Conditions: Carcinoma, Squamous Cell Head and Neck Neoplasms Oropharyngeal Neoplasms
Keywords: Human Papillomavirus Oropharynx Oropharyngeal Squamous Cell Carcinoma Squamous Cell Carcinoma Radiation Therapy Chemotherapy p16
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 115
Healthy volunteers: no

Brief summary:
The purpose of this research study is to learn about the effectiveness of using lower-intensity radiation and chemotherapy to treat human papillomavirus (HPV) associated low-risk oropharyngeal and/or unknown primary squamous cell carcinomas of the head and neck. The cure rate for this type of cancer is estimated to be high, \> 90%. The standard treatment for this cancer is 7 weeks of radiation with 3 high doses of cisplatin. Sometimes surgery is performed afterwards. This standard regimen causes a lot of side effects and long term complications. This study is evaluating whether a lower dose of radiation and chemotherapy may provide a similar cure rate as the longer, more intensive standard regimen. Patients in this study will receive 1 less week of radiation and a lower weekly dose of chemotherapy.

Detailed description:
The proposed study is a follow-up study to NCT01530997. In NCT01530997, patients with HPV positive and/or p16 positive low-risk oropharyngeal squamous cell carcinoma (OPSCC) received de-intensified chemoradiotherapy (CRT) followed by a limited surgical evaluation. The primary endpoint of NCT01530997 was the rate of pathological complete response (pCR) after CRT. Power computations were performed for N=40 and were based on the null hypothesis (H0) that the pCR for de-intensified chemoradiotherapy is at least 87%, the historical rate. The type 1 error for this calculation was 14.2%. 43 patients enrolled and 38 were evaluable for the primary endpoint. The observed pCR rate was 89% (34/38). Since the observed pCR rate was excellent in NCT01530997 and was in concordance with the expected rate, in the proposed study we will not mandate a post-CRT surgical evaluation. Instead a PET/CT 10 to 16 weeks post-CRT will be used to determine whether a surgical evaluation is needed.

Arms:
arm 1: Patients will receive Intensity Modulated Radiotherapy Treatments (IMRT), 60 Gy at 2 Gy/fx. The acceptable weekly chemotherapy regimens are Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (third choice), Carboplatin AUC 3 (fourth choice). Chemotherapy will be given intravenously weekly during IMRT, 6 total doses. Chemotherapy will not be given to patients with T0-2 N0-1 disease, ≤ 10 pack years smoking history. Decision for surgical evaluation will be based on the results of the PET/CT and clinical exam 10-16 weeks after CRT. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon. Patients with a negative PET/CT scan will be observed.

Interventions: intervention 1: Intensity Modulated Radiotherapy (IMRT) intervention 2: Cisplatin (or alternative) intervention 3: Assessment for surgical evaluation
Intervention descriptions: intervention 1: All patients will receive Intensity Modulated Radiotherapy Treatments (IMRT). Dose painting IMRT will be used and all doses will be specified to the planning target volume (PTV). The high risk planning target volume (PTV-HR) and standard risk planning target volume (PTV-SR) will be treated to the following respective total doses: 60 Gy and 54 Gy. The dose per fraction to the PTV-HR and PTV-SR will be 2 Gy per day and 1.8 Gy per day respectively. The PTV-HR will include the gross tumor and the PTV-SR will include areas at risk for harboring subclinical microscopic disease. intervention 2: Cisplatin is the preferred mandated first choice chemotherapy, however alternative weekly regimens are permissible. Justification for not using cisplatin must be documented. Chemotherapy will be given intravenously weekly during IMRT. 6 total doses will be given. It is preferred that the doses be administered on days 1, 8, 15, 22, 29, and 36; however, this is not mandatory. Chemotherapy will not be given to patients with T0-2 N0-1 disease, ≤ 10 pack years smoking history. intervention 3: Decisions for surgical evaluation will be based on the results of the PET/CT 10 to 16 weeks after CRT and clinical exam (including fiberoptic laryngoscopy) at that time. Other optional imaging studies may be performed. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon, with the goal being to remove any suspected residual tumor with a negative resection margin while maintaining organ preservation. This may include biopsies and/or oncological resections of the primary tumor and lymph node metastases. Patients with a negative PET/CT scan will be observed.

Protocol document:
Prot_SAP_001.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
SUMMARY OF CHANGES 
 
Protocol Amendment #3 
 
LCCC1413: De-intensification of Radiation and Chemotherapy for 
Favorable-Risk HPV-related Oropharyngeal Squamous Cell Carcinoma  
AMENDMENT INCORPORATES: 
_x_  Editorial, administrative changes 
_x_  Scientific changes  
__  Therapy changes  
__   Eligibility Changes  
Rationale for amendment: The purpose of this amendment is to remove secondary 
objectives and endpoints that collect quality of life data through patient-reported 
outcomes questionnaires 
Editorial, administrative changes: 
Changed the PI from Bhichamjit Chera, MD to Colette Shen, MD 
Removal of Co-Principal Investigators (Robert Amdur, Nathan Sheets, Mohit 
Kasibhatla, Benjamin Weinberg), Co-Investigators (Trevor Hackman, Juneko 
Grilley-Olson, Mark Weissler, William Funkhouser, Jr., Samip Patel, Adam 
Zanation, Jose Zevallos, Benjamin Huang, Jared Weiss, Neil Hayes, Shannon 
Aumer, Bryce B. Reeve, Terry Wong, Leroy G. Hoffman, Jr., Oludamilola A. 
Olajide, Susan G. Moore, Jeffrey M. Crone, Jeremiah C. Boles, JoEllen C. Speca, 
Roger Anderson, Courtney Bui, Achilles John Fakiris, Justin Wu, Nirav Dhruva, 
Robert Wehbie, John Werning, Heather Pacholke), and Study Coordinator 
(Rebecca Green) 
Changes in section numbering due to edits 
Scientific changes: 
Section 2.1  
Removal of Secondary Objectives 2.2.2 and 2.2.3 
Section 3.2 
Removal of Secondary Endpoints 3.2.2 and 3.2.3 
Section 5.9 
Removed Quality of Life and Patient-Reported Outcomes 
assessments that were required for Secondary Objectives 2.2.2 
and 2.2.3. (EORTC WLW-C30, EORTC QLQ-H&N35, PRO-
CTCAE,  and speech and swallowing evaluations). Also 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
removed references to these assessments in subsequent 
subsections. 
Section 7.2 
Removed data analyses specific to head and neck QOL 
assessments, PROs and speech and swallowing assessments 
Appendix 
Removed sample assessment forms for EORTC WLW-C30, 
EORTC QLQ-H&N35, EAT-10 Questionnaire, PRO-CTCAE 
Changes to Time and Events Table that reflect changes made 
in this amendment 
THE ATTACHED VERSION DATED October 24, 2024 INCORPORATES 
THE ABOVE REVISIONS  
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT 12/19/2016 
LCCC 1413: De-intensification of Radiation and Chemotherapy for Favorable-Risk 
HPV-related Oropharyngeal Squamous Cell Carcinoma 
 
AMENDMENT INCORPORATES (check all that apply): 
X    Editorial, administrative changes 
X    Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
Editorial, administrative changes 
Removal of Mark McCollough as Co-Investigator; addition of Benjamin Weinberg as 
Co-Investigator (cover pages) 
Scientific changes 
Revision to statistical considerations to be consistent with the increase in expected 
enrollment to 120 (section 7.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 12/19/2016 INCORPORATES THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
PROTOCOL AMENDMENT 10/19/2016 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
LCCC 1413: De-intensification of Radiation and Chemotherapy for Favorable-Risk 
HPV-related Oropharyngeal Squamous Cell Carcinoma 
 
AMENDMENT INCORPORATES (check all that apply): 
X    Editorial, administrative changes 
X    Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
X    Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
Editorial, administrative changes 
Add Terry Wong as co-investigator 
Clarification of Adverse Event reporting for UNC and affiliate sites (section 6.2). 
Scientific changes 
Revision to data analysis plan to allow for additional analyses of study data (section 7.2) 
Clarification of time points for QOL and Swallowing assessments (sections 3.2.2, 3.2.3, 
5.9.1, 5.9.2) 
Revision of Schema (section 5.1) to reflect new accrual of 120. 
Eligibility changes 
Revisions to eligibility criteria modifying time frame of select inclusion critieria (prior to 
treatment rather than prior to registration) and adding exclusion critieria (systemic lupus, 
psoriatic arthritis) (section 4.0 and appendix) 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 10/29/2016 INCORPORATES THE ABOVE REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1413: De-intensification of Radiation and Chemotherapy for Favorable-Risk 
HPV-related Oropharyngeal Squamous Cell Carcinoma 
 
Principal Investigator 
 
Colette Shen, M.D., Ph.D. 
UNC Dept. Radiation Oncology 
101 Manning Drive, CB #7512 
Chapel Hill, NC 27599-7512 
Phone: 984-974-8429 
Email: colette_shen@med.unc.edu 
 
 
Biostatistician  
Bahjat Qaqish, Ph.D. 
Associate Professor 
Department of Biostatistics 
135 Dauer Dr., Campus Box 7420 
Chapel Hill, NC  27599-7420 
919-966-7271 (phone)  
919-966-3804 (fax) 
Email: bahjat_qaqish@unc.edu 
 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: Departments of Radiation Oncology University of North Carolina and 
University of Florida 
 
Other participating institutions:  University of Florida, Gainesville, FL; Rex Healthcare, 
Raleigh, NC; High Point Regional Health, High Point, NC; Pardee Memorial Hospital, 
Hendersonville, NC 
 
Version Date:  10/24/2024 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name:  Colette Shen, MD   
 
PI Signature: _____________________________ 
 
Date:  10/24/2024


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UNIVERSITY OF NORTH CAROLINA 
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i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................1 
1.1 
Study Synopsis ......................................................................................................1 
1.2 
Standard of care CRT for OPSCC.........................................................................1 
1.3 
HPV related OPSCC .............................................................................................1 
1.4 
Prospective Clinical Data on HPV positive HNSCC ............................................2 
1.5 
De-intensification of Treatment ............................................................................3 
1.6 
LCCC 1120: Phase II Study of De-intensification of Radiation and 
Chemotherapy for Low-Risk HPV-related Oropharyngeal Squamous Cell Carcinoma ..3 
1.7 
Rationale................................................................................................................4 
2.0 
STUDY OBJECTIVES ...........................................................................................5 
2.1 
Primary Objective .................................................................................................5 
2.2 
Secondary Objectives ............................................................................................5 
3.0 
ENDPOINTS ...........................................................................................................5 
3.1 
Primary Endpoint ..................................................................................................5 
3.2 
Secondary Endpoints .............................................................................................5 
4.0 
PATIENT ELIGIBILITY ......................................................................................5 
4.1 
Inclusion Criteria ...................................................................................................5 
4.2 
Exclusion Criteria ..................................................................................................7 
5.0 
STUDY PLAN .........................................................................................................8 
5.1 
Schema ..................................................................................................................8 
5.2 
Pretreatment Evaluations.......................................................................................8 
5.3 
HPV and p16 testing .............................................................................................8 
5.4 
Radiation Therapy .................................................................................................9 
5.5 
Chemotherapy .....................................................................................................11 
5.6 
Post-Chemoradiotherapy Assessment of Clinical Response ...............................12 
5.7 
Surgery after CRT ...............................................................................................12 
5.8 
Other Therapy .....................................................................................................12 
5.9 
Patient Assessments ............................................ Error! Bookmark not defined. 
5.10 
Duration of Study ................................................................................................13 
5.11 
Duration of Follow Up ........................................................................................13 
6.0 
ADVERSE EVENTS ............................................................................................13 


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6.1 
Definition ............................................................................................................13 
6.2 
Reporting .............................................................................................................14 
6.3 
Treatment of Adverse Event ...............................................................................14 
7.0 
STATISTICAL CONSIDERATIONS ................................................................15 
7.1 
Study Design/Study Endpoints ...........................................................................15 
7.2 
Sample Size and Data Analysis Plan ..................................................................15 
7.3 
Safety Meetings ...................................................................................................16 
8.0 
STUDY MANAGEMENT ....................................................................................16 
8.1 
Institutional Review Board (IRB) Approval and Consent ..................................16 
8.2 
Required Documentation.....................................................................................16 
8.3 
Registration Procedures.......................................................................................17 
8.4 
Data Management and Monitoring/Auditing ......................................................17 
8.5 
Adherence to the Protocol ...................................................................................17 
8.6 
Amendments to the Protocol ...............................................................................19 
8.7 
Record Retention .................................................................................................19 
8.8 
Obligations of Investigators ................................................................................20 
9.0 
REFERENCES ......................................................................................................21 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
The proposed study is a follow-up study to LCCC 1120.  In LCCC 1120, patients with 
HPV positive and/or p16 positive low-risk oropharyngeal squamous cell carcinoma 
(OPSCC) received de-intensified chemoradiotherapy (CRT) followed by a limited 
surgical evaluation.  The primary endpoint of LCCC 1120 was the rate of pathological 
complete response (pCR) after CRT. Power computations were performed for N=40 and 
were based on the null hypothesis (H0) that the pCR for de-intensified 
chemoradiotherapy is at least 87%, the historical rate.  The type 1 error for this 
calculation was 14.2%.   43 patients enrolled and 38 were evaluable for the primary 
endpoint.  The observed pCR rate was 89% (34/38).  Since the observed pCR rate was 
excellent in LCCC 1120 and was in concordance with the expected rate, in the proposed 
study we will not mandate a post-CRT surgical evaluation.  Instead a PET/CT 10 to 16 
weeks post-CRT will be used to determine whether a surgical evaluation is needed. This 
study will be multi-institutional, with patients also enrolling at the University of Florida, 
Gainesville, Florida; Rex Cancer Center of Raleigh, Raleigh, North Carolina; High Point 
Regional Health, High Point, North Carolina; and Pardee Memorial Hospital, 
Hendersonville, North Carolina. 
1.2 
Standard of care CRT for OPSCC 
The standard treatment regimen for HPV-associated oropharyngeal or unknown primary 
squamous cell carcinoma of the head and neck is 70 Gy, 2 Gy per day, 35 fractions, over 
7 weeks with 2 to 3 doses of cisplatin 100mg/m2.  Most institutions perform a PET/CT at 
10 to 16 weeks after CRT to assess response.  Depending on the clinical response, 
patients may have to have a biopsy of the primary site and/or a neck dissection after 
treatment. Typically patients with a negative PET/CT scan are observed (i.e. no surgery).  
Standard CRT is associated with significant acute toxicity with most patients 
experiencing grade 3 and 4 acute toxicity during treatment.  Furthermore, approximately 
20% of patients will have Grade 3-4 long-term morbidity related to their definitive CRT. 
1.3 
HPV related OPSCC 
The incidence of OPSCC is increasing and is thought to be secondary to HPV infection 
of the oropharyngeal mucosa1-8.   Evidence is accumulating that suggests that HPV-
positive HNSCC may be a distinct clinical and biological entity.  The affected individuals 
are more likely to be white men, younger than 60 years of age, unmarried, and have a 
minimal history of alcohol or tobacco use3,9-30.  HPV-positive HNSCC has a higher 
response rate to neoadjuvant chemotherapy and in general has a better prognosis to 
therapy as compared to HPV-negative HNSCC10,13,18,19,22.  Biologically, the HPV 
oncoproteins E6 and E7 inactivate the tumor suppressor proteins p53 and pRb, 
respectively. Inactivation of pRB by E7 leads to upregulation of the p16 tumor suppressor 
protein.  Thus, overexpression of p16 may be regarded as a biomarker for HPV-positive 
HNSCC18,29.  Furthermore, HPV-positive HNSCC is more likely to be associated with a 
wild-type p53, unlike tobacco-induced HNSCC11.  Because of the observed improved 
prognosis and distinct molecular profile, some have suggested that HPV-positive tumors 


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may be more sensitive to CRT.  The standard CRT regimen for most HNSCC is 70 Gy 
with 3 cycles of concurrent cisplatin at 100mg/m231. Less intensive chemotherapy and/or 
radiation may be just as effective in HPV-related oropharyngeal HNSCC and reduce the 
severity of acute toxicity and long-term morbidity associated with CRT.  We recently 
completed a phase II study evaluating de-intensified CRT which showed promising 
results.  The proposed study will further study the efficacy of de-intensification.  
1.4 
Prospective Clinical Data on HPV positive HNSCC 
Numerous retrospective studies have shown that patients with HPV-positive HNSCC 
have a significantly better prognosis than patients with HPV-negative HNSCC5,25,29.  
These preliminary data have been verified in analyses of prospective clinical trials10,13,18.  
Fakhry et al. evaluated the HPV status of 96 patients with laryngeal or oropharyngeal 
SCC from an Eastern Cooperative Oncology Group (ECOG) phase II trial.  Patients with 
HPV positive tumors had higher response rates after induction chemotherapy (82% vs. 
55%, p = 0.01) and CRT (84% vs. 57%, p = 0.007) as compared to those with HPV-
negative tumors.  The 2 year overall survival was also improved - 95% (HPV positive) 
vs. 62% (HPV negative). Lassen et al. analyzed the Danish Head and Neck Cancer Group 
(DAHANCA) 5 trial and observed an improved local-regional control, disease specific 
survival, and overall survival in patients whose tumors were p16 positive (a surrogate 
marker for HPV) versus those who were p16 negative18.   
 
The RTOG 0129 prospective randomized trial also validated HPV positivity as being a 
strong, independent prognostic factor for overall and progression free survival10.   RTOG 
0129 compared accelerated fractionation radiotherapy with standard fractionation, both 
with concurrent cisplatin (2 cycles in the former and 3 cycles in the latter).  There was no 
statistical difference in overall or progression free survival between the two arms.  Post-
hoc analysis of HPV status and outcomes in the OPSCC subset showed a significant 
improvement in OS (82.4%, vs. 57.1% at 3 year; P<0.001) and PFS in the HPV positive 
tumors. After accounting for other prognostic factors, HPV positivity conferred a 58% 
reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66).   Locoregional 
control was improved in the HPV-positive tumors; however, distant metastatic control 
and the rate of second malignancies were similar for both HPV-positive and negative 
OPSCC subgroups. Through recursive portioning analysis this OPSCC cohort was 
stratified into low, intermediate, and high risk groups for death (3 year OS of 93%, 
70.8%, and 46.2% respectively).  The factors used for stratification, in order of 
importance, were:  HPV status, pack-years of tobacco smoking, tumor stage, and nodal 
stage.  To be categorized as having low risk of death, a patient must have a HPV-positive 
tumor and either have ≤ 10 pack years of tobacco smoking and any N stage or >10 pack 
years of tobacco smoking and N0-N2a nodal stage.  
 
O’Sullivan et al. conducted a large retrospective study of 899 OPSCCs patients treated at 
the Princess Margaret Hospital in Toronto, Canada32.  HPV status was ascertained in 505 
(56%):  382 HPV positive and 123 HPV negative.  All patients were treated with 
radiation alone or CRT from 2001 to 2009, with a median follow-up of 3.9 years.  
Recursive portioning analysis segregated HPV-positive patients into low (T1-3 N0-N2c) 
and high (T4 or N3) distant metastasis risk:  93% vs. 76% respectively.  Furthermore, 


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smoking > 10 pack years reduced overall survival but did not impact recurrence free 
survival (local, regional, and distant recurrences) in HPV-positive patients.  This suggests 
that other associated tobacco-related disease may be the reason for decreased survival in 
HPV-positive smokers vs. HPV-positive non-smokers.  Also, the recurrence free survival 
was excellent ( >90%) in low-risk HPV-positive patients with T1-2, N0-1 disease treated 
with RT alone vs. CRT.  Thus the addition of chemotherapy to radiation in this very 
favorable low-stage subset may not be necessary.  
1.5 
De-intensification of Treatment 
De-intensification of therapy is somewhat of a foreign concept for head and neck 
oncologists.  Historically the clinical outcomes of HNSCC have been dismal, with 
median 5 year OS for all comers being approximately 50%.  Because of the poor 
outcomes of HNSCC, the treatment paradigm has been to intensify therapy.  HPV-
positive OPSCC may be a unique clinical/biological entity that is associated with a 
significantly better prognosis because of a potentially increased sensitivity to CRT and 
thus amenable to de-escalation of therapy.  
 
Several co-operative groups are conducting trials evaluating the reduction of RT dose 
after neoadjuvant chemotherapy.  The Eastern Cooperative Oncology Group currently is 
conducting a phase II trial studying reduction of RT dose after neoadjuvant chemotherapy 
in HPV positive OPSCC33.  Dana-Farber Cancer Institute is also evaluating a 
modification of the RT dose after neoadjuvant chemotherapy34.  By increasing the 
duration and intensity of chemotherapy they will then de-escalate the radiation dose 
depending on the response to neoadjuvant chemotherapy.  This regimen of treatment is 
not pure de-intensification because one modality (i.e. chemotherapy) is being intensified 
so that another (i.e. radiation) can be de-intensified.  The overall treatment time is 
lengthened, thus prolonging the duration of acute toxicities.  Furthermore, as a whole, 
neoadjuvant chemotherapy does not improve outcomes in HNSCC35.  A meta-analysis 
has shown that the most effective combination of chemotherapy with RT is concurrent 
chemoradiotherapy35.  Another de-escalation strategy may be to reduce the intensity of 
chemotherapy.  Retrospective data from Princess Margaret Hospital suggest that the 
outcome of HPV-positive OPSCC treated with RT alone may be equivalent to CRT36.  
Our study will evaluate de-intensification of CRT by reducing the amount of both 
concurrent chemotherapy and radiation therapy, which will result in shortening treatment 
time by 1 week. 
1.6 
LCCC 1120: Phase II Study of De-intensification of Radiation and Chemotherapy 
for Low-Risk HPV-related Oropharyngeal Squamous Cell Carcinoma  
We conducted a phase II study evaluating the efficacy of de-intensified radiotherapy in a 
favorable subgroup of patients with OPSCC.  Eligible patients had HPV-positive and/or 
p16-positive OPSCC, T0 – T3, N0 – N2c, M0, and < 10 pack years of smoking. Patients 
received 60 Gy of Intensity Modulated Radiotherapy (IMRT) with concurrent weekly 
intravenous cisplatin (30 mg/m2).  Diagnostic imaging (CT and/or MRI) was obtained 4 
to 8 weeks after completion of CRT to assess response.  All patients had surgical 
resection of any clinically apparent residual primary tumor or biopsy of the primary site if 
there was no evidence of residual tumor and underwent a neck dissection to encompass at 


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least those nodal level(s) that were positive pre-treatment, within 4 to 14 weeks after 
CRT.  The primary endpoint of LCCC 1120 was the rate of pCR.  Longitudinal 
assessments of quality of life and patient reported outcomes were also obtained prior to, 
during, and after CRT.   Power computations were performed for N=40 and were based 
on the null hypothesis (H0) that the pCR for de-intensified chemoradiotherapy is at least 
87%, the historical rate.  The type 1 error for this calculation was 14.2%.  43 patients 
enrolled and 38 were evaluable for the primary endpoint.  The observed pCR rate was 
89% (34/38), which is excellent and within the expected result for a positive outcome.    
1.7 
Rationale 
Because of the positive results of our initial de-intensification study, we are proposing 
conducting a similar study with 5 major modifications: 
 
1.   Not require surgical evaluation after de-intensified CRT:  
Biopsy or surgery of the primary site adds morbidity without value. This assessment is no 
longer standard practice at most institutions and is not necessary in this setting based on 
the results of our initial study.  
 
Dissecting the neck adds significant morbidity. Standard practice today is to base the 
need for neck dissection on the results of 12 week PET-CT scan. We required neck 
dissection in all node positive cases in the initial study because we had no experience 
limiting the dose to 60 Gy with positive nodes. Based on the results of our initial study 
and national practice guidelines, we changed the protocol in the current study to require  
post CRT neck dissection only in cases where the ~12 week PET-CT is positive for 
residual adenopathy and there is no evidence of primary site recurrence or distant 
metastasis.   
 
2.   No chemotherapy in the most favorable subgroups: 
There are now multiple studies demonstrating very high cure rates with RT alone in 
patients with stage T1-2, N0-1 OPSCC with and without consideration of HPV or 
smoking status32,37. These data and the results of our initial study strongly suggest that 60 
Gy RT alone will be adequate for favorable prognosis cases in our study population. For 
this reason the current study dictates RT alone in: p16/HPV positive, T0-2, N0-1, ≤ 10 
pack years. 
 
3.   Expand the study to patients with smoking history of ≤ 30 pack-years with ≥5 years 
of abstinence from smoking: 
Tobacco use is a factor of secondary importance following stage and p16/HPV status. 
The O’Sullivan data suggests that moderate tobacco use did not affect cancer control 
rates in HPV-positive patients32.   In view of the excellent results in our initial study it is 
logical to expand the inclusion criteria of the current study to patients with a moderate 
smoking history.  
 
4.  Chemotherapy:  In our prior study, weekly cisplatin was the mandated chemotherapy 
regimen. However we were not able to offer our prior study to several patients with low-
risk OPSCC because of co-morbidities that precluded the use of cisplatin. There are many 


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other standardly used weekly chemotherapy regimens.  So as to increase patient 
eligibility, we have expanded the acceptable weekly chemotherapy regimens that may be 
used in this study.  Cisplatin is still the preferred, first choice option. 
 
5.  Changing the Primary Objective:  In our prior study the primary objective was pCR – 
since surgery was part of the treatment algorithm.  For the proposed study, the primary 
objective will be the more standard 2 year PFS. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate 2 year PFS after de-intensified CRT in HPV-positive and/or p16 positive 
favorable-risk OPSCC. 
2.2 
Secondary Objectives 
2.2.1 To assess the 2 year clinical outcomes of local control (LC), regional control (RC), local-
regional control (LRC), distant metastasis free survival (DMFS), and overall survival 
(OS). 
3.0 
ENDPOINTS 
3.1 
Primary Endpoint 
Patients with HPV-positive and/or p16-positive favorable-risk OPSCC will receive de-
intensified CRT.  The 2 year PFS will be evaluated.  Our null hypothesis (H0) is that the 
PFS rate is 87% and our alternate hypothesis (H1) is that the PFS rate is 80%. 
3.2 
Secondary Endpoints 
3.2.1 Clinical Outcomes:  Kaplan Meier estimates of LC, RC, LRC, DMFS, and OS will be 
calculated. 
4.0 
PATIENT ELIGIBILITY 
4.1 
Inclusion Criteria 
4.1.1 ≥ 18 years of age (no upper age limit) 


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4.1.2 T0-3, N0 to N2c, M0 squamous cell carcinoma of the oropharynx  
4.1.3 Biopsy proven squamous cell carcinoma that is HPV and/or p16 positive 
4.1.4 ≤ 10 pack-years smoking history or ≤ 30 pack-years smoking history WITH ≥ 
5 years abstinence from smoking 
4.1.5 Radiologic confirmation of the absence of hematogenous metastasis within 12 
weeks prior to treatment; at a minimum, chest x-ray is required. CT imaging of 
the chest or PET/CT is acceptable. 
4.1.6 ECOG Performance Status 0-1 
4.1.7 CBC/differential obtained within 8 weeks prior to treatment, with adequate 
bone marrow function defined as follows: 
4.1.7.1 Platelets ≥ 100,000 cells/mm3 
4.1.7.2 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8.0 g/dl is acceptable.) 
4.1.8 Adequate renal and hepatic function within 4 weeks prior to treatment, defined as 
follows: 
4.1.8.1 Serum creatinine < 2.0 mg/dl 
4.1.8.2 Total bilirubin < 2 x the institutional ULN 
4.1.8.3 AST or ALT < 3 x the institutional ULN. 
 
 
Note that physician attestation of patient having no known history of liver disease can 
take the place of bilirubin and AST/ALT labs. 
4.1.9 
Negative pregnancy test within 2 weeks prior to treatment for women of childbearing 
potential 
4.1.10 Women of childbearing potential and male participants who are sexually active must 
practice adequate contraception during treatment and for 6 weeks following treatment. 
4.1.11 Patients must be deemed able to comply with the treatment plan and follow-up schedule. 
4.1.12 Patients must provide study specific informed consent prior to study entry 
 


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4.2 
Exclusion Criteria 
4.2.1 Prior history of radiation therapy to the head and neck 
4.2.2 Prior history of head and neck cancer.  
4.2.3 Unresectable disease (e.g. immobile node on physical exam, nodal disease that 
radiographgically involves the carotid arteries, nerves) 
4.2.4 Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) 
4.2.5 Severe, active co-morbidity, defined as follows: 
4.2.5.1 Unstable angina and/or congestive heart failure requiring 
hospitalization within the last 6 months 
4.2.5.2 Transmural myocardial infarction within the last 6 months 
4.2.5.3 Acute bacterial or fungal infection requiring intravenous antibiotics at 
the time of registration 
4.2.5.4 Chronic Obstructive Pulmonary Disease exacerbation or other 
respiratory illness requiring hospitalization or precluding study 
therapy at the time of registration 
4.2.5.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation 
defects; Note, however, coagulation parameters are not required for 
entry into this protocol. 
4.2.5.6 Pre-existing ≥ grade 2 neuropathy 
4.2.5.7 Prior organ transplant 
4.2.5.8 Systemic lupus 
4.2.5.9 Psoriatic arthritis 
 
4.2.6 
Known HIV positive.  HIV positive patients are known to have worse clinical 
outcomes especially for local, regional, and distant cancer control.  This poorer 
prognosis is thought to be secondary to a compromised immune system.  Thus, 
de-escalation of radiation and chemotherapy is not justifiable. 
 
 


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5.0 
STUDY PLAN 
5.1 
Schema  
 
Figure 1:  Schema 
 
Figure 1:  The primary objective of this study is to assess the 2 year PFS of HPV-related 
favorable-risk OPSCC after de-intensified CRT. Chemotherapy will not be given to patients with 
T0-2 N0-1 disease, ≤ 10 pack years smoking history. 
5.2 
Pretreatment Evaluations:  All patients will have standard of care evaluation and 
staging procedures.   
5.2.1 Complete history and physical exam including weight and performance status.  
5.2.2 Completion of panendoscopy with directed biopsies and bilateral tonsillectomies if the 
primary is unknown is strongly recommended, but not required.   
5.2.3 Completion of the following radiological studies:  at least contrasted neck CT and chest 
x-ray.  Chest CT, PET/CT and/or MRI are optional studies. CT of the neck should have 
IV contrast unless contraindicated (allergy or adverse reaction or renal issues).  PET/CT 
is satisfactory and can be done instead of or in addition to contrasted neck CT and chest 
x-ray.  Pretreatment ultrasound evaluation with possible FNA is permissible to stage the 
neck prior to treatment. 
5.2.4 Complete dental evaluation is recommended.  
5.2.5 Completion of the following laboratory studies: CBC, serum chemistries, liver function 
tests, and pregnancy test if female.  
5.3 
HPV and p16 testing 
HPV and p16 testing will be performed via fluorescence in-situ hybridization and 
immunohistochemistry, respectively.  Methods and techniques for these tests have been 


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established by the UNCH, UF, and Rex Cancer Center of Raleigh Departments of 
Pathology and these biomarkers are already routinely examined for all head and neck 
tumor specimens obtained at these institutions. This testing may be performed on FNA 
tissue obtained from a neck node. 
5.4 
Radiation Therapy   
All patients will receive Intensity Modulated Radiotherapy Treatments (IMRT).  
Tomotherapy is allowed. 
5.4.1 CT simulation:  CT simulation will be obtained with IV contrast for treatment planning 
purposes for all patients.  The head and neck area will be immobilized with an aquaplast 
mask.  Patients will be positioned in the neck extended position. 
5.4.2 Target and Organ at Risk Volumes:   
5.4.2.1 Gross Tumor Volume (GTV):  is defined as all known gross disease determined 
on the CT simulation scan.  
5.4.2.2 High Risk Clinical Target Volumes (CTV-HR):  is defined as the GTV plus a  
non-uniformly expanded 5 to 10 mm to account for high risk areas of 
microscopic spread.  For situations where the primary tumor was removed with 
the biopsy (e.g. tonsillectomy) and the primary tumor cannot be seen on 
radiographic imaging the biopsy site will be included in the CTV-HR.  For 
patients with an unknown primary (T0) the ipsilateral oropharynx (base of 
tongue, tonsil, soft palate) will be included in the CTV-HR volume. 
5.4.2.3 Standard Risk Clinical Target Volume (CTV-SR):  is defined as the elective 
nodal regions.  The consensus guidelines for the node negative and node 
positive necks published by Gregoire et al. will be used as a guide to define the 
CTV-SR38,39. For the situation of the unknown primary (i.e. T0), the 
nasopharynx will be included in the CTV-SR.  The following guidelines will be 
used in delineating the CTV-SR. 
5.4.2.3.1  Node positive hemi-neck (ipsilateral or contralateral to the primary site)38:  
The following elective nodal regions should be included in the CTV-SR:  
Levels Ib-V and retropharyngeal. The cranial extent to the base of skull of 
Level II and retropharyngeal nodes should be electively irradiated. 
5.4.2.3.2  Ipsilateral node negative hemi-neck39:  The following elective nodal regions 
should be included in the CTV-SR:  Levels II –IV and retropharyngeal area.  
The cranial extent to the base of skull of Level II and retropharyngeal nodes 
should be electively irradiated.   
5.4.2.3.3 Contralateral node negative hemi-neck39:  The contralateral parotid may be 
spared by omitting irradiation of the cranial portion of Level II and 
retropharyngeal region, defined as the Level II, retropharyngeal region above 
the transverse process of the C1 vertebrae and/or where the posterior belly of 


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the digastric muscle crosses over the jugular vein.  Contralateral neck 
irradiation may be completely omitted for well lateralized tonsil cancers, 
defined as having no invasion of the base of tongue, and minimal invasion of 
the soft palate (i.e. > 1 cm from the uvula)40. 
5.4.2.3.4 Unknown Primary:  The above elective nodal irradiation guidelines will be 
used.  Furthermore the nasopharynx will be included in the CTV-SR. 
5.4.2.4 Planning Target Volumes (PTV):  To account for daily setup errors, the CTV-
HR will be expanded uniformly by 3 mm to create a High Risk Planning Target 
Volume (PTV-HR).  The CTV-SR will be expanded uniformly by 3 mm to 
create a Standard Risk Planning Target Volume (PTV-SR). 
5.4.2.5 Organs at Risk (OAR):  The following normal tissues will be segmented on CT 
simulation scan:  spinal cord, brainstem, parotids, cochleae, and larynx.    
5.4.2.6 Planning Risk Volumes (PRV):  OAR(s) will be uniformly expanded 3mm to 
create individual Planning Risk Volumes (PRV).   
5.4.3 Dose Specification:  Dose painting IMRT will be used and all doses will be specified to 
the PTV.  The PTV-HR and PTV-SR will be treated to the following respective total 
doses:  60 Gy and 54 Gy.  The dose per fraction to the PTV-HR and PTV-SR will be 2 
Gy per day and 1.8 Gy per day respectively.  Thus the total number of fractions will be 
30. All fields will be treated once a day Monday through Friday. 
5.4.4 IMRT Treatment Planning:  PTV’s and PRV will be included in the IMRT 
optimization. Seven to nine equidistant fields will be placed around the PTV.  None of 
the beams will directly oppose one another.  Dose objectives will be chosen for the IMRT 
optimization based on previous institutional experience.  Dose painting (i.e. simultaneous 
integrated boost) will be used to create one IMRT plan. The PTV-SR contours will 
encompass the PTV-HR contours.  The dose to the PTV-SR plan will be 54 Gy at 1.8 Gy 
per daily fraction in 30 fractions. The PTV-HR will be treated to 60 Gy at 2 Gy per daily 
fraction in 30 fractions. IMRT to treat the entire neck is preferred, however a matched 
low anterior neck field technique may be used only if it does not result in significant dose 
heterogeneity for the PTV-HR.   
 
The historical, standard radiation dose for definitive treatment of squamous cell 
carcinoma of the head and neck is 70 Gy.  Historically 70 Gy at 2 Gy per daily fraction is 
given to the gross tumor and 50 Gy at 2 Gy per daily fraction is given to areas at risk for 
harboring subclinical microscopic disease.  70 Gy is also the standard dose for HPV 
positive head and neck cancer.  70 Gy is the standard radiation dose in both study arms of 
the currently ongoing RTOG 1016 (Phase III trial of Radiotherapy plus Cetuximab versus 
Chemoradiotherapy in HPV-asssociated Oropharynx Cancer).  In the proposed study we 
will be giving 60 Gy at 2 Gy per daily fraction to the gross tumor and 54 Gy at 1.8 Gy per 
daily fraction to areas at risk for harboring subclinical microscopic disease.  Thus the 
proposed dose in our study is actually lower than historical standards and the current 
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5.4.5 Dose Constraints 
▪ PTV-HR and PTV-SR  
o 100% of the prescription should cover 95% of the PTV 
o No more than 20% of the PTV should receive ≥ 110% of the prescribed dose 
o No more than 1% of the PTV should receive ≤ 93% of the prescribed dose 
▪ Non-target Tissue 
o No more than 1% of the tissue outside the PTV should receive ≥ 110% of the 
prescribed dose 
▪ PRV 
o Spinal Cord:  0.1cc  50 Gy 
o Brainstem: 0.1cc  54 Gy 
o Parotid:  Mean dose < 26 Gy and/or 50% < 30 Gy 
o Cochlea:  Mean dose < 45 Gy 
o Larynx:  Mean dose < 41 Gy and/or 60 Gy to < 20% 
 
PTV coverage should not be compromised to meet the dose constraints of the parotid, 
cochlea, or larynx.  Sparing of these structures is left at the discretion of the treating 
radiation oncologists.  The dose constraints for the spinal cord and brainstem must be 
satisfied.  This may be done at the cost of altering the PTV.   
5.4.6 Treatment Verification:  Weekly orthogonal films or cone beam CT’s should be 
performed to verify patient setup (at least). 
5.4.7 Radiation Treatment Breaks:  Ideally, treatment breaks, if necessary, should not exceed 
5 treatment days at a time and 10 treatment days total. Treatment breaks should be 
allowed only for resolution of severe acute toxicity and/or for intercurrent illness and not 
for social or logistical reasons. 
5.5 
Chemotherapy:  In our initial study, LCCC 1120, all patients were started on a regimen 
of cisplatin 30mg/m2 given intravenously over 60 minutes weekly during IMRT; 6 total 
doses for a total of 180 mg/m2.   However, if cisplatin was not tolerated, it was 
permissible to switch to alternative, acceptable weekly chemotherapy regimens such as 
cetuximab, carboplatin, or carboplatin/taxol.  For the proposed study, cisplatin is the 
preferred mandated first choice chemotherapy, however alternative weekly regimens are 
permissible.  Typical reasons for a patient not being able to receive cisplatin include renal 
insufficiency and history of hearing loss.  Justification for not using cisplatin must be 
documented.  Analysis of a prospective national registry, Longitudinal Oncology 
Registry of Head and Neck Carcinoma (LORHAN), showed that the three most 
commonly prescribed concurrent (with radiation) regimens (in order) are single agent 
cisplatin (51%), single-agent cetuximab (21%), and carboplatin plus paclitaxel (7%).  
Single agent carboplatin was infrequently used (3%) (Wong et al. Cancer 
2011;117:1679–86.). The acceptable weekly chemotherapy regimens that may be used on 
this study are the following: 
• Cisplatin 30 to 40 mg/m2 (preferred, first choice) 
• Cetuximab 250mg/m2 (preferred, second choice) 
• Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (preferred, third choice) 


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• Carboplatin AUC 3 (preferred, fourth choice) 
Chemotherapy will be given intravenously weekly during IMRT. 6 total doses will be 
given. It is preferred that the doses be administered on days 1, 8, 15, 22, 29, and 36; 
however, this is not mandatory.  Chemotherapy will not be given to patients with T0-2 
N0-1 disease, ≤ 10 pack years smoking history. 
5.5.1 Dose Modifications for chemotherapy:  Because of the low weekly dosage of 
chemotherapy, we anticipate few dose modifications secondary to acute 
toxicities.  Dose modifications are allowed and will be directed by the treating 
medical oncologist according to his/her discretion on an individual patient 
basis.   
5.5.2 Changing Chemotherapy Regimens: In the event that cisplatin is held for 1 
week and the patient is still deemed unable to receive further weekly cisplatin 
(because of cisplatin-related toxicity), patient will be switched to another 
protocol-acceptable weekly chemotherapy regimen (cetuximab, 
carboplatin/taxol, or carboplatin). 
Other changes may be done on a case-by-case basis depending on the standard of 
practice of the treating medical oncologist.   
5.6 
Post-Chemoradiotherapy Assessment of Clinical Response 
PET/CT will be performed 10 to 16 weeks (optimally at week 12) after CRT to assess 
response.  All patients will be evaluated via clinical exam and fiberoptic laryngoscopy by 
the radiation oncologist and head and neck surgeon around the same time as the PET/CT 
scan.  Note that the fiberoptic laryngoscopy  need only be done once, at either 6 or 12 
weeks post-CRT, with additional laryngoscopy procedures performed at the discretion of 
the physician.  Decisions for surgical evaluation will be based on the results of the 
PET/CT and clinical exam at that time.  Other optional imaging studies may be 
performed (e.g. CT scan 4 to 6 weeks after completion of CRT).    
5.7 
Surgery after CRT 
Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of 
the surgeon.  This may include biopsies and/or oncological resections of the primary 
tumor and lymph node metastases. The type of surgical procedure will be left to the 
discretion of the surgeon however the goal will be to remove any suspected residual 
tumor with a negative resection margin while maintaining organ preservation.  Patients 
with a negative PET/CT scan will be observed.   
5.8 
Other Therapy 
5.8.1 
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  
5.8.1.1 
Antiemetics:  Prophylactic antiemetics and supportive therapy for nausea and 
vomiting are permitted and highly recommended in patients participating in 


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this study. These interventions should be made according to institutional 
guidelines. 
5.8.1.2 
Nutritional Supplementation:  Close monitoring of patients’ volume status 
and body weight is strongly recommended.  Nutritional supplementation 
through a nasogastric or gastrostomy feeding tube should be considered in 
patients who are unable to maintain hydration or experience more than 10% 
loss of body weight due to mucositis. 
5.8.2 Non-permitted Supportive Therapy 
5.8.2.1 
Hematopoietic Growth Factors:  Hematopoietic growth factors are not 
permitted during radiation therapy. Growth factors are only permitted if 
administered after radiation therapy has been completed. Erythropoiesis 
stimulating agents are not permitted. 
5.8.3 Other Supportive Care Clinical Studies:  Patients will be allowed to participate in 
other supportive care clinical studies that do not interfere with the treatment plan of the 
current study. 
5.8.4 Monitoring of Acute and Chronic Toxicities  
The NCI-CTCAE v4.0 criteria will be used to document acute and late adverse 
events/toxicities associated with CRT.   
5.9 
Duration of Study 
The primary endpoint of this study is to evaluate the 2 year PFS rate after de-intensified 
CRT in HPV-positive and/or p16 positive OPSCC.  Patient participation concludes after 
2 years of follow-up after completion of CRT.  Duration of Follow Up 
After completion of treatment patients will be followed according to our institutional 
standard practice:  clinical evaluations every 2 to 3 months for 2 years.   
 
Our routine standard practice for all of our head and neck cancer patients is to encourage 
post-treatment dental follow-up and care.  This study does not increase the need for post-
treatment dental care or increase the risk of dental complication.  In fact it may decrease 
the risk/incidence of post-treatment dental complications because the radiation dose is 
being reduced to 60 Gy.  Thus we will continue to practice our routine post-treatment 
dental care recommendations.   
 
See the Time and Events Table in the Appendix for a summary of the patient 
assessments/procedures and time periods. 
 
6.0 
ADVERSE EVENTS 
6.1 
Definition 
An adverse experience is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 


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necessarily have a causal relationship with this treatment.  An adverse experience or 
event (AE) can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of 
an AE (e.g., surgical insertion of central line) need not be considered AEs and should not 
be recorded as an AE.  Disease progression should not be recorded as an AE, unless it is 
attributable by the investigator to the study therapy. 
 
In this study, toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
6.2 
Reporting 
Patients will be receiving radiation, chemotherapy, and surgical treatments within the 
accepted standard of care.  We expect patients to experience the known toxicities that are 
associated with these standard treatments.  In the recently published RTOG 0129 study 
the overall rate of grade 3 or 4 acute toxic events was approximately 80% and the late 
grade 3 or 4 toxic events was approximately 25%.  Because we are de-intensifying the 
CRT by reducing the total dose of radiation to 60 Gy and administering Cisplatin 
30mg/m2 weekly (RTOG 0129 treated patients with at least 70 Gy of radiation and 2 
cycles of 100mg/m2 of cisplatin) the acute and late toxicities should not be greater than 
what has been historically observed. 
 
Affiliate Sites 
For all Grade 3 and above toxicities which occur to any patient in the course of their treatment 
on this study or following cessation of treatment, all Affiliate sites must inform the Study 
Coordinator within 24 hours of learning of its occurrence.  The study coordinator will record 
the toxicities and report them to the DSMC at the time of scheduled reviews.  Toxicities 
classified as unexpected, related to a subject’s participation in the research, and suggesting that 
the research places subjects or others at a greater risk of harm than was previously known will 
be reported to the IRB.    
 
UNC 
6.3 
Grade 3 and above toxicities which occur to any patient in the course of their 
treatment on this study or following cessation of treatment will be recorded by the 
Study Coordinator and reported to the DSMC at the time of scheduled reviews.  
Toxicities classified as serious, unexpected, AND related to treatment will be 
reported to the IRB.  Treatment of Adverse Event 
Patients who develop any adverse event while on study will receive standard of care 
treatment.  Radiation, cisplatin, and surgery are already standard of care treatments for 


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these patients.  Standard of care treatment for known potential adverse events from these 
treatments are established. 
7.0 
STATISTICAL CONSIDERATIONS 
7.1 
Study Design/Study Endpoints 
The main objective of this Phase-II trial is to estimate the two-year progression-free 
survival probability (PFSP) in this group of patients treated with de-escalated 
radiotherapy.  The planned total sample size is 120 patients. The recruitment phase is 
expected to last 24 to 36 months, with 40 to 60 patients accrued each year.  A minimum 
follow up of two years per subject implies a total study duration of 4 to 5 years.  Drop out 
is expected to be about 10%, based on a previous trial (LCCC 1120), hence we expect a 
total of 108 patients to complete the study.  
 
The statistical aim is phrased as a hypothesis test with the null hypothesis being that the 
two-year PFSP is 0.87 and the alternative hypothesis being that the two-year PFSP is 0.80 
(or less). If the null hypothesis is rejected the conclusion will be that the de-escalated 
treatment is inferior to the standard treatment. If the null hypothesis is not rejected the 
conclusion will be that the de-escalated treatment is at least as good as the standard RT. 
 
For a sample size of 108 patients who complete the study, the null hypothesis will be 
rejected if 21 or more patients fail. The same rejection rule applies for sample sizes from 
107 to 111, with Type-I error from 0.034 at n=107 to 0.049 at n=111.  For n=112 to 117 
the null will be rejected if 22 or more patients fail, with Type-I error .031 to .047.  Failure 
is defined as not reaching the two-year time point progression-free. Defining P(Reject 
H0) to be the probability of rejecting the null hypothesis, the performance of the test, 
with 108 patients who complete the study, is summarized in the following table. 
 
True 2-year PFSP 
P(Reject H0) 
0.87 
0.04 
0.80 
0.60 
0.77 
0.84 
0.75 
0.93 
 
7.2 
Data Analysis Plan 
The main hypothesis test will be performed as described above. Additionally, a Kaplan-
Meier curve will be estimated for PFS, local control, regional control, local-regional 
control, distant metastasis free survival and overall survival.  
 
In addition to the above, other exploratory analyses utilizing study-related data may be 
performed. 
 


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7.3 
Safety Meetings 
The principal investigator will provide continuous monitoring of patient safety in this 
study with periodic reporting to the Data Safety Monitoring Subcommittee (DSMS). 
 
The principal investigator will submit summaries, together with formatted reports, to the 
DSMS for review.  The reports will be reviewed at the time of the appointed meeting 
schedule established by this committee.  Following review, the DSMS will report its 
recommendations, together with the principal investigator report, to the Oncology PRC.  
These reports will be reviewed by the PRC at the time of the study’s annual IRB renewal.  
When warranted, the PRC and/or DSMS will have the prerogative to request additional 
information. 
8.0 
STUDY MANAGEMENT 
8.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations.  The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
 
Before recruitment and enrollment into this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 
8.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North Carolina. 
 
• A copy of the official IRB approval letter for the protocol and informed 
consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• A copy of the IRB-approved consent form 
• Executed clinical research contract 


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8.3 
Registration Procedures 
All patients must be registered with the Study Coordinators at the Departments of 
Radiation Oncology at the University of North Carolina, the University of Florida, Rex 
Cancer Center of Raleigh, High Point Regional Health, and Pardee Memorial Hospital 
before enrollment in the study.  For both UNC and Affiliate patients, prior to registration, 
eligibility criteria must be confirmed with the UNC Study Coordinator. 
8.4 
Data Management and Monitoring/Auditing 
The University of North Carolina will serve as the coordinating center for this trial.  All 
data will be collected, entered, and maintained in secured servers in the Departments of 
Radiation Oncology at the University of North Carolina, the University of Florida, Rex 
Cancer Center of Raleigh, High Point Regional Health, and Pardee Memorial Hospital by 
the Study Coordinators. De-identified, password protected data from patients enrolled at 
the University of Florida, Rex Cancer Center of Raleigh, High Point Regional Health, 
and Pardee Memorial Hospital will be electronically submitted to the Department of 
Radiation Oncology at the University of North Carolina via a secured computer server.  
The data will be pooled at UNC where personnel there will coordinate and manage data 
for quality control assurance and integrity.  Data analysis will take place at UNC as well.  
As an investigator initiated study, this trial will also be audited by the Lineberger Cancer 
Center audit committee every six months.   
8.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.   
8.5.1 Emergency Modifications 
UNC and Affiliate investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior UNC or their 
respective institution’s IRB/IEC approval/favorable opinion. 
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification form must 
be completed by UNC Research Personnel within five (5) business days of making the 
change. 
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as possible after 
the modification has been made, the implemented deviation or change and the reasons for 
it should be submitted to: 
 
o To UNC Principal Investigator for agreement  
o The Affiliate institution’s IRB for review and approval.  (Once IRB’s 
response is received, this should be forwarded to the UNC Study 
Coordinator). 
   


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8.5.2 Single Patient/Subject Exceptions 
For Institutions Relying on UNC’s IRB: 
Any request to enroll a single subject who does not meet all the eligibility criteria of this 
study requires the approval of the UNC Principal Investigator and the UNC IRB.  
 
For Institutions Relying on Their Own IRB: 
Any request to enroll a single subject who does not meet all the eligibility criteria of this 
study requires the approval of the UNC Principal Investigator and the participating 
institution’s IRB, per its policy.  Please forward the IRB response to the UNC Study 
Coordinator by facsimile or via email within 10 business days after the original 
submission.   
 
8.5.3 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the UNC IRB.  According to UNC’s IRB, a protocol deviation is any 
unplanned variance from an IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• Has harmed or increased the risk of harm to one or more research participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the investigator(s). 
• Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, 
please follow the guidelines below: 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies.  Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.   
 
For Institutions Relying on Their Own IRB: 
In addition to adhering to the policies regarding protocol compliance set forth by your 
institution’s IRB, the following is also required: 


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CONFIDENTIAL 
PI:  Colette Shen, MD 
 
UNIVERSITY OF NORTH CAROLINA 
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Protocol Deviations: Affiliate personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies.  Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Any protocol violation that occurs must be reported to your IRB 
per institutional policies and reported to the UNC Study Coordinator within 5 days. 
UNC-CH will determine if the violation affects the safety of the patient and integrity of 
the data.  Once your institution’s IRB response is received, please forward to the UNC 
Study Coordinator. 
8.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator at UNC.  It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.   
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent to 
UNC’s IRB for approval prior to implementation.   
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the UNC IRB approved amendment to their institution’s IRB 
for approval.  For multi-center studies, any affiliate site must submit their informed 
consent revisions to the UNC Study Coordinator prior to submission to their IRB.   
 
8.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of marketing 
application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 


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PI:  Colette Shen, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Version/Date:  10/24/2024 
 
 
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8.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  The Principal Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the study 
protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both 
during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits will be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of data. At 
the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 


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PI:  Colette Shen, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Version/Date:  10/24/2024 
 
 
21 
9.0 
REFERENCES 
 
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Chaturvedi A, Engels E, Anderson W, al. e. Incidence trends for human papillomavirus-
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D'Souza G, kreimer A, Viscidi R, al. e. Case-control study of human papillomavirus and 
oropharyngeal cancer. N Engl J Med. 2007;356:1944-56.  
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Frisch M, Hjalgrim H, Jaeger A, al. e. Changing patterns of tonsillar squamous cell 
carcinoma in the United States. Cancer Causes Control. 2000;11:489-95.  
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Gillison M, Koch W, Capone R, al. e. Evidence for a causal association between human 
papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92:709-20.  
6. 
Schantz S, Yu G. Head and neck cancer incidence trends in young Americans, 1973-
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Shiboski C, Schmidt B, Jordan R. Tongue and tonsil carcinoma:  increasing trends in the 
U.S. population ages 20-44 years. Cancer. 2005;103:1843-9.  
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Shiboski C, Shiboski S, S Silverman J. Trends in oral cancer rates in the United States, 
1973-1996. Community Dent oral Epidemiol. 2000;28(249-56) 
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Albers A, Visus C, Tsukishiro T, al. e. Alterations in the T-cell receptor variable beta 
gene-restricted profile of CD8+ T lymphocytes in the peripheral circulation of patients with 
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Ang K, Harris J, Wheeler R, al. e. Human paillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med. 2010;363:24-35.  
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Braakhuis B, Snijders P, Keune W, al. e. Genetic patterns in head and neck cancers that 
contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst. 2004;96:998-
1006.  
12. 
DeWeese T, Walsh J, Dillehay L, al. e. Human papillomavirus E7 and E7 oncoproteins 
alter cell cycle progression but not radiosensitivity of carcinoma cells treated with low-dose-rate 
radition. Int J Radiat Oncol Biol Phys. 1997;37:145-54.  
13. 
Fakhry C, Westra W, Li S, al. e. Improved survival of patients with human 
papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J 
Natl Cancer Inst. 2008;100:261-9.  
14. 
Gupta A, Lee J, Wilke W, al. e. Radiation response in two HPV-infected head-and-neck 
cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling 
through AKT. Int J Radiat Oncol Biol Phys. 2009;74:928-33.  
15. 
Hoffmann T, Sonkoly E, Hauser U, al. e. Alterations in the p53 pathway and their 
association with radio- and chemosensitivity in head and neck squamous cell carcinoma. Oral 
Oncol. 2008;44:1100-9.  
16. 
Klussmann J, Mooren J, Lehnen M, al. e. Genetic signatures of HPV-related and 
unrelated oropharyngeal carcinoma and their prognostic implications. Clin Cancer Res. 
2009;15:1779-86.  
17. 
Kumar B, Cordell K, Lee J, al. e. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and 
smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol. 
2008;26:3128-37.  


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UNIVERSITY OF NORTH CAROLINA 
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22 
18. 
Lassen P, Eriksen J, Hamilton-Dutoit S, al. e. Effect of HPV-associated p16INK4A 
expression on response to radiotherapy and survival in squamous cell carcinoma of the head and 
neck. J clin Oncol. 2009;27:1992-8.  
19. 
Licitra L, Perrone F, Bossi P, al. e. High-risk human papillomavirus affects prognosis in 
patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol. 
2006;24(5630-6) 
20. 
Lohavanichbutr P, Houck J, Fan W, al. e. Genomewide gene expression profiles of HPV-
positive and HPV-negative oropharyngeal cancer:  potential implications for treatment choices. 
Arch Otolaryngol Head Neck Surg. 2009;135:180-8.  
21. 
Martinez I, Wang J, Hobson K, al. e. Identification of differentially expressed genes in 
HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas. Eur J Cancer. 
2007;43:415-32.  
22. 
Mork J, Lie A, Glattre E, al. e. Human papillomavirus infection as a risk factor for 
squamous-cell carcinoma of the head and neck. N Engl J Med. 2001;344:1125-31.  
23. 
Padilla L, Leung B, Carson L. Evidence of an association between human papillomavirus 
and impaired chemotherapy-induced apoptosis in cervical cancer cells. Gynecol Oncol. 
2002;85:59-66.  
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Saxena A, Yashar C, Taylor D, al. e. Cellular response to chemotherapy and radiation in 
cervical cancer. Am J Obstet Gynecol. 2005;192:1399-403.  
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Schwartz S, Yueh B, McDougall J, al. e. Human paillomavirus infection and survival in 
oral squamous cell cancer:  a population-based study. Otolaryngol Head Neck Surg. 2001;125:1-
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26. 
Smeets S, Braakhuis B, Abbas S, al. e. Genome-wide DNA copy number alterations in 
head and neck squamous cell carcinomas with or without oncogene-expressing human 
papillomavirus. Oncogene. 2006;25:2558-64.  
27. 
Spanos W, Nowicki P, Lee D, al. e. Immune response during therapy with cisplatin or 
radiation for human papillomavirus-related head and neck cancer. Arch Otolaryngol Head Neck 
Surg. 2009;135(1137-46) 
28. 
Tseng C, Trimble C, Zeng Q, al. e. Low-dose radiation enhances therapeutic HPV DNA 
vaccination in tumor-bearing hosts. Cancer Immunol Immunother. 2009;58:737-48.  
29. 
Weinberger P, Yu Z, Haffty B, al. e. Molecular classification identifies a subset of human 
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Westra W, Taube J, Poeta M, al. e. Inverse relationship between human papillomavirus-
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Clin Cancer Res. 2008;14:366-9.  
31. 
Network NCC. NCCN Clinical Practice Guidelines in Oncology. 2011. 
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O'Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human 
papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J 
Clin Oncol. Feb 10 2013;31(5):543-50. doi:10.1200/JCO.2012.44.0164 
33. 
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Radiation Therapy in Treating Patients With HPV-Associated Stage III or Stage IV Cancer of the 
Oropharynx That Can Be Removed By Surgery. 
34. 
Docetaxel/Cisplatin/5-Fluorouracil (TPF) Human Papillomavirus (HPV) Squamous Cell 
Carcinoma Study. 


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UNIVERSITY OF NORTH CAROLINA 
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35. 
Pignon J, Maitre Al, Maillard E, al. e. Meta-analysis of chemotherapy in head and neck 
cancer (MACH-NC):  an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 
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36. 
O'Sullivan B, Huang S, Perez-Ordonez B, al. e. Outcome of Radiotherapy Alone in HPV 
Associated Oropharyngeal Cancer. Int J Radiat Oncol Biol Phys. 2010;78:S62-S63.  
37. 
Garden AS, Asper JA, Morrison WH, et al. Is concurrent chemoradiation the treatment of 
choice for all patients with Stage III or IV head and neck carcinoma? Cancer. Mar 15 
2004;100(6):1171-8. doi:10.1002/cncr.20069 
38. 
Gregoire V, Eisbruch A, Hamoir M, Levendag P. Proposal for the delineation of the 
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2006;79(1):15-20. doi:10.1016/j.radonc.2006.03.009 
39. 
Gregoire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and 
related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG 
consensus guidelines. Radiother Oncol. Dec 2003;69(3):227-36.  
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O'Sullivan B, Warde P, Grice B, et al. The benefits and pitfalls of ipsilateral radiotherapy 
in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys. Oct 1 2001;51(2):332-43.  
 
 
 


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PI:  Colette Shen, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Version/Date:  10/24/2024 
 
 
24 
10.0 APPENDIX 
Eligibility Checklist
 


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PI:  Colette Shen, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Version/Date:  10/24/2024 
 
 
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PI:  Colette Shen, MD 
 
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26 
 
 
 
Time and Events Table 
 
Assessments/Proc
edure 
Prior to CRT 
Weekly during 
CRT 
6-8 weeks 
after CRT 
10-16 weeks 
after CRT 
6 months 
after CRT 
Follow-up visits 
every 2-3 months 
for 2 years after 
CRT, every 6 
months for 3 years, 
then yearly ^^^ 
Follow-up visits 
every 6 months for 
2 years after CRT, 
then yearly 
Clinical evaluation 
× 
× 
 
× 
 
× 
 
Panendoscopy (if 
primary 
unknown)* 
× 
 
 
 
 
 
 
Contrasted neck 
CT (or PET/CT) 
× 
 
 
 
 
 
× 
Chest x-ray 
× 
 
 
 
 
 
 
Dental evaluation* 
× 
 
 
 
 
 
 
Labs: CBC, serum 
chemistries, liver 
function tests, 
pregnancy test (F) 
× 
 
 
 
 
 
 
HPV and p16 
testing 
× 
 
 
 
 
 
 
NCI-CTCAE 
(physician) 
× 
×*** 
 
× 
 
 
× 
Modified Barium 
Swallow and/or 
FEES 
× 
 
 
 
× 
 
 
Fiberoptic 
laryngoscopy 
× 
 
 
×^^ 
 
× 
 
PET/CT 
 
 
 
× 
 
 
 
Thyroid Function 
 
 
 
 
 
 
× 
Footnotes to Time & Events Table 


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PI:  Colette Shen, MD 
 
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* 
Strongly recommended, but not required.* Strongly recommended, but not required. 
** 
Weeks 3 and 6 only; the pre/end/post online questionnaire will be given in lieu of the weekly questionnaire 
at last weekly treatment. 
*** 
Weeks 3 and 6 only 
^  
This should be quantified with the Rosenbek Penetration Aspiration Scale. 
^^  
Laryngoscopy required at only one of these timepoints (i.e., 6 weeks of 12 weeks post-CRT). 
^^^  Exact timing of follow-up visits I flexible based on physician’s standard of care.