Conditions: Cervical Adenocarcinoma Cervical Adenosquamous Carcinoma Cervical Squamous Cell Carcinoma, Not Otherwise Specified Stage IB Cervical Cancer AJCC v6 and v7 Stage IIA Cervical Cancer AJCC v7 Stage IIB Cervical Cancer AJCC v6 and v7 Stage IIIB Cervical Cancer AJCC v6 and v7 Stage IVA Cervical Cancer AJCC v6 and v7
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 926
Healthy volunteers: no

Brief summary:
This randomized phase III trial studies how well giving cisplatin and radiation therapy together with or without carboplatin and paclitaxel works in treating patients with cervical cancer has spread from where it started to nearby tissue or lymph nodes. Drugs used in chemotherapy, such as cisplatin, carboplatin, and paclitaxel, work in different ways to stop the growth of \[cancer/tumor\] cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. External radiation therapy uses high-energy x rays to kill tumor cells. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. It is not yet known whether giving cisplatin and external and internal radiation therapy together with carboplatin and paclitaxel kills more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if the addition of adjuvant chemotherapy to standard cisplatin-based chemoradiation improves overall survival.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival rates. II. To determine acute and long-term toxicities. III. To determine patterns of disease recurrence. IV. To determine the association between radiation protocol compliance and outcomes.

V. To determine patient quality of life, including psycho-sexual health.

TERTIARY OBJECTIVES:

I. To determine the association between the results of a follow-up positron emission tomography (PET) scan performed 4-6 months post completion of chemoradiation and outcomes for all patients in the trial.

II. To determine the biological predictors of patients' outcomes based on translational laboratory studies of blood and tissue specimens.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cisplatin intravenously (IV) over 60-90 minutes on days 1, 8, 15, 22, and 29. Patients also undergo external-beam radiation therapy once daily, 5 days a week, for approximately 5 weeks. Patients then undergo high-dose rate, pulsed-dose rate, or low-dose rate intracavitary brachytherapy.

ARM II: Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients may undergo baseline tumor biopsy and blood collection for future correlative studies.

Patients complete the European Organization for Research and Treatment of Cancer (EORTC) Core questionnaire (QLQ-C30), the EORTC cervix cancer module (CX24), the ovarian cancer module (OV28), and the Sexual function-Vaginal Changes Questionnaire (SVQ) questionnaires at baseline, during, and after completion of study treatment.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms:
arm 1: Patients receive cisplatin IV over 60-90 minutes on days 1, 8, 15, 22, and 29. Patients also undergo external-beam radiation therapy once daily, 5 days a week, for approximately 5 weeks. Patients then undergo high-dose rate, pulsed-dose rate, or low-dose rate intracavitary brachytherapy. arm 2: Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Brachytherapy intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: External Beam Radiation Therapy intervention 5: Paclitaxel intervention 6: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Undergo brachytherapy intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo external beam radiation therapy intervention 5: Given IV intervention 6: Ancillary studies

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
 
 
The OUTBACK Trial 
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Version 5.0, 09 May 2016 
 
 
 
A Phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for 
locally advanced cervical cancer compared to chemoradiation alone: THE OUTBACK TRIAL 
(ANZGOG 0902) 
 
Version 5.0, dated 09 May 2016  
 
 
Principal Investigator: 
 
Associate Professor Linda Mileshkin 
 
 
 
 
 
Peter MacCallum Cancer Centre 
 
 
 
 
 
St Andrews Place 
 
 
 
 
 
East Melbourne VIC 3002, Australia 
 
 
 
 
 
 
 
Lead Radiation Oncologist: 
Associate Professor Kailash Narayan 
 
 
 
 
 
Peter MacCallum Cancer Centre (as above) 
 
Lead in Quality of Life: 
 
Professor Madeleine King 
Quality of Life Office  
Psycho-oncology Co-operative Research Group (PoCoG)  
School of Psychology, Brennan MacCallum Building  
University of Sydney NSW 2006, Australia 
 
Study Statistician: 
 
 
Professor Val Gebski 
NHMRC Clinical Trials Centre 
Locked Bag 77 
Camperdown NSW 1450, Australia 
 
 
Lead Collaborative Group: 
ANZGOG: This is an independent multi-centre investigator-
initiated study conducted under the auspices of ANZGOG. 
 
Coordinating Centre: 
 
NHMRC Clinical Trials Centre 
 
 
 
 
 
Lifehouse Building 
 
 
 
 
 
Level 6, 119 – 143 Missenden Road 
 
 
 
 
 
Camperdown NSW 2050, Australia 
 
 
 
 
 
Telephone: +61-2-9562-5000 
 
 
 
 
 
Fax: 
       +61-2-9562-5094 
 
Participating Collaborative  
Group: 
 
 
 
NRG Oncology (GOG & RTOG legacy groups) 
 
 


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Table of Contents 
 
1 
PROTOCOL AUTHORISATION PAGE ....................................................................................... 3 
2 
ABBREVIATIONS ....................................................................................................................... 4 
3 
SYNOPSIS ................................................................................................................................. 5 
4 
BACKGROUND INFORMATION ................................................................................................ 6 
5 
AIMS AND OBJECTIVES ......................................................................................................... 10 
6 
TRIAL DESIGN ......................................................................................................................... 10 
6.1 
Study Schema ................................................................................................................... 11 
6.2 
Randomisation .................................................................................................................. 12 
6.3 
Endpoints .......................................................................................................................... 12 
7 
SUBJECT POPULATION ......................................................................................................... 13 
7.1 
Inclusion criteria ................................................................................................................ 13 
7.2 
Exclusion criteria ............................................................................................................... 13 
7.3 
Withdrawal criteria ............................................................................................................ 14 
7.4 
Patient transfers ................................................................................................................ 14 
8 
TREATMENT OF SUBJECTS .................................................................................................. 15 
8.1 
Chemotherapy administration ........................................................................................... 15 
8.2 
Concomitant Medications/Treatments ............................................................................... 21 
8.3 
Radiotherapy Treatment ................................................................................................... 22 
9 
ASSESSMENT OF EFFICACY, SAFETY AND PATIENT QUALITY OF LIFE .......................... 32 
9.1 
Assessment of Efficacy and Baseline Measures ............................................................... 32 
9.2 
Assessment of patient quality of life .................................................................................. 32 
9.3 
Assessment of Safety ....................................................................................................... 34 
8.3.2 Reporting of Serious Adverse Events (including SUSARs)................................................ 35 
8.3.3 Pregnancy ......................................................................................................................... 36 
10 SCHEDULE OF ASSESSMENTS ............................................................................................. 37 
11 
STATISTICS ......................................................................................................................... 40 
11.1 
Sample Size ...................................................................................................................... 40 
11.2 
Statistical Analysis ............................................................................................................ 40 
11.3 
Secondary endpoint: Progression Free survival ................................................................ 41 
11.4 
Definition of study populations for analysis ........................................................................ 41 
11.5 
Interim analysis ................................................................................................................. 42 
12 
STUDY STRUCTURE .......................................................................................................... 43 
13 
ADMINISTRATIVE ASPECTS .............................................................................................. 44 
13.1 
Ethics and regulatory compliance ...................................................................................... 44 
13.2 
Confidentiality ................................................................................................................... 44 
13.3 
Protocol amendments ....................................................................................................... 44 
13.4 
Data Handling and Record Keeping .................................................................................. 44 
13.5 
Study Monitoring ............................................................................................................... 45 
13.6 
Audit and Inspection.......................................................................................................... 45 
13.7 
Clinical Study Report ......................................................................................................... 45 
13.8 
Publication Policy .............................................................................................................. 45 
14 
REFERENCES ..................................................................................................................... 46 
15 
LIST OF APPENDICES ........................................................................................................ 49 
Appendix 1. Participant information and consent forms ................................................................ 49 
Appendix 2. Quality of Life (QOL) forms ....................................................................................... 64 
Appendix 3. Definition of Corpus Positive disease on MRI ........................................................... 74 
Appendix 4. RECIST 1.1 Criteria .................................................................................................. 75 
Appendix 5. FIGO 2008 staging for carcinoma of the cervix uteri ................................................. 79 
Appendix 6. Information requirements for PET reports ................................................................. 80 
 
 


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1 PROTOCOL AUTHORISATION PAGE 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Original and signed document held at the NHMRC Clinical Trials Centre 
 
 
PROTOCOL Code:  ANZGOG0902 
Version 5.0, dated 09 May 2016 
 
A Phase III trial of adjuvant chemotherapy following chemoradiation as primary 
treatment for locally advanced cervical cancer compared to chemoradiation alone:  
THE OUTBACK TRIAL 
 


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2 
ABBREVIATIONS 
AP 
 
 
 
Anterior-Posterior 
ANZGOG 
 
 
Australia New Zealand Gynaecological Oncology Group 
AE 
 
 
 
Adverse Event 
ANC 
 
 
 
Absolute Neutrophil Count  
ALT 
 
 
 
Amino Alanine Transferase  
AST 
 
 
 
Aspartate Amino Transferase  
AUC 
 
 
 
Area Under the Curve 
CBC 
 
 
 
Complete Blood Count 
(e)CRF 
 
 
(electronic) Case Report Forms 
CTCAE 
 
 
Common Terminology Criteria for Adverse Events 
CXR 
 
 
 
Chest X-ray 
CT 
 
 
 
Computerised Tomography 
DRR 
 
 
 
Digital Reconstructed Radiograph 
EBRT  
 
 
External Beam Radiation Therapy 
ECOG  
 
 
Eastern Cooperative Oncology Group 
EORTC 
 
 
European Organization for Research and Treatment of Cancer 
FIGO  
 
 
International Federation of Gynecology and Obstetrics 
GCIG  
 
 
Gynecologic Cancer InterGroup 
G-CSF  
 
 
Granulocyte-Colony Stimulating Factor 
GFR 
 
 
 
Glomerular Filtration Rate 
GOG  
 
 
Gynecological Oncology Group 
Gy 
 
 
 
Gray 
HR 
 
 
 
Hazard Ratio 
HREC  
 
 
Human Research Ethics Committee 
IDSMC 
 
 
Independent Data Safety Monitoring Committee 
IMRT  
 
 
Intensity-Modulated Radiation Therapy 
IV 
 
 
 
Intravenous 
K 
 
 
 
Potassium 
L 
 
 
 
Litre 
ML 
 
 
 
Millilitre 
MRC  
 
 
Medical Research Council 
MRI 
 
 
 
Magnetic Resonance Imaging 
Mg 
 
 
 
Magnesium 
Na 
 
 
 
Sodium 
NCIC CTG 
 
 
National Canadian Institute of Cancer Clinical Trials Group 
NHMRC CTC 
National Health & Medical Research Council Clinical Trials Centre 
NS 
 
 
 
Normal Saline 
OS 
 
 
 
Overall Survival 
PA 
 
 
 
Posterior-Anterior 
PET 
 
 
 
Positron Emission Tomography 
PFS 
 
 
 
Progression Free Survival 
RT 
 
 
 
Radiation Therapy 
QA 
 
 
 
Quality Assurance 
QOL 
 
 
 
Quality of Life 
SAE 
 
 
 
Serious Adverse Event 
SUSAR 
 
 
Suspected Unexpected Serious Adverse Reaction 
TMC 
 
 
 
Trial Management Committee 
ULN 
 
 
 
Upper Limit of Normal  
 
 
 
 


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3 SYNOPSIS 
 
 
 
Title 
  
A phase III trial of adjuvant chemotherapy following chemo-radiation as primary 
treatment for locally advanced cervical cancer compared to chemo-radiation 
alone: The OUTBACK Trial 
Study Design  An international, prospective, multi-centre, randomised, phase III GCIG trial led 
by ANZGOG, in collaboration with the GOG, RTOG and  India,  
Patient 
population 
Patients with stage IB1 & positive nodes, IB2, IIA, IIB, IIIB or IVA cervical 
cancer suitable for primary treatment with chemo-radiation with curative 
intent.  
Intervention 
Radiotherapy regimen:  All patients (Arm A and B) will receive 45 – 50.4 Gy 
external beam radiation therapy (EBRT) delivered in fractions of 1.8 Gy to the 
pelvis, followed by brachytherapy.  
Chemotherapy regimen: Cisplatin will be given during the radiation at a dose of 
40mg/m2 weekly for 5 doses to all patients (Arm A and B). Within 4 weeks of 
completion of all radiation treatment, and following recovery from toxicities, 
patients in Arm B will be treated with an additional 4 cycles of 3 weekly adjuvant 
chemotherapy using carboplatin AUC 5 and paclitaxel 155 mg/m2. 
Primary  
Objective: 
To determine if the addition of adjuvant chemotherapy to standard cisplatin-
based chemo-radiation improves overall survival. 
Secondary 
objectives 
To determine: progression-free survival rates, acute and  
long-term toxicities, patterns of disease recurrence,  the association between  
radiation protocol compliance and outcomes and patient quality of life, including 
psycho-sexual health. 
 # patients 
900 
Planned 
duration 
3 – 4 years recruitment and 3-5 years follow-up 
Statistics 
A total sample size of 900 (450 per arm) will have 80% power with 95% 
confidence of detecting a reduction in the hazard of death of at least 32% 
(hazard ratio 0.68) from the control regimen (approximate 8% improvement in 
overall survival at 5 years from 72% to 80%) 


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4 BACKGROUND INFORMATION 
In the majority of developing countries, cervical cancer remains the number-one cause of cancer-
related deaths among women, with nearly 500,000 women diagnosed annually world-wide1. Cervical 
cancer incidence has decreased in developed countries since the widespread introduction of 
cervical screening2.  For example, there were 734 new cases reported in Australia in 2005, which 
represents a 33% decline compared to 1991, although incidence has not declined subsequently3.  
Cervical cancer remains one of the leading causes of cancer-related morbidity and mortality world-
wide, particularly in countries without screening programs, and in disadvantaged communities within 
developed countries with screening programs1,4,5. For example, Aboriginal and Torres Strait Islander 
women have double the incidence and 5 times the mortality risk than other Australians3,6,7. Human 
papilloma virus (HPV), particularly types 16 and 18, is significantly associated with subsequent 
development of cervical cancer, with an increased risk also seen amongst smokers1.   
Many patients with cervical cancer present with early-stage disease which is highly curable with 
surgical approaches or the use of chemo-radiation. However, a significant percentage of patients, 
particularly those who have not participated in screening programs, present with more advanced 
local disease and have much lower cure rates8-10. For example, in Australia, only 62% of eligible 
women had biennial participation in the National Screening Program during 2002-20063. The recent 
introduction of the cervical cancer vaccine for children and young adults will reduce cervical cancer 
rates for the future generations but not the current one. Realising the benefit of the vaccine is 
predicted to take some time given that the incidence of cervical cancer continues to rise with age, 
and that ongoing screening will be required in addition to the vaccine program, which needs to be 
initiated prior to the age of commencement of sexual activity to be effective11. 
Standard therapy 
The use of chemotherapy concurrent with radiation for cervical cancer has been proven to improve 
survival and has become established as standard care. A recent meta-analysis found that the 
addition of concurrent chemotherapy to radiation increased the 5 year overall survival rate by 6% 
(HR 0.81: 60 vs 66%)12. However, in this analysis the 5 year disease-free survival rate was only 58% 
in the chemoradiation group, which although superior to the 50% in those patients treated with 
radiation alone, still leaves much room for improvement as the majority of patients who relapse are 
incurable13. 
The main prognostic factor for outcome has traditionally been the FIGO staging system which is 
principally based on clinical examination alone for those patients deemed unsuitable for surgery. 
However, our centre and others have highlighted the significant prognostic role of both nodal and 
uterine corpus involvement as detected by imaging, with MRI and PET now accepted modalities for 
non-invasively determining these features14-16. Nodal involvement has been documented to predict 
disease relapse in multiple studies, however, it is not as yet considered by the current staging 
system14,17-20. Uterine corpus invasion tends to be associated with tumours that grow endophytically 


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and has also been shown to predict worse outcomes, in part because it appears to predict nodal 
metastasis21-26.  
For example, prospectively collected audit data from 436 patients treated at the Peter MacCallum 
Cancer Centre with primary chemo-radiation for locally advanced cervical cancer between 
December 1995 and December 2006 has demonstrated that patients with uterine involvement on 
MRI or node positive disease on PET scan have inferior survival outcomes. This group of patients 
reflects the current spectrum of patients being referred for chemo-radiation for cervical cancer, who 
often have never participated in the screening program8,9. The median age was 63 years with 43% 
having stage II disease and 21% stage III or IV respectively. At a median follow-up of 5 years, the 
estimated 5 year failure-free rate for the whole group was 55%, with a median overall survival rate of 
60%. 
Overall 144 patients (33%) developed recurrent disease with only a small number recurring at the 
primary site alone, and three quarters relapsing in multiple sites. In those with PET positive nodal 
disease (n=132), 50% of patients developed recurrent disease versus 22% in the PET negative, with 
a 5 year overall survival of 48% in the PET positive and 70% in the PET negative group. In those 
with evidence of corpus uterine involvement on MRI (n=226), 46% recurred as compared to 17% 
without corpus involvement, with similar differences in 5 year overall survival (54 vs 71%), and 
corpus uterine involvement appearing to be a surrogate for the development of node positive 
disease. In both groups, a significant percentage of the recurrences involved distant 
metastases23,27,28. Consequently in this trial we plan to stratify for the presence or absence of nodal 
disease, in addition to traditional factors such as FIGO stage, and will also perform a pre-planned 
subset analysis of the effect of adjuvant chemotherapy in these high-risk sub-groups. We also plan 
to try and validate within this prospective trial previous reports that a follow-up PET scan after 
completion of chemo-radiation can predict patient outcome29. 
The potential benefit from adjuvant chemotherapy 
It is possible that the addition of further cycles of adjuvant chemotherapy following completion of 
chemo-radiation will decrease distant metastases and improve survival. Previous small retrospective 
studies using older style chemotherapy agents, such as anthracyclines, suggested no benefit and 
increased toxicity with the addition of adjuvant chemotherapy following chemo-radiation. However, 
the GOG109 study randomised patients with high-risk cervical cancer, initially treated with radical 
hysterectomy and pelvic lymphadenectomy, who were found to have positive pelvic nodes and/or 
positive margins and/or microscopic parametrial involvement to adjuvant radiation alone or adjuvant 
chemo-radiation. The chemotherapy consisted of 4 cycles of cisplatin and 5FU given as 2 cycles 
concurrent with radiation and 2 cycles post radiation. Progression-free and overall survival rates 
were significantly improved for patients who received the chemotherapy. Although only 60% 
completed all planned chemotherapy, higher numbers of chemotherapy courses received were 
favourably associated with improved progression-free and overall survival rates30. This trial was one 
of 2 trials which gave additional chemotherapy after chemo-radiation and was considered in a 


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subset analysis within the meta-analysis. In this group an absolute benefit of 19% in 5 year survival 
(from 60 to 79%) was seen30,31.  
More recent data presented at ASCO 2009 by Duenas-Gonzalez et al. showed a benefit of adding 
concurrent gemcitabine to the standard regimen of weekly cisplatin during radiation, followed by 2 
further cycles of cisplatin-gemcitabine. This multi-centre randomised phase III trial performed in 
South America showed a statistically significant 9% improvement in the primary outcome of 
progression-free survival at 3 years from 65% to 74%, as well as in improvement in overall 
survival32. However, toxicity was significantly increased. Questions about the study have included 
uncertainty about the percentage of patients treated with radiation using Cobalt60 rather than a linear 
accelerator, and surprise about the very high rates of radiotherapy delivery reported, particularly 
given that prior investigators using similar doses of cisplatin plus gemcitabine concurrent with 
radiotherapy in phase 1 studies have been unable to safely deliver the regimen. It also remains 
unclear how much the additional chemotherapy during radiation is actually improving outcomes as 
opposed to increasing toxicity. Hence a confirmatory trial to explore the benefit of adjuvant 
chemotherapy in cervical cancer is warranted. Because distant relapse is the main cause of patient 
death, this study will use standard cisplatin-based chemo-radiation but then test the addition of 4 
cycles of adjuvant chemotherapy.  
Choice of adjuvant chemotherapy 
The combination of carboplatin and paclitaxel chemotherapy has been chosen for this study as it is 
active in metastatic cervical cancer and delivery has been shown to be feasible following pelvic 
chemo-radiation. In addition, cisplatin and paclitaxel have been demonstrated to have similar or 
better outcomes to cisplatin with topotecan, vinorelbine or gemcitabine for the treatment of 
metastatic disease in the recently published GOG 204 protocol. This combination has been 
recommended as an appropriate regimen to take forward as a standard control arm for future 
trials33. In this study the lowest response rate was seen in those patients treated with cisplatin and 
gemcitabine, hence this regimen has not been chosen for use in this study despite the results from 
the Duenas-Gonzalez study. Quality of life data was also assessed in this study. The investigators 
found that no doublet was clinically or statistically different from cisplatin and paclitaxel in quality of 
life or pain.  
Because of the concern about toxicity, especially neurotoxicity, with cisplatin, there has been 
interest in using carboplatin as a less toxic regimen. A trial published in 2005 looked at the 
combination of carboplatin and paclitaxel in advanced and recurrent cervical carcinomas and found 
a 20% partial response rate and a 20% complete response rate. The investigators concluded that 
carboplatin-paclitaxel was an active combination in advanced and recurrent cervical cancer34. 
Recently, a multi-institutional retrospective study reported on experience with paclitaxel and 
carboplatin versus paclitaxel and cisplatin in advanced-stage or recurrent cervical cancer. Moore et 
al found objective responses of 53% in the carboplatin group compared with 29% in the cisplatin 
group, with significantly less toxicity35. Internationally, there has been a trend towards using 


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carboplatin in cervical cancer, especially in patients previously treated with radio-sensitizing 
cisplatin36-38. Therefore, there is mounting evidence that the combination of paclitaxel and 
carboplatin is an effective and less toxic regimen in cervical cancer. The added benefit of ease of 
administration as a one day outpatient treatment makes this regimen an ideal choice to study in this 
population. 
Preliminary data from the ongoing protocol GOG 209, treating advanced or recurrent endometrial 
cancer with paclitaxel, doxorubicin and cisplatin or paclitaxel and carboplatin, showed increased 
hematologic toxicities when patients were previously irradiated. This finding led to a protocol dose 
reduction for paclitaxel and carboplatin for women who have previously undergone pelvic irradiation. 
Similar findings in terms of haematological toxicity and also neurological toxicity have been seen in 
recently published retrospective data36-38. Consequently, we have modified our starting doses in the 
treatment arm of paclitaxel and carboplatin to reflect these data. 
Assessment of patient quality of life including psycho-sexual health 
An important component of this study will be to assess patient self-reported quality of life following 
chemoradiation +/- adjuvant chemotherapy for cervical cancer within the setting of a prospective 
trial. It is well recognised from surveys of cervical cancer survivors that some women will have 
reduced quality of life, related to chronic toxicities including bowel, urinary and sexual problems after 
treatment with radiotherapy39-41. In some but not all reports, toxicity appears more pronounced in 
older patients42,43. However, there has been a lack of patient reported outcomes within chemo-
radiation studies to date, and this trial represents a unique opportunity to address this issue44,45. 
Collecting such data as part of this trial will help to define the scope of the problem and potentially 
identify which subsets of women are most at risk of having significant chronic toxicities including 
psycho-sexual problems after treatment. 
 
Taken together, these data reinforce the need for an adequately powered trial testing the role of 
adjuvant chemotherapy treatment in cervical cancer.  A phase III randomised trial, comparing 
chemo-radiation and adjuvant chemotherapy with chemo-radiation alone in patients with cervical 
cancer will establish the role of adjuvant chemotherapy in this patient population. 
 
 


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5 AIMS AND OBJECTIVES 
The aim of this study is to test the potential benefit of the addition of adjuvant chemotherapy 
following completion of primary chemoradiation for patients with locally advanced cervical cancer.  
The primary objective will be to determine if the addition of adjuvant chemotherapy to standard 
cisplatin-based chemoradiation improves overall survival. 
Secondary objectives will be to determine: 
• Progression-free survival rates 
• Acute and long-term toxicities 
• Patterns of disease recurrence 
• The association between radiation protocol compliance and outcomes 
• Patient quality of life, including psycho-sexual health 
 
Tertiary objectives will be to determine: 
• The association between the results of a follow-up PET scan performed 4 – 6 months post 
completion of chemo-radiation and outcomes for all patients in the trial 
• Biological predictors of patients outcomes based on translational laboratory studies of blood 
and tissue specimens 
 
6 TRIAL DESIGN 
The study design is a multi-centre randomised phase III trial. 
 
Arm A: Standard chemoradiation 
Arm B: Standard chemoradiation followed by 4 cycles of carboplatin and paclitaxel 
 
Patients in both arms will be treated with standard external beam radiation treatment to the pelvis and 
brachytherapy. Cisplatin will be given during the radiation at a dose of 40mg/m2 weekly for 5 doses. 
Within 4 weeks of completion of all radiation treatment, including the brachytherapy component, and 
following recovery from toxicities, patients in Arm B will be treated with 4 cycles of 3 weekly adjuvant 
chemotherapy using carboplatin AUC 5 and paclitaxel 155 mg/m2. 
 


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6.1 
Study Schema 
 
Eligible patients 
 RANDOMISE 
Arm A – Control Arm 
Concurrent chemoradiation 
Arm B – Intervention Arm 
Concurrent chemoradiation 
followed by adjuvant 
chemotherapy 
Patients with stage IB1 & positive nodes, IB2, IIA, IIB, IIIB or IVA 
cervical cancer who have given informed consent  
Follow up for a minimum of 3.5 years 
 
Max 6 weeks 


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6.2 
 Randomisation 
Patients will be randomised to either: standard chemoradiation or standard chemoradiation plus 
adjuvant chemotherapy, using the method of minimisation. Randomisation will be performed by sites 
through a web-based system. Randomisation will be 1:1 to each treatment arm and patients will be 
stratified by the following factors: 
Stratification factors 
• 
Pelvic or common iliac nodal involvement: Yes or No or Unknown (Patients may be considered 
node-positive based on staging PET/CT scan results, or staging CT/MRI results if >15mm 
short axis diameter, or surgical nodal biopsy or resection leading to abandonment of planned 
hysterectomy. The method of determining whether the patient has node positive disease 
should be recorded) 
Any node(s) within the pelvis below the common iliac bifurcation, such as obturator, internal or 
external iliac nodes are called pelvic nodes. Nodes above this bifurcation along the common 
iliac vessels up to the origin of common iliac vessels where the aorta bifurcates are called 
common iliac nodes. The aortic bifurcation occurs usually at the level of the fourth lumbar 
vertebrae (L4 Vertebra), just above the confluence of the left and right common iliac veins.  
• 
Requirement for extended-field radiotherapy treatment (Yes or No) 
If the pelvic field is at or below the intervertebral disc between L4-L5 it will be regarded as 
pelvic field. When the upper border of the treatment field is located above this plane, anywhere 
up to T12-L1, it will be regarded as EFRT. 
• 
FIGO 2008 Stage IB / IIA or IIB or IIIB / IVA  
• 
Age <60 or ≥60 years 
• 
Hospital/site 
6.3 
Endpoints 
The primary endpoint will be the overall survival rate at 5 years. 
The secondary endpoints will be: 
• 
The progression-free survival rate at 3 and 5 years 
• 
The rate of acute and long-term toxicities 
• 
The patterns of disease recurrence 
• 
Radiation protocol compliance 
• 
Patient self-reported quality of life including psychosexual health 
A tertiary endpoint will be: 
• 
The rate of complete and partial metabolic response on a PET scan performed 4 – 6 months 
after completion of chemo-radiation treatment 


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7 SUBJECT POPULATION 
7.1 
 Inclusion criteria 
Eligible patients will have locally advanced cervical cancer suitable for primary treatment with chemo-
radiation with curative intent, in addition to: 
• 
FIGO 2008 stage IB1 & node positive, IB2, IIA, IIB, IIIB or IVA disease.  
• 
Age 18 years or older 
• 
ECOG performance status 0 - 2 
• 
Histological diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous cell 
carcinoma of the cervix 
• 
WBC ≥ 3.0 x 109/L and ANC ≥ 1.5 x 109/L 
• 
Platelets ≥ 100 x 109/L 
• 
Bilirubin ≤ 1.5 x ULN 
• 
AST or ALT ≤ 2.5 x ULN (if both tests are done, both results need to be ≤ 2.5 x ULN) 
• 
Adequate renal function: creatinine ≤ ULN (CTC Grade 0) or calculated creatinine clearance 
(Cockcroft-Gault Formula) ≥ 60ml/min or ≥ 50 ml/min by EDTA creatinine clearance 
• 
Written informed consent 
7.2 
Exclusion criteria 
• 
Any previous pelvic radiotherapy 
• 
Para-aortic nodal involvement above the level of the common iliac nodes or L3/L4 (if biopsy 
proven, PET positive or ≥ 15mm short axis diameter on CT) 
• 
FIGO 2008 stage IIIA disease  
• 
Patients assessed at presentation as requiring interstitial brachytherapy treatment 
• 
Patients with bilateral hydronephrosis unless at least one side has been stented and renal 
function fulfils the required inclusion criteria 
• 
Previous chemotherapy for this tumour  
• 
Evidence of distant metastases 
• 
Prior diagnosis of Crohn’s disease or ulcerative colitis  
• 
Peripheral neuropathy > grade 2 (as per CTCAE v4) 
• 
Patients who have undergone a previous hysterectomy or will have a hysterectomy as part of 
their initial cervix cancer therapy. This includes patients with a prior history of supracervical 
hysterectomy 
• 
Patients with other invasive malignancies, with the exception of non-melanoma skin cancer 
and in situ melanoma, who had (or have) any evidence of the other cancer present within the 
last 5 years 
• 
Patients who are pregnant or lactating 
• 
Any contraindication to the use of cisplatin, carboplatin or paclitaxel chemotherapy 


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• 
Serious illness or medical condition that precludes the safe administration of the trial 
treatment including, but not limited to, ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements 
• 
Patients who are known to be HIV positive  
7.3 
Withdrawal criteria 
Participation in this study is voluntary; patients will be able to withdraw at any time.  A patient may 
withdraw, or be withdrawn, from study treatment for the following reasons: 
• Intercurrent illness which prevents further follow up 
• Withdrawal of consent for treatment by patient 
• Any alterations in the patient’s condition which justifies the discontinuation in the 
investigator’s opinion 
If a patient or investigator decides to stop the study treatment then the patient’s health status 
will be reviewed via continued study visits or phone contact, or from their general practitioner 
or medical records to allow collection of outcomes data. Follow-up assessments including 
completion of the quality of life questionnaires should still be completed as per section 9 if the 
patient is willing. In the event that a patient withdraws from the study entirely, the effective date 
of the notification will be the date on which their withdrawal is received by the OUTBACK study 
team. No information about the patient will be collected from that point in time onwards but any 
information collected prior to that date can be used and forms part of this study. 
7.4 
Patient transfers 
For patients moving from the area, every effort should be made for the patient to be followed up at 
another participating trial centre and for this trial centre to take over responsibility for the patient.  A 
copy of the patient CRFs will need to be provided to the new site after appropriate patient consent.  
Until the new centre formally agrees (in writing) to take over responsibility, the patient remains the 
responsibility of the original centre. 
 
 
 
 
 
 


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8 TREATMENT OF SUBJECTS 
Study treatment must start within 6 weeks after randomisation. 
8.1 
Chemotherapy administration 
Cisplatin, paclitaxel and carboplatin should be given in the doses and schedule detailed below, 
according to standard practice in the participating country. Suggested pre- and post-chemotherapy 
medication and hydration guidelines are detailed below. For detailed information on each drug, 
please refer to the relevant Summary of Product Characteristics in the package insert. 
 Dose calculation: The dose will be calculated using actual body weight. Dose capping of cisplatin 
and paclitaxel should not be done for obese patients as per the recent ASCO guidelines. The doses 
of all chemotherapy agents should be re-calculated if there is a weight change of >10% from 
baseline. Doses should not be increased following a dose reduction because of toxicity. 
8.1.1 Concurrent phase (both treatment arms) 
 
Agent 
Dose/day 
Route 
Frequency 
Cisplatin 
40 mg/m2 in 1000 ml 
NaCl 0.9% or 2.5-3%* 
IV in 1 hour with 
associated hydration 
Weekly for 5 doses** 
* According to local standard protocol. Cisplatin should only be given on a day that external-beam 
radiation is scheduled and must be given prior to radiation treatment on that day. Treatment should 
preferably be given on a Monday, Tuesday or Wednesday. Cisplatin should commence within the 
first 3 radiation treatments. Cisplatin should not be given on a day of brachytherapy treatment. 
** For consistency between treatment arms, all patients should be planned to receive 5 doses 
regardless of the radiation fractionation schedule planned. 
 
Published studies of prospective randomised trials to date have not compared whether there is a 
difference in outcome based on whether 5 or 6 cycles of weekly cisplatin are received during 
radiation. However, a retrospective review of data from the GOG120 and 165 studies found no 
difference in survival outcomes for patients treated with either 5 or 6 cycles of weekly cisplatin46. 
There has been a further recent retrospective study published of 118 patients treated with cisplatin-
based chemo-radiation for locally advanced cervical cancer in which no difference in survival was 
seen in patients treated with 5 or 6 cycles of weekly cisplatin, although inferior survival was seen in 
those treated with less than 5 cycles47. 
The MRC individual patient data meta-analysis reports that ‘for the eight trials that used cisplatin-
based chemo-radiotherapy, we found no evidence that the effect of chemo-radiotherapy differed 
according to the cycle length or the dose-intensity of cisplatin used’12. It has been noted in several 
trials that only 50-70% of patients are able to compete a full 6 cycles of cisplatin without dose 
decreases or delays due to toxicity, primarily haematologic46-49.  
 


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Suggested schedule for pre- and post-hydration: Pre-hydration: 1000 ml NaCl 0.9% in 2 hours 
followed by 400ml of 10% Mannitol over 30 minutes. Post-hydration: 1000 ml NaCl 0.9% in 2 hours, 
with adequate IV supplementation of Mg. Other schedules (if used in standard protocols) may be 
chosen at the participating centre’s discretion. 
8.1.1.1 Dose modifications of cisplatin 
All toxicities will be graded according to the US National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE). It is recommended that anaemia > grade 1 
(i.e. Hb <10 g/dL) during chemoradiation be corrected with blood transfusion as soon as possible. 
There will be no dose escalations in this study. Chemotherapy will not be administered during a 
radiation therapy delay. Radiotherapy will not be omitted or delayed for chemotherapy-related 
toxicities unless the investigator considers the patient too ill to be treated. If a cisplatin cycle is 
delayed due to a radiation therapy delay, then this can be made up if the patient is still receiving 
external beam radiation therapy in the 6th or 7th week of treatment. 
Initial treatment modifications will consist of cycle delay and/or dose reduction as directed. 
Treatment decision will be based on absolute neutrophil count (ANC) not total white blood cell count 
(WBC) on the day of treatment or no more than 72 hours prior. No cisplatin will be administered or 
resumed until ANC is ≥1.5 x 109/L and/or platelet count is ≥ 75 x 109/L. Chemotherapy will be 
delayed week-by-week until these levels are exceeded. External radiation should continue while 
cisplatin is being withheld. Patients who fail to recover from toxicities within 21 days will not 
receive further cisplatin.. Only one dose reduction is allowed for cisplatin. Patients in the 
experimental arm (Arm B) are allowed to continue with adjuvant chemotherapy if 
chemoradiation toxicities (with the exception of lymphocyte count) resolve to < grade 2. 
 
Drug 
Starting dose level 
Dose level -1 
Cisplatin 
40mg/m2 
30mg/m2  
 
DRUG-RELATED TOXICITY 
PARAMETER 
MODIFICATION 
Febrile neutropenia/ANC 
1st occurrence febrile 
neutropenia (≥ grade 3) or 
ANC < 0.5 x 109/L lasting > 7 
days 
Hold for 1 week. Repeat 
bloods. If ANC resolves to 
grade 1, resume at 1 dose 
level reduction. If ANC does 
not resolve to grade 1 
discontinue cisplatin 
Febrile neutropenia/ANC 
2nd occurrence 
Discontinue cisplatin 
ANC 
Uncomplicated (no 
fever/infection) ANC  
< 0.5 x 109/L  lasting < 7 days 
No dose reduction but not for 
re-treatment until ANC resolves 
to grade 1 


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Platelets 
1st occurrence grade 4 
thrombocytopenia or bleeding 
associated with grade 3 
thrombocytopenia 
Hold for 1 week. Repeat blood 
work. If platelets >75 x 109/L, 
resume at 1 dose level 
reduction. If thrombocytopenia 
does not resolve to grade 1 
discontinue cisplatin 
Platelets 
2nd occurrence of above 
Discontinue cisplatin 
Platelets 
Grade 3 – uncomplicated 
(absence of associated 
bleeding) 
Hold until platelets >75 x 109/L 
Resume at current dose level 
(no dose modification) 
Nausea/vomiting 
Grade 3 or 4 
Hold until resolved to grade 1 
with supportive therapy. 
Resume at 1 dose level 
reduction 
Nausea/vomiting 
2nd occurrence of above 
Discontinue cisplatin 
Serum creatinine/GFR 
 
GFR < 50 ml/min (Cockroft 
Gault), and/or Serum 
creatinine > 1.5 x ULN 
GFR < 40 ml/min (measured 
creatinine or EDTA clearance) 
Hold for 1 week. Repeat blood 
work. Resume if GFR recovers 
to above these levels at the 
same dose. Discontinue 
cisplatin if not recovered after 1 
week 
Neurotoxicity – peripheral 
neuropathy 
 ≥ Grade 2 
Hold until neuropathy resolves 
to grade 1. Resume at 1 dose 
level reduction. Discontinue 
cisplatin if neuropathy does not 
resolve within 21 days 
Tinnitus or hearing impaired 
Grade 3 or 4 
Discontinue cisplatin 
Tinnitus or hearing impaired 
Grade 2 
Hold until recovery to grade 1, 
then resume at one dose level 
reduction. An audiogram 
should be performed to clarify 
if possible irreversible hearing 
loss 
Fatigue 
Any grade 
No dose reduction 
 
 


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Other cisplatin –related non-
haematologic toxicity (except 
for non-clinically significant 
laboratory abnormalities such 
as lymphocyte count)  
≥ Grade 3  
Hold until toxicity resolved to 
grade 1, then resume at same 
dose. If toxicity does not 
resolve to grade 1 within 21 
days discontinue cisplatin 
 
8.1.2 Adjuvant phase (Arm B only) 
8.1.2.1 Carboplatin and paclitaxel dose 
Agent 
Dose/day 
Route 
Days 
Paclitaxel  
155 mg/m2  
IV in 3 hours 
1, 22, 43, 64 
Carboplatin 
AUC 5 
(calculated AUC) 
IV in 1 hour 
1, 22, 43, 64 
 
Four cycles of adjuvant therapy with carboplatin and paclitaxel will be given, at 3 week intervals. 
Nano –particle albumin bound paclitaxel must not be used. Adjuvant chemotherapy should be 
started within 4 weeks of completion of all radiotherapy, meaning all external beam radiotherapy and 
brachytherapy, and preferably 3-4 weeks after the last administration of cisplatin. If adjuvant 
chemotherapy is not planned to commence  for more than 6 weeks after completion of all 
radiotherapy, this should be discussed with the study chair. Before starting adjuvant chemotherapy, 
the toxicities of the concomitant chemoradiation should be resolved to less than grade 2 (except for 
lymphocyte count). Doses should be calculated based on the weight and laboratory results at the 
time of start of adjuvant chemotherapy. Dose capping of paclitaxel should not be used as per the 
ASCO Guideline for Chemotherapy Dosing in Obese adults. 
Carboplatin dose is to be  calculated according to the Calvert formula: 
 
Dose (mg) = target AUC x (GFR + 25),  
 
where AUC = Area under curve 
GFR should be calculated according to Cockcroft-Gault Formula for females: 
GFR (ml/min) = [1.05 x (140 – age) x weight (kg)] / serum creatinine (umol/L) 
Actual weight should be used for estimation of GFR for patients with BMI of less than 25.   
Adjusted weight should be used for estimation of GFR for patients with BMI of greater than or 
equal to 25. 
Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
A nuclear medicine GFR result may be performed if there is concern about the accuracy of a 
calculated GFR result, e.g. result > 100ml/min, serum creatinine very low, the patient is obese or 


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very underweight, or the patient has pre-existing renal impairment or ureteric obstruction. AUC for 
carboplatin should be recalculated in case of increasing serum creatinine (increase of 10% and/or 
out of normal range) and/or weight change of >10% from the start of adjuvant chemotherapy. 
The dose for paclitaxel should be recalculated in case of weight change of >10% from the start of 
adjuvant chemotherapy. 
The GFR used in the Calvert formula should not exceed 125 ml/min. If the calculated or measured 
value is > 125 ml/min then it should be capped at 125 ml/min.  
The maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
The maximum allowed dose of carboplatin is AUC 5 = 750 mg. 
 
8.1.2.2 Dose modifications for carboplatin and paclitaxel  
Adjustments for haematological toxicity 
Pre-treatment neutrophil count should be ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L on the day of 
treatment or within 72 hours prior. If counts are below these levels, treatment should be delayed one 
week. If counts have recovered after one week, treatment should proceed at the starting doses. If 
counts have not recovered after one week, treatment should be delayed an additional week. If 
counts have recovered after the additional week’s delay, doses should start at the reduced dose 
levels. If counts have not resolved after 2 weeks, no further chemotherapy should be given. 
 
Drug 
Starting dose level 
Dose level -1 
Carboplatin 
AUC 5 (calculated AUC) 
AUC 4 
Paclitaxel 
155 mg/m2 
135 mg/m2 
 
TOXICITY 
PARAMETER 
MODIFICATION 
Febrile neutropenia/ANC 
1st occurrence febrile 
neutropenia (≥ grade 3) or 
ANC < 0.5 x 109/L  lasting > 7 
days 
Hold for 1 week. Repeat blood 
work. If ANC resolves to grade 
1 resume at 1 dose level 
reduction. If ANC does not 
resolve to grade 1 by 2 weeks 
discontinue carboplatin and 
paclitaxel 
Febrile neutropaenia/ANC 
2nd occurence of above 
Discontinue carboplatin and 
paclitaxel 
 
 


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Platelets 
1st occurrence grade 4 
thrombocytopenia or bleeding 
associated with grade 3 
thrombocytopenia 
Hold for 1 week. Repeat blood 
work. If platelets >100 x 109/L  
resume at 1 dose level 
reduction. If thrombocytopenia 
does not resolve to grade 1 by 
2 weeks discontinue 
carboplatin and paclitaxel 
Platelets 
2nd occurrence of above 
Discontinue carboplatin and 
paclitaxel 
 
Adjustments for Non-Haematological toxicity 
The following table should be used for dose reductions in the event of any grade 3 or 4 non- 
haematological toxicity excluding alopecia, nausea or constipation that lasts for more than 1 week. 
In the event of a grade 3 or 4 non-haematological toxicity apart from those specifically discussed 
below, doses should be reduced by one dose level and treatment given after recovery of the toxicity 
to be less than grade 2, if recovery has not occurred after a week delay. If the toxicity does not 
recover to be less than grade 2 after 2 weeks, then no further chemotherapy should be given. If a 
patient develops recurrent grade 3 or 4 non haematological toxicity at dose level -2, the patient 
should come off study treatment. 
Drug 
Starting dose level 
Dose level -1 
Dose level -2 
Carboplatin 
AUC 5 
AUC 4 
Additional10% reduction in 
dose used for Dose level -1 
Paclitaxel 
155 mg/m2 
135 mg/m2 
110 mg/m2 
 
TOXICITY 
PARAMETER 
MODIFICATION 
Peripheral neuropathy 
≥ Grade 2  
Reduce paclitaxel by 1 dose 
level and delay subsequent 
therapy for a maximum of 2 
weeks until recovery to Grade 
1. If the neuropathy does not 
recover to be less than Grade 
2, the patient should continue 
with carboplatin alone 
 
 


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Hepatic toxicity  
≥ Grade 3 elevations in AST, 
ALT or bilirubin 
Reduce paclitaxel by 1 dose 
level, but NOT carboplatin, and 
delay subsequent therapy for a 
maximum of 2 weeks until 
recovery to Grade 2. If the 
hepatic toxicity does not 
recover to be less than Grade 
2 the patient should continue 
with carboplatin alone 
Serum creatinine 
≥ Grade 2 
Hold for 1 week. Repeat blood 
work. Delay subsequent 
therapy for a maximum of 2 
weeks until recovery to Grade 
1, then resume at one dose 
level reduction. If the creatinine 
does not recover to be less 
than Grade 2, then no further 
chemotherapy should be given 
 
The occurrence of a hypersensitivity reaction to paclitaxel is not considered a toxicity requiring dose 
adjustment and should be managed as per usual institutional practice. Patients may be retreated at 
full doses after management as per usual institutional practice. For example, following 
administration of medication to prevent hypersensitivity reactions, a slow initial infusion rate of 
paclitaxel should be utilized which is gradually increased to the standard infusion rate in the absence 
of a reaction. In case of severe hypersensitivity to paclitaxel, where rechallenge is not medically 
indicated or if repeated severe reaction at rechallenge, paclitaxel can be substituted by docetaxel 75 
mg/m2. In case of hypersensitivity to docetaxel as well or where docetaxel is not available, continue 
with carboplatin AUC 5. In case of severe hypersensitivity to carboplatin, where rechallenge is not 
medically indicated or if repeated severe reaction at rechallenge, carboplatin could be substituted by 
cisplatin 50 mg/m 2.   
8.2 
Concomitant Medications/Treatments 
8.2.1 Concomitant chemoradiation: 
Anti-emetic therapy before the start of cisplatin: aprepitant 125 mg, dexamethasone 8 mg, 
ondansetron 8 mg; or use a standard combination of a corticosteroid and a 5HT-antagonist (the use 
of aprepitant is at discretion of the participating centre). 
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8.2.2 Adjuvant chemotherapy: 
Premedication before the start of carboplatin and paclitaxel: dexamethasone 20 mg i.v., phenergan 
25 mg orally, ranitidine 50 mg i.v. and a 5HT-antagonist (the use of aprepitant is at discretion of the 
participating centre) or a similar schedule at the discretion of the participating centre. 
After administration of chemotherapy, anti-emetic therapy is at the discretion of the participating 
centre. 
Use of G-CSF is permitted for secondary prophylaxis after a neutropenic complication according to 
the American Society of Clinical Oncology guideline (2006 Update of ASCO Recommendations for 
the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline).   
Further anti-cancer therapy should not be instituted following completion of study treatment unless 
progressive disease is documented. 
8.3 
Radiotherapy Treatment 
This is a prospective multi-national trial investigating the addition of adjuvant chemotherapy 
following completion of primary chemo-radiation for patients with locally advanced cervical cancer. 
The incidence of cervix cancer has decreased in developed countries, but remains one of the 
leading causes of cancer-related morbidity and mortality in developing countries. Many of the trial 
participants are likely to be from developing countries. It is recognised that these countries have 
limited resources and infrastructure. Their participation is necessary not only for the successful 
completion of this study but to ensure that any treatment protocols that are developed through such 
studies are applicable in countries where cervix cancer is most prevalent. The protocols and quality 
assurance criteria for this trial have been designed to enable participation from both advanced and 
developing countries and centres.  
 
Radiation therapy (RT) must be started within six weeks of randomisation; CT scan or MRI of the 
pelvis is recommended but not required for external RT field and block definition. 
 
8.3.1 Standardized Radiotherapy 
External beam radiotherapy followed by intracavitary brachytherapy. 
 
External Irradiation 
8.3.1.1 EBRT Radiation Equipment 
Radiation beams must be of megavoltage energy with a source to surface distance (SSD) of 80 cm 
or greater. Use of linear accelerators and Cobalt 60 units are allowed. 
 
8.3.1.2 EBRT Technique and Doses 
All patients should be treated with whole pelvic radiotherapy. Those with common iliac nodal 
disease should be treated with extended field radiotherapy (EFRT). 


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A four-field box technique with parallel opposed AP/PA and two opposing lateral fields is 
recommended. AP/PA only fields are allowed in thin women at the discretion of the treating 
physician. A thin woman is defined as one for whom the AP/PA midplane percent depth dose is 72% 
or more, or for isocentric treatments, the tissue-maximum ratio (TMR) is 0.82 or more. 
Due to constraints on quality assurance capabilities highly conformal techniques such as IMRT and 
Rapid Arc are not permitted  
Patients will receive 45 – 50.4 Gy external beam radiation therapy (EBRT) delivered in fractions of 
1.8 Gy to the pelvis.  
Patients with involved nodes where EFRT may be needed will receive 45 Gy in fractions of 1.8 Gy to 
extended field. 
Treatments are to be delivered daily. At the end of EBRT, if intracavitary brachytherapy (BT) cannot 
be performed, shrinking field technique should be employed to bring gross tumour volume, with 
adequate margins, to a minimum of 65 Gy. An attempt should be made to exclude small bowel from 
the treatment field after 50.4 Gy. Interstitial brachytherapy is not permitted on this study. 
 
8.3.1.3 EBRT Treatment aids/equipment 
Patients may be treated with bladder distension. Bowel exclusion devices (e.g. belly boards) are 
allowed. 
 
8.3.1.4 Parametrial or nodal boost 
Parametrial or nodal boost is allowed at the discretion of the treating radiation oncologist.  Nodal 
involvement is defined as any pelvic or common iliac nodes if they are either PET positive or their 
short axis diameter is > 15mm on CT and/or MRI or if nodes are found to be histologically positive 
on surgical sampling. 
Doses to the parametrial/nodal boost should not exceed 10 Gy with a total dose to the sidewall not 
to exceed 65 Gy at midplane.  Fractions of 1.8-2 Gy can be used. Point B may be used as the 
calculation point dose site if the boost is in the parametrial region.   
For a parametrial boost the superior border should be reduced to include only the true pelvis. The 
upper border of the true pelvis field is defined as 1.0 cm above the inferior aspect of the sacroiliac 
joint.  
If nodal involvement is documented, fields with up to 2.0 cm margin around the gross nodal disease 
as seen on the CT scan, MRI or PET is recommended. Nodal boost fields can be delivered via 
conformal fields. 
 
8.3.1.5 Timing of the parametrial and/or nodal boosts 
The nodal / parametrial boosts can occur after completion of EBRT and in between the 
brachytherapy insertions. 
 
 
 


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8.3.1.6 EBRT Fractionation 
Conventional fractionation will consist of one fraction per day, total five fractions per week. 
(Exceptions are six fractions per week for 1 -2 weeks to ensure overall treatment time stays within 
limits and to facilitate brachytherapy bookings.) 
 
8.3.1.7 Therapy interruptions 
Reasons for interruption to external beam radiation of greater than one week, (7 consecutive days), 
should be recorded. 
 
8.3.1.8 EBRT imaging for localization and verification 
Diagnostic CT scan or MRI is strongly recommended for pre-treatment planning. 
All patients must undergo simulation using x-ray or CT for localization and verification of external 
beam treatment portals.  
 
8.3.1.9 External radiation fields  
The external beam target volume should encompass, with adequate margins, the gross tumour 
volume (GTV) which includes the primary cervical tumour and its gross extension and any grossly 
involved lymph nodes. Clinical target volume should include the GTV, parametria, uterus, upper half 
of the vagina, internal, external and distal common iliac nodes, and utero-sacral ligaments. 
 
8.3.1.10   Four-field external beam technique  
 
Whole Pelvis AP/PA fields:  
Radiation portals should consist of a typical pelvic field, the upper border being L5 – S1 or L4-L5. 
The lateral borders should be marked 2 cm lateral to true pelvis and inferior borders at the lower 
margins of the obturator foramina or 3 cm below the known inferior extent of the gross disease 
(whichever is most caudal). Where possible, the femoral heads should be blocked. 
 
Whole Pelvis Lateral fields: 
The upper and lower borders of the lateral fields should be the same as in the AP/PA fields. The 
anterior border of the pelvic field should be 1 cm anterior to the superior edge of pubic symphysis 
and the posterior border should intersect the S2-S3 space or 3 cm posterior to the uterine outline or 
any gross disease whichever is greater. Custom shielding should be designed such that gross 
disease is encompassed with at least a 2 cm margin. The outer table of the sacrum may be blocked 
to protect the sacral plexus on lateral fields, and the small bowel should be blocked in the anterior-
superior lateral fields.  
 
 
 


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EFRT AP/PA fields 
See whole pelvis description for pelvic limits. 
These fields should encompass the highest involved node with a margin of 3 cm or one vertebral 
body cephalad, to a maximum upper level of L1/L2 vertebral space.  Lateral margins above L4 
vertebral body should be at least 6 cm wide or a minimum of 2 cm lateral to the lateral border of 
involved lymph node, whichever is greater. Special consideration should be taken to block the 
kidneys. The dose should be no higher than 1.8 Gy per fraction. 
 
EFRT Lateral fields 
See whole pelvis description for pelvic limits 
The anterior border of chimney part of EFRT should be 3 cm anterior to the anterior surface of the 
vertebral body or 2 cm anterior to the anterior surface of any enlarged node. Posterior border of the 
chimney field should follow the spinal curve with a 5 -7 mm margin anterior to the spinal canal 
provided the involved nodes are adequately covered.  
 
8.3.2 Intracavitary Brachytherapy 
8.3.2.1 Brachytherapy (BT) Radiation Equipment 
Intracavitary treatment will be delivered with standard applicators; tandem and ovoids or tandem and 
ring. A tandem and cylinder is allowed only for patients where tandem and ovoid application is not 
possible due to extent of disease or vaginal anatomy. 
 Interstitial brachytherapy should not be part of the original treatment plan for radiotherapy. Patients 
assessed as requiring interstitial brachytherapy at diagnosis are not eligible. However, if it is felt to 
be clinically imperative to change the plan after treatment start to deliver interstitial brachytherapy 
because of poor response of the tumour to external beam radiotherapy then this should be 
recorded. 
The dose prescription and reporting in this situation will be the isodose line at the perimeter of the 
implanted volume, where dosimetric constraints similar to “point A” will apply.  
 
8.3.2.2 BT Doses 
Brachytherapy should deliver a dose to the primary tumour such that the primary tumour receives 80 
– 86.4 Gy in total, from the combination of EBRT and BT. See Tables 1 and 2 for examples. 
 
Table 1.  LDR – Point A determined implant 
Total EBRT (Gy) at 
1. 8 Gy/fx 
Number of LDR 
Fractions 
Dose per 
fraction (Gy) 
Total LDR point 
A dose (Gy) 
Total point A 
dose (Gy) 
45 
1 
35-40 
35-40 
80-85 
45 
2 
18-20 
36-40 
81-85 
50.4 
1 
30-35 
30-35 
80.4-85.4 
50.4 
2 
15-18 
30-36 
80.4-86.4 
 
 


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Table 2.  HDR- Point A determined implant or volume directed approach 
Total EBRT (Gy) 
at 1.8 Gy/fx 
# HDR fractions 
HDR Point A 
dose/fraction 
(Gy) 
Total HDR Point A 
dose (Gy) 
Total Point A 
 EQD2 –Gy10  
45 
3 
8.4 
25.2 
82.9 
45 
4 
6.8 
27.2 
82.3 
45 
5 
5.8 
29.0 
82.4 
 
 
 
 
 
50.4 
3 
7.5 
22.5 
82.4 
50.4 
4 
6.1 
24.4 
82.3 
50.4 
5 
5.2 
26 
82.5 
Where EQD2 = Total Biological Equivalent Dose in 2 Gy Fractions  
 
8.3.2.3 BT imaging for localization and verification 
Orthogonal x-ray films, ultrasound, CT or MRI can be used to calculate dosimetry for brachytherapy 
insertions. 
Ideally, soft tissue imaging (trans-abdominal ultrasound, CT or MRI) with applicator in-situ should be 
performed at each insertion to confirm the position of the tandem within the uterus.  
 
8.3.2.4 BT dose prescription 
Dose can be prescribed to Point A, or user defined target volumes. See study handbook for 
definitions. 
 
8.3.2.5 BT dose reporting 
Point A dose will be reported for all patients by all participating centers. 
In addition to Point A dose, the centers using 3D imaging may also report the D90 to the Gec-
ESTRO defined high risk clinical target volume (HR-CTV). See study handbook for definitions. 
 
8.3.3 Timing and fractionation of LDR & PDR Brachytherapy  
Following the completion of whole pelvic RT, the patient will receive an intracavitary implant. The 
patient may receive LDR intracavitary BT in one or two applications at the discretion of the radiation 
oncologist. The first insertion should be performed promptly upon completion of whole pelvic RT. If 
two implants are contemplated, the second implant should be completed within three weeks of the 
completion of whole pelvic RT, (total treatment time should be less than or equal to 56 days). 
 
8.3.3.1 Total Normal Tissue Tolerances (EBRT + LDR BT) 
International Commission on Radiation Units (ICRU)  
ICRU 38 Bladder reference point ≤ 75 Gy 
ICRU 38 Rectal reference point ≤ 70 Gy 
Vaginal Mucosa ≤ 130Gy 
 
 
 


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8.3.4 Timing and fractionation of HDR brachytherapy 
HDR brachytherapy may start in week 4, 5 or at the end of external beam radiotherapy. If HDR 
brachytherapy begins during EBRT, EBRT should not be given on the day of brachytherapy. If 
brachytherapy starts in week 4, there should be a maximum of one insertion per week. If the 
brachytherapy starts in week 5 or at the end of EBRT, two insertions per week may be done. This 
will enable treatment to be completed within eight weeks (EBRT plus brachytherapy). Three to five 
fractions of HDR brachytherapy are permitted as described in the study handbook. 
 
8.3.4.1 Total Normal Tissue Tolerances (EBRT + HDR BT) 
Normal tissue doses should be calculated.  
ICRU 38 Rectal reference point ≤ 70 Gy3  (EQD2 using α/β=3 for late effects) 
ICRU 38 Bladder reference point ≤ 75 Gy3 (EQD2 using α/β=3 for late effects) 
Vaginal Mucosa ≤ 130 Gy3 (EQD2 using α/β=3 for late effects) 
 
 
 


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Table 3. HDR- Normal tissue dose constraints. Guideline and examples to dose per fraction of HDR Physical 
dose per fraction, total physical dose (EBRT+BT) and total dose (EBRT+BT) EQD2 
 
 
 
Total 
EBRT 
at 1.8 
Gy/fx 
 
 
# HDR 
fraction
s 
 
 
 
HDR 
Point A  
dose/fracti
on 
 
 
      
      Gy 
 
 
 
Maximum 
physical 
dose per fx 
 for bladder  
 
 
      
       Gy 
 
 
Total 
(EBRT+BT) 
maximum 
Physical 
bladder 
dose  
 
 
      Gy 
 
 
(EQD2 Gy3) 
 
 
Maximum 
Physical 
dose per fx 
for rectum 
 
 
      
     Gy 
 
Total 
(EBRT+BT) 
Maximum 
physical 
rectal dose  
 
 
  
    Gy 
  
 
(EQD2 Gy3) 
 
Maximu
m 
Physical 
dose per 
fx for 
vaginal 
mucosa 
 
     Gy 
 
Total 
(EBRT+BT) 
Maximum 
physical 
vaginal 
mucosa 
dose  
 
 
     Gy 
 
 
(EQD2 Gy3) 
45 
3 
8.4 
5.9 
45+17.7= 
 
62.7 Gy 
 
(74.7 Gy3) 
5.3 
45+15.9= 
 
60.9 Gy 
 
(69.6 Gy3) 
10.6 
45+31.8= 
 
76.8 Gy 
 
(129.7 Gy3) 
45 
4 
6.8 
5 
45+20= 
 
60 Gy 
 
(75.2 Gy3) 
4.5 
45+18= 
 
63 Gy 
 
(70.2 Gy3) 
9 
45+36= 
 
81 Gy 
 
(129.6 Gy3) 
45 
5 
5.8 
4.3 
45+21.5= 
 
66.5 Gy 
 
(74.6 Gy3) 
3.9 
45+19.5= 
 
64.5 Gy 
 
(70.1 Gy3) 
7.9 
45+39.5= 
 
84.5 Gy 
 
(129.3 Gy3) 
50.4 
3 
7.5 
5.3 
50.4+15.9= 
 
 66.3 Gy 
 
(74.8 Gy3) 
4.6 
50.4+13.8=  
 
64.2 Gy 
 
(69.4 Gy3) 
10.2 
50.4+30.6= 
 
 81 Gy 
 
(129.3 Gy3) 
50.4 
4 
6.1 
4.5 
50.4+18=  
 
68.4 Gy 
 
(75.4 Gy3) 
3.9 
50.4+15.6= 
 
 66 Gy 
 
(69.9 Gy3) 
8.7 
50.4+34.8= 
 
 85.2 Gy 
 
(129.8 Gy3) 
50.4 
5 
5.2 
3.9 
50.4+19.5= 
 
 69.9 Gy 
 
(75.3 Gy3) 
3.4 
50.4+17= 
 
67.4 Gy 
 
(70.1 Gy3) 
7.6 
50.4+38=  
 
88.4 Gy 
 
(128.9 Gy3) 
 
 
As in LDR brachytherapy, every attempt should be made to deliver tumouricidal doses, even if the 
late responding tissues receive a slightly higher dose. 
 
8.3.5 Total treatment time (EBRT + BT) 
The total elapsed time for completion of external beam to the whole pelvis, intracavitary BT, and 
parametrial / nodal RT shall not exceed eight weeks (56 days).  
8.3.6 Radiation therapy quality control and documentation 
As part of the radiotherapy quality control carried out by the Imaging and Radiation Oncology Core  
(IROC), off-site dosimetry audits will be performed.  
 


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Data needs to be submitted for selected cases within 3 months of the patient completing 
radiotherapy treatment.  
 
8.3.6.1 EBRT: 
The first two patients: 
Simulation films or digitally reconstructed radiograph (DRRs) (for all treatment fields and phases of 
treatment including EBRT boosts) from each participating centre will be submitted to the NHMRC 
CTC or IROC directly. 
Portal films verifying the position of the external beam films taken during the first week of treatment 
will be obtained and submitted to the NHMRC CTC or IROC directly.  
 
If the simulator films/ DRRs are acceptable, then simulator films/ DRRs from every 10th patient will 
be submitted. If the first two patient simulator films/DRRs are unsatisfactory, then centres will be 
requested to send more simulator films/DRRs until they are in compliance with the protocol. 
 
8.3.6.2 Documentation requirements EBRT 
Field outlines are required for all treatment fields. These should be displayed on the simulation films 
or DRRs. 
Portal films, daily treatment records, treatment plan including isodose distribution through the centre 
of the treatment volume, and dosimetry calculations. Also submit online a completed External Beam 
Summary Form (found at http://rpc.mdanderson.org under Forms). 
 
8.3.6.3 Compliance Criteria for standard radiation therapy 
Per protocol: See section 8.3.1.1 – 12 
 
8.3.6.4 Variation Acceptable: 
 
Total treatment time up to 67 days. 
 
External beam dose of 43.6-51.9 Gy 
 
Boost dose of 10 Gy with total external beam dose ≤ 65 Gy 
Total dose to point A as outlined in Tables 1 and 2 +/- 5% 
 
8.3.6.5 Deviation unacceptable 
Total treatment time of more than 67 days 
External beam dose of less than 43.6 or greater than 51.9 Gy 
Boost site that exceeds 65 Gy total external beam dose. 
Total dose to Point A less than or more than 5% of doses outlined in Tables 1 and 2 
 
 
 
 


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8.3.6.6 Brachytherapy: 
Simulation films, DRR’s or ultrasound views (sagittal, coronal and/or axial reconstructions) for the 
first intracavitary insertion will be submitted to the NHMRC CTC or IROC directly at the completion 
of treatment. 
Centres are encouraged to provide confirmation of the tandem position within the uterine cavity with 
either ultrasound imaging, CT or MRI. Such imaging (preferably sagittal) during or after each 
insertion, should be obtained and submitted to the NHMRC CTC or IROC directly. 
 
 8.3.6.7 Documentation requirements Brachytherapy 
Simulator films, DRRs or CTs or ultrasound images with applicator in-situ for each intracavitary 
placement, treatment plan (to include source activities, dwell times, dwell positions and isodose 
lines). Also submit a completed online Gynecological Brachytherapy Protocol Compliance form 
(located at http://rpc.mdanderson.org under Forms). 
 
8.3.6.8 Compliance criteria for brachytherapy 
Per protocol: see sections 8.3.2, 8.3.3, 8.3.4. 
 
8.3.6.9 Variation Acceptable: 
Brachytherapy starting in week 4 or 5 of EBRT. 
 
8.3.6.10 Variation unacceptable: 
Use of interstitial brachytherapy unless as per 8.3.2.1 due to poor response of the primary tumour to 
external beam radiotherapy. 
 
8.3.7 Total Dose (EBRT + BT) Specification  
Total dose will be a combination of the external beam dose at the midplane and the brachytherapy 
dose using Point A.  
 
8.3.7.1Total dose reporting 
Doses shall be reported as physical dose received.   
EBRT whole pelvis/extended field (i.e. 45 – 50.4 Gy) 
Central structures: PT A: EBRT + BT  e.g. 45 Gy + 2 x 20.00 Gy = 85 Gy (LDR) 
                              ICRU 38 Bladder reference point:   EBRT + BT 
                              ICRU 38 Rectal reference point:   EBRT +  BT  
                              Vaginal mucosa dose:    EBRT + BT 
 
Boosts:  Nodal boost:               EBRT + nodal boost    
              Parametrial boost:      EBRT + parametrial boost  
 


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8.3.8 Overall Compliance criteria 
 
8.3.8.1 
 
 Per Protocol: see sections 8.3.1 – 10, 8.3.2, 8.3.3, 8.3.4. 
 
8.3.8.2 Variation acceptable 
 
• 
Total treatment completed within 56 days (+20% = 67 days) 
• 
Total dose received to Point A inclusive of EBRT and BT = 80 – 86.4 Gy +/- 5%  
 
8.3.8.3 Deviation unacceptable 
 
• 
Total treatment greater than 67 days  
• 
Total dose received at Point A less than 76 Gy or greater than 90.7 Gy 
If an unacceptable deviation is recorded due to low dose to point A, the investigators will be 
asked to clarify if image guided brachytherapy was used or not used. If image guided 
brachytherapy was used, the investigator will be asked to specify the dose received to 90% 
high-risk clinical target volume (HR CTV). This response will be recorded alongside the point 
A dose. 
 
 
 


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9 ASSESSMENT OF EFFICACY, SAFETY AND PATIENT QUALITY OF LIFE 
9.1 
Assessment of Efficacy and Baseline Measures 
All patients will undergo routine baseline investigations including appropriate clinical review, 
baseline bloods and CT scan as outlined in section 10. A baseline MRI and PET or PET/CT scan 
should also be performed if available to sites to determine if the patient has PET positive nodal 
disease and/or corpus uterine invasion (Appendix 3). CT and/or MRI results should be used to 
determine RECIST 1.1 measurements.  It is recommended that PET scans are performed in 
accordance with the standard operating procedures recommended by the American College of 
Radiology Imaging Network (ACRIN) at: 
http://www.acrin.org/CORELABS/PETCORELABORATORY/PETSOPS/tabid/484/Default.aspx 
 In consenting patients, (optional) baseline biopsy samples and a sample of whole blood and plasma 
will be stored at the site for future translational studies. In addition, at suitable sites patients requiring 
another biopsy for clinical reasons (such as confirmation of diagnosis) will be asked to consent to 
donate fresh frozen tissue for planned translational research studies.  
Patients will be followed weekly during chemo-radiation and 3 weekly during adjuvant chemotherapy 
with routine clinical review, toxicity grading and bloods. Patients will be followed up every 3 months 
for 2 years, and then 6 monthly to 5 years. All follow-up time points are calculated from the date of 
randomisation. Each patient is planned to complete the study treatment unless disease progression 
occurs or toxicity prohibits further therapy. Regardless of whether the treatment is completed, each 
patient will be followed quarterly for two years and then every six months for three additional years 
or until death. Following completion of all study treatment, response to treatment will be determined 
by clinical examination and CT chest/abdomen/pelvis result (or MRI if this was used for baseline 
RECIST measurements) performed 6 months post randomisation according to RECIST 1.1.  A PET 
scan, or preferably PET-CT should be repeated at 4-6 months post completion of chemo-radiation if 
available to the site. A CT scan should also be performed at the time of any relapse, in order to 
determine the patterns of relapse seen. Progression free survival (PFS) is defined as the time from 
randomisation to disease progression as determined by the investigator or death from any cause. 
Overall survival is defined as the time from randomisation until death from any cause. 
9.2 
Assessment of patient quality of life 
Five questionnaires with proven validity and reliability will be used at the follow-up time-points 
specified in section 10 (Appendix 2). General quality of life will be measured with European 
Organization for Research and Treatment of Cancer (EORTC) Core questionnaire (QLQ-C30)50. It is 
a cancer-specific questionnaire with 30 items which summarize as five functioning scales (physical, 
cognitive, emotional, social and role functioning), a global health status/quality of life scale, three 
symptom scales (pain, fatigue and nausea/vomiting), and six single items assessing additional 
symptoms and perceived financial impact. To evaluate specific symptoms occurring after radiation 


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therapy and chemotherapy we will use the EORTC cervix cancer module (CX24)51 and a subset of 
measures from the ovarian cancer module (OV28)52. The measures to be used from the OV28 will 
be: items 31-37 to measure abdominal and gastrointestinal symptoms, items 38-40, 43-45 and 47 to 
measure chemotherapy side-effects, and items 52-54 to measure attitude to disease and 
treatment52.Together the CX24 and OV28 will provide the following summary scales: symptom 
experience, abdominal/gastrointestinal symptoms; other chemotherapy side-effects; 
hormonal/menopausal symptoms; body image/attractiveness; attitude to disease and treatment; 
vaginal/sexual function and lymphoedema51,52.   'In addition, two questions from the EORTC prostate 
cancer module (PR25) have been added to assess limitations to daily activities caused by urinary 
(Q39) and bowel (Q40) problems. As psycho-sexual health is a particular focus in this study, we will 
also use the Sexual function-Vaginal Changes Questionnaire (SVQ)53. Ten of its items are 
applicable to all patients, summarising as three scales (intimacy, sexual interest and global sexual 
satisfaction). A further ten items for sexually active respondents provide an additional two scales: 
vaginal changes and sexual functioning. In addition, the reliable and validated FACT/GOG 
neurotoxicity 4 item subscale will be used to specifically assess for the impact of any peripheral 
neuropathy seen in the trial54. A standardised checklist will be used to capture reasons for non-
completion of the quality of life questionnaires. If a quality of life questionnaire is not available in a 
language that the patient can complete then it should be omitted. Questionnaires should not be 
completed using an interpreter. 
The quality of life data will be used to determine the following objectives and test the related 
hypotheses. 
OBJECTIVES 
1. To determine the prevalence of women in each arm reporting long-term symptom issues after 
treatment as measured by the symptom-specific subscales of the measures. 
2. To determine the duration of any patient-reported long-term symptom issues in each arm. 
3. To measure the long-term impact of treatment on psycho-sexual health in each arm. 
4. To correlate the scores obtained from the various sub-scales with global quality of life. 
5. To correlate the scores obtained from the various symptom sub-scales with toxicity as measured 
by the physician using CTCAE v4.0. 
6. To identify subsets of women at greater than average risk of long-term symptom issues or 
impairments in psychosexual health who could be targeted in the future for supportive care 
interventions. 
 
HYPOTHESES TO TEST 
1. That a significant component of women in both arms will report long-term problems with bowel, 
bladder and psycho-sexual function that impact on quality of life. 


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2. That patients in the adjuvant chemotherapy arm will have a short-term detriment in quality of life 
(with particular impacts on fatigue and neurotoxicity), but that this returns to be similar to the control 
arm by about a year. 
3. That patients will report more toxicity issues using the patient reported outcome measures than 
clinicians using the CTCAE v4.0. 
4. That particular subsets of women will have more QOL detriment than average e.g. those who are 
sexually active, pre-menopausal or single at baseline. 
9.3 
Assessment of Safety 
9.3.1 Definitions 
An ADVERSE EVENT (AE) is any untoward medical occurrence in a patient or clinical 
investigational subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment.  An AE can therefore be any unfavourable or unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal investigational product, whether or not considered related to the medicinal 
product (see below). 
Adverse events include the following: 
- 
All suspected adverse drug or device reactions 
- 
All reactions from drug or device – overdose, abuse, withdrawal, sensitivity, toxicity or failure 
of expected pharmacological action (if appropriate) 
- 
Apparently unrelated illnesses, including the worsening (severity, frequency) of pre-existing 
illnesses 
- 
Injury or accidents. 
- 
Abnormalities in physiological testing or physical examination that require clinical 
intervention or further investigation (beyond ordering a repeat examination) 
- 
Laboratory abnormalities that require clinical intervention or further investigation (beyond 
ordering a laboratory test). 
Any untoward event that occurs after the protocol-specified reporting period which the Investigator 
believes may be related to the drug or device. 
AEs must be reported as AEs even if they do not meet SAE criteria. 
 
A SERIOUS ADVERSE EVENT (SAE) is any untoward medical occurrence that at any dose: 
- 
results in death, 
- 
is life-threatening (i.e. the subject is at risk of death at the time of the event), 


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- 
requires inpatient hospitalisation or prolongation of existing hospitalisation, 
- 
results in persistent or significant disability or incapacity, 
- 
 is a congenital anomaly/birth defect, 
- 
other important medical events which, in the opinion of the investigator, are likely to become 
serious if untreated, or as defined in the protocol 
NOTES: 
(i) The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
(ii) Important medical events which may not be immediately life-threatening or result in 
death or hospitalization but which may jeopardize the patient or may require intervention 
to prevent one of the listed outcomes in the definition above should also be considered 
serious.  
A SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) is an SAE that is 
related to the drug or device and is unexpected (i.e. not listed in the investigator brochure or 
approved Product Information; or is not listed at the specificity or severity that has been observed; or 
is not consistent with the risk information described in the Subject Information Sheet and Informed 
Consent Form or elsewhere in the protocol. (FDA, Safety Reporting Requirements for INDs and 
BA/BE Studies, draft guidance, September 2010)).   
An event is causally related if there is a reasonable possibility that the intervention caused the AE, 
i.e. there is evidence to suggest a causal relationship between the drug and the event (FDA, Safety 
Reporting Requirements for INDs and BA/BE Studies, draft guidance, September 2010). 
For the purposes of this study, the following adverse events are not reported as SAEs: 
• 
Hospitalisations related to disease progression 
• 
Administration of chemotherapy; or 
• 
Administration of a study procedure; or  
• 
Unrelated scheduled elective surgery; or 
• 
Convenience purposes, e.g. transportation difficulties, timing of blood transfusion 
9.3.2 Reporting of Serious Adverse Events (including SUSARs) 
The investigator is responsible for reporting all Serious Adverse Events (including SUSARs) 
occurring during the study to the NHMRC Clinical Trials Centre within 1 working day of the 
investigator becoming aware of the event using the SAE form.  SAEs must be reported up to 30 
days from the end of study intervention. 


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SAE reports should be reported to the CTC as per the procedure documented in the Study Manual. 
For the purpose of this study, SAEs occuring prior to commencement of study treatment do not need 
to be reported. 
The CTC will provide SUSAR reports and SAE line listings to Investigators for submission to Human 
Research Ethics Committees (HRECs) as required. The CTC will be responsible for providing 
reports to the Lead HREC. 
The investigator must notify the local HREC as required.  
The study sponsor/CTC will submit ‘reportable safety events’ to the TGA in Australia and to national 
coordinating centres to provide to the regulatory authorities in other participating countries for which 
the CTC is responsible.  
The following information will be recorded for each Serious Adverse Event:   
• 
Event description including classification according to NCI CTCAE 
• 
Primary and secondary diagnoses of event (If death/hospitalisation) 
• 
Severity / Worst Grade 
• 
Attribution to study intervention  
• 
Expectedness (listed in IB/product information) 
• 
Action taken with study intervention   
• 
Impact of SAE (e.g. hospitalisation details) 
• 
Outcome of SAE including end date if recovered 
9.3.3 Pregnancy  
In the event of a pregnancy occurring during the course of a study, the subject must be withdrawn 
from study drug immediately. Pregnancies occurring up to 6 months after the completion of the 
study must also be reported to the investigator.  The investigator should counsel the patient; discuss 
the risks of continuing with the pregnancy and the possible effects on the foetus.  
The NHMRC Clinical Trials Centre must be notified within 1 working day using the SAE form and the 
subject followed during the entire course of the pregnancy and postpartum period. Parental and 
neonatal outcomes must be recorded even if they are completely normal.  
 
 
 
 


 
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10 SCHEDULE OF ASSESSMENTS 
Checklist for investigators at baseline, treatment and follow up A:  
 
All follow-up time points are taken from the date of randomisation 
Baseline B  
(Before 
Randomisation) 
 
During 
Chemoradiation 
 
Week 0 - 5 
Adjuvant 
Chemotherapy (Arm 
B only) 
Every 3 weeks: 
before each cycle of 
treatment 
End of Treatment C, I 
3 - 24 months: J 
every 3 months 
24 - 60 months: J 
every 6 months 
Medical history and 
demographics 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
Pelvic exam 
X 
If clinically 
indicated 
 
If clinically indicated 
X 
X 
Assessment of toxicity 
 
X 
X 
X 
X 
X 
Performance status (ECOG) 
X 
 
X 
X 
 
 
Weight 
X 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Chest/abdominal/pelvis CT 
XE 
 
 
 
XD 
If clinically 
indicated D 
PET scan (if available) 
XE 
 
 
 
XF 
 
MRI (pelvis) 
XE 
 
 
 
XE 
 
Tumour assessment by 
RECIST 1.1 
X 
 
 
 
X D,E 
 
Full blood examination  
(WCC, ANC, Hb, Platelets) 
X 
X 
X 
X 
If clinically 
indicated 
 


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Electrolytes  
(Na, K, Mg, Ca, PO4) 
X 
X 
X 
X 
If clinically 
indicated 
 
Serum creatinine 
X 
X 
X 
X 
If clinically 
indicated 
 
Creatinine clearance 
(Cockcroft-Gault) 
X 
 
X 
 
 
 
Bilirubin, Alk Phos, ALT, 
AST 
X 
 
X 
X 
If clinically 
indicated 
 
Pregnancy test 
If clinically 
indicated 
 
 
 
 
 
HIV test 
If clinically 
indicated 
 
 
 
 
 
Quality of Life 
questionnaires  
(EORTC QLQ C30, CX24, 
OV28, FACT, SVQ) 
X 
 
X 
X 
X 
XG 
Biopsy sample & blood 
sample (if consented to 
translational research 
component) 
XH 
 
 
 
 
 
 
A Follow-up time points start from the date of randomization (not from conclusion of therapy). Patients in Arm A can omit the  3 month follow-up visit, if this 
time-point will be assessed as part of the completion of treatment visit. Patients in Arm B can omit the 3 month follow-up visit as this will fall into the 
treatment period. Patients in Arm B can omit the 6 month follow-up if this time-point will be assessed as part of the end of adjuvant chemotherapy 
treatment visit. 
Follow-up visits should be scheduled +/- 2 weeks of the calculated follow-up time point. 
B Baseline assessments should occur within 6 weeks of randomisation. Estimate of tumour size at clinical pelvic examination should be documented. 
Treatment should start no more than 6 weeks after randomisation. Baseline demographic assessment should include recording of race and smoking 
status (smoker, non-smoker [less than 100 cigarettes in lifetime], ex-smoker [quit smoking more than 1 year ago]). Of note any required blood tests may 


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be taken on or up to 72 hours prior to the date of baseline assessment. If baseline bloods are taken within one week prior to start of treatment then they 
do not need to be repeated prior to the start of treatment. 
C Review at approximately 4 weeks post completion of all study treatment  
D To be performed once at 6 months post randomisation and then repeated if relapse clinically suspected 
E Both MRI and PET scan should be performed at baseline if available to the site. Only MRI or PET/CT results (not PET alone) should be used to 
determine nodal status for the purposes of stratification/randomisation. If the patient has had both a routine PET/low-dose CT and MRI pelvis then a 
separate CT chest/abdo/pelvis is not required. In this situation, MRI rather than CT should be repeated once only at 6 months post randomisation in order 
to obtain RECIST measurements. The MRI should also be repeated at 6 months if the baseline MRI was the imaging modality used for RECIST 
measurements. 
 If the patient has had a routine PET/low-dose CT at baseline but no MRI pelvis then a separate CT chest/abdo/pelvis is required both at baseline and 6 
months post randomization. However, if CT component of the PET was done using full IV contrast and is considered suitable to perform RECIST 
measurements, then a separate CT chest/abdo/pelvis is not required. Refer to Appendix 6 for information requirements for PET reports. 
F PET scan (preferably PET/CT) to be repeated (if available to the site) once only at 4 - 6 months post completion of chemo-radiation (for both arms). 
Refer to Appendix 6 for information requirements for PET reports. 
G Quality of life questionnaires to be completed out to 36 months post randomisation. Quality of life questionnaires do not need to be completed once a 
patient has relapsed or is diagnosed with a 2nd primary cancer. If a quality of life questionnaire is not available in a language that the patient can complete 
then it should be omitted. Questionnaires should not be completed using an interpreter. 
H In patients consenting to the translational component of the study, a sample of tumour, blood for DNA and plasma will be collected for future 
translational studies. Refer to the study handbook for additional information about how these specimens should be collected and stored. 
I If the assessment for the end of treatment visit coincides (+/- 2 weeks) with the 3 or 6 month follow-up visit, then only one visit is needed where data for 
both end of treatment and follow-up is collected. 
J Post disease progression patients should be followed for survival and details of anti-cancer treatments given should be recorded.


 
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11 STATISTICS 
This is a Phase III trial examining the impact of 4 cycles of carboplatin and paclitaxel as adjuvant 
treatment after initial concurrent chemoradiation for patients with locally advanced cervical cancer 
suitable for curative therapy. The questions addressed by this study are the effect of adjuvant 
chemotherapy post chemo-radiation on overall and progression-free survival. The primary outcome 
of the study is overall survival. 
11.1 Sample Size 
The overall trial sample size has been planned to ensure sufficient power for demonstrating an 
overall survival advantage of chemo-radiation and adjuvant chemotherapy compared with chemo-
radiation alone. The expected 5-year overall survival rate for this population is approximately 60% - 
65%, based on the pivotal studies included in the MRC individual patient data meta-analysis12. An 
absolute reduction in mortality of at least 10% would be considered clinically worthwhile. However, 
it is anticipated that the cohort of patients recruited into this trial is likely to be at a lower risk than 
the cohorts in the published meta–analysis. Thus a control 5-year rate would be closer to 70-75%.  
Based on an exponential distribution, the table below shows the sample sizes required for different 
mortality reductions based on 95% confidence and 80% power, a minimum of a 48 month accrual 
period and a minimum of 42 months follow-up. Rather than adjust directly for non-adherence, the 
difference margin has been reduced to 8% to allow for a modest dilution due to drop-outs (patients 
allocated to receiving adjuvant chemotherapy arm but then not receiving the treatment) 
 
                                                                                         
 
 
 
 
Table is based on a 8% margin with 100% adherence 
 
Based on this table, a total sample size of 900 (450 per arm) will have 80% power with 95% 
confidence of detecting a reduction in the hazard of death of at least 32% (hazard ratio 0.68) from 
the control regimen (approximate 8% improvement in overall survival at 5 years from 72% to 80%) 
and allowing for some lost to follow-up and a further 4% cross-over rate. Additionally, this sample 
size will have > 80% power to detect a 10% survival difference (after accounting for non-
adherence) if the control rate is marginally higher (75%), or lower (70%). The expected event rate 
at the completion of the study is 234 deaths. 
11.2 Statistical Analysis 
Effectiveness analyses will be performed on an intention to treat basis and toxicity analyses by 
treatment received.  All comparisons will be 2-tailed and death from any cause will be considered 
as an event.  Nominal significance levels will be 0.05 for comparison of overall and progression 
OS at 5 years (%) 
Total sample size 
Hazard ratio 
70 vs 78 
874 
0.70 
72 vs 80 
828 
0.68 
73 vs 81 
804 
0.67 


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free survival. Primary time-to-event analyses will be described with Kaplan-Meier curves and 
unadjusted logrank tests. Exploratory multivariable modelling will be performed adjusting for 
baseline levels of key prognostic factors using proportional hazards or other appropriate regression 
models.  The proportion of patients achieving a complete or partial tumour response in each 
treatment group will be compared with either chi-squared or exact tests (conditional binomial exact 
test).  Results will be provided with estimates and confidence intervals where feasible. Specific 
sub-group analyses will be performed to assess if the effect of treatment differs according to the 
treatment received or stratification variables, i.e. nodal involvement, clinical tumour stage and age. 
An exploratory analysis of the impact on outcome of the presence of uterine corpus invasion on 
baseline MRI will also be performed. 
 
Quality of life assessments: All patients with a valid baseline and at least one follow-up QOL 
questionnaire will be included in the analysis. QOL will be collected every 3 months in the first two 
years and every 6 months in the third year until disease progression or 36 months from 
randomisation. To evaluate the differences between the treatment groups with respect to the effect 
of treatment burden on life-quality during and up to 3 years after treatment, the summary scales 
from the QLQ-C30, CX24/OV28, FACT and SVQ will be modelled using regression and other 
appropriate statistical methods.   
We plan to collect quality of life data on all patients able to complete one of the currently available 
translations of the questionnaires. For the EORTC measures a sample size of 550 patients with 
quality of life data will provide over 90% power to detect a 10 point difference on a 100 point scale 
with standard deviation of 30 points  and using a notional significance level of 2p <0.01 to account 
for the multiple comparisons55,56.  
11.3 Secondary endpoint: Progression Free survival 
Progression free survival (PFS) is defined as the time from randomisation to the time of disease 
progression as determined by the investigator (by clinical, radiological or pathological means) or 
death from any cause. Patients without an event prior to the study close-out date will be censored 
at the study close-out date or at the date of last contact if the patient is lost to follow-up. If a patient 
receives a subsequent anti-cancer therapy without prior documentation of disease progression, the 
patient will be censored at the date the patient was last seen for tumour assessment before 
starting the new anti-cancer therapy.  
11.4 Definition of study populations for analysis 
• 
The primary analysis population for the primary efficacy endpoints will be based upon the 
intention to treat (ITT) principle population, while a sensitivity analysis will be undertaken on 
the evaluable population. Secondary efficacy endpoints will be reported for the ITT population 
only. The ITT principle calls for the analysis of all patients randomised to the treatment group 
originally allocated regardless of which treatment regimen the patient actually received. 


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• 
Safety population: All randomised patients who receive at least 1 dose of study treatment. The 
primary safety analysis will be based on an all patients treated. Patients are counted in the 
group according to the treatment they actually receive. 
 
11.5 Interim analysis 
 
For efficacy: At the end of the study, approximately 220 deaths are expected after 3-years of 
follow-up. A formal interim analysis for efficacy is planned after a total of 120 deaths have been 
observed in the study. Comparisons will be performed at the nominal significance level 2p=0.003 
based on the O’Brien-Fleming boundary to preserve an overall type I error probability of no more 
than 0.05. If this boundary is crossed, consideration will be given to stopping the trial. Any such 
decision would also take into consideration the maturity of the data (in terms of median follow-up 
etc.) and not necessarily just that the stopping boundary has been crossed.  
For futility: An interim analysis for futility is planned using the PFS rate, as this is a major 
secondary end-point that will have a higher event rate than overall survival. The secondary 
endpoint is PFS and it is anticipated that after 3-years the PFS rate in the control arm will be 
approximately 65%, based on pivotal studies included in the MRC individual patient data meta-
analysis12, while the rate in the intervention arm is expected to be 75%. However, patients not 
relapsing before 3 years could be considered as having a negligible risk of relapsing (i.e. cure) and 
for those who do relapse; their median time to relapse is approximately 12 months. Based on a 
Gompertz survival distribution, at the end of the study, a total 235 patients would be expected to 
progress after 3 years of follow-up. A relative reduction in PFS of less than 13% (HR 0.87, absolute 
benefit of 3.8%) would not be considered sufficient to change clinical practice and the study would 
not be considered as demonstrating a clinically worthwhile benefit. An interim analysis after 70% of 
the information is available (after 165 patients have progressed) corresponds to a futility boundary 
for the HR of 0.89 (and an estimated HR of 0.99). If after 165 progressions have been observed, 
the lower 95% CI is greater than 0.89, the study will be considered futile to achieve its target 
benefit57. 
 
The interim analyses will be reported to an Independent Safety and Data-Monitoring Committee 
(IDSMC) who will advise the trial steering committee on the safety and feasibility of the study.   
There will be regular monitoring of the study for safety by an Independent Safety Data Monitoring 
Committee (IDSMC) who will review the safety profile of the patients in the trial and make 
recommendations to the trial steering committee. 
Consideration will be given to modifying the treatment or stopping the trial early based on the 
reports of the IDSMC if: 
a) 
The efficacy or futility boundaries are crossed in the formal interim analyses outlined above 
triggered by the number of events (progressions, deaths); 
b) 
a clearly more effective therapy becomes available. 


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c) 
the toxicity appears to be excessive 
 
The toxicity would be considered excessive if during the carboplatin and paclitaxel chemotherapy 
treatment there is a significantly higher than expected rate of life threatening neutropenic sepsis or 
grade 4 peripheral neuropathy than would be expected when carboplatin and paclitaxel is used to 
treat ovarian cancer. Toxicity rates will be formally evaluated after 60 (approx 30 per arm) and 150 
(approx 75 per arm) patients have completed all study treatment. This is expected to be 
approximately 7 months after the 60th and 150th  patients  have been randomised. The goal of 
these interim evaluations of toxicity is to ensure that there is not an excessive rate of neurological 
or haematological toxicity in the intervention arm. 
Expected toxicities of peripheral neuropathy and febrile neutropenia are estimated to be at most 
15% (grade 3 and 4) in the intervention  (adjuvant chemotherapy) arm. These rates will be 
specificially  considered by the IDSMC and it is envisaged that if the rate of these toxicities in the 
adjuvant chemotherapy group (Arm B) greatly exceeds the rate of toxicity experienced in the 
standard care group (Arm A) (eg. by more than 25% meaning that the 95% one-sided confidence 
interval for the difference in the rates includes a 25% detriment), then consideration will be given to 
dose adjustment or stopping the study based on the oversight and advice of the IDSMC.   
 
12 STUDY STRUCTURE 
ANZGOG will be the lead group for this GCIG study, in collaboration with the NHMRC CTC, 
University of Sydney which is the coordinating centre for the trial. The Principal Investigator and 
the NHMRC CTC are responsible for the day to day running of the trial as detailed in trial 
handbook and local standard operating procedures. The NHMRC CTC will in addition prepare 
reports for the Trial Management Committee (TMC), TMC Executive and IDSMC, including interim 
analysis, and will make safety and progress reports to the Ethics and Regulatory authorities and to 
GCIG groups for their regulatory and ethics requirements as needed. The TMC will include a 
representative from each participating cooperative group and country.  The TMC will meet by 
teleconference as required and will aim to meet face-to-face at least once per year. The TMC 
responsibilities include protocol development, study planning, monitoring and progress, review of 
serious adverse events. A TMC Executive Committee who would meet on a more frequent basis 
may be selected from the TMC in order to expedite decision-making and would be led by the 
Principal Investigator. 
In addition, the TMC has responsibilities to all study sites in taking all reasonable steps to ensure 
the proper conduct of the study as regards ethics, protocol adherence, integrity and validity of the 
data recorded on the case report forms.  
An Independent Data Safety Monitoring Committee (IDSMC) will be appointed by the TMC and 
consist of a minimum of an independent medical oncologist, radiation oncologist and statistician. 


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This committee will undertake reviews of all collected patient data at specified time points during 
the study to assess safety aspects of the study regimens. 
 
13 ADMINISTRATIVE ASPECTS 
13.1 Ethics and regulatory compliance 
This study will be conducted according to the Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95) annotated with TGA comments (Therapeutic Goods Administration DSEB July 
2000) and in compliance with applicable laws and regulations. The study will be performed in 
accordance with the NHMRC National Statement on Ethical Conduct in Human Research (© 
Commonwealth of Australia 2007) and the principles laid down by the World Medical Assembly in 
the Declaration of Helsinki 2004.  The investigator shall comply with the protocol, except when a 
protocol deviation is required to eliminate immediate hazard to a subject.  In this circumstance the 
NHMRC CTC, principal investigator and HREC must be advised immediately. 
13.2 Confidentiality 
The study will be conducted in accordance with applicable Privacy Acts and Regulations.  All data 
generated in this study will remain confidential.  All information will be stored securely at the 
NHMRC CTC, University of Sydney and will only be available to staff directly involved with the 
study. 
13.3 Protocol amendments 
Changes and amendments to the protocol can only be made by the Trial Management Committee. 
Approval of amendments by the Institutional HREC is required prior to their implementation. In 
some instances, an amendment may require a change to a consent form.  The Investigator must 
receive approval/advice of the revised consent form prior to implementation of the change.  
The investigator should not implement any changes to, or deviations from, the protocol except 
where necessary to eliminate immediate hazard(s) to trial subject(s). 
13.4 Data Handling and Record Keeping 
Trial data will be recorded on the (e-)CRFs provided.  All required data entry fields will be 
completed.  Data corrections will be done according to the instructions provided.  The investigator 
will be asked to confirm the accuracy of completed CRFs by signing key CRFs as indicated. 
Source documents pertaining to the trial must be maintained by investigational sites.  Source 
documents may include a subject's medical records, hospital charts, clinic charts, the investigator's 
subject study files, as well as the results of diagnostic tests such as X-rays, laboratory tests, and 
electrocardiograms. The investigator's copy of the case report forms serves as part of the 
investigator's record of a subject's study-related data.   


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All study-related documentation will be maintained for 15 years following completion of the study or 
according to local regulatory requirements.   
13.5 Study Monitoring 
Data from this study will be monitored according to the study monitoring plan. In Australia and New 
Zealand sites will be monitored by Clinical Trials Program staff from the NHMRC Clinical Trials 
Centre (NHMRC CTC).  For international sites monitoring will be the responsibility of the National 
Coordinating Office. Monitoring will include centralized review of CRFs and other study documents 
for protocol compliance, data accuracy and completeness.  Monitoring may include monitoring 
visits to investigational sites for source data verification, review of the investigator’s site file and 
drug handling records.  The monitoring staff will be given direct access to source documents, 
CRFs and other study-related documents.  By signing the informed consent form, the subject gives 
authorized monitoring staff direct access to their medical records and the study data.  
13.6 Audit and Inspection 
This study may be subject to audit or inspection by representatives of ANZGOG or the NHMRC 
CTC), or representatives of regulatory bodies (e.g. Therapeutic Goods Administration). 
13.7 Clinical Study Report 
A Clinical Study Report will be issued which may form the basis of a manuscript intended for 
publication.  The Clinical Study Report or summary thereof will be provided to relevant grant 
funding bodies, all investigational sites, as well as submitted to HRECs. 
13.8 Publication Policy 
The Trial Management Committee will appoint a Writing Committee to draft manuscripts based on 
the trial data.  Manuscripts will be submitted to peer-reviewed journal(s).  The first publication will 
be the report of the full trial results based on the main protocol using the study group name, with 
subsequent publications of data subsets. The Writing Committee will develop a publication plan, 
including authorship, target journals and expected dates of publication, in accordance with the 
ANZGOG publication policy.  
 
 


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King MT. The interpretation of scores from the EORTC quality of life questionnaire QLQ-
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15 LIST OF APPENDICES 
Appendix 1. Participant information and consent forms for ANZGOG sites 
[HOSPITAL LETTERHEAD] 
 
 
 
PARTICIPANT INFORMATION AND CONSENT FORM 
 
A Phase III trial of adjuvant chemotherapy following chemoradiation as primary 
treatment for locally-advanced cervical cancer compared to chemoradiation 
alone 
THE OUTBACK TRIAL 
 
 
 
 
 
 
Principal Investigator:    [name of site principal investigator] 
The sponsor for this study in Australia and New Zealand is the University of Sydney. 
We are inviting you to join this clinical research study because you have been 
diagnosed with cervical cancer (cancer of the cervix). This Participant Information 
Form contains detailed information about the research study.  Its purpose is to 
explain to you as openly and clearly as possible all the procedures involved in the 
study before you decide whether or not to take part in it. 
Please read this Participant Information Form carefully.  Feel free to ask questions 
about any information in the document.  You may also wish to discuss the study with 
a relative or friend or your local health worker.   
Once you understand what the study is about and if you agree to take part in it, you 
will be asked to sign the Patient Consent form.  By signing the Patient Consent Form, 
you indicate that you understand the information and that you give your consent to 
participate in the research project. 
You will be given a copy of the Participant Information and Patient Consent Form to 
keep as a record. 
 
1.  What is the purpose of this study? 
The standard treatment for the type of cervical cancer you have is currently 
radiotherapy combined with chemotherapy (chemo-radiation).  Radiotherapy to the 
pelvis destroys potential cancer cells in the pelvic area and significantly reduces the 
risk of tumour recurrence in the pelvic area. Giving chemotherapy using a drug called 
Cisplatin during radiotherapy has been shown to increase its effectiveness and is part 
of standard treatment.  
Studies among patients with other cancer types have shown that the addition of more 
chemotherapy after chemo-radiation reduces the risk of tumour recurrence at other 
places in the body. This has not yet been established for cervical cancer patients. 
Giving additional chemotherapy after initial standard treatment is known as ‘adjuvant 
chemotherapy’. 
The objectives of this trial are to find out whether adjuvant chemotherapy (using two 
other drugs) after chemo-radiation will increase the chances of survival and reduce 
the risk of tumour recurrence in the pelvis and other places. The risk and severity of 


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side effects and quality of life during and after treatment will also be evaluated and 
compared.  This trial will help the researchers understand the safety and 
effectiveness of the treatment.  
In this trial one group will receive standard chemo-radiation alone, whereas the other 
group will receive standard chemo-radiation and then additional chemotherapy. 
One of the chemotherapy drugs used in this study, paclitaxel, is not currently 
registered in Australia for use in the treatment of cervical cancer but is registered and 
commonly used for the treatment of other cancers such as breast and ovarian 
cancer.  It is also available and commonly used in many other countries for the 
treatment of secondary cervical cancer. The other two chemotherapy drugs used, 
cisplatin and carboplatin, are part of standard treatment for cervical cancer. The drug 
paclitaxel is being supplied by Hospira for patients in this study in Australia. 
The institution/hospital where you are being treated will be paid a nominal amount to 
cover their costs related to your participation in the study. The sponsor and the 
investigator do not have a financial interest in the outcome of this study. 
A total of 900 women will participate in this study from Australia, New Zealand and 
other countries.  
 
2.  Why have I been asked to participate in this study? 
You have been asked to join this study because you have been diagnosed with 
cervical cancer, which is locally-advanced and therefore not suitable for surgery.   
Chemo-radiation is the standard treatment for the type of cervical cancer you have 
and will be given to all women in this trial. 
You have been asked to take part in this clinical trial, to try to find out if extra 
chemotherapy after the standard chemo-radiation, will reduce the possibility of the 
cancer returning,  
If you choose not to take part in this study, the alternative is that your doctor would 
treat you with chemo-radiation as per standard therapy.  
 
3.  What if I don’t want to take part in this study, or if I want to 
withdraw later? 
Participation in this study is voluntary.  It is completely up to you whether or not you 
wish to participate.  Your choice not to participate will not affect the treatment you 
receive now or in the future.  Whatever your decision, it will not affect your 
relationship with the staff caring for you.  
Before you make your decision, the Investigator or a member of the study team will 
be available so you can ask any questions you have about the study.  You can ask 
for any information you want.  Please sign the Patient Consent Form only after you 
have had a chance to ask your questions and have received satisfactory answers. 
New information about the treatment being studied may become available during the 
course of the study.  You will be kept informed of any significant new findings that 
may impact on your willingness to continue in the study. 
You may withdraw from this study at any time. There is a difference between 
withdrawing from the study treatment and withdrawing from the study entirely. If you 
decide to withdraw, please notify a member of the research team beforehand.  This 
notice will allow your doctor to inform you if there are any health risks or special 
requirements linked to withdrawing.   
If you decide to discontinue the study treatment, you will be asked to attend follow-up 
visits to allow collection of information regarding your health status.  Alternatively, the 
investigator/sponsor will request your permission to access your medical records for 
collection of follow-up information for research and analysis.  
In the event that you withdraw from the study entirely, the effective date of the 
notification will be the date on which your withdrawal is received by the OUTBACK 


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study team. No information about you will be collected from that point in time 
onwards but any information collected about you prior to that date can be used and 
forms part of this study. 
Your study doctor may withdraw you from the study if he/she does not think it is in 
your best interest to continue or if you are unable to complete the study procedures. 
 
4.  What does this study involve? 
If you decide to participate in this study you will be randomly assigned by a computer 
to one of two groups. Neither you nor your doctor will be able to choose which group 
you are assigned to. 
The researchers want to compare the effect on survival, any side effects this 
treatment may cause and the effect of this treatment on your quality of life compared 
to the standard treatment. 
Control Arm:  This group will receive the current standard treatment for this type of 
cancer and side effects and quality of life information will be collected to compare 
with the intervention group. This group will receive chemo-radiation (standard 
radiotherapy plus cisplatin chemotherapy) only. 
Intervention Arm:  This group will receive the treatment that involves more than the 
standard treatment for this type of cancer. This group will receive chemo-radiation 
(standard radiotherapy plus cisplatin chemotherapy), followed by carboplatin and 
paclitaxel chemotherapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Schema 
 
 
Study Treatment 
Before starting the study treatment there will be a baseline assessment which 
includes the following: medical history, physical examination, weight, pelvic 
examination, blood tests and scans (CT scan for everyone plus a MRI and PET scan 
if this is available through your treatment centre). 
If clinically indicated there may be a pregnancy test to exclude pregnancy. 
The chemo-radiation treatment will take up to 6 weeks and is given to all patients. It 
consists of external beam radiotherapy, given 5 days per week and an intravenous 
infusion of the chemotherapy drug cisplatin given on one day of the week during the 
radiotherapy treatment. Following external beam radiotherapy, internal radiation 
(brachytherapy) will be administered.  This involves placement of a radioactive source into 
your uterus, cervix and vagina for a specific period of time, after which the radioactive 
source will be removed.  Chemo-radiation including brachytherapy is part of the standard 
Eligible patients 
 RANDOMISE 
Control Arm 
Standard radiotherapy plus 
chemotherapy  
Intervention Arm 
Standard radiotherapy plus 
chemotherapy, followed by 
additional chemotherapy 
Patients with certain types of cervical 
cancer who have given informed 
consent 
Follow-up period  


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treatment given to all patients. Your radiation oncologist will explain in detail about your 
brachytherapy timing and number of treatments. 
 
If you are randomised to the intervention group, after the chemo-radiation (including 
brachytherapy) treatment has been completed and you have recovered from any 
side-effects (after approximately four weeks), you will be given four further infusions 
of carboplatin plus paclitaxel chemotherapy. Prior to this chemotherapy you will also 
receive a pre-medication to prevent an allergic reaction or other side effects. The 
chemotherapy will be given on one day every three weeks. It will take approximately 
six hours to give the carboplatin plus paclitaxel chemotherapy. You will not be able to 
drive yourself home after chemotherapy, as the pre-medication can make some 
patients slightly drowsy.  
If you are in the intervention group, receiving the additional chemotherapy you will 
need to give 4 more blood samples (2 teaspoons per sample) than would normally be 
taken, to check your blood results prior to the additional chemotherapy treatments. 
There will also be four extra hospital visits for the chemotherapy to be given after 
your radiotherapy has been completed. 
For all patients in the trial, after completion of treatment the study doctor will assess 
how your cancer has responded.  This assessment will include a physical and pelvic 
examination and blood tests. A CT scan (and a PET scan if available) will be 
repeated 4 – 6 months after completion of the chemo-radiation. You will continue to 
be seen by the study doctor once every three months for the first two years, and once 
every six months for three more years. These follow up visits will include a physical 
and pelvic examination.  
You will be asked to fill in short questionnaires about your quality of life before you 
start treatment, after completing chemo-radiation and (if applicable) after the 
additional chemotherapy has been completed. You will also be asked to complete the 
questionnaires every 3 months during the first 2 years of follow-up after treatment 
and then every 6 months in the third year. These questionnaires will assist the team 
to find out how you are feeling in yourself and the effect treatment has upon you and 
your daily activities. These questionnaires should take about 30 minutes to complete.   
If you agree to participate in this study, you will be asked to sign the Patient Consent 
Form. 
 
 
5.  Are there risks to me in taking part in this study? 
Medical treatments often cause side effects. You may have none, some, or all of the 
effects listed below, and they may be mild, moderate or severe. If you have any of these 
side effects, or are worried about them, talk with your doctor.  Your doctor will also be 
looking out for side effects. In addition, there may be risks associated with this study that 
are presently unknown or unforeseeable.  The researchers don’t know whether giving the 
additional chemotherapy treatment in this study might increase the chance of you getting 
short or longer-term side effects. 
Many side effects go away shortly after treatment ends. However, sometimes side effects 
can be serious, long lasting or permanent. If a severe side effect or reaction occurs, your 
doctor may need to stop your treatment. Tell your doctor if you have any problems. Your 
doctor will discuss the best way of managing any side effects with you. 
 
General side effects of radiotherapy (part of standard of care treatment):  
The side-effects of radiation may include any, all or none of the following. 
Common side-effects (in more than 1 in 10 patients) 
• Diarrhoea  


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• Burning or pain when passing urine 
• Bowel cramps or abdominal pain 
• Tiredness 
• Loss of appetite 
• Loss of pubic hair 
• Menopause: Radiotherapy may cause your ovaries to stop working 
permanently. If you haven’t already been through menopause you may 
experience menopausal symptoms such as hot flushes 
Less common side-effects (in more than 1 in 20 patients) 
• Reddening, itching or in some cases blistering of the skin and other tissues in 
the pubic area which is exposed to the radiation beam 
• Nausea or vomiting 
• Effect on the vagina: Some women experience mild vaginal irritation and 
discharge during and shortly after treatment. Radiotherapy may also cause 
internal scar tissue to form, which sometimes shortens and narrows the 
vagina. These changes can be prevented or minimised with the use of a 
vaginal dilator (also called a vaginal cylinder) which your treatment team will 
instruct you to use.  
Most of these side-effects can be controlled with medication and will usually get 
better when the radiation is completed. Rarely (in  less than 1 in 10 patients), 
radiation may cause some permanent damage to the small or large intestine, 
rectum, ureter, bladder or lymph nodes in the pelvic area causing swelling of the 
legs which is known as lymphoedema. Sometimes complications from the 
brachytherapy treatment can also result in damage to the uterus, which generally 
gets better without the need for specific treatment. These problems may require 
medication such as antibiotics or very rarely hospitalisation or a surgical 
procedure to repair or manage. Very rarely (in less than 1 in 1000 patients), nerve 
damage may occur which may cause numbness or weakness in the legs.  
 
General side effects of chemotherapy:  
The most common general side-effects of chemotherapy include tiredness, nausea 
and vomiting (which is usually minimal with standard anti-nausea medication), mouth 
sores, loss of appetite and taste changes. Blood counts (white blood cells, red blood 
cells, and platelets) and electrolyte salts (sodium, potassium, magnesium) may also 
be lowered.  A decrease in these blood counts may increase your risk of infection, 
fatigue, and abnormal bleeding.  
Prior to chemotherapy you will be given a pre-medication which can help with some 
of the side-effects. You will also be given some medication to take at home after 
treatment to help prevent and manage any nausea and vomiting. These medications 
can sometimes cause temporary problems with headache, constipation and trouble 
sleeping. 
Cisplatin is the drug that is given during chemo-radiation as part of standard therapy 
for your cancer. Common side effects (in more than 1 in 10 patients) include 
tiredness, and nausea. Less commonly it may cause damage to your kidneys (less 
than 1 in 100 patients), which may rarely be permanent. In order to prevent this extra 
fluid is given into a vein with the treatment and you will also be advised to increase 
your fluid intake by mouth. In addition a close eye will be kept on kidney function with 
regular blood tests before each treatment. Less common side effects (less than 1 in 
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loss of hearing, problems with balance, or numbness and tingling in the fingers or 
toes. Development of blood clots can also occur rarely, in part because the cancer 
may pre-dispose to this. 
Carboplatin is one of the two drugs that will be given after your chemo-radiation if 
you are in the intervention group. It is similar to cisplatin but side effects are generally 
less marked.  
Common (in more than 1 in 10 patients) 
• Lowering of blood counts leading to an increased risk of infection, bleeding or 
need for a blood transfusion 
• Nausea 
• Taste changes 
• Tiredness (fatigue) 
Uncommon (in less than 1 in 10 patients) 
• Sores in the mouth 
• Kidney damage, which is usually reversible 
• Nerve damage such as numbness and tingling in the hands and feet that in 
more severe cases can lead to difficulty walking or buttoning clothes. This may 
take many months to resolve after chemotherapy is completed and rarely can 
be permanent. 
Rare (in less than 1 in 100 patients) 
• Hearing damage, which is very rarely severe or permanent 
Paclitaxel is the second of the 2 drugs given after your chemo-radiation if you are in 
the intervention group. It does cause hair loss which starts 2 -3 weeks after the first 
dose. It is, however, temporary and your hair will start to re-grow about 3-6 weeks 
following treatment. As well as losing the hair on your head there will be thinning of 
your eyebrows, eyelashes and other body hair. 
Common (in more than 1 in 10 patients) 
• Lowering of blood counts leading to an increased risk of infection, bleeding or 
need for a blood transfusion 
• Hair loss 
• Tiredness (fatigue) 
• Nerve damage such as numbness and tingling in the hands and feet that may 
lead to difficulty walking or buttoning clothes. This may take many months to 
resolve after chemotherapy is completed and rarely can be permanent. 
• Muscle and joint aches 
• Constipation 
Uncommon (in less than 1 in 10 patients) 
• Sores in the mouth 
• Abnormalities in the heart rate such as a slow regular pulse which is not 
harmful  
• Nausea 
• Diarrhoea 
• Liver blood test abnormalities 
• Allergic reactions causing hives, wheezing and low blood pressure 
Rare (in less than 1 in 100 patients) 
• Temporary visual disturbances such as the sensation of flashing lights or 
blurred vision  
• Serious abnormalities of the heart rhythm 
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It is important that women participating in this study are not pregnant and do not become 
pregnant during the study as the study procedures may damage an unborn baby.  If you 
are a woman of childbearing age and there is any possibility that you are pregnant, your 
doctor will need to perform a urine pregnancy test before you start in the study. If 
necessary, you should use reliable contraception (such as oral or implanted contraceptive 
or an IUD) during the course of the study.  If you think you may be pregnant, it is important 
to let your doctor know immediately. 
Your treatment may cause temporary or permanent sterility.  Please discuss this with your 
doctor if you have any concerns about future fertility. 
 
6.  What happens if I suffer injury or complications as a result of the 
study? 
If you suffer any injuries or complications as a result of this study, you should contact 
the study doctor as soon as possible, who will assist you in arranging appropriate 
medical treatment.  Treatment for the injury or complication will be provided free-of-
charge at a public hospital. 
You may have a right to take legal action to obtain compensation for any injuries or 
complications resulting from the study.  Compensation may be available if your injury 
or complication is sufficiently serious and is caused by unsafe drugs or equipment, or 
by the negligence of one of the parties involved in the study (for example, the 
researcher, the hospital, or the treating doctor).  If you receive compensation that 
includes an amount for medical expenses, you will be required to pay for your 
medical treatment from those compensation monies. 
You do not give up any legal rights to compensation for your injury or compensation 
by participating in this study.  If you are not eligible for compensation for your injury or 
complication under law, but are eligible for Medicare, then you can receive any 
medical treatment required for your injury or complication free of charge as a public 
patient in any Australian public hospital. 
 
7.  Will I benefit from the study? 
The study aims to further medical knowledge and may improve future treatment of 
cervical cancer, however it may not directly benefit you.  Some studies have 
suggested that extra chemotherapy may increase the chance of cure whilst others 
have shown no advantage. We hope that by carrying out this study we will be able to 
confirm if extra chemotherapy treatment after standard chemo-radiation can increase 
the likelihood of cure of cervical cancer. 
 
8.  Will taking part in this study cost me anything? 
There will be no costs to you during the study for medical services or laboratory tests 
that are required as part of the study and outside the standard of care for your 
disease. Any costs related to the standard of care treatment for your disease at your 
hospital will still apply. Taking part in this study may result in added costs to you such 
as transport. You will not be paid for participation in this study.   
.   
9.  How will my confidentiality be protected? 
Nursing and medical staff, including your general practitioner, involved in your care 
will know whether or not you are participating in this study.  Any identifiable 
information that is collected about you in connection with this study will remain 
confidential and will not be disclosed without your permission, except as required by 
law. 
Your health records and any information obtained during the study may be examined 
by authorised representatives of the hospital’s Health Research Ethics Committee, 
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or by regulatory authorities such as the Australian Government’s Therapeutic Goods 
Administration (TGA) or as required by law, for the purposes of verifying the study 
procedures or data.  By signing the Consent Form, you authorise access to this 
confidential information to the relevant study personnel and regulatory authorities as 
noted above.   
 
10.  What happens with the results? 
Your doctor will inform you about your own results where relevant. 
The results of this study will be analysed after all participants have been followed up 
for 3 years. When this study is completed and the results have been analyzed, the 
results will be published and presented in peer reviewed journals, at 
national/international cancer conferences or at other professional forums.  You will 
not be personally identified in any report or publication. Once the results are available 
you will be able to ask your doctor about these. 
 
11.  What happens to my treatment when the study is finished? 
Once your treatment is completed you will continue to see your doctor on a regular 
basis. These appointments are scheduled every 3 months for the first 2 years, and 
every six months for a further 3 years. The total follow-up period will be 5 years. 
Any decision about further treatment will be made by your treating doctor in 
consultation with you. 
 
12.  Further Information or any problems 
If you require further information or if you have any problems concerning this study 
(for example, any side effects), you can contact the principal investigator or study 
staff.  The investigators responsible for this study are [list the names and contact 
phone numbers, including after hours numbers]. 
Name:  [Site principal investigator or study team contact person] 
Position: 
Telephone: 
 
13.  Who should I contact if I have concerns about the conduct of 
this study? 
This study has been approved by Cancer Institute NSW Clinical Research Ethics 
Committee. If you have concerns or complaints about the conduct of this study, you 
should contact [name] who is the person nominated by the Human Research Ethics 
Committee to receive complaints from research participants.  You should contact 
them on [number] and quote [HREC project number]. 
Name:  [This person should be someone independent of the study] 
Position: 
Telephone: 
 
Thank you for taking the time to consider being part of this study. 
If you wish to take part in this study, please sign the attached consent form. 
 
This information sheet is for you to keep. 
 


 
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 [Hospital letterhead] 
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       PARTICIPANT CONSENT FORM 
 
I, ....................................................................................................................... [name]  
 
Of...........................................................……………………………………….. [address]  
have read and understood the Information for Participants on the above named 
research study. I understand that I am agreeing to participate in a research study. 
I have been made aware of the procedures involved in the study, including any 
known or expected inconvenience, risk, discomfort or side effect, and of their 
implications as far as they are currently known by the researchers. 
I understand that the research project will be carried out according to the principles in 
the National Health & Medical Research Council Statement on Ethical Conduct in 
Research Involving Humans.  
I freely choose to participate in this study and understand that I can withdraw at any 
time. 
I also understand that the research study is strictly confidential. 
I hereby agree to participate in this research study. 
 
NAME:......................................…  
 
SIGNATURE: 
......................................… 
 
DATE ......................................… 
 
NAME OF INVESTIGATOR:             ……………………………… 
 
SIGNATURE OF INVESTIGATOR:  …………………………. …….. 
 
DATE: 
 
……………………………. 
 
 
 


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PARTICIPANT INFORMATION AND CONSENT FORM 
Translational Research 
 
Study Title:  A Phase III trial of adjuvant chemotherapy following 
chemoradiation as primary treatment for locally advanced cervical cancer 
compared to chemoradiation alone 
THE OUTBACK TRIAL 
 
 
Principal Investigator:    [name of site principal investigator] 
The sponsor for this study in Australia and New Zealand is the University of Sydney. 
Hospira is providing one of the study drugs called paclitaxel for Australian sites.This form 
is in addition to the consent form you signed for the OUTBACK main study.  
You are being asked to take part in this research project because you have 
consented to participate in the OUTBACK main study. 
This Participant Information contains information about the additional blood and tissue 
component of this study.  Its purpose is to explain to you as openly and clearly as possible 
all the procedures involved before you decide whether or not to take part in it. 
Please read this Participant Information carefully.  Feel free to ask questions about any 
information in the document.  You may also wish to discuss the study with a relative or 
friend or your local health worker. Feel free to do this. 
Once you understand what the study is about and if you agree to take part in it, you will be 
asked to sign the Consent Form.  By signing the Consent form, you indicate that you 
understand the information and that you give your consent to participate in the research 
project. 
You will be given a copy of the Participant Information and Consent form to keep as a 
record. 
 
1.  What is the purpose of this study? 
The purpose of the study is to collect blood and tissue samples for future laboratory 
testing. Research will be undertaken to determine ways to improve how we deliver therapy 
for cervical cancer and manage side effects, as well as how the disease arises in the first 
place. We will also try and determine why some patients might benefit from treatment 
more than others. This is what is referred to as ‘Translational Research’.  


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This may include testing to see if genetic reasons can be identified that explain why some 
patients may benefit more from the treatment being given in this study  than others, such 
as genetic differences in the way that your body handles chemotherapy drugs or reacts to 
radiotherapy. All future research for which your samples will be used will relate to cervical 
cancer. Genetic testing for diseases that may run in families will not be performed on your 
samples. 
2.  What does the study involve? 
We are requesting your consent to allow us to use, for research purposes, any tissue 
samples that may have been taken from you previously as a biopsy or during surgery.  
These tissue samples are routinely stored in pathology stores as required by law. 
Additionally, one blood sample will be taken by a qualified practitioner at the beginning of 
the study (approximately 35 ml, which equals about 2 tablespoons). When you give blood, 
you may feel faint, or experience mild pain, bruising, irritation or redness at the site where 
the blood is taken from. In rare cases, you may get an infection. Some of this blood 
sample will be used to get a sample of your genetic material (DNA inherited from your 
mother and father). 
If you require another biopsy for clinical reasons (such as confirmation of diagnosis) some 
additional fresh frozen tissue from that biopsy will be collected for planned laboratory 
studies. If you do not need another biopsy for clinical reasons, then you DO NOT require a 
repeat biopsy to participate in this study.  
All samples (tissue/blood) will be stored at the hospital site for the duration of the study. At a 
future point in time the samples will be shipped to a central laboratory for testing. 
You will not receive any payment for taking part in this translational research.  
There will not be any anticipated expenses for you while taking part in this translational 
research. 
The choice whether to participate or not is entirely up to you. Your ability to 
participate in the main study will not be affected in any way by your decision.  
 
3.  What will be done with my samples? 
The samples will be coded with a number and will NOT be labeled with any information 
that directly identifies you.  The connection between the code and your name will only be 
kept by your study doctor.  Your samples will be given the same code as your other study 
information and kept in locked storage.  Anyone who works with your samples will hold the 
information and results in confidence. Your samples may be kept for up to 15 years after 
the end of the study.  Any samples remaining at that time will be destroyed.  
Therefore, all current and future studies will only be conducted if they have achieved the 
approval of a Human Research Ethics Committee (HREC), which is comprised of clinical, 
scientific and community representatives and operates under national guidelines.  In 
addition any studies will also require approval by the Australia New Zealand 
Gynaecological Oncology Group (ANZGOG). 
Some research studies may involve sending your samples or de-identified health 
information interstate/overseas.  If so, these researchers are required to demonstrate (to a 
local HREC) that they meet the appropriate Australian standards of ethics and privacy as 
detailed above before any samples or health information will be released.  


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Whilst the aim of our research is to improve the health of our community, sometimes 
research may lead to findings that result in the development of a commercial test or 
treatment.  Australian law indicates that there is no financial reward or payment to you in 
this event. 
 
4.  Protecting your privacy  
We seek your consent to access medical information kept about you that is relevant to 
medical research, including information that may come from hospital case notes, GP 
records, past diagnoses or information held by the Department of Health. 
Samples will be identified by a code only and it will not be possible for researchers using 
them to link this to your personal information themselves.  We abide by all state and 
Federal Privacy legislation at all times. 
It is important to note that there may be circumstances under Privacy legislation where 
disclosure of your health information kept by the study sponsor (University of Sydney) 
could be obtained, if requested, for example, as a result of a court order.   
 
5.  What will happen with the results? 
Your doctor will inform you about your own results where relevant. 
If you give us your permission by signing the Consent Form, we plan to discuss/publish the 
results.  That involves: 
 Writing up the study results for peer-reviewed journals 
 Sharing the results with other academic research groups, universities, or 
companies, to better understand cervical cancer or to further develop anti-cancer 
drugs 
 Using the results to plan new studies to learn more about cervical cancer or other 
conditions 
In any publication, information will be provided in such a way that you cannot be identified. 
Results of the study will be provided to you, if you wish, by your study doctor. 
 
6.  What are the potential risks? 
 If you allow us to use your tissue, these samples are not intended to be used in your 
diagnosis or treatment. Risks of blood samples being drawn include pain, bruising, 
bleeding, temporary redness of the skin at the injection site, infection and light-
headedness.  Care will be taken to avoid these difficulties.   
 
7.  What are the potential benefits? 
 It is unlikely that the research performed will be of direct benefit to you.  The results may 
help us to better understand how to diagnose or treat patients with your type of cancer 
more effectively.  
 


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8.  What if I change my mind?  
Your tissue will be stored until it is used up or you contact the ANZGOG to request its 
destruction.  If you wish to have your sample withdrawn, or stop access to your health 
information, please notify your doctor in writing.  A letter confirming removal of your 
sample and/or health information will be sent to you.  
 
9.  What happens to my tissue if I die? 
In the event of your death, we will continue to store tissue and make it available to 
researchers.  Your tissue will continue to be used in cervical cancer research subject to 
the conditions described in section 3.   
 
10.  Further Information or Any Problems 
If you require further information or if you have any problems concerning this project, you 
can contact one of the researchers or the study coordinator. Contact numbers are: 
 
Dr                    
   (Principal Investigator) 
 
 
     Telephone:  
Dr                     
   (Investigator) 
 
 
 
     Telephone:  
Dr  
 
 
   (Oncology Research Fellow) 
 
     Telephone:  
 
After hours you can call the hospital switchboard on and ask for the oncology registrar on 
call. 
The Clinical Trial Coordinator for this study is ………..and he/she can be contacted on 
………..  
 
11. Other Issues 
If you wish to contact someone independent of the study about ethical issues or your 
rights, you may contact  ……….. Chairperson of the…………. Human Research Ethics 
Committee, Phone ……... You will need to give the name of one of the researchers given 
in section 10 above. 
 
12.  Ethical Guidelines 
This project will be carried out according to the National Statement on Ethical Conduct in 
Research Involving Humans (2007) produced by the National Health and Medical 
Research Council of Australia.  This statement has been developed to protect the interests 
of people who agree to participate in human research studies. 
 
Thank you for taking the time to consider being part of this study. 
If you wish to take part in this study, please sign the attached consent form. 
This information sheet is for you to keep. 


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         PARTICIPANT CONSENT FORM 
 
I, ....................................................................................................................... [name]  
 
of...........................................................……………………………………[address] have read and 
understood the  
 
Information for Participants on the above named research study.  
I understand that I am agreeing to participate in a research study. 
I have been made aware of the procedures involved in the study, including any known or expected 
inconvenience, risk and of their implications as far as they are currently known by the researchers. 
I understand that the research project will be carried out according to the principles in the National 
Health & Medical Research Council Statement on Ethical Conduct in Research Involving Humans.  
 
I freely choose to donate: 
(please tick boxe(s) below) 
□  my tissue (from previous biopsy, and future biopsy if clinically indicated) 
□  my blood (35ml blood sample) 
and understand that I can withdraw my tissue or blood at any time. 
 
I also understand that the research study is strictly confidential. 
I hereby agree to participate in this research study. 
 
NAME:  
 
 
 
......................................… 
 
SIGNATURE:  
 
 
......................................… 
DATE:  
 
 
 
......................................… 
 
NAME OF WITNESS:  
 
.....................................… 
SIGNATURE OF WITNESS:  
......................................… 
 
NAME OF INVESTIGATOR:             ………………………..  
SIGNATURE OF INVESTIGATOR:  …………………………. 
 


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Appendix 2. Quality of Life (QOL) forms 
 
 


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Appendix 3. Definition of Corpus Positive disease on MRI 
A tumour is said to be corpus invasive if the tumour is seen to infiltrate beyond the cervico-uterine 
plane into the isthmus and beyond. The junction of uterus and cervix is best observed in the MR 
images taken in the sagittal plane. The cervico-uterine junction is located where internal cervical os 
continues with the uterine cavity. In a patient whose entire cervix is distorted by the presence of 
cervix cancer, the cervico-uterine junction is identified where the proximal outer contour of the cervix 
abruptly widens to merge with the corpus.  
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4. RECIST 1.1 Criteria 
Response Evaluation Criteria in Solid Tumours (RECIST v1.1)  
These instructions are based on the guidelines recommended in Eisenhauer EA, Therasse P, 
Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). (Eur J Cancer 2009; 45: 228-47) 
 
1. Evaluable for response. 
All patients who have received at least one cycle of therapy and have their disease re-evaluated 
will be considered evaluable for response (exceptions will be those who exhibit objective disease 
progression prior to the end of cycle 1 who will also be considered evaluable). Patients on therapy 
for at least this period and who meet the other listed criteria will have their response classified 
according to the definitions set out below. 
 
2. Disease and lesion definitions 
2.1 Measurable Disease. Measurable tumour lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 
20 mm with chest x-ray, and as ≥10 mm with CT scan or clinical examination. Bone 
lesions are considered measurable only if assessed by CT scan and have an identifiable 
soft tissue component that meets these requirements (soft tissue component > 10 mm 
by CT scan).  Malignant lymph nodes must be ≥ 15mm in the short axis to be 
considered measurable; only the short axis will be measured and followed. All tumour 
measurements must be recorded in millimetres. Previously irradiated lesions are not 
considered measurable unless progression has been documented in the lesion. 
 
2.2 Non-measurable Disease. All other lesions (or sites of disease), including small lesions 
are considered non-measurable disease. Bone lesions without a measurable soft tissue 
component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin 
and abdominal masses followed by clinical examination are all non-measurable. Lesions 
in previously irradiated areas are non-measurable, unless progression has been 
demonstrated. 
 
2.3 Target Lesions. When more than one measurable tumour lesion is present at baseline 
all lesions up to a maximum of 5 lesions in total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological lymph nodes must meet the criterion of having a 
short axis of ≥ 15 mm by CT scan and only the short axis of these lymph nodes will 
contribute to the baseline sum. All other pathological lymph nodes (those with a short 
axis ≥ 10 mm but <15 mm) should be considered non-target lesions. Nodes that have a 
short axis < 10 mm are considered non-pathological and should not be recorded or 
followed (see 10.2.4). At baseline, the sum of the target lesions (longest diameter of 
tumour lesions plus short axis of target lymph nodes: overall maximum of 5) is to be 
recorded. 
 
 
After baseline, a value should be provided on the CRF for all identified target lesions for 
each assessment, even if very small.  If extremely small and faint lesions cannot be 
accurately measured but are deemed to be present, a default value of 5 mm may be 
used. If lesions are too small to measure and indeed are believed to be absent, a default 
value of 0 mm may be used. 
 
2.4 Non-target Lesions. All non-measurable lesions (or sites of disease) plus any 
measurable lesions over and above those listed as target lesions are considered non-


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target lesions. Measurements are not required but these lesions should be noted at 
baseline and should be followed as “present” or “absent”. 
 
3.  Response Definitions 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
Complete Response (CR): disappearance of all target and non-target lesions and 
normalization of any specified tumour markers (no tumour markers for this trial). 
Pathological lymph nodes must have short axis measures < 10mm (Note: continue to 
record the measurement even if < 10mm and considered CR).  Residual lesions (other than 
nodes < 10mm) thought to be non-malignant should be further investigated (by cytology or 
PET scans) before CR can be accepted. Confirmation of response is sometimes required in 
studies where objective tumour response is the primary endpoint, and the details of 
confirmation are then specified in the body of the protocol.   
 
Partial Response (PR): at least a 30% decrease in the sum of measures for target lesions 
(longest diameter for tumour lesions and short axis measure for target lymph nodes), taking 
as reference the baseline sum of diameters. Non target lesions must be non-PD. 
Confirmation of response is sometimes required in studies where objective tumour 
response is the primary endpoint, and the details of confirmation are then specified in the 
body of the protocol.  
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of ≥ 5mm. Appearance of new lesions will also 
constitute progressive disease (including lesions in previously unassessed areas). In 
exceptional circumstances, unequivocal progression of non-target disease may be 
accepted as evidence of disease progression, where the overall tumour burden has 
increased sufficiently to merit discontinuation of treatment or where the tumour burden 
appears to have increased by at least 73% in volume. Modest increases in the size of one 
or more non-target lesions are NOT considered unequivocal progression.  If the evidence of 
PD is equivocal (target or non-target), treatment may continue until the next assessment, 
but if confirmed, the earlier date must be used. 
 
Table 1: Integration of Target, non-Target and New lesions into response assessment: 
 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
category also requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of specified 
tumour markers, AND 
lymph nodes <10mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/  
not all evaluated 
No 
PR 
SD 
Non-PD/  
not all evaluated 
No 
SD 
Documented at least once ≥ 
4 wks. from baseline [note, 
protocol may define;  6-8 
weeks is recommended] 
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any  
PD 
 


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Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of specified 
tumour markers AND 
lymph nodes < 10mm 
No Target 
Non-CR/non-PD 
No 
Non-
CR/non-
PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. This is a reason for stopping therapy, but is NOT objective PD.  
Every effort should be made to document the objective progression even after discontinuation 
of treatment. 
 
 
4. Response Duration 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including 
baseline). 
 
5. Stable Disease Duration 
Stable disease duration will be measured from the time of start of treatment (or randomisation for 
randomized studies) until the criteria for progression are met, taking as reference the smallest sum 
on study (including baseline). 
 
6. Methods of Measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy, which may be treatment 
arm dependent, unless the protocol specifies otherwise. While on study, all lesions recorded at 
baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For 
lesions which fragment/split add together the longest diameters of the fragmented portions; for 
lesions which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
6.1 Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10mm as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by colour photography including a ruler to estimate the 
size of the lesion is recommended. If feasible, imaging is preferred. 
 
6.2 Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions. However, lesions > 20 mm on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
 
6.3 CT, MRI. CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. 


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When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (e.g. for body scans). While PET scans are not considered adequate 
to measure lesions, PET-CT scans may be used providing that the measures are 
obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
 
6.4 Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT is advised.   
 
6.5 Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response or surgical resection is an endpoint. 
 
6.6 Tumour Markers. Tumour markers alone cannot be used to assess objective tumour 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response.  There are no specified 
tumour markers for this trial. 
 
6.7 Cytology, Histology. These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumour types 
such as germ cell tumours, where known residual benign tumours can remain). When 
effusions are known to be a potential adverse effect of treatment (e.g. with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumour has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease. 
 


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Appendix 5. FIGO 2008 staging for carcinoma of the cervix uteri 
 
 
 


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Appendix 6. Information requirements for PET reports 
 
The following information is required to complete the PET-related case report forms: 
 
• 
 Blood glucose level prior to PET scan  
• 
Uptake time 
• 
Method of scan (PET/CT or PET only) 
• 
Liver SUV average 
• 
Cervix SUV max 
• 
Nodes involved (location, number of nodes, SUV max)