A Randomized Phase III Trial Comparing Radical Hysterectomy and Pelvic Node Dissection vs Simple Hysterectomy and Pelvic Node Dissection in Patients With Low-Risk Early Stage Cervical Cancer (SHAPE)
Phase: NA
Conditions: Cervical Cancer
Sponsor: Canadian Cancer Trials Group

 
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CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION: 2012-JUL-06 
 
ADMINISTRATIVE UPDATE #1: 2012-AUG-01 
 
ADMINISTRATIVE UPDATE #2: 2012-OCT-19 
 
ADMINISTRATIVE UPDATE #3: 2013-FEB-04 
 
AMENDMENT #1: 2013-OCT-09 
 
AMENDMENT #2: 2014-AUG-27 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A RANDOMIZED PHASE III TRIAL COMPARING RADICAL HYSTERECTOMY AND  
PELVIC NODE DISSECTION VS SIMPLE HYSTERECTOMY AND PELVIC NODE DISSECTION  
IN PATIENTS WITH LOW-RISK EARLY-STAGE CERVICAL CANCER 
 
A Gynecologic Cancer Intergroup (GCIG) Trial led by the CCTG 
 
GCIG Trial Designation: The SHAPE Trial:  
Simple Hysterectomy And Pelvic node dissection in Early cervix cancer 
 
CCTG Protocol Number: CX.5 
KGOG Protocol Number: KGOG 1033 
AGO-AUSTRIA Protocol Number: AGO 36 SHAPE 
UK NCRI Protocol Number: SHAPE 
ICORG Protocol Number: ICORG:14-02 
BGOG Protocol Number: BGOG-CX2 
DGOG Protocol Number: SHAPE 
Fudan University Shanghai Cancer Center Protocol Number: SHAPE 
GINECO Protocol Number: CE104 
 
 
CCTG STUDY CHAIR: 
MARIE PLANTE 
 
KGOG STUDY CHAIR: 
JAE-WEON KIM 
 
AGO-AUSTRIA CHAIR: 
CHRISTIAN MARTH 
 
UK NCRI CHAIR: 
JOHN TIDY 
 
ICORG CHAIR: 
NOREEN GLEESON 
 
BGOG CHAIR: 
FREDERIC GOFFIN 
 
DGOG CHAIR: 
COR DE KROON 
 FUDAN UNIVERSITY SHANGHAI CHAIR: 
XIAOHUA WU 
 
GINECO CHAIR: 
GWENAEL FERRON 
 
 
CCTG TRIAL COMMITTEE: 
SARAH FERGUSON 
 
 
TONY FYLES 
 
SENIOR INVESTIGATOR: 
LOIS SHEPHERD 
 
BIOSTATISTICIAN: 
DONGSHENG TU 
 
QUALITY OF LIFE COORDINATOR: 
LORI BROTTO 
 
HEALTH ECONOMICS COORDINATOR: 
JANICE KWON 
 
PATHOLOGY COORDINATOR: 
JOCELYNE ARSENEAU 
 
RADIOLOGY COORDINATOR: 
MOSTAFA ATRI 
 
STUDY COORDINATOR: 
SELENE MILLER 
 
 
SPONSOR: 
CCTG 
 
(For contact information of study personnel see Final Page.) 
 

 
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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 
 
1.0 
OBJECTIVES .................................................................................................................................. 4 
1.1 
Primary Objective ............................................................................................................................ 4 
1.2 
Secondary Objectives....................................................................................................................... 4 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ............................................................... 5 
2.1 
Overview  ......................................................................................................................................... 5 
2.2 
Management of Patients with Low-risk Cervical Cancer ................................................................ 6 
2.3 
The Feasibility of Sentinel Node (SN) Mapping ............................................................................. 9 
2.4 
The Roles of Adjuvant Therapy ..................................................................................................... 10 
2.5 
Patient Reported Outcomes ............................................................................................................ 11 
2.6 
Evaluation of Other Adverse Events .............................................................................................. 16 
2.7 
Health-Related Economic Evaluation ............................................................................................ 16 
2.8 
Processes for Surgical Quality Control .......................................................................................... 18 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION .................................................................. 19 
 
4.0 
TRIAL DESIGN ............................................................................................................................ 20 
4.1 
Stratification ................................................................................................................................... 20 
4.2 
Randomization ............................................................................................................................... 20 
4.3 
Inclusion of Minorities ................................................................................................................... 20 
 
5.0 
STUDY POPULATION ................................................................................................................ 21 
5.1 
Eligibility Criteria .......................................................................................................................... 21 
5.2 
Ineligibility Criteria ....................................................................................................................... 23 
 
6.0 
PRE-TREATMENT EVALUATION ............................................................................................ 24 
 
7.0 
ENTRY/RANDOMIZATION PROCEDURES ............................................................................ 25 
7.1 
Entry Procedures ............................................................................................................................ 25 
7.2 
Stratification ................................................................................................................................... 25 
7.3 
Randomization ............................................................................................................................... 25 
 
8.0 
TREATMENT PLAN .................................................................................................................... 26 
8.1 
Hysterectomy Procedure ................................................................................................................ 27 
8.2 
Lymphadenectomy and Sentinel Node Mapping ........................................................................... 27 
8.3  
Principles of Adjuvant Treatment .................................................................................................. 28 
8.4 
Concomitant Therapy..................................................................................................................... 28 
 
9.0 
EVALUATION AFTER PROTOCOL AND NON-PROTOCOL TREATMENT ....................... 29 
9.1 
Evaluation After Completion of Protocol Therapy ........................................................................ 30 
9.2  
Evaluation After Recurrence .......................................................................................................... 31 
 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ................................................. 32 
10.1 
Definitions ..................................................................................................................................... 32 
10.2 
Evidence of Disease Recurrence .................................................................................................... 33 
10.3 
Dating of First Recurrence ............................................................................................................. 33 
10.4 
Management Following Recurrence .............................................................................................. 33 

 
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11.0 
SERIOUS ADVERSE EVENT REPORTING .............................................................................. 34 
11.1 
Definition of a Reportable Serious Adverse Event ........................................................................ 34 
11.2 
Serious Adverse Event Reporting Instructions .............................................................................. 34 
11.3 
Reporting Safety Reports to Investigators ..................................................................................... 35 
 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ..... 36 
12.1 
Therapy After Protocol Treatment ................................................................................................. 36 
12.2 
Follow-Up After Protocol Treatment ............................................................................................. 36 
12.3 
Lost to Follow Up .......................................................................................................................... 36 
 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ....................................... 37 
13.1 
Central Review of Diagnostic Imaging and Quality Assurance Procedure ................................... 37 
13.2  
Pathology Quality Assurance ......................................................................................................... 37 
13.3 
Surgical Quality Assurance Procedure .......................................................................................... 37 
13.4 
Central Pathology Review ............................................................................................................. 38 
 
14.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 39 
14.1 
Objectives and Design ................................................................................................................... 39 
14.2 
Primary Endpoints and Analysis .................................................................................................... 39 
14.3 
Sample Size and Duration of Study ............................................................................................... 41 
14.4 
Safety Monitoring .......................................................................................................................... 41 
14.5 
Interim Analysis ............................................................................................................................. 41 
14.6 
Analysis for Quality of Life ........................................................................................................... 42 
14.7 
Economic Analysis ........................................................................................................................ 42 
 
15.0 
PUBLICATION POLICY ............................................................................................................. 43 
15.1 
Authorship of Papers, Meeting Abstracts, Etc ............................................................................... 43 
15.2 
Responsibility for Publication ........................................................................................................ 44 
15.3 
Submission of Material for Presentation or Publication ................................................................ 44 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES .............................................. 45 
16.1 
Regulatory Considerations ............................................................................................................. 45 
16.2 
Inclusivity in Research ................................................................................................................... 45 
16.3 
Obtaining Informed Consent .......................................................................................................... 46 
16.4 
Discontinuation of the Trial ........................................................................................................... 46 
16.5 
Retention of Patient Records and Study Files ................................................................................ 47 
16.6 
Centre Performance Monitoring .................................................................................................... 47 
16.7 
On-Site Monitoring/Auditing ......................................................................................................... 47 
 
17.0 
REFERENCES .............................................................................................................................. 49 
 
APPENDIX I - PATIENT EVALUATION FLOW SHEET ...................................................................... 54 
APPENDIX II - PERFORMANCE STATUS SCALES/SCORES ............................................................ 55 
APPENDIX III - 2009 FIGO NOMENCLATURE .................................................................................... 56 
APPENDIX IV - DOCUMENTATION FOR STUDY .............................................................................. 57 
APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ................. 58 
APPENDIX VI - QUALITY OF LIFE ASSESSMENT ............................................................................. 59 
APPENDIX VII - HEALTH UTILITIES ASSESSMENT ......................................................................... 74 
APPENDIX VIII - COVID-19 AND EMERGENCY SITUATIONS AND COMPLIANCE ................... 88 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 

 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
(This form must be completed for all Canadian institutions prior to local activation). 
 
I understand that this protocol and any supplementary information that may be added to this document 
contains information that is confidential and proprietary and must be kept in confidence. 
 
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 ofCCTG. 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 enrolment 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 toCCTG. The study may 
be terminated at any time by CCTG with or without cause. 
 
 

 
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Will your centre be performing sentinel node mapping for patients randomized to the CX.5 trial? 
(please indicate your answer by checking the appropriate box below) 
 
 No, our centre will not be performing sentinel node mapping for any patients randomized to the CX.5 
trial. 
 
 Yes, our centre will be performing a sentinel node mapping procedure for some or all patients 
randomized to the CX.5 trial. 
 
I attest that all surgeons who will perform sentinel node mapping for CX.5 patients have previously 
performed the procedure for at least 10 prior endometrial or cervical cancer patients. 
 
 
_____________________________ 
______________________ 
_________________________ 
Qualified Investigator Signature 
Printed Name 
Date 
 
 
Protocol Number: CCTG CX.5 
 
CENTRE: ___________________________________________ 

 
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TREATMENT SCHEMA 
 
This is a multi-centre, international, prospective, randomized phase III trial of radical hysterectomy and 
pelvic node dissection versus simple hysterectomy and pelvic node dissection in patients with previously 
untreated, low-risk cervical cancer. 
 
Stratification 
1. Cooperative Group 
2. Intended use of sentinel node mapping (yes vs. no) 
3. Stage (IA2 vs. IB1) 
4. Histological type (squamous vs. adenocarcinoma/adenosquamous) 
5. Grade (1-2 vs. 3 vs. not assessable) 
 
Low-risk cervical cancer as defined by: 
• squamous cell, adenocarcinoma, 
adenosquamous carcinoma 
• Stage IA2 and modified IB1  
• ≤ 10mm stromal invasion on 
LEEP/cone 
• < 50% stromal invasion on MRI 
• max dimension of < 20 mm  
• Grade 1-3 or not assessable 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
ARM 1 (Control) 
Radical Hysterectomy* 
Pelvic relapse 
 
 
 
Arm 2 (Experimental) 
Simple Hysterectomy* 
* 
Regardless of treatment assignment, surgery will include pelvic lymph node dissection with optional sentinel 
lymph node (SN) mapping. If SN mapping is to be done, the mode is optional, but the laparoscopic approach is 
preferred. 
Planned sample size: 700 (non-inferiority at 0.05 level with 85% power) 
 
Primary Endpoint 
• 
Pelvicrecurrence rate at 3 years. 
 
Secondary Endpoints 
• 
To compare the two treatment arms with respect to: 
– 
Pelvic relapse-free survival 
– 
Extra pelvic relapse-free survival 
– 
Relapse-free survival (any site) 
– 
Overall survival 
– 
Treatment-related adverse events 
– 
Patient Reported Outcomes including global quality of life and measures of sexual health 
– 
Cost-effectiveness and cost-utility 
 
• 
To observe rates of the following in this patient population: 
– 
Sentinel node detection 
– 
Parametrial involvement 
– 
Involvement of surgical margins 
– 
Pelvic node involvement 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate whether treatment with simple hysterectomy and pelvic node dissection is non-inferior 
to treatment with radical hysterectomy and pelvic node dissection in terms of pelvic relapse-free 
survival at 3 years 
 
1.2 
Secondary Objectives 
 
• 
To compare the two treatment arms with respect to: 
– 
Pelvic relapse-free survival 
– 
Extra pelvic relapse-free survival 
– 
Relapse-free survival (any site) 
– 
Overall survival 
– 
Treatment-related adverse events 
– 
Patient Reported Outcomes including global quality of life and measures of sexual health 
– 
Cost-effectiveness and cost-utility 
 
• 
To observe rates of the following in this patient population: 
– 
Sentinel node detection 
– 
Parametrial involvement 
– 
Involvement of surgical margins 
– 
Pelvic node involvement 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
2.1 
Overview 
 
Cancer of the cervix is the second leading worldwide cause of cancer death in women. Most recent 
global statistics indicate that in 2002, the estimated incidence was 493,243 new cases with 273,505 
deaths [Parkin 2006]. The disease is much more prevalent in developing as opposed to developed 
nations. There is an almost two-fold increase in lifetime probability risk of developing cervical 
cancer (1.48% vs. 0.76%) and a more than three-fold increase in dying from it (0.84% vs. 0.25%) 
in underdeveloped countries [Global Cancer Facts and Figures 2007]. In Canada, the projected number 
of new cases in 2010 was 1300, with 370 deaths [Canadian Cancer Statistics, 2010].  
 
As a result of effective screening in developed countries, the overall incidence of cervical cancer 
has decreased over the past 20 years, while the proportion of younger women presenting with low-
risk early-stage disease has increased. As surgical therapy is highly efficacious in providing durable 
disease control in women with low-risk disease, these patients are at risk of suffering “survivorship” 
issues related to long-term surgical effects, including compromised sexual, bowel and bladder 
function, as well as infertility. The CCTG CX.5 / GCIG SHAPE trial uses a non-inferiority design 
to test whether, in the long-term, less invasive surgical approaches can maintain high rates of 
disease control and improve quality of life through a reduction in late-effects associated with the 
surgical procedure. 
 
Data from the recent 24th annual International Federation of Gynecology and Obstetrics (FIGO) 
report indicates that the 5-year stage-specific overall survivals of patients with stage IA2 squamous 
carcinoma were 99.1% (97.1% for adenocarcinoma) and for stage IB1 squamous carcinoma were 
92.3% (91.8% for adenocarcinoma) [FIGO Annual Report, 2009]. The FIGO report emphasizes that 
from an international perspective, extensive practice variation occurs in managing patients with 
micro-invasive disease. Overall, 75% of patients were treated with surgery alone. Among these 
patients, one-third underwent conization, one-third simple hysterectomy (with or without 
lymphadenectomy) and one-third radical hysterectomy (again with or without lymphadenectomy). 
The remaining 25% of patients received some form of adjuvant therapy. Overall, 20% of patients 
underwent lymph node removal, presumably when lymphovascular involvement was detected on 
the conization specimen [FIGO Annual Report, 2009]. The major reason for such discrepant practices 
is the lack of high-quality evidence upon which clinicians can base their decisions and advice to 
these women. There is a need to standardize treatments and potentially identify the patient and 
disease specifics associated with advantages with radical or more limited surgical approaches.  
 
There are no studies comparing the efficacy and morbidity of simple hysterectomy to that of radical 
hysterectomy in patients with early-stage disease. However, as the purpose of removing the 
parametria at the time of the hysterectomy is to ensure safe and wide margins around the cervical 
tumour and/or to remove potential spread to the parametrial lymph nodes and, as will be described 
below, the occurrence of disease in these locations is essentially nonexistent in patients with low-
risk disease, important advantages may be associated with a simple hysterectomy. This premise 
provides the foundation for this trial.  
 

 
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2.1.1 
Staging of Cervical Cancer 
 
According to FIGO classification, there are four stages of cervical cancer (see Appendix III), which 
include the two most common histologic forms, squamous (~70%) and adenocarcinoma (~30%). 
Determination of staging relies primarily on clinical evaluation. “Early-stage” cancer is referred to 
stages IA2-IB1, which are both amenable to surgical treatment. Stage IA2 is based on the 
microscopic evaluation of the cervical lesion, usually removed by conization, and includes stromal 
invasion measuring < 5mm in depth and < 7mm in lateral extension. Stage IB1 refers to larger 
lesions that remain limited to the cervix and measure < 4 cm in maximum diameter. The 5-year 
survivals of patients with stage IA2 disease is 98% and for IB1is 92%.  
 
Radical hysterectomy with complete pelvic lymph node dissection is the standard treatment for 
“early-stage” disease. As the primary mode of tumour dissemination is via lymphatics, either 
proximally to the parametrial tissue or directly to the pelvic lymph node, node status is one of the 
most important prognostic factors. The rate of lymph node metastasis is approximately 5% in IA2 
disease and 15% in stage IB1 disease. The 5-year survival in node negative IB1 patients is in the 
range of 96%, whereas it reduces to 79% in node positive patients. 
 
“Low-risk” disease refers to patients with early-stage disease who have stage IA2 or stage IB1 and 
lesions measuring less than 2 cm in size with less than 50% stromal invasion [Schmeler, 2011]. In 
these patients, the risk of lymph node metastasis is < 5% and parametrial extension is < 1%. In the 
CCTG CX.5 / GCIG SHAPE trial, we will evaluate patients with low-risk disease. We hypothesize 
that less radical surgery (simple hysterectomy) will be associated with similar efficacy and less 
surgical morbidity than more radical surgery. According to local practices, we will include lymph 
node assessment through the less morbid approach of sentinel node mapping. 
 
2.2 
Management of Patients with Low-risk Cervical Cancer 
 
For over a century, radical hysterectomy with pelvic lymphadenectomy has been the standard 
surgical approach for patients with stage IA2- IB1 disease. Various rates of important acute 
morbidities have been reported following radical hysterectomy, with differences likely reflecting 
the rigor of assessment. Complications include urinary and rectal dysfunction, ureteral and vesical 
fistulas (2%), intraoperative bleeding, infections and lymphedema [Sood 2002]. Urinary dysfunction 
includes difficulty voiding, postoperative urinary retention and loss of urinary sensation. According 
to Ceballos, overall morbidity of radical hysterectomy reaches 10%, with a 2% risk of ureteric 
injury and a 7% risk of lymphedema [Ceballos 2006]. Matsuura reported that complete pelvic lymph 
node dissection is associated with up to a 20% risk of lymphocyst formation, 10-15% risk of 
lymphedema, and rare cases of neural or vascular damage [Matsuura 2006]. Others report severe 
perioperative complications in 10-15% of cases [Averette 1993; Benedetti-Panici 2005]. Urological and 
rectal dysfunction related to nerve injury has been reported in up to 20-30% of cases [Averette 1993; 
Benedetti-Panici 2005]. Sood evaluated the incidence of bowel symptoms, changes in anorectal 
physiology and quality of life after radical hysterectomy and concluded that bowel dysfunction is 
common and due to pudendal neuropathy, autonomic dysfunction or both [Sood 2002; Sartori 1997].  
 
Late complications are also important. Even though sensory and motor bladder dysfunction affect 
a majority of women in the immediate postoperative period, and may be a function of the extent of 
the operation, 1-2% will have long-term detrusor dysfunction or markedly decreased sensory 
function leading to inferior scores in assessments of quality of life [Sood 2002]. Late complications 
can also include hydronephrosis and lymphedema in up to 16% of cases [Magrina 1995]. 

 
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Landoni prospectively assessed outcomes in patients randomized to undergo a type 2 or type 3 
radical hysterectomy as treatment for stage IB disease. No differences in overall recurrence or 
survival were detected, but long-term urologic morbidity was seen with the more radical procedure 
[Landoni 2001]. Benedetti-Panici prospectively compared 63 patients who underwent a modified 
radical hysterectomy to 20 patients who underwent a radical hysterectomy and demonstrated a 
significant difference in morbidity, particularly long-term bladder dysfunction (11% vs. 70%); they 
also reported a significant reduction in operating time, blood transfusion and hospital stay [Benedetti-
Panici 2005]. These data have led to the conclusion that bladder dysfunction is related to the extent 
of the parametrial dissection. 
 
2.2.1 
Outcomes Justifying Testing of Less Radical Approaches in Stage IA2 
 
There is a growing body of literature suggesting that more conservative surgery can safely be 
performed in patients with stage IA2 disease, providing careful pathological evaluation is 
undertaken. A literature review performed by van Meurs identified 1063 patients with stage IA2 
disease and reported an overall recurrence rate of 3.6% [van Meurs 2009]. No patients had parametrial 
infiltration and 4.8% (range 0 to 9.7%) were found to have lymph node metastasis, indicating the 
importance of accurate measurement of depth and lateral extension of microinvasive disease, 
particularly with adenocarcinomas. This principle is highlighted by the author’s finding that 
following a thorough review of 47 cases that were previously identified in the Netherland registry 
as having IA2 disease, only 14 cases (30%) fulfilled criteria for stage IA2 [van Meurs 2009]. These 
authors also noted that the rate of lymph node metastasis was 12% in patients with lymphovascular 
space involvement (LVSI) compared with 1.3% in LVSI negative patients [van Meurs 2009]. 
 
However, other investigators have not observed the same risks to be associated with LVSI. Rogers 
conducted an extensive literature review and compared the rate of lymph node metastasis and 
recurrence in a series that used strict FIGO-defined selection criteria for microinvasion with a series 
that did not comply with this definition [Rogers 2009]. In the former group, the rates of node 
metastasis and recurrence were 0.5% and 2.9%, whereas rates were 7.3% and 3.1% in the latter 
group. Careful pathological assessment is thus essential when considering conservative treatment. 
 
These data are supported by findings of Bisseling, who reviewed more than 1565 patients with 
microinvasive adenocarcinomas, of which 52% (814) underwent lymph node dissection [Bisseling 
2007]. Lymph node metastases were identified in only 1.5% of cases. The presence of LVSI did not 
seem to be associated with nodal metastasis. Parametria were removed in 713 cases (46%) and 
reported in 356 cases; none of these cases were found to have parametrial involvement. The authors 
emphasized the difficulty in distinguishing microinvasive adenocarcinoma from adenocarcinoma 
in situ and the importance of obtaining multiple serial sections for review by an experienced 
gynecologic pathologist. The authors conclude that: i) in cases with extensive LVSI positivity, 
lymph node dissection is advised; ii) given the low-risk of lymph node metastasis, lymph node 
dissection may not be necessary in the vast majority of stage IA2 cases, although sentinel node 
mapping may be of interest as a less morbid alternative; and, iii) the very low rate of parametrial 
infiltration does not justify its routine removal. Therefore, local treatment together with lymph node 
assessment, particularly in the presence of LVSI would be the favored approach for patients with 
stage IA2 adenocarcinomas [Bisseling 2007]. Of note, microinvasive adenocarcinomas do not appear 
to be associated with higher rates of lymph node metastasis as compared with stage-matched 
squamous carcinoma [Rogers 2009]. 

 
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In 92 patients with IA2 disease treated with radical hysterectomy, Jones found no cases with 
pathologic involvement of the parametrial or regional lymph nodes [Jones 1993]. On a subsequent 
pathologic analysis of 25 patients with microinvasive adenocarcinomas, again no cases with lymph 
node metastasis and no parametrial invasion were detected. Poynor concluded that conisation alone 
(if fertility preservation is desired) or simple hysterectomy should be considered adequate treatment 
for microinvasive adenocarcinomas [Poynor 2006]. 
 
The Gynecologic Oncology Group (GOG) reported results of a prospective study of 51 patients 
with stage IA2 disease confirmed by conization and treated with radical hysterectomy [Creasman 
1998]. No patients had residual disease detected with the pathologic hysterectomy specimen, 
including none with lymph node metastasis [Creasman 1998]. Recently, Suri confirmed that patients 
with IA2 disease and negative pathologic margins following a loop electrosurgical excision 
procedure (LEEP) or cone procedure have a very low-risk of disease detection on the radical 
hysterectomy pathology specimen [Suri 2009]. In their series of 42 patients, only one patient was 
found to have positive nodes (2.4%) and in this patient LVSI was present on her cone specimen. 
The authors concluded that in carefully selected women with IA2 disease and negative pathology 
margins with LEEP or cone procedures could be treated more conservatively, but patients with 
LVSI may require nodal assessment [Suri 2009]. 
 
2.2.2 
Outcomes Justifying Testing of Less Radical Approaches in Stage IB1 
 
Fewer data are available regarding the safety of conservative treatment for the subset of patients 
with early-stage IB1 disease, defined as a tumour measuring less than 2 cm. In a retrospective study 
of 842 patients, Covens questioned the necessity of the parametrectomy based on observing a rate 
of parametrial extension of 0.6% and 2 and 5-year recurrence-free survivals of 98% and 96% in 
patients with low-risk features (tumour < 2cm, depth of stromal invasion < 10mm and negative 
pelvic nodes) [Covens 2002]. Wright conducted a retrospective review of 594 patients who underwent 
a radical hysterectomy; 0.4% of patients with lesions measuring < 2cm, negative nodes and no 
LVSI had parametrial spread and their recurrence rate was 0.7% [Wright 2007]. The authors 
concluded that simple hysterectomy in combination with pelvic lymphadenectomy may be 
adequate treatment for these patients. In a similar study plus literature review of 799 patients, only 
0.63% of those with low-risk features had parametrial spread [Stegeman 2007]. Further supporting 
data include: 
• 
In a retrospective analysis of 120 patients by Steed, no patients with negative nodes had 
parametrial infiltration. Parametrial infiltration was associated with tumour size (3 vs. 2 cm) 
and depth of stromal invasion [Steed 2006].  
• 
In a retrospective analysis of 83 patients by Kinney, no parametrial node metastases were seen 
in those with lesions measuring < 2cm in diameter and negative LVSI. Only 4 patients had 
pelvic node metastasis (4.8%), and the 5-year survival was 97.6% [Kinney 1995]. 
• 
In a retrospective analysis of 136 patients by Frumovitz, no patients with tumours measuring 
< 2cm with negative LVSI had parametrial infiltration [Frumovitz 2009]. This group is now 
prospectively testing conservative surgery for patients with tumours < 2 cm who are LVSI 
negative.  
• 
Coutant has reported that tumour size < 2cm and absence of LVSI are the most relevant 
preoperative factors that predict for parametrial infiltration [Coutant 2009].  
 

 
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2.2.3 
Testing of Simple Hysterectomy 
 
There is only one published prospective study evaluating less radical surgery in early-stage cervical 
cancer [Pluta 2009]. Pluta reported the outcomes of 60 patients with lesions measuring < 2cm and 
< 50% stromal invasion who then underwent sentinel node mapping followed by complete pelvic 
lymphadenectomy and simple vaginal hysterectomy. All patients underwent preoperative MRI to 
evaluate for parametrial spread; the sensitivity of this modality is reported to be 89% [Postema 2000]. 
Among these patients, 5 were found to have lymph node metastasis (8.3%) and 3 had LVSI. With 
a median follow-up of 47 months, no recurrences have been observed in either the 55 node-negative 
patients or the 5 node-positive patients. These results form the basis and rationale for the current 
proposal.  
 
Based on the above data, routine parametrectomy in patients with low-risk disease appears to be 
potentially unnecessary given the very low rate of parametrial extension seen with retrospective 
reviews and acknowledging the morbidity of the procedure. However, there are no randomized 
trials demonstrating the safety of simple hysterectomy in low-risk stage IB1 patients. This trial will 
provide a unique opportunity to compare the rate of lymph node metastasis, parametrial infiltration 
and outcome between the two procedures, and produce results that can drive a change in clinical 
practice. 
 
2.3 
The Feasibility of Sentinel Node (SN) Mapping 
 
The risk of lymph node metastasis in low-risk patients is < 5% [Kinney 1995]. Even though it is not 
part of the FIGO staging, the presence of lymph node metastasis is one of the most important 
prognostic markers in cervical cancer [Takeda 2002]; FIGO reports that for patients with stage IB1 
disease, 5-year survivals are 95.7% for patients with negative nodes and 78.8% in node-positive 
patients. In that report, the rate of lymph node metastasis in stage IA2 was 2.3% but increases to 
15% for those with stage IB1 disease [FIGO Annual Report, 2009]. The data described in Section 2.1.1 
confirm a low-risk of lymph node metastasis when lesions measure < 2cm. Similarly, data 
evaluating over 600 patients undergoing radical trachelectomy, where the vast majority of patients 
have lesions measuring < 2 cm, indicate a low-risk of pelvic node metastasis, a recurrence rate < 
5%, a death rate 3%, and survival comparable to the radical hysterectomy cohort [Plante 2008; Beiner 
2008, Plante 2011]. Thus, strategies to evaluate lymph node status may be particularly important, 
making many investigators uncomfortable with the concept of abandoning lymph node evaluation.  
 
Traditional lymph node evaluation may be associated with significant morbidity, including 
intraoperative vessel damage, nerve injuries, and postoperative development of lymphocele and 
lymphedema in up to 15-20% of cases [Matsuura 2006]. The concept of SN mapping is to reduce 
morbidity associated with lymphadenectomy while providing accurate assessment of lymph node 
status. In vulvar cancer, SN mapping has reduced the rate of lymphedema of the legs from 25% 
following standard inguinofemoral lymphadenectomy to 1.9% after SN mapping [Van der Zee 2008]. 
This experience has also shown that accuracy of the SN mapping procedure is highly dependent on 
development of expertise, case load, adhering to strict guidelines, integration of a multidisciplinary 
team (nuclear medicine, pathologist) and availability of the technology [Van der Zee 2008].  

 
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Mapping of SNs has been recently studied in cervical cancer. Pooled data from 20 studies that 
include 802 cases show a sensitivity of 93% and a false-negative rate of 6.8% [Levenback 2008]. 
Hauspy challenged these false negative results and determined that the true false negative rate is 
closer to 2%. Major causes of false negativity related to inadequate technique including limited or 
incomplete data on the laterality of the SN detection versus the side of the positive node, unilateral 
SN detection only and evaluation of only macroscopically involved nodes [Hauspy 2007]. The SN 
mapping technique has been shown to be more effective when lesions measure < 2 cm and Rob has 
reported a detection rate of 100% and false negative rate of 0% in patients with lesions measuring 
< 2cm using a combined technique that incorporates blue dye and technetium99 [Rob 2005]. The SN 
literature also demonstrates that in low-risk patients, the status of the SN is highly correlated with 
the risk of parametrial invasion [Strnad 2008]; Strnad reported no parametrial invasion in 53 patients 
with early cervical cancer and negative SN results [Strnad 2008].  
 
A recent publication suggests that SN mapping may be more accurate than standard 
lymphadenectomy because SNs submitted for pathological evaluation are identified through an 
ultrastaging procedure [Gortzak-Uzan 2010]. In a subgroup of 36 patients with cervical cancer with 
bilateral negative SNs, final pathology evaluating ultrastaging-negative nodes did not identify 
metastasis in those non-sentinel nodes (false positive rate 0) [Popa 2006]. Euscher has reported a 
25% increase in the detection of lymph node metastasis in patients with cervical cancer who 
undergo an ultrastaging procedure [Euscher 2008]. Similarly, Marchiole identified micrometastasis 
in 5/26 patients (19%) following ultrastaging and serial pathologic sectioning and 
immunohistochemistry [Marchiole 2005]. The clinical significance of micrometastasis discovered by 
ultrastaging remains unsettled, but accumulating evidence suggests that micrometastasis may be 
associated with increases in recurrence rate and inferior disease-free and overall survivals [Marchiole 
2005; Horn 2008; Juretzka 2004; Darai 2008; Cibula 2012]. Additional advantages of the SN mapping may 
be the detection of unusual or aberrant lymphatic drainage to the common iliac or low para-aortic 
regions, which are areas not routinely sampled with pelvic lymphadenectomy [Rob 2005; Plante 2003; 
Roy 2011].  
 
In patients with low-risk disease, SN mapping is an attractive alternative to reduce the morbidity 
of the complete lymph node dissection. This trial will provide the opportunity to determine the rate 
of SN detection in patients with lesions < 2cm, the proportion of micrometastasis. 
 
2.4 
The Roles of Adjuvant Therapy 
 
Post-operative adjuvant radiation-based treatment is at the discretion of investigators as per local 
institutional policy. 

 
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2.5 
Patient Reported Outcomes 
 
2.5.1 
Global Quality of Life and Quality of Life Outcomes (QoL) Most Relevant to Pelvic Surgery 
 
Quality of life outcomes are relevant in cervix cancer patients in several domains, including 
global/functioning domains as well as domains specific to the pelvic consequences of surgery. In 
this study, therefore, we will assess QOL outcomes using both the EORTC QLQ-C30 core 
questionnaire and the QLQ-C24 module, as they have been shown to appraise QoL following 
treatment. In a study of 190 women with histologically confirmed FIGO Stages I through IV 
cervical cancer, administration of the EORTC Core QoL instrument and the QLQ-CX24 Cervical 
Cancer specific module found that most scales on the QLQ-CX24 correlated weakly with the QLQ-
C30 scales (all correlations < 0.40) with a higher correlation between the Symptom Experience 
domain and the core module scales (r = 0.40-0.48) [Greimel 2006]. Items on the Symptom Experience 
scale included assessment of abdominal, bowel, and bladder pain and symptoms, as well as vaginal 
pain and discharge. Women receiving treatment reported significantly more symptoms than those 
who completed treatment on the Sexual/Vaginal functioning and the Symptom Experience scale. 
In a long-term study of treatment-related symptoms in 121 women with early-stage cervical cancer 
tested 7.3-9.7 years following diagnosis, women receiving surgery and radiation therapy reported 
significantly worse QoL outcomes on several scales compared to women receiving surgery only, 
or to those receiving surgery/chemotherapy [Greimel 2008]. On the QLQ-CX24 module, the three 
treatment groups significantly differed on items pertaining to frequent urination, leaking of urine, 
and feeling of a tight vagina in the surgery/radiation therapy group compared to the other two 
groups. Compared to reference data provided in the study taken from 1139 women without a history 
of cancer, women receiving surgery only had significantly higher three symptom scales and none 
of the functioning scales. No data were provided on the comparisons of these groups with the non-
cancer reference group on the QLQ-CX24 domains. In both trials, all statistically significant effects 
were also considered to be clinically significant according to a >10 point mean difference. 
 
In their pilot study comparison of simple vaginal hysterectomy plus laparoscopic 
lymphadenectomy versus radical hysterectomy for early-stage cervical cancer, Pluta and colleagues 
found it was feasible and safe to reduce the radicality of hysterectomy [Pluta 2009]. Radical resection 
of the parametria is associated with damage to the innervation of the rectum and bladder, leading 
to long-term bowel and bladder side effects which negatively impact on QoL. This pilot study did 
not report on the changes in these QoL domains. In a different pilot study which compared 12 
premenopausal women treated with radical hysterectomy for cervical cancer with 12 
premenopausal women treated with simple hysterectomy for benign reasons, the incidence of bowel 
and bladder dysfunction was highest in the radical hysterectomy group but the groups did not 
statistically differ from one another - perhaps attributable to the small sample sizes [Maas 2004].  
 

 
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2.5.2 
Sexual Health 
 
Unlike hysterectomy for benign conditions, in which the type of hysterectomy does not appear to 
affect sexual function [Roovers 2003; Thakar 2002], radical hysterectomy for early-stage cervical cancer 
is well documented to be associated with negative sexual side effects. In one of the earliest 
prospective trials, 61 women with stage IA, IB, or IIA disease who underwent radical hysterectomy 
with or without pelvic radiation took part in a 2-hour interview and completed questionnaires 
[Schover 1989]. Sexual desire, intercourse frequency, and range of activities decreased by one year 
post-surgery. Subjective excitement and vaginal lubrication decreased at one year and there were 
more frequent diagnoses of sexual arousal disorders. Psychological symptoms, however, improved 
over this period of time. In their long-term examination of QoL symptoms following early-stage 
cervical cancer using the Sexual Activity Questionnaire [Thirlaway 1996], Greimel and colleagues 
found that 43.3% of the sample reported not being sexually active, with the leading reasons being 
absence of a partner and lack of sexual desire [Greimel, 2008]. Among the sexually active group, 
women receiving surgery/radiation therapy had the lowest rates of sexual frequency compared to 
the other two treatment groups. Women currently receiving treatment had significantly more Sexual 
Worry on the QLQ-CX24 compared to the group off-treatment [Greimel 2006], but the groups did 
not differ on current sexual activity. 
 
More recently, studies examining effects of radical hysterectomy have considered more specific 
indices of sexual functioning. Given that overall sexual frequency may not change and other factors 
may determine why women engage in sexual activity, frequency is not considered to be a good 
indicator of sexual response. A Swedish retrospective study comparing 256 women previously 
treated for cervical cancer (90% had undergone a radical hysterectomy) and 350 community non-
cancer controls failed to detect differences between groups in the frequency of reduced sexual 
desire [Bergmark 1999]. However, among women treated for cervical cancer, there was a higher level 
of distress due to the reduced desire and more frequent reporting of reduced vaginal lubrication, 
which was significantly more distressing than that experienced in the control group. More women 
in the treatment group had reduced genital swelling, and reduced vaginal length, and these changes 
were more distressing for the cancer group than for non-cancer controls. The authors attributed 
these changes to reduced estrogen supply. These findings suggest that whereas sexual symptoms 
and overall sexual frequency may not be affected, women’s perceptions of their sexuality may be 
and therefore result in significant sexual distress. This finding (of no change in sexual symptoms 
despite changes in sexual distress) is a common feature in the sexual dysfunction literature and 
provides the impetus for our focus on sexual distress as a study endpoint [Hayes 2008]. 
 
In another study, conducted in Denmark, 173 women with early-stage cervical cancer who had 
been treated with radical hysterectomy and pelvic lymphadenectomy were compared with a control 
sample (n = 328) recruited from the general Danish population [Jensen 2004]. Questionnaires were 
completed at symmetric time intervals consistent with 5-weeks and 3, 6, 12, 18, and 24 months 
following surgery. Lack of sexual interest and lack of lubrication were common in the first 2 years 
among survivors, as were severe dyspareunia in the first 3 postoperative months and severe orgasm 
problems and reduced vaginal size interfering with intercourse ability for the first 6 postoperative 
months. There were psychological symptoms including anxiety over sexual activity and 
dissatisfaction with appearance after sex. After one year, one-third of survivors continued to report 
reduced sexual interest, vaginal lubrication, and vaginal dimensions as compared with the control 
group.  

 
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Nerve-sparing techniques as part of radical hysterectomy involve identification and preservation of 
the hypogastric nerve, the inferior hypogastric plexus within the parametrium and the most distal 
part of the inferior hypogastric plexus. A Dutch study compared nerve-sparing radical hysterectomy 
with conventional radical hysterectomy using endpoints of genital sexual arousal as measured by a 
vaginal photoplethysmograph [Pieterse 2008]. Women were recruited following surgery provided no 
chemotherapy or radiation therapy had been administered. The report included 13 women in the 
conventional radical hysterectomy group, 10 in the nerve-sparing hysterectomy group and a control 
sample of 14 women without sexual difficulties recruited from the community. Genital arousal (as 
assessed with a vaginal photoplethysmograph) was significantly lower in the conventional radical 
hysterectomy group as compared with each of the other groups. The authors attributed differences 
to fewer autonomic nerve fibres in the vascular smooth muscle of the vagina of women treated with 
conventional radical hysterectomy.  
 
Maas and colleagues tested the hypothesis that damage to pelvic autonomic nerves during radical 
hysterectomy leads to interference with genital arousal response and can be detected using vaginal 
photoplethysmography during sexual stimulation [Maas 2004]; this research included 12 
premenopausal women treated for cervical cancer with radical hysterectomy, 12 premenopausal 
women treated with simple hysterectomy for benign reasons (e.g. uterine fibroids), and 17 age-
matched healthy controls. Women who had undergone radical hysterectomy had a significantly 
lower maximum genital arousal response; those treated by simple hysterectomy did not differ from 
the controls. No differences in strongest subjective sexual arousal were detected between any of 
the groups.  
 
Some studies show fewer significant differences in sexual functioning between groups of women 
who have received radical versus simple hysterectomy. A prospective comparison of 20 women 
with stage IB cervical cancer treated with radical hysterectomy who did not receive radiotherapy 
or chemotherapy and 18 women treated for benign conditions with simple hysterectomy included 
evaluations performed preoperatively and 4 and 8 months postoperatively; women in the benign 
group showed steady improvements in all areas of sexual functioning, whereas women with 
cervical cancer showed a trend towards deteriorating sexual functioning. The authors attributed 
deterioration to reduced estrogen supply and to autonomic nerve damage [Grumann 2001]. Moreover, 
in both groups, all women resumed sexual intercourse by the end of the follow-up period, with no 
significant differences between the groups on this measure.  
 
In another trial comparing women with early-stage cervical cancer treated with radiation therapy 
alone (n = 37), radical hysterectomy alone (n = 37), and a no-cancer control group (n = 40), failed 
to detect differences in 7-yr post-treatment scores of psychological functioning as assessed by the 
Brief Symptom Inventory and Global Severity Index [Frumovitz 2005]. No differences were observed 
between the surgery and control groups in menopausal symptoms; women receiving radiotherapy 
had significantly more menopausal symptoms. Women receiving radiotherapy had significantly 
worse scores for sexual arousal, lubrication, orgasmic ability, and level of satisfaction, with no 
group differences between the women receiving surgery only and the control group.  

 
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Taken together, this literature suggests that while hysterectomy for benign conditions is associated 
with few long-term adverse sexual outcomes, most studies of radical hysterectomy for cervical 
cancer demonstrate negative outcomes, particularly for genital arousal and sexual distress. Nerve-
sparing techniques appear to attenuate some of these effects. To date, there has been no clear, 
prospective, systematic study comparing radical versus simple hysterectomy for early-stage 
cervical cancer that addresses sexual endpoints given that prior studies compared cancer versus no-
cancer samples and these groups differ significantly in terms of diagnosis and treatment-related 
implications for sexual functioning, not the least of which is postoperative adjuvant treatment, 
symptoms of cancer before treatment, and the psychological impact of cancer and its treatment. 
Ours, therefore, represents the first study to directly compare women with cancer receiving standard 
versus less invasive surgery on sexual and quality of life outcomes. 
 
2.5.3 
Summary of Quality of Life – Related Hypotheses  
 
Given that evidence of fewer side effects with a less radical procedure may drive women’s 
decisions for treatment, examination of these symptom domains is considered to be of major 
importance in this trial. We will, therefore, explore three key hypotheses regarding these 
QoL/sexual health secondary endpoints:  
 
Hypothesis 1: We hypothesize that both groups will experience an increase in bowel and bladder 
side effects, but that the impact of treatment will be of lesser magnitude, on average, in women 
managed with simple hysterectomy relative to the radical hysterectomy group. This hypothesis will 
be tested by using outcomes on the QLQ-CX24 QOL module of the EORTC QLQ-C30 instrument 
(see below).  
 
Hypothesis 2: We hypothesize that both groups will have an increase in sexual distress, (as 
measured by the Female Sexual Distress Scale-Revised, FSDS-R), and that the radical 
hysterectomy group will show a greater increase relative to the simple hysterectomy group.  
 
Hypothesis 3: We hypothesize that both groups will show a decrease in overall sexual function (as 
measured by the Female Sexual Function Index, FSFI, Total Score), and that the radical 
hysterectomy group will show a greater decrease relative to the simple hysterectomy group. 
 
Exploratory hypotheses: We hypothesize that most domains of the FSFI (e.g. desire, arousal, 
lubrication, orgasm, pain, satisfaction) will decrease in both surgery groups, and that the radical 
hysterectomy group will show a greater decrease relative to the simple hysterectomy group. 
 
2.5.4 
Quality of Life Instruments  
 
The relative impact of surgery on pelvic symptoms will be evaluated with the 24-item Cervical 
Cancer Module (EORTC QLQ-CX24), which has three multi-item subscales: Symptom 
Experience, Body Image, and Sexual/Vaginal functioning, and five single items pertaining to 
menopausal symptoms, lymphedema, lower back pain, tingling and numbness, and sexual 
enjoyment. Higher scores correspond to worse symptoms except for items 49 and 54. Specifically, 
we will focus on the Symptom Experience subscale, which includes items pertaining to difficulty 
with bowel, bladder, and vaginal symptoms, and items can be analyzed separately. The QLQ-CX24 
discriminates well between patient subgroups on the basis of treatment modality as well as stage of 
disease and is available in a variety of languages [Greimel 2006]. Cronbach’s alpha ranges from 0.72-
0.87 for the multi-item domains. 

 
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In addition to this module, the core questionnaire, the EORTC QLQ-C30, will be administered. 
This is a well validated 30-item questionnaire consisting of five function scales (physical, role, 
emotional, cognitive, and social), three symptom scales (fatigue, nausea/emesis, and pain), six 
single-items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), along with a global QoL score [Aaronson 1993]. Higher scores on the functioning domains 
and the overall QoL domain correspond with better functioning whereas higher scores on the 
symptom domains correspond with poorer functioning. During validation studies, over 80% of 
women were able to complete the EORTC QLQ-C30 and QLQ-CX24 in less than 15 minutes. For 
estimation of effect sizes in this trial, we will use the data from the validation study of the QLQ-
CX24 cited in Greimel [Greimel 2006]. Although a minimal important difference has not been 
established for this specific module, we will use 7 points (1/2 a standard deviation unit) as an 
indicator of meaningful clinical difference, as has been done in comparable studies [Norman 2003; 
Sloan 2006]. 
 
Sexual distress is what motivates individuals to seek treatment for sexual difficulties. Given this, 
and given the finding that changes in genital sensations/arousal are considered to be the primary 
source of symptom-associated distress following surgical treatment of cervical cancer, sexual 
distress will be considered our primary outcome and overall sexual functioning as a secondary 
outcome within the sexual health analyses [Bergmark 2002].  
 
The FSFI [Rosen 2000] is a validated measure of sexual desire, orgasm, lubrication, pain, and 
satisfaction widely available in a variety of languages. It is a 19-item self-report measure of female 
sexual function that provides scores on six domains of sexual function as well as a total score. 
Domains include: Desire (2 items), Arousal (4 items), Lubrication (4 items), Orgasm (3 items), 
Satisfaction (3 items), and Pain (3 items). Items are scored on a 5-point Likert scale with higher 
scores corresponding with better sexual functioning. The FSFI has been shown to reliably 
discriminate women with Female Sexual Arousal Disorder from sexually-healthy controls on each 
of the six domains of sexual function as well as the Full Scale score [Rosen 2000]. The FSFI was 
found to be internally consistent (Cronbach’s alpha ranged between 0.82 and 0.98;) and test-retest 
reliabilities using a 4-week interval ranged between r = 0.79 and 0.86 [Rosen 2000].  
 
The FSDS-R [Derogatis 2002, Dergogatis, 2008] is a 13-item measure of sexually-related distress 
available in English and French. Items are scored on a 5-point Likert scale. Scores range from 0 – 
48, where higher scores represent higher levels of sexual distress. The FSDS-R has been shown to 
have good discriminant validity for differentiating between sexually dysfunctional and sexually 
functional women [Derogatis 2002, Dergogatis, 2008]. There is also satisfactory consistency, test-retest 
reliability, and moderate correlations with measures of nonsexual distress.  

 
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Table 1:  
Quality Of Life Instruments (in addition to the Global Quality of Life instrument 
EORTC QLQ-C30) 
 
Instrument 
Estimated 
mean 
baseline 
Estimated 
change with 
simple hyst. 
Estimated 
change with 
radical hyst. 
Difference we 
wish to test for 
(delta) i.e. the 
differential 
between arms 
Estimated pooled std 
deviation of the 
scores 
EORTC CX.24 
symptom 
subscale 
3 
+3 
(mean score 6) 
+10 (mean 
score 13) 
7 
13.5 
FSDS-R total 
score 
22* 
+5 
+10 
5 
10 
FSFI Total Score 
33.3* 
-5 
-10** (mean 
score 23) 
5 
21 
*  
Brotto, 2008 
** 
Serati, 2009 
 
2.6 
Evaluation of Other Adverse Events 
 
Evaluation of other adverse events will follow standard CCTG policies and will be graded using 
the Common Terminology Criteria for Adverse Events (CTCAE) (Appendix V). Thus, adverse 
events that are patient-reported, detected by medical examination or are laboratory / imaging 
abnormalities will be included. The CTCAE v 4.0 entities that relate to surgical morbidities will be 
emphasized in the CX.5 analysis.  
 
2.7 
Health-Related Economic Evaluation 
 
2.7.1 
Health Economics 
 
The topic of health economics is important to cancer patients, health care providers, policy makers, 
and society, as it evaluates the value of an intervention. Value is determined by examining the costs 
and benefits associated with an intervention and its management and can consider the benefits of 
prolongation of survival and/or QoL. Determining economic values is of relevance in CX.5, as they 
represent important secondary endpoints that may be policy drivers if non-inferiority of the primary 
and secondary endpoints related to efficacy is established. In comparison with radical 
hysterectomy, simple hysterectomy is hypothesized to be associated with less peri-operative 
morbidity, including hospital length-of-stay, transfusion requirements etc., and fewer and less 
severe long-term adverse effects, which may translate into improved survivorship. The economic 
analyses will compare the incremental costs and benefits associated with providing simple vs. 
radical hysterectomy both with respect to cost-effectiveness and cost-utility. Economic evaluations 
will be assessed from the public payer perspective and selective societal aspects will be measured 
as well. 

 
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2.7.2  Costing and Cost-Effectiveness  
 
The health economic evaluation will be completed using standard CCTG economic-related case 
report forms and source documentation for each subject in Canada, the United Kingdom and other 
countries where assessment is feasible. Health care resource utilization related to the study 
intervention will be documented including supportive care medications, laboratory tests, imaging 
studies, radiotherapy, transfusions, hospitalization, and outpatient care, including physician, 
emergency room and home care visits will be documented. Resource utilization will be measured 
at baseline and at predetermined intervals on both arms of the study. Costs will be presented in 
Canadian currency in 2011 dollars. Unit costs will be applied to resource utilization to determine 
the cost per resource. Unit costs will be obtained from standard sources including provincial 
sources, literature and others. Effectiveness will be presented as pelvic relapse-free life expectancy 
in years and quality-adjusted life expectancy. 
 
2.7.3  Cost-Utility 
 
Health-related utility scores value preference for a health state on a scale with 0 and 1 representing 
death and perfect health respectively. Quality-adjusted life years (QALY) are derived by combining 
the utility score with the time period for the health state. The QALY is a common outcome 
measuring effectiveness in health economics since reimbursement decisions must consider how 
allocation of health resources affects the population as a whole. In particular, the cost-effectiveness 
of an intervention can be compared across different diseases and conditions with the QALY.  
 
Utility scores can be obtained indirectly through generic multi-attribute QoL instruments such as 
the EQ-5D or Health Utilities Index. Preference weights are available for these instruments to 
convert the QoL variables into a utility score. Quality of life instruments may be disease specific 
or generic in nature. Generic instruments may be applied to all diseases, facilitating comparisons 
of quality of life across different populations. Instruments that focus on disease-specific aspects of 
quality of life may be able to detect smaller changes in aspects of QoL that are specific to the patient 
population evaluated. However, the QoL attributes measured may not be applicable for all diseases. 
 
The EQ-5D is a validated generic QoL measure [EurolQoL 1990]. The descriptive system consisting 
of five health dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety 
depression. Patients are asked to choose one point that best describes their current health state for 
each dimension from a three-point Likert scale. The scale is commonly coded as 1, 2, or 3 where 1 
represents no problems, 2 represents some problems, and 3 represents extreme problems. Patients 
are also asked to rate their current health state on a 20 cm vertical feeling thermometer or visual 
analogue scale (VAS) on the second page. The VAS is anchored by 0 (worst imaginable health 
state) and 100 (best imaginable health state). 
 
An index or utility score can be derived from the descriptive system based on preference weights 
[Dolan 1997; Shaw 2005]. Health states, based on the 5 domains, are linked to a single utility score 
with 0 and 1 representing death and perfect health, respectively. Five health domains on a three-
point scale results in a total of 243 possible health states. In extreme cases, a negative utility score 
representing a health state worse than death may be assigned.  
 

 
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2.7.4 
Summary of Health Economic – Related Hypotheses 
 
Given that simple hysterectomy may be associated with fewer short and long-term side effects, 
superior QoL and health-related utility scores may be associated with this procedure and may drive 
women’s decisions for treatment. Furthermore, it is possible that simple hysterectomy will be 
associated with use of fewer health care resources in the immediate postoperative period, including 
reduced hospital length of stay and need for management of postoperative complications. The 
economic hypotheses tested will thus include:  
 
Hypothesis 1: We hypothesize that, in comparison with radical hysterectomy, health care-related 
resource utilization will be less in the simple hysterectomy group, as there will be fewer immediate 
postoperative and long-term management requirements. If non-inferiority of the primary and 
secondary efficacy outcomes is established, benefits resulting from a reduction in health care 
resource utilization will be associated with a favourable incremental cost-effectiveness ratio (cost 
per life-year gained). 
 
Hypothesis 2: Building upon hypothesis #1, we further hypothesize that simple hysterectomy will 
be associated with fewer long-term adverse events and improved survivorship, and will thus be 
associated with superior health-related utility scores, resulting in an acceptable incremental cost-
utility ratio (cost per quality adjusted life year gained).  
 
2.8 
Processes for Surgical Quality Control 
 
While this trial is designed to be pragmatic in nature and to test “real-world” practices, there is a 
need for assurances that the CX.5 results are robust and represent a true comparison of the two 
surgical approaches. Several processes are thus included in the CX.5 trial to facilitate this 
evaluation, including: 
 
Description of Surgical Requirements: The surgical interventions, including the requirements that 
limit the extent of a simple hysterectomy and more extensive requirements of a radical 
hysterectomy, are detailed in Section 8.1 and the Surgery/Pathology Manual. 
 
Systematic Pathologic Evaluation: Tissue removed at surgery is to undergo a standardized 
pathologic review process as described in the Surgery/Pathology Manual, with findings recorded 
in a standardized manner using a pathology checklist, as indicated in the Surgery/Pathology 
Manual. The data from the pathology checklist will be entered into the trial’s database and 
evaluated using standardized processes. 
 
Photographs of the Pathology Specimen: The gross pathology specimen will be photographed, as 
described in the Surgery/Pathology Manual. These photographs, along with the pathology 
checklist, will be reviewed by the CX.5 Study Chair to determine that the allocated surgical 
procedure was performed. 

 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
The CX.5 trial compares radical and simple hysterectomy as therapy for patients with early stage 
cervical cancer. Details of the surgical procedures are described in Section 8.0 and in the Surgery 
Pathology Manual. 

 
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4.0 
TRIAL DESIGN 
 
This is a randomized, non-blinded, multicenter, international phase III Gynecologic Cancer 
Intergroup (GCIG) trial coordinated by the Canadian Cancer Trials Group.  
 
4.1 
Stratification 
 
Patients will be stratified by: 
1. Cooperative Group 
2. Intended use of sentinel node mapping (yes vs. no) 
3. Stage (IA2 vs. IB1) 
4. Histological type (squamous vs. adenocarcinoma/adenosquamous) 
5. Grade (1-2 vs. 3 vs. not assessable) 
 
4.2 
Randomization 
 
Patients will be randomized (in a 1:1 ratio) to one of the following two arms:  
 
Arm 
Treatment Strategy 
Arm 1 
Radical hysterectomy with pelvic node dissection  
Arm 2 
Simple hysterectomy with pelvic node dissection 
 
The planned sample size is 700. 
 
All patients will be followed until death or trial completion.  
 
4.3 
Inclusion of Minorities 
 
There are no exclusions based on race or ethnicity in this trial. 
 
To date, there is no evidence of superiority of one form of treatment over another according to 
racial or ethnic group. The appropriate racial/ethnic mix will be recruited to this study based on the 
epidemiology of cervix cancer in the participating centres. 

 
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5.0 
STUDY POPULATION 
 
This study will recruit patients with previously untreated, histologically confirmed, low-risk early-
stage invasive cervical cancer. Patients will be approached based on the following criteria: 
1. Clinical examination of the cervix AND local pathology review of the loop electrosurgical 
excision procedure (LEEP), cone or biopsy specimen. 
2. Staging assignment to IA2 or modified IB1 is according to the 2009 FIGO system (Appendix 
III). 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed prior to performing the randomization. 
 
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. For the safety of the patients, as well as 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. 
 
Patients must fulfil all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Histologically confirmed adenocarcinoma, squamous, or adenosquamous cancer of the cervix. 
Diagnosis has been made by LEEP, cone or cervical biopsy and has been reviewed and confirmed 
by the local reference gynecological pathologist. 
 
5.1.2 
Patient has been classified as low-risk early-stage cervical cancer. These patients include:  
• 
FIGO Stage IA2 [FIGO Annual Report, 2009], defined as: 
o evidence of disease by microscopy;  
– 
for patients who underwent a LEEP or cone:  
 histologic evidence of depth of stromal invasion > 3.0 and < 5.0 mm based on the 
local reference pathologist’s measurement of the LEEP or cone specimen; 
 histologic evidence of lateral extension that is < 7.0 mm based on the local reference 
pathologist’s measurement of the LEEP or cone specimen; and  
 negative margins  (patients with positive margins are considered IB1, see below) 
– 
for patients who underwent a cervical biopsy only: 
 radiologic evidence of less than 50% stromal invasion based on pelvic MRI  
 
• 
FIGO Stage IB1 [FIGO Annual Report, 2009] with favourable (low risk) features, defined as: 
o measured stromal invasion and lateral extension that meet the criteria for IA2 (see above) 
but with positive margins; 
o evidence of disease by clinical exam; lesion must clinically measure ≤ 20 mm 
o evidence of disease by microscopy;  
– 
for patients who underwent a LEEP or cone:  
 histologic evidence of depth of stromal invasion between 5.1-10 mm and/or lateral 
extension between 7.1-20.0 mm based on the local reference pathologist’s 
measurement of the LEEP or cone specimen NB: the maximum depth of stromal 
invasion must be ≤ 10 mm. 

 
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- 
for patients who underwent a cervical biopsy only: 
 radiologic evidence of less than 50% stromal invasion based on pelvic MRI  
 lateral extension ≤ 20 mm based on clinical exam or radiologic imaging 
 
In addition to above criteria on maximal stromal invasion of ≤ 10 mm, the lesion must be no larger 
than 20 mm in any dimension by any assessment method (MRI, clinical or histological exam). 
To ensure patients meet this criterion, investigators may need to sum the lesion measurements from 
biopsy and other methods that evaluate it in the same plane. For questions on eligibility with respect 
to this criterion please contact CCTG before randomization. 
 
Patients are eligible irrespective of the presence or absence of lymph-vascular space involvement 
(LVSI).  
 
5.1.3 
Physical examination, recto-vaginal examination and visualization of the cervix by speculum or 
colposcopic examination have been done after the initial diagnostic procedure (LEEP, cone or 
biopsy) and prior to randomization. Staging criteria described in 5.1.2 must be satisfied based on 
these examinations.  
 
5.1.4 
Chest x-ray or CT scan of chest AND pelvic MRI* done after initial diagnostic procedure (LEEP, 
cone or biopsy) and prior to randomization. Staging criteria described in 5.1.2 must be satisfied 
based on these examinations. 
 
The CT should be a 16 slice (or higher) helical scanner. Oral and intravenous contrasts are preferred 
(unless there is a contraindication to the use of contrast) with scan obtained in the portal phase at a 
slice thickness of 5mm or lower 
 
Pelvic MRI should be performed on a 1.5 or 3 Tesla magnet with pelvic phased-array coils. The 
MR pulse sequences will consist of T1 gradient echo in the axial plane at 5 mm slice thickness and 
fast spin echo in the axial, sagittal, and coronal planes at 4 mm slice thickness. The short axis 
(perpendicular to the tumour’s long axis) with a 3 mm slice thickness is required in the best plane 
to show the maximum thickness of stromal invasion. Use of an anti-peristaltic agent is mandatory 
while intravenous use of gadolinium or diffusion-weighted imaging (DWI) is optional. 
 
*  Note: pelvic MRI is optional if the patient has stage IA2 disease and underwent a LEEP or 
cone. 
 
5.1.5 
After consideration of a patient’s medical history, physical examination and laboratory testing, 
patients must be suitable candidates for surgery as defined by the attending physician / investigator. 
 
5.1.6 
Patients must have no desire to preserve fertility. 
 

 
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5.1.7 
Patients fluent in English or French must be willing to complete the Quality of Life Questionnaire. 
The baseline assessments must be completed within 6 weeks prior to randomization. Inability 
(illiteracy in English or French, loss of sight, or other equivalent reason) 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. As additional GCIG groups join the 
study, more translations of some of the questionnaires may be added.  
 
Patients fluent in English or French who reside in Canada and the United Kingdom must agree to 
participate in the economic evaluation component of this trial and complete the Health Economics 
Questionnaire. Similarly, patients fluent in English or French accrued from other GCIG groups who 
are participating in the economic evaluation must be willing to complete the Health Economics 
Questionnaires. 
 
5.1.8 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrolment in the trial to document 
their willingness to participate.  
 
5.1.9 
Patients must be accessible for treatment and follow-up. Investigators must assure themselves the 
patients randomized on this trial will be available for complete documentation of the treatment, 
adverse events, and follow-up. 
 
5.1.10 Surgery is to be done within 20 weeks of initial diagnosis (NO EXCEPTIONS). The 20-week 
period includes time required for diagnosis, referral, diagnostic staging, randomization and 
scheduling of the surgical procedure. 
 
5.1.11 Patients must be ≥ 18 years old. 
 
 
5.2 
Ineligibility Criteria 
 
Patients who fulfil any of the following criteria are not eligible for admission to the study. 
 
5.2.1 
Patients with FIGO 1A1 disease [FIGO Annual Report, 2009]. 
 
5.2.2 
History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively 
treated in-situ cancer of the cervix, or other solid tumours, Hodgkin’s lymphoma or non-Hodgkin’s 
lymphoma curatively treated with no evidence of disease for > 5 years. 
 
5.2.3 
Patients with evidence of lymph node metastasis on preoperative imaging or histology. 
 
5.2.4 
Patients who have had or will receive neoadjuvant chemotherapy. 
 
5.2.5 
Patients who are pregnant. 
 
5.2.6 
Patients for whom adjuvant radiation and/or chemotherapy is planned. 

 
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6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations/Activity 
Timing 
Diagnostic Procedure 
• LEEP, cone or biopsy1 
Prior to randomization 
History and Physical 
Exam including 
• recto-vaginal examination with speculum or 
colposcopy2 
• medical, surgical and obstetrical history 
• co-morbidities 
• performance status 
• height and weight 
• tobacco smoking history 
After diagnostic procedure 
and within 12 weeks of 
randomization 
Other Investigations 
• pregnancy test 3 
Prior to randomization 
Adverse Events 4  
• baseline adverse events evaluation 
Within 14 days prior to 
randomization 
Radiology 
• chest x-ray or chest CT scan 
• pelvic MRI 5 – see Section 5.1.5 for specific 
requirements of MRI 
After diagnostic procedure 
and prior to randomization 
Patient Reported 
Outcomes 
• Quality of Life questionnaire  
(composed of the QLQ-C30, QLQ-CX24)  
• Sexual Health questionnaire  
(composed of the FSDS-R and the FSFI) 6 
• Health Economics questionnaire  
(composed of the HUI3 and EQ-5D) 7  
Within 6 weeks prior to 
randomization. 
1. 
The initial diagnostic specimen must be reviewed by the Local Reference Pathologist (LRP) per the criteria outlined in the 
Surgery/Pathology manual (see LEEP/cone/biopsy checklist). 
2. 
A recto-vaginal examination is preferred but not mandatory. A bimanual exam is also acceptable. 
3. 
A pregnancy test is only required for women of childbearing potential. This test can be a serum test or a urine test. 
4. 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0 (Appendix V). 
5. 
Pelvic MRI is not required for patients with stage IA2 disease who underwent a LEEP or cone.  
6. 
For patients who consented to this optional study component. 
7. 
Mandatory for English and French speaking patients from Canada, the UK and France. 

 
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7.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All randomizations 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/randomizing patients will be provided at the time of study activation and will also be 
included in the “EDC Data Management Guidebook”, posted on the CX.5 trial specific web-site. 
If sites experience difficulties accessing the system and/or randomizing patients please contact the 
help desk (link in EDC) or the CX.5 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 at the time of study entry: 
• trial code (CCTG CX.5) 
• investigator CCTG user ID 
• patient's initials (may be coded)  
• informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
• stratification factors  
 
7.2 
Stratification 
 
Subjects will be stratified by: 
1. Cooperative Group 
2. Intended use of sentinel node mapping (yes vs. no) 
3. Stage (IA2 vs. IB1) 
4. Histological type (squamous vs. adenocarcinoma/adenosquamous) 
5. Grade (1-2, vs. 3 vs. not assessable) 
 
7.3 
Randomization 
 
Randomization will be given by the CCTG website. 
 
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. 
 
All 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 randomization. 
 
All randomized patients are to be followed until death or trial closure. The follow-up requirements 
for ineligible patients are submission of the Form 1 eligibility checklist and initial evaluation form 
plus minimal follow-up using a Form 5M.  

 
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8.0 
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. Specific details related 
to trial conduct by each participating GCIG group are included in the Group-Specific Appendix 
provided by each Group.  
 
After randomization, protocol-assigned surgery must take place within 8 weeks.  
 
Regardless of when the patient is randomized, protocol surgery must be performed within 20 weeks 
of the date of the initial pathologic diagnosis (NO EXCEPTIONS). A schema of the treatment plan 
is shown below. 
 
The decision regarding the use of SN lymph node mapping must be made at the time of 
randomization. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Regardless of treatment assignment, surgery will include pelvic lymph node dissection with optional sentinel lymph node (SN) 
mapping. If SN mapping is to be done, the mode is optional, but the laparoscopic approach is preferred. 
Eligible patients  
(see Section 5.0) 
Randomization 
Continue with protocol mandated follow-up (see Section 9.0) 
Any additional treatment is given at the investigator’s discretion per local practice 
Additional disease identified: 
intra-operative findings of 
positive lymph nodes and/or 
extrauterine spread 
(frozen section analysis is not permitted) 
Lymph nodes 
negative and no 
evidence of 
disease spread 
Lymph nodes 
negative and no 
evidence of 
disease spread 
Lymph Node 
Dissection 
Lymph Node 
Dissection 
Radical Hysterectomy 
Simple Hysterectomy 
Arm 1 (Control) 
Radical hysterectomy &  
PLND +/- SLN mapping* 
Arm 2 (Experimental) 
Simple hysterectomy &  
PLND +/- SLN mapping* 
Sentinel Node 
Mapping Not 
Performed
Sentinel Node 
Mapping 
Performed
Sentinel Node 
Mapping 
Performed
Sentinel Node 
Mapping Not 
Performed

 
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8.1 
Hysterectomy Procedure 
 
Patients meeting the entry criteria will be randomized prior to surgery to either undergo a radical 
hysterectomy and bilateral pelvic node dissection or simple hysterectomy and bilateral pelvic node 
dissection. It is understood that both types of hysterectomy are to be performed by a trained 
gynecologic oncologist.  
 
All patients entered on this study are expected to undergo their assigned treatment as per the details 
below. In some cases, obvious evidence of lymph node involvement or extrauterine spread may be 
detected during surgery. If this occurs, then protocol-mandated surgery may be abandoned (see 
section 8.2.4 for further details). 
 
All patients should be managed with prophylactic antibiotics and anticoagulants pre and post-
operatively as per local institutional standards.  
 
Arm 1 - Radical Hysterectomy (Type 2) 
 
This procedure may be performed abdominally, laparoscopically, robotically or vaginally. The 
uterus, cervix, medial 1/3 of parametria, 2 cm of the uterosacral ligaments and upper 1-2 cm of the 
vagina are to be removed en bloc. The uterine artery is ligated laterally to the ureters and the ureters 
are unroofed to the ureterovesical junction. 
 
Arm 2 – Simple Hysterectomy (Extrafascial Hysterectomy) 
 
This procedure may be performed abdominally, laparoscopically, robotically or vaginally. 
Extrafascial hysterectomy involves removal of the uterus with cervix without adjacent parametria. 
The uterine arteries are transected medial to the ureters at the level of the isthmus and the 
uterosacral ligaments are transected at the level of the cervix. Surgeons should pay special attention 
to make sure that the whole cervix is removed. As such, a maximum 0.5 cm of vaginal cuff can be 
removed to ensure the complete removal of the cervix. 
 
8.2 
Lymphadenectomy and Sentinel Node Mapping 
 
Protocol therapy on both treatment arms will include pelvic lymph node dissection. Centres may 
choose to perform sentinel node mapping for some or all of their CX.5 patients if that is part of 
their usual practice. For centers not performing sentinel node mapping, a complete pelvic node 
dissection is considered protocol therapy. All the nodes are submitted for routine pathological 
analysis as per the Surgery/Pathology Manual. Frozen section analyses of sentinel nodes are not 
permitted for this trial unless the node is visually suggestive of metastatic spread.  
 
8.2.1 
Pelvic Lymphadenectomy 
 
This procedure can be performed by open or laparoscopic technique. Bilateral skeletonization is to 
be performed with removal of all lymph node tissue from lower half of common iliac vessels, 
external iliac vessels, internal iliac vessels and the obturator fossa. The anatomic boundaries are to 
include the lower half of the common iliac artery proximally, the deep circumflex iliac vein distally, 
the mid portion of the psoas muscle laterally, to the ureters medially and above the obturator nerve 
in the obturator fossa inferiorly. 
 
Following the complete bilateral pelvic node dissection, the nodes are submitted for routine 
pathological analysis as per the Surgery/Pathology Manual. 

 
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8.2.2 
Sentinel Node (SN) Mapping 
 
Only experienced surgeons are permitted to perform sentinel node biopsies as part of this trial. To 
be eligible for this procedure, individual surgeons will be required to have successfully performed 
at least 10 previous SN procedures in cervix or endometrial cancer patients. Following the surgery, 
a quality assurance exercise will be conducted in the first 5 CX.5 patients treated by each surgeon. 
Please see section 13.3.2 for full details regarding this quality assurance exercise. 
 
Investigators must identify whether sentinel node mapping will be performed prior to enrolling 
the patient in the trial. The SN mapping should be preferably done by laparoscopy and excised 
SNs are to be submitted for ultrastaging on final pathology (serial sectioning and 
immunohistochemistry) as per the Surgery/Pathology Manual. Additional details of the SN 
mapping technique are outlined in the Surgery/Pathology Manual. 
 
8.2.3 
Management of Patients with Intra-operative Findings of More Advanced Stages of Cervical 
Cancer  
 
If lymph node metastasis and/or other extrauterine spread are identified during surgery, patients 
should be offered additional management according to local policy.  
 
8.2.4 
Para-aortic Lymphadenectomy 
 
This procedure can be performed by an open or laparoscopic technique. The right sided para-aortic 
lymphadenectomy will involve removal of all lymph node tissue anterior to the inferior vena cava 
below the level of the inferior mesenteric artery proximally and to the upper half of the common 
iliac artery distally. The left sided para-aortic lymphadenectomy will involve removal of all lymph 
node tissue between the aorta and left ureters from the level of the inferior mesenteric artery 
proximally to the upper half the left common iliac artery. 
 
8.3  
Principles of Adjuvant Treatment 
 
The decision as to whether participants will require radiation-based adjuvant therapy following 
hysterectomy will be made by the treating physician per local policy. If required, adjuvant therapy 
is to be administered according to institutional treatment policies and will be recorded on trial case 
report forms. 
 
8.4 
Concomitant Therapy 
 
8.4.1 
Permitted 
 
Patients may utilize any non-anti-cancer therapies. Use of over-the-counter and complementary 
therapies is permitted. Complementary therapies should be disclosed to the investigator during the 
period of time during which the patient is receiving protocol treatment.  
 
8.4.2 
Not Permitted 
 
Other recognized anticancer therapies (e.g. other chemotherapy, biologic therapies) are not 
permitted as part of protocol therapy. 

 
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9.0 
EVALUATION AFTER PROTOCOL AND NON-PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. The schedule for 
evaluation after protocol commences as follows: 
 
1.  Patients completing simple or radical hysterectomy as per-protocol: the “end of treatment date” 
is considered the date of surgery.  
 
2.  Patients who do not undergo a hysterectomy:  the “end of treatment” is considered the date that 
the decision was made not to have surgery, or the date of the surgical attempt (if applicable). 
 
Patients are to be seen 4-6 weeks after the end of treatment (as defined above) and then again at 3 
months after the end of protocol treatment. After this, the visits are q3 monthly for year one, q4 
monthly for year two, q6 monthly for year three then q12 months until death or trial completion. 
At follow up patients will be assessed for local pelvic disease, extra pelvic relapse, and for treatment 
morbidity. Data collected at each post-treatment follow-up after the end of treatment will include 
documentation of adverse effects of surgery, status of disease and details of any new post protocol 
anticancer treatments delivered.  
 
Patients agreeing to inclusion in the Quality of Life and Sexual Health components will complete 
questionnaires at 3 months, 6 months, 12 months, 24 months, 36 months from end of treatment and 
at disease recurrence. Patients from Canada, the UK and France agreeing to inclusion in the Health 
Economics component will complete questionnaires at each follow-up visit from the end of 
treatment (until disease recurrence) and at the time of disease recurrence. Additional evaluations 
required at these visits include general performance status, patient weight and Resource Utilization 
Assessment. 

 
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9.1 
Evaluation After Completion of Protocol Therapy 
 
The information below is captured using the Follow-Up Report. 
 
Investigations 
Timing from the End of Treatment until 
first disease recurrence or study closure 
(see definition in Section 9.0) 
Physical Exam 
including: 
• performance status 
• weight 
• tobacco smoking status  
Year One – 41 and 12 weeks then q 3 
monthly 
Year Two – q 4 monthly 
Year Three – q 6 monthly 
Then q 12 months. 
Pelvic exam 
• recto-vaginal examination with 
speculum or colposcopy2  
Year One – q 3 monthly 
Year Two – q 4 monthly 
Year Three – q 6 monthly 
Then q 12 months. 
Radiology 
• CT scan of abdomen and pelvis 
• chest radiograph 
As clinically indicated 
Adverse 
Events3 
• Patients must be evaluated for related 
adverse events at each follow-up visit.  
Year One – 41 and 12 weeks then q 3 
monthly 
Year Two – q 4 monthly 
Year Three – q 6 monthly 
Then q 12 months. 
Resource 
Utilization 
Assessment 
(RUA) 
• Supportive care medications, 
laboratory tests, imaging studies, 
radiotherapy, transfusions, 
hospitalization, and outpatient care, 
including physician, emergency room 
and home care visits4.  
Year One – 41 and 12 weeks then q 3 
monthly 
Year Two – q 4 monthly 
Year Three – q 6 monthly 
Then q 12 months. 
Patient 
Reported 
Outcomes 
• Quality of Life questionnaire  
(composed of the QLQ-C30, QLQ-
CX24) 
• Sexual Health questionnaire  
(composed of the FSDS-R and the 
FSFI)4  
At 3 months, 6 months, 12 months, 24 
months, 36 months and at first disease 
recurrence (if applicable). 
• Health Economics questionnaire  
(composed of the HUI3 and EQ-5D) 5 
Year One – 41 and 12 weeks then q 3 
monthly 
Year Two – q 4 monthly 
Year Three – q 6 monthly 
Then q 12 months until study closure and 
at first disease recurrence (if applicable). 
1. This visit may be done up to 6 weeks after surgery. 
2. A recto-vaginal examination is preferred but not mandatory. A bimanual exam is also acceptable. 
3. Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 (Appendix V). Only AEs deemed possibly, probably, or definitely related to 
protocol therapy need to be reported. 
4. For patients who consented to this optional study component and/or select GCIG groups . 
5. Mandatory for English and French speaking patients from Canada, the UK and select GCIG groups. 
 

 
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9.2  
Evaluation After Recurrence 
 
 
Investigations 
Evaluations after pelvic and/or extra pelvic recurrence  
Timing from the date of first 
recurrence 
(see Section10.3) 
Physical Exam 
including: 
• performance status 
• weight 
• tobacco smoking status 
At the time of first recurrence* AND 
Years One to Three – q 6 monthly 
Then q 12 months until study closure. 
Pelvic Exam 
• recto-vaginal examination with 
speculum or colposcopy** 
Radiology 
• CT or MRI scan of abdomen and pelvis 
• chest radiograph 
If clinically indicated 
Adverse 
Events*** 
• Patients must be evaluated for related 
adverse events at each follow-up visit.  
Years One to Three – q 6 monthly 
Then q 12 months until study closure. 
* 
A full “work-up” for pelvic recurrence is required at the time extra-pelvic recurrence is diagnosed. 
** A recto-vaginal examination is preferred but not mandatory. A bimanual exam is also acceptable. 
*** Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 (Appendix V). Only AEs deemed possibly, probably, or definitely related to 
protocol therapy need to be reported. 
 

 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
As relapse-free survival is an important endpoint in this study, it is vital that it be adequately and 
precisely documented. 
 
10.1 
Definitions 
 
The major parameters of outcome are pelvic recurrence rate at 3 years, pelvic and extra-pelvic 
relapse-free survival and overall survival.  
 
10.1.1 Pelvic recurrence rate at 3 years is defined as a probability of pelvic recurrence within 3 years 
from randomization  A pelvic recurrence is defined as a recurrence within the pelvis, below the 
pelvic brim and inferior to the L4-L5 vertebral level. Pelvic recurrences will include disease 
recurrence in the vaginal vault, parametrium and pelvic lymph nodes (including the common iliac 
nodes). 
 
10.1.2 Pelvic Relapse-Free Survival is defined as the date from randomization to the date of first 
documented reappearance (recurrence) of disease provided that this recurrence is in the pelvis.  
 
10.1.3 Extra-Pelvic Relapse-Free Survival is defined as the date from randomization to the date of first 
documented reappearance (recurrence) of disease provided that this recurrence is outside of the 
pelvis. An extra-pelvic recurrence is defined as a recurrence outside of the pelvis, including above 
the pelvic brim and/or superior to the L4-L5 vertebral level. Extra-pelvic recurrences will include 
the para-aortic lymph nodes.  
 
10.1.4 Recurrence is defined as new clinical, imaging or cellular/tissue-based specimen evidence of 
cervical cancer since study entry.  
 
10.1.5 Site of First Recurrence (i.e. para-aortic or supraclavicular lymph nodes, lung, liver, bone, etc.) will 
be documented.  
 
10.1.6 Overall Survival is defined as the time from randomization until death from any cause. For living 
patients, the date corresponding to the most recent date of patient contact (regardless of whether 
this date is protocol required) will be used.  

 
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10.2 
Evidence of Disease Recurrence 
 
Evidence of disease recurrence may be based on clinical, imaging or cellular/tissue based specimen 
evidence. Ideally, recurrence is based on a cellular or tissue – based analysis. In specific 
circumstances, imaging tests may provide compelling evidence of disease recurrence and the 
subsequent management of the patient is based on these results. Rarely, clinical findings 
unsupported by a specimen-based analysis or definitive imaging are considered to show sufficient 
evidence of disease recurrence. For the CX.5 protocol, the following policies for determining 
evidence of disease recurrence will apply: 
 
i)  Cellular/tissue-based specimen evidence: Histologic evidence is considered the gold standard 
for disease recurrence. When a histologic sample has not been obtained, but there are definitive 
cytologic findings of recurrent cervical cancer, the patient will be considered to have recurrent 
cervical cancer based on the results of a specimen analysis. 
 
ii)  Imaging based evidence: Imaging-based evidence will be considered sufficient for a diagnosis 
of recurrent cervical cancer if these findings are considered unequivocal OR are subsequently 
supported by specimen-based evidence. 
 
iii)  Clinical evidence: Clinical-based evidence will be considered sufficient for a diagnosis of 
recurrent cervical cancer if this evidence is unequivocal (e.g. speculum/colposcopic 
visualization; a palpable mass) AND is subsequently supported by specimen-based evidence 
OR unequivocal imaging evidence. When clinical evidence is supported by imaging findings 
that are considered sufficient to justify recommencing therapy for cervical cancer, the imaging 
findings will be judged as providing unequivocal evidence of recurrent cervical cancer. 
 
10.3 
Dating of First Recurrence 
 
This should always be based on the onset of a sign but never on the onset of a symptom. The date 
of first detection of a palpable and/or visible lesion is acceptable only when these findings are 
unequivocal and a diagnosis of tumour involvement is subsequently established by pathological or 
radiologic confirmation. The diagnosis of recurrent disease by radiographs or scans alone should 
be dated from the date of the first unequivocally positive record, even if this is determined in 
retrospect. Initial recording of dates of first recurrence and death should be made as they occur by 
those who are responsible for the care of the patient. Dates that are based on suspicion alone without 
unequivocal evidence will be reviewed by the CCTG trial team to establish their accuracy through 
subsequent behaviour. In addition, the case records of those patients not reported as having 
recurrent disease will be scrutinized regularly to check that review is continuing and to ensure 
consistent recording. 
 
10.4 
Management Following Recurrence 
 
Patient management following recurrence is at the discretion of the investigator. Protocol follow-
up should continue until trial completion.  

 
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11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
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 V). 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 
toCCTG.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events which are unexpected and related to protocol treatment (as defined 
in Section 8) must be reported in an expedited manner (see Section 11.2 for reporting 
instructions). These include events occurring during protocol treatment and at any time afterwards. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
known complications. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol treatment cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that: 
− 
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. 
 
11.2 
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 CX.5 section of the CCTG website (www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 

 
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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: 
 
CX5 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
Note: Centres outside of Canada are asked to please refer to their group-specific appendix for 
additional, detailed instructions regarding SAE reporting. 
 
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 CX.5 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).  
 
11.3 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and relevant information from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to theCCTG. 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 CX.5 web-based safety monitoring utility. 
 
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. 
The date of REB Submission for these SAEs will need to be entered into the CCTG trial CX.5 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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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
Patients may not receive protocol treatment (as defined in Section 8) in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree. 
• 
Request by the patient. 
 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if 
patients do not undergo surgery and/or no longer attend the participating institution. 
 
12.1 
Therapy After Protocol Treatment 
 
The management of patients who complete protocol treatment (or who never undergo protocol 
treatment) is left to the discretion of the Investigator. The visit schedule for those patients who 
receive other anti-cancer therapy should not be modified as endpoints will be assessed for as long 
as the patient can be followed and an intent-to-treat analysis will be performed. 
 
12.2 
Follow-Up After Protocol Treatment 
 
Follow-up will continue after treatment completion to monitor patients for study endpoints. 
Participants should be followed by in-person clinic visits to the greatest extent possible. Follow-up 
assessment by telephone or other remote method is allowed, if permitted by local policy, only in 
emergency situations (refer to Appendix VIII) or for participants who have permanently ceased 
follow-up at the recruiting centre but are not lost to follow up. In the latter circumstance, the 
recruiting centre will remain responsible for procuring and reporting follow-up data per protocol 
schedule. The recruiting centre should document the reason why in-person follow-up visits are 
unable to continue at their centre and how relevant study data will be obtained for future follow up 
periods. 
 
12.3 
Lost to Follow Up  
 
Participants will only be declared lost to follow up (LTFU) if there has been a minimum of 3 
unsuccessful contact attempts documented over 2 or more years after the last date of successful 
contact. Required methods of contact include contacting the participant by telephone and searching 
relevant medical records, if permitted by local site policy. All participant contact attempts must be 
clearly documented in the patient’s medical record. 
 

 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Review of Diagnostic Imaging and Quality Assurance Procedure 
 
There will be no up-front central radiology review for this study. De-identified MRI scans may be 
collected by CCTG and reviewed by the CX.5 Radiology Coordinator should the need arise. It is 
recommended that each site designate a Local Reference Radiologist (LRR) who will be 
responsible for reviewing the pre-study MRIs for all CX.5 patients; however, this is not mandatory. 
The description of the MRI specifications outlined in section 5.1.5 was designed to facilitate and 
standardize the diagnostic imaging for this trial. 
 
13.2  
Pathology Quality Assurance 
 
Each CCTG participating centre will identify one Local Reference Pathologist (LRP) who is the 
designated gynecologic pathologist (on the Participants List). For non CCTG centres, this process 
will be described in your cooperative group procedures document. 
 
The LRP will be responsible for reviewing: 
1. The diagnostic pathology specimen for all study patients to confirm their eligibility for the trial. 
The LEEP/Cone/Biopsy Checklist that is part of the Surgery/Pathology Manual was designed 
to facilitate and standardize this review. 
2. The post-surgical hysterectomy and lymphadenectomy/sentinel node specimens. The 
Hysterectomy Checklist that is part of the Surgery/Pathology Manual was designed to facilitate 
and standardize this review. 
3. The specimen that diagnoses disease recurrence.  
Note: CCTG may require that any or all of the abovementioned specimens be submitted for central 
pathology review (see section 13.4) 
 
13.3 
Surgical Quality Assurance Procedure 
 
13.3.1 Hysterectomy 
 
A photograph of the “unpinned” hysterectomy (modified radical or simple) specimen will be 
submitted as part of the supporting documentation required for the Surgery Report. The CX.5 Study 
Chair will review these pictures along with other supporting documentation as part of the surgical 
quality assurance process. Please see the Surgery/Pathology manual for submission details. 
 
13.3.2 Sentinel Node Mapping Procedure 
 
It is understood that patients will undergo surgery performed by a trained gynecologic oncologist. 
Prior to local activation, the site must declare: 
1. Whether or not they will be employing sentinel node mapping for their CX.5 patients.  
2. Whether each gynecologic oncology surgeon listed on the Participants List has treated at least 
10 cervical and/or endometrial cancer patients using the SN mapping technique per the 
standards outlined in the protocol and this manual. 
 
Then, the first 5 cases for each qualified surgeon performing sentinel node mapping as part of the 
CX.5 trial must undergo a quality assurance exercise. This exercise will consist of the following 
steps: 
 
Centre completes all required case report forms (baseline report and surgery form) and 

 
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submits the required supporting documentation (de-identified operative and pathology reports)  
Note: this is required for ALL patients randomized to CX.5 
 
Centre provides a de-identified photograph of the preoperative lymphoscintigram and  
de-identified photographs of the detection of blue sentinel nodes bilaterally.  
Please see the Surgery/Pathology manual for submission details. 
Note: this is required for the first 5 patients who undergo SN mapping per surgeon. If 
lymphoscinitgram is not routinely done at the institution, please contactCCTG. 
 
CCTG sends a summary of the CRFs, copies of the operative and pathology reports  
and the SN photographs to the appropriate reviewer. 
 
The reviewer communicates back to CCTG about the status of the review and  
CCTG then provides the site with the reviewer’s comments.  
This may require several iterations before the review is complete. 
 
After all 5 cases are reviewed and considered satisfactory,  
the quality assurance exercise is complete. 
Note: it is recommended that this exercise is completed as soon as possible following each surgery so 
that important feedback may be communicated back to the surgeon before another patient undergoes 
protocol treatment. It is not expected that this exercise will delay a potential randomization or a 
patient’s surgery; unless under exceptional circumstances. 
 
13.4 
Central Pathology Review 
 
There will be no up-front central pathology review for this study; however, tissue samples from 
procedures that show disease recurrence may be collected for central review by the CX.5 trial 
Pathology Coordinator should the need arise. 
 

 
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14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
The primary objective of this study is to compare the pelvic recurrence rate at 3 years of patients 
with low-risk cervical cancer defined as lesions less than 2 cm, at least 3mm of intact cervical 
stroma or with less than 50% stromal invasion and randomized to receive simple hysterectomy and 
pelvic node dissection or radical hysterectomy and pelvic node dissection. Secondary objectives 
include comparisons of pelvic relapse-free survival, overall survival, extra pelvic relapse-free 
survival, rate of sentinel node detection, rate of parametrial, margins and pelvic nodes involvement, 
treatment-related adverse events, and quality of life (including sexual health). Eligible patients will 
be randomized in a 1:1 ratio to one of the two treatment arms using the minimization method and 
the following stratification factors: cooperative group, intended use of SN mapping (yes vs. no); 
stage (IA2 vs. IB1), histological type (squamous vs. adenocarcinoma, adenosquamous) and tumour 
grade (1-2 vs. 3 vs. not assessable).  
 
14.2 
Primary Endpoints and Analysis 
 
Pelvic recurrence rate at 3 years, the primary endpoint of this study, will be estimated by the 
Kaplan-Meier estimate for the 1-probability of pelvic relapse-free survival (PRFS) at 3 years, where 
the PRFS is defined as the time from randomization to the time when any documented evidence of 
recurrence within the pelvic field (see Sections 10.0-10.3). Patients who relapsed outside of the 
pelvic field or died before the documentation of pelvic relapse will be censored at the time of first 
documented extra pelvic relapse or death. If the patient is alive without any relapse at the time of 
final analysis, PRFS will be censored on the date of the last disease assessment. All patients will 
be included in the analyses in the arms to which they are randomized regardless of whether they 
receive the assigned treatment (intention-to-treat). Upper limit of a one-sided 95% confidence 
interval for the difference in the pelvic recurrence rates at 3 years between simple hysterectomy to 
radical hysterectomy will be calculated based on the Greenwood estimate for the variance of the 
estimated 3 year PRFS and non-inferiority of simple hysterectomy to radical hysterectomy will be 
claimed when this upper limit is lower than or equal to 4%. A “per-protocol” sensitivity analysis 
based on only eligible patients who have received any study treatment and analyzed based on arms 
they are treated will also be performed for non-inferiority testing. 
 
The experience of PRFS, a secondary endpoint of the study, will be described by the Kaplan-Meier 
method for all randomized patients in both treatment groups on the base of intention-to-treat. Based 
on Jung et al. (sample size computation for two-sample non-inferiority log-rank test, [Jung, 2005]), 
non-inferiority of simple hysterectomy to radical hysterectomy will be claimed when the upper 
limit of a one-sided 95% confidence interval for the hazard ratio of simple hysterectomy to radical 
hysterectomy, derived from a stratified Cox model adjusting for stratification factors at 
randomization and with a single treatment covariate, is lower than or equal to 2.04. The non-
inferiority margin 2.04 for hazard ratio is corresponding to a margin of 4% for the 3 year PRFS 
between simple hysterectomy and radical hysterectomy when the 3-year PRFS in radical 
hysterectomy was estimated at 96%. A “per-protocol” sensitivity analysis will also be performed.  
 
Other secondary efficacy endpoints include (1) overall survival, defined as time from 
randomization to the time of death from any cause. Patients who are alive at the time of the final 
analysis or who have become lost to follow-up will be censored at their last contact date; and (2) 
extra pelvic relapse-free survival free survival, defined as time from randomization to the time of 
first documented relapse outside the pelvic field. Patients who had pelvic relapse or died before 
extra pelvic relapse will be censored at time of pelvic relapse or death. Patients who are alive 
without any recurrent disease at the time of the final analysis will be censored at their last disease 

 
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assessment dates. Analyses for these secondary efficacy endpoints will be done using similar 
methodology for PRFS. For the rest of the secondary endpoints, the rate of sentinel node detection 
and rate of parametrial, margins and pelvic nodes involvement, they will be compared between two 
arms using a Fisher’s exact test. 

 
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All patients who have received study treatment will be included in the adverse events analysis based 
on arms they are treated. Adverse events will be graded using the NCI Common Toxicity Criteria 
Version 4.0. The incidence of adverse events will be summarized by type of adverse event and 
severity. A Fisher’s exact test will be used as needed to compare adverse events between the two 
arms. 
 
14.3 
Sample Size and Duration of Study 
 
It is estimated that the pelvic recurrence rate at 3 years for the radical hysterectomy is around 4% 
and we would consider simple hysterectomy is non-inferior to radical hysterectomy if its pelvic 
recurrence rate at 3 years is 8% orless, With 350 patient randomized to each of the two treatment 
arms, the study will have around 85% power to conclude the non-inferiority at 0.05 level when the 
pelvic recurrence rate at 3 years is the same in the two arms. Final analysis will be performed when 
the last patient randomized has been followed for 3 years. 
 
14.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by Central Office. Their frequencies will be 
reported annually at investigators' meetings. In addition adverse events will be reviewed by the 
DSMC every 6 months and also by the Safety Conference Committee according to CCTG policy. 
As well, the annual report will include number of cases in each arm with positive nodes (abandoned 
protocol treatment). 
 
14.5 
Interim Analysis 
 
No interim analysis will be performed. 
 

 
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14.6 
Analysis for Quality of Life 
 
The quality of life and sexual health of patients in this study will be assessed by respectively 
EORTC QLQ-C30 core questionnaire with its module QLQ-CX24, the Female Sexual Function 
Index (FSFI), and the Female Sexual Distress Scale (FSDS-R). The EORTC QLQ-C30 and QLQ-
CX24 are self-administered cancer specific questionnaires with multi-dimensional scales. QLQ-
C30 consists of both multi-item scales and single item measures, including five functional domains, 
a global quality of life domain, three symptom domains, and six single items, while QLQ-CX24 
has three multi-item subscales: symptom experience, body Image, and sexual/vaginal functioning, 
and five single items pertaining to menopausal symptoms, lymphedema, lower back pain, tingling 
and numbness, and sexual enjoyment. FSFI is a 19-item self-report measure of female sexual 
function that provides scores on six domains of sexual function (desire, arousal, lubrication, 
orgasm, satisfaction, and pain) as well as a total score. The FSDS-R is a 13-item unidimensional 
measure of sexually-related distress. Scoring of the quality of life and sexual health data will be 
completed following the procedures recommended by the EORTC Study Group on Quality of Life 
and other published algorithms.  
 
The quality of life and sexual health data will be analyzed to look for statistically and clinically 
significant differences between two treatment arms. Questionnaire compliance rates will first be 
ascertained for each group at each measurement time point. Mean scores at baseline and the change 
scores from baseline at each follow-up assessment time point will be calculated for each subscale 
and summary scores and compared between two arms by Wilcoxon test. The profile of change 
scores over time between two treatment arms will be compared using linear mixed models.  
 
The basic hypotheses in QOL and sexual health data analysis are, on average, women managed 
with simple hysterectomy had lower change scores from baseline on QLQ-CX24 symptom subscale 
and FSDS-R total score and higher change scores from baseline on FSFI total score relative to 
women in the radical hysterectomy group. Based on estimates of pooled standard deviations of 
13.5, 10 and 21 respectively for change scores on QLQ-CX24 symptom subscale and FSDS-R and 
FSDS-R total score, we need respectively a total of 120, 130 and 560 women with QOL and sexual 
health assessments to detect respectively 7, 5, 5 points difference between two treatment arms with 
80% power and two-sided 0.05 level in these subscale and scores.  
 
14.7 
Economic Analysis 
 
Cost-effectiveness and cost-utility analyses will be performed based on respectively cost per life-
year gained and cost per quality adjusted life year gained. The mean and standard deviation of cost-
effectiveness and cost-utility ratio will be calculated and the bootstrap method will be used to derive 
the confidence intervals. 

 
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15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc 
 
15.1.1 The results of this study will be published. Normally, authorship includes the naming of individual 
authors. As per CCTG authorship policies, publication of the final analysis of the primary outcome 
includes: 
• 
The first author will generally be the chair of the study. 
• 
The second author will normally be the CCTG Senior Investigator and the last (Senior) author 
will be the CCTG Gynecology Committee Chair. The CCTG Authorship policy indicates 
criteria that must be satisfied by the Disease Site Committee Chair in order to be recognized as 
Senior Author. When the time frame and duration of a study preclude the Site Chair from 
meeting these criteria, the CCTG Senior Investigator will normally be the senior Author.  
• 
The CCTG Senior Biostatistician will normally be the second last (Co-senior) author. 
• 
Additional authors, as allowed by journal policies, 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. Normally, these authors will include those investigators forming the CCTG 
Trial Committee. 
• 
Each participating centre is to identify a reference pathologist. The reference pathologists are 
considered contributing investigators and will be identified as individuals in relevant 
publications. Typically such recognition is placed within an appendix, including 
supplementary online appendices. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
• 
In the event of a separate paper dealing with the economic outcomes, the first author will 
generally be the Committee on Economic Analysis liaison on the trial committee. 
 
For Intergroup trials, such as CX.5, a member of a cooperative group that has contributed at least 
5% to the total accrual will be included. An additional member from that group will be included 
for each additional increase of 10% to the total accrual (i.e. 2 authors for > 15%, 3 authors for 
> 25%, etc.). Each cooperative group will be asked to identify the author(s) to be named. 
 
For separate papers dealing with secondary endpoints, the first author will generally be the CCTG 
investigator named as responsible for that endpoint (e.g. QoL, economics, etc.). For subset 
analyses, the first author will be assigned on a prospective basis in a manner consistent withCCTG’s 
policies, which state: “The nature of a cooperative group requires that collaborations be nurtured. 
The most prestigious of authorship positions (First Author, Senior Author) must therefore be 
appropriately distributed among the individuals eligible for these positions across the reports 
associated with a project. Similarly, positions of Other Contributing Authors should be distributed 
to account for contributions to a project, including trial accrual.” These principles include the 
recognition of investigators based with collaborating cooperative groups.  

 
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15.1.2 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)." 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write a manuscript describing 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 CCTG Central Office reserves 
the right to make other arrangements to ensure timely publication. 
 
15.2.1 Dissemination of Trial Results 
 
CCTGwill 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). 
 
15.3 
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. 
Supporting groups and agencies will be acknowledged. 

 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
All institutions outside of Canada should refer to their group-specific appendix for additional 
instructions regarding regulatory requirements. 
 
16.2 
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 isCCTG’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 enrolment 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.  

 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in an CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
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 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.  
 
For institutions outside of Canada, please refer to your group-specific appendix for additional 
detailed instructions regarding informed consent. 
 
16.4 
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 theCCTG), 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. 

 
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16.5 
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. 
 
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.  
 
For international participating regions, local regulatory guidance should be followed with respect 
to duration of records retention, unless otherwise contractually dictated. 
 
16.6 
Centre Performance Monitoring 
 
For CCTG centres, this study is eligible for inclusion in the CTTG Centre Performance Index (CPI). 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at CCTG 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). 
Other GCIG groups are to follow their Standard Operating Procedures for on-site monitoring. 
 
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.  
 
For institutions outside of Canada, please refer to your group-specific appendix for additional 
details regarding on-site monitoring. 

 
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16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, is to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except 
the QoL questionnaires. For details of accessing the EDC system and completing the on-line Case 
Report Forms please refer to the “Randomization and Data Management Guidebook” posted on the 
CX.5 area of the CCTG web-site (www.ctg.queensu.ca). 
 

 
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17.0 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Pre-
random-
ization 
4-6 weeks after the end 
of treatment 
After end of treatment - q 3 
months for year one, q 4 
months for year 2, q 6 months 
for year 3, then annually 
After Recurrence1 
Physical 
 
 
 
 
Height 
X 
 
 
 
Weight 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
Medical, surgical and 
obstetrical history 
X 
 
 
 
Co-morbidities 
X 
 
 
 
Tobacco smoking history 
X 
X 
X 
X 
Pelvic Exam: Recto-vaginal 
examination with speculum or 
colposcopy 2 
X 
 
X 
X3 
Radiology 
 
 
 
 
Chest CT or Chest X-Ray 
X 
As clinically indicated 
Abdominal/Pelvic CT 
 
Pelvic MRI 
X4 
Other Investigations 
 
 
 
 
LEEP/Cone biopsy 
X 
 
 
 
Pregnancy Test 
X5 
 
 
 
Adverse Events 
 
 
 
 
Adverse Events 
X 
X6 
X6 
X6 
Quality of Life 
 
 
 
 
Quality of Life questionnaire 
(composed of the QLQ-C30, 
QLQ-CX24) 
Sexual Health questionnaire 
(composed of the FSDS-R and  
the FSFI)7 
X 
 
X8 
 
Economic Analysis9 
 
 
 
 
Health Economics 
questionnaire (composed of the 
HUI3 and EQ-5D) 
X 
 
X10 
 
Resource Utilization 
Assessment 
 
X 
X 
 
1. This column also applies to those patients who do not receive protocol therapy (i.e. do not undergo a radical or simple 
hysterectomy). 
2. A recto-vaginal examination is preferred but not mandatory. A bimanual exam is also acceptable. 
3. For patients whose 1st recurrence is extra-pelvic recurrence, a pelvic exam is mandatory until pelvic recurrence is seen. 
4. Pelvic MRI is not required for patients with stage IA2 disease who underwent a LEEP or cone. 
5. Pregnancy test may be repeated again prior to surgery as per local policy. 
6. Only AEs deemed possibly, probably, or definitely related to protocol therapy need to be reported. 
7. For patients who consented to this optional study component. 
8. Quality of Life and Sexual Health questionnaires are required at month 3, 6, 12, 24 and 36 and first disease recurrence 
9. For patients in Canada, the UK and France only. 
10. Health Economics questionnaire is also due at the time of first disease recurrence.  

 
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APPENDIX II - 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 III - 2009 FIGO NOMENCLATURE 
 
Table 1: Carcinoma of the cervix uteri: FIGO nomenclature (2009) 
 
Stage I  
The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded).  
IA  
Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion < 5 
mm and largest extension < 7 mm.  
IA1  
Measured stromal invasion of ≤ 3.0 mm in depth and horizontal extension of < 7.0 mm. 
IA2  
Measured stromal invasion of > 3.0 mm and not > 5.0 mm with a lateral extension of not > 7.0 
mm.  
IB  
Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage 
IA. * 
IB1  
Clinically visible lesion < 4.0 cm in greatest dimension.** 
IB2  
Clinically visible lesion > 4.0 cm in greatest dimension.  
Stage II  
Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third 
of the vagina.  
IIA  
Without parametrial invasion but extension to the upper two thirds of the vagina.  
IIA1  
Clinically visible lesion < 4.0 cm in greatest dimension. 
IIA2 
Clinically visible lesion > 4.0 cm in greatest dimension. 
IIB  
With obvious palpable parametrial invasion.  
Stage III  
The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes 
hydronephrosis or non-functioning kidney.  
IIIA  
Tumour involves lower third of the vagina, with no extension to the pelvic wall.  
IIIB  
Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney. 
Stage IV  
The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa 
of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to 
Stage IV.  
IVA  
Spread of the growth to adjacent organs.  
IVB  
Spread to distant organs. 
*  All macroscopically visible lesions – even with superficial invasion – are allotted to stage IB carcinomas. The involvement of 
vascular / lymphatic spaces should not change the stage allotment.  
** For the purposes of the CX.5 trial, “low-risk” IB1 lesions must be ≤ 10mm in stromal invasion and must be ≤ 20mm in 
maximum dimension. 

 
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APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization and will apply to all eligible patients.  
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except the 
quality of life questionnaire, sexual health questionnaire and the health economics questionnaire. 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 CX.5 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 
Required 
To be completed 
electronically 
De-Identified Supporting Documentation 
Required1 
Eligibility Checklist Prior to randomization 
At the time of randomization  
Baseline Report 
Prior to protocol surgery 
Within 6 weeks after 
randomization 
• Consent form signature pages (Canadian 
patients only) 
• Copies of pathology reports (from initial 
diagnosis and LRP review) and radiology 
reports2 
• PROs3 
LEEP/cone/biopsy 
Checklist 
Surgery Report 
4-6 weeks after protocol 
surgery 
Within 8 weeks after surgery 
• Operative report 
• Pathology report 
• Photograph of hysterectomy specimen for 
surgical QA4 
• Lymphocintogram and photographs for SN 
mapping QA5 
Adjuvant Therapy 
Report 
Upon the completion of 
adjuvant therapy 
Within 8 weeks after the 
completion of adjuvant 
therapy 
-- 
Follow-Up Report 
Year One – q 3 monthly6 
Year Two – q 4 monthly 
Year Three – q 6 monthly 
Then q 12 months until 
study closure.7 
Within 8 weeks of the visit 
date 
• Pelvic exam notes 
• Radiology reports (if done) 
• Pathology/cytology/surgical reports (if done) 
• PROs3 
Recurrence Report 
At the time of first pelvic 
and/or extra-pelvic disease 
recurrence 
Within 8 weeks of the date 
of recurrence 
• Pelvic exam notes 
• Radiology reports (if done) 
• Pathology/cytology/surgical reports (if done) 
• PROs3 
Short Follow-up 
Report 
q 6 monthly from the date 
of the most recent 
recurrence 
Within 8 weeks of the visit 
date 
• Pelvic exam notes (if done) 
• Radiology reports (if done) 
• Pathology/cytology/surgical reports (if done) 
Death Report 
At the time of patient death Within 8 weeks of patient 
death 
Autopsy report (if done) 
SAE Report8 
At the time of the event 
See section 11.0 
 
1.  Supporting Documentation should be uploaded into the EDC system Supporting Document Upload Tool after the eCRF has been submitted 
electronically.  
2. Original diagnostic specimen and/or MRI images may be requested for central review purposes (see Section 13). 
3. Patient Reported Outcomes (QoL, Sexual Health, Health Economics) for applicable patients should be uploaded into the EDC system Supporting 
Document Upload Tool after the eCRF has been submitted electronically. 
4. See Section 13 and the Surgery/Pathology manual for full details. 
5. For sites performing SN mapping (see Section 13 and the Surgery/Pathology manual). 
6. The reporting period for the first Follow-Up Report will start from the date of the 4-6 week post-surgery visit and collect data up until the date of 
the first follow-up visit. 
7. Calculated from the date of protocol surgery.  
8. See section 11.0 Serious Adverse Event Reporting for details. 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
CCTG TRIAL: CX.5 
 
 
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APPENDIX VI - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
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 questionnaire. 
 
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. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or 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. 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
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2. Pretreatment 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, et cetera. 
 
The 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 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, she 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. 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. 
 
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. 
 
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 her that the questionnaire was not completed. Ask the 
patient if she 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. 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
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61 
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If this is not feasible, then ask the patient if she 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 she is 
not literate in either English or French (or other languages that the questionnaire may be available in). 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 or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then she is NOT eligible and should NOT 
be put on study. 
 
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. 
 

 
 
Quality of Life Questionnaire – ENGLISH 
 
CCTG Trial: CX.5 
 
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 (3) 
 Prior to randomization 
 At the time of first recurrence 
 
After surgery prior to recurrence: 
 3 months 
 6 months 
 12 months  
 24 months 
 36 months 
 Other ______________________ (specify) 
 
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: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
Page 1 of 5 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (C) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 EORTC QLQ-C30 
Page 2 of 5 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5. EORTC QLQ-C30 
Page 3 of 5 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
 
 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 EORTC QLQ-CX24 
Page 4 of 5 
Please go on to the next page 
EORTC QLQ-CX24 QUESTIONNAIRE 
 
Patients sometimes report that they have the following symptoms. Please indicate the extent to which 
you have experienced these symptoms or problems, please answer by circling the number that best 
applies to you. 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. Have you had cramps in your abdomen? 
1 
2 
3 
4 
 
 
 
 
 
32. Have you had difficulty in controlling your bowels? 
1 
2 
3 
4 
 
 
 
 
 
33. Have you had blood in your stools (motions)? 
1 
2 
3 
4 
 
 
 
 
 
34. Did you pass water/urine frequently? 
1 
2 
3 
4 
 
 
 
 
 
35. Have you had pain or a burning feeling when urinating? 
1 
2 
3 
4 
 
 
 
 
 
36. Have you had leaking of urine? 
1 
2 
3 
4 
 
 
 
 
 
37. Have you had difficulty emptying your bladder? 
1 
2 
3 
4 
 
 
 
 
 
38. Have you had swelling in one or both legs? 
1 
2 
3 
4 
 
 
 
 
 
39. Have you had pain in your lower back? 
1 
2 
3 
4 
 
 
 
 
 
40. Have you had tingling or numbness in your hands or 
feet? 
1 
2 
3 
4 
 
 
 
 
 
41. Have you had irritation or soreness in your vagina or 
vulva? 
1 
2 
3 
4 
 
 
 
 
 
42. Have you had discharge from your vagina? 
1 
2 
3 
4 
 
 
 
 
 
43. Have you had abnormal bleeding from your vagina? 
1 
2 
3 
4 
 
 
 
 
 
44. Have you had hot flushes and/or sweats? 
1 
2 
3 
4 
 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 EORTC QLQ-CX24 
Page 5 of 5 
 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
45. Have you felt physically less attractive as a result 
 
of your disease or treatment? 
1 
2 
3 
4 
 
 
 
 
 
46. Have you felt less feminine as a result 
 
of your disease or treatment? 
1 
2 
3 
4 
 
 
 
 
 
47. Have you felt dissatisfied with your body? 
1 
2 
3 
4 
 
During the past 4 weeks: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
48. Have you worried that sex would be painful? 
1 
2 
3 
4 
 
 
 
 
 
49. Have you been sexually active? 
1 
2 
3 
4 
 
Answer the following questions only if you have been  
sexually active during the past 4 weeks: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
50. Has your vagina felt dry during sexual activity? 
1 
2 
3 
4 
 
 
 
 
 
51. Has your vagina felt short? 
1 
2 
3 
4 
 
 
 
 
 
52. Has your vagina felt tight? 
1 
2 
3 
4 
 
 
 
 
 
53. Have you felt pain during sexual intercourse or any other 
sexual activity? 
1 
2 
3 
4 
 
 
 
 
 
54. Was sexual activity enjoyable to you? 
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. 

 
 
Sexual Health Questionnaire (FSDS-R & FSFI) – ENGLISH 
 
CCTG Trial: CX.5 
 
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 (3) 
 Prior to randomization 
 At the time of first recurrence 
 
After surgery prior to recurrence: 
 3 months 
 6 months 
 12 months  
 24 months 
 36 months 
 Other ______________________ (specify) 
 
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: ____ ____ ____ 
 
NCIC CTG Trial CX.5 FSDS-R Questionnaire 
Page 1 of 5  
Please go on to the next page 
 
FSDS-R QUESTIONNAIRE - FEMALE SEXUAL DISTRESS SCALE-Revised  
CCTG CX.5 
 
INSTRUCTIONS 
 
Below is a list of feelings and problems that women sometimes have concerning their sexuality. Please read each item 
carefully, and circle the number that best describes HOW OFTEN THAT PROBLEM HAS BOTHERED YOU OR CAUSED 
YOU DISTRESS DURING THE PAST 30 DAYS INCLUDING TODAY*. Circle only one number for each item, and take 
care not to skip any items. If you change your mind, erase your first circle carefully. Read the example before beginning, and 
if you have any questions please ask about them. 
 
* AT BASELINE ONLY: If there has been a period of no sexual activity (whether with a partner or on your own) 
because of a recent medical procedure, please complete this with the most recent 4-week period that did include sexual 
activity. 
 
 
Example: How often did you feel: Personal responsibility for your sexual problems. 
 
 
NEVER 
RARELY 
OCCASIONALLY 
FREQUENTLY 
ALWAYS 
 
0 
1 
2 
3 
4 
 
 
 
 
HOW OFTEN DID YOU FEEL: 
NEVER 
RARELY 
OCCASIONALLY 
FREQUENTLY 
ALWAYS 
1. 
Distressed about your sex life 
 
0 
1 
2 
3 
4 
2. 
Unhappy about your sexual relationship 
0 
1 
2 
3 
4 
3. 
Guilty about sexual difficulties 
0 
1 
2 
3 
4 
4. 
Frustrated by your sexual problems 
0 
1 
2 
3 
4 
5. 
Stressed about sex 
0 
1 
2 
3 
4 
6. 
Inferior because of sexual problems 
0 
1 
2 
3 
4 
7. 
Worried about sex 
0 
1 
2 
3 
4 
8. 
Sexually inadequate 
0 
1 
2 
3 
4 
9. 
Regrets about your sexuality 
0 
1 
2 
3 
4 
10. Embarrassed about sexual problems 
0 
1 
2 
3 
4 
11. Dissatisfied with your sex life 
0 
1 
2 
3 
4 
12. Angry about your sex life 
0 
1 
2 
3 
4 
13. Bothered by low sexual desire 
0 
1 
2 
3 
4 
 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5. FSFI Questionnaire 
Page 2 of 5 
Please go on to the next page 
FSFI QUESTIONNAIRE - CCTG CX.5 
Female Sexual Function Index (FSFI) © 
 
These questions ask about your sexual feelings and responses during the past 4 weeks. Please answer the 
following questions as honestly and clearly as possible using the scale to the right. Your responses will be kept 
completely confidential. If you choose not to answer a particular question, please proceed to the next question.  
 
 
In answering these questions, the following definitions apply: 
 
Sexual activity can include caressing, foreplay, masturbation, and vaginal intercourse. 
 
Sexual intercourse is defined as penile penetration (entry) of the vagina. 
 
Sexual stimulation includes situations like foreplay with a partner, self-stimulation (masturbation), or sexual 
fantasy. 
 
Sexual desire or interest is a feeling that includes wanting to have a sexual experience, feeling receptive to a 
partner’s sexual initiation, and thinking or fantasizing about having sex. 
 
Sexual arousal is a feeling that includes both physical and mental aspects of sexual excitement. It may include 
feelings of warmth or tingling in the genitals, lubrication (wetness), or muscle contractions. 
 
 
Circle only one item per question. 
Question 
Response options (please circle) 
1. 
Over the past 4 weeks, how satisfied have you been with your 
overall sexual life? 
5  = Very satisfied 
4  = Moderately satisfied 
3  = About equally satisfied & dissatisfied 
2  = Moderately dissatisfied 
1  = Very dissatisfied 
2. 
Over the past 4 weeks, how often did you feel sexual desire or 
interest? 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 
3. 
Over the past 4 weeks, how would you rate your level (degree) of 
sexual desire or interest? 
5  = Very high 
4  = High 
3  = Moderate 
2  = Low 
1  = Very low or none at all 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5. FSFI Questionnaire 
Page 3 of 5 
Please go on to the next page 
Question 
Response options (please circle) 
4. 
Over the past 4 weeks, did you engage in sexual activity of any 
kind with a partner and/or by yourself (masturbation)? 
0   = No sexual activity (neither with a 
partner nor by myself) 
1   = Sexual activity with a partner only 
1   = Sexual activity by myself only 
1   = Sexual activity both with a partner  
and by myself 
If you selected “0 = No sexual activity (neither with a partner nor by myself)”, please skip remaining 
questions on this questionnaire. If you selected any other response, please continue. 
5. 
Over the past 4 weeks, how often did you feel sexually aroused 
(“turned on”) during sexual activity or intercourse? 
X  = No sexual activity 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 
6. 
Over the past 4 weeks, how would you rate your level of sexual 
arousal (“turned on”) during sexual activity or intercourse? 
X  = No sexual activity 
5  = Very high 
4  = High 
3  = Moderate 
2  = Low 
1  = Very low or none at all 
7. 
Over the past 4 weeks how confident were you about becoming 
sexually aroused during sexual activity or intercourse? 
X  = No sexual activity 
5  = Very high confidence 
4  = High confidence 
3  = Moderate confidence 
2  = Low confidence 
1  = Very low or no confidence 
8. 
Over the past 4 weeks, how often have you been satisfied with 
your sexual arousal (excitement) during sexual activity or 
intercourse? 
X  = No sexual activity 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 
9. 
Over the past 4 weeks, how often did you become lubricated 
(“wet”) during sexual activity or intercourse? 
X  = No sexual activity 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5. FSFI Questionnaire 
Page 4 of 5 
Please go on to the next page 
Question 
Response options (please circle) 
10. Over the past 4 weeks, how difficult was it for you to become 
lubricated (“wet”) during sexual activity or intercourse? 
X  = No sexual activity 
1  = Extremely difficult or impossible 
2  = Very difficult 
3  = Difficult 
4  = Slightly difficult 
5  = Not difficult 
11 
Over the past 4 weeks, how often did you maintain your 
lubrication (“wetness”) during sexual activity or intercourse? 
X  = No sexual activity 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 
12. Over the past 4 weeks, how difficult was it to maintain your 
lubrication (“wetness”) during sexual activity or intercourse? 
X  = No sexual activity 
1  = Extremely difficult or impossible 
2  = Very difficult 
3  = Difficult 
4  = Slightly difficult 
5  = Not difficult 
13. Over the past 4 weeks, when you had sexual stimulation, how 
often did you reach orgasm (climax)? 
X  = No sexual activity 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 
14. Over the past 4 weeks, when you had sexual stimulation, how 
difficult was it you to reach orgasm (climax)? 
X  = No sexual activity 
1  = Extremely difficult or impossible 
2  = Very difficult 
3  = Difficult 
4  = Slightly difficult 
5  = Not difficult 
15. Over the past 4 weeks, how satisfied were you with your ability 
to reach orgasm (climax) during sexual activity or intercourse? 
X  = No sexual activity 
5  = Very satisfied 
4  = Moderately satisfied 
3  = About equally satisfied & dissatisfied 
2  = Moderately dissatisfied 
1  = Very dissatisfied 

This box to be completed by the clinical research associate: Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5. FSFI Questionnaire 
Page 5 of 5 
Question 
Response options (please circle) 
16. Over the past 4 weeks, how satisfied have you been with the 
amount of emotional closeness during sexual activity between 
you and your partner? 
X  = No partner 
5  = Very satisfied 
4  = Moderately satisfied 
3  = About equally satisfied & dissatisfied 
2  = Moderately dissatisfied 
1  = Very dissatisfied 
17. Over the past 4 weeks, how satisfied have you been with your 
sexual relationship with your partner? 
X  = No partner 
5  = Very satisfied 
4  = Moderately satisfied 
3  = About equally satisfied & dissatisfied 
2  = Moderately dissatisfied 
1  = Very dissatisfied 
18. Over the past 4 weeks, how often did you experience discomfort 
or pain following vaginal penetration? 
X  = Did not attempt penetration 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 
19. Over the past 4 weeks, how often did you experience discomfort 
or pain during vaginal penetration? 
X  = Did not attempt penetration 
5  = Almost always or always 
4  = Most times (more than ½ the time) 
3  = Sometimes (about ½ the time) 
2  = A few times (less than ½ the time) 
1  = Almost never or never 
20. Over the past 4 weeks, how would you rate your level (degree) of 
discomfort or pain during or following vaginal penetration? 
X  = Did not attempt penetration 
5  = Very high 
4  = High 
3  = Moderate 
2  = Low 
1  = Very low or none at all. 
 
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 #3: 2022-MAR-16 
 
CCTG TRIAL: CX.5 
 
 
CONFIDENTIAL 
74 
CONFIDENTIAL 
APPENDIX VII - HEALTH UTILITIES ASSESSMENT 
 
Introduction 
 
Note: Health Utilities Assessment applies to Canadian and UK centres only. Patients from these centres 
should complete the quality of life assessment before the health utilities assessment. 
 
The assessment of overall health benefits is complicated by the need for a measure that can combine various 
benefits, such as overall survival, progression 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. 
 
Instructions for Administration of a Health Utilities Questionnaire 
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. 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
CCTG TRIAL: CX.5 
 
 
CONFIDENTIAL 
75 
CONFIDENTIAL 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or 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 she 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, she should still complete the questionnaire prior to 
treatment. 
 
4. Assessments During Follow-up 
 
The health utilities questionnaire should be given to the patient before being seen by the doctor, at every 
follow-up visit, as required by the protocol schedule in section 9.1 or until deterioration to ECOG PS 4 
or hospitalization for end-of-life-care. 
 
To minimize missing health utilities data, if the patient is no longer attending clinic during the scheduled 
follow-up period, the patient should be contacted by phone to ask him/her to complete the questionnaire 
and mail it to the clinic. To facilitate this, ensure that after randomization 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 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. 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
CCTG TRIAL: CX.5 
 
 
CONFIDENTIAL 
76 
CONFIDENTIAL 
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. 
 
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 economics 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 she 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 she is willing to complete a questionnaire over the 
phone. If the patient agrees, read out questions 1-5 and range of possibilities, and record the 
answers. The visual analogue scale should not be completed in this case. 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. 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
CCTG TRIAL: CX.5 
 
 
CONFIDENTIAL 
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D. The patient is no longer attending clinic during the scheduled follow-up period. 
 
Should the patient no longer be attending clinic, she should be contacted by phone to ask her to 
complete the questionnaire and mail it to the clinic. To facilitate this, ensure that after 
randomization 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 Health Utilities Component 
 
The only time that we will not require a patient to complete the health utilities questionnaires is if she 
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 Health Utilities Questionnaire 
 
If a patient speaks and reads English or French, but does not wish to complete the questionnaires then 
she is NOT eligible and should NOT be put on study. 
 
8. 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 HUI3 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. 
 
 

 
 
Health Utilities Questionnaire – ENGLISH 
CCTG Trial: CX.5 
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 (3) 
 Prior to randomization 
 At the time of first recurrence 
 
After surgery prior to recurrence: 
 3 months 
 6 months 
 9 months    
 12 months  
 16 months 
 20 months 
 24 months 
 30 months 
 36 months 
 Other ______________________ (specify) 
 
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: 
_________ 
 
©Health Utilities Inc. (HUInc.) 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
Page 1 of 9 
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HUI23S1E.15Q (Health Utilities Index Mark 3 (HUI3) Questionnaire © copyright 2002 Health Utilities Inc. All rights reserved.) 
Health Utilities Index Mark 3 (HUI3) Questionnaire 
 
CCTG: CX.5 
 
This questionnaire contains a set of questions which ask about various aspects of your health. When answering 
these questions please think about your health and your ability to do things on a day-to-day basis, during the 
past week. For each question, please select one answer that best describes your level of ability or disability 
during the past week. Please answer all the questions yourself by circling the letter (a, b, c, …) beside the 
answer that best applies to you. Choose the best single response that applies to you. There are no right or wrong 
answers; what we want is your opinion about your abilities and feelings. To define the past week period, please 
think about what the date was 7 days ago and recall the major events that you have experienced during this 
period. Please focus your answers on your abilities, disabilities and how you have felt during the past week. 
 
You may feel that some of these questions do not apply to you, but it is important that we ask the same 
questions of everyone. Also, a few questions are similar; please excuse the apparent overlap and answer each 
question independently. 
 
The information that you provide is for research purposes and will remain strictly confidential. The individuals 
(e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to these questions -- 
if you wish them to know this information, please bring it to their attention. 
 
 
 
1. Which one of the following best describes your ability, during the past week, to see well enough to read 
ordinary newsprint? 
 
a. 
Able to see well enough without glasses or contact lenses. 
 
b. 
Able to see well enough with glasses or contact lenses. 
 
c. 
Unable to see well enough even with glasses or contact lenses. 
 
d. 
Unable to see at all. 
 
 
2. Which one of the following best describes your ability, during the past week, to see well enough to recognize 
a friend on the other side of the street? 
 
a. 
Able to see well enough without glasses or contact lenses. 
 
b. 
Able to see well enough with glasses or contact lenses. 
 
c. 
Unable to see well enough even with glasses or contact lenses. 
 
d. 
Unable to see at all. 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
Page 2 of 9 
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HUI23S1E.15Q (Health Utilities Index Mark 3 (HUI3) Questionnaire © copyright 2002 Health Utilities Inc. All rights reserved.) 
3. Which one of the following best describes your ability, during the past week, to hear what was said in a group 
conversation with at least three other people? 
 
a. Able to hear what was said without a hearing aid. 
 
b. Able to hear what was said with a hearing aid. 
 
c. Unable to hear what was said even with a hearing aid. 
 
d. Unable to hear what was said, but did not wear a hearing aid. 
 
e. Unable to hear at all. 
 
 
4. Which one of the following best describes your ability, during the past week, to hear what was said in a 
conversation with one other person in a quiet room? 
 
a. 
Able to hear what was said without a hearing aid. 
 
b. 
Able to hear what was said with a hearing aid. 
 
c. 
Unable to hear what was said even with a hearing aid. 
 
d. 
Unable to hear what was said, but did not wear a hearing aid. 
 
e. 
Unable to hear at all. 
 
 
5. Which one of the following best describes your ability, during the past week, to be understood when speaking 
your own language with people who do not know you? 
 
a. 
Able to be understood completely. 
 
b. 
Able to be understood partially. 
 
c. 
Unable to be understood. 
 
d. 
Unable to speak at all. 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
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HUI23S1E.15Q (Health Utilities Index Mark 3 (HUI3) Questionnaire © copyright 2002 Health Utilities Inc. All rights reserved.) 
6. Which one of the following best describes your ability, during the past week, to be understood when speaking 
with people who know you well? 
 
a. 
Able to be understood completely. 
 
b. 
Able to be understood partially. 
 
c. 
Unable to be understood. 
 
d. 
Unable to speak at all. 
 
 
7. Which one of the following best describes how you have been feeling during the past week? 
 
a. 
Happy and interested in life. 
 
b. 
Somewhat happy. 
 
c. 
Somewhat unhappy. 
 
d. 
Very unhappy. 
 
e. 
So unhappy that life was not worthwhile. 
 
 
8. Which one of the following best describes the pain and discomfort you have experienced during the past 
week? 
 
a. 
Free of pain and discomfort. 
 
b. 
Mild to moderate pain or discomfort that prevented no activities. 
 
c. 
Moderate pain or discomfort that prevented some activities. 
 
d. 
Moderate to severe pain or discomfort that prevented some activities. 
 
e. 
Severe pain or discomfort that prevented most activities. 
 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
Page 4 of 9 
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HUI23S1E.15Q (Health Utilities Index Mark 3 (HUI3) Questionnaire © copyright 2002 Health Utilities Inc. All rights reserved.) 
9. Which one of the following best describes your ability, during the past week, to walk? Note: Walking 
equipment refers to mechanical supports such as braces, a cane, crutches or a walker. 
 
a. 
Able to walk around the neighbourhood without difficulty, and without walking equipment. 
 
b. 
Able to walk around the neighbourhood with difficulty; but did not require walking equipment or the 
help of another person. 
 
c. 
Able to walk around the neighbourhood with walking equipment, but without  
the help of another 
person. 
 
d. 
Able to walk only short distances with walking equipment, and required a wheelchair to get around the 
neighbourhood. 
 
e. 
Unable to walk alone, even with walking equipment. Able to walk short distances with the help of 
another person, and required a wheelchair to get around the neighbourhood. 
 
f. 
Unable to walk at all. 
 
 
10. Which one of the following best describes your ability, during the past week, to use your hands and fingers? 
 
Note: Special tools refers to hooks for buttoning clothes, gripping devices for opening jars or lifting small 
items, and other devices to compensate for limitations of hands or fingers. 
 
a. Full use of two hands and ten fingers. 
 
b. Limitations in the use of hands or fingers, but did not require special tools or the help of another person. 
 
c. Limitations in the use of hands or fingers, independent with use of special tools (did not require the help 
of another person). 
 
d. Limitations in the use of hands or fingers, required the help of another person for some tasks (not 
independent even with use of special tools). 
 
e. Limitations in the use of hands or fingers, required the help of another person for most tasks (not 
independent even with use of special tools). 
 
f. Limitations in the use of hands or fingers, required the help of another person for all tasks (not 
independent even with use of special tools). 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
Page 5 of 9 
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HUI23S1E.15Q (Health Utilities Index Mark 3 (HUI3) Questionnaire © copyright 2002 Health Utilities Inc. All rights reserved.) 
11. Which one of the following best describes your ability, during the past week, to remember things? 
 
a. Able to remember most things. 
 
b. Somewhat forgetful. 
 
c. Very forgetful. 
 
d. Unable to remember anything at all. 
 
 
12. Which one of the following best describes your ability, during the past week, to think and solve day to day 
problems? 
 
a. Able to think clearly and solve day to day problems. 
 
b. Had a little difficulty when trying to think and solve day to day problems. 
 
c. Had some difficulty when trying to think and solve day to day problems. 
 
d. Had great difficulty when trying to think and solve day to day problems. 
 
e. Unable to think or solve day to day problems. 
 
 
13. Which one of the following best describes your ability, during the past week, to perform basic activities? 
 
a. Eat, bathe, dress and use the toilet normally. 
 
b. Eat, bathe, dress or use the toilet independently with difficulty. 
 
c. Required mechanical equipment to eat, bathe, dress or use the toilet independently. 
 
d. Required the help of another person to eat, bathe, dress or use the toilet. 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
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HUI23S1E.15Q (Health Utilities Index Mark 3 (HUI3) Questionnaire © copyright 2002 Health Utilities Inc. All rights reserved.) 
14. Which one of the following best describes how you have been feeling during the past week? 
 
a. 
Generally happy and free from worry. 
 
b. 
Occasionally fretful, angry, irritable, anxious or depressed. 
 
c. 
Often fretful, angry, irritable, anxious or depressed. 
 
d. 
Almost always fretful, angry, irritable, anxious or depressed. 
 
e. 
Extremely fretful, angry, irritable, anxious or depressed; to the point of needing professional help. 
 
 
15. Which one of the following best describes the pain or discomfort you have experienced during the past week? 
 
a. 
Free of pain and discomfort. 
 
b. 
Occasional pain or discomfort. Discomfort relieved by non-prescription drugs or self-control activity 
without disruption of normal activities. 
 
c. 
Frequent pain or discomfort. Discomfort relieved by oral medicines with occasional disruption of normal 
activities. 
 
d. 
Frequent pain or discomfort; frequent disruption of normal activities. Discomfort required prescription 
narcotics for relief. 
 
e. 
Severe pain or discomfort. Pain not relieved by drugs and constantly disrupted normal activities. 
 
 
16. Overall, how would you rate your health during the past week? 
 
a. 
Excellent. 
 
b. 
Very good. 
 
c. 
Good. 
 
d. 
Fair. 
 
e. 
Poor. 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
Page 7 of 9 
Please go on to the next page 
 
HUI23S1E.15Q (Health Utilities Index Mark 3 (HUI3) Questionnaire © copyright 2002 Health Utilities Inc. All rights reserved.) 
17. How did you complete the questionnaire? Please select the one answer that best describes your situation. 
 
a. 
By myself, without any help from anyone else. 
 
b. 
By myself, except someone else circled the answers on the questionnaire form for me. 
 
c. 
With the help of someone else. 
 
d. 
This questionnaire was completed by a family member, without help from the subject or patient. 
 
e. 
This questionnaire was completed by a nurse or other health professional, without help from the subject 
or patient. 
 
Please specify type of health professional: ______________________________ 
 
f. 
This questionnaire was completed by another person, without help from the subject or patient. 
 
 
Please specify relationship to subject or patient: ________________________ 
 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________ Pt. Initials: ____ ____ ____ 
 
NCIC CTG Trial CX.5 
Page 8 of 9 
Please go on to the next page 
 
© EuroQoL Group 1990 
EQ-5D Questionnaire 
 
CCTG: CX.5 
 
 
By placing a tick in one box in each group below, please indicate which statements best describe your own health 
state today. 
 
 
 
1. Mobility 
a. I have no problems in walking about 
 
b. I have some problems in walking about 
 
c. I am confined to bed 
 
 
 
2. Self-Care 
a. I have no problems with self-care 
 
b. I have some problems washing or dressing myself 
 
c. I am unable to wash or dress myself 
 
 
 
3. Usual Activities (e.g. work, study, housework, family or leisure activities) 
a. I have no problems with performing my usual activities 
 
b. I have some problems with performing my usual activities 
 
c. I am unable to perform my usual activities 
 
 
 
4. Pain/Discomfort 
a. I have no pain or discomfort 
 
b. I have moderate pain or discomfort 
 
c. I have extreme pain or discomfort 
 
 
 
5. Anxiety/Depression 
a. I am not anxious or depressed 
 
b. I am moderately anxious or depressed 
 
c. I am extremely anxious or depressed 
 
 

 
NCIC CTG Trial CX.5 
Page 9 of 9 
© EuroQoL Group 1990 
 
To help people say how good or bad a health state is, we have drawn a scale 
(rather like a thermometer) on which the best state you can imagine is marked 
100 and the worst state you can imagine is marked 0. 
 
We would like you to indicate on this scale how good or bad your own health 
is today, in your opinion. Please do this by drawing a line from the box below 
to whichever point on the scale indicates how good or bad your health state is 
today. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
2 0 
1 0 
100 
Worst 
imaginable 
health state 
0 
Best  
imaginable 
health state 
Your own 
health state 
today 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
CCTG TRIAL: CX.5 
 
 
CONFIDENTIAL 
88 
CONFIDENTIAL 
APPENDIX VIII - COVID-19 AND EMERGENCY SITUATIONS AND COMPLIANCE 
 
Management of Protocol Variances in Emergency Situations  
 
Compliance with the trial protocol should be ensured to every extent possible. However, 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 emergency situations.  
 
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, 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.     
 
1.0 
Remote Monitoring/Auditing  
 
CCTG site monitoring/auditing will be conducted at participating centres during the duration of 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 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. 
 

 
PROTOCOL AMENDMENT #3: 2022-MAR-16 
 
CCTG TRIAL: CX.5 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
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) 
Selene MillerStudy Coordinator 
CCTGEmail: 
smiller@ctg.queensu.ca 
613-533-6430 
613-533-2941 
or: 
Dr. Lois Shepherd 
Senior Investigator 
CCTGEmail: 
lshepherd@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Marie Plante 
Study Chair 
Email: 
marie.plante@crhdq.ulaval.ca  
 
 
SERIOUS ADVERSE EVENTS 
(SAEs) 
Selene Miller 
Study Coordinator 
CCTGEmail: 
smiller@ctg.queensu.ca 
613-533-6430 
613-533-2941