A Phase II Study of Glottic Larynx Stereotactic Ablative Radiotherapy (LT-SABR) for Early-Stage Glottic Larynx Cancer
Phase: NA
Conditions: Glottic Carcinoma
Sponsor: University of Texas Southwestern Medical Center

 
STU122017-043, Sher, FormA-ResearchProtocol, Mod_29, 02-07-22 
 
 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018, 07/2020 
 
SCCC-01318: STU 122017-043 
A Phase II Trial of Glottic Larynx Stereotactic Ablative Radiotherapy (LT-SABR) for  
Early-Stage Glottic Larynx Cancer  
 
Principal Investigator:  
David J. Sher, MD, MPH 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
University of Texas at Southwestern Medical Center 
 
 
 
 
2280 Inwood Road 
 
 
 
 
Dallas, TX 75390 
 
 
 
 
Phone: 214-645-7607 
 
 
 
 
Fax: 214-648-9533 
 
 
 
 
Email: david.sher@UTSouthwestern.edu 
 
Co-Principal Investigator: 
Baran Sumer, MD 
 
 
 
 
Department of Otolaryngology 
 
 
 
 
 
Biostatistician: 
 
Chul Ahn, PhD 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, TX 75390 
 
 
 
 
Phone: (214) 648-9418  
 
 
 
 
chul.ahn@utsouthwestern.edu 
 
 
 
 
 
Study Drug/Treatment: 
None 
 
Funding Source:  
Departmental 
 
NCT Number: 
NCT03548285 
 
Initial version: 
1.0 
 
Amended: 
 
 
 
 
 
 
 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 
Protocol History 
V2 
08/22/2018 
V3 
05/15/2019 
V4 
09/23/2019 
V5 
01/10/2020 
V6 
03/01/2021 
V7 
01/07/2022 

 
STU122017-043, Sher, FormA-ResearchProtocol, Mod_29, 02-07-22 
 
 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018, 07/2020 
 
 
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. 
 
 
Amendment/Version #: _________7____________________ 
 
 
STU 122017-043 
A Phase II Trial of Glottic Larynx Stereotactic Ablative Radiotherapy (LT-SABR) for Early-Stage 
Glottic Larynx Cancer  
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................. 2 
STUDY SUMMARY .......................................................................................................................... 3 
1.0 BACKGROUND AND RATIONALE .......................................................................................... 4 
1.1 
Disease Background........................................................................................................ 4 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 5 
1.3 
Other Agents .................................................................................................................... 5 
1.4 
Rationale .......................................................................................................................... 5 
1.5 
Correlative Studies ........................................................................................................ 10 
2.0 STUDY OBJECTIVES .............................................................................................................. 10 
2.1 
Primary Objectives ......................................................................................................... 10 
2.2 
Secondary Objectives .................................................................................................... 10 
2.3 
Exploratory Objectives ................................................................................................... 11 
2.4 
Endpoints ....................................................................................................................... 11 
3.0 PATIENT ELIGIBILITY ............................................................................................................ 11 
3.1 
Inclusion Criteria ............................................................................................................ 12 
3.2 
Exclusion Criteria ........................................................................................................... 12 
   4.0 TREATMENT PLAN .............................................................................................................. 13 
4.1 
Treatment Dosage and Administration .......................................................................... 13 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 16 
4.3 
Concomitant Medications/Treatments ........................................................................... 16 
4.4 
Other Modalities or Procedures ..................................................................................... 16 
4.5 
Duration of Therapy ....................................................................................................... 16 
4.6 
Duration of Follow Up .................................................................................................... 16 

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4.7 
Removal of Patients from Protocol Therapy .................................................................. 16 
4.8 
Patient Replacement ..................................................................................................... 16 
5.0 STUDY PROCEDURES ........................................................................................................... 17 
5.1 
Screening/Baseline Procedures .................................................................................... 18 
5.2 
Procedures During Treatment ....................................................................................... 18 
5.3 
Follow-up Procedures .................................................................................................... 19 
5.4 
Time and Events Table .................................................................................................. 19 
5.5 
Removal of Subjects from Study ................................................................................. 190 
6.0 MEASUREMENT OF EFFECT .............................................................................................. 200 
7.0 ADVERSE EVENTS ............................................................................................................... 200 
7.1 
Experimental Therapy.................................................................................................. 200 
7.2 
Adverse Event Monitoring ........................................................................................... 200 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 23 
7.4 
Unblinding Procedures .................................................................................................. 25 
7.5 
Stopping Rules .............................................................................................................. 25 
8.0 DRUG/TREATMENT INFORMATION ..................................................................................... 25 
9.0 CORRELATIVES/SPECIAL STUDIES .................................................................................... 25 
9.1 
Specimen Banking ....................................................................................................... 255 
10.0 STATISTICAL CONSIDERATIONS .................................................................................... 255 
10.1 
Study Design/Study Endpoints .......................................................................... ……….25 
10.2 
Sample Size and Accrual ............................................................................................ 256 
10.3 
Data Analyses Plans.................................................................................................... 266 
11.0 STUDY MANAGEMENT ........................................................................................................ 28 
11.1 
Conflict of Interest ........................................................................................................ 288 

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11.2 
Institutional Review Board (IRB) Approval and Consent ............................................. 288 
11.3 
Required Documentation ............................................................................................. 298 
11.4 
Registration Procedures .............................................................................................. 299 
11.5 
Data Management and Monitoring/Auditing ................................................................ 299 
11.6 
Adherence to the Protocol ............................................................................................. 30 
11.7 
Amendments to the Protocol ......................................................................................... 31 
11.8 
Record Retention ........................................................................................................... 31 
11.9 
Obligations of Investigators ........................................................................................... 31 
12.0 REFERENCES ....................................................................................................................... 32 
13.0 APPENDICES ........................................................................................................................ 34 

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1 
LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBCT 
Cone Beam Computed Tomography 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DM 
Distant Metastasis 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
DSS 
Disease Specific Survival 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GRBAS 
Grade-Roughness-Breathiness-Aesthenicity-Strain 
H&P 
History & Physical Exam 
HPV 
Human Papillomavirus 
HRPP 
Human Research Protections Program 
IDE 
Investigational Device Exemption 
IHC 
Immunohistochemistry 
IMRT 
Intensity Modulated Radiation Therapy 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
LC 
Local Control 
LR 
Local Recurrence 
LRC 
Locoregional Control 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
OFLR 
Out of Field Local Recurrence 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 

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PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RC 
Regional Control 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Regional Recurrence 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SEER 
Surveillance Epidemiology and End Results 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
VHI 
Voice Handicap Index 
VMAT 
Volumetric Modulated Arc Therapy 
WBC 
White Blood Cells 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBRT 42.5 Gy in 5 fractions 
Follow for 3 years following 
treatment, including disease 
recurrence and patient-reported 
outcome results 
Scope at 1, 3, 6, 9, 12, 18, 24, 
30, and 36 months, or when 
clinically indicated 
Patient registration 
CT neck with contrast at 10-12 
weeks following treatment 
58.08 Gy in 16 daily fractions 
Moderate-risk 
Low-risk 

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3 
STUDY SUMMARY 
Title 
Phase II Trial of Stereotactic Body Radiotherapy (SBRT) for Early-
stage Glottic Larynx Cancer  
Short Title 
A Prospective Phase II Trial of SBRT for Early Glottic Larynx Cancer 
Protocol Number 
122017-043 
Phase 
Phase 2 
Methodology 
Prospective Study 
Study Duration 
3 years to accrue plus additional 3 years of follow-up 
Study Center(s) 
Single center 
Objectives 
To determine the local control and quality-of-life outcomes of using 
SBRT for early-stage glottic larynx cancer 
Number of Subjects 
25 
Diagnosis and Main 
Inclusion Criteria 
Stage I-II glottic larynx cancer 
Study Product(s), Dose, 
Route, Regimen 
Highly focal SBRT, delivered either every other day (low-risk) or daily 
(moderate-risk) 
Duration of administration 
3 weeks 
Reference therapy 
N/A 
Statistical Methodology 
The study has 85.6% power to detect a local control probability 
difference of 15% (95% vs. 80%) using a two-sided, one-sample log-rank 
test at a 0.10 significance level.  
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
 
Laryngeal cancer is the most common non-cutaneous head and neck malignancy 
affecting an estimated 13,430 patients in 2016 in the United States.[1] Over 75% of laryngeal 
cancers involve the true vocal cords or the glottic larynx, with over 90% of these cancers detected 
at early-stages (defined as carcinoma in situ and cT1-T2 tumors) when they are potentially 
curable using a single-modality.  Local therapies are highly effective at curing early-stage glottic 
larynx cancer, as rates of nodal involvement and metastatic disease are less than 5%.[2-4] 
Treatment outcomes with radiation or surgical approaches for early-stage glottic cancer yield 
local control rates for Tis and T1 tumors typically greater than 90%, and for T2 tumors 70-80%, 
with ultimate local control rates exceeding 90% after surgical salvage.[2, 5] 
 
Treatment Options 
 
 
There are multiple voice-preserving local treatment options for early-stage glottic 
laryngeal cancer in the current NCCN guidelines.[6] These include conventional or minimally 
hypofractionated radiation therapy, transoral oral laser microsurgery (TLM) or open CO2 laser 
surgery, and hemilaryngectomy.  Radiation therapy delivered in a small dose per fraction to the 
glottic larynx remains a common treatment for Stage Tis, T1, and T2 glottic tumors. Among 2338 
patients treated with T1 glottic cancers in the Linked SEER-Medicare data files from 1991-2009, 
47% were treated with radiation alone, 39% with local surgery and radiation, and 14% with local 
surgery alone.[7] Treatment with radiation therapy is typically delivered in 2 to 2.25 Gy daily 
fractions over 5.5-7 weeks.[8, 9] Endoscopic surgery via CO2 laser excision involves the removal 
of the gross tumor with a 2-3 mm margin thereby preserving the involved vocal cord while 
achieving reasonable voice outcomes.[10] Hemilaryngectomy is another surgical voice 
preservation option particularly for selected Stage T2 lesions where the involved vocal cord and 
paraglottic space are removed, with additional resection of the ipsilateral arytenoid and/or anterior 
commissure if involved.[10, 11] 
 
Radiation Therapy Technique 
 
 
Classically, early glottic larynx cancers were treated with an opposed lateral technique, 
were 2 opposing radiation beams were designed using a 5 x 5 cm or 6 x 6 cm field to cover the 
entire glottic larynx. This technique was effective and necessary before radiation treatments were 
able to be designed using CT planning, with the added ability of being able to measure dose to 
specific anatomic regions. With the advent of CT-based planning both 3D conformal radiation 
therapy (varying radiation fields to offer a more conformal dose distribution) and intensity 
modulated radiation therapy (IMRT; inverse radiation planning designed to limit the dose to 
specific organs while maximizing dose to a target), radiation treatment for early glottic larynx 
cancers has become more complex.  
 
Carotid Sparing Radiation Therapy 
 
 
Treatment using opposed lateral technique often includes both carotid arteries in the 
field, delivering a high dose to a ~5-6 cm of both carotid arteries. The data addressing the risk of 
stroke following radiation to the carotid arteries is controversial, although population-based 
studies have suggested an increase in late risk of ischemic events following radiation therapy of 
head and neck cancers.[12, 13] Because of the concern of unnecessary and potentially avoidable 
radiation therapy to the carotid arteries, dosimetric studies of early glottic larynx cancer began to 
emerge which demonstrating a significantly reduced radiation dose to the carotids with 3D 
conformal radiation planning and further dose reduction to the carotid arteries with IMRT.[14-17] 
Following these studies, many groups have begun to report outcomes with IMRT for treatment of 
early larynx cancers and all groups, thus far, have reported local control rates of >80%.[18-20] 
 

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Hypofractionated radiation therapy 
 
 
Hypofractionated laryngeal irradiation initially began during World War II due to a 
shortage of hospital beds and despite the use of rather primitive radiation techniques, the cure 
rates were similar between 5 week and 3 week treatment courses.[21] In a more contemporary 
radiation setting, a randomized phase III clinical trial from Japan showed promising outcomes 
with a mildly hypofractionated radiation approach of 56.25-63 Gy in 2.25 Gy daily fractions for 
early stage glottic larynx cancer. The trial demonstrated an improved local control, of 92% vs. 
77% at 5 years in favor of hypofractionation compared with conventional 60-66 Gy in 2 Gy daily 
fractions; the toxicity outcomes were similar with both approaches.[9] As a result of this trial, 63 
(T1)-65.25 (T2) Gy in 28-29 fractions is one of the two recommended radiation regimens for early 
glottis cancer in the U.S.[22] These trials support the feasibility of moderate hypofractionation in 
the current clinical landscape. Extreme hypofractionation remains a possibility to improve both 
patient convenience and treatment cost.  
 
In fact, we have completed a phase I dose-escalation trial of larynx stereotactic body 
radiotherapy (SBRT), and the results will be detailed throughout this discussion.  
 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
 
Radiotherapy is well established and a recommended treatment for treatment of early 
glottic larynx cancer by the NCCN. Additionally, a few separate groups have reported outcomes 
with hypofractionated radiation regimens with minimal late grade 3 or greater toxicities.  
 
Study 
Site 
Design 
N 
Stage 
Fractionation 
Dose / 
Fraction 
Target 
Late toxicities 
Al-Mamgani 
et al, 
2015[23] 
Rotterdam, 
Netherlands 
Prospective 
collected 
30 
T1a 
58.08 in 16 fractions 
3.63 Gy 
Single 
cord 
1/30 temp 
laryngeal 
edema 
Ermis et al. 
2015[24] 
Yorkshire, 
UK 
Retrospective 
  
Tis-
T2 
55 Gy in 20 fractions 
2.75 Gy 
Larynx 
1/132 (<1%) 
non-fx larynx 
Laskar et al, 
2012[25] 
Mumbai, 
India 
Retrospective 
652 
T1 
50 Gy in 15 
fractions, 55 Gy in 
16 fractions, 60 Gy 
in 24 fractions, 62.5 
Gy in 25 fractions 
3.3 Gy, 
3.43 Gy, 
2.5 Gy, 
2.5 Gy 
Larynx 
23.4% 
Persistent 
Laryngeal 
edema 
Short et al, 
2006[26] 
Aukland, NZ 
Retrospective 
145 
T1-T2 
52.5-55 Gy in 20 
fractions 
2.63 Gy, 
2.75 Gy 
Larynx 
One grade 3 
toxicity 
Gowda et al, 
2003[27] 
Manchester, 
UK 
Retrospective 
200 
T1 
50-52.5 Gy in 16 
fractions 
3.12 Gy, 
3.28 Gy 
Larynx 
1/200 (0.5%) 
severe late 
toxicity 
 
Table 1. Published hypofractionated radiation therapy studies addressing early stage larynx cancer with 
associated local control and late toxicities. 
 
1.3 
Other Agents 
 
All patients on the study will be treated with radiotherapy alone.  
1.4 
Rationale 
 
This study is premised on two related but different concepts. The first is that treatment 
volume reduction should lead to significantly improved acute and late laryngeal function, including 
voice and swallowing outcomes. The second is that for many patients, the treatment volume is 
small enough to compact the treatment schedule into just 5 fractions, which should lead to vastly 

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improved convenience. In fact, a shorter radiation therapy treatment course over 2.5-3 weeks, 
compared with the typical 5.5-6 weeks offers both a logistical advantage by improving not only 
the convenience, but also a potential cost advantage be requiring less treatment time on the 
machine.  
 
A few considerations are necessary when considering treatment with highly focal 
radiotherapy, with or without extreme hypofractionation:  
 
 
Does focal treatment of the glottic larynx reduce dose to surrounding organs 
while offering similar rates of local control rates compared with treatment of the 
entire larynx?  
 
Can hypofractionated radiation therapy be delivered with acceptable acute and 
late toxicities?  
 
What treatment dose and fractionation is appropriate for the phase II portion of 
this trial?  
 
What radiation modality is the best option for delivery of dose-escalated, focal 
glottic larynx cancer? 
 
Local control and organ sparing with a highly focal treatment  
 
 
Based on data supporting focal IMRT technique for limiting radiation dose to the carotid 
arteries, a few academic groups have investigated a more focal radiation field by targeting the 
involved cord or site of disease, rather than unnecessarily radiating the entire larynx in every 
case. This highly-focused radiation therapy offers potential advantages, in both the ability to limit 
radiation dose to the uninvolved vocal cord, arytenoids, laryngeal cartilages, pharynx, spinal cord 
and carotid arteries, while allowing for dose-escalated radiation therapy to the disease itself. 
 
 
A group from the Erasmus medical center recently published a report where they treated 
31 patients with T1a glottic larynx cancers with single vocal cord irradiation to the entire cord 
using IMRT and daily cone beam CT scans for setup.[23] The clinical target volume (CTV) 
included the entire cord from a 1mm axial-sliced planning scan, as well as the maximal intensity 
projection from a 4D respiratory-gated CT scan. For tumors involving the anterior commissure 
(AC), the entire AC was included in the CTV. From the CTV, the group expanded 3mm 
circumferentially and 5mm superior-inferior for all but the initial 4 patients. With the reduced 
treatment volumes, they employed a higher dose per fraction at 3.63 Gy x 16 fractions and 
reported 100% local control at 2 years with no grade 3 or greater late toxicities. There was only 1 
case of laryngeal edema in an actively smoking patient, and it fully resolved with steroids. 
Importantly, 78% of patients on this study were characterized as smoking. In addition, the median 
planning target volume (PTV) size was 10.6 cc, with a range of 8.1-13.7 cc. This is highly 
promising and supports the early results from our phase I trial, which will be described next.  
 
 
For the phase I portion of our trial, we similarly focused our treatment volumes on the 
tumor alone and used a 4D CT gated breathing scan to develop the CTV with an added 2 mm, 
and then we circumferentially added a 3 mm PTV to create the final treated volume. A total of 30 
patients were enrolled. With this highly focal treatment volume, we have achieved high local 
control rates of the first 2 dose levels (Figure 1) while substantially limiting the radiation dose 
delivered to nearby organs (Table 1). The 13 patients enrolled on the highest dose arm (42.5 Gy 
in 5 fractions) have not experienced any local failures thus far. 
 

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Figure 1. Kaplan Meier plots of local control of the first 2 dose levels including a) 4 patients 
treated with 50 Gy in 5 fractions with a 2-year actuarial local control of 75% (median follow-up 29 
months [range 28-32]) and b) 12 patients treated with 45 Gy in 10 fractions with a 2-year actuarial 
local control of 84.4% (median follow-up 20 months [range 12-25]).  
 
 
 
Safety of Dose-Escalated Radiation Therapy 
 
 
Table 2 demonstrates the late toxicities that have been reported with hypofractionated 
radiation therapy using different doses. The only series reporting toxicities with single vocal cord 
irradiation was Al Mamgani et al.[23] who reported no grade 3 or greater late toxicities at a 
median follow-up of 30 months. The group did report grade 2 acute dermatitis among 7 (23%) or 
dysphagia among 10 (33%) patients and only a single patient with grade 2 laryngeal edema that 
resolved with steroids. 
 
Study 
Site 
Design 
N 
Stage 
Fractionation 
Dose / 
Fraction 
Target 
Local 
control 
Late toxicities 
Al-Mamgani 
et al, 
2015[23] 
Rotterdam, 
Netherlands 
Prospective 
collected 
30 
T1a 
58.08 in 16 fractions 
3.63 Gy 
Single 
cord 
100% at 2 
years 
1/30 temp 
laryngeal 
edema 
Ermis et al. 
2015[24] 
Yorkshire, 
UK 
Retrospective 
132  
Tis-
T2 
55 Gy in 20 
fractions 
2.75 Gy 
Larynx 
85.6% at 
5 years 
1/132 (<1%) 
non-fx larynx 
Laskar et al, 
2012[25] 
Mumbai, 
India 
Retrospective 
652 
T1 
50 Gy in 15 
fractions, 55 Gy in 
16 fractions, 60 Gy 
in 24 fractions, 62.5 
Gy in 25 fractions 
3.3 Gy, 
3.43 Gy, 
2.5 Gy, 
2.5 Gy 
Larynx 
84% at 10 
years 
23.4% 
Persistent 
Laryngeal 
edema 
Short et al, 
2006[26] 
Aukland, NZ 
Retrospective 
145 
T1-T2 
52.5-55 Gy in 20 
fractions 
2.63 Gy, 
2.75 Gy 
Larynx 
95% 
(LRC) at 5 
years 
One grade 3 
toxicity 
Gowda et al, 
2003[27] 
Manchester, 
UK 
Retrospective 
200 
T1 
50-52.5 Gy in 16 
fractions 
3.12 Gy, 
3.28 Gy 
Larynx 
93% at 5 
years 
1/200 (0.5%) 
severe late 
toxicity 
 
Table 2. Published hypofractionated radiation therapy studies addressing early stage 
larynx cancer with associated local control and late toxicities. 
 
 
From the phase I portion of our study, there have been only 3 cases of grade 2 or 
greater soft tissue necrosis. Because of these small numbers, statistical comparisons are not 
informative. The three cases are briefly summarized below: 
 
 
Active smoking male with a large volume irradiated (17 cc) on dose level 2 (45 Gy in 10 
fractions), required a tracheostomy and gastrostomy due to necrosis 5 months after 
treatment. He subsequently experienced a local failure. 
 

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 
Active smoking male with a large volume irradiated (21.3 cc) on dose level 3 (42.5 Gy in 
5 fractions). He required a feeding tube and had profound dysphonia 6 months after 
treatment, but he has since recovered with conservative measures, such that he can now 
eat most foods and communicate over the phone.  
 
 
Non-smoking male with a relatively small volume irradiated (4.9 cc) on dose level 3 (42.5 
Gy in 5 fractions). He spent 24-48 hours in a casino and then developed odynophagia 
and dysphonia from necrosis 17 months after treatment. These complications have 
completely recovered with conservative measures. 
 
In summary, 2 of 7 patients with large volume PTVs (10 cc or higher) developed 
symptomatic necrosis, and 2 of 6 active smokers developed symptomatic necrosis. Of note, 5 
additional patients quit within 1 month of starting radiotherapy, and none developed a 
complication.  
 
 
From a voice quality perspective, the Voice Handicap Index results were excellent, such 
that only two patients (out of 30) experienced a worsening of their VHI score. In both cases, the 
ipsilateral arytenoid dose was 31% higher than the prescription dose in the first cohort. Although 
these numbers are very small, we are extrapolating this result to minimize the arytenoid dose in 
the future and keep it within 102% of the prescription dose.  
 
Radiation Dose and Fractionation for the current study 
 
 
The goal of treatment with radiation therapy is to deliver as high of a dose as possible to 
the target (tumor), while minimizing the dose to the normal tissues where late-side effects can 
drastically affect patient quality of life. Radiation dose delivered in the tissues can be accurately 
calculated using a universal survival curve (USC), which includes both the linear quadratic model 
and the multitarget model. To estimate the tumoricidal dose and late-toxicity dose delivered by 
different radiation fractionation schemes, a biologically effective dose (BED) is typically reported 
[28].  
 
BEDα/β = nd (1 + d/(α/β)), where n= number of fractions delivered, and d= dose / fraction. 
 
 
Assuming an α/β of 10 for a rapidly growing tumor and an α/β of 3 for late toxicities of 
normal tissues, the BED of prior hypofractionated radiation regimens are shown in Table 3. 
  
 
Study 
Fractionation 
Dose / 
Fraction 
BED10 
BED3 
Proposed 
Phase II Doses 
Moderate risk: 58.08 Gy in 16 fx 
Low-risk: 42.5 Gy in 5 fx 
3.63 Gy 
8.5 Gy 
79.2 Gy 
78.6 Gy 
128.4 Gy 
162.9 Gy 
UTSW Phase I 
50 Gy in 15 fractions 
45 Gy in 10 fractions 
42.5 Gy in 5 fractions 
3.33 Gy 
4.5 Gy 
8.5 Gy 
66.7 Gy 
65.3 Gy 
78.6 Gy 
105.6 Gy 
112.5 Gy 
162.9 Gy 
Al-Mamgani et 
al, 2015[23] 
58.08 in 16 fractions 
3.63 Gy 
79.2 Gy 
128.4 Gy 
Ermis et al. 
2015[24] 
55 Gy in 20 fractions 
2.75 Gy 
70.1 Gy 
105.4 Gy 
Short et al, 
2006[26] 
52.5-55 Gy in 20 fractions 
2.63 Gy, 
2.75 Gy 
66.3 Gy 
70.1 Gy 
98.5 Gy 
105.4 Gy 
Yamazaki et al, 
2006[9] 
63 Gy in 28 fractions 
2.25 Gy 
77.2 Gy 
110.3 Gy 

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Conventional 
66 Gy in 33 fractions 
70 Gy in 35 fractions 
2 Gy 
79.2 Gy 
84 Gy 
110 Gy 
116.7 Gy 
 
Table 3. Biologically effective doses (BED) of prior hypofractionated radiation regimens used for 
early stage glottic larynx cancer, assuming an α/β of 10 for a rapidly growing tumor, an α/β of 6 
for a slow-moderate growing tumor and an α/β of 3 for late toxicities of normal tissues. 
 
 
Given that patients with a larger PTV and active smoking history were at greater risk for 
toxicity (albeit encompassing only 3 patients in total) in our study, we have therefore decided to 
treat this population with the Dutch regimen. In particular, patients with: 
 
 
PTV greater than or equal to 10 cc 
 
Smoking within 1 month of registration 
 
will be treated with daily SBRT at a dose of 58.08 Gy in 16 fractions. Because patients with small 
tumors from the phase I portion of the trial had minimal toxicity with treatment, we propose to 
continue the dose of 42.5 Gy in 5 fractions for tumors less than 10 cc.  
 
Radiation Therapy Delivery 
 
 
There are a number of different techniques used to deliver highly-focal, inverse planned 
radiation therapy. The Erasmus group used a static-field IMRT approach.[23] Static-field IMRT is 
a commonly used approach where the beam angles are pre-chosen and then the radiation 
delivery is inversely planned by the planning system. The downside of static-field IMRT is that 7-9 
beam treatment requires up to 30 minutes to complete.  
 
 
Another approach for treating a highly focal target that we employed in the phase I 
portion of the study, is to treat with a Cyberknife treatment planning system. The advantage of the 
Cyberknife system is that the radiation beams can be delivered from hundreds of different non-
coplanar beam angles without manual adjustment of the treatment table. This technique proved 
to be effective given the high local control rates in the phase I portion of the trial, and it will be a 
treatment option for the phase II portion of the trial. However, the Cyberknife treatment planning 
system does have 2 specific drawbacks. First, unlike treatment planning systems that align 
patients prior to treatment using a cone-beam CT (CBCT) scan, the Cyberknife uses orthogonal 
x-rays to verify target position. Because the larynx isn’t clearly visible using orthogonal x-rays, it 
must be tracked using fiducial markers. Fiducial markers placed either on the skin or 
subcutaneously outside of the larynx might not accurately represent where the larynx is located, 
especially if the patient has substantial external neck motion (i.e. substantial neck motion when 
breathing). The second limitation of using Cyberknife technology is the prolonged treatment time 
compared with other techniques. In the phase I portion of our study, the median treatment time on 
the Cyberknife was 38 minutes and ranged from 20-54 minutes. This is a long time to be 
positioned in an aquaplast treatment mask, provided there are suitable alternatives available, and 
it allows for more time where a mobile structure like the larynx can move out of the tracked 
treatment field (i.e. with swallowing).  
 
 
A third option for treating a focal larynx cancer is with the use of volumetric modulated arc 
therapy (VMAT), which is essentially an IMRT treatment delivered from nearly 360 degrees 
around the patient. This allows for many more beam angles than static field IMRT and it also 
allows for a much quicker treatment. One group recently compared 2-arc VMAT with a typical 8-
field IMRT plan for early stage larynx cancer and reported that both target volume coverage and 
homogeneity were comparable between VMAT and IMRT, while VMAT was superior for carotid-
artery sparing. Additionally, VMAT delivery time was significantly faster than with IMRT (3-5 
minutes vs. 5-10 minutes).[29] Another study supports the substantially reduced treatment time 
with arc therapy vs. IMRT.[30] Because of the promising results with VMAT treatment delivery, 
either modality (i.e. CyberKnife or VMAT) is acceptable for treatment on this protocol.  

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Summary points 
 
1. Local control rates using a highly focal radiation target appear to be as good as 
conventional radiation therapy (≥80%) 
 
2. Highly focal radiation therapy targeting only the involved site of disease plus a small 
margin delivers an extremely low dose of radiation dose nearby structures based on 
both the Dutch Erasmus and the UT Southwestern Phase I studies. 
 
3. A reduced dose to nearby structures might improve toxicities, such as esophagitis 
and stroke from carotid atherosclerosis and could reduce the decline in voice function 
from contralateral cord dose. However, long-term follow-up of voice quality of life 
following focal larynx radiation therapy is not yet available from the phase I portion of 
this trial. 
 
4. Hypofractionated radiation therapy appears to be safe, although there were three 
cases of soft tissue necrosis in the phase I trial. Current smoking status and larger 
PTV volume (> 10cc) all had qualitatively higher rates of necrosis. 
 
5. Based on the phase I study, we propose using a dose of 42.5 Gy in 5 fractions for 
low-risk tumors: tumors with a PTV < 10cc, no recent smoking, and disease limited to 
the vocal process. This provides both an adequate tumoricidal dose, and a limited 
dose to normal tissues. Remaining patients will be irradiated using the Dutch 16 
fraction regimen. 
 
6. Treatment with either Cyberknife or VMAT will be acceptable.  
 
 
 
 
With these observations, this study aims to maintain a high rate of local control while 
maintaining acceptable acute side-effects and improving late side-effects. We anticipate that this 
approach will improve late toxicities, patient convenience, and treatment cost. Moreover, because 
the delivered biologically equivalent dose is the same as conventional radiotherapy but delivered 
over a substantially shorter time period, it is also possible that local control will be superior with 
this technique as well.  
 
1.5 
Correlative Studies 
 
1.5.1. 
For patients treated with VMAT, we will perform an analysis of CBCT imaging 
during treatment, to determine the optimal patient-specific PTV margin. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To determine the risk of local failure following SBRT treatment of early glottic 
larynx cancers. 
 
2.2 
Secondary Objectives 
 
2.2.1 
To determine patient-reported outcomes (PRO) following treatment with SBRT. 

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2.2.2 
To describe the rates of grade 3-5 acute and late toxicities following treatment 
with SBRT. 
 
2.2.3 
To characterize patient utilities using EQ5D following treatment with SABR. 
 
2.2.4 
To determine the patterns-of-failure following SBRT. Specifically, 2-year 
cumulative risk of in-field, marginal, and out-of-field local failure, regional and 
distant failure, laryngectomy-free survival, disease-specific survival and overall 
survival following treatment with SBRT. 
 
2.3 
Exploratory Objectives 
 
2.3.1. 
Identify a method to optimize PTV margins for patients treated with VMAT. 
 
2.3.2. 
Identify tissue and circulating predictors  of locoregional failure.  
 
2.4 
Endpoints 
 
2.4.1 
Primary endpoint: 2-year risk of local failure (i.e. anywhere in the larynx) following 
SBRT treatment of early glottic larynx cancer 
 
2.4.2 
Secondary endpoints: 
 
2.4.2.1 Patient-reported outcomes: Difference in PRO voice quality measures 
between baseline and 1, 3, 6, 12, 18 and 24 months following treatment: 
 
2.4.2.1.1  
VHI voice-quality score 
2.4.2.1.2  
MDADI 
 
 
2.4.2.2 Rate of grade 3-5 acute (start of treatment through 90 days from the 
completion of treatment) and late (after 90 days from the completion of 
treatment) adverse events, according to NCI’s CTCAE v4.0 toxicity 
criteria.  
 
2.4.2.3 Average patient utilities (derived from EQ-5D) at baseline, 6, 12 and 24 
months from the end of treatment 
 
2.4.2.5 Cumulative risk of marginal and out-of field local failure at 2 years from 
the start of treatment with death and prior in-field local failure as a 
competing risk 
 
2.4.2.6 Cumulative incidence of regional failure and distant metastasis at 2 
years, with death and prior locoregional failure as competing risks 
 
 
 
2.4.2.7 Laryngectomy-free survival probability at 2 years  
 
2.4.2.8 Overall survival at 2 years 
 
3.0 
SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 

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3.1 
Inclusion Criteria 
 
3.1.1 
Pathologically-proven diagnosis of squamous cell carcinoma in situ, squamous 
cell carcinoma or squamous cell variants (sarcomatoid, verrucous, basaloid, and 
papillary subtypes) involving the glottic larynx. 
 
3.1.2 
Clinical stage I-II (AJCC, 7th edition) with direct laryngoscopy showing no 
evidence of greater than stage II true glottic larynx cancer and PET/CT or CT 
neck showing no evidence of regional disease. 
 
3.1.3 
Age ≥ 18 years. 
 
3.1.4 
ECOG Performance Status 0-2  
 
3.1.5 
Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 90 days following 
completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
3.1.5.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, marital status, having undergone a tubal ligation, or 
remaining celibate by choice) who meets the following criteria: 
 
 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
3.1.6 
Negative serum or urine pregnancy test within 2 weeks before registration for 
women of childbearing potential. 
 
3.1.7 
Ability to understand and the willingness to sign a written informed consent. 
 
3.1.8 
Patients with cognitive impairment or other limited decision making capacity with 
the ability to understand and willingly sign written informed consent or have the 
consent signed by a designated legally authorized representative (LAR). 
3.2 
Exclusion Criteria 
 
3.2.1 
AJCC stage III or stage IV larynx cancer 
 
3.2.2 
Involvement of the arytenoid cartilage beyond the vocal process. 
 
3.2.3 
Prior chemotherapy for treatment of the targeted larynx lesion. 
 
3.2.4 
Synchronous primaries in the head and neck 
 
3.2.5 
Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation fields.  
 
3.2.6 
Subjects smoking in excess of 1 pack of cigarettes per day. 
 
3.2.7 
Subjects may not be receiving any other investigational agents. 

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3.2.8 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that, in the opinion of the 
investigator, would limit compliance with study requirements. 
 
3.2.9 
Subjects must not be pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
Radiation will be delivered twice per week for 5 fractions (42.5 Gy cohort, low-risk) or 
daily for 16 fractions (58.08 Gy cohort, moderate-risk).  
 
Low-risk is defined by: 
 
 
PTV less than 10 cc, AND 
 
No reported smoking within 1 month from registration 
 
 
Moderate-risk is defined by: 
 
 
PTV greater than or equal to 10 cc, OR 
 
Smoking within 1 month from registration (no more than 1 pack per day) 
 
 
4.1.1 
Radiation Therapy 
 
4.1.1.1 CT simulation 
 
 
Patients will be simulated in a thermoplastic mask extending from the 
scalp through upper chest (e.g. “5 point mask”), using 1 mm thick slices. 
For SBRT planning, a CT simulation with IV contrast and a 4-D 
respiratory CT-scan focusing on the larynx are recommended but not 
required.  
 
 
For Cyberknife patients treated with skin tracking, four gold fiducials will 
be placed on the skin, two on each side of the neck and at different 
vertical alignments in the vicinity of the larynx. Small tattoos will be 
placed at the site of each skin fiducial in order to replicate the fiducial 
placement for treatment. 
 
 
For VMAT patients, the isocenter will be placed on the mask.  
 
4.1.1.2 Primary tumor delineation and targeting 
 
 
GTV: The gross tumor volume (GTV) will be contoured based on 
laryngoscopic findings by the investigator. Additional anatomic tumor 
location information obtained from biopsy procedure can be used to help 
guide GTV volumes. GTV volumes should be confirmed in both the 
sagittal and coronal views to verify that the involved areas of the vocal 
cord are covered.  

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ITV: From the 4DCT at the time of simulation, the MIP, average, 
maximum inhalation and maximum exhalation scans from the 4D CT 
scan will be imported. The ITV should include the GTV plus any motion 
seen on the 4DCT scans.  
 
 
CTV: this trial will not include a CTV volume. 
 
 
PTV: The planning target volume (PTV) will include the ITV plus a 3 mm 
left-right and anterior-posterior expansion and a 5 mm cranio-caudal 
expansion.  
 
 
 
 
4.1.1.3 Dose prescription 
 
Patients treated on the 5 fraction regimen will be irradiated two times per 
week, with at least 2 days between fractions (i.e. Monday-Wednesday). 
Attempts should be made to start treatment on a Wedneday and end 
treatment on a Monday, to minimize the total treatment time.  
 
Patients treated on the 16 fraction regimen will be irradiated once per 
day, every day.  
 
 
 
4.1.1.4  Treatment planning 
 
Patients will be treated using either CyberKnife or VMAT. Voxel doses 
will be calculated using the smallest voxel resolution available (i.e. 1.5 for 
VMAT plans in Eclipse and 1.25 for Cyberknife). 
 
4.1.1.5 Coverage constraints 
 
All plans must be normalized such that 95% of the volume of each PTV 
is covered by the prescription dose.  
 
At a volume of 0.03 cc within each PTV volume, the dose should not 
exceed 115% of the prescription anywhere in the plan.  
 
The arytenoid should not receive more than 102% or 105% of the 
prescription for the 5 and 16 fraction regimens, respectively. 
 
4.1.1.6 OAR constraints: 5 fraction 
 
MANDATORY (see below):  
Spinal cord: Dmax (0.035cc)  < 20 Gy  
Spinal cord + 5 mm: Dmax (0.035cc) < 25 Gy 
Ipsilateral arytenoid: Dmax (0.035cc) < 43.35 Gy (102% of prescription) 
 
 
RECOMMENDED:  
Uninvolved vocal cord(s): Dmax (0.035cc)  <41.4 Gy, Dmean <36.8 Gy 
Contralateral arytenoid: Dmax (0.035cc) < 23 Gy  
Ipsilateral carotid: Dmax (0.035cc)  <23 Gy, Dmean <11.2 Gy 
Contralateral carotid: Dmax (0.035cc)  <23 Gy, Dmean <11.2 Gy 
Laryngeal cartilage: Dmax (0.035cc)  <46 Gy 
Cricoid cartilage: Dmax (0.035cc)  <41.4 Gy 
Inferior constrictor and cricopharyngeus: Dmax (0.035cc)  <23 Gy 
Thyroid gland: Dmean <15.3 Gy 

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4.1.1.7 OAR constraints: 16 fraction 
 
MANDATORY (see below):  
Spinal cord: Dmax (0.035cc)  < 35 Gy  
Spinal cord + 5 mm: Dmax (0.035cc) < 40 Gy 
Ipsilateral arytenoid: Dmax (0.035cc) < 61 Gy (105% of prescription) 
 
 
RECOMMENDED:  
Uninvolved vocal cord(s): Dmax (0.035cc)  < 56.3 Gy, Dmean <50.05 Gy 
Contralateral arytenoid: Dmax (0.035cc) < 31.3 Gy  
Ipsilateral carotid: Dmax (0.035cc) < 31.3 Gy, Dmean <15.2 Gy 
Contralateral carotid: Dmax (0.035cc)  < 31.3 Gy, Dmean <15.2 Gy 
Laryngeal cartilage: Dmax (0.035cc)  < 62.6 Gy 
Cricoid cartilage: Dmax (0.035cc)  < 56.3 Gy 
Inferior constrictor and cricopharyngeus: Dmax (0.035cc)  < 31.3 Gy 
Thyroid gland: Dmean <20.8 Gy 
 
 
The standard names for these structures and compliance criteria are below. 
 
 
 
 
Name 
Per protocol 
Variation acceptable 
Variation 
unacceptable 
PTV 
 >95% of PTV 
covered by the 
prescription dose 
 
Max hot spot <115% 
<95%, ≥90% of PTV 
covered by prescription 
dose 
 
>115%, <120% 
< 90% 
 
 
 
> 120% 
IL_arytenoid and 
CL_arytenoid 
Max hot spot < 
102% (5 fraction) 
Max hot spot < 
105% (16 fraction) 
Max hot spot < 105% (5 
fraction) 
Max hot spot < 108% (16 
fraction) 
Max hot spot > 
105% (5 
fraction) 
Max hot spot < 
108% (16 
fraction) 
Cord 
< 20 Gy (5 fraction) 
< 35 Gy (16 fraction) 
>20 Gy, < 25 Gy (5 fx) 
>35 Gy, < 37.5 Gy (16 fx) 
> 25 Gy 
> 37.5 Gy 
Cord_exp 
< 25 Gy (5 fraction) 
< 40 Gy (16 fraction) 
>25 Gy, < 30 Gy (5 fx) 
>40 Gy, < 42.5 Gy (16 fx) 
> 30 Gy 
> 42.5 Gy 
OARS 
Description 
See Section 4.1.9.2 for constraints 
VC_uninv 
Uninvolved vocal cord and arytenoid, either 1 or both uninvolved 
vocal cords contoured with a 2 mm separation from PTV 
Carotid_IL 
Ipsilateral carotid contoured from the inferior aspect of the hyoid to 
1 cm below the cricoid 
Carotid_CL 
Contralateral carotid contoured from the inferior aspect of the 
hyoid to 1 cm below the cricoid 
Arytenoid_IL 
Ipsilateral arytenoid contoured on the bone window with a 2 mm 
separation from PTV 
Arytenoid_CL 
Contralateral arytenoid contoured on the bone window with a 2 
mm separation from PTV 
Laryngeal_cartilage 
Laryngeal cartilage contoured with a 3-5 mm brush with a 2 mm 
separation from PTV 
Cricoid_cartilage 
Cricoid cartilage contoured with a 3-5 mm brush with a 2 mm 
separation from PTV 

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Thyroid 
Enhancing thyroid gland 
IC_CP 
Inferior constrictor & cricopharyngeaus contoured from the inferior 
aspect of the hyoid to 1 cm below the inferior aspect of the cricoid 
 
 
4.1.1.8  
Treatment fractionation 
 
5 fraction: Patients will receive one fraction per day, twice per week, with at least 
two days between fractions.  
 
16 fraction: Patients will receive one fraction per day, 5 days per week 
 
 
4.1.1.9 Treatment delivery 
 
The CyberKnife machine provides multiple systems that can be used for setting 
up and imaging patients. The majority of patients in the phase I study were 
treated with spine tracking, and there were no marginal failures (i.e. no data to 
suggest the tumors were “missed.”); moreover, the spine and larynx are 
intimately related to each other anatomically.  
 
We also used skin markers for tracking in 2 patients, and it was successful in 1 
patient and non-usable in the second patient.  
 
Thus the daily imaging technology will be up to physician discretion. Either spine 
tracking or skin fiducials may be used. 
 
For treatment with VMAT, daily pre-treatment CBCT must be used for verification 
of patient set-up and successful treatment delivery with VMAT. At least one intra-
arc CBCT is mandatory, as is a post-treatment CBCT. 
 
 
4.1.1.10 
Documentation and quality assurance 
 
 
Every CT simulation scan with target and normal structures will be reviewed by 
the PI and co-PI.  
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table in Section 5.4. Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 4.0.  
 
4.2.1.  Radiation Therapy 
The dose constraints for radiation therapy are described in 4.1.1.6 and 4.1.1.7. 
No alterations in treatment doses are allowable per protocol.  
4.3 
Concomitant Medications/Treatments 
Supportive medications may be given at any point during the treatment course at the 
discretion of the treating physicians.  These medications include: 
 
 
Anti-emetics 
 
Non-opiate and opiate pain medications 
 
Anti-diarrheals 

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 
Nutritional supplementation 
 
Anti-depressants 
 
 
 
The use of anti-oxidant vitamins in excess of a daily vitamin is not allowed. 
4.4 
Other Modalities or Procedures 
For patients receiving 5 fractions, we recommend administering a dexamethasone 4 mg 
oral tablet one hour prior to each radiation treatment session at the discretion of the 
treating physician. 
4.5 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until: 
 
Local, in-field disease progression 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
4.6 
Duration of Follow Up 
Subjects will be followed for a minimum of 3 years after completion of treatment or until 
death, whichever occurs first. Specifically, subjects will be followed at 1, 3, 6, 9, 12, 18, 
24, 30, and 36 months following treatment. Subjects removed from therapy for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
4.7 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the subject was removed in the Case Report Form. The subject should be followed-up 
per protocol.  
 
Patients who are not able to complete the treatment or required follow-up procedures due 
to cognitive impairment will be removed from the study and treated and/or followed using 
standard-of-care procedures. 
4.8 
Subject Replacement 
Subjects may be replaced in the study if they do not complete radiotherapy. Inadequate 
receipt of treatment may lead to a higher than expected recurrence rate, and therefore 
these patients may be replaced.  Patient replacement must be verified through review of 
the case by the P.I. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 

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5.1.1 Informed Consent 
 
5.1.1.1. Patients with cognitive impairment will be approached for trial if all other eligibility 
criteria are met and determined if s/he can sign willingly or require a LAR at enrollment.  
5.1.2 Medical history 
Complete medical and surgical history, history of infections 
5.1.3 Demographics 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight, office 
laryngoscopy and assessment of performance status (see Appendix A) 
5.1.7 PET-CT or CT scan of neck 
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for Adverse Event 
monitoring and reporting. All acute and late adverse events from protocol radiation 
therapy will be reported and scored for severity using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. A copy of the 
CTCAE v4.0 can be downloaded from the CTEP home page 
(http://ctep.info.nih.gov). 
5.1.9 Pregnancy test (for females of child bearing potential) 
See section 3.1.5.1 for definition.  
5.1.10 QoL Questionnaires and Symptom Questionnaires  
EORTC QLQ-C30, H&N 35, VHI, and EQ-5D. These forms will be referred to 
collectively as QoL Questionnaires.  
5.2 
Procedures During Treatment 
5.2.1 
Day 1 
 First fraction of radiotherapy per standard, departmental stereotactic protocol 
 
5.2.2 
Weekly during treatment 
 Clinical assessment including ECOG PS 
 Toxicity assessment 
 
5.2.3 
Four weeks after treatment end 
 Interim history 
 Physical exam, vital signs, ECOG PS (vital signs are not required when 
patient has a Telehealth visit) 
 Flexible laryngoscopy to assess tumor response and toxicity 
 Quality of life and voice quality assessment 

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5.3 
Follow-up Procedures 
Patients will be seen by a radiation oncologist at 1 month (+/- 1 week) and 3 months (+/- 
1 week) from the completion of treatment. More frequent visits are encouraged if the 
patient requires additional help with recovery and rehabilitation 
 
Patients will then be seen every 3 months (+/- 2 weeks) for the first year, and then at 
least every 6 months (+/-2 weeks) until the end of the 3rd year. Subsequent and 
intervening follow-up visits will be made per physician preference. These protocol 
mandated procedures will occur at each follow-up: 
 
 Interim history 
 Physical exam, vital signs, ECOG PS (vital signs are not required when patient has a 
Telehealth visit) 
 Laryngoscopy to assess tumor response and toxicity 
 Quality of life and voice quality assessment (months 1, 3, 6, 12, 18, 24 and 36) 
5.4 
Time and Events Table  
 
 
 
Pre-study 
Weekly 
during 
RT 
4 weeks after 
completion 
Follow-up* 
 
Assessment 
 
X 
X 
 
Informed Consent 
X 
 
 
 
History and Physical Exam 
X 
 
X 
X 
Performance Status 
X 
X 
X 
X 
Toxicity Evaluations 
 
X 
X 
X 
PET/CT or CT-scan of Neck  
X& 
 
 
X (3 months) 
Laryngoscopy 
X 
 
X 
X 
Serum or urine β-HCG 
(females) 
X 
 
 
 
HR-QoL/Utility Forms 
1) EQ-5D 
2) EORTC-QLQ C30 
+ HN 35 
3) VHI 
X 
 
X 
X  
(months 1, 3, 6, 
12, 18, 24 and 
36) 
 
& PET/CT can also be performed in place of baseline CT Neck and Chest 
 
* These protocol mandated procedures will occur at each follow-up: 
 Interim history 
 Physical exam, vital signs, ECOG PS (vital signs are not required when 
patient has a Telehealth visit) 
 Laryngoscopy to assess tumor response and toxicity 
 Quality of life and voice quality will be assessed at visits 1, 3, 6, 12, 18, 24 
and 36 months from the end of treatment. 
 
Neck CT or PET-CT is required 3 months (+/- 1 week) after the completion of radiotherapy, but 
subsequent scans only for a clinical indication.  
 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 

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behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject demonstrates disease progression (unless continued treatment with 
study drug/treatment is deemed appropriate at the discretion of the investigator); 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
If a research subject cannot be located to document survival after a period of 2 
years, the subject may be considered “lost to follow-up.” All attempts to contact 
the subject during the two years must be documented. 
6.0 
MEASUREMENT OF EFFECT 
 
Early-stage larynx cancers are almost never visible on neck CT. The imaging is not used for 
response assessment but rather assessment of occult nodal disease (at diagnosis) or 
subsequent nodal recurrence (at 3 months). Clinical examination is sufficient at other time points. 
 
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy 
This treatment is hypofractionated radiotherapy as described above.   
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are assessed in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
 death. 

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7.2.1 
Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporally 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research.   
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the start of treatment, through 90 days 
post treatment will be considered acute adverse events.  
Late Adverse Events  
Adverse effects occurring in the time period from the end of acute monitoring, to 36 
months post treatment, will be defined as late adverse events. These events will include 
all adverse events reported directly to a member of the study team and will be captured, 
assessed, graded and reported as appropriate.  
 
In addition, the study team will review encounters in the following select specialty 
categories relevant to study endpoints: radiation oncology, medical oncology, and 
otolaryngology. The queried encounters will be limited in scope based on categorization of 
events; namely, encounters that related to any head and neck or gastrointestinal event or 
problem. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE will 
be scored on the Adverse Event log according to the general guidelines provided by the 
NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
OHRP and UTSW HRPP define serious adverse events as those events, occurring at 
any dose, which meets any of the following criteria:  
 
results in death; 
 
is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 
 
results in inpatient hospitalization1,2 or prolongation of existing hospitalization; 
 
results in a persistent or significant disability/incapacity; 
 
results in a congenital anomaly/birth defect; or 

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 
based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring >24 hour inpatient admission to the hospital would be a serious 
adverse event for any research participant; likewise, in a study investigating end-stage 
cancer care, any hospitalization or death which occurs during the protocol-specified 
period of monitoring for adverse and serious adverse events would be a serious adverse 
event, even if the event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery that prolongs the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor 
treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be 
reported either as a routine AE or in an expedited report. 
7.2.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  

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All adverse events will be followed up according to good medical practices.  
 
7.3 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the 
SCCC DSMC 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within the acute adverse events reporting period 
as defined in section 7.2.1. Any event that occurs during the late adverse event period as 
defined in section 7.2.1 and is attributed (possibly, probably, or definitely) to the treatment 
must also be reported accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
 
the drug package insert (if applicable); 
 
the current Investigator’s Brochure (if applicable) 
 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
7.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
SAEs and UPIRSOs at all sites, which occur in research subjects on protocols for which 
the SCCC is the DSMC of record require reporting to the DSMC regardless of whether 
IRB reporting is required. All SAEs occurring during the protocol-specified monitoring 
period and all UPIRSOs should be submitted to the SCCC DSMC within 5 business days 
of the PI or delegated study team members awareness of the event(s). In addition, for 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events or unanticipated problems. 
 
The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are submitted to the SCCC 
DSMC Coordinator.  This may be facilitated by the IIT project manager, study team, sub-
site, or other designee.  Hardcopies or electronic versions of the eIRB Reportable Event 
report; FDA Form #3500A forms, or other sponsor forms, if applicable; and/or any other 
supporting documentation available should be submitted to the DSMC Coordinator.  The 
DSMC Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE or UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 
 

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further action is required. (See Appendix III of the SCCC DSMC Plan for a template Serious 
Adverse Event Form which may be utilized). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the IIT Project or designee ensures that all participating 
sites are notified of the event and resulting action, according to FDA guidance for 
expedited reporting. DSMC Chairperson reviews all SAEs and UPIRSOs upon receipt 
from the DSMC Coordinator.  The DSMC Chairperson determines whether action is 
required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
Telephone reports to:  
Dr. David Sher, M.D. 
Phone: 214-645-8525 
Written reports to: 
David J. Sher, M.D. 
The University of Texas Southwestern Medical Center 
ATTN: Sarah Neufeld, Project Manager 
2201 Inwood Road 
Dallas, TX. 75390-9303 
Fax: 214-648-5923 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP policy, UPIRSOs are incidents, experiences, outcomes, etc. 
that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, not 
included in the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working days of 
study team awareness. 
 

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For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of study team awareness. Investigators must 
report to their relying IRB according to the relying IRB’s policy. In addition, the external 
IRB’s responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/hrpp/quality-assurance/  
 
 
7.4 
Unblinding Procedures 
N/A 
7.5 
Stopping Rules 
 
N/A 
8.0 
DRUG/TREATMENT INFORMATION 
Not applicable for this trial.  
9.0 
CORRELATIVES/SPECIAL STUDIES 
9.1 
Specimen Banking 
 
No specimen banking will be explicitly performed for this study.  
 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
 
10.1.1  Primary endpoint: 2-year risk of local failure (i.e. anywhere in the larynx) following 
SBRT treatment of early glottic larynx cancer 
 
10.1.2 Secondary endpoints: 
 
10.1.2.1  
Patient-reported outcomes: Difference in PRO measures 
between baseline and 1, 3, 6, 12, 18, 24 and 36 months 
following treatment: 
 
 
 
10.1.2.1.1 VHI voice-quality score 
 
 
10.1.2.1.2  EORTC QLQ30 and HN35 scores 
 
 
 

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10.1.2.2 
Rate of grade 3-5 acute (start of treatment through 90 days from 
the completion of treatment) and late (after 90 days from the 
completion of treatment) adverse events, according to NCI’s 
CTCAE v4.0 toxicity criteria.  
 
 
10.1.2.3 
Average patient utilities (derived from EQ-5D) at baseline and 1, 
3, 6, 12, 18, 24 and 36 months from the end of treatment 
 
10.1.2.4 
Cumulative risk of marginal and out-of field local failure at 2 
years from the start of treatment with death and prior in-field 
local failure as a competing risk 
 
10.1.2.5 
Cumulative incidence of regional failure and distant metastasis at 
2 years, with death and prior locoregional failure as competing 
risks 
 
 
 
10.1.2.6 
Laryngectomy-free survival probability at 2 years  
 
10.1.2.7 
Overall survival at 2 years 
 
10.2 
Sample Size and Accrual 
 
The general perception in the radiotherapy community is that radiotherapy for early stage 
glottic larynx cancer leads to a local control probability of approximately 95%.  Given 
there are some T2 patients on the study (bigger tumors), we use the 2-year local control 
rate of 90% rather than 95% with the non-inferiority margin of 15%. The hazard rates for 
2-year local control probabilities of 90% and 75% are 0.0527 and 0.1438, respectively. 
With a sample size of 25 patients, this study has more than 80% power to detect a non-
inferiority against an upper hazard ratio bound of 2.73 (=0.1438/0.0527) using a log-rank 
test at a significance level of 0.1 when the actual hazard ratio is 1.0 and the reference 
group hazard rate is 0.0527. Patients will be accrued for a period of 3 years with 2-year 
follow-up. This assumes that a local control outcome inferior to 75% would obviate the 
potential benefit of highly focal radiation treatment. 
 
Our prior phase I study included a nearly identical patient population and took just over 3 
years to complete; however, this protocol has 2 periods of a 90 day halt on new accrual 
because it was a phase I study. Therefore we expect the present proposal to be 
completed in 2.5 to 3 years.  
 
10.3 
Data Analyses Plans 
 
10.3.1  Primary endpoint: 2-year cumulative risk of local failure (i.e. anywhere in the 
larynx) following SBRT treatment of early glottic larynx cancer 
 
 
This endpoint will be calculated using cumulative incidence statistics, with death 
as a competing risk.  
 
 
10.3.2 Secondary endpoints: 
 
 
Patient-reported outcomes: Difference in PRO voice quality measures between 
baseline and 1, 3, 6, 12, 18, 24, and 36 months following treatment: 
 

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10.3.2.1 
VHI voice-quality score 
 
10.3.2.2 
EORTC QLQ-C30 
 
Global health status 
 
Physical functioning scale 
 
Role functioning scale 
 
Emotional functioning scale 
 
Cognitive functioning scale 
 
Social functioning scale 
 
10.3.2.3 
EORTC HN35 
 
Speech 
 
Social eating 
 
Social contact 
 
These patient reported outcomes are single numeric scores that are collected at 
baseline, 1, 3, 6, 12, 18, 24 and 36 months from treatment. Patients with disease 
recurrence will be excluded. The changes in these outcomes from baseline to 
these timepoints will be analyzed using generalized estimated equations (GEE).   
 
 
10.3.2.4 
Rate of grade 3-5 acute (start of treatment through 90 days from 
the completion of treatment) and late (after 90 days from the 
completion of treatment) adverse events, according to NCI’s 
CTCAE v4.0 toxicity criteria.  
 
 
Only adverse events assessed to be definitely, probably, or possibly related to 
protocol treatment will be considered. The rates of all Grade 3-5 adverse events, 
and death during or within 30 days of discontinuation of protocol treatment will be 
characterized. Predictors of high-grade acute and late toxicity will be determined 
using multivariable logistic regression.  
 
 
10.3.2.5 
Average patient utilities (derived from EQ-5D) at baseline, 3, 6, 
12, 18, 24 and 36 months from the end of treatment 
 
The average patient utilities (derived from EQ-5D) at baseline, 3, 6, 12, 18, 24 
and 36 months from the end of treatment will be described. Changes in patient 
utility will be analyzed using generalized estimated equations (GEE). These 
models will be used to estimate the beta coefficient for dysphonia and grade 2-3 
dysphagia, to produce an estimate of the utility decrement from this toxicity.  
 
10.3.2.6 
Cumulative risk of marginal and out-of-field local failure at 2 
years from the start of treatment with death and prior in-field 
local failure as a competing risk 
 
These outcomes will be calculated using classic cumulative incidence statistics, 
and the Fine-Gray method will be used to calculate univariable predictors of  
recurrence.  
 
10.3.2.7 
Cumulative incidence of regional failure and distant metastasis at 
2 years, with death and prior locoregional failure as competing 
risks 
 
These outcomes will be calculated using classic cumulative incidence statistics, 
and Gray’s test will be used to calculate univariable predictors of  
recurrence.  

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10.3.2.8 
Laryngectomy-free survival probability at 2 years  
 
Kaplan-Meier statistics will be used, with death or laryngectomy serving as 
events. 
 
10.3.2.9 
Overall survival at 2 years 
 
Kaplan-Meier statistics will be used. 
 
 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
 
11.2 
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 must 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 onto this study, the subject 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 subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject 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 subject and by the person who conducted the 
informed consent discussion. 
 
For patients with cognitive impairment or other limited decision making capacity, the 
subject and/or their LAR will be given a full explanation of the study and will be given the 
opportunity to review the consent form. Consent form may be signed by the patient 
and/or legal guardian if investigator determines that subject is willingly able to sign and 
complete protocol specific procedures for the duration of the study. Safeguards and/or 
precautions that will be taken to minimize risks/harms during the conduct of the study for 
individuals with cognitive impairment or other limited decision making capacity include, 
but is not limited to: 
 
Extra time to review to the ICF (e.g. phone call over the phone with the patient or 
LAR, then present ICF and give days to weeks for full consideration of all 
benefits and risks) 

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 
Peer to peer conversation, if requested by the patient and/or LAR, between the 
treating research physician and the patient’s primary caregiver, to discuss the 
protocol treatment and discuss the trial’s impact to the patient’s ongoing care. 
This will require a signed medical release waiver 
 
Discuss the option of having a social worker involved as needed not only for the 
patient and LAR to receive resources as needed, but also to advise the research 
team of any potential risks/harms to the patient due to the patient’s impairment 
and its progression 
11.3 
Required Documentation (for multi-site studies) 
 
Not applicable.  
11.4 
Registration/Randomization Procedures 
 
Research staff will have online access to UTSW REDCap, and all patients will be 
registered electronically through REDCap. All subjects consenting to participate in any 
aspect of the trial must be registered on REDCap before initiating protocol activities. The 
eligibility checklist and confirming documentation will be entered electronically through 
the system.  
 
All research data will be recorded and entered into Case Report Forms using REDCap.  
 
Following registration, research staff from CRO will review all relevant data to ensure 
eligibility criteria have been met.   
 
The first number of the subject’s ID will refer to the treatment site. The ordering is: 
 
01: UTSW 
 
We will use this system in the future event of collaboration with other departments.  
 
New subjects will receive a secondary number beginning with 001 upon study consent 
such that the first subject consented is numbered 001, the second subject consented 
receives the number 002, etc. Upon confirmation of eligibility and enrollment as per the 
afore-mentioned instructions, the subject will be assigned a tertiary number in the order 
of enrollment.  
 
For example, the first patient consented and enrolled at UTSW will have the number 01-
001-001.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study id in Velos upon updating the status to enrolled. 
 
The numbering schema should clearly identify the site number; the sequential number of 
the subject enrolled as well as the status of the subjects enrolled so that the number of 
subjects consented versus the number of subjects actually enrolled may be easily 
identified.  
11.5 
Data Management and Monitoring/Auditing 
 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for this and all SCCC Investigator Initiated Trials. REDCap will be used for 

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electronic case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project. 
 
Trial monitoring will be conducted no less than annually and refers to the review of trial 
related activity and documentation performed by the DOT, which includes but is not 
limited to accuracy of case report forms, protocol compliance, timeliness and accuracy of 
Velos entries and AE/SAE management and reporting. Documentation of trial monitoring 
will be maintained along with other protocol related documents and will be reviewed 
during internal audit. 
 
Toxicity reviews will be performed at the end of study. These reviews will be documented 
by the study team and/or the UTSW Simmons Comprehensive Cancer Center (SCCC) 
Data Safety Monitoring Committee (DSMC).   
 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all serious 
adverse events and UPIRSOs in real time as they are reported and reviews adverse 
events on a quarterly basis.  The quality assurance activity for the Clinical Research 
Office provides for periodic auditing of clinical research documents to ensure data 
integrity and regulatory compliance.  A copy of the DSMC plan is available upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The Quality Assurance 
Coordinator (QAC) works as part of the DSMC to conduct regular audits based on the 
level of risk. Audit findings are reviewed at the next available DSMC meeting.  In this 
way, frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is 
determined by the DSMC Chairman and a number of factors such as the phase of the 
study; the type of investigational agent, device or intervention being studied; and 
monitoring required to ensure the safety of study subjects based on the associated risks 
of the study. Protocol-specific DSMC plans must be consistent with these principles.  
11.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
11.6.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
 intentional on part of the investigator; or 
 in the investigator’s control; or 
 not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that require prospective 
IRB approval before being implemented. Call the IRB if your request is 
urgent. If IRB approval is not obtained beforehand, this constitutes a major 
deviation. For eligibility waivers, studies which utilize the SCCC-DSMC as the 
DSMC of record must also obtain approval from the DSMC prior to submitting 
to IRB for approval. 

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11.6.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
 avoid immediate apparent harm, or 
 protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
11.6.3 Serious Noncompliance (formerly called major deviations or violations): 
include any departure from IRB-approved research that: 
 
Increase risk of harm to subject; and/or  
 
Adversely affects the rights, safety, or welfare of subjects (any of which may 
also be an unanticipated problem); and/or 
 
adversely affects the integrity of the data and research (i.e., substantially 
compromises the integrity, reliability, or validity of the research) 
 Reporting requirement: Serious Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
11.6.4 Continuing Noncompliance: includes a pattern of repeated noncompliance (in 
1 or more protocols simultaneously, or over a period of time) which continues 
after initial discovery, including inadequate efforts to take or implement corrective 
or preventative action within a reasonable time frame.  
 Reporting requirement*: Continuing Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
 
11.6.5    Noncompliance (that is neither serious nor continuing; formerly called 
minor deviations) any departure from IRB-approved research that: 
 
Does not meet the definition of serious noncompliance or continuing 
noncompliance 
 Reporting requirement*: Noncompliance that is neither serious nor 
continuing should be tracked and summarized the next IRB continuing review, 
or the notice of study closure- whichever comes first. 
 
*Reporting Requirements reflect UTSW HRPP/IRB guidelines; participating sites should follow 
the reporting guidelines for their IRB of record 
 
11.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  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.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.8 
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). 
 

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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 the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. 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. 
11.9 
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 may 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. 
 
12.0 
REFERENCES 
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Parsons JT, Mendenhall WM, Stringer SP, et al. Radiotherapy Alone for Moderately 
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Rubinstein M, Armstrong WB. Transoral laser microsurgery for laryngeal cancer: a primer 
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Pfister DG, Spencer S, Brizel DM, et al. Head and Neck Cancers, Version 1.2015. J Natl 
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Misono S, Marmor S, Yueh B, et al. T1 glottic carcinoma: do comorbidities, facility 
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Mendenhall WM, Amdur RJ, Morris CG, et al. T1-T2N0 squamous cell carcinoma of the 
glottic larynx treated with radiation therapy. J Clin Oncol 2001;19(20):4029-36. 

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9. 
Yamazaki H, Nishiyama K, Tanaka E, et al. Radiotherapy for early glottic carcinoma 
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Wetmore SJ, Key JM, Suen JY. Laser therapy for T1 glottic carcinoma of the larynx. Arch 
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Ogura JH. Management of early cancer of the vocal cord--laryngofissure, 
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Smith GL, Smith BD, Buchholz TA, et al. Cerebrovascular disease risk in older head and 
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Dorresteijn LD, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after 
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Rosenthal DI, Fuller CD, Barker JL, Jr., et al. Simple carotid-sparing intensity-modulated 
radiotherapy technique and preliminary experience for T1-2 glottic cancer. Int J Radiat Oncol Biol Phys 
2010;77(2):455-61. 
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Gomez D, Cahlon O, Mechalakos J, et al. An investigation of intensity-modulated 
radiation therapy versus conventional two-dimensional and 3D-conformal radiation therapy for early stage 
larynx cancer. Radiat Oncol 2010;5:74. 
16. 
Chera BS, Amdur RJ, Morris CG, et al. Carotid-sparing intensity-modulated radiotherapy 
for early-stage squamous cell carcinoma of the true vocal cord. Int J Radiat Oncol Biol Phys 
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17. 
Matthiesen C, Herman Tde L, Singh H, et al. Dosimetric and radiobiologic comparison of 
3D conformal, IMRT, VMAT and proton therapy for the treatment of early-stage glottic cancer. J Med 
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Zumsteg ZS, Riaz N, Jaffery S, et al. Carotid sparing intensity-modulated radiation 
therapy achieves comparable locoregional control to conventional radiotherapy in T1-2N0 laryngeal 
carcinoma. Oral Oncol 2015;51(7):716-23. 
19. 
Choi HS, Jeong BK, Jeong H, et al. Carotid sparing intensity modulated radiotherapy on 
early glottic cancer: preliminary study. Radiat Oncol J 2016;34(1):26-33. 
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Berwouts D, Swimberghe M, Duprez F, et al. Intensity-modulated radiotherapy for early-
stage glottic cancer. Head Neck 2016;38 Suppl 1:E179-84. 
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Paterson R. Studies in optimum dosage. Br J Radiol 1952;25(298):505-16. 
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Pfister DG, Ang K, Brockstein B, et al. NCCN Practice Guidelines for Head and Neck 
Cancers. Oncology (Williston Park) 2000;14(11A):163-94. 
23. 
Al-Mamgani A, Kwa SL, Tans L, et al. Single Vocal Cord Irradiation: Image Guided 
Intensity Modulated Hypofractionated Radiation Therapy for T1a Glottic Cancer: Early Clinical Results. Int 
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Ermis E, Teo M, Dyker KE, et al. Definitive hypofractionated radiotherapy for early glottic 
carcinoma: experience of 55Gy in 20 fractions. Radiat Oncol 2015;10:203. 

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25. 
Laskar SG, Baijal G, Murthy V, et al. Hypofractionated radiotherapy for T1N0M0 glottic 
cancer: retrospective analysis of two different cohorts of dose-fractionation schedules from a single 
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Short S, Krawitz H, Macann A, et al. TN/TN glottic carcinoma: a comparison of two 
fractionation schedules. Australas Radiol 2006;50(2):152-7. 
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Gowda RV, Henk JM, Mais KL, et al. Three weeks radiotherapy for T1 glottic cancer: the 
Christie and Royal Marsden Hospital Experience. Radiother Oncol 2003;68(2):105-11. 
28. 
Fowler JF. 21 years of biologically effective dose. Br J Radiol 2010;83(991):554-68. 
29. 
Kim YS, Lee J, Park JI, et al. Volumetric modulated arc therapy for carotid sparing in the 
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Atalar B, Gungor G, Caglar H, et al. Use of volumetric modulated arc radiotherapy in 
patients with early stage glottic cancer. Tumori 2012;98(3):331-6. 
 
 
 
 
 
 
 
 
 
 
 
13.0 
APPENDICES 
 
Appendix A: ECOG Performance Status 
 
 
ECOG PERFORMANCE SCALE 
 
0  
Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100). 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry work of a light or 
sedentary nature. For example, light housework, office work (Karnofsky 70-80). 
 
2  
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours (Karnofsky 50- 60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50% or more of waking hours 
(Karnofsky 30-40). 
 
4  
Completely disabled. Cannot carry on self-care. Totally confined to bed or (Karnofsky 10-20). 
 
5 
Death (Karnofsky 0). 
 
 
 
 

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Appendix B: EORTC QLQ-C30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix C: EORTC QLQ-H&N35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix D: Voice Handicap Index (VHI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix E: EQ 5D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Patient's initials: _______________  
Today's date: _______________