are accrued) experience grade 
3+ toxicity for esophageal toxicity or mucosal toxicity that are probably, possibly, or definitely 
related to study treatment, accrual to the study will be suspended to allow for investigation. After 
consideration by the study team and the primary data safety monitoring board, a decision will be 
made as to whether accrual can be resumed. In addition, all adverse event patterns will be 
monitored by an independent UC Davis DSMB on a limited review basis. 
 
 
14.0 
Data Review and Management 
 
14.1 
Patient Registration 
 
Once signed, informed consent has been obtained and all pretreatment evaluations have been 
performed, patients will be entered on study according to UCD Clinical Trials Support Unit 
(CTSU) policy. To register a patient, the research nurse or data manager must complete the 
Eligibility Checklist and the Patient Registration Form. A patient accession number will then be 
assigned. Study therapy may not be initiated until the patient is registered. In accordance with 
UCD CTSU policy an original signed and dated participant Informed Consent document will 
reside in a secured location within the UCD Radiation Oncology Department. Copies of the 
signed and dated Informed Consent document will be provided to the study participant and UCD 
Health System Information Management for inclusion in the participant’s UCD Health System 
Medical Record. 
 
14.2 
Data Collection 
 
All data will be collected using the UCD Database System (eVELOS) forms. All data forms will be 
completed, submitted and processed in accordance with UCD CTSU policies. See Appendix VI. 

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number. J Clin Oncol 2008; 26: 3138-3146. 

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APPENDIX I 
 
 
 
ZUBROD PERFORMANCE SCALE 
 
0 Fully active, able to carry on all pre-disease activities without restriction 
(Karnofsky 90-100). 
 
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 (Karnofsky 70-80). 
 
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 (Karnofsky 50- 
60). 
 
3 Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours (Karnofsky 30-40). 
 
4 Completely disabled. Cannot carry on self-care. Totally confined to bed or 
(Karnofsky 10-20). 
 
5 Death (Karnofsky 0). 

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APPENDIX II 
AJCC STAGING SYSTEM, 6th Edition 
HEAD & NECK 
 
 
 
STAGING-PRIMARY TUMOR (T) 
TX: Primary tumor cannot be assessed 
T0: No evidence of primary tumor 
Tis: Carcinoma in situ 
 
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. 
 
Hypopharynx 
T1: Tumor limited to one subsite of hypopharynx and 2 cm or less in greatest dimension. 
T2: Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures more 
than 2 cm but not more than 4 cm in greatest diameter without fixation of hemilarynx. 
T3: Tumor measures more than 4 cm in greatest dimension or with fixation of hemilarynx. 
T4a: Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus or central 
compartment soft tissue. 
T4b: Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal 
structures. 
 
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. 

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APPENDIX II (Continued) 
AJCC STAGING SYSTEM, 6th Edition 
HEAD & NECK 
 
 
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. 
 
REGIONAL LYMPH NODES (N) Excluding Nasopharynx 
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 greatest dimension. 
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. 
 
DISTANT METASTASIS (M) 
MX: Distant metastasis cannot be assessed 
M0: No distant metastasis 
M1: Distant metastasis 

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APPENDIX II (Continued) 
AJCC STAGING SYSTEM, 6th Edition 
HEAD & NECK 
 
 
 
 
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 

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APPENDIX III 
 
 
MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS 
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. 
 
Group 1 
Includes edentulous patients. They may require surgical removal of any symptomatic cysts, 
infected retained root tips, or alveolar hyperplasia. These patients require hygiene instruction and 
precautionary instruction about 
trauma with premature use of a prosthesis. 
 
Group 2 
Includes those with poor dental hygiene, including those patients whose teeth are beyond repair 
by ordinary dental procedure, those with generalized oral sepsis, those with generalized 
periodontal disease, and those with chronic periapical abscesses or granulomas. 
 
Procedures performed on this group include removal of all remaining teeth prior to irradiation with 
primary closure and surgical preparation of the alveolar ridges to laterally support a prosthesis. 
There should be antibiotic coverage during the healing stage and adequate time prior to the start 
of radiation therapy. These patients need complete hygiene instruction and precautionary 
instruction about premature use of a prosthesis. 
 
Group 3 
Includes those in whom dental condition is fair, including those patients whose teeth are restored, 
ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions are not 
in proximity to the pulp, and no more than 20 restorable carious lesions are present. X-ray 
examinations show at least 1/2 of the bone still present around root surfaces. These patients 
require removal of any teeth that are 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. 
 
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. 
 
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. 
 
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 

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

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APPENDIX IV 
University of Washington Quality of Life Questionnaire 
Version 4 
 
This questionnaire asks about your health and quality of life over the past seven days. 
Please answer all of the questions by ticking one box for each question. 
1.   Pain. (Tick one box:  ) 
I have no pain. 
There is mild pain not needing medication. 
I have moderate pain - requires regular medication (e.g. paracetamol). 
I have severe pain controlled only by prescription medicine (e.g. morphine) 
I have severe pain, not controlled by medication. 
 
2.   Appearance. (Tick one box:  ) 
 
There is no change in my appearance. 
The change in my appearance is minor. 
My appearance bothers me but I remain active. 
I feel significantly disfigured and limit my activities due to my appearance. 
I cannot be with people due to my appearance. 
 
3.   Activity. (Tick one box:  ) 
 
I am as active as I have ever been. 
There are times when I can't keep up my old pace, but not often. 
I am often tired and have slowed down my activities although I still get out. 
I don't go out because I don't have the strength. 
I am usually in bed or chair and don't leave home. 
 
4.   Recreation. (Tick one box:  ) 
 
There are no limitations to recreation at home or away from home. 
There are a few things I can't do but I still get out and enjoy life. 
There are many times when I wish I could get out more, but I'm not up to it. 
There are severe limitations to what I can do, mostly I stay at home and watch TV. 
I can't do anything enjoyable. 
 
5.   Swallowing. (Tick one box:  ) 
 
I can swallow as well as ever. 
I cannot swallow certain solid foods. 
I can only swallow liquid food. 
I cannot swallow because it "goes down the wrong way" and chokes me. 
 
6.   Chewing. (Tick one box:  ) 
 
I can chew as well as ever. 
I can eat soft solids but cannot chew some foods. 
I cannot even chew soft solids. 

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7. Speech. (Tick one box:  ) 
 
My speech is the same as always. 
I have difficulty saying some words but I can be understood over the phone. 
Only my family and friends can understand me. 
I cannot be understood. 
 
8.   Shoulder. (Tick one box:  ) 
 
I have no problem with my shoulder. 
My shoulder is stiff but it has not affected my activity or strength. 
Pain or weakness in my shoulder has caused me to change my work / hobbies. 
I cannot work or do my hobbies due to problems with my shoulder. 
 
9.   Taste. (Tick one box:  ) 
 
I can taste food normally. 
I can taste most foods normally. 
I can taste some foods. 
I cannot taste any foods. 
 
10. Saliva. (Tick one box:  ) 
 
My saliva is of normal consistency. 
I have less saliva than normal, but it is enough. 
I have too little saliva. 
I have no saliva. 
 
11. Mood. (Tick one box:  ) 
 
My mood is excellent and unaffected by my cancer. 
My mood is generally good and only occasionally affected by my cancer. 
I am neither in a good mood nor depressed about my cancer. 
I am somewhat depressed about my cancer. 
I am extremely depressed about my cancer. 
 
12. Anxiety. (Tick one box:  ) 
 
I am not anxious about my cancer. 
I am a little anxious about my cancer. 
I am anxious about my cancer. 
I am very anxious about my cancer. 
 
 
Which issues have been the most important to you during the past 7 days? 
Tick  up to 3 boxes. 
 
Pain 
Swallowing 
Taste 
Appearance 
Chewing 
Saliva 
Activity 
Speech 
Mood 
Recreation 
Shoulder 
Anxiety 

Page 53 of 57 
CCRO022 
Version Date: 07/12/12 
 
 
 
 
 
 
GENERAL QUESTIONS 
 
Compared to the month before you developed cancer, how would you rate your health- 
related quality of life? (Tick one box:  ) 
 
Much better 
Somewhat better 
About the same 
Somewhat worse 
Much worse 
 
In general, would you say your health-related quality of life during the past 7 days has 
been: (Tick one box:  ) 
 
Outstanding 
Very good 
Good 
Fair 
Poor 
Very poor 
 
Overall quality of life includes not only physical and mental health, but also many other 
factors, such as family, friends, spirituality, or personal leisure activities that are important to 
your enjoyment of life. Considering everything in your life that contributes to your personal 
well-being, rate your overall quality of life  during the past 7 days. (Tick one box:  ) 
 
Outstanding 
Very good 
Good 
Fair 
Poor 
Very poor 
 
 
Please describe any other issues (medical or nonmedical) that are important to your quality of 
life and have not been adequately addressed by our questions (you may attach additional 
sheets if needed). 

Page 54 of 57 
CCR0022 
Version Date: 07/12/12 
 
 
D
 
 
 
APPENDIX V 
 
 
 
 
FACT-H&N (Version 4) 
 
 
Below is a list of sta tements that other people with your illness have said are impmtant. Please circle 
or mark  one number per line to indicate your  response as it applies  to the  past 7 davs. 
 
 
 
  
PHYSICAL WELL-BEING  
 
ot 
A littl  
Som- 
Quit 
Vry 
at all  
bit 
wha t 
a bit 
much 
 
 
GPl 
I have a Jack of energy ....................................................... 
0 
2 
3 
4 
 
GP2 
I have nausea ...................................................................... 
0 
2 
3 
4 
 
GPl  
Because of my physical condition, I have trouble 
meeting the needs of my family ................ 
0 
2 
3 
4 
 
GP4 
I have pain .......................................................................... 
0 
2 
3 
4 
 
GP5 
I am bothered by side effects of treannent ......................... 
0 
2 
3 
4 
 
GP6 
I feel ill ............................................................................... 
0 
2 
3 
4 
 
GP7 
I am forced to spend time in bed .................... ................... 
0 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
i\"ot 
A littl  
Som- 
Quit 
vry 
at all  
bit 
what  
a bit 
much 
 
 
GSl 
I feel close to my friends.................................................... 
0 
2 
3 
4 
 
GS2 
I get emotional support from my family ............................ 
0 
2 
3 
4 
 
GSl 
I get support from my friends............................................. 
0 
2 
3 
4 
 
GS4 
My family has accepted my illness .................................... 0 
2 
3 
4 
 
GSl  
I am satisfied with family con11nunication about my 
illness.................................................................................. 
0 
2 
3 
4 
 
GS6 
I feel close to my partner (or the person who is my main 
support) .............................................................   ................. 0 
2 
3 
4 
 
QJ 
 Regardless ofyour current ll!l·el of sexual acfil·iv, please 
ai/Sll'er tile following question. ifyou prefer nor to ai1S1J"er it, 
please mark rliis box 
and go ro the nexi seciion. 
 
GS7 
I am satisfied with my sex life ............................................ 
0 
2 
3 
4 
 
 
 
 
b ,lb (UWo,.rnl) 
Copyn;ht  1987, r m 
16 NO\·tmbtr 2007 
Pa;e lo£ 3 

CCR0022 
Version Date: 07/12/12 
 
 
Not 
A little Some- 
a t all 
bit 
what 
J
J
 
 
 
 
 
FACT-H&N (Version 4) 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
EMOTIONAL WELL-BEING 
 Not 
A little   Some-    Quite 
 Very 
at all  bit 
what 
a bit 
much 
 
 
GEl 
I feel sad .............................................................................. 
0 
2 
.., 
4 
 
GEl 
I am satisfied with how I am coping with my illness..........  
0 
2 
3 
4 
 
GEl 
I am losing hope in the fight against my illness.................. 
0 
2 
3 
4 
 
GE4 
I feel ne1vous....................................................................... 
0 
2 
3 
4 
 
GEl 
I wony about dying............................................................. 0 
2 
.., 
4 
 
GE6 
I wony that my condition will get worse............................ 
0 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
Quite 
 Very 
a bit 
much 
 
 
GFI 
I am able to work (include work at home) .......................... 
0 
2 
3 
4 
GFJ 
My work (include work at home) is fulfilling..................... 
0 
2 
3 
4 
Gfl 
I am able to enjoy life.......................................................... 
0 
2 
.., 
J 
4 
Gf4 
I have accepted my illness................................................... 
0 
2 
3 
4 
Gfl 
I am sleeping well ............................................................... 
0 
2 
3 
4 
Gf6 
I am enjoying the things I usually do for ftm ...................... 
0 
2 
.., 
J 
4 
GF1 
I am content with the quality of my life right now.............. 
0 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EnIU:h (UWnrsal) 
Cop)right 1987,1997 
16 Nonmbtr 2007 
POl&t 2oC3 

CCR0022 
Version Date: 07/12/12 
 
 
Not at A little Some- Quite Very 
all 
bit 
what 
a bit 
much 
 
 
 
 
FACT-H&N (Version 4) 
 
 
Please circle or mark one number per line to indicate your response as it applies to the nast 7 
days. 
 
 
ADDITIONAL CONCERNS 
 
 
 
H&NI 
I am able to eat the foods tha t I like.................................... 
0 
2 
.)  
4 
 
H&N2 
My mouth is d1y .................................................................. 
0 
2 
.)  
4 
 
H&NJ 
I have trouble breathing ...................................................... 0 
2 
.)  
4 
 
H&N4 
My voice has its usual quality and strength ........................ 0 
2 
3 
4 
 
H&Nl 
I am able to eat as much food as I want .............................. 
0 
2 
3 
4 
 
H&N6 
I am unhappy with how my face and neck look..................  
0 
2 
3 
4 
 
H&N7 
I can swallow naturally and easily ...................................... 
0 
2 
3 
4 
 
H&NS 
I smoke cigarettes or other tobacco products......................  
0 
2 
.)  
4 
 
H&N9 
I drink alcohol (e.g. beer, wine, etc.)................................... 0 
2 
.)  
4 
 
H&N 
I am able to communicate with others ................................ 
0 
2 
10 
.)  
4 
 
H&N 
I can eat solid foods.............................................................  
0 
2 
II 
.)  
4 
 
H&N 
I have pain in my mouth, throat or neck ............................. 
0 
2 
3 
4 
12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
!nJ;IBh(UniYtr.;ll.} 
Cop,.;,t>t 1987, 1997 
16Nonmbtr2007 
Pat 3of3 

CCRO022 
Version Date: 02.25.14 
 
 
 
APPENDIX VI Data Submission Schedule 
 
 
 
 SUBMIT WITHIN 24 HOURS OF REGISTRATION: 
Patient Registration Form 
 
 SUBMIT WITHIN 14 DAYS OF REGISTRATION: 
In‐House Pre‐Study Evaluation Form (IH‐102) 
 
 SUBMIT WITHIN 7 DAYS OF SCREENING FAILURE: 
Patient Screen Failure Form 
 
 SUBMIT WITH 14 DAYS OF CYCLE COMPLETION: 
Adverse Event-Drug Relationship Form 
 
 SUBMIT WITHIN 14 DAYS OF END OF EACH TREATMENT CYCLE: 
In‐House Treatment Cycle Form (IH‐201) 
 
 SUBMIT WITHIN 14 DAYS OF EACH RESPONSE ASSESSMENT: 
Tumor Measurement Log 
 
 SUBMIT WITHIN 14 DAYS OF OFF TREATMENT: 
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301) 
 
 SUBMIT WITHIN 14 DAYS OF KNOWLEDGE OF DEATH IF PATIENT IS STILL ON 
STUDY OR 30–DAYS IF OFF STUDY: 
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301) 
 
 SUBMIT WITHIN 2 DAYS OF KNOWLEDGE OF PROTOCOL DEVIATION: 
Clinical Trials Support Unit: Notice of Protocol Deviation 
 
 SUBMIT WITHIN 14 DAYS OF EACH REQUIRED FOLLOW‐UP ENCOUNTER: 
Follow‐Up Form (IH‐302) 
 
 ALL SERIOUS ADVERSE EVENTS MUST BE REPORTED AS OUTLINED IN THE 
PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 57 of 57 

CCRO022:  Paclitaxel + Carboplatin                                                Consent                                                                                              Page 1 of 13 
Head & Neck Cancer 
 
CCRO022_Consent_02.25.14_unmarked 
Protocol Version Date:  02.25.14 
 
 
 
 
 
 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
Medical Research Studies 
 
The rights below are the rights of every person who is asked to be in a medical research study.  As an 
experimental subject, you have the following rights: 
 
1) To be told what the study is trying to determine. 
 
2) To be told what will happen to you and whether any of the procedures, drugs, or devices is different from 
what would be used in standard practice. 
 
3) To be told about the frequent and/or important risks, side effects, or discomforts of the things that will 
happen to you for research purposes. 
 
4) To be told if you can expect any benefit from participating and, if so, what the benefit might be. 
 
5) To be told the other choices you have and how they may be better or worse than being in the study. 
 
6) To be allowed to ask any questions concerning the study, both before agreeing to be involved and during 
the course of the study. 
 
7) To be told what sort of medical treatment is available if any complications arise. 
 
8) To refuse to participate or to change your mind about participating after the study is started. This decision 
will not affect your right to receive the care you would receive if you were not in the study. 
 
9) To receive a copy of the signed and dated consent form. 
 
10) To be free of pressure when considering whether you wish to agree to be in the study. 
 
If you have other questions, please ask the researcher or research assistant.  In addition, you may contact the 
Institutional Review Board, which is concerned with protecting volunteers in research projects.  You may reach 
the IRB office by calling (916) 703-9151, from 8:00 a.m. to 5:00 p.m., Monday through Friday, or by writing to 
the Institutional Review Board, CTSC Bldg., Suite 1400, Rm. 1429, 2921 Stockton Blvd., Sacramento, 
California 95817. 
 
 
 
 
           Signature of Subject or                                             Date 
           Legal Representative  
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
359512
03-07-2014

CCRO022:  Paclitaxel + Carboplatin                                                    Consent                                                                                        Page 2 of 13 
Head & Neck Cancer 
 
 
 
 
 
Initials of Participant 
 
CCRO022_Consent_02.25.14_unmarked 
Protocol Version Date:  02.25.14 
 
 
                                      
UNIVERSITY OF CALIFORNIA, DAVIS 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
 
Principal Investigator:     
Megan Daly  (Radiation Oncology) 
Co-Principal Investigator:   
Karen Kelly, MD (Hematology Oncology) 
 
STUDY TITLE:  CCRO022: Phase II Trial Of Induction Chemotherapy Followed By Attenuated Chemoradiotherapy For 
Locally Advanced Head And Neck Squamous Cell Carcinoma Associated With Human Papillomavirus (HPV) [Protocol 
version: 02.25.14] 
 
INTRODUCTION 
 
This is a research study.  Research studies only include subjects who choose to participate.  Your study doctor will 
explain the clinical trial to you.  As a study participant you have the right to know about the procedures that will be used in 
this research study so that you can make the decision whether or not to participate.  The information presented here is to 
make you better informed so that you may give or withhold your consent to participate in this research study.  Please take 
your time to make your decision and discuss it with your family, friends, or with your personal physician.  If you have any 
questions, you can ask your study doctor for more explanation.   
 
You are being asked to take part in this study because you have advanced head and neck cancer. We hope to learn more 
about a less aggressive regimen of radiation therapy for your type of cancer.  You must be 18 years of age or older.  In 
order to participate in this study, it will be necessary to give your written consent.  
 
WHY IS THIS STUDY BEING DONE? 
 
The purpose of this study is to determine whether your human papillomavirus (HPV)-positive head and neck cancer can 
be treated with a less aggressive regimen of radiation therapy and chemotherapy (paclitaxel) after initially receiving two 
cycles of chemotherapy (carboplatin/paclitaxel). If you agree to enroll on this study, you will be receiving a lower dose 
radiation therapy in the chemoradiotherapy phase of treatment than is typically used for head and neck cancer. The 
purpose of this study is to see if using this less aggressive regimen improves the tolerability of treatment and results in 
cure rates as high as standard treatment. 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
We plan to enroll up to 50 people at UC Davis Cancer Center. 
 
BEFORE YOU BEGIN THE STUDY 
 
If you choose to take part in this study and sign this informed consent form, you will complete “pre-study screening tests” 
to determine if you meet the study requirements.  Some of these exams, tests or procedures are part of regular cancer 
care and may be done even if you do not join the study.   The pre-study screening tests are listed below and on the next 
page. 
 
Pre-study Screening Tests: 
• 
Physical examination by several doctors (including a radiation oncologist and a medical oncologist (a 
chemotherapy doctor)) 
• 
Evaluation of your weight and ability to carry out daily activities 
• 
Chest x-ray or CT (Computed Tomography) scan of your chest. A CT scan uses special x-ray equipment to make 
detailed pictures of body tissues and organs. 
• 
CT scan or an MRI (Magnetic Resonance Imaging) of your head and neck. MRI uses a strong magnetic field to 
look at one part of your body) 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
359512
03-07-2014

CCRO022:  Paclitaxel + Carboplatin                                                    Consent                                                                                        Page 3 of 13 
Head & Neck Cancer 
 
 
 
 
 
Initials of Participant 
 
CCRO022_Consent_02.25.14_unmarked 
Protocol Version Date:  02.25.14 
 
 
                                      
 
BEFORE YOU BEGIN THE STUDY (continued) 
Pre-study Screening Tests: (continued) 
• 
Combination of PET (Positron Emission Tomography)/CT scan of your body. A PET scan is a computerized 
image that looks at the activity of tumor cells in your entire body and that requires injection of a special marker 
into your vein, such as sugar (glucose) combined with a low-dose radioactive substance (a tracer). A camera 
records the tracer’s signal as it travels through your body. 
• 
Routine blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
• 
Quality of Life questionnaire 
• 
For women able to have children, a pregnancy blood test (about 1-2 teaspoons of blood will be required)  
• 
If your study doctor recommends: 
o 
Dental evaluation before receiving radiation 
o 
Hearing test 
o 
Evaluation of your diet and ability to chew and swallow to see if a feeding tube is needed 
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? 
 
If you decide to participate in this study, you will receive 2 cycles of chemotherapy (paclitaxel and carboplatin) given three 
weeks apart. Before each dose of chemotherapy, you will be given some medicine through your vein to prevent an allergic 
reaction. Then you will be given chemotherapy through your vein for approximately two hours. You will not receive 
radiation therapy on the day you receive the initial chemotherapy.  
 
Your blood pressure and overall physical condition will be closely monitored while you receive chemotherapy and for at 
least one hour afterwards. If you have a severe allergic reaction to the initial chemotherapy or any later doses, the study 
doctor will treat you for the reaction, and you may not receive further chemotherapy on this study. You and the study 
doctor can discuss other treatments that you can receive off study.  
 
If you tolerate the initial dose of chemotherapy well, approximately two weeks later, you will begin receiving radiation 
therapy combined with chemotherapy. All patients will receive daily radiation therapy, Monday through Friday. Each 
radiation treatment will take about 20 minutes. Your study doctor will discuss with you how exactly your radiation therapy 
will be given. After completing the initial chemotherapy and prior to the beginning of radiation therapy, a physical 
examination (including endoscopy which is an examination of the throat and voice box with a mirror and/or flexible lighted 
tube inserted through your mouth) will be performed.  This information will be used to determine how long you will receive 
radiation therapy. 
 
• 
If the tumor was felt to have shrunk significantly after initial chemotherapy, you will receive radiation therapy once 
a day, Monday through Friday, for about 5 weeks. 
• 
If the tumor response was felt to be less significant after initial chemotherapy, you will receive radiation therapy 
once a day, Monday through Friday, for about 6 weeks. 
 
All patients also will receive chemotherapy (paclitaxel), through the vein, weekly during treatment. This will take 60 
minutes. Some patients may stay overnight in the hospital after each chemotherapy treatment to receive medicines to 
replace body fluids.  
 
* Another way to find out what will happen to you during the study is to read the chart on the next page. Start reading at 
the top and read down the list, following the arrows. 
 
 
 
 
 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
359512
03-07-2014

CCRO022:  Paclitaxel + Carboplatin                                                    Consent                                                                                        Page 4 of 13 
Head & Neck Cancer 
 
 
 
 
 
Initials of Participant 
 
CCRO022_Consent_02.25.14_unmarked 
Protocol Version Date:  02.25.14 
 
 
                                      
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? (continued) 
 
 
                                                       
 
 
 
 
 
 
 
 
 
 
               Tumor did not shrink significantly                                                 Tumor shrunk 
 
 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
 
 
 
 
Evaluation of Treatment: 
Eight to twelve weeks after completion of all treatment, patients will have a CT scan or MRI of the head and neck and an 
additional PET/CT to evaluate the effect of treatment on their cancer.  
 
Tests and Procedures: 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need the 
following tests and procedures during the study. They are part of regular cancer care. 
• 
Physical examination by your several doctors 
• 
Evaluation of your weight and ability to carry out daily activities 
• 
Blood tests after each cycle of initial chemotherapy and then every week during radiation therapy about 2-3 
teaspoons of blood will be taken from your vein 
• 
Evaluation of any side effects you may be having 
 
WHEN I AM FINISHED WITH THE TREATMENT 
 
You will need the following tests and procedures. These are done to see how you and your cancer was affected by the 
treatment you received.  
 
At 4 weeks after treatment: 
• 
Physical examination 
• 
Evaluation of your weight and ability to carry out daily activities 
• 
Blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
• 
Evaluation of any side effects you may be having 
• 
Completion of 2 quality of life questionnaires (requiring about 5-10 minutes to fill out) 
 
 
 
 
 
Initial Chemotherapy (No radiation therapy) 
(Paclitaxel + Carboplatin) 
 
Radiation Therapy 
Once a day (Monday through Friday) for  
about 6 weeks 
 
+ 
 
Paclitaxel  
Radiation Therapy 
Once a day (Monday through Friday) for  
about 5 weeks 
 
+ 
 
Paclitaxel  
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
359512
03-07-2014

CCRO022:  Paclitaxel + Carboplatin                                                    Consent                                                                                        Page 5 of 13 
Head & Neck Cancer 
 
 
 
 
 
Initials of Participant 
 
CCRO022_Consent_02.25.14_unmarked 
Protocol Version Date:  02.25.14 
 
 
                                      
WHEN I AM FINISHED WITH THE TREATMENT (continued) 
 
At 8-12 weeks after treatment: 
• 
Physical examination 
• 
CT scan or MRI of the head and neck 
• 
PET/CT scan of the body 
• 
Completion of 2 quality of life questionnaires (requiring about 5-10 minutes to fill out) 
 
At 6, 9, and 12 months from the start of treatment: 
• 
Physical examination 
• 
Evaluation of your weight and your ability to carry out your daily activities 
• 
Evaluation of any side effects you may be having 
• 
Blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
 
Every 3 months for year 2, every 6 months for years 3-5: 
• 
Physical examination 
• 
Blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
 
HOW LONG WILL I BE IN THE STUDY? 
 
You will be asked to participate for as long as your cancer is not growing and you are not having any unmanageable side 
effects. After you are finished with treatment, the study doctor will ask you to visit the office for routine follow-up exams, 
beginning 4 weeks after completion of treatment and then at 8-12 weeks after completion of treatment. As part of long-
term follow-up, you will be seen at 6, 9, and 12 months from the start of treatment. For year 2, you will be seen every 3 
months then every 6 months for years 3-5.  
 
CAN I STOP BEING IN THE STUDY? 
 
Yes.  You can decide to stop at any time.  Tell your study doctor if you are thinking about stopping or decide to stop.  Your 
doctor will tell you how to stop safely.  It is important to tell the study doctor if you are thinking about stopping so any risks 
from the treatment can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you.   
 
Your study doctor may stop you from taking part in this study at any time if he or she believes it is in your best interest; if 
you do not follow the study rules; or if the study is stopped. 
 
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? 
 
You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side 
effects. However, researchers don’t know all the side effects that may happen. Side effects may be mild or very serious. 
Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop 
radiation and chemotherapy, if you receive chemotherapy. In some cases, side effects can be serious, long lasting, or 
may never go away. As in any treatment with side effects, there also is a risk of death.  You should talk to your study 
doctor about any side effects that you have while taking part in the study. 
 
Combining chemotherapy with radiation to the head and neck can increase the effectiveness of radiation therapy on your 
cancer, but also can increase the side effects of radiation on normal tissue in treatment area. In addition, receiving a 
combination of chemotherapy with radiation can result in the side effects described below being more likely or more 
severe. 
 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
359512
03-07-2014

CCRO022:  Paclitaxel + Carboplatin                                                    Consent                                                                                        Page 6 of 13 
Head & Neck Cancer 
 
 
 
 
 
Initials of Participant 
 
CCRO022_Consent_02.25.14_unmarked 
Protocol Version Date:  02.25.14 
 
 
                                      
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
Risks Associated with Radiation to the Head and Neck: 
Likely: 
• 
Sores in the mouth and/or throat which can make it difficult to chew and or swallow foods 
• 
Mouth dryness or changes in taste and/or smell that may be permanent 
• 
Thick saliva 
• 
Hoarseness 
• 
Tanning or redness of the skin in the head and neck area being treated with radiation 
• 
Ear pain and/or pressure 
• 
Fatigue 
• 
Weight loss 
• 
Permanent hair loss in the area treated with radiation 
 
Less Likely, But Serious: 
• 
Decrease in function of the thyroid gland that may require you to take thyroid replacement medicine to prevent 
you from feeling tired or sleepy 
• 
Serious damage to the spinal cord, nerves in the neck, throat, jawbone, voice box, skin, or other parts of the head 
and neck that may require a major operation to correct and, rarely, can even be life threatening 
• 
Pain or scarring around nerves in the shoulder that could cause numbness and/or weakness 
• 
Breathing problems 
• 
Difficulty with swallowing and eating for which you might need a long term feeding tube; 
• 
Inhaling food and/or liquids into the lungs – which could also result in pneumonia. 
• 
Serious ear infections and/or hearing loss 
• 
Damage to the spinal cord leading to permanent weakness and/or symptoms like a “stroke” 
• 
Permanent hair loss (of the face/chin/neck) 
• 
Loss of teeth, or cavities in the teeth, and/or hypersensitivity of teeth 
 
Risks Associated with PET/CT scans: 
A PET/CT scan involves exposure to a low dose of radiation from an injection of a radioactive substance (a tracer). The 
risk from this level of radiation exposure is about 60% of the allowable annual dose for radiation workers (such as an x-ray 
technician) and is small when compared with other everyday risks. Ask the study doctor if you would like more information 
about exposure. 
 
Less Likely: 
• 
Discomfort from lying still on an enclosed scanning table 
• 
Bruising or bleeding or infection at the site of the injection of the tracer 
 
Rare but Serious: 
• 
An allergic reaction to the radioactive substance 
 
Risks Associated with Carboplatin:  
Likely: 
• 
Decrease in blood counts, which can lead to a risk of infection and/or bleeding 
• 
Anemia (decrease in red blood cells) 
• 
Loss of appetite and/or taste; metallic taste in your mouth 
• 
Nausea and/or vomiting 
• 
Fatigue 
• 
Generalized loss of strength 
• 
Hearing loss, ringing in the ears 
• 
Loss of muscle or nerve function that may cause weakness or numbness in your hands/feet 
• 
Loss of appetite and weight loss 
• 
Low magnesium in the blood, which could result in muscle cramps and/or weakness 
• 
Low calcium in the blood 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
359512
03-07-2014

CCRO022:  Paclitaxel + Carboplatin                                                    Consent                                                                                        Page 7 of 13 
Head & Neck Cancer 
 
 
 
 
 
Initials of Participant 
 
CCRO022_Consent_02.25.14_unmarked 
Protocol Version Date:  02.25.14 
 
 
                                      
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
Risks Associated with Carboplatin: (continued) 
Likely: (continued) 
• 
Kidney damage 
 
Less Likely: 
• 
Allergic reactions (sweating, difficulty breathing, rapid heartbeat) 
• 
Muscle cramps or spasm 
• 
Facial swelling 
• 
Loss of taste 
• 
Loss of coordination 
• 
Involuntary movement 
• 
Restlessness 
• 
Loss of hair, which is temporary 
• 
Blood clots 
• 
Low blood pressure 
 
Less Likely, But Serious: 
• 
Seizures 
• 
A severe allergic reaction, which could be life threatening 
• 
Decrease in the kidneys’ ability to handle the body’s waste, which may be permanent 
• 
Calcium or potassium levels so low that it may affect heart function 
• 
Decrease in liver function 
• 
Another cancer called acute leukemia 
• 
A condition called hemolytic uremic syndrome that involves decreased red blood cells and platelets, fever, and 
kidney failure 
 
Possible allergic reactions to Carboplatin: 
Carboplatin also may cause allergic reactions such as hives, itching, and/or skin rash. Some patients have had allergic 
reactions with the first dose of carboplatin, but some patients have had reactions with later doses. The allergic reactions 
also can be severe, involving shortness of breath, wheezing, difficulty swallowing, lightheadedness, very low blood 
pressure, and rarely, heart attack and/or death. If you have a severe reaction, your doctor will treat you for the reaction, 
and you will not receive further treatment on this study. If you have a delayed severe reaction after receiving carboplatin, 
you must immediately tell your doctor. 
 
Risks Associated with Paclitaxel: 
Likely: 
• 
Weakness 
• 
Headache 
• 
Fever 
• 
Dry skin 
• 
Low calcium in the blood 
• 
Low magnesium in the blood, which could result in muscle cramps and/or weakness 
 
Less Likely: 
• 
Inflammation under fingernails and/or toenails, which can last for several months  
• 
Mouth sores 
• 
Nausea and/or vomiting 
• 
Diarrhea 
• 
Constipation 
• 
Upset stomach 
• 
Reduced appetite, which could lead to weight loss 
• 
Stomach pain 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
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WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
Risks Associated with Paclitaxel (continued): 
Less Likely: (continued): 
• 
Chills 
• 
Dehydration 
• 
Trouble sleeping 
• 
Tiredness and/or sluggishness 
• 
Feeling depressed 
• 
Muscle aches 
• 
Joint or back pain 
• 
Build-up of fluid in ankles, feet, and/or legs 
• 
Shortness of breath 
• 
Hair loss 
• 
Inflammation of the lining of the eye 
 
Less Likely, But Serious: 
• 
Reduced blood counts, which could lead to an increased risk of infection, weakness, and/or in bleeding and 
bruising easily; this lowering of blood counts can lead to need for treatment with antibiotics, transfusions, or 
hospitalization if severe. 
• 
Calcium or potassium levels so low that it may affect heart function 
• 
Blood clots within a blood vessel in the lungs, legs, pelvis, or other places 
• 
Kidney failure, which could lead to being hospitalized, or rarely, to death 
 
Rare: 
• 
Changes in blood tests that check how your liver is working 
 
Rare, But Serious: 
• 
Scarring of lung tissue, which could be life threatening or lead to death 
• 
Heart attack 
• 
Blood clots outside of the lungs, legs, and pelvis 
 
 
Risks Associated with Paclitaxel and Radiation Therapy: 
The combination of paclitaxel with chemotherapy and radiation therapy could increase the likelihood and/or severity of the 
side effects of chemotherapy and radiation therapy. The combination also could increase the risk of heart damage, 
including heart attack, abnormal heart rhythms, and/or heart failure, which could lead to death. 
 
Additional Risks: 
 
Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs and scans 
in this study can affect an unborn baby. Women who are able to have children will have a pregnancy test before beginning 
treatment. Women should not breastfeed a baby while on this study and for at least 60 days after the last study treatment. 
It is important you understand that you need to use birth control while on this study and for at least 60 days after the last 
study treatment. Check with your study doctor about what kind of birth control methods to use and how long to use them. 
Some methods might not be approved for use in this study. There is a risk of not being able to have children in the future 
due to the chemotherapy. If you think that you may want to have children in the future, discuss this with the study doctor. 
 
Venipuncture/Intravenous (IV) Needle Insertion:  Routine laboratory tests and the research blood draws, which may 
result in bruising, infection and minor pain or discomfort comparable to a needle prick. 
 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
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WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
Radiological Risks:  This study involves a radiation exposure that is higher than most other diagnostic tests using 
ionizing radiation. The exposure to radiation from this procedure might result in a slight increase in cancer risk in normal 
healthy individuals.  However, since you already have cancer, a risk estimate cannot be accurately determined. The 
amount of radiation for this research study is low compared to the radiation dose from the treatment of your cancer. 
 
Privacy Risks: There may also be risks to your privacy.  The researchers will store study records and other information 
about you in a secure location and will grant access only to those with a need to know.  However, just like with other 
personal information kept by your health care providers, your banks, and others, even these safeguards cannot guarantee 
absolute protection of the data.  If private information gets into the wrong hands, it can cause harm.  Although rare, there 
are reported cases of breaches that have resulted in discrimination in insurance or employment.   
 
For more information about risks and side effects, ask your study doctor. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
You may not benefit from taking part in this research.  The information we get from this study may help us to learn more 
about this study treatment, and this may help future cancer patients. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
 
Your alternative is not to take part in this study.  If you choose not to take part in this study, your future care will not be 
affected.  Your other choices may include: 
 
 
Getting treatment or care for your cancer without being in a study 
 
Participating in a different study, if available 
 
Getting no treatment 
 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite 
problems, and other problems caused by the cancer.  It does not treat the cancer directly, but instead tries to 
improve how you feel.  Comfort care tries to keep you as active and comfortable as possible. 
 
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
 
We will do our best to make sure that your personal information will be kept private.  However, we cannot guarantee total 
privacy. Your personal information may be given out if required by law.  
 
If information from the study is published or presented at scientific meetings, your name and other personal information 
will not be used.     
 
Organizations that may look at and/or copy your research records for research, quality assurance, and data analysis include: 
 
The investigators involved in the conduct of this study and their designees 
 
The UC Davis Institutional Review Board (IRB) 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov.   This Web site will not include 
information that can identify you.   At most, the Web site will include a summary of study results.   You can search this 
Web site at any time.  
 
You will be asked to sign a separate form to give your permission for us to access protected health information (e.g., your 
medical record). 
 
 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
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WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? (continued) 
Your Social Security number may be accessed and used for the purposes of registration and follow-up for this study. This 
is for research purposes only and is separate from your medical care outside of this research study. The policies and 
guidelines of UC Davis will be followed to secure and use your Social Security number. If you do not want your Social 
Security number accessed and used for research purposes, your care will not be affected, and you will still be able to take 
part in this research study. 
 
Please write your initials next to "Yes" or "No", depending on your decision to let us access and use your Social Security 
number for research purposes. 
 
Yes   
 
  (Initials)      
 
No  
 
 (Initials) 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?  
 
It is important that you promptly tell the Researcher if you believe that you have been injured because of taking part in this 
study. If you are injured as a result of being in this study, the University of California will provide necessary medical 
treatment. The costs of the treatment may be covered by University or the study sponsor or may be billed to your 
insurance company just like other medical costs. The University and the study sponsor do not normally provide any other 
form of compensation for injury. You do not lose any legal rights by signing this form. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
There will be no charge to you or your insurance company for processing the research blood draws or research studies on 
your tumor biopsy tissue and blood. They will be paid for by the study.  However, if the specimens are obtained during a 
standard diagnostic procedure, that procedure will be charged to you or you insurance company in the usual way. 
 
Paclitaxel and Carboplatin are commercially available and will be billed to you and/or your insurance company. 
 
You or your insurance carrier will be responsible for the associated costs of administering paclitaxel and carboplatin 
including infusion room charges, all routine laboratory tests, x-rays, scans, clinic visits or hospital stays.  
 
Whenever possible, pre-authorization will be obtained.  If the costs are not covered, these costs will be discussed prior to 
proceeding with the study. 
 
The UC Davis Pharmacy, Investigational Drug Service (IDS) will provide drug charge information to patients when 
requested.  The IDS can be reached at (916) 703-4093. 
 
WILL I BE COMPENSATED FOR BEING IN THIS STUDY? 
 
You will not be compensated for your participation in this study. 
 
Samples taken during this study may be used for research and development purposes not related to your treatment or 
condition.  You will not have any property rights or ownership interest in products or data which may be derived from your 
samples. 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  If you 
decide to take part in this study, you may leave the study at any time.  No matter what decision you make, there will be 
no penalty to you and you will not lose any of your regular benefits.  Leaving the study will not affect your medical care.  
You can still get your medical care from our institution.   
 
We will tell you about new information or changes in the study that may affect your health or willingness to continue in 
the study.   
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
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DOES THE RESEARCHER HAVE A FINANCIAL INTEREST IN THIS RESEARCH STUDY?  
 
The Principal Investigator does not have any personal or financial interest in this study.  
 
ADDITIONAL STUDIES  
 
Please note: This section of the informed consent form is about additional research that is being done with 
people who are taking part in the main study. You may take part in this additional research if you want to.  You 
can still be a part of the main study even if you say ‘no’ to taking part in this additional research. You can say 
“yes” or “no” to each of the following studies. Below, please mark your choice for each study. 
 
Quality of Life Study 
We want to know your view of how your life has been affected by cancer and its treatment. This “quality of life” study looks 
at how you are feeling physically and emotionally during your cancer treatment. It also looks at how you are able to carry 
out your day-to-day activities. 
 
This information will help doctors better understand how patients feel during treatments and what effects the medicines 
are having. In the future, this information may help patients and doctors as they decide which medicines to use to treat 
cancer. 
 
You will be asked to complete 2 questionnaires at the following times: before starting treatment, 4 weeks- and 12 weeks 
after treatment. It takes about 5 to 10 minutes to fill out each questionnaire. 
 
If any questions make you feel uncomfortable, you may skip those questions and not give an answer. 
 
If you decide to take part in this study, you will be asked to fill out the 2 questionnaires. You may change your mind about 
completing the questionnaires at any time. Just like in the main study, we will do our best to make sure that your personal 
information will be kept private. 
 
Please write your initials next to your answer  
I choose to take part in the Quality of Life Study. I agree to fill out the Quality of Life Questionnaires. 
 
YES ____________  (Initials)   
 
 
NO ____________ (Initials)  
 
WILL SPECIMENS (tissue, blood, urine or other body materials) TAKEN FROM ME BE USED FOR FUTURE 
RESEARCH PURPOSES?   
 
You have had a biopsy to see if you have cancer.  Your doctor removed some body tissue to do some tests.  The results 
of these tests were given to you by your doctor and are being used to plan your care. 
 
We would like to keep some of the tissue that is left for future research purposes.  In addition to the tumor tissue, we 
would like to collect your blood before treatment, weekly during radiation therapy, and at 3 months after the completion 
of treatment. 
 
Your specimen(s) will only be used for research purposes.  If you agree, these specimen(s) will be kept and used to 
learn more about your disease as well as other diseases.   
 
The research that may be done with your specimen(s) will not benefit you directly nor have an effect on your care.  It 
might help people who have your disease and other diseases in the future.  Any reports about the research, done with 
your specimen(s), will not be shared with you or your doctor and the reports will not be put in your health record. 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
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WILL SPECIMENS (tissue, blood, urine or other body materials) TAKEN FROM ME BE USED FOR FUTURE 
RESEARCH PURPOSES?  (continued) 
Your name, address, phone number and any other identifying information will be taken off anything associated with your 
specimen before it is given to the researcher.  This would make it very difficult for any research results to be linked to 
you or your family.  To help protect your privacy, people outside the research process will not have access to results 
about any one person. 
 
The benefits of research using specimens include learning more about what causes diseases, how to prevent them, how 
to treat them, and how to cure them.  There are very few risks to you.  The greatest risk is the release of information 
from your health records which may be necessary for us to obtain along with your specimens.  We will protect your 
records so that your name, address, and phone number will be kept private.   
 
Please read each question below and think about your choice.  After reading each question, initial next to “YES” or “NO”.  
If you have any questions, please discuss this with the researcher. 
 
1. My tissue/blood  may be kept for use in future research:     YES______ NO______ 
 
2. Someone may contact me in the future to ask me to use my specimens in future research:    YES_____ 
NO______ 
 
For further information on the use of specimens for future research purposes and your rights as a research participant, 
please visit:  http://research.ucdavis.edu/IRBAdmin/Participants. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
If you have any questions, please ask us. If you have questions regarding the research treatments or if you think you may 
have been injured as a result of your participation, please contact the doctor supervising your treatment or Megan Daly, 
MD, the principal investigator, by calling (916) 734-8252 or by writing to them at the Radiation Oncology clinic, UC Davis 
Cancer Center, 4501 X Street, Sacramento, CA  95817. If you are unable to the reach the Principal Investigator of this 
study, please contact the clinical research coordinator (CRC) responsible for your care. The CRC's contact information will 
be provided to you. The CRC will assist you in contacting another investigator for this study.  In addition, there is a 24-
hour emergency telephone number for the hospital, which is able to contact the Radiation Oncologist on callMegan Daly, 
MD, or one of their associates at any time of the day or night. That number is (916) 734-2011. 
 
Contact information for each site (including the 24-hour emergency number) is summarized below:  
UC Davis Medical Center/UC Davis Cancer Center 
Megan Daly, M.D. 
 
 
 
(916) 734-8252 
24-hour emergency phone number:  
 
(916) 734-2011 (ask for the radiation oncologist on call) 
 
For questions about your rights while taking part in this study call the IRB Administration at (916) 703-9151 or write to 
IRB Administration, CTSC Building, Suite 1400, Room 1429, 2921 Stockton Blvd., Sacramento, CA 95817.  The IRB 
Administration will inform the Institutional Review Board which is a group of people who review the research to protect 
your rights.  The IRB Administration has also developed a web site designed to make you familiar with your rights.  The 
web site discusses your basic rights as a research participant, an explanation of the informed consent process, the 
basic requirement that written consent be in a language understandable to you, and suggested sample questions to ask 
the research investigator regarding your participation in the study.  This web site can be accessed at:  
www.research.ucdavis.edu/IRBAdmin.
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
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WHERE CAN I GET MORE INFORMATION? 
  
You may call the National Cancer Institute's Cancer Information Service at:   
  
1-800-4-CANCER (1-800-422-6237)  
  
You may also visit the NCI Web site at http://cancer.gov/   
  
•   For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/   
•   For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/   
 
VOLUNTARY CONSENT: 
 
My signature below will indicate that I have decided to participate in this study as a research subject.  I have read and 
understand the information above.  I understand that I will be given a signed and dated copy of this consent form and 
the Bill of Rights.   
 
 
 
_____________________________________________  
______________________________________ 
Signature of Subject 
 
 
 
 
 
Print Name of Subject 
 
_________________ 
Date 
 
_____________________________________________  
______________________________________ 
Signature of Person Obtaining Consent  
 
 
Print Name of Person Obtaining Consent 
 
_________________ 
Date 
  
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
359512
03-07-2014