A Prospective, Randomized Phase II Study of Surgery With or Without Adjuvant Stereotactic Body Radiotherapy (SBRT) in Patients With Previously-Irradiated Head and Neck Cancer
Phase: NA
Conditions: Head and Neck Cancer
Sponsor: David A. Clump, MD, PhD

 
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SURGERY WITH OR WITHOUT STEROTACTIC BODY RADIOTHERAPY 
  
A Prospective Randomized Phase II Study of Surgery with or without Adjuvant 
Stereotactc Body Radiotherapy (SBRT) in Patients with Previously-Irradiated Head and 
Neck Cancer 
(Version Dated 2020-04-29) 
 
Principal Investigator: 
 
 
David A. Clump, MD, PhD 
 
 
 
 
 
UPMC Cancer Center 
 
 
 
 
 
Mary Hillman Jennings Radiation Oncology Center 
 
 
 
 
 
MHJROC Posner Tower, 1st Floor 
 
 
 
 
 
5230 Centre Avenue 
 
 
 
 
 
Pittsburgh, PA  15232 
 
 
 
 
 
clumpda2@upmc.edu  
 
 
 
 
 
Ph: (412) 623-6720 
 
 
 
 
 
Fax: (412) 623-4050 
 
Study Co-Investigators:  
 
Radiation Oncology 
 
 
 
 
 
Steven A. Burton, MD (burtons@upmc.edu ) 
 
 
 
 
 
Robert L. Ferris, MD, PhD (ferri@upmc.edu ) 
 
 
 
 
 
John Vargo, MD (vargoja4@upmc.edu ) 
 
 
 
 
 
 
Hematology Oncology 
 
 
 
 
 
James Paul Ohr, MD (ohrj@upmc.edu ) 
 
 
 
 
 
 
 
 
 
 
 
Otolaryngology 
 
 
 
 
 
Umamaheswar Duvvuri, MD (duvvuriu@upmc.edu ) 
 
 
 
 
 
Jonas T. Johnson, MD (johnsonjt@upmc.edu ) 
 
 
 
 
 
Seungwon W. Kim, MD (kimsw2@upmc.edu ) 
 
 
 
 
 
Carl Snyderman, MD (snydermanch@upmc.edu ) 
 
Biostatistics 
              Hong Wang, PhD (how8@pitt.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ………………………………………………………………….… 3 
 
1.0  
BACKGROUND ………………………….…………………………………...…..……5 
 
2.0  
OBJECTIVES …………………………………………………………………..………7 
 
3.0  
INVESTIGATIONAL PLAN…………………………………………….………….... 8 
 
4.0  
SUBJECT SELECTION AND ELIGIBILITY.………………………………….…..11 
 
5.0  
TREATMENT EVALUATION, ADMINISTRATION, AND MODIFICATION…13 
 
6.0  
STATISTICAL CONSIDERATIONS………………………………………..……….14 
 
7.0  
DATA SAFETY AND MONITORING………...……...……………….…..…………16 
 
8.0      REFERENCES ………………………………………………………………………....17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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PROTOCOL SUMMARY 
 
Title 
A Prospective Randomized Phase II Study of Surgery with or without Adjuvant 
Stereotactc Body Radiotherapy (SBRT) in Patients with Previously-Irradiated Head and 
Neck Cancer 
 
Objectives 
The primary objective of this study is to compare the 1-year local control in patients with 
operable, recurrent previously-irradiated squamous cell head-and-neck cancers with or 
without adjuvant SBRT.  
 
The secondary objectives of this study are: 
1. To determine the locoregional progression-free survival (PFS) distant PFS, overall PFS 
(local + regional + distant), and overall survival (OS). 
2. To evaluate the acute and late toxicities of adjuvant SBRT in the re-irradiation setting 
following salvage surgery. 
3. To determine prognostic factors that may predict the likelihood of local failure, regional 
failure, or OS in this cohort to guide future management. 
4. To compare the impact of adjuvant SBRT versus a wait-and-see approach on patient 
reported quality of life (PR-QoL). 
5. To compare surgical versus SBRT-induced immunological serum markers in relation to 
local control. 
 
Patient population 
In order to be eligible for this study, patients must have a pathologically proven recurrent or 
second-primary head-and-neck cancer with no evidence of distant matastases. Patients mut be at 
least 18 years of age and able to give informed consent. They must have a Karnofsky 
Performance Status ≥ 60. 
 
Number of patients 
42 
 
Study design and methodology 
This is a prospective, double-arm phase II study. The treatment schema detail is in Section 6.3. 
 
Treatment administered 
Patients will  or will not receive adjuvant Stereotactic Body Radiotherapy (SBRT) at various 
levels depending upon tumor volume. Subsequent evaluations will measure the efficacy of the 
adjuvant SBRT. 
 
Efficacy data collected 
The following evaluations will be performed to assess the efficacy of preoperative stereotactic 
radiation therapy: 

 
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• Objective local control rate measuring tumor volume 
• Health Related Quality of Life assessment using the University of Washington Quality-
of-Life-Revised (UW-Qol-R) 
 
Safety data collected 
The following evaluations will be conducted to assess the safety of radiosurgery: 
• Recording of all toxicity data per NCI CTCAE version 4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1.0 BACKGROUND 
 
1.1 Salvage Surgery for Recurrent Head-and-Neck Cancers 
Recurrent and second-primary head-and-neck cancers (rHNC) in a previously-irradiated 
field represent a therapeutic challenge (1). Even with adjuvant therapy, rHNC occurs in 
≥20-30% of high-risk postoperative patients and ≥30% of patients treated with definitive 
chemoradiotherapy (2-3). While there are no randomized data to test the benefits of 
salvage surgery after prior irradiation, for patients who can have surgical resection, based 
on available data, surgical resection represents the currently accepted standard of care (4- 
5). However, even patients with resectable rHNC are at high-risk for subsequent failure 
(67% overall failure rates). In patients with close or positive surgical margins following 
salvage surgery, recurrence rates of nearly 100% have been reported (6). To improve 
tumor control in this setting adjuvant re-irradiation techniques along with chemotherapy 
has been used with mixed but limited success (7-10). 
 
1.2 Adjuvant Re-Irradiation 
The only phase III experience evaluating adjuvant therapy after surgical salvage is from the 
Institute Gustave-Roussy (7). In this phase III study, 130 previously-irradiated rHNC 
patients were randomized following salvage surgery to chemotherapy + re-irradiation 
(CT/Re-RT) versus observation. Chemotherapy consisted of six cycles of hydroxyurea and 
continuous infusion 5-FU, while adjuvant re-irradiation was delivered to a total dose of 60 
Gy in a split-course fashion (the contemporaneous RTOG standard). Disease-free survival 
(DFS), but not overall survival (OS), was improved with the addition of adjuvant CT/Re-RT 
(the study was not powered for OS). However, this treatment was not without toxicity. 
Grade 3 or 4 mucositis was seen in 28% of patients and 39% of patients had grade 3 or 4 
late toxicity versus only 10% of patients in the observation arm. This is the only level I 
evidence for adjuvant therapy in re-irradiation setting. Thus the data supports the role of 
re-irradiation in improving local control albeit with the expense of significant toxicity. 
 
1.3 Stereotactic Body Radiotherapy 
Stereotactic body radiotherapy (SBRT), is a treatment technique that incorporates advances in radiation 
planning and delivery to provide highly conformal doses of radiation with a 
steep-dose gradient to surrounding critical organs-at-risk. Since 2001, researchers at the 
University of Pittsburgh Cancer Institute have been pioneers in the use of frameless 
extracranial SBRT for a variety of benign and malignant lesions. The advantages of SBRT in 
the setting of re-treatment of high-risk patients with head and neck carcinomas are a highly 
conformal treatment volume that affords a small number of fractions, decreased overall 
treatment time, and radiobiological advantages (where acute responding tissue is better 
spared with higher doses per fraction/lower overall dose to) minimizing acute toxicity. 
 
1.4 Experiences with SBRT at the University of Pittsburgh 
Stereotactic body radiotherapy (SBRT) has emerged as a promising treatment option in 
patients with unresectable rHNC. Initial phase I dose-escalation study from the University 
of Pittsburgh Cancer Institute established the safety of SBRT up to 44 Gy in 5 fractions 
(11). Numerous subsequent international single-institution studies have confirmed the 
primary benefits of SBRT relative to conventional re-irradiation ± chemotherapy for 
unresectable rHNC: decreased toxicity with comparable tumor control/survival (12-17). 

 
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Further studies from the University of Pittsburgh Cancer Institute have established a dose 
volume response model and shown similar outcomes for non-squamous versus squamous 
histologies (18-19). Moreover, longitudinal prospective evaluations of patient-reported 
quality of life (PR-QoL) have shown that improved tumor control associated with SBRT 
reirradiation ameliorates decreased PR-QoL resulting from rSCCHN which transcended all 
measured domains in a validated PR-QoL assessment tool. This improvement was 
independent of age, use of cetuximab, tumor volume, and interval since prior irradiation 
(20). Finally, recent prospective data has suggested that the addition of cetuximab to SBRT 
may improve tumor control without significant increases in re-irradiation toxicity for 
unresectable rHNC (21-22). While there is growing evidence for SBRT in unresectable rHNC, 
there is limited data in the adjuvant setting (23). We recently reported our experience using 
SBRT following salvage surgery for patients with compromised/positive surgical margins 
and extra-nodal extension at high-risk for recurrence (24). Based on these results, SBRT 
may improve tumor control relative to salvage surgery alone and reduce toxicity relative to 
conventional adjuvant radiotherapy ± chemotherapy in rHNC (see Table 1). We seek to 
confirm these retrospective observations with the prospective trial evaluating SBRT to 
observation post-surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2.0 OBJECTIVES 
 
 
Primary 
 
2.1  To compare the 1-year local control in patients with operable, recurrent previously-irradiated  
        squamous cell head-and-neck cancers with or without adjuvant SBRT. 
 
 
Secondary 
 
2.2  To determine the locoregional progression-free survival (PFS) distant PFS, overall PFS 
        (local + regional + distant), and overall survival (OS). 
 
2.3  To evaluate the acute and late toxicities of adjuvant SBRT in the re-irradiation setting 
       following salvage surgery. 
 
2.4  To determine prognostic factors that may predict the likelihood of local failure, regional 
       failure, or OS in this cohort to guide future management. 
 
2.5  To compare the impact of adjuvant SBRT versus a wait-and-see approach on patient 
       reported quality of life (PR-QoL). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3.0 INVESTIGATIONAL PLAN 
 
3.1 Overall design and plan of the study 
Detailed visit-by-visit study procedures and a study flow chart are provided in Section 6.3.  Prior 
to enrollment, all subjects will be evaluated with medical records to confirm patient received 
diagnosis of recurrent or second-primary head-and-neck squamous cell carcinomas. Additionally, 
these records will confirm the patient had had macroscopic complete (R0/R1) salvage surgery and 
previous radiation. Patients will receive a Stereotactic Body Radiotherapy and then followed 
periodically for up until 2 years. 
 
3.2 Screening procedures 
• Medical history (including review of pathology and laboratory values) and physical 
examination 
• Pathologic confirmation of diagnosis and disease status/staging with biopsy to rule out 
metastatic disease (if necessary) 
• Baseline laboratory assessment, including CBC and blood chemistry 
• Urine or blood β-HCG within 14 days prior to study start for females who are not at least 
one year post-menopausal or who have not undergone a surgical sterilization procedure 
• CT or PET-CT of the neck and chest 
• Baseline Quality of Life Assessment 
 
3.3 Personnel performing the procedures 
All procedures will be performed by appropriate certified medical personnel, including, but not 
limited to physicians, nurses, technologists and research staff. 
 
3.4 Location and duration of procedures 
All study visits will take place on an outpatient basis in the UPMC Shadyside Radiation 
Oncology Department. However, it is possible that a subject may be an inpatient at the 
time of diagnosis. All procedures will be performed by appropriate certified medical personnel. 
 
3.5 Timeline of study procedures 
Once eligible by screening and enrolled in study, patients will be randomized into one of two arms. 
One arm will receive SBRT treatment for 1 – 2 weeks. The second arm will receive no SBRT and 
will continue with standard of care treatment. Patients will be followed for 8-12 weeks after 
treatment and every 3-6 months for up to 24 additional months. Extended long-term follow-up will 
occur as clinically indicated until death. 
 
3.6 Research Activities 
 
3.6.1 Pretreatment Evaluation 
The following tests/procedures will be performed within 3 months prior to registration unless 
otherwise specified: 
• Medical history and physical examination 
• Pathologic confirmation of diagnosis and disease status/staging with biopsy to rule out 
metastatic disease if necessary 
• Baseline laboratory assessment, including CBC and blood chemistry 

 
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• Urine or blood β-HCG within 14 days prior to study start for females who are not at least 
one year post-menopausal or who have not undergone a surgical sterilization procedure 
• CT (computed tomography) scan or FDG-PET-CT (18F-fluorodeoxyglucose positron 
emission tomography/computed tomography) of the neck and chest 
• Baseline Quality of Life Assessment (University of Washington – Quality of Life – 
Revised (UW-QoL-R) 
 
3.6.2 Randomization 
Once the participant is deemed eligible for the study based upon the screening procedures, the 
patient will be randomized. The randomization of subjects to one of the two treatment arms will 
be in a 1:1 ratio, between the presence or absence of SBRT treatment. The Hillman Cancer 
Center biostatics facility has a randomizer, an intranet application for randomly assigning 
patients to different thresholds, which will be used for the randomization in the trial. 
 
3.6.3 Treatment 
Steriotactic Body Radiotherapy (SBRT) will be performed on 1 of the treatment arms. Group 
1 will receive SBRT for 1-2 weeks. 
 
3.6.3.1 Tumor Volume 
Tumor volumes <25cc will receive 40Gy (5 fractions of 8Gy per fraction). Tumor volumes ≥25cc 
will receive 44-50Gy (5 fractions of 8.8 – 10 Gy per fraction). Ideally, all tumor volumes ≥25cc 
will receive 50Gy over 5 fractions; however, at the discretion of the treating radiation oncologist 
based on tumor bed volume, prior radiation dose, and proximity to critical organs, the dose can be 
reduced to 44 Gy over 5 fractions. 
 
3.6.3.2 Randomized Arm 
Patients randomized to the adjuvant SBRT arm will receive 40-50Gy in 5 fractions on non-
consecutive days in 1-2 weeks on an outpatient basis. SBRT should be completed at a minimum 
of 4-weeks following salvage surgery, with a maximum of 12-weeks. CTV (clinical target volume) 
will represent the tumor bed/high-risk region as defined by head and neck surgeon and radiation 
oncologist. A maximum of 5mm expansion from CTV to PTV (planning target volume) shall be 
applied 
 
 
Treatment Volumes < 25cc will receive 40Gy (5 fractions of 8 Gy per fraction) 
 
Treatment Volumes ≥ 25cc will receive 44-50Gy over 5 fractions (5 fractions of 8.8Gy per  
 
 
 
 
fraction). Ideally, all tumors volumes ≥ 25cc will receive 50Gy over  
5 fractions; however, at the discretion of the treating radiation  
oncologist based on tumor volume, prior radiation dose and  
proximity to critical organs, the dose can be reduced to 44Gy over 5  
fractions as outlined in prior SBRT protocols. 
 
 
3.6.3.3 Specifications 
SBRT treatments are to be delineated using CT-based planning with custom thermoplastic 
mask for immobilization. SBRT is to be delivered using linear accelerators commissioned to 
deliver SBRT such as Cyberknife™ M6 (Accuracy, Inc., Sunnyvale, CA) Trilogy™ or 
TrueBeam™ STx (Varian Medical Systems Inc., Palo Alto, CA), with daily image guidance to 

 
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set-up verification and assessment of intra- and inter-fraction motion. 
 
3.6.4 Follow-up/Long-term follow-up/Extended long-term follow-up procedures 
Follow-up evaluations will be completed in patients in both arms (SBRT and wait-and see). 
They will be carefully followed every 3-6 months for 24 months or until death. Evaluations 
will consist of the following: 
• Interim medical history and physical examination 
• Careful documentation of Toxicity According to National Cancer Institute Common 
Toxicity Criteria Events Scale version 4.0 
• Follow-up Patient-Reported Quality of Life Assessment (PR-QoL) 
• FDG PET-CT at 8-12 weeks post-treatment then every 12 weeks 
 
 
TABLE 1: Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.5 Methods of Measurement 
The methods of measurement are as follows: 
 
CT, PET/CT, or MRI are the best currently available methods for measuring disease status. 
Lesions that can be accurately measured in at least one dimension ≥ 10mm (1.0 cm). If 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
 
Clinically detected lesion will only be considered measurable when superficial (vis-à-vis skin 
nodules and palpable lymph nodes). Documentation should include color photography and 
ruler estimation of size. 
 
3.6.6 Evaluation of Disease Status and Survival 
Survival and time to progression will be measured from the date of salvage surgery to date 
of death, appearance of new metastatic lesion, or objective tumor progression. 
 
 
 
 
 
 
 
Pre-Study 
During 8-12 
weeks 
Q 12-24 weeks SBRT Post for 
2-years 
History 
+ 
Physical 
 
X 
 
X 
 
X 
 
X 
Imaging 
X 
X 
X 
 
QoL 
Assessment 
 
X 
 
X 
 
X 
 
Clinical Visit 
Assessment 

 
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4.0 SUBJECT SELECTION AND ELIGIBILITY 
 
4.1 Selection of subjects 
Forty-two (42) patients with recurrent or second-primary head-and-neck squamous cell 
carcinomas within a previously-irradiated field with high-risk features (compromised/positive 
surgical margins or extra-nodal extension) following macroscopic complete (R0/R1) salvage  
surgery will be recruited for this randomized phase II study. 
 
4.2 Identification and initiation of contact with study participants 
Potential research subjects are first identified by their primary doctor/clinical team. The 
research project will be discussed by the caregiver with the patient. If interested, the 
patient will be informed at this time either to contact the research team to express his/her 
interest in participating. Other subjects are referred in specifically for possible participation 
in a study which they or their physicians are aware of based on publications which list 
clinical trials at UPCI. "Cold-calling" will not be used to recruit subjects. Potential subjects 
will be approached by clinicians who are directly involved in their care. "Finder's fees" for 
referring a potential subject for participation in a research study are prohibited. 
 
Physicians and other health care professionals in the area are aware of active studies at 
UPMC Radiation Oncology Department by means of various publications including the World 
Wide Web. Such publication and Web listings are not advertisements for specific studies. 
Rather, they are public listings of trials available. 
 
Once a subject is identified as a potential participant in a research study as indicated above, 
he/she is screened for eligibility. No identifiable information (e.g. name, diagnosis, 
treatment, etc.) will be released until the subject has given written authorization. No 
research-related procedures (including review of the subject's medical records) will be 
performed until the subject has provided written informed consent. The consent process will 
be carried out as a joint effort among the subject's physicians, the study coordinators, and 
a physician who is listed as an investigator on the study. 
 
4.3 Inclusion criteria 
Each patient must meet all of the following inclusion criteria for study enrollment: 
• Age ≥18 with ability to provide written informed consent 
• Pathologically proven recurrent or second-primary head-and-neck cancer receiving prior 
radiotherapy with or without chemotherapy 
• Prior radiotherapy to a dose of ≥50Gy 
• No evidence of distant metastases 
• Macroscopic complete salvage surgery with curative intent (surgery was not performed 
only for biopsy or palliation). Final pathology and imaging must indicate a R0 or R1 
resection (no gross disease remaining). 
• High-risk pathologic features must be present: compromised/positive surgical margins  
(≤ 2mm) or extra-nodal extension (patient with other high-risk features gross perinueral 
invasion, bone invasion, angiolyphatic invasion, or a constellation of these factors may be 
eligible based on case-by-case basis at discretion of principal investigator). 
• Karnofsky Performance Status ≥60 (ECOG 0-2) 

 
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• Any number or type of prior chemotherapy is allowed (patient may receive concurrent or 
adjuvant systemic therapy such as cetuximab at the discretion of the treating oncologic 
team). 
 
4.4 Exclusion criteria 
Patients meeting any of the following exclusion criteria are not eligible for enrollment: 
• Evidence of distant metastases on any staging or imaging modality 
• Women who are breast feeding, or have a positive pregnancy test (reproductive age 
should use effective birth control during study if randomized to SBRT treatment arm) 
• Any patient with gross residual disease following salvage surgery 
• Any co-morbidity or condition of sufficient severity to limit full compliance with the 
protocol per assessment by the principal investigator. 
 
4.4.1 Specific criteria to exclude pregnant females and feta/neonatal exposure 
 
For all females who are not at least one year post-menopausal or who have not undergone a 
surgical sterilization procedure, a urine pregnancy test will be done. If this is positive or 
questionable a serum pregnancy test will be done. The results of the pregnancy test must be 
negative in order for the patient to participate in this study. 
 
Women who are pregnant or breastfeeding are excluded from participation in this study. All 
females of childbearing potential must have a serum pregnancy test within 14 days of the 
radiation. The results of the pregnancy test must be negative for the patient to participate 
in this study. 
 
Subjects will be informed by the study staff that is extremely important that they not 
become pregnant or father a baby while participating in this study, and that avoiding sexual 
activity is the only certain method of preventing pregnancy. However, if a subject chooses 
to be sexually active, he or she must agree to use an appropriate "double barrier" method 
of birth control starting from the subject's participation in the screening process to include a 
negative pregnancy test to continue as a study participant and continuing until two weeks 
following the subject's participation in the study. The methods of birth control should 
include intrauterine device (IUD), contraceptive sponge and spermicide, in addition to male 
use of a condom, or the female should be using prescribed birth control implant. Subjects 
will be instructed to notify the study doctor of their birth control method prior to the start of 
the study, and also if they plan to change their birth control method. 
 
Subjects that choose to be sexually active must be made aware that even with the use of 
birth control measures, pregnancy could still result. Subjects will be informed that if they 
become pregnant or impregnate a woman while taking part in this study, they must 
immediately notify one of the doctors listed on the consent form. 
 
The information listed above will be relayed to applicable subjects by the study staff. It will 
also be listed in the consent form, a copy of which will be provided to the patients for them 
to take home. 
 

 
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5.0 TREATMENT EVALUATION, ADMINISTRATION, AND MODIFICATION 
 
5.1 Primary outcome variables to be evaluated 
 
(1) Primary endpoint - local progression-free survival (LPFS), defined as the time from the 
date of randomization to the date of local progression or the date of death from any cause. 
Subjects who are alive and have not progressed will be censored at their last follow-up date. 
(2) Regional PFS, distant PFS, PFS (local + regional + distant): The definition of these 
endpoints is similar to LPFS. 
(3) Overall Survival: time from the date of randomization to the date of death due to any 
cause. 
(4) Acute and late toxicities of adjuvant SBRT. Acute toxicity is defined as toxicity occurring 
within 3 months of completion of SBRT. Late toxicity is defined as toxicity occurring later 
than 3 months after SBRT treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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6.0 STATISTICAL CONSIDERATIONS 
 
6.1 Study objectives and design 
The primary objective is to compare the 1-year local control in patients with 
operable, recurrent previously-irradiated squamous cell head-and-neck cancers with or 
without adjuvant SBRT. 
 
Secondary objectives include to determine the locoregional progression-free survival (PFS) 
distant PFS, overall PFS (local + regional + distant), and overall survival (OS); to evaluate the  
acute and late toxicities of adjuvant SBRT in the re-irradiation setting following salvage surgery; 
to determine prognostic factors that may predict the likelihood of local failure, regional failure, 
or OS in this cohort to guide future management; and to compare the impact of adjuvant SBRT 
versus a wait-and-see approach on patient reported quality of life (PR-QoL), 
 
This clinical trial is planned as a prospective, randomized, two-arm Phase II study. 
 
6.2 Sample size and accrual rate 
Forty (40) patients will be screened for each arm of the trial so that 21 subjects will be cleared to 
participate in research procedures in each arm of the trial.  
 
The following assumptions are used in determining the sample size for this study: 
Primary endpoint: local progression-free survival (LPFS) 
One-sided type I error rate: 0.10 
Statistical power: 90% 
One-year LPFS for surgery alone: 20% 
One-year LPFS for surgery + SBRT: 52% 
Randomization: 1:1 
2-year accrual period and one year follow-up following closure of accrual 
5% lost to follow-up in each arm 
 
To have 90% power to detect the above 32% difference in one-year LPFS, using a onesided 
log-rank test with a 0.1 level of significance, 21 patients are required in each arm. 
The randomization of subjects to one of the two treatment arms will be in a 1:1 ratio. The 
UPCI Biostatistics Facility has a randomizer, an intranet application for randomly assigning 
patients to different treatments, which will be used for the randomization in this trial. 
 
6.3 Statistical approach and analysis 
 
(1) Efficacy Analysis Set: includes all enrolled and randomized patients. Subjects will be 
analyzed according to their randomized treatment group assignment. 
(2) Safety Analysis Set: The safety analysis will be performed according to the actual 
treatment received. 
 
 
 
 

 
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6.4 Analysis of primary and secondary endpoints  
 
Survival endpoints will be estimated by the Kaplan-Meiermethod and the corresponding median 
survival times (with 95% confidence interval) reported. The one-year LPFS will also be 
estimated along with its 95% confidence interval. Survival will be compared between the two 
arms with the one-sided log-rank test. Effect of treatment and other variables (e.g., baseline 
characteristics, biomarkers etc) on survival will be explored with Cox regression models. 
 
For the quality of life (QoL) data analysis, each item of the UW-QoL-R will be individually 
assessed. The mean and standard deviation of the observed data will be summarized at 
each collection time and plotted against time, from baseline through the end of patient 
follow-up. Generalized linear models (such as cumulative logit models) for repeated 
measures will be used to explore if there are significant changes in PR-QOL over time. 
 
Using NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0), the number of 
patients experiencing adverse events over their course of treatment will be characterized by 
type of adverse event and grade, by the time of onset in relation to the first day of therapy, 
and whether the event is clinically significant. Attribution of adverse events to treatment 
(unrelated, unlikely, possibly, probably, or definitely) will also be summarized for any serious 
adverse events (SAEs), CTCAE grade 3 or higher. The percentage of patients experiencing 
SAEs that are considered to be treatment-related (probable or definite) will be determined. 
The percentages of patients experiencing the acute/late toxicities associated with SBRT will 
also be estimated along with their exact 95% confidence intervals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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7.0 DATA SAFETY AND MONITORING 
 
7.1 Data monitoring plan 
All research-related procedures will be conducted by certified medical personnel. The study 
staff will monitor the subjects closely throughout the study for any adverse events, and 
subjects will be strongly encouraged to report all issues to the study staff. All supportive 
measures consistent with optimal patient care will be given throughout the study. 
 
All subject data will be collected by the University of Pittsburgh Cancer Institute’s 
Department of Radiation Oncology’s Protocol Office. All data will be secured in a password 
protected file with observance of all applicable HIPAA regulation. A data safety monitoring 
board comprised of the PI, physicians, residents, fellows, physics, statistician and research 
manager will meet monthly to evaluate toxicity for this trial. Subjects/adverse events will 
be discussed at these monthly disease center meetings. Unexpected serious adverse events 
will be reported to the IRB and DSMC, and minutes of the monthly disease center meetings 
will be reviewed at the DSMC meetings. 
Reports will be submitted annually at the time of the yearly renewal. 
 
7.2 Adverse events 
All serious AE shall be reported meeting criteria for reporting can be found on the University 
of Pittsburgh Institutional Review Board’s website at http://www.irb.pitt.edu. In the event 
of such adverse event, the investigator must report the event(s) via phone within 24 hours 
and a written report filed within 24 hours to the Principal Investigator, or the University of 
Pittsburgh Cancer Institute’s Department of Radiation Oncology’s Protocol Office. 
All adverse events will be reported as per the University of Pittsburgh IRB web site at 
www.irb.pitt.edu . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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8.0  REFERENCES 
 
1. Patel PR, Slama JK.  Reirradiation for recurrent head and neck cancer.  Expert Rev 
Anticancer Ther 2012;12:1177-89. 
 
2. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without 
concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 
2004;350:1945–1952. 
 
3. Brockstein B, Haraf DJ, Rademaker AW, et al. Patterns of failure, prognostic factors and 
survival in locoregionally advanced head and neck cancer treated with concomitant 
chemoradiotherapy: A 9-year, 337-patient, multi-institutional experience. Ann Oncol 
2004;15:1179–1186. 
 
4. McDonald MW, Lawson J, Garg MR, et al.  ACR appropriateness criteria of recurrent head 
and neck cancer after prior definitive radiation.  Int J Radiat Oncol Biol Phys 2011;80:1292-
8.  
 
5. Goodwin WJ, Jr.  Salvage surgery for patients with recurrent squamous cell carcinoma of the 
upper aerodigestive tract: when do the ends justify the means?  Laryngoscope  2000;110:1-
18. 
 
6. Zafereo ME, Hanasono MM, Rosenthal DI, et al.  The role of salvage surgery in patients 
with recurrent squamous cell carcinoma of the oropharynx.   Cancer 2009;115:5723-33. 
 
7. Janot F, de Raucourt D, Benhamou E, et al. Randomized trial of postoperative reirradiation 
combined with chemotherapy after salvage surgery compared with salvage surgery alone in 
head and neck carcinoma. J Clin Oncol 2008;26:5518–5523. 
 
8. Kasperts N, Slotman BJ, Leemans CR, et al. Results of postoperative reirradiation for 
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