A Phase II Single Arm Trial of Elective Volume Adjusted De-Escalation Radiotherapy (EVADER) in Patients With Low-Risk HPV-Related Oropharyngeal Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Oropharyngeal Cancer
Sponsor: Canadian Cancer Trials Group

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
INITIAL VERSION:  2019-FEB-07 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE II SINGLE ARM TRIAL OF ELECTIVE VOLUME ADJUSTED DE-ESCALATION 
RADIOTHERAPY (EVADER) IN PATIENTS WITH LOW-RISK HPV-RELATED 
OROPHARYNGEAL SQUAMOUS CELL CARCINOMA 
 
CCTG Protocol Number: HN.10 
 
 
STUDY CHAIR: 
Scott Bratman 
 
 
TRIAL COMMITTEE: 
Eric Berthelet 
 
 
James Butler 
 
 
John de Almeida 
 
 
Irene Karam 
 
 
Ur Metser 
 
 
Robert Olson 
 
 
Craig Pochini 
 
 
John Waldron 
 
 
Eugene Yu 
 
 
SENIOR INVESTIGATOR: 
Wendy Parulekar 
 
 
BIOSTATISTICIAN: 
Wei Tu 
 
 
RT PHYSICS AND QA COORDINATOR: 
Andrea McNiven 
 
 
QUALITY OF LIFE COORDINATOR: 
Winson Cheung  
 
 
HEALTH ECONOMICS COORDINATOR: 
Marc Gaudet 
 
 
STUDY COORDINATOR: 
Sarah Hunter 
 
 
REGULATORY SPONSOR: 
CCTG 
 
 
(For contact information of study personnel see Final Page.) 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
CONFIDENTIALITY STATEMENT 
 
This protocol contains information that is confidential and proprietary. The contents of this protocol, its 
amendments and any information that may be added to this document or provided as a part of the conduct 
of this trial may not be used for any other purpose and may not be disclosed to any other person or entity 
without the prior written permission of CCTG (and other applicable parties as designated by CCTG). 
 

 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) ................................................................................... 1 
 
TREATMENT SCHEMA....................................................................................................................................... 2 
 
1.0 
OBJECTIVES ........................................................................................................................................... 3 
1.1 
Primary Objective ..................................................................................................................................... 3 
1.2 
Secondary Objectives ................................................................................................................................ 3 
1.3 
Tertiary Objectives .................................................................................................................................... 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 4 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION ............................................................................. 6 
3.1 
Radiotherapy ............................................................................................................................................. 6 
3.2 
Systemic Therapy ...................................................................................................................................... 6 
 
4.0 
STUDY POPULATION ........................................................................................................................... 7 
4.1 
Eligibility Criteria ..................................................................................................................................... 7 
4.2 
Ineligibility Criteria ................................................................................................................................... 8 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT........................................................................................................................................... 9 
5.1 
Follow-up for Ineligible Patients ............................................................................................................ 10 
 
6.0 
ENTRY/REGISTRATION PROCEDURES .......................................................................................... 11 
6.1 
Entry Procedures ..................................................................................................................................... 11 
6.2 
BSA Calculation...................................................................................................................................... 11 
6.3 
Registration ............................................................................................................................................. 11 
 
7.0 
TREATMENT PLAN ............................................................................................................................. 12 
7.1 
Systemic Therapy Options ...................................................................................................................... 12 
7.2 
Radiation Treatment Plan........................................................................................................................ 12 
7.3 
Surgical Treatment Plan of the Neck ...................................................................................................... 26 
7.4 
Concomitant Therapy .............................................................................................................................. 27 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS .......................................................... 28 
8.1 
Definitions ............................................................................................................................................... 28 
8.2 
Evaluation of Efficacy ............................................................................................................................ 29 
8.3 
Methods of Measurement........................................................................................................................ 31 
8.4 
Evaluation of Endpoints .......................................................................................................................... 33 
 
9.0 
SERIOUS ADVERSE EVENT REPORTING ....................................................................................... 35 
9.1 
Definition of a Reportable Serious Adverse Event ................................................................................ 35 
9.2 
Serious Adverse Event Reporting Instructions ....................................................................................... 35 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting ............................ 36 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 37 
9.5 
Reporting Serious Adverse Events to Investigators ............................................................................... 38 
 
10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 39 
10.1 
Criteria for Discontinuing Protocol Treatment ....................................................................................... 39 
10.2 
Therapy After Protocol Treatment is Stopped ........................................................................................ 39 
10.3 
Follow-up Off Protocol Treatment ......................................................................................................... 39 
 
 

 
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11.0 
CENTRAL REVIEW PROCEDURES .................................................................................................. 40 
11.1 
Central Data Review ............................................................................................................................... 40 
11.2 
Central Radiology Review ...................................................................................................................... 40 
11.3 
Central Pathology Review ...................................................................................................................... 40 
11.4 
Central Radiotherapy Review ................................................................................................................. 40 
 
12.0 
CORRELATIVE STUDIES ................................................................................................................... 41 
12.1 
Protocol-Mandated Correlative Studies .................................................................................................. 41 
12.2 
Optional Banking of Samples ................................................................................................................. 42 
 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................... 44 
13.1 
Objectives and Design ............................................................................................................................ 44 
13.2 
Primary Endpoints and Analysis ............................................................................................................. 44 
13.3 
Sample Size and Duration of Study ........................................................................................................ 44 
13.4 
Safety Monitoring ................................................................................................................................... 44 
13.5 
Interim Analysis ...................................................................................................................................... 44 
13.6 
Quality of Life Analysis .......................................................................................................................... 44 
13.7 
Economic Analyses ................................................................................................................................. 44 
 
14.0 
PUBLICATION POLICY ...................................................................................................................... 45 
14.1 
Authorship of Papers, Meeting Abstracts, Etc........................................................................................ 45 
14.2 
Responsibility for Publication................................................................................................................. 45 
14.3 
Submission of Material for Presentation or Publication ......................................................................... 45 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES....................................................... 46 
15.1 
Regulatory Considerations ...................................................................................................................... 46 
15.2 
Inclusivity in Research ............................................................................................................................ 46 
15.3 
Obtaining Informed Consent................................................................................................................... 46 
15.4 
Discontinuation of the Trial .................................................................................................................... 48 
15.5 
Retention of Patient Records and Study Files ........................................................................................ 48 
15.6 
Centre Performance Monitoring ............................................................................................................. 48 
15.7 
On-Site Monitoring/Auditing.................................................................................................................. 48 
 
16.0 
REFERENCES ........................................................................................................................................ 49 
 
APPENDIX I -  
PERFORMANCE STATUS SCALES/SCORES ............................................................... 53 
APPENDIX II -  
EXAMPLES OF VOLUME-REDUCED ENI TREATED LEVELS ON HN.10 .............. 54 
APPENDIX III -  
DOCUMENTATION FOR STUDY ................................................................................... 57 
APPENDIX IV -  
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .................... 60 
APPENDIX V -  
QUALITY OF LIFE ASSESSMENT ................................................................................. 61 
APPENDIX VI -  
PRO-CTCAE QUESTIONNAIRE ...................................................................................... 72 
APPENDIX VII -  LOST PRODUCTIVITY QUESTIONNAIRE ................................................................... 81 
APPENDIX VIII -  HEALTH UTILITIES ASSESSMENT ............................................................................... 91 
APPENDIX IX -  
THE TNM CLASSIFICATION OF MALIGNANT TUMOURS ...................................... 98 
APPENDIX X -  
EMERGENCY SITUATIONS AND COMPLIANCE ....................................................... 99 
 
LIST OF CONTACTS ............................................................................................................................. Final Page 
 

 
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CCTG TRIAL: HN.10 
 
 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, in accordance with any modifications that may 
occur over the duration of the study, and according to Good Clinical Practice and any applicable local 
regulations. I will make a reasonable effort to complete the study within the time designated. I confirm that 
I and study personnel participating under my supervision have adequate resource to fulfill their 
responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG to study personnel 
under my supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study. 
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of CCTG. The foregoing shall not apply to disclosure required 
by governmental regulations or laws; however, I will give prompt notice to CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrollment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG HN.10 
 
 
CENTRE: ___________________________________________ 

 
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TREATMENT SCHEMA 
 
This is a phase II, single arm, open-label, multi-centre cooperative group trial of elective volume adjusted 
de-escalation radiotherapy in patients with low-risk human papillomavirus (HPV)-related oropharyngeal 
squamous cell carcinoma (OPSCC). 
 
Pathologically-proven 
OPSCC 
 
p16+ or HPV+ 
 
Clinical stage 
T1-3 N0-1 M0 
(UICC/AJCC 8th Ed.) 
 
No prior radiotherapy 
or chemotherapy 
R 
E 
G 
I 
S 
T 
E 
R 
Treatment 
Option #1 
 
Radiotherapy (Standard Fractionation): 
Reduced ENI Volumes 
35 fractions, 5/wk, 7 wks 
70Gy/56Gy 
 
Cisplatin: 
100 mg/m2 on day 1, 22, and 43 
or 
40 mg/m2 /wk for 7 wks 
 
(Allowed for T3 N0-1, T2 N1, and T1 N1 with single node 
>3cm or multiple ipsilateral nodes) 
 
Treatment 
Option #2 
 
Radiotherapy Alone (Accelerated Fractionation): 
Reduced ENI Volumes 
35 fractions, 6/wk, 6 wks 
70Gy/56Gy 
 
(Mandatory for T1-2 N0 and for T1 N1 with single node ≤ 3 
cm; allowed for other patients who are not eligible for 
cisplatin) 
 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate the efficacy of primary definitive radiotherapy (RT) or chemoradiotherapy (CRT) 
utilizing volume reduced elective nodal irradiation (ENI) as measured by 2-year event-free survival 
(EFS) in patients with low-risk HPV-related OPSCC. 
 
1.2 
Secondary Objectives 
 
To evaluate overall survival, local control, regional control, local-regional control, out-of-field 
regional control, distant metastasis free survival, early and late toxicities of treatment, subjective 
swallowing functions, quality of life (QOL), utilization of healthcare resources, work productivity, 
and prognostic biomarkers. 
 
1.3 
Tertiary Objectives 
 
To assemble an imaging and biospecimen bank for future research that could improve risk 
stratification and patient selection for volume-reduced ENI. 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Oropharyngeal squamous cell carcinoma (OPSCC) that is related to human papillomavirus (HPV) 
infection is increasing in incidence within Canada and worldwide and is now the most common 
category of head and neck squamous cell carcinoma (HNSCC) in Canada [Canadian Cancer Statistics 
2016]. Standard treatment of HPV-related OPSCC includes radiotherapy (RT) often with concurrent 
chemotherapy (CRT). These treatments are highly effective but cause significant short- and long-
term toxicities. Several de-escalated treatment strategies are now being investigated in favourable 
prognosis patients. One approach that has not been sufficiently evaluated is reducing the regions of 
the lymph nodes in the neck that are treated with RT. 
 
Definitive treatment of OPSCC: Curative treatment strategies involving RT for OPSCC are 
associated with significant morbidity due to the intensity of the treatment and the anatomic location 
of the disease [Beetz 2012; Christianen 2012; Goepfert 2017; Kelly 2016; Lagendijk 2008; Machtay 2008; Ward 
2016]. Efforts to reduce dose to normal tissues involved in swallowing and salivary function, such 
as the implementation of parotid-sparing and pharyngeal-sparing intensity-modulated radiotherapy 
(IMRT) have helped to reduce these risks to a moderate degree, but many patients still endure 
significant toxicities that impair their objective swallowing and salivary functions to an extent that 
impacts quality of life (QOL), utilization of healthcare resources, and work productivity [Beetz 2012; 
Kohler 2013; Roe 2014; Yong 2012; Sturgis 2011; Chen 2017; Chera 2015; Lee 2016]. Therefore, new and 
creative approaches for reducing toxicity and improving QOL while maintaining high cure rates 
are needed. 
 
Treatment de-escalation for HPV-related OPSCC: Standard treatment for HPV-related OPSCC 
includes RT or CRT. These treatments are highly effective at curing most patients with HPV-related 
OPSCC. Short- and long-term toxicities from treatment can be significant, however, leading to the 
recognition that de-escalated treatment strategies should be investigated for a subset of favorable 
prognosis patients [Marur 2016]. Several de-escalation clinical trials for low-risk HPV-related 
OPSCC are currently ongoing or recently completed [Kelly 2016; Woody 2016; Nevens 2017; Nuyts 2013; 
Sanguineti 2014; Kjems 2016; Huang 2017; O'Sullivan 2001]. These trials are investigating the impact of (1) 
reduced RT dose or (2) reduced chemotherapy dose or intensity. In contrast, few studies are 
investigating the impact of reducing the volume of RT. 
 
Rationale for volume de-escalation for low-risk HPV-related OPSCC: Definitive RT for OPSCC 
typically includes prophylactic elective nodal irradiation (ENI) of uninvolved cervical nodal levels 
on one or both sides of the neck. Comprehensive ENI involves treatment of bilateral cervical lymph 
node chains from the retropharyngeal lymph node regions cranially to just above the clavicles 
caudally. ENI is intended to treat microscopic tumour deposits and reduce the risk of regional 
recurrence. Comprehensive ENI treatment fields likely result in overtreatment of most OPSCC 
patients. Eliminating regions with very low likelihood (< 5%) of subclinical tumour involvement 
[Li 2013; Seol 2016] from the ENI fields is a creative strategy for reducing toxicity of treatment while 
maintaining high rates of disease control. Volume-reduced ENI for HPV-related OPSCC has been 
evaluated in retrospective studies; for example omission of the contralateral cervical lymph node 
regions from the standard ENI treatment fields has been shown to be safe and effective in carefully 
selected patients with lateralized OPSCC [Villaflor 2016; de Almeida 2016]. Prospective studies have 
demonstrated safety and lower toxicity when using volume-reduced ENI in patients with 
nasopharynx cancer [Moore 2012; Pearce 2015] or when treating only involved lymph nodes in patients 
with OPSCC who respond to aggressive multi-drug induction chemotherapy [Caparrotti 2017]. 
 
 

 
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Rationale for QOL and resource utilization studies: Recent interest in de-escalation protocols for 
low-risk HPV-related OPSCC stems from the recognition that: 1) standard treatments result in 
overtreatment of most patients; and 2) HPV-related OPSCC afflicts generally younger and healthier 
individuals in the prime of their working years [Marur 2016]. Overtreatment leads to unnecessary 
toxicity, reduces QOL, increases resource utilization, and results in lost productivity [Machtay 2008; 
Kohler 2013; Yong 2012; Chen 2017; Chera 2015; Ringash 2017; Vainshtein 2015]. OPSCC patients often require 
increased medical and/or surgical management of osteoradionecrosis, esophageal stricture, trismus, 
and xerostomia [Aerts 2014; Leijenaar 2015]. Furthermore, ~30% of patients require emergency care 
during treatment, and ~40% report a change in work status after treatment [Kohler 2013]. The impact 
of overtreatment on QOL has been reported to differ between HPV-related and HPV-unrelated 
OPSCC [Gross 2014]. The long-term impact of OPSCC treatment on QOL is thought to stabilize by 
2 years post-treatment [Bratman 2016], suggesting that this duration of follow up is sufficient for 
prospective studies. 
 
Rationale for correlative studies: The goal of personalized cancer medicine is to deliver the 
appropriate intensity of treatment to each individual patient in order to maximize the likelihood of 
cure while minimizing side effects. De-escalated treatment approaches are best suited for patients 
with the most favorable prognosis, for whom the reduced intensity treatment is still sufficient for 
cure. Based on clinical stage and HPV-driven tumour biology, this study will select a group of low-
risk patients with high EFS with inclusion criteria that are similar to other de-escalation studies 
[Kelly 2016; Woody 2016; Nevens 2017]. However, the identification of additional biomarkers for more 
refined risk stratification remains an important research objective. Multiple putative prognostic 
biomarkers are suitable for validation in the context of de-escalated therapy. For example, 
quantitative radiomic analysis of primary tumours in lung cancer and head and neck cancer patients 
has identified a 4-feature signature that consistently predicts adverse outcomes [Goodman 2015; Cancer 
Genome Atlas Network 2015; Kwan 2018]. Other studies have demonstrated the poor prognostic 
association of HPV genotype and of TP53 mutation with concurrent chromosome 3p deletion [Wan 
2017; Bratman 2015; Lin 2004; Ahn 2014]. Circulating tumour DNA is an established risk marker across 
all cancers [Cao 2012; Dahlstrom 2015], with robust data from nasopharynx cancer demonstrating the 
poor prognostic association of elevated baseline plasma EBV DNA levels [Chaturvedi 2013]. Thus, it 
is likely that plasma HPV DNA levels in this population will also identify patients who are not 
suitable for treatment with de-escalated therapy. 
 
 

 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Radiotherapy 
 
Radiotherapy is a standard treatment option for patients with OPSCC, either alone or in 
combination with systemic therapy 
(https://www.nccn.org/professionals/physician_gls/default.aspx). 
 
See Section 7.2 for permitted radiotherapy schedules. 
 
3.2 
Systemic Therapy 
 
Systemic therapy given concurrently with radiotherapy is a standard treatment option for patients 
with OPSCC clinically staged: T3 N0-1 M0; T2 N1 M0; and T1 N1 M0 with either a single node 
> 3 cm or multiple ipsilateral nodes (NCCN Guidelines V2.2018). The systemic therapy on this 
study will be cisplatin. 
 
3.2.1 
Cisplatin 
 
Cisplatin has biochemical properties similar to those of bifunctional alkylating agents producing 
inter-strand and intra-strand cross-links in DNA. It is apparently not cell-cycle specific. 
 
Cisplatin in administered as intravenous injection (1 mg/ml). 
 
The major toxic effects are gastrointestinal, haematopoetic, otologic, neurologic and renal. 
 
Serious 
toxic 
effects 
include 
anaphylaxis, 
infections, 
myelosupression, 
neuropathy, 
leukoencephalopathy, posterior reversible encephalopathy, renal failure and venous or arterial 
thromboembolism. 
 
See Product Monograph May 30 2017 for additional information. 
 
Cisplatin will be administered on trial according to institutional practice. 
 
Cisplatin is commercially available and will not be supplied for this study. 
 
See Section 7.0 for permitted dose administration schedules. 
 
 

 
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4.0 
STUDY POPULATION 
 
This is a phase II, single arm, open-label, multi-centre cooperative group trial of elective volume 
adjusted de-escalation radiotherapy in patients with low-risk HPV-related oropharyngeal squamous 
cell carcinoma. 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
4.1 
Eligibility Criteria 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy and to ensure that the results of this study can be useful for making treatment decisions 
regarding other patients with similar diseases, it is important that no exceptions be made to these 
criteria for admission to the study. 
 
These eligibility criteria are expected to be followed. Any proposed variance must be discussed 
with CCTG prior to patient enrollment: 
 
4.1.1 
Patients with pathologically proven diagnosis of HPV-related OPSCC. HPV association will be 
determined locally by either p16 immunohistochemistry (> 70% of tumour cells demonstrating 
strong diffuse staining) or direct detection of HPV DNA sequences (e.g. by PCR or in situ 
hybridization), and must be performed on a core needle or surgical biopsy specimen of the primary 
tumour or involved cervical lymph node. 
 
4.1.2 
Clinical stage T1-3 N0-1 M0 (UICC/AJCC 8th Ed.) 
 
4.1.3 
Patients must be eligible for definitive RT or CRT. 
 
4.1.4 
Must be ≥ 18 years of age. 
 
4.1.5 
Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
 
4.1.6 
Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health 
economics questionnaires in either English or French. The baseline assessment must be completed 
within required timelines, preferably prior to registration, but must be done prior to treatment after 
enrollment. Inability (lack of comprehension in English or French, or other equivalent reason such 
as cognitive issues or lack of competency) to complete the questionnaires will not make the patient 
ineligible for the study. However, ability but unwillingness to complete the questionnaires will 
make the patient ineligible. 
 
4.1.7 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial to document 
their willingness to participate. 
 
 

 
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4.1.8 
Patients must be accessible for treatment and follow-up. Investigators must assure themselves the 
patients enrolled on this trial will be available for complete documentation of the treatment, adverse 
events, and follow-up. 
 
4.1.9 
In accordance with CCTG policy, protocol treatment is to begin within 3 weeks of patient 
registration. 
 
4.1.10 Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method. A woman is considered to be of “childbearing potential” if she has had menses at any time 
in the preceding 12 consecutive months. In addition to routine contraceptive methods, “effective 
contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (or 
with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Section 5.0); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
4.1.11 The following radiological investigations must be done within 8 weeks of registration: 
• 
CT or MRI of head and neck (MRI is recommended for base-of-tongue primary tumours); 
• 
PET-CT scan. 
 
4.1.12 Patient must consent to provision of, and investigator(s) must confirm location and commit to 
obtain a representation of formalin fixed paraffin block of non-cytology tumour tissue in order that 
the specific correlative marker assays described in Section 12 (Correlative Studies) may be 
conducted. Please see the Correlative Manual for details. 
 
4.1.13 Patient must consent to provision of samples of blood and plasma (for circulating cell free DNA) 
in order that the specific correlative marker assays described in Section 12 (Correlative Studies) 
may be conducted. 
 
4.1.14 Prior or Concurrent Malignancies 
 
Patients with a prior or concurrent malignancy whose natural history or treatment does not have 
the potential to interfere with the safety or efficacy assessment of the investigational regimen are 
eligible for this trial. 
 
4.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
4.2.1 
Previous chemotherapy or radiotherapy treatment for head and neck cancer. 
 
4.2.2 
Patients with an unknown primary. 

 
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5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT  
 
All patients entered on study must be evaluated according to the schedule outlined below with 
documentation submitted according to the schedule in Appendix III. 
 
Required Investigations 
Pre-study 
During Protocol 
Therapy  
(start of treatment until 
the end of RT) 
After Protocol Therapy 
until 
Recurrence/Progression 
Post Recurrence or Local, 
Regional or Distant 
Progression1 
History and Physical Exam 
 
 
 
 
Including: height2, weight, BSA, 
tobacco use, performance status, 
mucosal clinical assessment 
≤ 28 days 
Weekly 
1, 3, 6, 9, 12, 15, 18, 21, 
24, 28, 32, 36 months 
post RT then q6 months 
until 60 months post RT 
q6 monthly from the date of 
first failure3 
Direct or indirect visualization of 
tumour and surrounding area per local 
standards 
≤ 8 weeks 
 
3, 6, 9, 12, 15, 18, 21, 
24, 28, 32, 36 months 
post RT then q6 months 
until 60 months post RT 
At discretion of the 
investigator 
Laboratory Procedures/Assessments 
 
 
 
 
CBC with differential, creatinine, 
bilirubin, AST, ALT, ALP, LDH, 
albumin, total protein, glucose, 
magnesium, calcium, sodium, 
potassium, chloride, PTT, PT/INR 
As clinically indicated 
TSH (Free T4 will be measured if TSH is 
abnormal) 
≤ 14 days 
As clinically indicated 
12 and 24 months  
post RT 
As clinically indicated 
Radiology 
 
 
 
 
CT or MRI of head and neck (MRI is 
recommended for base-of-tongue 
primary tumours) 
≤ 8 weeks 
Full staging required if 
failure documented 
during treatment 
At 3 and 6 months post 
RT, and as clinically 
indicated 
At the discretion of the 
investigator 
Chest CT or chest X-ray 
As clinically 
indicated 
As clinically indicated 
PET-CT scan 
≤ 8 weeks 
At the discretion of the investigator 
Adverse Events 
 
 
 
 
Adverse event assessment4 
≤ 14 days 
Weekly 
1, 3, 6, 9, 12, 15, 18, 21, 
24, 28, 32, 36 months 
post RT then q6 months 
until 60 months post 
RT5 
As clinically indicated 
PRO-CTCAE selected items 
≤ 14 days 
Last week of RT 
3, 6, 12, 24, and 36 
months post RT 
 
Other Investigations 
 
 
 
 
Pregnancy Test6 
≤ 14 days 
 
 
 
Audiogram11 
≤ 8 weeks 
 
6 months post RT 
 
Tumour HPV status by IHC, PCR, or 
ISH7 
For all 
patients 
 
 
 
Biopsy8 
 
Recommended for confirmation of first recurrence, first distant metastases or first 
local/regional progression. 
Phone contact follow-up9 
 
 
Annually after 60 
months post RT 
 
 
footnotes on next page … 
 
 

 
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Required Investigations 
Pre-study 
During Protocol 
Therapy  
(start of treatment until 
the end of RT) 
After Protocol Therapy 
until 
Recurrence/Progression 
Post Recurrence or Local, 
Regional or Distant 
Progression1 
Correlative Studies 
 
 
 
 
Archival Tumour Tissues (for HPV 
genotyping and mutation testing) 
Submit ≤ 4 
weeks after 
registration 
 
 
 
Whole blood and plasma (for 
circulating cell free DNA [cfDNA]) 
After patient 
consent, 
prior to start 
of treatment 
 
1 month post RT 
 
Radiomic 
analysis 
of 
protocol-
mandated imaging 
No additional investigations are required other than collection of protocol-mandated imaging 
(diagnostic, simulation/planning and relapse CT and/or MRI). 
Quality of Life 
 
 
 
 
FACT-H&N10 
≤ 14 days 
Last week of RT 
3, 6, 12, 24, 36 months 
post RT 
 
Swallowing Related Quality of Life 
 
 
 
 
MDADI 
≤ 14 days 
Last week of RT 
3, 6, 12, 24, 36 months 
post RT 
 
Economic Analysis 
 
 
 
 
Health Utilities Index (EQ-5D-5L) 
≤ 14 days 
Last week of RT 
3, 6, 12, 24, 36 months 
post RT 
 
Resource Utilization Assessment 
 
Last week of RT 
6, 12, 24, 36 months 
post RT 
 
Lost Productivity Questionnaire 
 
Last week of RT 
6 and 12 months post 
RT 
 
Swallowing Status 
 
 
 
 
FOIS 
≤ 14 days  
 Last week of RT 
3, 6, 12, 24, 36 months 
post RT 
 
PSS-HN 
≤ 14 days  
Last week of RT 
3, 6, 12, 24, 36 months 
post RT 
 
1. As defined in Section 8. 
2. Height is only required at baseline. 
3. Weight and performance status only. 
4. Adverse events will be recorded and graded according to the CTCAE v 5.0 (Appendix VI). 
5. During the follow-up period, only treatment-related AEs will be collected. 
6. For women of child-bearing potential. May be urine or serum. Pregnancy test (in women of childbearing potential), as part of Pre-Study 
Evaluation, may include an ultrasound to rule-out pregnancy. 
7. HPV testing will be done locally. Reports showing positive immunostaining for p16 or positive HPV detection using PCR or in situ 
hybridation (ISH) must be submitted for each patient. 
8. Must be a needle core biopsy; FNA is not acceptable. 
9. Annual contact by phone or equivalent means to verify patient status, disease status and adverse events related to protocol treatment. 
10. The FACT-H&N questionnaire should be completed before the MDADI, EQ-5D-5L and PRO-CTCAE. 
11. Audiogram may be omitted at baseline and at the 6-month time point provided that this is aligned with institutional policy and there are no 
associated safety implications to the patient. If pre-registration audiogram is performed, it may be delayed until after enrollment but before 
commencement of therapy to accommodate delays in scheduling. The rationale for not ordering/delaying the test should be indicated in the 
source documentation 
 
5.1 
Follow-up for Ineligible Patients 
 
For patients declared ineligible and/or who have received no protocol therapy, a Baseline Report 
and annual follow-up using the Short Follow-Up Report must be submitted. 
 
Patients declared ineligible but who have received at least one dose of protocol therapy should be 
followed according to protocol to allow for treatment and adverse event assessments to be collected. 
 
Note: The dates of objective progression and death must be reported for ineligible patients. 
 
 

 
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6.0 
ENTRY/REGISTRATION PROCEDURES 
 
6.1 
Entry Procedures 
 
All registrations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
registering patients will be provided at the time of study activation and will also be included in the 
“EDC Data Management Guidebook”, posted on the HN.10 trial specific web-site. If sites 
experience difficulties accessing the system and/or registering patients, please contact the help desk 
(link in EDC) or the HN.10 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG HN.10); 
• 
patient's initials (may be coded); 
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed; 
• 
tissue banking/optional consent version date; 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values; 
• 
BSA, height and weight. 
 
6.2 
BSA Calculation 
 
In calculating surface areas, actual heights and weights should be used, that is, there will be no 
downward adjustment to “ideal” weight. This principle applies to individuals whose calculated 
surface area is 2.2 m2 or less. In those rare cases where a patient's surface area is greater than 2.2, 
the actual surface area or 2.2 may be used. CCTG BSA calculations are based on the Mosteller 
formula. 
 
6.3 
Registration 
 
Registration will be provided electronically. 
 
At the time of enrollment, all data reported within the Patient Enrollment folder must be accurate, 
complete and verifiable against source documentation. If a system query is issued indicating that 
the patient is not eligible, enrollment within the EDC system will not proceed. CCTG should be 
contacted for assistance if needed. Under no circumstances should inaccurate data be entered in 
order to permit enrollment. 
 
Note: 
The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting registration. 

 
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7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 3 weeks of patient 
registration. 
 
7.1 
Systemic Therapy Options 
 
For patients with OPSCC clinically staged (AJCC 8th Ed.) as T3 N0-1 M0, T2 N1 M0, or T1 N1 
M0 with either a single node > 3 cm or multiple ipsilateral nodes, systemic therapy may be 
administered concurrent with RT. For patients with clinical stage T1-2 N0 or T1 N1 with a single 
node ≤ 3 cm, no systemic therapy is permitted; these patients will be treated with accelerated 
fractionation RT alone. 
 
Systemic therapy may consist of cisplatin given either once every 3 weeks or once weekly. 
 
Patients with contraindication(s) to cisplatin will be treated with accelerated fractionation RT alone. 
 
7.1.1 
Cisplatin Therapy 
 
Cisplatin will be administered (concurrent with conventional fractionation RT) according to one of 
the following treatment schedules:  
 
Cisplatin: 40 mg/m2/once weekly during RT, for a maximum of 7 doses. 
 
Cisplatin: 100 mg/m2 day 1, 22 and 43 of RT. 
 
Dose adjustments will be based on institutional guidelines and Product Monograph. 
 
Antiemetic, hydration (pre and post) and other supportive care will be administered according to 
institutional guidelines and Product Monograph. 
 
7.2 
Radiation Treatment Plan 
 
Participating patients will be managed with RT at a dose of 70 Gy in 35 fractions to high dose 
regions and 56 Gy in 35 fractions to elective dose regions. Volume-reduced ENI will be used for 
all patients, with the extent of ENI determined by the subsite of the primary tumour within the 
oropharynx and by the number and distribution of involved cervical lymph nodes (Appendix II). 
 
Treatment options will include: 
• 
RT with conventional fractionation, 5 fractions per week over 7 weeks, and with concurrent 
cisplatin; or, 
• 
RT alone with accelerated fractionation, 6 fractions per week over 6 weeks. 
 
 

 
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7.2.1 
Glossary for Radiotherapy Section 
 
Table 1: Glossary of terms and contoured structures: 
 
IMRT 
Intensity Modulated Radiation Therapy  
VMAT 
Volumetric Modulated Arc Therapy 
CT 
Computed Tomography  
CTV 
Clinical Target Volume  
DRR 
Digitally Reconstructed Radiographs 
DVH 
Dose Volume Histogram 
ECE 
Extracapsular Extension 
ENI 
Elective Nodal Irradiation 
GTV 
Gross Tumour Volume 
MRI 
Magnetic Resonance Imaging 
OAR 
Organs-at-Risk  
PET 
Positron Emission Tomography 
PRV 
Planning Organ-at-Risk Volume 
PTV 
Planning Target Volume  
ROI 
Region of Interest 
QARC 
Quality Assurance Review Centre 
 
7.2.2 
Centre Credentialing for Delivery of Radiotherapy Technique 
 
All centres participating in the study will require credentialing for the delivery of IMRT or VMAT 
prior to local activation. 
 
Radiation therapy credentialing for this study will be done by the Quality Assurance Review Centre 
(QARC) (www.qarc.org). The credentialing process will involve completion of a facility 
questionnaire in addition to the completion of a benchmark case provided by QARC. Facilities that 
have been previously credentialed to deliver IMRT and/or VMAT through active participation in 
CCTG HN6, CCTG HN9, EORTC 1219, NRG HN001 or HN002 will be exempt from the 
benchmark test case. Other previous credentialing may also be acceptable at the discretion of 
QARC. The facility questionnaire must be completed by all sites, including those previously 
credentialed. Procedures, information and forms for this credentialing process can be found at 
http://www.qarc.org. 
 
7.2.3 
Patient Evaluation  
 
It is recommended that subjects undergo a complete dental evaluation. Any required dental work 
should be completed prior to radiotherapy. All subjects should undergo a nutritional evaluation 
prior to and during treatment. Prophylactic gastrostomy tube placement prior to treatment is not 
mandatory but encouraged particularly for patients being treated with concurrent cisplatin and 
should be performed if deemed appropriate. All patients should be reviewed by the treating 
radiation oncologist weekly during treatment for assessment of toxicity and treatment response. 
Patients with significant weight loss and/or response in bulky tumours may require replanning, if 
in the opinion of the treating radiation oncologist, delivery of the original plan may be 
compromised. 
 
 

 
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7.2.4 
Equipment and Treatment Delivery 
 
All patients will be managed with either IMRT or VMAT delivered on linear accelerators with 
photon beam energy of 4MV or greater. 
 
7.2.5 
Treatment Planning 
 
CT-based treatment planning is mandatory for all patients. All planning should be volumetric with 
dose volume histogram (DVH) assessments to ensure PTV coverage and OAR and PRV exclusion 
within study specifications (see Section 7.2.8). Every effort should be made to limit dose to 
noncritical normal tissues where possible. Corrections must be made for tissue heterogeneity. The 
dose calculation grid resolution should be less than or equal to 3 mm on a voxel edge. 
 
All plans will be generated by an inverse planning approach utilizing commercially available 
planning systems. 
 
7.2.6 
Positioning and Immobilization 
 
Patients will be treated in the supine position with arms at their side. All patients will be 
immobilized in a thermoplastic mask at the time of CT simulation and treatment. Shoulder 
immobilization is required and can be achieved by inclusion in the mask or other methods. 
 
7.2.7 
Simulation and Planning CT Scan 
 
CT-based simulation and planning is mandatory for all patients. Treatment planning CT scans will 
be acquired with the patient in the treatment position and immobilization device. All tissues to be 
irradiated must be included in the planning CT scan. The scanning limits should at least encompass 
the orbits superiorly to 1 cm below the suprasternal notch inferiorly. CT scan thickness must be 
≤ 3 mm. The use of intravenous CT contrast agents is permitted when clinically indicated. All 
specified target volumes and organs-at-risk (OAR) will be contoured on the planning CT scan. For 
purposes of contouring, MRI and positron emission tomography (PET) images, if available and 
clinically indicated, may be co-registered with the planning CT data set. Use of MRI (for staging 
and/or simulation) is recommended for base-of-tongue primary tumours. 
 
7.2.8 
Volume Definitions 
 
Nomenclature: 
All contoured objects will be assigned names according to the descriptions below and/or Tables 
2-5. 
 
 
 

 
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Table 2: Contoured target volumes: 
 
Dose Level 
Contour Name 
Description 
Notes 
High 
GTVp 
Primary gross tumour 
volume 
 
High 
CTVp_7000 
5 mm expansion on GTVp May be trimmed according to 
anatomical barriers to spread 
High 
PTVp_7000 
3-5 mm expansion on 
CTVp_7000 
 
High 
Eval_PTVp_7000 
PTVp_7000 trimmed from 
critical OARs and skin 
 
High 
GTVn_2_R 
Nodal gross tumour 
volume within right level 
II 
GTVn_[X]_[R/L] 
nomenclature: X denotes the 
nodal level [Grégoire 2014] and 
R/L denotes the laterality 
High 
GTVn_23_L 
Nodal gross tumour 
volume that spans left 
levels II and III 
 
High 
CTVn_2_R_7000 
5 mm expansion on 
GTVn_2_R 
May be trimmed according to 
anatomical barriers to spread 
High 
PTVn_2_R_7000 
3-5 mm expansion on 
CTVn_2_R_7000 
 
High 
Eval_PTVn_2_R_700
0 
PTVp_7000 trimmed from 
critical OARs and skin 
 
High 
Eval_PTV_7000 
Merged volume 
Union of 70 Gy Eval volumes 
Low 
CTVp_5600 
10 mm expansion on 
GTVp 
May be trimmed according to 
anatomical barriers to spread 
Low 
PTVp_5600 
3-5 mm expansion on 
CTVp_5600 
 
Low 
Eval_PTVp_5600 
PTVp_5600 trimmed from 
critical OARs and skin 
 
Low 
CTVn_R_5600 
Right neck ENI CTV 
CTVn_[R/L] nomenclature: 
R/L denotes the laterality 
Low 
PTVn_R_5600 
3-5 mm expansion on 
CTVn_R_5600 
 
Low 
Eval_PTVn_R_5600 
PTVn_R_5600 trimmed 
from critical OARs and 
skin 
 
Low 
Eval_PTV_5600 
Merged volume 
Union of 56 Gy Eval volumes 
Intermediate* CTVp_6300 
Optional expansion on 
GTVp 
Permitted in cases of 
uncertainty as to the extent of 
the GTVp; may replace 
CTVp_5600  
Intermediate 
PTVp_6300 
3-5 mm expansion on 
CTVp_6300 
 
Intermediate 
Eval_PTV_6300 
PTVp_6300 trimmed from 
critical OARs and skin 
 
* Intermediate dose level is optional for the primary site and is not allowed for nodal sites. 
 
 

 
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Gross Tumour Volume (GTV): 
The GTV represents grossly involved regions of primary tumour (GTVp) or involved nodes 
(GTVn). These regions will be defined based on clinical examination, examination under 
anesthetic, and CT scan. When indicated and available, MRI and/or PET scans may also be used to 
define the extent of the GTV. 
 
Cervical lymph nodes in the drainage area of the tumour will be contoured individually as GTVn 
targets (i.e. separate GTVn targets for each gross node, except in cases of nodal conglomerates) 
when meeting one or more of the following criteria:  
• 
exceeding one or both size criteria as defined below:  
− maximal axial longitudinal diameter (long axis) > 15 mm for jugulodigastric and 
submandibular nodes, > 10 mm for all other nodes except retropharyngeal nodes, and 
> 8 mm for retropharyngeal nodes;  
− minimum axial diameter (short axis) of > 11 mm for jugulodigastric nodes and > 10 mm 
for all other nodes;  
• 
evidence of necrosis;  
• 
extracapsular extension (ECE) based on irregular borders or invasion of adjacent structures 
radiographically;  
• 
significant PET avidity as defined below:  
− uptake above liver avidity for nodes with maximal axial longitudinal diameter ≥ 10 mm;  
− uptake above blood pool for nodes with maximal axial longitudinal diameter < 10 mm 
(especially if morphologically suspicious);  
• 
biopsy demonstrating the presence of cancer. 
 
Additional morphologic features may also be considered when contouring GTVn targets, including:  
• 
length-to-width ratio in the axial plane of < 2 (i.e. round node vs. lima bean–shaped node), 
especially if PET avidity is above blood pool;  
• 
a group of three or more nodes in the drainage area of the tumour that are round or borderline 
by size criteria (e.g. maximal axial longitudinal diameter 9-15 mm and/or minimum axial 
diameter 8-10 mm), especially if PET avidity is above blood pool. 
 
Clinical Target Volumes (CTV): 
CTVs are contoured in relation to the gross targets and regions of potential subclinical spread they 
are intended to encompass, and according to the dose they are intended to receive. Although defined 
as a 3D expansion of these targets, CTVs should be limited by potential barriers to tumour spread 
such as air cavities, external contour and boney or fascial planes through which tumour spread is 
not possible or apparent. Dose to be delivered to CTVs are provided in subsequent sections. 
 
CTVs for the Primary Site and Involved Nodes: 
The primary site GTVp will be encompassed by a high dose CTVp_7000 with a margin of 5 mm. 
Exceptions to the 5 mm minimum are regions limited by potential barriers to tumour spread as 
described above. CTVp_5600 is a further expansion of 5 mm on the CTVp_7000 (total of 10 mm 
margin around GTVp). In cases of uncertainty as to the extent of the GTVp, another CTV delivering 
an intermediate dose level (CTVp_6300) may be used to replace the subclinical dose CTVp_5600 
expansion around this GTV. 
 
 

 
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Each grossly involved nodal volume (GTVn_[X]_[R/L]) will be encompassed by a separate high 
dose CTVn_[X]_[R/L]_7000 volume with a margin of 5 mm. Exceptions to the 5 mm minimum 
are regions limited by potential barriers to tumour spread as described above. No CTVn_6300 
volumes are permitted in necks. 
 
CTVs for Neck Regions of Subclinical Disease (Elective Nodal Irradiation): 
Elective nodal irradiation (ENI) regions will be included in the CTVn_L_5600 (left neck ENI 
regions) and the CTVn_R_5600 (right neck ENI regions). The included ENI levels will depend on 
the location and extent of the existing grossly involved nodes and primary site, with the intent of 
treating levels that harbor nodes at > 5% risk of subclinical spread of tumour. Neck CTVs will be 
defined according to the tables below, with additional details provided in Appendix II and the 
DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines 
[Grégoire 2014]. 
 
Table 3: ENI levels to be included based on primary location, T category, and N category: 
 
Base-of-Tongue Primary 
AJCC 8th Ed. Stage 
ENI levels to be included in the CTVn_[R/L]_5600 
[Grégoire 2014] 
T category 
N category 
Ipsilateral neck 
Contralateral neck 
T1-2 
N0 
 II 
• 
II 
T1-2 
N1 
 II, III, and VIIb;  
 IV and V to be included 2 cm 
below the caudal edge of any 7000 
cGy CTVn volume 
 Ib to be included only if involved 
by gross nodal disease 
• 
II 
T3 
N0 
 II and III 
 VIIa and VIIb to be included for 
posterior pharyngeal wall 
involvement or > 1 cm soft palate 
involvement 
• 
II and III 
T3 
N1 
 II, III, and VIIb;  
 IV and V to be included 2 cm 
below the caudal edge of any 7000 
cGy CTVn volume 
 VIIa to be included for posterior 
pharyngeal wall involvement or 
> 1 cm soft palate involvement 
 Ib to be included only if involved 
by gross nodal disease 
• 
II and III 
 
 
 

 
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Palatine Tonsil Primary 
AJCC 8th Ed. Stage 
ENI levels to be included in the CTVn_[R/L]_5600 
[Grégoire 2014] 
T category 
N category 
Ipsilateral neck 
Contralateral neck 
T1-2 
N0 
 II 
 VIIa and VIIb to be included for 
posterior pharyngeal wall 
involvement or > 1 cm soft palate 
involvement 
 II to be included for base-of-
tongue involvement extending 
to within 1 cm of midline 
 II, VIIa and VIIb to be included 
for posterior pharyngeal wall 
involvement or soft palate 
involvement extending to within 
1 cm of midline 
T1-2 
N1 
 II, III, and VIIb;  
 IV and V to be included 2 cm 
below the caudal edge of any 7000 
cGy CTVn volume 
 VIIa to be included for posterior 
pharyngeal wall involvement or 
> 1 cm soft palate involvement 
 Ib to be included only if involved 
by gross nodal disease 
 II to be included for base-of-
tongue involvement extending 
to within 1 cm of midline 
 II, VIIa and VIIb to be included 
for posterior pharyngeal wall 
involvement or soft palate 
involvement extending to within 
1 cm of midline 
T3 
N0 
 II and III 
 VIIa and VIIb to be included for 
posterior pharyngeal wall 
involvement or > 1 cm soft palate 
involvement 
 II to be included for base-of-
tongue involvement extending 
to within 1 cm of midline 
 II, VIIa and VIIb to be included 
for posterior pharyngeal wall 
involvement or soft palate 
involvement extending to within 
1 cm of midline 
T3 
N1 
 II, III, and VIIb;  
 IV and V to be included 2 cm 
below the caudal edge of any 7000 
cGy CTVn volume 
 VIIa to be included for posterior 
pharyngeal wall involvement or 
> 1 cm soft palate involvement 
 Ib to be included only if involved 
by gross nodal disease 
 II to be included for base-of-
tongue involvement extending 
to within 1 cm of midline 
 II, VIIa and VIIb to be included 
for posterior pharyngeal wall 
involvement or soft palate 
involvement extending to within 
1 cm of midline 
 
Soft Palate Primary 
AJCC 8th Ed. Stage 
ENI levels to be included in the CTVn_[R/L]_5600 
 [Grégoire 2014] 
T category 
N category 
Ipsilateral neck 
Contralateral neck 
T1-3 
N0 
 II, VIIa, and VIIb 
 II, VIIa, and VIIb 
T1-3 
N1 
 II, III, VIIa, and VIIb;  
 IV and V to be included 2 cm 
below the caudal edge of any 7000 
cGy CTVn volume 
 Ib to be included only if involved 
by gross nodal disease 
 II, VIIa, and VIIb 
 
 

 
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Unilateral Neck Treatment: 
Unilateral neck treatment should be performed for patients with palatine tonsil primary unless gross 
disease extends to within 1 cm of midline (along base-of-tongue, posterior pharyngeal wall, and/or 
soft palate), in which case bilateral neck treatment should be performed covering the ENI levels as 
specified above. Bilateral neck treatment should be performed for patients with base-of-tongue or 
soft palate primary. 
 
Planning Target Volume (PTV): 
The PTVs are geometric expansions of the CTVs to account for internal motion and residual set-
up error. The PTVs represent the volumes to which dose will be prescribed, delivered and 
evaluated. All CTVs will have a corresponding PTV which will represent at least a 3-5 mm 
expansion of the CTV in all planes. For centres utilizing daily volumetric image-guided radiation 
therapy (IGRT), smaller PTV margins of 3-4 mm will be permitted to continue as long as they have 
their own immobilization data to support this. 
 
Modification of PTVs to create Eval_PTVs: 
In instances where the PTV overlaps a critical OAR (Table 4) or it’s associated PRV, the PTV will 
be modified to exclude the PRV. 
 
When expansion of a CTV results in PTVs that extend beyond the patient’s surface, or within 5 mm 
of the patient surface, the PTV should be constrained to 5 mm within the external contour. A 3 mm 
constraint may be used if disease is near the skin surface. For situations where disease is at or just 
below the surface, the use of tissue equivalent material (bolus) is required. 
 
These modified PTV volumes are the evaluation volumes that will be used to assess dose coverage. 
Eval_PTV_#### (without any identification of primary or nodal PTV) will be a merged volume for 
evaluation (the union of all PTVs for a specific dose level). Eval_PTV doses are defined in Table 6. 
 
Organs-at-Risk (OAR): 
Critical OARs must be contoured on every CT slice in which they appear. Critical OARs are spinal 
cord, brainstem and brain. Optic nerves, optic chiasm, and globes should be contoured and dose 
evaluated for cases in which the treated volumes (PTVs) are within 1 cm of any of these structures, 
otherwise they can be omitted. When at risk, and hence contoured, the optic structures would be 
regarded as critical OARs. Other OARs to be contoured include parotid glands, mandible, 
submandibular glands, glottic larynx, and midline mucosa. Brachial plexus should be contoured 
ipsilateral to any gross nodes below the level of C5 otherwise can be omitted. Critical OAR dose 
limits are defined in Table 4 and dose limits for other OARs in Table 5. 
 
Planning Organ-at-Risk Volume (PRV): 
Critical OARs requiring PRVs include spinal cord and brainstem. PRVs will represent 3-5 mm 
expansions of the critical OARs to account for interfraction patient and organ motion and for 
purposes of dose assessment and limitation during the planning and review process. For spinal cord, 
5 mm PRV expansion is required, regardless of local IGRT practice. For centres utilizing daily 
volumetric IGRT, 3-4 mm PRV expansion will be permitted for brainstem. 
 
 

 
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7.2.9 
Dose Limits to Normal Tissues 
 
The dose delivered to normal structures (OARs and PRVs) will be determined by review of both 
DVHs and axial dose distributions for the OARs and PRVs as defined above. Strict dose limitations 
are assigned to the critical OARs listed in Table 4 and may not be exceeded under any 
circumstances. The dose limits of other OARs (Table 5) should be achieved as long as these 
structures are not directly involved by tumour and/or dose to the adjacent PTVs is not compromised 
to do so. The volumes listed in Tables 4 and 5 will be contoured for all cases. 
 
Table 4: Critical OAR dose limits: 
 
Region of Interest (ROI) 
Standard Names 
Criterion 
Dose Limit 
Brainstem 
Brainstem 
Max dose to 0.1 cc 
50 Gy 
PRV Brainstem 
Brainstem_PRV03 
Max dose to 0.1 cc 
60 Gy 
Spinal Cord 
SpinalCord 
Max dose to 0.1 cc 
45 Gy 
PRV Spinal Cord 
SpinalCord_PRV05 
Max dose to 0.1 cc 
52 Gy 
Brain 
Brain 
Max dose to 0.1 cc 
70 Gy 
Optic Nerves 
OpticNrv_R or L 
Max dose to 0.1 cc 
42 Gy 
Chiasm 
Chiasm 
Max dose to 0.1 cc 
42 Gy 
 
Non-targeted Neck CTVs: 
The dose delivered to neck nodal regions that are not part of any PTV will be evaluated as specified 
in Table 5. Neck nodal levels Ib, II, III, IV, V, VIIa, and VIIb are to be contoured. Separate 
structures are to be created for the right and left necks, but separate sub-structures for each nodal 
level are not required. The volume that does not overlap with any of the PTVs will be designated 
ref_Neck_R or ref_Neck_L. Both sides must be contoured even in cases where unilateral neck 
treatment is performed. Contouring of nodal levels is to be performed according to the DAHANCA, 
EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines [Grégoire 2014]. 
 
As mentioned above, dose to PTVs should not be compromised to achieve the dose limits stipulated 
in Table 5. 
 
 
 

 
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Table 5: Other (non-critical) OAR dose limits: 
 
Region of Interest (ROI) 
Standard Names 
Scenario or Criterion 
Dose Limit 
Submandibular Glands 
Submand_R or L 
When the adjacent level II 
is included in CTVs 
 
When the adjacent level II 
is not included in CTVs 
Mean: < 39 Gy 
 
 
Mean: < 26 Gy 
Larynx 
Larynx 
When bilateral level III is 
included in CTVs 
 
When unilateral level III is 
included in CTVs 
 
When neither level III is 
included in CTVs 
Mean: < 45 Gy 
 
 
Mean: < 35 Gy 
 
 
Mean: < 15 Gy 
Parotid Glands 
Parotid_R or L 
Mean 
 
D50% 
< 26 Gy  
 
< 30 Gy 
Oral Cavity 
OralCavity 
Mean 
< 30 Gy 
Lips 
Lips 
Mean 
< 25 Gy 
Pharyngeal constrictors 
Musc_Constrict 
Mean 
< 45 Gy 
Cervical Esophagus 
Esophagus 
Mean 
< 35 Gy 
Mandible 
Mandible 
Max dose to 0.1 cc 
< 73.5 Gy within 
Eval_PTV_7000 and 
< 70 Gy outside of 
Eval_PTV_7000 
Contoured* neck nodal 
levels Ib, II, III, IV, V, 
VIIa, and VIIb outside the 
PTVs 
ref_NECK_R or L 
The treated neck  
(i.e. each neck in bilateral 
cases or the treated neck in 
unilateral neck cases) 
 
The untreated neck  
(i.e. the untreated neck in 
unilateral neck cases) 
V25: < 50 cc 
 
 
 
V25: < 10 cc 
Unspecified normal tissues 
outside defined PTVs 
External-PTV 
Max dose to 1 cc 
< 73.5 Gy 
*  Comprehensive neck volumes (both sides: ref_NECK_R and ref_NECK_L) must be contoured for all cases in 
order to assess dose to non-targeted neck levels. Efforts should be made to minimize the volume of each ref_Neck 
ROI that receives > 25 Gy. Dose limits apply to each ref_NECK ROI individually. 
 
7.2.10 Planning Procedures 
 
Planning Priorities: 
For purposes of plan optimization, the priorities are: 1) critical OAR and PRV, 2) PTV coverage, 
3) non-critical OAR, 4) undefined normal tissue. 
 
Beam Arrangement: 
The beam arrangements will be those necessary to treat the defined target volumes (see 
Section 7.2.8) and spare OARs. Beam arrangements are discretionary and defined to achieve study 
dosimetric goal specifications. 
 
 

 
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Beam Segmentation and Optimization: 
Beam segmentation and optimization is at the discretion of the planner, subject to institutional 
practice. 
 
7.2.11 Dose Reporting 
 
Dose is to be prescribed to an isodose line that encompasses the respective PTV and satisfies the 
dose heterogeneity criteria in Section 7.2.12. 
 
7.2.12 Dose Heterogeneity 
 
Dose heterogeneity limits to PTVs are illustrated in Table 5. Plan normalization should provide 
coverage of 95% of the PTV_7000 with the prescription dose (70 Gy). No more than 1% of any 
PTV will receive less than 93% of the prescribed dose. Maximum doses to Eval_PTV_7000, 
Eval_PTV_5600 and Eval_PTV_6300 (optional) are 115%, 125% and 120% of their prescribed 
doses respectively. However, it is recognized that small volumes of lower dose PTVs surrounding 
or adjacent to higher dose PTVs may exceed this (see Table 6). 
 
Table 6: Planning target volume dose limits: 
 
 
Eval_PTV_7000 
Eval_PTV_5600 
Eval_PTV_6300 
(optional) 
Percent Volume 
(% of 70Gy) 
(% of 56Gy) 
(% of 63Gy) 
< 5% 
< 100% 
< 100% 
< 100% 
< 1% 
< 93% 
< 93% 
< 93% 
 
 
 
 
0% 
> 115% 
> 125%* 
> 120%* 
< 20% 
> 110% 
> 110%* 
> 110%* 
Mean dose 
≤ 105% 
 
 
* 
These limits are applicable to portions of Eval_PTV_5600 and Eval_PTV_6300 which (i) do not overlap higher-
dose PTVs and (ii) are not adjacent to higher-dose PTVs 
 
7.2.13 Dose Fractionation Schemes 
 
Radiotherapy will be delivered to a prescribed dose of 70 Gy in 35 fractions of 2 Gy. Permitted 
fractionation schemes include: 
• 
Conventional fractionation, 5 fractions per week over 7 weeks, when delivered with concurrent 
cisplatin; or 
• 
Accelerated fractionation, 6 fractions per week over 6 weeks, when delivered alone. The sixth 
fraction can be delivered on a weekend or as a second treatment on a weekday, provided that 
the treatment interval is at least 6 hours. 
 
Treatment breaks should be minimized, and twice-daily radiation treatments are encouraged to 
make up for unexpected treatment breaks or hospital closures. When twice-daily radiation 
treatments are delivered as part of planned accelerated fractionation or to make up missed 
treatments, the minimum treatment interval is 6 hours. 
 
 

 
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IMRT Dose Specifications:  
A single-phase IMRT plan will be given delivering 35 fractions, 
• 
PTV_7000 will receive 2 Gy per fraction. 
• 
PTV_5600 will receive 1.6 Gy per fraction. 
• 
PTV_6300 (optional) will receive 1.8 Gy per fraction. 
 
7.2.14 Treatment Delivery 
 
Patient Set Up and Verification Imaging: 
Patients will be positioned for treatment on the treatment bed within their immobilization mask and 
aligned according to marks placed on this mask to indicate the isocenter.  Image guided radiation 
therapy (IGRT) is to be completed to verify patient positioning. Daily IGRT is strongly 
recommended, however, the minimum requirement is weekly imaging, starting on the first day of 
treatment. 
 
On-board volumetric imaging (e.g. kilovoltage (kV) or megavoltage (MV) conebeam CT (CBCT)) 
is recommended to be used and compared to the planning CT to verify daily positioning.  
Alternatively, this can be done with portal images of orthogonal fields localizing the isocentre 
placement for IMRT plans. Image matching will be based on alignment of regional boney 
landmarks with offsets of greater than 3 mm requiring patient repositioning. Imaging post-
recommendation is recommended but not required. 
 
7.2.15 Corrections For Radiotherapy Treatment Interruptions 
 
Treatment interruptions of a single day will be compensated for with the addition of a second daily 
treatment on one day of the week preceding or following the interruption. These treatments should 
have a strict minimum interfraction interval of 6 hours. For patients receiving accelerated 
fractionation the compensatory second fraction should have a minimum two-day separation from 
the regularly scheduled two fraction day. A maximum of three such compensatory treatments will 
be permitted during the treatment course. Interruptions not compensated for will be recorded and 
accounted for in the determination of protocol compliance according to Section 7.2.16. 
 
7.2.16 Compliance Criteria 
 
Radiation treatment related deviations outside protocol recommendations and likely to influence 
clinical outcome will be considered as major. Such deviations could include failure to identify and 
treat appropriate targets and excessive treatment of non-target tissues. These determinations will 
be made during the plan review process. Deviations outside protocol recommendations and unlikely 
to influence clinical outcome will be considered as minor. 
 
Treatment Interruptions: 
Treatment breaks must be clearly indicated in the treatment record along with the reasons for the 
treatment breaks. Treatment breaks should be allowed only for resolution of severe acute toxicity 
and/or for intercurrent illness and not for social or logistical reasons 
 
Single day interruptions will be compensated for according to guidelines in Section 7.2.15 for a 
maximum of 3 treatment day interruptions. 
 
 

 
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Any uncompensated treatment break(s) for any non-medical reason exceeding two sequential 
treatment days or 5 total days during the course of treatment will be considered as a protocol 
deviation. 
 
Treatment interruptions of 3-5 sequential treatment days at a time for any reason will be considered 
a minor deviation and more than 5 sequential treatment days at a time will be considered as a major 
deviation. 
 
Over the full course of treatment total treatment breaks of 6-10 days for any non-medical reason 
will be considered a minor deviation and if more than total 10 treatment days will be considered as 
a major deviation. 
 
Dose Delivery 
Major and minor dose delivery deviations for PTVs are described relative to dose objectives in the 
RTQA & Radiomics Manual on the HN.10 trial specific website. To be categorized as a major 
protocol deviation a plan will be determined to have i) failed to meet dose criteria and ii) such 
failure will have to be deemed as likely to have an adverse impact on patient outcome at the time 
of central review of the volumes and distributions.  
 
The reviewers recognize achieving 100% of the dose to 95% of the Eval_PTVs will be challenging 
for cases in which the Eval_PTV is in close proximity to a critical OAR (Table 4) and/or skin 
surface, however these objectives would be expected to be achieved otherwise. Summary of minor 
and major deviations relating to target coverage is summarized in Table 7.  
 
Non-compliance with the dose limitations assigned to critical OARs (Table 4) will always be 
considered a major deviation. Non-compliance with the dose limits of “other OARs” (Table 5) will 
be analyzed case per case by the reviewers to define if they should be considered deviations or not. 
Cases for which the doses to these OARs exceed the protocol limits due to proximity to PTVs will 
not be considered deviations. For example, exceeding dose limits to parotid glands is acceptable 
when needed to achieve acceptable dose to an adjacent or overlapping PTV. 
 
Table 7: Major and Minor Dose Delivery Deviations for Planning target volumes. 
 
 
Eval_PTV_
7000 
Eval_PTV_5600 
Eval_PTV_6300 
(optional) 
Dose Criteria for Deviations 
Percent Volume 
(% of 70Gy) 
(% of 56Gy) 
(% of 63Gy) 
Minor Deviation 
(% Volume) 
Major 
Deviation (% 
Volume) 
< 5% 
< 100% 
< 100% 
< 100% 
 
>5% 
< 1% 
< 93% 
< 93% 
< 93% 
1-3% 
>3% 
 
 
 
 
 
 
0% 
> 115% 
> 125%* 
> 120%* 
 
 
< 20% 
> 110% 
> 110%* 
> 110%* 
 
 
Mean dose to 
Eval_PTV_7000 
≤ 105% 
 
 
105-107% of 70 
Gy 
>107% of 70 
Gy 
* 
These limits are applicable to portions of Eval_PTV_5600 and Eval_PTV_6300 which (i) do not overlap higher-
dose PTVs and (ii) are not adjacent to higher-dose PTVs. 
 
 

 
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7.2.17 Central Radiotherapy Quality Assurance Review 
 
Central quality assurance review of radiation delivery will consist of two components:  
i) real time rapid review of contoured targets (GTVs, CTVs, PTVs), OARs, and diagnostic 
imaging prior to commencement of treatment; 
ii) post treatment final review of radiotherapy plans. 
 
Radiotherapy quality assurance reviews will be conducted centrally through QARC for all patients. 
Procedures, information and forms about the external review process can be found at 
http://www.qarc.org. Data required for plan documentation and quality assurance will be submitted 
according to QARC guidelines. 
 
The real time rapid review and final review will be performed for every case. 
 
Real Time Rapid Review: 
The simulation scan, contours (targets and OARs as defined in Tables 2-5), diagnostic head and 
neck cross-sectional imaging (CT, MRI, PET), and supporting documentation is to be submitted 
and approved by QARC prior to commencement of treatment. This should be done as soon as 
possible to enable modifications to the contours to conform with the protocol. Feedback from the 
Rapid Review will be returned to the treating centre within 2 working days. The treating centre will 
implement corrective action if applicable and respond to QARC recommendations prior to 
commencement of treatment. 
 
Final Review: 
The required documentation is to be submitted to QARC within 2 weeks of treatment completion. 
A written report of the Final Review will be created by QARC. Additional details can be found in 
the RTQA & Radiomics Manual. 
 
7.2.18 Central Review of Regional Failures 
 
With reduction of the elective nodal irradiation volumes, there may be increased risk of out-of-field 
regional recurrence. Rigorous analysis of patterns of failure in the neck will be important for 
informing the results of this study and any future studies that utilize a similar treatment approach. 
 
Any subject with regional recurrence in the lymph nodes of the neck (either as first or subsequent 
recurrence) will require central review of the radiological images (CT, MRI, and/or PET-CT) 
obtained at the time of recurrence in order to categorize the regional recurrence as in-field or out-
of-field. The radiological images showing regional recurrence will be submitted within 4 weeks of 
confirming the recurrence. 
 
The recurrent tumour volume will be identified on the earliest available diagnostic scan that shows 
the recurrent node. If the identified recurrent lymph node corresponds to a lymph node that was 
present on the planning scan, the node from the planning scan will be contoured and named 
“RECUR_NODE.” Otherwise, the identified recurrent lymph node volume will be contoured on 
the radiological images obtained at the time of recurrence and named “RECUR_NODE”; following 
registration to the planning scan, the RECUR_NODE volume will be transferred to the planning 
CT structure set. 
 
The radiation dose received by the RECUR_NODE volume will be determined. 
 
 

 
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An “in-field regional recurrence” will be defined in cases in which ≥ 95% of RECUR_NODE was 
within the 95% isodose of PTV_5600. 
 
An “out-of-field regional recurrence” will be defined in cases in which < 95% of RECUR_NODE 
was within the 95% isodose of PTV_5600. 
 
7.3 
Surgical Treatment Plan of the Neck 
 
Patients will have an evaluation of their primary tumour and neck (CT, MRI, and/or PET-CT) 12 
weeks following the completion of radiotherapy (Section 5.0). 
 
Institutional policies will be followed regarding surgical treatment of the neck for suspected 
residual, recurrent, or progressive nodal disease. Guidance is provided below regarding surgical 
treatment of the neck in specific settings. Regardless of the policy adopted for the management of 
the neck, any surgical intervention requires that new or persistent nodal disease be deemed operable 
by the treating surgeon. 
 
7.3.1 
Surgical Treatment Plan for Node-Positive Patients With Residual Abnormal Treated Lymph 
Nodes at 12 Weeks 
 
The decision to undertake a neck dissection as a result of residual abnormal lymph nodes in the 
treatment field will be based on the clinical and radiographic examinations at 12 weeks post 
radiotherapy and institutional policies regarding planned neck dissections. Because of high rates of 
eventual CR in the neck for HPV positive patients presenting with involved lymph nodes coupled 
with low rates of pathologic positivity in residual nodes, it is suggested that centres follow the 
algorithm presented below: 
 
Elective neck dissection should be completed ≤ 20 weeks following completion of radiotherapy. 
 
Nodal disease* at week 12 
Recommendation 
No new or persistent disease 
Follow as per protocol (Section 5.0) 
Persistent treated nodes < 2 cm 
Repeat imaging in < 2 months 
Persistent treated nodes > 2 cm with evidence of regression 
Repeat imaging in < 2 months 
Persistent treated nodes > 2 cm with no regression or progression 
compared to baseline 
Neck dissection 
Persistent treated nodes of any size with significant PET avidity 
(if performed as per institutional standards) 
Consider neck dissection as per 
institutional policy 
* on clinical and/or radiographic examinations 
 
7.3.2 
Surgical Treatment Plan for Patients With New Abnormal Lymph Nodes 
 
New lymph nodes that are abnormal based on the clinical and radiographic examinations at 
12 weeks post radiotherapy or on any subsequent examinations should be biopsied without delay 
to confirm regional recurrence. 
 
 

 
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For a negative biopsy, at the discretion of the treating team, the subject may undergo re-attempt at 
biopsy, repeat imaging within 1-2 months, or proceed directly to prompt neck dissection. 
 
For a positive biopsy, full re-staging examinations must be performed (Section 5.0). For isolated 
biopsy-proven regional recurrence, prompt neck dissection is recommended, provided that the 
disease is deemed to be operable by the treating surgeon. For inoperable isolated regional 
recurrence, salvage re-irradiation with or without concurrent chemotherapy may be employed at 
the discretion of the treating team. If there is overlap of the re-irradiation treatment field with the 
original treatment field, twice daily hyperfractionated radiotherapy should be performed in order 
to minimize potential late toxicity. 
 
7.4 
Concomitant Therapy 
 
7.4.1 
Permitted 
 
Patients will receive ongoing supportive and symptom control (e.g. nutritional support including G 
tubes insertion, analgesics for pain) as indicated throughout the study. Other ancillary treatments 
such as intravenous hydration will be given as medically indicated. All treatment must be recorded 
in the case report forms. 
 
7.4.2 
Not Permitted 
 
Administration of any other anti-cancer therapy is not permitted while the patient is receiving 
protocol therapy. Thereafter, patients may be treated at the investigator’s discretion. 
 
 

 
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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for Adverse Events 
 
All patients will be evaluable for adverse event evaluation from the time of their first treatment. 
 
8.1.2 
Evaluable for Quality of Life Assessment 
 
All patients who have completed the quality of life questionnaire are evaluable for quality of life. 
 
8.1.3 
Evaluable for Health Economics Assessment 
 
 All enrolled patients are evaluable for health economics. Those who have completed the resource 
utilization and lost productivity questionnaires will be evaluable for cost-utility analyses. 
 
8.1.4 
Evaluable for Event-free Survival 
 
Event-free survival (EFS) is defined as the time from the date of registration to the date of first 
record of any of the following events: 
• 
Investigator determined: 
− 
Local-regional progression or recurrence. 
− 
Distant metastasis. 
• 
Surgery: 
− 
Surgery 
at 
any 
time 
for 
clinical 
or 
radiological 
(RECIST 
1.1) 
disease 
persistence/progression/recurrence 
at 
the 
primary 
tumour 
site 
with 
tumour 
present/unknown on final pathology. 
− 
Neck dissection or surgery performed for clinical or radiological (RECIST 1.1) disease 
persistence/recurrence/progression within the target volumes > 20 weeks from the end of 
radiation therapy with tumour present/unknown on final pathology. 
− 
Neck dissection or surgery performed for clinical or radiological disease 
recurrence/progression outside the target volumes or without documentation of the site of 
failure at any time after registration with tumour present/unknown on final pathology. 
• 
Non-protocol RT, chemotherapy, or biologic therapy (for the current cancer diagnosis) without 
documentation of the site of failure. 
• 
Death due to any cause. 
 
8.1.5 
Local-regional Control (LRC) 
 
Local-regional control is defined as the time from the date of registration to the date of  any of the 
following, whichever comes first:  
• 
Surgery of primary tumour at any time performed for clinical or radiological (RECIST 1.1) 
disease persistence/progression/recurrence with tumour present/unknown on final pathology 
 
 

 
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• 
Neck dissection > 20 weeks from the end of radiation therapy performed for clinical or 
radiological (RECIST 1.1) disease persistence/progression/recurrence within target volumes 
with tumour present/unknown on final pathology 
• 
Neck dissection at any time after registration performed for clinical or radiological (RECIST 
1.1) disease recurrence/progression outside the target volumes or without documentation of the 
site of failure with tumour present/unknown on final pathology. 
• 
the first record of appearance (radiological or clinical) of local or regional disease 
progression/recurrence.  
 
Distant recurrence/progression diagnosed before local-regional failure and death in absence of 
local-regional failure are not considered events of interest, but as competing risks events in the 
analysis of this endpoint. Subjects without any of the listed events (i.e. events of interest or 
competing risks events) are censored at the date of the most recent follow-up examination. 
 
8.1.6 
Out-of-field Regional Control 
 
Time to out-of-field regional failure is defined as the time from the date of registration to the date 
of the first record of appearance of regional progression/recurrence outside the treatment field, or 
to the date of neck dissection at any time after registration with tumour present/unknown performed 
for clinical or radiological disease progression outside the target volumes, whichever comes first. 
 
Local or distant recurrence/progression diagnosed before out-of-field regional failure and death in 
absence of out-of-field regional failure are not considered events of interest, but as competing risks 
events in the analysis of this endpoint. Subjects without any of the listed events (i.e. events of 
interest or competing risks events) are censored at the date of the most recent follow-up 
examination. 
 
8.1.7 
Distant Metastasis Free Survival (DMFS) 
 
Distant metastasis free survival is defined as the time from the date of registration to the date of 
first record of appearance of distant metastasis or death for any cause. Local-regional failure or 
second cancers diagnosed before the distant metastases are not considered events of interest for this 
endpoint. Subjects alive and free of distant metastasis are censored at the date of the most recent 
follow-up examination. 
 
8.1.8 
Overall Survival (OS) 
 
Overall survival is defined as the time from the date of registration to the date of death for any 
cause. The follow-up of subjects still alive will be censored at the date of last visit/contact. 
 
8.2 
Evaluation of Efficacy 
 
The efficacy endpoints will be measured clinically and radiologically using the revised 
international criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid 
Tumours) committee. 
 
 

 
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8.2.1 
Measurable Disease 
 
Categorization of measurable disease will be based on the RECIST 1.1 criteria with clinical 
examination as appropriate. 
 
Measurable tumour lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray and as ≥ 10 mm with CT 
scan or clinical examination. Bone lesions are considered measurable only if assessed by CT scan 
and have an identifiable soft tissue component that meets these requirements (soft tissue component 
≥ 10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumour measurements must be 
recorded in millimetres (or decimal fractions of centimetres). Previously irradiated lesions are not 
considered measurable unless progression has been documented in the lesion. 
 
8.2.2 
Non-measurable Disease 
 
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitic involvement of lung or skin and abdominal masses followed by clinical examination 
are all non-measurable. Lesions in previously irradiated areas are non-measurable, unless 
progression has been demonstrated. 
 
8.2.3 
Target Lesions 
 
When more than one measurable tumour lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis of ≥ 15 mm by 
CT scan and only the short axis of these nodes will contribute to the baseline sum. All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target 
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed (see 8.2.4). At baseline, the sum of the target lesions (longest diameter of 
tumour lesions plus short axis of lymph nodes: overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately measured 
but are deemed to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be used. 
 
8.2.4 
Non-target Lesions 
 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”. 
 
 

 
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8.3 
Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
8.3.1 
Clinical Lesions 
 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10mm as 
assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging 
is preferred. 
 
8.3.2 
Chest X-ray 
 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
≥ 20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung. 
 
8.3.3 
CT, MRI 
 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). Other specialized imaging or other 
techniques may also be appropriate for individual case [Eisenhauer 2009]. For example, while PET 
scans are not considered adequate to measure lesions, PET-CT scans may be used providing that 
the measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
 
8.3.4 
Ultrasound 
 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
 
8.3.5 
Endoscopy, Laparoscopy 
 
The utilization of these techniques for objective tumour evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response or surgical resection is an endpoint. 
 
 

 
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8.3.6 
Cytology, Histology 
 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumour types such as germ cell tumours, where known 
residual benign tumours can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when 
the measurable tumour has met criteria for response or stable disease is advised to differentiate 
between response or stable disease and progressive disease. 
 
8.3.7 
Date of Objective Failure (see Section 8.4.6) 
 
This is defined as the date of the first of the following events, whichever comes first: 
• 
The first record of appearance (radiological or clinical) of local or regional disease 
progression/recurrence. 
• 
The first record of appearance (radiological or clinical) of distant metastasis. 
• 
Non-protocol RT, chemotherapy, or biologic therapy (for the current OSCC) without 
documentation of the site of failure. 
• 
Surgery of primary tumour site at any time performed for clinical or radiological (RECIST 1.1) 
disease persistence/progression/recurrence with tumour present/unknown on final pathology. 
• 
Neck dissection or surgery performed for clinical or radiological (RECIST 1.1) disease 
persistence/recurrence/progression within the target volumes > 20 weeks from the end of 
radiation therapy with tumour present/unknown on final pathology. 
• 
Neck 
dissection 
or 
surgery 
performed 
for 
clinical 
or 
radiological 
disease 
recurrence/progression outside the target volumes or without documentation of the site of 
failure at any time after registration with tumour present/unknown on final pathology. 
• 
Death due to any cause. 
 
8.3.8 
Date of Progression 
 
The date of progressive disease is defined as the first day when RECIST (version 1.1) criteria for 
PD are met. The criteria for PD are met when there is at least a 20% increase in the sum of diameters 
of measured lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of ≥ 5mm. Appearance of new lesions will also constitute 
progressive disease (including lesions in previously unassessed areas). In exceptional 
circumstances, unequivocal progression of non-target disease may be accepted as evidence of 
disease progression, where the overall tumour burden has increased sufficiently to merit 
discontinuation of treatment or where the tumour burden appears to have increased by at least 73% 
in volume. Modest increases in the size of one or more non-target lesions are NOT considered 
unequivocal progression. If the evidence of PD is equivocal (target or non-target), treatment may 
continue until the next assessment, but if confirmed, the earlier date must be used. 
 
 

 
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8.4 
Evaluation of Endpoints 
 
As event-free survival is the primary endpoint in this study, it is vital that it be adequately and 
precisely documented. Due to the difficulties in objectively assessing response following radiation, 
response will not be a study endpoint but measurements will be recorded to assist with 
determination of progressive disease and local-regional failure status. Measurements will be taken 
from CT or MRI and the same method should be used to follow subjects. All subjects will have a 
clinical and radiological (CT or MRI +/- PET per institutional standards) assessment at 3 months 
post-completion of RT as defined in Section 5.0. 
 
8.4.1 
Local Recurrence or Progression  
 
Local failure will be primarily determined by evidence of progression or recurrence clinically or 
radiologically. For clinical and radiographic assessments, RECIST 1.1 criteria for progressive or 
recurrent disease shall be used whenever applicable. In the case of nonmeasurable disease or in 
circumstances where laryngeal edema complicates the interpretation of radiological measurements, 
unequivocal clinical description of disease progression or recurrence is required. Biopsy proof (fine 
needle aspirate is not sufficient) of progressive/recurrent disease is desirable but is not essential if 
progression/recurrence is documented clinically. Any form of surgery at the primary site will be 
considered local progression/recurrence unless the pathology shows no evidence of disease.  
 
8.4.2 
Regional Lymph Node Recurrence or Progression 
 
Neck 
dissection 
performed 
for 
clinical 
or 
radiological 
(RECIST 
1.1) 
disease 
persistence/progression/recurrence within target volumes after 20 weeks from the end of radiation 
therapy with evidence of tumour present or unknown will be considered a treatment failure.  
 
Neck dissection performed at any time after registration for clinical or radiological (RECIST 1.1) 
disease recurrence/progression outside the target volumes or without documentation of the site of 
failure with tumour present/unknown will be considered a treatment failure. 
 
Development of any new clinically or biopsy proven malignant regional nodes not present at 
baseline or clinically or biopsy proven recurring or progressing nodes will be considered evidence 
of regional recurrence/progression. 
 
8.4.3 
Out-of-field Regional Failure 
 
An out-of-field regional failure is defined as regional recurrence or progression outside the 
treatment field. Subjects with clinical or radiological evidence concerning for nodal failure outside 
the treatment field should have pathologic confirmation and restaging for local and distant disease. 
A positive biopsy and/or a neck dissection at any time after registration performed for suspected 
nodal failure outside the treatment field that is positive/unknown for tumour on pathology will be 
considered out-of-field regional failure. Subjects who do not have a neck dissection because their 
neck disease is judged to be unresectable will only be deemed to have failure in the neck after 
biopsy or cytological confirmation is obtained or disease progression is documented. 
 
If failure is not confirmed, subjects may be observed with CT repeated at 3 monthly intervals or 
following local institutional guidelines to confirm stability or regression of the lymph nodes. 
 
 

 
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Categorizing regional failure as in-field or out-of-field will be done by the local investigator based 
on review of the original treatment volumes and the site of tumour recurrence in the neck. Post-hoc 
central review of the patterns of regional failure will also be performed on all subjects that have 
regional failure (either as first or subsequent recurrence). 
 
8.4.4 
Local-regional Failure 
 
This is defined as local failure, regional failure or both. For the purposes of determining site of first 
failure the category of both will be applicable if local and regional failure occurs within one month 
of each other. 
 
8.4.5 
Distant Metastasis 
 
This is defined as the presence of positive pathological or radiological evidence of recurrent disease 
at any site of the body with the exception of those defined as ‘local’ or ‘regional’. 
 
When distant metastases are the first indication of relapse, then the patient must be examined for 
local-regional disease. 
 
8.4.6 
Event-Free Survival Endpoint 
 
First Event 
Event-free Survival 
None 
Censored 
Local-regional progression or recurrence 
Failure 
Distant metastasis 
Failure 
Non-protocol RT, chemotherapy, or biologic therapy (for the current 
OPSCC) without documentation of the site of failure 
Failure 
Surgery of primary site (at any time after RT) with tumour present/unknown 
Failure 
Neck dissection with tumour present/unknown, > 20 weeks from end of RT 
Failure 
Neck dissection (at any time after registration) with tumour 
present/unknown outside the treatment field  
Failure 
Death due to study cancer or from unknown causes 
Failure 
Death due to any other reason 
Failure 
 
Note: The following are not considered events: 
• 
Second primary neoplasm which is defined as a primary head and neck tumour which does not 
fulfill the criteria for local progression/recurrence or a neoplasm arising from a non-head and 
neck site; 
• 
Surgery of primary with no tumour on pathology specimen; 
• 
Planned neck dissection for disease inside the treatment field ≤ 20 weeks from end of RT; 
• 
Neck dissection with no tumour on pathology specimen. 
 
 

 
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9.0 
SERIOUS ADVERSE EVENT REPORTING 
 
This protocol does not contain investigational agent(s), and adverse events occurring as a result of 
this commercially available treatment should be reported to CCTG in the manner described below. 
In addition, your local Research Ethics Board (REB) should be notified. 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix IV). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG. 
 
9.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events which are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 9.2 for reporting instructions). These include 
events occurring during the treatment period (until 30 days after last protocol treatment 
administration) and at any time afterwards. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information contained in the product monograph or package insert. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol agent cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
9.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the HN.10 section of the CCTG website (www.ctg.queensu.ca). 
 
 

 
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Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website 
 
FAX paper SAE Report to: 
 
HN.10 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application. 
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the HN.10 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application. 
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430). 
 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting 
 
9.3.1 
Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 4.1.10. Investigators 
may wish to additionally advise the female partners of male participants about pregnancy 
prevention guidelines when appropriate and compliant with local policy. 
 
9.3.2 
Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants and 
female partners of male participants. Pregnancies occurring up to 6 months for female participants 
and up to 24 months for female partners of male participants after the completion of study treatment 
must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage, under the 
“Toolbox” link. 
 
 

 
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Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca). 
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
9.3.3 
Exposure Reporting (Non-study Participants) 
 
The investigator is required to report to CCTG any incidence of exposure to study agent(s). 
Exposure is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- study 
participant (an individual who is not otherwise participating in this clinical trial). An example of 
an exposure includes a non-study participant swallowing study medication. The investigator is 
responsible for determining significance, based on the agent to which the individual is exposed. 
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of the 
exposure, using the CCTG Exposure Reporting Form available from the trial webpage, under the 
“Toolbox” link. 
 
Once informed consent has been obtained, the form should be updated to provide further exposure 
information and to reflect the outcome of the exposure as the information becomes available upon 
appropriate follow-up of the exposed individual for a period of 30 days. All follow-up reports must 
be submitted to CCTG in a timely manner. A copy of the signed exposure follow-up consent 
signature page must also be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613 -533-
2812/ safety-desk@ctg.queensu.ca). 
 
If the exposure results in death; is life-threatening; requires inpatient hospitalization or prolongation 
of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital 
anomaly/birth defect, then an SAE report must be additionally submitted as described above. 
 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada for those events which meet 
regulatory requirements for expedited reporting, i.e. events which are BOTH serious AND 
unexpected, AND which are thought to be related to protocol treatment (or for which a causal 
relationship with protocol treatment cannot be ruled out). 
 
 

 
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9.5 
Reporting Serious Adverse Events to Investigators 
 
CCTG will notify Investigators of all serious adverse events from this trial that are reportable to 
regulatory authorities in Canada as reported to CCTG. This includes all serious events that are 
unexpected and related (i.e. possibly, probably, or definitely) to protocol treatment. The reports 
will be posted to the CCTG trial HN.10 web-based safety monitoring utility. Investigators must 
review and document in the trial files proof of review of these events as per ICH GCP. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes 
and any other event required by their REB. The date of REB Submission for these SAEs will need 
to be entered into the CCTG trial HN.10 web based safety monitoring utility and documentation of 
REB submission must be retained in the study binder on site. The REB submission template 
provided by CCTG can be used to assist with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 
 
 

 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
10.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 7.0. 
• 
Disease progression, recurrence, or treatment failure as defined in Section 8.4.6. 
• 
Request by the patient. 
• 
Completion of therapy as outlined in Section 7.0. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
 
10.2 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
10.3 
Follow-up Off Protocol Treatment 
 
Please see Section 5.0. 
 
For phase Ib and phase II studies, continued follow up after progression (on treatment or during 
follow up), using an abbreviated form (including subsequent therapies) every 6 months is required 
until CCTG advises centres that the final analysis has been performed and follow up can be 
discontinued. If patient is unable to return to participating centre for follow up, please contact 
CCTG to discuss possible options prior to considering ‘withdrawal of consent’ processes. Remote 
oversight allowing data submission may be feasible. 
 
Final report (Form 6) will be required only on patients who die during protocol therapy, within 30 
days after last dose, or within the protocol defined follow-up period for patients as above. Due 
within 2 weeks of knowledge of death (see Appendix III - Documentation for Study). 
 
 

 
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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Central Data Review 
 
CCTG receives core support from the Canadian Cancer Society. To ensure efficient use of limited 
funding, the CCTG has, over the past 40 years, optimized their risk based trial oversight and 
monitoring program. A critical component is central data review of submitted deidentified source 
documents, allowing source data verification and confirmation of key aspects including eligibility, 
endpoints and safety outcomes. Depending on the trial’s design, these source documents may 
include such source documents as surgical and histopathology reports to confirm disease stage and 
type, imaging reports to confirm extent of disease and assess efficacy, or include submission of 
tumour samples (to confirm diagnosis and eligibility or DICOM images (to verify response or 
radiation therapy planning). These source documents are reviewed by experienced data managers 
and physicians and are critical to ensuring the accuracy of the data and consistency of conclusions 
drawn. 
 
The collection of this critical data involves uploading documents through the password protected 
and secure CCTG electronic Supporting Document Upload Tool (SDUT) data capture linked 
system. See Appendix III (Documentation for Study) for details of supporting document 
requirements for this trial and for requirements for the redaction of personal identifiers. Although 
it remains the centres responsibility to ensure adequate redaction of any information provided to 
CCTG, submitted source documents are reviewed prior to acceptance at CCTG; in the case of 
incomplete redaction, documents are removed and the site assigned a violation and required to 
resubmit. 
 
All patients will provide written informed consent for submission of source documents, and the 
rationale and documents to be collected will be detailed in the informed consent document. 
 
11.2 
Central Radiology Review 
 
For any patient with local-regional failure, central radiology review will be performed to confirm 
site of failure. Please refer to Section 7.2.18. 
 
11.3 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
11.4 
Central Radiotherapy Review 
 
All patients will undergo central review of radiotherapy contours and plans. Please refer to 
Section 7.2.17. 
 
 

 
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12.0 
CORRELATIVE STUDIES 
 
When considering the implementation of de-escalated treatment approaches such as the reduction 
of radiotherapy treatment volumes, it is important to be able to accurately categorize a patient’s 
prognosis. Currently, risk stratification for HPV-related OPSCC relies primarily on clinical stage. 
We will evaluate 4 putative prognostic biomarkers to assess their prognostic significance in this 
cohort of low-risk patients receiving de-escalated treatment. These putative prognostic biomarkers 
are: 1) a 4-feature radiomic signature; 2) HPV genotype in tumour tissue; 3) TP53 mutation with 
chromosome 3p deletion; and 4) HPV DNA levels in baseline plasma cell-free DNA. The 
association of each putative prognostic biomarker with EFS will be determined using the Cox 
proportional hazards method. Discriminative performance of the putative prognostic biomarkers 
will be compared with each other and with clinical features using the concordance index. 
 
A detailed Correlative Studies Manual will be provided on the HN.10 trial specific website, which 
will include details regarding sample preparation, handling and shipping. 
 
Specimens collected may be used by researchers now or in the future to better understand the nature 
of HPV-related OPSCC and how patients respond to treatment. Samples will be used for research 
purposes only and will not be sold. Patients will not be identified by name. The only identification 
of tissue will be by a patient study number assigned at the time of registration to the trial the 
surgical/ histology number and/or patient initials. Material issued to researchers will be anonymized 
and only identified by a coded number. 
 
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out. 
 
All patients on whom a diagnostic tumour block is collected will be aware of this retrieval and will 
have given their consent. 
 
12.1 
Protocol-Mandated Correlative Studies 
 
Radiologic Image and RT Structure Collection: 
The submission of a RT planning CT scans with associated contours is mandatory for participation 
in this trial. 
 
The association of a published radiomic signature with EFS will be determined in this population 
of HPV-related OPSCC patients treated with reduced ENI volumes. Specifically, the 4-feature 
radiomic signature of Aerts et al.[Aerts 2014] will be derived from each gross tumour volume contour 
using PyRadiomics or comparable software. 
 
Tumour Tissue Collection: 
The submission of a representative block of the diagnostic tumour tissue at the request of the CCTG 
Central Tumour Bank is mandatory for participation in this trial. One tumour block is requested 
from a biopsy of the primary oropharyngeal tumour. If no primary cancer blocks are available, one 
block of metastatic lymph node tissue can be sent instead. Where local centre regulations prohibit 
submission of blocks of tumour tissue, the approval of the CCTG must be sought prior to 
registration of the first patient to allow cores (two 2 mm cores of tumour from the block) and a 
predetermined number of slides of representative tumour tissue to be substituted in response to the 
Central Tumour Bank request. 
 
 

 
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Somatic mutations and HPV genotype will be detected within tumour DNA in order to determine 
their prognostic significance in patients treated with reduced ENI volumes. Genomic DNA will be 
extracted from tumour blocks and peripheral blood leukocytes (germ line) and will be subjected to 
high throughput sequencing using published methods [Newman 2014]. Briefly, DNA libraries will be 
constructed from tumour genomic DNA and germline genomic DNA. Targeted sequencing will be 
performed in order to detect frequent OPSCC-associated HPV genotypes as well as mutations 
within TP53 and genetic deletions within FHIT (chromosome 3p14 marker). 
 
Blood and Plasma Collection: 
The submission of whole blood and plasma is also mandatory for participation in this trial. 
 
Whole blood will be used as a source of germ line DNA (from peripheral blood leukocytes) for 
targeted sequencing of the TP53 and FHIT genes and comparison with tumour DNA as described 
above. 
 
Plasma will be used for detection of circulating tumour-derived HPV DNA (ctDNA) levels in pre-
treatment and post-treatment plasma. The levels of ctDNA will be measured and correlated with 
EFS in order to determine prognostic significance. Cell-free DNA will be extracted from plasma 
and subjected to droplet digital PCR or high throughput sequencing in order to detect HPV 
sequences. The number of HPV copies per milliliter plasma will be determined for comparison 
with EFS and with the other putative prognostic biomarkers. 
 
12.2 
Optional Banking of Samples 
 
Banking of Radiologic Images and RT Structures: 
Mandatory submission of RT planning CT scans with associated contours has been described 
above. The subsequent banking of collected data is not mandatory for participation in the study, 
but the participation of all centres is strongly encouraged. Data will be banked by QARC 
(www.qarc.org). 
 
Proposals to use the banked data for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the data will take place and any proposals approved will have undergone ethics 
approval. 
 
Banking of Tumour Tissue: 
Mandatory submission of tumour tissue has been described above. The subsequent banking of 
collected diagnostic tissue is not mandatory for participation in the study, but the participation of 
all centres is strongly encouraged. Blocks and blood will be carefully banked as part of the CCTG 
tissue/tumour bank at Queen’s University in Kingston, Ontario. 
 
After patient consent, collection of paraffin tumour blocks will preferred, as one of the objectives 
will be to create tissue micro arrays. These will optimize the amount of tissue available to 
investigators and permit the preservation of the tumour block submitted. If tumour blocks are 
unavailable, then two x 2 mm cores of tumour from the block and 30 specimen slides are preferred. 
If, at any time, the submitting hospital requires the block to be returned for medical or legal 
concerns, it will be returned by courier on request. 
 
 

 
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Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 
 
Banking of Blood and Plasma: 
Mandatory submission of whole blood and plasma has been described above. The subsequent 
banking of collected samples is not mandatory for participation in the study, but the participation 
of all centres is strongly encouraged. Samples will be carefully banked as part of the CCTG 
tissue/tumour bank at Queen’s University in Kingston, Ontario. 
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 
 
 

 
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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
This is a phase II single arm trial. 
 
The primary objective is to evaluate the efficacy of primary definitive RT or CRT utilizing volume-
reduced ENI as measured by 2-year EFS in patients with low-risk HPV-related OPSCC. 
 
The secondary objectives are to evaluate overall survival, local control, regional control, local-
regional control, out-of-field regional control, distant metastasis free survival, early and late 
toxicities of treatment, subjective swallowing functions, QOL, resource utilization and lost 
productivity, and prognostic biomarkers. 
 
The tertiary objectives are to assemble an imaging and biospecimen bank for future research that 
could improve risk stratification and patient selection for volume-reduced ENI. 
 
13.2 
Primary Endpoints and Analysis 
 
The primary endpoint is 2-year EFS. 
 
13.3 
Sample Size and Duration of Study 
 
We estimate 2-year EFS to be 91% (Ha) for low-risk HPV-related OPSCC. Assuming that the 
experimental treatment will be considered as ineffective if the 2-year EFS is ≤ 85% (H0), with 
one-sided alpha of 0.1, a sample size of 100 patients will have 80% power to detect a 6% difference 
of 2-year EFS. With 3 years of accrual and 2 years of follow-up, the total duration of this study will 
be 5 years. A total of 304.7 person-years of follow-up is needed for the final analysis. The null 
hypothesis (H0) will be rejected when the observed survival rate is 88.85% or higher (i.e. if there 
are 18 or fewer EFS events observed). 
 
13.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators’ meetings. 
 
13.5 
Interim Analysis 
 
A built in interim futility analysis is planned when 162.9 person-years of follow-up are observed. 
The alternative hypothesis (Ha) will be rejected at significant level 0.05 when 12 or more EFS 
events are observed. The interim analysis is expected to occur 38 months after trial activation. 
 
13.6 
Quality of Life Analysis 
 
Descriptive summary statistics will be reported from QOL instruments. 
 
13.7 
Economic Analyses  
 
Data regarding resource utilization data and productivity loss will be analysed using descriptive 
summary statistics. This data will allow us to establish direct comparison with data from other 
CCTG studies. 
 
 

 
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14.0 
PUBLICATION POLICY 
 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
14.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group may be credited as 
authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the correlative sciences (quality of life 
outcomes, health economics and biologics) the first author will generally be the 
corresponding Coordinator on the trial committee. 
 
14.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
14.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following the analysis of study results the 
draft is not substantially complete, the central office reserves the right to make other arrangements 
to ensure timely publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
14.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by the CCTG 
Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. 
Individual participating centres may not present outcome results from their own centres separately. 
Supporting groups and agencies will be acknowledged. 
 
 

 
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15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
15.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
15.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion. 
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs. 
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately. 
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs. 
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable). 
 
Subjects who were competent at the time of enrollment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation. 
 
15.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in a CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
 

 
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Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study. 
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial. 
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject. 
 
15.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up consent form will not be required by 
CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure Follow-up” can be found 
on the trial webpage. The appropriate consent form must be used to obtain consent from any non-
trial participant (such as the pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 
 
Obtaining Consent for Research on Children  
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian. 
 
For reporting an exposure, the parent/guardian is required to sign an “Exposure Follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
 

 
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15.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why. 
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
15.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained in accordance with ICH-GCP. 
 
In accordance with GCP 4.9.5, essential documents must be retained for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. In most cases, this 
will be for 10 years following the completion of the trial (10 years post final analysis, last data 
collected, or closure notification to REB, whichever is later) at the centre, or until notified by CCTG 
that documents no longer need to be retained. 
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access. 
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained. 
 
15.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI). 
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
15.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
The above mentioned documentation, in addition to any submitted source documents, may be 
accessed remotely in the event of a public health emergency either through remote access to 
Electronic Medical Records or through a secure file sharing portal. 
 
 

 
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16.0 
REFERENCES 
Aerts HJ, Velazquez ER, Leijenaar RT, Parmar C, Grossmann P, et al. (2014) Decoding tumour phenotype by 
noninvasive imaging using a quantitative radiomics approach. Nat Commun 5: 4006. 
Ahn SM, Chan JY, Zhang Z, Wang H, Khan Z, et al. (2014) Saliva and plasma quantitative polymerase chain 
reaction-based detection and surveillance of human papillomavirus-related head and neck cancer. JAMA 
Otolaryngol Head Neck Surg 140: 846-854. 
Basch, E., Reeve, B. B., Mitchell, S. A., Clauser, S. B., Minasian, L. M., et al. (2014). Development of the 
National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse 
events (PRO-CTCAE). Journal of the National Cancer Institute, 106(9). dju244. doi:10.1093/jnci/dju244 
Beetz I, Schilstra C, van Luijk P, Christianen ME, Doornaert P, et al. (2012) External validation of three 
dimensional conformal radiotherapy based NTCP models for patient-rated xerostomia and sticky saliva among 
patients treated with intensity modulated radiotherapy. Radiother Oncol 105: 94-100. 
Bratman SV, Bruce JP, O'Sullivan B, Pugh TJ, Xu W, et al. (2016) Human Papillomavirus Genotype Association 
With Survival in Head and Neck Squamous Cell Carcinoma. JAMA Oncol 2: 823-826. 
Bratman SV, Newman AM, Alizadeh AA, Diehn M (2015) Potential clinical utility of ultrasensitive circulating 
tumor DNA detection with CAPP-Seq. Expert Rev Mol Diagn 15: 715-719. 
Cao H, Banh A, Kwok S, Shi X, Wu S, et al. (2012) Quantitation of human papillomavirus DNA in plasma of 
oropharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 82: e351-358. 
Canadian Cancer Statistics Advisory Committee. Canadian Cancer Statistics 2016. Toronto, ON: Canadian 
Cancer Society; 2016. Available at: cancer.ca/Canadian-Cancer-Statistics-2016-EN   (accessed 2019FEB13). 
Cancer Genome Atlas Network (2015) Comprehensive genomic characterization of head and neck squamous 
cell carcinomas. Nature 517: 576-582. 
Caparrotti F, Huang SH, Lu L, Bratman SV, Ringash J, et al. (2017) Osteoradionecrosis of the mandible in 
patients with oropharyngeal carcinoma treated with intensity-modulated radiotherapy. Cancer. 
Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Curado MP, Ferlay J, et al. (2013) Worldwide trends in 
incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol 31: 4550-4559. 
Chen AM, Felix C, Wang PC, Hsu S, Basehart V, et al. (2017) Reduced-dose radiotherapy for human 
papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. Lancet 
Oncol 18: 803-811. 
Chera BS, Amdur RJ, Tepper J, Qaqish B, Green R, et al. (2015) Phase 2 Trial of De-intensified Chemoradiation 
Therapy for Favorable-Risk Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma. Int 
J Radiat Oncol Biol Phys 93: 976-985. 
Christianen ME, Schilstra C, Beetz I, Muijs CT, Chouvalova O, et al. (2012) Predictive modelling for swallowing 
dysfunction after primary (chemo)radiation: results of a prospective observational study. Radiother Oncol 105: 
107-114. 
Dahlstrom KR, Li G, Hussey CS, Vo JT, Wei Q, et al. (2015) Circulating human papillomavirus DNA as a 
marker for disease extent and recurrence among patients with oropharyngeal cancer. Cancer 121: 3455-3464. 
de Almeida JR, Moskowitz AJ, Miles BA, Goldstein DP, Teng MS, et al. (2016) Cost-effectiveness of transoral 
robotic surgery versus (chemo)radiotherapy for early T classification oropharyngeal carcinoma: A cost-utility 
analysis. Head Neck 38: 589-600. 
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney 
M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in 
solid tumors: Revised RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
CONFIDENTIAL 
50 
CONFIDENTIAL 
Goepfert RP, Lewin JS, Barrow MP, Gunn GB, Fuller CD, et al. (2017) Long-Term, Prospective Performance 
of the MD Anderson Dysphagia Inventory in "Low-Intermediate Risk" Oropharyngeal Carcinoma After 
Intensity Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys 97: 700-708. 
Goodman MT, Saraiya M, Thompson TD, Steinau M, Hernandez BY, et al. (2015) Human papillomavirus 
genotype and oropharynx cancer survival in the United States of America. Eur J Cancer 51: 2759-2767. 
Grégoire V, Ang K, Budach W, Grau C, Hamoir M, Langendijk JA, et al.(2014) Delineation of the neck node 
levels for head and neck tumours: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, 
TROG consensus guidelines. Radiother Oncol 110:172–81. 
Gross AM, Orosco RK, Shen JP, Egloff AM, Carter H, et al. (2014) Multi-tiered genomic analysis of head and 
neck cancer ties TP53 mutation to 3p loss. Nat Genet 46: 939-943. 
Huang SH, Waldron J, Bratman SV, Su J, Kim J, et al. (2017) Re-evaluation of Ipsilateral Radiation for T1-
T2N0-N2b Tonsil Carcinoma at the Princess Margaret Hospital in the Human Papillomavirus Era, 25 Years 
Later. Int J Radiat Oncol Biol Phys 98: 159-169. 
Kelly JR, Husain ZA, Burtness B (2016) Treatment de-intensification strategies for head and neck cancer. Eur J 
Cancer 68: 125-133. 
Kjems J, Gothelf AB, Hakansson K, Specht L, Kristensen CA, et al. (2016) Elective Nodal Irradiation and 
Patterns of Failure in Head and Neck Cancer After Primary Radiation Therapy. Int J Radiat Oncol Biol Phys 94: 
775-782. 
Kohler RE, Sheets NC, Wheeler SB, Nutting C, Hall E, et al. (2013) Two-year and lifetime costeffectiveness of 
intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy for head-and-neck 
cancer. Int J Radiat Oncol Biol Phys 87: 683-689. 
Kwan JYY, Su J, Huang SH, Ghoraie LS, Xu W, Chan B, Yip KW, Giuliani M, Bayley A, Kim J, Hope AJ, 
Ringash J, Cho J, McNiven A, Hansen A, Goldstein D, de Almeida JR, Aerts HJ, Waldron JN, Haibe-Kains B, 
O'Sullivan B, Bratman SV, Liu FF. Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-
related Oropharyngeal Carcinoma. Int J Radiat Oncol Biol Phys. 2018 Feb 01. PMID: 29506884. 
Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, Leemans CR, Aaronson NK, et al. (2008) Impact of late 
treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. 
J Clin Oncol 26: 3770-3776. 
Lee N, Schoder H, Beattie B, Lanning R, Riaz N, et al. (2016) Strategy of Using Intratreatment Hypoxia Imaging 
to Selectively and Safely Guide Radiation Dose De-escalation Concurrent With Chemotherapy for 
Locoregionally Advanced Human Papillomavirus-Related Oropharyngeal Carcinoma. Int J Radiat Oncol Biol 
Phys 96: 9-17. 
Leijenaar RT, Carvalho S, Hoebers FJ, Aerts HJ, van Elmpt WJ, et al. (2015) External validation of a prognostic 
CT-based radiomic signature in oropharyngeal squamous cell carcinoma. Acta Oncol 54: 1423-1429. 
Li JG, Yuan X, Zhang LL, Tang YQ, Liu L, et al. (2013) A randomized clinical trial comparing prophylactic 
upper versus whole-neck irradiation in the treatment of patients with node-negative nasopharyngeal carcinoma. 
Cancer 119: 3170-3176. 
Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, et al. (2004) Quantification of plasma Epstein- Barr virus 
DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 350: 2461-2470. 
Machtay M, Moughan J, Trotti A, Garden AS, Weber RS, et al. (2008) Factors associated with severe late 
toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin 
Oncol 26: 3582-3589. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
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51 
CONFIDENTIAL 
Marur S, Li S, Cmelak AJ, Gillison ML, Zhao WJ, et al. (2016) E1308: Phase II Trial of Induction Chemotherapy 
Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPVAssociated Resectable 
Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group. J Clin Oncol: 
JCO2016683300. 
Moore EJ, Hinni ML, Olsen KD, Price DL, Laborde RR, et al. (2012) Cost considerations in the treatment of 
oropharyngeal squamous cell carcinoma. Otolaryngol Head Neck Surg 146: 946-951. 
Nevens D, Duprez F, Daisne JF, Dok R, Belmans A, et al. (2017) Reduction of the dose of radiotherapy to the 
elective neck in head and neck squamous cell carcinoma; a randomized clinical trial. Effect on late toxicity and 
tumor control. Radiother Oncol 122: 171-177. 
Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, et al. (2014) An ultrasensitive method for quantitating 
circulating tumor DNA with broad patient coverage. Nature medicine 20: 548-554. 
Nuyts S, Lambrecht M, Duprez F, Daisne JF, Van Gestel D, et al. (2013) Reduction of the dose to the elective 
neck in head and neck squamous cell carcinoma, a randomized clinical trial using intensity modulated 
radiotherapy (IMRT). Dosimetrical analysis and effect on acute toxicity. Radiother Oncol 109: 323-329. 
O'Sullivan B, Warde P, Grice B, Goh C, Payne D, et al. (2001) The benefits and pitfalls of ipsilateral radiotherapy 
in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys 51: 332-343. 
Pearce AM, Hanly P, Timmons A, Walsh PM, O'Neill C, et al. (2015) Productivity Losses Associated with Head 
and Neck Cancer Using the Human Capital and Friction Cost Approaches. Appl Health Econ Health Policy 13: 
359-367. 
Ringash J, Fisher R, Peters L, Trotti A, O'Sullivan B, et al. (2017) Effect of p16 Status on the Quality-of-Life 
Experience During Chemoradiation for Locally Advanced Oropharyngeal Cancer: A Substudy of Randomized 
Trial Trans-Tasman Radiation Oncology Group (TROG) 02.02 (HeadSTART). Int J Radiat Oncol Biol Phys 97: 
678-686. 
Roe JW, Drinnan MJ, Carding PN, Harrington KJ, Nutting CM (2014) Patient-reported outcomes following 
parotid-sparing intensity-modulated radiotherapy for head and neck cancer. How important is dysphagia? Oral 
Oncol 50: 1182-1187. 
Sanguineti G, Pai S, Agbahiwe H, Ricchetti F, Westra W, et al. (2014) HPV-related oropharyngeal carcinoma 
with Overt Level II and/or III metastases at presentation: The risk of subclinical disease in ipsilateral levels IB, 
IV and V. Acta Oncol 53: 662-668. 
Seol KH, Lee JE (2016) Patterns of failure after the reduced volume approach for elective nodal irradiation in 
nasopharyngeal carcinoma. Radiat Oncol J 34: 10-17. 
Sturgis EM, Ang KK (2011) The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change 
our treatment paradigms? J Natl Compr Canc Netw 9: 665-673. 
Vainshtein JM, Moon DH, Feng FY, Chepeha DB, Eisbruch A, et al. (2015) Long-term quality of life after 
swallowing and salivary-sparing chemo-intensity modulated radiation therapy in survivors of human 
papillomavirus-related oropharyngeal cancer. Int J Radiat Oncol Biol Phys 91: 925-933. 
Villaflor VM, Melotek JM, Karrison TG, Brisson RJ, Blair EA, et al. (2016) Response-adapted volume de-
escalation (RAVD) in locally advanced head and neck cancer. Ann Oncol 27: 908-913. 
Wan JC, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, et al. (2017) Liquid biopsies come of age: 
towards implementation of circulating tumour DNA. Nat Rev Cancer 17: 223-238. 
Ward MC, Ross RB, Koyfman SA, Lorenz R, Lamarre ED, et al. (2016) Modern Image-Guided Intensity- 
odulated Radiotherapy for Oropharynx Cancer and Severe Late Toxic Effects: Implications for Clinical Trial 
Design. JAMA Otolaryngol Head Neck Surg 142: 1164-1170. 
 
 

 
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Woody NM, Koyfman SA, Xia P, Yu N, Shang Q, et al. (2016) Regional control is preserved after dose de-
escalated radiotherapy to involved lymph nodes in HPV positive oropharyngeal cancer. Oral Oncol 53: 91-96. 
Yong JH, Beca J, O'Sullivan B, Huang SH, McGowan T, et al. (2012) Cost-effectiveness of intensity-modulated 
radiotherapy in oropharyngeal cancer. Clin Oncol (R Coll Radiol) 24: 532-538. 
 
 

 
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APPENDIX I - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 
 
 

 
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APPENDIX II - EXAMPLES OF VOLUME-REDUCED ENI TREATED LEVELS ON HN.10 
 
 
 
 

 
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APPENDIX III - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of registration and will apply to all eligible patients. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For details of 
accessing the EDC system and completing the on-line Case Report Forms please refer to the “CCTG EDC 
Generic Data Management Guidebook” posted on the HN.10 area of the CCTG web-site 
(www.ctg.queensu.ca). 
 
The ELECTRONIC CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Timing 
To be completed electronically 
Supporting Documentation1 
Mandatory Submission 
To be uploaded immediately 
after the report they refer to has 
been submitted electronically 
Submission On 
Request 
To be uploaded 
immediately after request 
Eligibility Checklist 
 
At the time of registration 
Signature pages of main and 
optional consent forms2 
diagnostic pathology 
report(s) 
HPV (p16, PCR, or ISH) 
result 
radiology reports (including 
CT/MRI head and neck, CT 
chest x-ray  
relevant physical exam 
notes 
tumour measurement 
worksheet 
ECG, LVEF, QOL 
additional clinical, 
laboratory or imaging 
reports that may impact 
on decision regarding 
eligibility 
Baseline Report 
 
Within 2 weeks of registration 
Correlative Studies 
Report 
(Tumour, Blood, and 
Imaging) 
Continuous 
running-log folder 
Information pertaining to 
tumour tissue submission 
must be completed as soon as 
possible after registration, and 
tissue submitted within 4 
weeks of registration. 
 
 
 
Information pertaining to 
baseline/pretreatment blood 
collection for correlative 
studies (i.e. whole blood and 
plasma) must be completed 
within 2 weeks of registration. 
Information pertaining to post 
registration collection 
samples (i.e. whole blood and 
plasma) for correlative studies 
and banking should be 
completed within 2 weeks 
after collection of blood 
specimens. 
Radiotherapy Report  
Required at 
completion of 
radiotherapy 
Within 4 weeks of completion 
of treatment.  
If available/applicable: 
CT/MRI head and neck, CT 
chest 
other radiology reports 
tumour measurement 
worksheet 
physical exam notes (as 
applicable) 
ECG, LVEF, QOL, 
additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of  safety 
Systemic Treatment 
Report  
Every 4 weeks 
while the patient is 
on treatment. 
Within 2 weeks of the end of 
each 4 week reporting period. 
table continues on next page ... 
 
 

 
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Electronic Folder 
Timing 
To be completed electronically 
Supporting Documentation1 
Mandatory Submission 
To be uploaded immediately 
after the report they refer to has 
been submitted electronically 
Submission On 
Request 
To be uploaded 
immediately after request 
Follow Up Report 
1, 3, 6, 9, 12, 15, 
18, 21, 24, 28, 32, 
36 months post RT 
then q6 months 
until 60 months 
post RT. 
Within 2 weeks of follow-up 
visit 
If available/applicable: 
tumour measurement 
worksheet 
CT/MRI head and neck 
CT chest report 
other radiology reports 
physical exam notes (as 
applicable)  
Additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of safety 
Relapse/Progression 
Report 
Upon the patient’s 
objective disease 
progression / 
relapse 
Within 4 weeks of 
confirmation  
radiology, operative, 
physical exam and 
pathology reports  
 
Telephone Follow-up 
Report 
Annually after 60 
months post-RT 
Within 4 weeks of the phone 
call 
If available/applicable: 
tumour measurement 
worksheet 
CT/MRI head and neck 
CT chest report 
other radiology reports 
physical exam notes (as 
applicable)  
 
Short Follow-up 
Report 
Every 6 months 
after objective 
disease progression 
Within 2 weeks of follow-up 
visit 
 
 
Death Report 
When patient dies 
Within 4 weeks of patient’s 
death 
autopsy report if performed 
Additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of cause of 
death 
SAE Report3 
At time of event 
and reported to 
CCTG 
Within 1 working day3 
 
Additional clinical, 
laboratory or imaging 
reports that may inform 
evaluation of  safety 
including, admission 
and discharge 
summaries/notes 
1 
 Scan and upload in the EDC Supporting Document Upload Tool (SDUT) - please refer to the slide set on the HN.10 website for guidance. 
Source documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, and/or serious adverse 
events.  EDC forms submitted without supporting documentation are not considered submitted and will be reflected in the Centre 
Performance Index (CPI) as not submitted. All patient identifiers, other than the CCTG patient ID assigned at enrollment, and any other 
prohibited personal information must be fully and completely redacted (blacked-out) on all source documentation, per national and local 
privacy protection regulations and requirements. Acceptable methods include: 
• 
fully opaque sticker/tab placed over the identifiers prior to scanning 
• 
fully opaque black marker; prior to upload please ensure that the information is no longer visible on the scanned document 
• 
electronic black box placed over identifiers in PDF document that is subsequently printed and then scanned. (NOTE: do not send the 
unprotected PDF file with black boxes included as those can be moved / removed easily after opening) 
• 
electronic stripping of identifiers prior to upload (typically only possible for DICOM images) 
Note that supporting documents must include the participant’s trial code, CCTG patient serial number, and participant initials (or a two/three 
masking letter code assigned by your centre) 
2 
For Canadian centres: it is acceptable to submit only the signature page(s) of the main consent and only the check box page(s)/signature 
page(s) of the optional consent provided that the version date of the consent form is indicated. Centres are expected to redact the participant’s 
name and signature on the submitted copy, leaving only a portion visible (e.g. initials or loops) to confirm that a person has signed but that 
cannot identify that individual. 
3 
See Section 9.0 Serious Adverse Event Reporting for details. 
 
 

 
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The collection of the following information will NOT be done through the EDC system. Instead submit as 
follows: 
 
Data 
Timing 
Collection /Submission 
Comments 
FACT H&N 
 Prior to registration 
 Last week of radiotherapy  
 After RT (prior to PD): 3, 6, 12, 24 and 36 
months 
On paper; site CRA to enter 
relevant data (as required) in the 
EDC system within 
corresponding folders 
Retain questionnaires  
at the site 
EQ-5D-5L 
Questionnaire 
MDADI 
PRO-CTCAE 
Lost Productivity 
Questionnaire 
 During the last week of RT 
 After RT (prior to PD): 6 and 12 months 
* See Appendices V, VI, VII and VIII. If the questionnaire is completed on paper then it should be scanned and uploaded to the EDC 
Supporting Document Upload Tool. 
 
 

 
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APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 

 
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APPENDIX V - QUALITY OF LIFE ASSESSMENT 
 
This study will use five patient-reported questionnaires: 
 
Quality of Life:  
1. FACT-H&N is a quality of life questionnaire specific for head and neck cancer  
2. MDADI assesses swallowing related quality of life and is specific for head and neck cancer 
 
Adverse Events:  
3. PRO-CTCAE is a relatively new instrument in the process of validation for patient self-report of 
toxicity. 
 
Health Economics: 
4. EQ-5D-5L is a health utility instrument. 
5. Lost Productivity Questionnaire is a questionnaire for economic evaluation. 
 
The five questionnaires are formatted as separate documents. Accordingly, if paper versions of the 
questionnaires are being used (see instructions for Administration of a Quality of Life Questionnaire 
below), the CRA will need to give attention to the order of the documents and their scheduled assessment. 
 
The patient should first complete the FACT-H&N followed by the other questionnaires in any order. 
 
The Lost Productivity Questionnaire should be completed after the FACT-H&N, MDADI, EQ-5D-5L and 
PRO-CTCAE have been completed, on the last week of radiotherapy. See Appendix VII. 
 
Please make every effort to have the patient complete the correct questionnaires in order at the scheduled 
assessment. 
 
Scheduled Assessment 
Questionnaire 
Within 2 weeks prior to registration 
FACT-H&N, MDADI, EQ-5D-5L, PRO-CTCAE 
Last week of radiotherapy 
FACT-H&N, MDADI, EQ-5D-5L, PRO-CTCAE, Lost Productivity 
3 months post radiotherapy 
FACT-H&N, MDADI, EQ-5D-5L, PRO-CTCAE 
6 months post radiotherapy 
FACT-H&N, MDADI, EQ-5D-5L, PRO-CTCAE, Lost Productivity 
12 months post radiotherapy 
FACT-H&N, MDADI, EQ-5D-5L, PRO-CTCAE, Lost Productivity 
24 months post radiotherapy 
FACT-H&N, MDADI, EQ-5D-5L, PRO-CTCAE 
36 months post radiotherapy 
FACT-H&N, MDADI, EQ-5D-5L, PRO-CTCAE 
 
Instructions for Administration of a Quality of Life Questionnaire 
 
The instructions below are intended as a guide for the administration of the Quality of Life questionnaires. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
 

 
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The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-registration (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pre-treatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g. psychological distress, social disruption, side 
effects, etcetera. 
 
The CRA should collect the questionnaire as soon as it has been completed. For paper questionnaires, 
the CRA should check to see that each question has been answered and gently remind the patient to 
answer any inadvertently omitted questions. If a patient states that s/he prefers not to answer some 
questions and gives a reason(s), the reason(s) should be noted on the questionnaire. If a specific reason 
is not given, this also should be noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to 
treatment. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. 
In that case, you may express sympathy that things are below par, but state that this is exactly the 
information we require if we are to understand more about how quality of life is affected. You may 
also remind them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
5. What If . . . 
 
The patient should complete the questionnaires at the clinic. There may be circumstances when the 
patient does not complete the questionnaire as required in the clinic. Three situations are described 
below. In these cases, it is beneficial if quality of life data can still be collected. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient. 
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the 
phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible. 
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, 
and failing to comply with the patient's wishes is likely to result in the questionnaire not being 
completed at all, then the patient may take the questionnaire home with instructions that it is to be 
completed the same day. When the questionnaire is returned, the date on which the questionnaire 
was completed should be noted and a comment made on the questionnaire as to why the patient 
took it away from the clinic before completion. 
 
6. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
does not understand either English or French. In other words, if the assistance of a translator is required 
to comprehend the questions and reply, the questionnaires should not be completed. Translation of the 
questions is not acceptable. Please indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English and/or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire 
should be read to them and the answers recorded by a health care professional (e.g. preferably the 
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who 
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient 
is completing the questionnaire at home, and a telephone interview by the clinical research associate is 
not possible, then a spouse or friend may read the questions to the patient and record the answers. 
However, this method should be a last resort, and the spouse or friend should be instructed to not coach 
or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 

 
 
FACT Head & Neck 
 
Quality of Life Questionnaire – ENGLISH 
 
CCTG Trial: HN.10 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to registration      Last week of radiotherapy 
 
Post Radiotherapy Treatment, Prior to Progression 
 month 3      month 6      month 12      month 24      month 36 
The FACT-H&N questionnaire should be completed before the MDADI, EQ-5D-5L, PRO-CTCAE and Lost 
Productivity Questionnaire (when applicable). 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy            mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 

This box to be completed by the clinical research associate:  Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 
 
Page 1 of 3 
Please go on to the next page 
FACT H&N (Version 4) US English - Copyright 1987, 1997 
FACT-H&N (Version 4) 
 
Below is a list of statements that other people with your illness have said are important. By circling one (1) 
number per line, please indicate how true each statement has been for you during the past 7 days. 
 
 
PHYSICAL WELL-BEING 
Not  
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 I have a lack of energy .............................................................  
0 
1 
2 
3 
4 
GP2 I have nausea ............................................................................  
0 
1 
2 
3 
4 
GP3 Because of my physical condition, I have trouble  
meeting the needs of my family ...............................................  
0 
1 
2 
3 
4 
GP4 I have pain ................................................................................  
0 
1 
2 
3 
4 
GP5 I am bothered by side effects of treatment ...............................  
0 
1 
2 
3 
4 
GP6 I feel ill .....................................................................................  
0 
1 
2 
3 
4 
GP7 I am forced to spend time in bed ..............................................  
0 
1 
2 
3 
4 
 
 
 
SOCIAL/FAMILY WELL-BEING 
Not  
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GS1 I feel close to my friends ..........................................................  
0 
1 
2 
3 
4 
GS2 I get emotional support from my family ..................................  
0 
1 
2 
3 
4 
GS3 I get support from my friends...................................................  
0 
1 
2 
3 
4 
GS4 My family has accepted my illness ..........................................  
0 
1 
2 
3 
4 
GS5 I am satisfied with family communication about my  
illness........................................................................................  
0 
1 
2 
3 
4 
GS6 I feel close to my partner (or the person who is my  
main support) ...........................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
 
 
 
 
GS7 
Regardless of your current level of sexual activity, please  
answer the following question. If you prefer not to answer 
 it, please check this box  and go to the next section. 
 
 
 
 
 
I am satisfied with my sex life .................................................  
0 
1 
2 
3 
4 

This box to be completed by the clinical research associate:  Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 
 
Page 2 of 3 
Please go on to the next page 
FACT H&N (Version 4) US English - Copyright 1987, 1997 
FACT-H&N (Version 4) 
 
By circling one (1) number per line, please indicate how true each statement has been for you  
during the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not  
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GE1 I feel sad ................................................................................... 
0 
1 
2 
3 
4 
GE2 I am satisfied with how I am coping with my illness ...............  
0 
1 
2 
3 
4 
GE3 I am losing hope in the fight against my illness .......................  
0 
1 
2 
3 
4 
GE4 I feel nervous ............................................................................  
0 
1 
2 
3 
4 
GE5 I worry about dying ..................................................................  
0 
1 
2 
3 
4 
GE6 I worry that my condition will get worse .................................  
0 
1 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
Not  
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GF1 I am able to work (include work at home) ............................... 
0 
1 
2 
3 
4 
GF2 My work (include work at home) is fulfilling .......................... 
0 
1 
2 
3 
4 
GF3 I am able to enjoy life............................................................... 
0 
1 
2 
3 
4 
GF4 I have accepted my illness........................................................ 
0 
1 
2 
3 
4 
GF5 I am sleeping well .................................................................... 
0 
1 
2 
3 
4 
GF6 I am enjoying the things I usually do for fun ........................... 
0 
1 
2 
3 
4 
GF7 I am content with the quality of my life right now .................. 
0 
1 
2 
3 
4 
 

This box to be completed by the clinical research associate:  Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 
 
Page 3 of 3 
FACT H&N (Version 4) US English - Copyright 1987, 1997 
FACT-H&N (Version 4) 
 
By circling one (1) number per line, please indicate how true each statement has been for you  
during the past 7 days. 
 
 
ADDITIONAL CONCERNS 
Not  
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
H&N 
1 
I am able to eat the foods that I like .........................................  
0 
1 
2 
3 
4 
H&N 
2 
My mouth is dry .......................................................................  
0 
1 
2 
3 
4 
H&N 
3 
I have trouble breathing ...........................................................  
0 
1 
2 
3 
4 
H&N 
4 
My voice has its usual quality and strength .............................  
0 
1 
2 
3 
4 
H&N 
5 
I am able to eat as much food as I want ...................................  
0 
1 
2 
3 
4 
H&N 
6 
I am unhappy with how my face and neck look.......................  
0 
1 
2 
3 
4 
H&N 
7 
I can swallow naturally and easily ...........................................  
0 
1 
2 
3 
4 
H&N 
8 
I smoke cigarettes or other tobacco products ...........................  
0 
1 
2 
3 
4 
H&N 
9 
I drink alcohol (e.g. beer, wine, etc.) .......................................  
0 
1 
2 
3 
4 
H&N 
10 
I am able to communicate with others .....................................  
0 
1 
2 
3 
4 
H&N 
11 
I can eat solid foods..................................................................  
0 
1 
2 
3 
4 
H&N 
12 
I have pain in my mouth, throat or neck ..................................  
0 
1 
2 
3 
4 
 
 
Please check to make sure you have answered all the questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you. 

 
 
MDADI 
 
Quality of Life Questionnaire – ENGLISH  
 
CCTG Trial: HN.10 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to registration      Last week of radiotherapy 
 
Post Radiotherapy Treatment, Prior to Progression 
 month 3      month 6      month 12      month 24      month 36 
The FACT-H&N questionnaire should be completed before the MDADI, EQ-5D-5L, PRO-CTCAE and Lost 
Productivity Questionnaire (when applicable). 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home  clinic  another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy          mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 

This box to be completed by the clinical research associate:                       Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 
Page 1 of 2 
Please go on to the next page 
M.D. Anderson Swallowing Inventory (MDADI) - English  
The M. D. Anderson Swallowing Inventory (MDADI) 
 
This questionnaire asks for your views about your swallowing ability. This information will help us understand 
how you feel about swallowing. 
 
The following statements have been made by people who have problems with their swallowing. Some of these 
statements may apply to you. 
 
Please read each statement and circle the response which best reflects your experience in the past week. 
 
My swallowing ability limits my day to day activities 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
E2. I am embarrassed by my eating habits 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
F1. People have difficulty cooking for me 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
P2. Swallowing is more difficult at the end of the day 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
E7. I do not feel self-conscious when I eat. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
E4. I am upset by my swallowing problem. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
P6. Swallowing takes great effort. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
E5. I do not go out because of my swallowing problem. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
F5. My swallowing difficulty has caused me to lose 
income. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
P7. It takes me longer to eat because of my swallowing 
problem 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 

This box to be completed by the clinical research associate:                       Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 
Page 2 of 2 
M.D. Anderson Swallowing Inventory (MDADI) - English  
 
P3. People ask me, “Why can’t you eat that?” 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
E3. Other people are irritated by my eating problem. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
P8. I cough when I try to drink liquids. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
F3. My swallowing problems limit my social and 
personal life. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
F2. I feel free to go out to eat with my friends, neighbors, 
and relatives. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
P5. I limit my food intake because of my swallowing 
difficulty. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
P1. I cannot maintain my weight because of my 
swallowing problem. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
E6. I have low self-esteem because of my swallowing 
problem. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
P4. I feel that I am swallowing a huge amount of food. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
F4. I feel excluded because of my eating habits. 
Strongly 
Agree 
Agree 
No 
opinion 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
 
Thank you for completing this questionnaire! 
 
 
Please check to make sure you have answered all the questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you. 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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CONFIDENTIAL 
72 
CONFIDENTIAL 
APPENDIX VI - PRO-CTCAE QUESTIONNAIRE 
 
PRO-CTCAE 
It is recognized that clinician-reported adverse events (AEs) may substantially under-report the incidence 
and severity of symptoms occurring as a consequence of treatment [Basch 2014]. In response to this 
awareness, the NCI has developed a set of patient-reported items (called PRO-CTCAE) that complement 
the CTCAE and capture the patient’s perspective on the subjective aspects of adverse events [Basch 2014]. 
The potential for under-reporting of adverse events is particularly likely with symptoms such as fatigue, 
pain, and depression, which can only be gauged accurately by the person experiencing the symptom, and 
with long-term head and neck symptoms, such as mouth dryness, voice hoarseness, and difficulty 
swallowing, which are often subtle and may be difficult for clinicians to grade using standard CTCAE 
grading methods. Several CTCAE scales (e.g. taste changes, hair loss) only include 2-3 severity ratings, 
whereas the PRO-CTCAE offers a 5-point response scale. 
 
PRO-CTCAE H&N information will complement the clinician CTCAE reporting, as well as the other PRO 
measures. 
 
A collection of 18 H&N specific PRO-CTCAE H&N items is proposed for comparison with the prior 
CCTG HN.9 and RTOG/NRG 1016 protocols, which have overlapping inclusion criteria relative to HN.10. 
Inclusion of these items in HN.10 will facilitate an exploratory analysis comparing clinician-rated adverse 
events with patient scores on analogous issues, build experience within CCTG in the use of these 
instruments, and contribute to the ongoing validation of the PRO-CTCAE system. 
 

 
  
NCI PRO-CTCAE - at Registration 
 
Quality of Life Questionnaire – ENGLISH  
 
CCTG Trial: HN.10 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to registration 
 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home  clinic  another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
      yyyy            mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 

This box to be completed by the clinical research associate:                       Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 - At Registration 
Page 1 of 3 
Please go on to the next page 
NCI PRO-CTCAE
TM Item Library Version 1.0  
As individuals go through treatment for their cancer they sometimes experience different symptoms and side effects. For 
each question, please check or mark an X in the one box that best describes your experiences over the past 7 days ... 
 
The first time you complete this questionnaire, you will also be asked a question on the highest level of school you have 
and how easy the questions are for you to understand. You will not have to reply about your understanding of the 
questions the next time you complete the questionnaire. 
 
What is the highest level of school that you have completed? Mark only one. 
 Grade school or some high school 
 High school graduate or equivalent 
 Some college/technical school 
 College graduate (4-year degree) 
 Advanced degree (such as MS, JD, Ph.D.) 
 
1. 
In the last 7 days, what was the SEVERITY of your DRY MOUTH at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
2. 
In the last 7 days, what was the SEVERITY of your DIFFICULTY SWALLOWING at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
3. 
In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
4. 
In the last 7 days, what was the SEVERITY of your HOARSE VOICE at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
5. 
In the last 7 days, what was the SEVERITY of your PROBLEMS WITH TASTING FOOD OR DRINK at their 
WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
6. 
In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
7. 
In the last 7 days, how OFTEN did you have NAUSEA? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
 

This box to be completed by the clinical research associate:                       Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 - At Registration 
Page 2 of 3 
Please go on to the next page 
NCI PRO-CTCAE
TM Item Library Version 1.0  
8. 
In the last 7 days, how OFTEN did you have VOMITING? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
9. 
In the last 7 days, what was the SEVERITY of your CONSTIPATION at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
10. 
In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA)? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
 
11. 
In the last 7 days, what was the SEVERITY of your SKIN BURNS FROM RADIATION at their WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 Not applicable 
 
12. 
In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN YOUR HANDS OR FEET 
at its WORST?? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS OR FEET INTERFERE with 
your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
13. 
In the last 7 days, what was the SEVERITY of your DIZZINESS at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did DIZZINESS INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
14. In the last 7 days, what was the SEVERITY of RINGING IN YOUR EARS at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
15. 
In the last 7 days, how OFTEN did you have PAIN? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
In the last 7 days, what was the SEVERITY of your PAIN at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did PAIN INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
16. 
In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF ENERGY at its 
WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY INTERFERE with your 
usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 

This box to be completed by the clinical research associate:                       Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 - At Registration 
Page 3 of 3 
NCI PRO-CTCAE
TM Item Library Version 1.0  
Do you have any other symptoms that you wish to report? 
 Yes 
 No 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
Thank you for completing this questionnaire! 
 
 
Please check to make sure you have answered all the questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you. 
 

 
 
NCI PRO-CTCAE - Post Registration 
 
Quality of Life Questionnaire – ENGLISH  
 
CCTG Trial: HN.10 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Last week of radiotherapy 
 
Post Radiotherapy Treatment, Prior to Progression 
 month 3      month 6      month 12      month 24      month 36 
The FACT-H&N questionnaire should be completed before the MDADI, EQ-5D-5L, PRO-CTCAE and Lost 
Productivity Questionnaire (when applicable). 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home  clinic  another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy           mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 
 
 

This box to be completed by the clinical research associate:  Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 - Post Registration 
Page 1 of 3 
Please go on to the next page 
NCI PRO-CTCAE
TM Item Library Version 1.0  
As individuals go through treatment for their cancer they sometimes experience different symptoms and side effects. For 
each question, please check or mark an X in the one box that best describes your experiences over the past 7 days ... 
 
1. 
In the last 7 days, what was the SEVERITY of your DRY MOUTH at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
2. 
In the last 7 days, what was the SEVERITY of your DIFFICULTY SWALLOWING at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
3. 
In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
4. 
In the last 7 days, what was the SEVERITY of your HOARSE VOICE at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
5. 
In the last 7 days, what was the SEVERITY of your PROBLEMS WITH TASTING FOOD OR DRINK at their 
WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
6. 
In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
7. 
In the last 7 days, how OFTEN did you have NAUSEA? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
8. 
In the last 7 days, how OFTEN did you have VOMITING? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
9. 
In the last 7 days, what was the SEVERITY of your CONSTIPATION at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
10. In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA)? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 

This box to be completed by the clinical research associate:  Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 - Post Registration 
Page 2 of 3 
Please go on to the next page 
NCI PRO-CTCAE
TM Item Library Version 1.0  
11. In the last 7 days, what was the SEVERITY of your SKIN BURNS FROM RADIATION at their WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 Not applicable 
 
12. In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN YOUR HANDS OR FEET 
at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS OR FEET INTERFERE with 
your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
13. In the last 7 days, what was the SEVERITY of your DIZZINESS at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did DIZZINESS INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
14. In the last 7 days, what was the SEVERITY of RINGING IN YOUR EARS at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
15. In the last 7 days, how OFTEN did you have PAIN? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost constantly 
In the last 7 days, what was the SEVERITY of your PAIN at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did PAIN INTERFERE with your usual or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
16. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF ENERGY at its 
WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY INTERFERE with your usual 
or daily activities? 
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 

This box to be completed by the clinical research associate:                       Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 - Post Registration 
Page 3 of 3 
NCI PRO-CTCAE
TM Item Library Version 1.0  
Do you have any other symptoms that you wish to report? 
 Yes 
 No 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
Thank you for completing this questionnaire! 
 
 
Please check to make sure you have answered all the questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you. 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
CONFIDENTIAL 
81 
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APPENDIX VII - LOST PRODUCTIVITY QUESTIONNAIRE 
 
Introduction 
 
Economic evaluations assess the benefits and costs of an intervention for consideration whether the 
intervention may be worth its “costs” -- including financial, toxicity, and social costs. 
 
The collection of information about costs is becoming common in clinical trial protocols. Direct costs 
include the costs of treatment, such as drug therapy and hospital admission. However, there are also indirect 
costs, such as costs to the patient and society, for example through lost productivity or loss of work. The 
collection of information about indirect costs is also becoming common in clinical protocols. In clinical 
trials, lost productivity and patient costs are most often collected using a patient self-reported questionnaire 
(similar to the collection of quality of life data). 
 
Data on costs, both direct and indirect, can be used in various ways, including (a) to support approval of 
new drug applications or patient management strategies, (b) to provide the best value for health care dollars 
within and across diseases and health, and (c) to compare costs and benefits of various financial and 
organizational aspects of health care services. 
 
In the future, approval of new therapies or patient management strategies will most likely be based on a 
combination of health benefit and cost data. This may be formally done using economic analysis techniques. 
 
Instructions for Administration of the Lost Productivity Questionnaire 
 
Please see the instructions for Administration of a Quality of Life Questionnaire in Appendix V. 
 
The instructions below are intended as a guide for the administration of the Lost Productivity Questionnaire 
 
1. Preamble 
 
Lost productivity data are collected for research purposes, and will not be used for the patient’s 
individual medical care. The assessment is in the form of a self-reported questionnaire. Therefore, it 
must be completed by the patient only, without translation, coaching or suggestions as to the "correct" 
answer by relatives or health care personnel. 
 
The scheduled time to obtain the questionnaires is at the: 
 
• last week of radiotherapy and at 6 and 12 months post radiotherapy 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pre-Treatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, for example productivity, change in work status, 
caregiver assistance, and so on. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
CONFIDENTIAL 
82 
CONFIDENTIAL 
The Clinical Research Associate (CRA) should collect the questionnaire as soon as it has been 
completed. For paper questionnaires, the CRA should check to see that each question has been 
answered and gently remind the patient to answer any inadvertently omitted questions. If a patient 
states that s/he prefers not to answer some questions and gives a reason(s), the reason(s) should be 
noted on the questionnaire. If a specific reason is not given, this also should be noted on the 
questionnaire. 
 
3. Assessments During Treatment 
 
The Lost Productivity Questionnaire should be given to the patient on the final day of treatment, as 
required by the schedule in the protocol. 
 
4. Assessments During Follow-up 
 
The questionnaire should be given to the patient before being seen by the doctor, on follow-up visits as 
required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because he/she may feel 
unwell. In that case, you may express sympathy that things are below par, but state that this is 
exactly the information we require if we are to understand more about how overall health is 
affected. You may also remind them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better! 
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some trials 
may require the patient to take the questionnaire home with them after leaving the clinic, and complete it 
on the specific day, because a return visit to the clinic is not scheduled. 
 
However, there may be circumstances when the patient does not complete the questionnaire as required in 
the clinic. Three situations are described below. In these cases, it is beneficial if productivity data can still 
be collected. 
 
5. What If… 
 
5A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets 
to give the questionnaire to the patient. 
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one. 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the 
phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
CONFIDENTIAL 
83 
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5B. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, 
and failing to comply with the patient's wishes is likely to result in the questionnaire not being 
completed at all, then the patient may take the questionnaire home with instructions that it is to 
be completed the same day. When the questionnaire is returned, the date on which the 
questionnaire was completed should be noted and a comment made on the questionnaire as to 
why the patient took it away from the clinic before completion. 
 
5C. The patient is no longer attending clinic during the scheduled follow-up period. 
 
Should the patient no longer be attending clinic, he/she should be contacted by phone to ask 
him/her to complete the questionnaire and mail it to the clinic. In order to facilitate this, ensure 
that after registration all patients are provided with 2 blank questionnaires and 2 clinic-addressed 
stamped envelopes. When the questionnaire is returned, the date on which the questionnaire was 
received should be recorded on the questionnaire. The date on which the questionnaire was 
completed should be noted on the appropriate case report form, as well as where and why the 
patient completed the questionnaire outside of the clinic. If the patient has deterioration to ECOG 
PS 4 or hospitalization for end of life care they need not be contacted for questionnaire 
completion. 
 
6. Waiving the Lost Productivity Component 
 
The only time that we will not require a patient to complete the Lost Productivity questionnaires is if 
s/he is not literate in either English or French. In other words, if the assistance of a translator is required 
to comprehend the questions and reply, the questionnaires should not be completed. Translation of the 
questions is not acceptable. Please indicate on questionnaire. 
 
7. Unwillingness to Complete Lost Productivity Questionnaire 
 
If a patient speaks and reads English or French, but does not wish to complete this questionnaire then 
s/he is still eligible and could be put on study. 
 
8. Inability to Complete Lost Productivity Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the Lost Productivity Questionnaire in the clinic, 
the questionnaire should be read to them and the answers recorded by a health care professional (e.g. 
preferably the clinical research associate assigned to the trial, but another clinic nurse, a doctor or social 
worker who is familiar with the instructions for administering the questionnaires would be acceptable). 
If the patient is completing the questionnaire at home, and a telephone interview by the clinical research 
associate is not possible, then a spouse or friend may read the questions to the patient and record the 
answers. However, this method should be a last resort, and the spouse or friend should be instructed to 
not coach or suggest answers to the patient. Whichever method is used, it should be recorded on the 
questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 

 
 
Lost Productivity Questionnaire – ENGLISH 
 
CCTG Trial: HN.10 
 
This page only to be completed by the Clinical Research Associate 
 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
 
Scheduled time to obtain this Lost Productivity Questionnaire: please check () 
 Last week of radiotherapy (RT) 
 6 months post RT 
 12 months post RT 
 
The Lost Productivity Questionnaire should be completed after the FACT-H&N, MDADI, EQ-5D-5L and PRO-CTCAE 
have been completed. 
 
 
 
Date Questionnaire Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy           mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 
 

This box to be completed by the clinical research associate:             Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
 
CCTG Trial HN.10 Lost Productivity Questionnaire 
Page 1 of 6 
Please go on to the next page 
HN.10 - Lost Productivity Questionnaire 
 
 
To the patient:  
 
We would like to ask you several questions about the work that you do for pay. The 
answers to these questions will allow us to study the financial impact of head and neck 
cancer and its treatment. The information collected will be used for research purposes 
only. 
 
We would appreciate it if you answered all of the questions; however, you do not need 
to answer any question you do not wish to answer. The answers provided will not affect 
your medical care. 
 
 
 
Section A: General Questions 
 
1) 
What type of medical insurance do you currently have? 
 
(Check  all that apply.) 
 Provincial health insurance 
 Individual / group health 
 Other (specify): __________________________________ 
 
 
2) 
If you are working for pay or have done paid work in the past, what would best describe your 
field of employment? (Check  one only. Choose your most recent employment; if more than  
one paid job at once, choose the employment involving the most time commitment.) 
 
 Management 
 Business/ finance/ administrative  
 Natural and applied sciences 
 Health services 
 Education  
 Government services 
 Social science  
 Religion 
 Art/culture 
 Recreation and/or sport 
 Sales and/or service 
 Trades/ transport/ construction 
 Primary industry 
 Processing/manufacturing/utilities 
 Other (specify): ______________ 
 
 Not applicable; no paid work  
COMMENTS: ________________________ 
____________________________________ 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
 
CCTG Trial HN.10 Lost Productivity Questionnaire 
Page 2 of 6 
Please go on to the next page 
3) 
Which of the following best describes your work status at this time?  
(Check one only.) 
 Working full-time for pay (> 30 hours per week) -- (includes self-employed) 
 Working part-time for pay (< 30 hours per week) -- (includes self-employed) 
 On sick leave from full- or part-time work: (Date leave started:  
______________________) 
 
 
 (Year – Month – Day) 
 On disability leave from full- or part-time work: (Date leave started: ______________________) 
 
 
 (Year – Month – Day) 
 Unemployed 
 Retired  
 Homemaker/ Stay at home parent or caregiver 
 Other, specify ________________________________________________________ 
 
 
4) 
Since the start of treatment, has there been any change in your work status compared to before 
that?  
 
(Check  one only.)  
 No, no change 
 Yes, started working full time hours (> 30 hours per week)  
 Yes, started working part time hours (< 30 hours per week)  
 Yes, started sick or disability leave: (Date leave started:  
____________________) 
 
 
 (Year – Month – Day) 
 Yes, quit work/ became unemployed or retired: (Date leave started:  ____________________) 
 
 
 (Year – Month – Day) 
 Yes, other: specify _____________________________________________________ 
 
 
5)  
Since the start of treatment, how much time have you been unproductive (unable to work or do 
usual household activities) due to not feeling well, receiving treatment and / or being in hospital 
for your head and neck cancer?  
 
(Check  one only.) Estimate to the nearest ½ day; assume 1 day is 8 hours. 
 none (0 days) 
 < 1 day (specify # of hours: _____)  
 1 to 3 days (specify # of days: _____) 
 More than 3 days (specify # of days ________) 
 Don’t know – can’t remember 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
 
CCTG Trial HN.10 Lost Productivity Questionnaire 
Page 3 of 6 
Please go on to the next page 
6a)  
Since the start of treatment, how much paid work time have you missed due to illness, 
treatment and/ or being in hospital for your head and neck cancer?  
 
(Check  one only.) Estimate to the nearest ½ day; assume 1 day is 8 hours. 
 none (0 days) 
 < 1 day (specify # of hours: ________) 
 1 to 3 days (specify # of days: ________) 
 More than 3 days (specify # of days ________) 
 Not applicable – not currently working 
 Don’t know – can’t remember 
 
 
6b)  
Since the start of treatment, how much unpaid work time have you missed due to illness, 
treatment and/ or being in hospital for your head and neck cancer?  
 
(Check  one only.) Estimate to the nearest ½ day; assume 1 day is 8 hours. 
 none (0 days) 
 < 1 day (specify # of hours: ________) 
 1 to 3 days (specify # of days: ________) 
 More than 3 days (specify # of days ________) 
 Not applicable – not currently working 
 Don’t know – can’t remember 
 
 
7) 
Please rate your activity level on average since the start of treatment (circle applicable number): 
 
 
0 
1  
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Exhausted 
 
 
 
 
 
 
 
 
 
Normal  
 
in bed all day  
 
 
 
 
 
 
 
 activity level 
 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
 
CCTG Trial HN.10 Lost Productivity Questionnaire 
Page 4 of 6 
Please go on to the next page 
Paid Assistance and Professional Care for Your Head and Neck Cancer 
 
8) 
Since the start of treatment, how much paid health and / or home worker time have you 
needed?  
(Examples include a home visiting nurse or someone to do blood work, VON, home care worker.)  
 
(Check  one only.) Estimate to the nearest ½ day; assume 1 day is 8 hours. 
 none (0 days) 
 < 1 day (specify # of hours: ________ and also the # of visits involved: ________)  
 1 to 3 days (specify # of days: ________ and also the # of visits involved: ________) 
 More than 3 days (specify # of days: ________ and also the # of visits involved: ________) 
 Don’t know – can’t remember 
 
 
9) 
Since the start of treatment, how much other paid assistance have you needed? 
(Examples include a translator to attend doctor visits, a driver to take you to appointments). 
 
(Check  one only.) Estimate to the nearest ½ day; assume 1 day is 8 hours. 
 none (0 days) 
 < 1 day (specify # of hours: ________) Specify type of assistance: ___________________ 
 1 to 3 days (specify # of days: ________) Specify type of assistance: _________________ 
 More than 3 days (specify # of days: ________) Specify type of assistance: ____________ 
 Don’t know – can’t remember 
 
 
Unpaid Caregiver(s) 
 
10) 
Since the start of treatment, who has primarily helped to look after your needs without formal 
pay?  
 
(Check  all that apply.)  
 No one (no unpaid caregiver) 
 Spouse 
 Child/Parent 
 Other relative 
 Friend 
 Neighbor 
 Other (specify) _____________ 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
 
CCTG Trial HN.10 Lost Productivity Questionnaire 
Page 5 of 6 
Please go on to the next page 
11) 
Since the start of treatment, how much time has your unpaid caregiver(s) helped you?  
 
(Check  one only.) Estimate to the nearest ½ day; assume 1 day is 8 hours. 
 none (0 days) 
 < 1 day (specify # of hours: ________) 
 1 to 3 days (specify # of days: ________) 
 More than 3 days (specify # of days: ________) 
 Don’t know – can’t remember 
 Not applicable – I have no unpaid caregiver(s) 
 
 
12) 
Since the start of treatment, how many paid work days at his or her paying job(s) has your 
unpaid caregiver(s) missed in order to help you? 
 
(Check  one only.) Estimate to the nearest ½ day; assume 1 day is 8 hours. 
 none (0 days) 
 < 1 day (specify # of hours: ________) 
 1 to 3 days (specify # of days: ________) 
 More than 3 days (specify # of day: ________) 
 Don’t know 
 Not applicable – no unpaid caregiver(s) or unpaid caregiver(s) not currently working for pay 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
 
CCTG Trial HN.10 Lost Productivity Questionnaire 
Page 6 of 6 
Section B. Financial Implications 
 
Your Personal Financial Implications Concerning This Medical Visit 
 
1.  
Did you miss work to attend this medical appointment?  
 
 Yes  No  If No, go to question 4 
 
2.  
How many hours of work did you miss today to attend your appointment? _______ hours 
 
3.  
Did the number work hours you missed affect your pay or was the time granted by your employer? 
 
 It affected my pay  It was time granted by my employer 
 
4.  
Estimate the total time you had to devote to this appointment, including transportation, waiting time, 
meeting with the doctor. 
 
 
____________ hours and ____________ minutes 
 
5.  
What means of transportation did you use to come to this appointment? 
 
 Private: (car) Estimate the round trip distance in kilometers: ________km 
 
 Public transportation (bus, metro, train, taxi) 
 
6.  
Quantify your expenses from this appointment. 
 
(Please, enter “0” if you had no expenses): 
 
 Parking:  
$ ________________  
 Public transportation:  
Taxi: 
$ ________________ 
 
 
 
Bus/Metro/Train: 
$ ________________ 
 Babysitter: 
$ ________________ 
 Other: (e.g. meals) ___________________  
$ ________________ 
 
7. 
What is your usual yearly gross (before taxes) household income? (all income data will be anonymized and 
kept entirely confidential. It will be used only by the research team) 
 
 < $10,000  
 $10,000 to $19,999 
 $20,000 to $29,999 
 $30,000 to $39,999 
 $40,000 to $49,999 
 $50,000 to $59,999 
 $60,000 to $69,999 
 $70,000 to $79,999 
 $80,000 to $89,999 
 $90,000 to $99,999 
 $100,000 to $124,999 
 $125,000 to $149,999 
 ≥ $150,000 
 
Please check to make sure you have answered all the questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: __________________ 
 
Thank you 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
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APPENDIX VIII - HEALTH UTILITIES ASSESSMENT 
 
Introduction 
 
The assessment of overall health benefits is complicated by the need for a measure that can combine various 
benefits, such as overall survival, disease free survival, and quality of life into a single measure of benefit. 
Patients may value particular benefits differently. There is no obvious way to add together independently 
collected benefits for an individual or for a trial to yield a measure of overall benefit. Health utilities are a 
measure of how people value particular health outcomes. They provide a common denominator that can be 
combined with survival to form a measure of overall health benefits. 
 
Such a measure of overall health benefit can then be used as part of a health economic analysis. Health 
economic analyses assess the benefits and costs of an intervention, for consideration whether the 
intervention may be worth its "costs" -- including financial, toxicity, and social costs. 
 
The collection of information about health utilities is becoming more common in clinical protocols. In 
clinical trials, health utilities are most often collected using a patient self-reported questionnaire (similar to 
the collection of quality of life data). 
 
Health utility and quality of life assessments provide different but complementary information. 
• 
Health utility is a measure of preference for a given health state that acknowledges the risk and 
uncertainty of outcomes in choices patients face and in clinical decision-making. 
• 
They can be used as a weighting factor to adjust survival by quality of life. 
• 
Depending on whether a disease-specific or generic quality of life instrument is used, often only utility 
assessments may be able to compare patient groups with different diseases. 
• 
Only utilities provide a single meaningful measure that can be incorporated in health policy and health 
economic analyses. 
 
Health utilities data can be used in a variety of ways: 
• 
to try and achieve the best possible outcome for patients and populations; 
• 
to evaluate the extent of change in health benefits of an individual, group, or population across time; 
• 
to evaluate new treatments, technologies, and patient management strategies; 
• 
to support approval of new drug applications or patient management strategies; 
• 
to try to provide the best value for health care dollars within and across diseases and health; 
• 
to compare costs and benefits of various financial and organizational aspects of health care services. 
 
In the future, approval of new therapies or patient management strategies will most likely be based on a 
combination of health benefit and cost data. This may be formally done using health utilities as part of a 
health economic analysis. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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Instructions for Administration of a Health Utilities Questionnaire 
 
Please see the instructions for Administration of a Quality of Life Questionnaire in Appendix V. 
 
The instructions below are intended as a guide for the administration of the Health Utilities Questionnaire 
 
1. Preamble 
 
Health utilities data are collected for research purposes, and will not be used for the patient’s individual 
medical care. The assessment is in the form of a self-report questionnaire. Therefore, it must be 
completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-registration (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pre-treatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, 
symptoms, side-effects, et cetera. 
 
The Clinical Research Associate (CRA) should collect the questionnaire as soon as it has been 
completed, check to see that each question has been answered and gently remind the patient to answer 
any inadvertently omitted questions. If a patient states that s/he prefers not to answer some questions 
and gives a reason(s), the reason(s) should be noted on the questionnaire. If a specific reason is not 
given, this also should be noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The health utilities questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to 
treatment. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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4. Assessments During Follow-up 
 
The health utilities questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. 
In that case, you may express sympathy that things are below par, but state that this is exactly the 
information we require if we are to understand more about how overall health is affected. You may 
also remind them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better! 
 
5. What If… 
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
However, there may be circumstances when the patient does not complete the questionnaire as 
required in the clinic. Four situations are described below. In these cases, it is beneficial if health 
utilities data can still be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient. 
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the 
phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible. 
 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, 
and failing to comply with the patient’s wishes is likely to result in the questionnaire not being 
completed at all, then the patient may take the questionnaire home with instructions that it is to be 
completed the same day. When the questionnaire is returned, the date on which the questionnaire 
was completed should be noted and a comment made on the questionnaire as to why the patient 
took it away from the clinic before completion. 
 
D. The patient is no longer attending clinic during the scheduled follow-up period. Should the 
patient no longer be attending clinic, he/she should be contacted by phone to ask him/her to 
complete the questionnaire and mail it to the clinic. In order to facilitate this, ensure that after 
registration all patients are provided with 2 blank questionnaires and 2 clinic-addressed stamped 
envelopes. When the questionnaire is returned, the date on which the questionnaire was received 
should be recorded on the questionnaire. The date on which the questionnaire was completed 
should be noted on the appropriate case report form, as well as where and why the patient 
completed the questionnaire outside of the clinic. 
 
6. Inability to Complete Health Utilities Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the EQ-5D-5L assessment in the clinic, the 
questionnaire should be read to them and the answers recorded by a health care professional (e.g. 
preferably the clinical research associate assigned to the trial, but another clinic nurse, a doctor or social 
worker who is familiar with the instructions for administering the questionnaires would be acceptable). 
If the patient is completing the questionnaire at home, and a telephone interview by the clinical research 
associate is not possible, then a spouse or friend may read the questions to the patient and record the 
answers. However, this method should be a last resort, and the spouse or friend should be instructed to 
not coach or suggest answers to the patient. Whichever method is used, it should be recorded on the 
questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 

 
 
EQ-5D-5L 
 
Health Utilities Questionnaire – ENGLISH  
 
CCTG Trial: HN.10 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to health utilities assessment: please check () 
 Prior to registration  Last week of radiotherapy 
Post Radiotherapy Treatment, Prior to Progression 
 month 3      month 6      month 12      month 24      month 36 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home  clinic  another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
      yyyy            mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 
 

This box to be completed by the clinical research associate:                       Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
CCTG Trial HN.10 
Page 1 of 2 
Please go on to the next page 
 
© 2009 EuroQol Group EQ-5D-5L™ 
EQ-5D-5L Questionnaire 
 
CCTG : HN10 
 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems in walking about 
 
I have slight problems in walking about 
 
I have moderate problems in walking about 
 
I have severe problems in walking about 
 
I am unable to walk about 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 

 
CCTG Trial HN.10 
Page 2 of 2 
 
 
© 2009 EuroQol Group EQ-5D-5L™ 
The worst health 
you can imagine 
 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please check to make sure you have answered all questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you. 
 
YOUR HEALTH TODAY = 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The best health you 
can imagine 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
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APPENDIX IX - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS 
 
The 7th Edition of the TNM Classification of Malignant Tumours has recently been released. To facilitate 
this process, educational resources have been made available to promote the use of staging (visit 
http://www.cancerstaging.org). These staging criteria should be used for new trials. 
 
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
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APPENDIX X - EMERGENCY SITUATIONS AND COMPLIANCE 
 
Management of Protocol Variances in Emergency Situations 
 
Compliance with the trial protocol should be ensured to every extent possible, however in emergency 
situations, specific variances from the protocol that occur as a result of efforts to minimize or eliminate 
hazards and protect the safety and well-being of patients are permissible. 
 
In these rare circumstances, minor deviations that do not impact patient safety or willingness to participate 
or trial integrity, which have been justified and documented in the medical record by the QI/SI will not be 
considered to be REB reportable deficiencies requiring action, but must be reported to CCTG (e.g. in 
Electronic Data Capture (EDC) or using trial specific deviation logs as directed by CCTG) within 4 weeks 
of the end of the Emergency Situation, unless otherwise instructed by CCTG, and to your REB at the next 
amendment or annual approval. 
 
Centres should also discuss these reporting requirements with their local REB, and review the trial website 
for additional guidance specific to the trial. 
 
Minor Protocol Deviations: 
• 
Missed or delayed protocol mandated visits or investigations on treatment or in follow up. 
• 
Changes in study drug distribution (e.g. drug distributed remotely or IV drug given at satellite site), 
providing permitted by local SOPs, or written procedure established and is approved by CCTG or 
acceptable per further instruction from CCTG. Note there will be no exceptions for injectable/IV 
investigational agents as must be administered at participating site. 
• 
Alternative methods for safety assessments (e.g. telephone contact, virtual visit, alternative location for 
assessment). 
• 
Patient care and evaluations provided by non-research staff, providing overseen by QI/SI who must 
make all treatment decisions and ensure that all required information and results will be reported to 
allow central data submission. Includes physical exam, clinical laboratory tests, research blood 
collections that can be shipped centrally, imaging, non-investigational drug therapy*, standard radiation 
therapy, surgery, and other interventions that do not require protocol-specified credentialing*.  
*Must be approved by CCTG or acceptable per further instruction from CCTG. 
• 
Re-treatment following extended treatment delays if protocol specifies that excessive delays require 
discontinuation, providing other protocol requirements for discontinuation have not been met and either 
discussed with CCTG or acceptable per further instruction from CCTG. 
 
Note:  
− Applicable only to COVID-19 and other CCTG designated emergency situations. 
− No waivers will be given for eligibility, including performance of protocol mandated tests/imaging.  
− Deficiencies will be issued if patients are enrolled when trial is on accrual hold, for unreported Serious 
Adverse Events as well as changes in drug distribution/administration and/or re-treatment after 
extended treatment delays when not discussed and approved by CCTG or acceptable per further 
instruction from CCTG. 
− Deviations or changes that are believed to impact patient safety, compromise the study integrity or 
affect willingness to participate are still considered Major Protocol Violations and must be reported to 
CCTG and your REB. These include more than a minimal delay in protocol therapy administration.  
 

 
PROTOCOL AMENDMENT #1: 2020-DEC-14 
 
CCTG TRIAL: HN.10 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
ELIGIBILITY CHECKLIST 
Must be completed prior to 
allocation. 
Susan Casey 
Clinical Trials Assistant, CCTG 
Email: 
scasey@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Sarah Hunter 
Study Coordinator, CCTG 
Email: 
shunter@ctg.queensu.ca 
or: 
Dr. Wendy Parulekar 
Senior Investigator, CCTG 
Email: 
wparulekar@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Scott Bratman 
Study Chair 
Email: 
Scott.Bratman@rmp.uhn.ca 
416-946-2132 
416-946-6561 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for 
details of reportable events. 
Dr. Wendy Parulekar 
Senior Investigator, CCTG 
Email: 
wparulekar@ctg.queensu.ca 
or: 
Sarah Hunter 
Study Coordinator, CCTG 
Email: 
shunter@ctg.queensu.ca 
613-533-6430 
613-533-2941