Download OE05 Protocol - MRC Clinical Trials Unit

OE05
A randomised controlled trial comparing standard
chemotherapy followed by resection versus ECX
chemotherapy followed by resection in patients with
resectable adenocarcinoma of the oesophagus.
OE05 CLINICAL PROTOCOL
Version 6.0: 23rd December 2009
EUDRACT Number: 2004-000241-37
CTA: 00316/0014/001/001
ISRCTN: 01852072
Authorised by:
Professor Derek Alderson
Surgical Chief Investigator
Professor David Cunningham
Oncological Chief Investigator
Signature:…………………………..…….…
Date:
Date:
Signature:…………………………………
Dr. Ruth Langley
Project Lead, MRC Clinical Trials Unit
Signature:
Date:
MRC OE05
A randomised controlled trial comparing standard chemotherapy followed by resection
versus ECX chemotherapy followed by resection in patients with resectable
adenocarcinoma of the oesophagus
This document is intended to describe a trial developed on behalf of the National Cancer
Research Institute (NCRI) Upper GI Cancer Group and to provide information about procedures
for entering patients. It is not intended that the protocol be used as an aide-memoir or guide for
the treatment of other patients. Amendments may be necessary; these will be circulated to
known centres in the trial, but centres entering patients for the first time are advised to contact
the MRC Clinical Trials Unit, Cancer Division, London to confirm the details of the protocol in
their possession.
Clinical problems relating to this study should be referred to the relevant Chief Investigator. If in
doubt, contact the MRC Clinical Trials Unit, Cancer Division, London (Tel: 020 7670 4700).
Surgical Chief Investigator
Oncological Chief Investigator
Professor Derek Alderson
Barling Professor of Surgery
Academic Department of Surgery
Room 29, 4th Floor
Queen Elizabeth Hospital
Edgbaston
Birmingham B15 2TH
Tel No: 0121 627 2276
Fax No: 0121 472 1230
Email: [email protected]
Professor David Cunningham
Dept of Oncology
Royal Marsden Hospital
Downs Rd, Sutton
Surrey SM2 5PT
Tel: 020 8661 3156
Fax: 020 8643 9414
Email: [email protected]
MRC OE05 Clinical Trials Team
Cancer Group, MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA
Switchboard: 020 7670 4700 Fax: 0207 670 4818
Email: [email protected]
Project Leader
Ruth Langley
0207 6704718
Trials Manager
Paul Cortissos
0207 6704795
Data Manager
Dipa Noor
0207 6704804
Senior Statistician
Sally Stenning
020 7670 4707
Sponsor: Medical Research Council
David Harrop
Head of Centre, MRC Centre London
Ground Floor, Stephenson House, 158-160 North Gower Street, London NW1 2DA
Tel: 0207 670 4625 Fax: 0207 670 4691
RANDOMISATIONS
020 7670 4777 (Mon - Fri, 9am – 5pm)
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CONTENTS
1
SUMMARY.......................................................................................................................... 1
1.1
2
TRIAL OUTLINE .............................................................................................................. 1
BACKGROUND .................................................................................................................. 2
2.1
INTRODUCTION .............................................................................................................. 2
2.2
RELEVANT TRIALS ......................................................................................................... 2
3
OBJECTIVES ..................................................................................................................... 6
4
DESIGN .............................................................................................................................. 6
5
SELECTION OF PATIENTS ............................................................................................... 7
5.1
INCLUSION CRITERIA:..................................................................................................... 7
5.2
EXCLUSION CRITERIA: ................................................................................................... 8
5.3
CENTRE ACCREDITATION & APPROVAL PROCESS ............................................................ 9
5.4
TRIAL DRUG SUPPLY - CAPECITABINE ........................................................................... 10
5.5
RANDOMISATION OF PATIENTS ..................................................................................... 11
5.6
ENROLMENT IN TRANS-OE05 (TISSUE AND BLOOD COLLECTION FOR TRANSLATIONAL
RESEARCH)
6
7
8
9
............................................................................................................................ 12
WITHDRAWAL OF PATIENTS ......................................................................................... 12
6.1
WITHDRAWAL FROM TRIAL INTERVENTIONS ................................................................... 12
6.2
WITHDRAWAL FROM THE TRIAL COMPLETELY ................................................................ 13
6.3
PATIENT TRANSFERS ................................................................................................... 13
ASSESSMENTS AND PROCEDURES............................................................................. 13
7.1
PRE-CHEMOTHERAPY INVESTIGATIONS......................................................................... 13
7.2
POST-CHEMOTHERAPY INVESTIGATIONS ....................................................................... 14
7.3
PATIENT FOLLOW UP ................................................................................................... 16
TREATMENT .................................................................................................................... 18
8.1
CHEMOTHERAPY REGIMENS ......................................................................................... 18
8.2
ECX CHEMOTHERAPY ................................................................................................. 21
8.3
ANTI-EMETICS ............................................................................................................. 26
8.4
TOXICITY .................................................................................................................... 27
8.5
SURGERY ................................................................................................................... 28
DURATION OF TRIAL ...................................................................................................... 31
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10
SAFETY REPORTING ...................................................................................................... 31
10.1
DEFINITIONS ............................................................................................................... 31
10.2
INSTITUTION/INVESTIGATOR RESPONSIBILITIES ............................................................. 33
10.3
MRC CTU RESPONSIBILITIES ...................................................................................... 35
11
ANCILLARY STUDIES ..................................................................................................... 37
11.1
QUALITY OF LIFE (IN SELECTED CENTRES)..................................................................... 37
11.2
HEALTH ECONOMICS ................................................................................................... 39
11.3
CENTRAL PATHOLOGY REVIEW .................................................................................... 40
11.4
TRANS-OE05: TISSUE AND BLOOD COLLECTION FOR TRANSLATIONAL RESEARCH .......... 42
11.5
RADIOLOGY REVIEW .................................................................................................... 47
12
STATISTICAL CONSIDERATIONS .................................................................................. 48
12.1
OUTCOME MEASURES .................................................................................................. 48
12.2
SAMPLE SIZE ............................................................................................................... 48
12.3
PLANNED ANALYSES .................................................................................................... 49
13
MONITORING AND QUALITY ASSURANCE................................................................... 51
13.1
INTERIM ANALYSIS ....................................................................................................... 51
13.2
SITE VISITS ................................................................................................................. 51
14
ETHICAL CONSIDERATIONS.......................................................................................... 52
15
SPONSORSHIP ................................................................................................................ 52
16
INDEMNITY ...................................................................................................................... 53
17
FINANCE .......................................................................................................................... 53
18
TRIAL COMMITTEES ....................................................................................................... 54
19
PUBLICATION POLICY.................................................................................................... 54
20
REFERENCES.................................................................................................................. 55
21 GLOSSARY AND ABBREVIATIONS……………………………………………………………88
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INDEX OF APPENDICES
APPENDIX A
WHO Performance Status…………………………………………………………………..58
APPENDIX B
Surface Area Nomogram……………………………………………………………………59
APPENDIX C
The Chemotherapy Regimens ……………………….…………………………………….60
APPENDIX D
Safety Reporting Flowchart…………………………………………………………………62
APPENDIX E
CTCAE Toxicity Criteria……………………………………………………………………..63
APPENDIX F
Summary of Product Characteristics – Undesirable Effects…………………………….66
APPENDIX G
Cockgroft and Gault Formula……………………………………………………………….82
APPENDIX H
How to calculate the number of capecitabine tablets to dispense following dose
reduction……………………………………………………………………………………...83
APPENDIX I
Trial Committees……………………………………………………………………………..84
APPENDIX J
Summary of Protocol Amendments………………………………………………………..86
INDEX OF TABLES
TABLE 1
Trial Assessments…………………………………………………………………………...15
TABLE 2
Time Points for Forms……………………………………………………………………….17
TABLE 3
Recommended Hydration for Cisplatin……………………………………………………19
TABLE 4
Cisplatin Dose Modification for the CF arm……………………………………………….20
TABLE 5
Capecitabine Dose Calculation according to BSA………………………………………..21
TABLE 6
Dose Modification for ECX Based on Neutrophil Count…………………………………23
TABLE 7
Dose Modification for ECX Based on Platelet Count…………………………………….23
TABLE 8
Cisplatin & Capecitabine Dose Modification Based on Creatinine Clearance………...24
TABLE 9
Management of Stomatitis, Diarrhoea Nausea & Vomiting……………………………..26
TABLE 10
Definitions of SAEs………………………………………………………………………….32
TABLE 11
Definitions of Causality……………………………………………………………………..34
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1 Summary
DIAGNOSIS
1.1
Resectable adenocarcinoma of the
oesophagus or oesophago-gastric
junction (types 1 and 2)
Trial Outline
RANDOMISE
STANDARD CHEMOTHERAPY
2 cycles of Cisplatin and 5FU (CF),
followed by Surgery
Cycle 1
Cisplatin & 5FU
over 4 days
3 Weeks
ECX CHEMOTHERAPY
4 cycles of Epirubicin, Cisplatin and
Capecitabine (ECX), followed by Surgery
Cycle 1
ECX
3 weeks
Cycle 2
Cycle 2
ECX
Cisplatin & 5FU
Over 4 days
3 weeks
4-6 weeks after the last
Cycle 3
ECX
administration of 5FU
i.e. day 4 of
3 weeks
cycle 2
Cycle 4
ECX
SURGERY
3 weeks
4-6 weeks after the last
administration of
capecitabine i.e. day 21
SURGERY
Follow up every 3 months for the first year and then every
6 months until 3 years, then annually thereon, until death.
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2 Background
2.1
Introduction
Cancer of the oesophagus causes over 7,000 deaths in the UK each year and the incidence is
increasing at a rate greater than that of any other cancer in the Western World. Surgical
resection of the primary tumour is the only modality offering the prospect of cure. Approximately
20% of patients are alive after 3 years and even those with apparently resectable disease
frequently relapse with local or distant recurrence.
The Medical Research Council OE02 trial (ISRCTN 43987580) showed that survival was
significantly prolonged by giving two cycles of pre-operative chemotherapy with cisplatin and 5fluorouracil (5FU) (CF) [1]. However, 3-year survival rates of around 30% are the best that can
be expected with this approach, and thus there is an urgent need to develop new treatment
approaches which can improve survival rates further still. The current trial addresses the
following question: does chemotherapy with epirubicin, cisplatin and capecitabine (ECX) confer
a statistically significant survival advantage over standard pre-operative chemotherapy with (CF)
in patients with resectable adenocarcinoma of the oesophagus or oesophago-gastric junction?
2.2
Relevant Trials
The OE02 trial [1] was conducted to assess the effects of pre-operative chemotherapy on
survival, dysphagia and performance status in patients with resectable oesophageal cancer of
any cell type. Patients were randomised to either resection alone, or two 4-day cycles, 3 weeks
apart, of cisplatin 80mg/m2 by 4-hour infusion plus 5FU 1,000mg/m2/day by continuous infusion
for 4 days, followed by resection. With 802 patients randomised, this was the largest randomised
trial examining the role of pre-operative chemotherapy in oesophageal cancer. The results of
OE02 have shown a significant benefit in survival for the chemotherapy arm (HR 0.79; 95% CI
0.67-0.93; p = 0.004). The survival rate at 2 years was 43% (chemotherapy + surgery) compared
with 34% (surgery alone). Disease-free survival was also better in the chemotherapy group, and
there was no evidence of a differential treatment effect according to histology, age, sex, site of
tumour, performance status or dysphagia. This study did not include a formal assessment of
health-related quality of life. In the chemotherapy arm, surgical resection was more often
complete, and resected specimens showed smaller tumours, less extension into surrounding
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tissue, and less lymph node involvement. As a result of this trial, pre-operative chemotherapy
using the short well tolerated OE02 regimen has become widely accepted as standard in the UK,
and is, therefore, an obvious control regimen for new trials.
A logical next step to OE02, which used only two cycles of chemotherapy in modest dosage, is
to assess a chemotherapy regimen that is currently considered optimal for advanced
oesophageal and gastric cancer. A recent phase III trial showed that, in advanced gastric
adenocarcinoma, CF was equivalent to the combination of 5FU, doxorubicin and methotrexate
(FAMTX) [2]. However, a similar randomised trial in advanced oesophagogastric cancer has
demonstrated that the combination of epirubicin, cisplatin and continuous infusion 5FU (ECF) is
superior to FAMTX [3] and by implication also to CF. This trial was confined to adenocarcinoma
and undifferentiated carcinoma. Importantly, the ECF study showed that in patients with locally
advanced disease response rates were 56% (95% CI, 40% - 72%) with ECF versus 23% with
FAMTX (p=0.003), with median survival times of 8.7 months in the ECF arm compared with 6.1
months for FAMTX (p=0.0005). Of the 47 patients with inoperable locally advanced disease who
received ECF, 19 were downstaged allowing surgical resection compared with only 6 patients
receiving FAMTX. Among patients receiving ECF, a histologically complete resection was
performed in 10 cases with 3 cases of pathological complete response, whereas a complete
resection was performed in 4 cases in the FAMTX arm with no evidence of pathological
complete response. The activity of ECF in advanced oesophago-gastric cancer has been
confirmed in a further randomised study which showed that ECF was equivalent to mitomycin,
cisplatin and continuous infusion 5FU in terms of response rates and survival but that overall QL
was superior using ECF [4].
Excellent response rates observed during phase II testing led to ECF being considered the
regimen of choice when the MRC ST02 trial (MAGIC) was launched in 1994. MAGIC (ISRCTN
93793971) randomised 503 patients with adenocarcinoma of the stomach and lower third
oesophagus between peri-operative ECF chemotherapy and surgery versus surgery alone. In
the ECF arm, 3 cycles were given pre-operatively and 3 post-operatively. MAGIC completed
accrual in 2002, the final analysis has shown smaller tumours and increased resection rates in
the patients treated with chemotherapy, as well as significantly improved progression-free and
overall survival (hazard ratio of 0.66 (95%CI: 0.53 - 0.81) p=0.0001 for progression-free survival
and hazard ratio of 0.75 (95% CI: 0.60 - 0.93), p=0.009 for overall survival both in favour of the
combined arm). The latter translates into five year survival rates of 36% for the chemotherapy
and surgery arm versus 23% for surgery alone [5].
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A number of centres in the UK have piloted pre-operative chemoradiotherapy regimens to
assess their feasibility for inclusion in a new trial, based upon work by Walsh and colleagues
which demonstrated a significant survival advantage for patients treated by multimodal therapy
versus surgery alone [6]. Modification to this approach by the use of infusional chemotherapy in
conjunction with radiation seemed initially advantageous [7] and has been evaluated in nearly
100 patients in three of the UK centres involved in planning this trial. Despite observed
pathological complete response rates of 30-35%, this treatment has led to an unacceptable level
of morbidity and mortality. Significant complications have been observed in 30-50% of patients
and post-operative mortality rates vary between 7% and 15%. After much discussion, the trial
management group have decided that in the light of these findings, further modification is
required to ensure safety and acceptability in a multicentre setting.
There is also increasing evidence that in squamous cell carcinoma chemoradiotherapy alone
can be associated with five year survival figures comparable to those seen with surgery [8, 9].
Because squamous cell carcinoma is generally seen in an older population than
adenocarcinoma and more likely to be associated with significant cardiorespiratory disease
which might preclude surgery, it was additionally felt that the inclusion of squamous cell
carcinomas in the current trial proposal would not be appropriate at this time.
Capecitabine (Xeloda) is an oral, tumour selective fluoropyrimidine carbamate. It is designed to
be sequentially converted to 5FU by 3 enzymes located in the liver and in tumours. The final
step is the conversion of 5’ deoxy-5-fluorouridine (5’DUFR) to 5FU by thymidine phosphorylase
(dThdPase) in tumours. It can be used in schedules that provide prolonged 5FU exposure at
lower peak concentrations than those observed with bolus intravenous 5FU schedules, thus
simulating continuous infusion of 5FU. These protracted oral administration schedules reduce
the occurrence of toxic effects such as neutropenia and stomatitis that are associated with a
high peak plasma 5FU concentration. Tumour selectivity has been studied in patients receiving
capecitabine twice daily for 5 to 7 days before surgical resection of primary colorectal tumours,
liver metastases or both [10]. 5FU concentrations were found to be 3.2 times greater in primary
tumours than surrounding healthy tissue, 1.17 times greater in liver metastases than noncancerous liver tissue and 20 times greater in primary tumour than in the plasma. These results
demonstrated the preferential activation of capecitabine to 5FU in colorectal tumour after oral
administration to patients.
Two phase III randomised trials comparing capecitabine with bolus 5FU have been reported in
advanced colorectal cancers involving 1,207 patients showing a superior response rate with
capecitabine (25.7% vs. 16.7% p<0.0002) [11, 12]. Diarrhoea, stomatitis, nausea and alopecia
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occurred in fewer patients treated with capecitabine (p<0.001), but hand-foot syndrome occurred
more in capecitabine treated patients than bolus 5FU treated patients (6% vs 53%) [13]. Survival
was equivalent between the two treatment groups [11-13].
Capecitabine provides a promising alternative to continuous intravenous infusion of 5FU which is
cumbersome to use and compromises patients’ independence. Moreover, the elimination of
ports and pumps required for intravenous infusion; avoidance of the associated complications
with intravenous catheters and the possible better toxicity profile requiring less in-patient stay
and out-patient visits may translate into cost-saving measures for the health service [14]. In
addition, it would encourage patients’ active participation in their treatment programme.
The combination of epirubicin, cisplatin and capecitabine (ECX) is also being tested in an ongoing multicentre randomised trial in oesophago-gastric cancer [15]. In this trial, capecitabine
was initially given as 1,000mg/m2/day continuously but preliminary data suggested that ECX has
similar efficacy and toxicity profile to ECF and the dose of capecitabine has been escalated to
1,250mg/m2/day. At an interim analysis, after 204 randomised patients, objective response rates
were 31% and 33% for the 5FU containing arms, compared to 35% and 52% for the
corresponding capecitabine containing arms [16]. This dose and schedule has, therefore, been
adopted in the present study. In the light of the definitive findings from the OE02 and ECF trials,
there is a clear need to compare the ECX regimen and, as a control, the OE02 regimen as preoperative treatment in resectable oesophageal cancer.
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3 Objectives
The primary objective of the trial is to evaluate whether pre-operative prolonged ECX
chemotherapy improves survival and quality of life (QL) when compared to standard
chemotherapy in patients undergoing oesophagectomy for adenocarcinoma of the oesophagus.
4 Design
This is an open randomised controlled phase III clinical trial designed to compare pre-operative
ECX chemotherapy to standard pre-operative chemotherapy, in patients with resectable
adenocarcinoma of the oesophagus.
A minimum of 842 patients will be randomised to receive either 2 cycles of CF chemotherapy, or
4 cycles of ECX chemotherapy prior to resection, in a 1:1 ratio. Patients will be followed for
survival, recurrence-free survival, QL (in selected centres, see section 10.1) and treatment
morbidity/mortality. With the different numbers of treatment cycles, the different number of drugs
and the different modes of administration of the drugs used between the two arms, it is
impractical to blind this study.
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5 Selection of Patients
5.1
Inclusion Criteria:
1. Histologically verified adenocarcinoma of the oesophagus or type 1 and type 2
adenocarcinoma of the oesophago-gastric junction [17].
2. Adenocarcinoma as above, which includes disease staged as T1 N1, T2 N1, T3 N0, and
T3 N1 as assessed by spiral CT and endoscopic ultrasound (EUS). Also T4 tumours that
i.
involve only the diaphragm or crura OR
ii.
invade only the mediastinal pleura.
3. The N1 definition in the inclusion above criteria above is based on staging using TNM 5th
or 6th edition. From January 2010, TNM7 classification will become active. Should you
use TNM7 for staging of patient's disease, please note that all patients staged as
T1N1/N2/N3 , T2N1/N2/N3, T3 any N will be eligible for participation in the OE05 trial.
4. Tumours with nodal disease (N1) affecting the origin of the left gastric and splenic artery
with the coeliac axis (hitherto staged as M1a) can be included.
5. WHO performance status 0 or 1 (Appendix I).
6. Proven respiratory and cardiac function, to the following levels: FEV1 >1.5 litres; cardiac
ejection fraction ≥50% on echocardiography or MUGA. These assessments should
normally be performed within 4 weeks prior to randomisation. If assessments are > 4
weeks or results are borderline please contact the Chief Investigator via the OE05 Trial
Manager.
7. Patients with high frequency hearing loss can be included in the trial and treated with
cisplatin. However, if there is deterioration of hearing then cisplatin should be substituted
with carboplatin (see section 8.1.3 and 8.2.2).
The following assessments (i.e. 6 and 7) should normally be performed within 1 week
prior to randomisation. If assessments are > 1 week or if results are borderline, please
contact the Chief Investigator via the OE05 Trial Manager.
8. Proven hepatic and haematological function to the following levels: liver function tests not
more than 1.5 x normal; white blood cell count ≥3 x 109/l; platelets ≥100 x 109/l.
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9. Adequate renal function: glomerular filtration rate (GFR) ≥60ml/minute calculated or
measured (see appendix G). If the calculated GFR is <60ml/min then a measured GFR
is required. The measured GFR should always take precedence over the calculated
GFR.
10. Written informed consent
5.2
.Exclusion Criteria:
1. Uncontrolled angina pectoris, myocardial infarction within 6 months, heart failure,
clinically significant uncontrolled cardiac arrhythmias, or any patient with a clinically
significant abnormal ECG. Patients with abnormal left ventricular ejection fraction (LVEF)
determined on MUGA scan or echocardiography, including areas of abnormal
contractility, should also be excluded.
2. Oesophageal tumours staged as T1 N0 and stage T2 N0.
3. Patients with any previous treatment for oesophageal carcinoma.
4. Type 3 oesophago-gastric tumours. Lower limit of endoscopically visible primary tumour
should not involve stomach for more than 2cm and no evidence of full thickness disease
below the diaphragm on laparoscopy.
5. T4 tumours invading contiguous structures other than diaphragm, crura or mediastinal
pleura.
6. Patients with disease in any of the following areas on the CT scan, EUS or other staging
investigation:
a) Evidence of metastases in liver, lung, bone or other distant metastases.
b) Para aortic lymphadenopathy >1cm diameter on CT or >6mm diameter on
endoscopic ultrasound (EUS).
c) Invasion of tracheo-bronchial tree, aorta, pericardium or lung.
7. Lymphadenopathy encasing the coeliac axis (as described above, single nodes lying
anterior to the origin of the splenic artery and anterior to the origin of the coeliac axis are
not excluded).
8. Any patient with a single significant medical condition which is thought likely to
compromise his or her ability to tolerate any of the above therapies.
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9. No previous malignancy thought would affect the treatment or follow-up of the patient in
the trial. Patients that have received previous chemotherapy or radiotherapy should be
discussed with the Chief Investigator via the Trial Management Group for approval.
10. Pregnant or lactating women and fertile women who will not be using adequate
contraception during the trial.
11. Patients with mild/intermittent tinnitus can be randomised to OE05 but patients with
more severe tinnitus should not be randomised
12. Patients with known positive serology for HIV, Hepatitis C or active Hepatitis B are
excluded from the trial.
5.3
Centre Accreditation & Approval Process
Centres will be required to complete the OE05 accreditation form at the same time as applying
for their site specific assessment (SSA).
Pre-requisites for centre participation are:i.
A full multi-disciplinary team should be in place.
ii.
Experience with two-phase oesophagectomy and two-field lymphadenectomy.
Participating surgeons should have experience with two phase oesophagectomy and
two-field lymphadenectomy (it is recommended that unproctored surgeons should have
performed a minimum of 12 such operations prior to commencement of the trial)
iii.
Access to contrast enhanced spiral or multi-slice CT and EUS.
iv.
The clinical trial centre has appropriate pathologists who are experienced in the reporting
of oesophageal cancer. Centres are normally expected to support the OE05 pathology
review and the Trans-OE05 study (tissue sample collection).
v.
The clinical trial centre has experienced radiologists who are willing to report findings as
required on the pre-randomisation and pre-surgery tumour assessments.
The following accreditation documentation must be received by the MRC CTU in order for
a centre to become an approved OE05 centre:
Completed investigator statement (signed by the Principal Investigator and lead surgeon)
Principal Investigators CV (2 pages only)
Investigator Site File Assessment Form
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Pharmacy Master File Assessment Form
Completed delegation log (signature and delegation of responsibilities of all staff involved
in the trial)
Full contact details for all staff involved in the trial
Confirmation of R&D approval
Laboratory ranges
Confirmation of participation in QL study (signed by Principal Investigator)
Once all of the above documents have been received, confirmation of centre approval will be
sent to the Principal Investigator and first point of contact at each centre by the OE05 trial team
at the MRC CTU.
5.3.1
MHRA CTA Approval for Participation in the Study
All clinicians who wish to participate in the trial must have MHRA approval under the OE05
Clinical Trials Authorisation (CTA). Clinicians must therefore notify the OE05 Trial Manager of
their intentions to participate in the trial by completing the delegation log and contact details in
the accreditation form, in order to gain MHRA approval.
Additional clinicians, from accredited centres, should fax a completed delegation log to the OE05
Trial Manager before attempting to randomise into the trial.
5.4
Trial Drug Supply - Capecitabine
An OE05 pharmacy information pack will be sent to the named pharmacist recorded on the
OE05 accreditation form. The pack will include record sheets for drug accountability and
capecitabine drug order forms, drug destruction report and OE05 capecitabine drug labels. As
capecitabine is not licensed for treating oesophageal cancer the OE05 trial stock must be
labelled for “clinical trial use only”, before being dispensed to the patient. The “OE05 clinical trial”
labels will be included in the pharmacy information pack.
Roche will be notified to dispatch the initial supply of capecitabine (3 packs of 500mg tablets and
3 packs of 150mg tablets) to the newly approved pharmacy, once the CTU have received the
completed accreditation documents.
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5.5
Randomisation of Patients
Before a patient is randomised to the OE05 trial, written informed consent must be
obtained. When obtaining consent from a patient, the OE05 trial and the current version
of the OE05 patient information sheet (PIS) should be introduced in full. Written
confirmation that patient has given their consent to participate in the trial should be
recorded by a qualified, experienced nurse or a clinician according to local practice.
The investigator should keep a patient screening log and enrolment log of all patients
being considered for the OE05 trial. This may be requested for monitoring purposes
during the trial.
When a patient is confirmed as eligible and has given their written informed consent
(Appendix III), the Randomisation Form (OE05/1) and On Study Form (OE05/2) should
be completed.
If the centre is taking part in the QL study (section 11.1) the baseline QL questionnaire
(OE05/QL(1)) must also be completed before the patient is informed which treatment has
been allocated.
With randomisation form in hand, telephone the MRC CTU (Tel: +44 (0)20 7670 4777)
between 09h00 and 17h00 Monday to Friday to randomise the patient.
RANDOMISATIONS
Tel: +44 (0)20 7670 4777 (Mon – Fri, 09:00 – 17:00)
At randomisation, the patient will be allocated a trial number and treatment regimen, which
should be recorded on the randomisation form. Written confirmation of the patient’s entry into the
trial, the trial number and treatment allocated will be sent to the hospital by post. Following
randomisation the Randomisation Form and On Study Form should be sent immediately to the
MRC CTU with the baseline QL Questionnaire, where applicable.
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5.6
Enrolment in Trans-OE05 (Tissue and Blood collection for translational
research)
Participation in the Trans-OE05 study is open to all centres. In order to collect tissue and blood
samples for the translational research patients are required to sign the Trans-OE05 consent
form. Although most patients are expected to consent to participation in the translational study,
the wishes of patients who do not want to be involved in the additional translational sample
collection will be respected and they will be allowed to enter the clinical trial only.
A 20ml EDTA blood sample should be collected from patients that consent to Trans-OE05
before commencing OE05 treatment.
Patients that were entered into the OE05 trial prior to the commencement of the Trans-OE05
study will not be able to contribute their blood samples to the study. For more information on the
Trans-OE05 study, please see section 11.4
6 Withdrawal of Patients
Patients should be given every encouragement to adhere to protocol treatment and follow-up, in
order to reduce biases. However, a patient has the right to withdraw consent for participation in
any aspect of this trial at any time.
They may refuse to take certain treatments, attend
scheduled follow-up visits, or move from the area (see section 6.3). Clear distinction must be
made as to whether the patient is withdrawing from trial treatments/procedures whilst allowing
further follow-up, or whether the patient refuses any further trial treatments/procedures and
follow up participation. In all instances the MRC CTU should be informed as soon as possible.
6.1
Withdrawal from Trial Interventions
A patient may withdraw, or be withdrawn, from trial treatment for the following reasons:
i.
Tumour progression whilst on therapy.
ii.
Patient withdraws consent from protocol treatment.
iii.
Unacceptable toxicity.
iv.
Intercurrent illness which prevents further treatment.
v.
Any change in the patient’s condition which, in the clinician’s opinion, justifies the
discontinuation of treatment.
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The reason should be recorded on the Tumour Assessment Form (OE05/4)
6.2
Withdrawal from the Trial Completely
If a patient explicitly withdraws consent to have any data recorded their decision must be
respected and the Trial Manager must be notified in writing. Patients can change their minds
about withdrawal at any time and re-consent to participate in the trial. Follow-up data should be
collected only from the point of when consent was reinstated.
6.3
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 patients OE05 CRFs will need to be provided to the new site.
7 Assessments and Procedures
7.1
Pre-Chemotherapy Investigations
Assessment of hearing and associated interpretation of results and administration of
chemotherapy can be according to local practice.
7.1.1
Tumour Staging Assessments (timing of investigations is given in table 1)
Each of the tumour staging investigations outlined below should be aimed at being performed
within 4 weeks prior to randomisation.
However if this is not possible, the last staging
investigation, which may include CT, EUS, PET/CT, and laparoscopy, should normally be
performed within 4 weeks prior to randomisation. If the last staging investigation is > 4 weeks
please contact the Chief Investigator via the OE05 Trial Manager.
1. Spiral/multi-slice CT with oral contrast or water. Maximum slice width 5mm. IV
contrast/venous phase. CT must include abdomen and chest. Neck and pelvis fields are
optional.
2. An EUS should be attempted for a patient to be eligible for OE05. A partial EUS e.g
scoping of the tumour and proximal gullet still provides some information. Staging data
from PET/CT compliments this and there are special probes to use if the there is a
stricture.
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3. Laparoscopy where clinically indicated. It is mandatory for T3 tumours with significant
infra-diaphragmatic component.
4. Bone scans and PET scans are optional, and should be performed according to local
practice.
5. Laparoscopic ultrasound and intraperitoneal cytology are optional, and should be
performed according to local practice.
Please note that EUS should be used to stage local disease (tumour and nodes) and that
these results should be taken over CT and CT should be used to stage distant spread.
6. Pre-chemotherapy assessment of audiological function to be made according to local
practice.
7.2
Post-chemotherapy Investigations
7.2.1
Trial Assessments:
1. A clinical examination, to include an assessment of fitness for surgery.
2. Spiral/multi-slice CT with oral contrast or water within 2 weeks of completion of
chemotherapy. Maximum slice width 5mm. IV contrast/venous phase. CT must include
abdomen and chest. Neck and pelvis fields are optional.
3. Re-discussion of the patient at the MDT is optional, but recommended.
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Table 1: Trial Assessments
Required Trial Assessments
Pre-Randomisation
Before each cycle
Pre-surgery
Follow-up
Clinical Examination
Y
Y
Y
Y
CT scan-abdomen & chest
(neck pelvis optional)
Y
Y
As clinically
indicated
EUS
Y
Spirometry
FEV should be ≥1.5 l
Y
Within 4 weeks prior to randomisation
ECHO or MUGA
Ejection fraction should be ≥ 50%
Y
Within 4 weeks prior to randomisation
ECG
Y
Within 4 weeks prior to randomisation
FBC
Y
Neutrophils ≥1.5 x 109/l
9
Platelets ≥100 x 10 /l
Y
Neutrophils ≥1.0x109/l
9
Platelets ≥75 x 10 /l
Glomerular Filtration Rate
(measured or estimated)
Y
Y
1 week before randomisation and
before each cycle of chemotherapy
U&E serum creatinine Ca2+Mg 2+
Liver Function Tests
Y
Y
1 week before randomisation and
before each cycle of chemotherapy
Nutritional Assessments
Y
Y
Laparoscopy
Y(if indicated)
Within 4 weeks prior to randomisation
Bone scans
optional
Within 4 weeks prior to randomisation
PET/CT scan
optional
Audiogram
optional
If necessary
Y
Y
Time Point
See note 1
Pre surgery scans should be within 2
weeks of completing chemotherapy
See note 1
1 week before randomisation and
before each cycle of chemotherapy
1 week before randomisation
During chemotherapy
Before surgery
Post Surgery
At follow up visits
See note 1
optional
optional
Note 1: The last staging investigation, which may include an EUS, CT, PET/CT or laparoscopy should normally be within 28 days prior to
randomisation, if not please contact the Chief Investigator via the OE05 Trial Manager. Chemotherapy should start within 1 week of
randomisation.
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7.3
Patient Follow up
At each visit, a full clinical assessment should be made. Patients should be monitored for the
onset of local recurrence or distant metastases and appropriate investigations carried out to
confirm or refute their presence.
If the patient does not follow the protocol at any stage, or protocol treatment is stopped for
whatever reason, the patient should remain in the trial for the purposes of follow-up and data
analysis. Patients enrolled from the UK will be followed up in the long-term through usual
mechanisms which may include flagging with the NHS Information Centre or similar approaches
7.4 Time points for forms (Table 2)
Follow up forms (OE05/8) should be completed every 3 months for 1 year, every 6 months for
years 2, then annually until death. If the patient attends between these appointments and a new
event occurs, then an additional Follow up form (OE05/8) should be completed. Follow-up forms
should also be used when there is information concerning new events (such as local recurrence,
detection of metastases or death from any cause), if the patient does not attend clinic or if the
patient receives further treatment.
During treatment, if required, a Serious Adverse Event Form (OE05/10) should be completed
(see section 10). A Cause of Death form (OE05/9) should be completed in the event of the death
of a patient.
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Table 2: Time points for forms
Time
Form(s)
Randomisation
Randomisation Form (OE05/1)
On-Study Form (OE05/2)
Quality of Life (OE05/QL)*
Day 14 of cycle 2 of Chemotherapy
Quality of Life (OE05/QL)*
Day 14 of cycle 4 of Chemotherapy
(ECX arm only)
Quality of Life (OE05/QL)*
End of neoadjuvant treatment
Chemotherapy Form (OE05/3)
Tumour Assessment Form (OE05/4)
Immediately before surgery
Quality of Life (OE05/QL)*
After surgery
Surgery Form (OE05/5)
Pathology Form (OE05/6)
6 weeks post-operatively
Post-Operative Form (OE05/7)
3 months post-operatively
Follow up Form (OE05/8)
Quality of Life (OE05/QL)*
6 months post-operatively
Follow up Form (OE05/8)
Quality of Life (OE05/QL)*
9 months post-operatively
Follow up Form (OE05/8)
Quality of Life (OE05/QL)*
12 months post-operatively
Follow up Form (OE05/8)
Quality of Life (OE05/QL)*
18 months post-operatively
Follow up Form (OE05/8)
Quality of Life (OE05/QL)*
24 months post-operatively
Follow up Form (OE05/8)
Quality of Life (OE05/QL)*
Annually thereafter
Follow up Form (OE05/8)
* QL questionnaires only apply to those patients entered by a centre participating in the
Quality of Life study. For further information please refer to section 11.1 Quality of Life.
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8 Treatment
8.1
Chemotherapy Regimens
Patients are randomised to receive either:
1. Standard chemotherapy (section 8.1.2)
2. ECX chemotherapy (section 8.2)
Treatment should commence within 1 week of randomisation for both treatment arms. Appendix
VI contains descriptions of the trial regimens. It is the responsibility of the treating Clinician to
ensure that the protocol is followed. Dose modifications should only be made after consulting the
protocol (if in doubt, please discuss with the MRC CTU).
Body surface area should be
calculated using the DuBois and DuBois formula (see nomogram in Appendix V). Prophylactic
anti-emetics and hydration should be administered according to standard local practice.
8.1.1
Management of Cardiac Toxicity Whilst Receiving Fluoropyrimides:
Fluoropyrimidines (Capecitabine and 5-FU) are known to uncommonly cause cardiotoxicity,
including myocardial infarction, angina, dysrhythmias and impairment of cardiac function. These
are more common in patients with a prior history of coronary artery disease. Caution must be
exercised in patients with a history of significant cardiac disease, arrhythmias and angina
pectoris.
A syndrome of angina-like chest pain may uncommonly occur, which is thought to relate to
coronary artery spasm. If patients develop angina-like pain whilst receiving capecitabine or 5FU,
then treatment should be discontinued immediately pending further cardiology assessment. All
cardiac toxicities should be reported on the OE05 SAE form (OE05/10).
8.1.2
Standard Chemotherapy Regimen (CF)
Two 3 weekly cycles of cisplatin and 5FU. Cisplatin 80mg/m2 to be given by intravenous infusion
according to local policy on day 1. A recommended hydration regimen is given in table 3. A total
dose of 4g/m2 of 5FU is given by intravenous infusion over 4 days at a rate of 1g/m2/day. In
patients with central lines, ambulatory pumps should be used according to standard local
practice to administer the 5FU infusion. In patients receiving 5FU via peripheral canulae, the
5FU should be administered in 1 litre of normal saline. Warfarin 1mg PO daily is recommended
as prophylaxis against venous thrombosis in patients with central lines.
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Table 3: Recommended Hydration for Cisplatin (Local policy may be substituted if
preferred)
Time (T)
Recommended Medication
T -1 hour
Frusemide 40mg IV/ PO stat
Normal saline 1 litre + KCl 20mmol over 60 mins
Cisplatin (CF arm: 80mg/m2 and ECX arm: 60mg/m2) IV in 1 litre normal saline
+ KCl 20mmol over 4 hours
T=0
Mannitol (20%) 100mls IV concurrently with cisplatin
T +4 hrs
Normal saline 1 litre + KCl 20 mmol over 2 hours
T +6 hrs
Normal saline 500mls + KCl 10mmol over 1 hour
Then advise patients to drink 2 litres of fluids over the next 24 hours.
8.1.3
Dose Modifications Standard Chemotherapy (CF)
Protocol chemotherapy may have to be modified for the second course if toxicity arises following
the first. Full blood count and serum creatinine should be measured prior to the 2nd cycle.
Haematological Toxicity
If the neutrophil count is <1.0x109/l or the platelet count <75x109/l, delay the second course of
chemotherapy for 1 week and repeat blood counts. If blood counts have recovered (i.e. the
neutrophil count is ≥1.0x109/l and the platelet count is ≥75x109/l), treat with a 25% reduction of
both cisplatin and 5FU. If, on repeating the blood count after the week’s delay, the blood counts
have not recovered delay the second course by one further week, and give it with a 50% dose
reduction of both cisplatin and 5FU, once the blood counts have recovered.
If cisplatin is substituted with carboplatin, the patient neutrophil count should be ≥1.5x109/l and
the platelet count should be ≥100x109/l, before each cycle of treatment commences.
Stomatitis, Diarrhoea, Nausea & Vomiting
If CTC grade 3 or 4 oral mucositis or diarrhoea occurs during the first course, the daily dose of
5FU in the second course should be reduced to 750mg/m2/day.
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Renal Toxicity
Creatinine clearance prior to starting treatment should be greater than or equal to 60mls/min.
Thereafter, serum creatinine should be measured before each course of cisplatin. If the serum
creatinine rises above normal, creatinine clearance measurement or calculation should be
repeated and the dose of cisplatin adjusted as indicated in table 4.
Table 4: Cisplatin Dose Modifications for the CF arm
Creatinine clearance
Cisplatin Dose
≥60 mls/min
100%
50-59 mls/min
50%
40-49 mls/min
50%
30-39 mls/min
Replace cisplatin with
carboplatin
Substituting Cisplatin with Carboplatin
Substituting cisplatin with carboplatin, in patients whose creatinine clearance is
<40mls/min, cisplatin should be replaced by carboplatin at a dose of AUC5 (Area Under
the Curve).
Neurotoxicity / ototoxicity
Patients with CTC grade 2 or greater neurotoxicity or new functional deterioration in hearing,
new tinnitus or new significant high frequency hearing loss on audiogram should have cisplatin
discontinued. In this situation, carboplatin at a dose of AUC5 may be substituted at the discretion
of the investigator.
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8.2
ECX Chemotherapy
Four 3 weekly cycles of epirubicin, cisplatin and capecitabine. Epirubicin 50mg/m2 and cisplatin
60mg/m2 are given by intravenous infusion on day 1 according to local policy. Capecitabine is
given orally continuously for 12 weeks at a total daily dose of 1,250mg/m2 i.e. two doses of
625mg/m2 per day.
8.2.1
Administered Dose of Capecitabine
The daily dose of capecitabine is based on 1250mg/m2/day but will be rounded to the nearest
achievable dose based on the 3 BSA levels and will be administered according to Table 5.
An example of how to calculate the total cycle dose, which is required on the chemotherapy CRF
is given below:
If BSA is 1.7, then the total daily dose prescribed (based on banding) will be 2150mg.
Total cycle dose is 2150 x 21 day = 45150 mg
Capecitabine tablets should be administered morning and evening and swallowed with water
within 30 minutes after a meal. If two different doses are given between the morning and
evening, then the higher dose should be given in the evening.
Table 5: Capecitabine Dose Calculation, According to Body Surface Area
BSA (m2)
Total daily
Number of tablets
Number of tablets
dose (mg)
administered in the morning
administered in the evening
150mg
500mg
150mg
500mg
<1.6
1800
2
1
0
2
1.6-1.8
2150
0
2
1
2
>1.8
2500
0
2
0
3
(Dose level = 1,250mg/m2/day in two divided doses, or 625mg/m2 twice daily. Capecitabine is
available as 150mg and 500mg tablets only)
In patients with mild renal impairment (creatinine clearance between 61-80ml/min at baseline),
no adjustment of the starting does of capecitabine is required. In patients whose renal function
deteriorates during the study, dose adjustments should be made according to Section 8.2.2
(Table 8).
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For patients who have difficulty swallowing capecitabine, the tablets can be dissolved in water.
The solution may also be administered through a naso-gastric or other enteral feeding tube. The
solution has a very bitter taste and a fruit juice (e.g. raspberry juice) can be added to make the
solution more palatable.
8.2.2
Dose Modifications for ECX Chemotherapy
Please note that if the dose of capecitabine is reduced for any reason, treatment should stop at
day 84, and not continue until completion of tablet course.
An example of how to calculate the number of capecitabine tablets to dispense following a dose
reduction is provided in Appendix H.
8.2.3
Capecitabine Diary Cards
In order to assess patient compliance in taking the full prescribed capecitabine dose per cycle,
patients will be given a capecitabine diary card to complete. A new capecitabine diary card
should be given to the patient at the start of each cycle. Research staff should ensure that the
diary card is collected at the end of each cycle and the number of unused tablets, if any, are
recorded on the Chemotherapy Form (OE05/3).
DPD deficiency
With any 5FU regimen, the occasional patient is encountered (approximately 1-3%) who has
markedly exaggerated toxicity due to reduced 5FU catabolism. If this occurs, await full recovery.
Re-start capecitabine at a 50% reduction.
Haematological Toxicities
Check FBC on (or up to 3 working days before) day 1 of each cycle
CTC grade 3 infection/fever associated with neutropenia (neutrophil count <1.0x109/l) at
any time on treatment requires a subsequent 25% dose reduction of epirubicin
CTC grade 4 infection/fever associated with neutropenia at any time on treatment
requires a subsequent 50% dose reduction of epirubicin.
If neutropenia/thrombocytopenia is present on day treatment is due, dose reduce as
indicated in tables 6 and 7.
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Table 6: Dose Modifications for ECX Based on Neutrophil Count (on day of treatment)
Neutrophil
CTC
count (x109/l)
Action
grade
≥1.0
0-2
Full dose of all drugs
0.5-0.9
3
Stop capecitabine and delay epirubicin & cisplatin until
recovery (e.g. 1 week later). Restart capecitabine at full dose.
Reduce epirubicin by 25% on subsequent cycles. Restart
cisplatin at full dose
<0.5
4
Stop capecitabine and delay epirubicin & cisplatin until
recovery (e.g. 1 week later). Restart capecitabine at full dose.
Reduce epirubicin by 50% on subsequent cycles. Restart
cisplatin at full dose
Table 7: Dose modifications for ECX Based on Platelet Count (on day of treatment)
Platelet count
CTC
Action
grade
(x109/l)
≥75
0-1
Full dose of all drugs
50-74
2
Stop capecitabine and delay epirubicin & cisplatin until
recovery (e.g. 1 week later). Restart capecitabine at full dose.
Restart cisplatin at full dose. Reduce epirubicin by 25% on
subsequent cycles.
25-49
3
Stop capecitabine and delay epirubicin & cisplatin until
recovery (e.g. 1 week later). Restart capecitabine at full dose.
Restart cisplatin at full dose. Reduce epirubicin by 50% on
subsequent cycles.
<25
4
Stop capecitabine and delay cisplatin until recovery (e.g. 1
week later). Restart capecitabine at full dose. Restart cisplatin
at full dose. Omit epirubicin from subsequent cycles.
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Cardiac Toxicity
Please also see section 8.1.1 Management of cardiac toxicity whilst receiving fluoropyrimides
Cardiac Failure. Any patient who develops unexplained cardiac failure while on
treatment should undergo evaluation of cardiac function with a MUGA or ECHO and an
ECG. If left ventricular function is less than the local lower limit of normal range then
epirubicin should be omitted until function returns to acceptable levels.
All cardiac toxicities must be reported on the OE05 SAE form (OE05/10)
Liver Toxicity
Bilirubin If bilirubin increases to >1.5x ULN (upper limit of normal range), epirubicin
should be omitted until bilirubin returns to acceptable levels.
Raised Transaminases Capecitabine undergoes hepatic metabolism.
Patients on
capecitabine may have temporary treatment related elevation of transaminases.
An
isolated rise in transaminase above 5x ULN during treatment is likely to be treatmentrelated, and capecitabine should be interrupted until recovery
Renal Toxicity
Creatinine clearance prior to treatment should be greater than or equal to 60mls/min.
Thereafter, serum creatinine should be measured before each course of cisplatin. If the
serum creatinine rises above normal, creatinine clearance measurement or calculation
should be repeated and the dose of cisplatin adjusted as indicated in table 8.
Table 8: Cisplatin & Capecitabine Dose Modifications for the ECX arm Based on
Creatinine Clearance
Creatinine
Cisplatin Dose
Capecitabine Dose
≥60 mls/min
100%
100%
50-59 mls/min
50%
100%
40-49 mls/min
50%
75%
30-39 mls/min
Replace cisplatin
75%
clearance
with carboplatin
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As with cisplatin, capecitabine doses may require modification if the creatinine clearance
declines. If the serum creatinine rises above normal, creatinine clearance measurement or
calculation should be repeated and the dose of capecitabine adjusted as indicated in table 8.
Capecitabine can resume at normal dose upon recovery of renal function. The cisplatin dose
should continue at the reduced level.
Substituting Cisplatin with Carboplatin
Substituting cisplatin with carboplatin, in patients whose creatinine clearance is
<40mls/min, cisplatin should be replaced by carboplatin at a dose of AUC5 (Area Under
the Curve) so that patients receive epirubicin, carboplatin and capecitabine (E-Carb-X).
Neurotoxicity / Ototoxicity
Patients with CTC grade 2 or greater neurotoxicity or new functional deterioration in hearing,
new tinnitus or new significant high frequency hearing loss on audiogram should have cisplatin
replaced with carboplatin at a dose of AUC5, so that patients receive epirubicin, carboplatin and
capecitabine (E-Carb-X).
Plantar-Palmar erythema (PPE)
On development of grade 1 PPE, continue capecitabine but commence pyridoxine 50mg
tds.
For CTC grade 2, stop capecitabine and commence pyridoxine 50mg tds. On resolution
of toxicity, restart capecitabine with 15% dose reduction.
For CTC grade 3, stop capecitabine and commence pyridoxine 50mg tds. On resolution
of toxicity, restart capecitabine with 30% dose reduction.
For recurrent CTC grade 3, stop capecitabine. On resolution of toxicity, restart
capecitabine with 50% dose reduction.
If PPE CTC grade 2-3 occurs after 10 weeks, stop capecitabine. On resolution of toxicity,
NO dose reduction is necessary.
When capecitabine is stopped for toxicity the doses are omitted, not delayed.
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Stomatitis, Diarrhoea, Nausea & Vomiting
For CTC grade 2-3 toxicity, stop capecitabine and administer appropriate symptomatic
management (e.g. sucralfate for stomatitis, codeine phosphate for diarrhoea). If toxicity is
adequately controlled with symptomatic measures alone within 2 days, then capecitabine may
be restarted at 100% full dose. If toxicity persists, dose reductions as indicated in table 9 should
be made. Doses of capecitabine should be rounded to the nearest 150mg tablets. When
capecitabine is stopped for toxicity the doses are omitted, not delayed.
Table 9: Management of Stomatitis, Diarrhoea, Nausea and Vomiting
Incidence
Grade 2
Grade 3
Grade 4
1st appearance
Interrupt treatment until
resolved to grade 0-1,
then continue
capecitabine at same
dose.
Interrupt treatment until
resolved to grade 0-1,
then continue
capecitabine at 75% of
original dose with
prophylaxis where
possible.
Discontinue treatment
unless Investigator
considers it to be in the
best interest of the
patient to continue at
50% of original dose,
once toxicity has resolved
to grade 0-1 (after
discussion with the study
Chief Investigator).
2nd appearance Interrupt treatment until
of same toxicity resolved to grade 0-1,
then continue
capecitabine at 75% of
original dose.
Interrupt treatment until
resolved to grade 0-1,
then continue
capecitabine at 50% of
original dose.
Discontinue treatment
3rd appearance
of same toxicity
Interrupt treatment until
resolved to grade 0-1,
then continue
capecitabine at 50% of
original dose.
Discontinue treatment
N/A
4th appearance
of same toxicity
Discontinue treatment
N/A
N/A
8.3
Anti-Emetics
All patients must receive adequate anti-emetic therapy prior to the administration of platinum. It
is recommended that a 5HT3 antagonist (e.g. Granisetron) or aprepritant and dexamethasone
8mg IV are administered prior to each cycle of treatment. Dexamethasone 4mg tds orally for 2
days and metoclopramide 10mg tds orally for 3 days should continue over days 1-3 of each
treatment cycle.
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8.3.1
Concomitant Treatment
No concomitant cytotoxic treatment or radiotherapy is permitted during the trial. The following
medications are contraindicated when taking capecitabine:
brivudine or sorivudine may produce a dangerous interaction with capecitabine. These
medications are not licensed in the UK but may be prescribed for viral infections in other
countries.
The following medications may interact with capecitabine. These medications are not
contraindicated but should be avoided unless there is no reasonable alternative:
warfarin: INR control may be affected by capecitabine. Patients receiving capecitabine
and warfarin will require more frequent INR monitoring.
phenytoin: blood phenytoin levels may increase with capecitabine.
folic acid: multivitamin supplements containing folic acid should be avoided as it could
potentially increase capecitabine toxicity
allopurinol: potentially reduces the effectiveness of capecitabine.
interferon α: reduces maximal tolerated dose of capecitabine
8.4
Toxicity
Toxicity will be measured using Common Toxicity Criteria version 3.0, (Appendix VI). The
common toxicities of the individual agents are outlined below: For a more detailed list please see
Appendix VII.
5FU
stomatitis, nausea, vomiting, plantar/palmer erythema, diarrhoea
Epirubicin
alopecia, nausea, vomiting, myelosuppression, myocardial
dysfunction
Cisplatin
peripheral neuropathy, renal toxicity, ototoxicity, low frequency
hearing loss, nausea, vomiting and tinnitus, myelosuppression.
Capecitabine
plantar/palmar erythema, nausea and vomiting, diarrhoea, stomatitis,
myelosuppression
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8.5
Surgery
Surgery should be performed within 4-6 weeks after completion of protocol chemotherapy, (i.e.
Day 4 of cycle 2 in CF arm and day 21 of cycle 4 of the ECX arm), certainly no later than 6
weeks post-chemotherapy.
The operation consists of a two-phase oesophagectomy (abdomen and right or left chest
approach) with a two-field lymphadenectomy (abdomen and thorax). The abdominal phase
should be carried out first. A synchronous operation involving two teams is not recommended
but is acceptable if all other aspects of the surgery can be completed as per protocol. Stomach
is the preferred organ for reconstruction.
In order to standardise surgical procedures across the treatment arms, the surgical
procedures described below should be performed for both treatment arms.
However, centres who wish to enter patients into the OEO5 trial and perform the operation as a
total minimally invasive procedure should contact the OE05 Trial Manager. In order to maintain
surgical quality assurance, each surgeon that wishes to perform a total minimally invasive
procedure for OE05 patients, will be asked to provide summary evidence of their previous 20
total minimally invasive operations documenting lymph node yields in both the abdomen and the
mediastinum and post-operative complication rates. To achieve 20 oesophagectomy cases
without withdrawing from recruiting to OE05, it would be permissible to include laparoscopic
operations for squamous cell cancers and for high grade dysplasia, however, at least 10 of the
20 cases should be either T3 or N1.
8.5.1
The abdominal phase of the operation can be undertaken by an open or
laparoscopic method
1. The incision is at the surgeon’s preference
2. The intra-abdominal contents should be carefully inspected, both visually and manually,
paying particular attention to the omentum and peritoneal surfaces in the supracolic
compartment for peritoneal metastases and the para-aortic region in patients with
otherwise resectable nodal disease.
3. Suspicious peritoneal deposits, enlarged para-aortic nodes and any other lesion
considered consistent with haematogenous metastasis, should be dealt with by frozen
section biopsy. Gastric mobilisation can proceed but the operation should be terminated
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if there is unequivocal evidence on frozen section that there is disease outside the
proposed surgical field.
4. Complete gastric mobilisation should be achieved, based on the right gastroepiploic and
right gastric arteries. Where the stomach is unavailable as a suitable conduit, colonic
transposition should be performed according to surgeon's preference.
5. Pyloroplasty , pyloromyotomy or no drainage are options at the surgeon’s preference.
6. The coronary vein should be divided as low as possible, where it disappears behind the
hepatic artery at the upper border of the pancreas. The left gastric artery should be
divided at its origin. The lymph nodes on the left gastric artery and lesser curve must
always be included en bloc.
7. Lymphadenectomies along the hepatic artery and splenic artery will be performed, either
en bloc or separately at the surgeon’s discretion.
8. The hepatic artery dissection should remove all nodal tissue overlying the hepatic artery
proper and the common hepatic artery. (This ensures removal of all group 8 nodes).
9. Lymphadenectomy on the splenic artery extends from the origin of this vessel as far
lateral as the point of ligation of the uppermost posterior short gastric vessel. (This
ensures complete removal of station 11 nodes).
10. The dissection at the diaphragm is designed to minimise the risk of a positive radial
resection margin. The exact extent of this dissection will be influenced by the results of
pre-operative staging, as well as intra-operative assessment. The aim of the surgery
should be to remove sufficient crural fibres and a cuff of diaphragm, to minimise the risk
of local recurrence when the primary tumour is at this level. Mobilisation of the left lateral
segments of the liver, division of the inferior phrenic vein well to the right and to the left of
the oesophagus, facilitates excision of an inverted V-shaped segment of diaphragm in
continuity with the crura. Both pleural cavities may be opened, although this can be
deferred until the thoracic phase.
11. Removal of the pericardial fat pad anteriorly and strips of parietal pleura should usually
be achieved at this stage, to again minimise the risk of a positive radial margin, although
these steps can be undertaken during the thoracic phase of the operation.
12. Preparation of the transection site on the lesser curve, without compromise to the extent
of lymphadenectomy, can be undertaken at this stage or during the thoracic phase at the
surgeon’s discretion.
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13. The placement of a feeding jejunostomy, intra-abdominal and intra-thoracic drains are
options at the surgeon’s discretion.
14. The abdominal phase should result in a dissection which has removed lymph nodes from
stations 1, 2, 3, 7, 8 and 11.
8.5.2
Thoracic Phase
1. The chest can be opened through either a right or left thoracotomy. The mediastinal
pleura overlying the oesophagus should be excised in continuity with the oesophagus.
2. The posterior limit of the dissection should be the antero-lateral wall of the aorta, so that
the thoracic duct is mobilised with the oesophagus and peri-oesophageal tissues.
3. The thoracic duct is ligated and divided at the level of the diaphragm and at the upper
level of transection.
4. Having encircled the oesophagus at or close to the diaphragm (preferably during the
abdominal phase), the mediastinal pleura overlying the left side of the oesophagus
should also be excised to above the level of the tumour.
5. Para-oesophageal and diaphragmatic nodes (groups 108, 110, 111) are removed in
continuity with the oesophagus.
6. Lymph nodes at the tracheal bifurcation and along the right and left main bronchi to the
pulmonary hilus, can be removed en bloc or separately at the surgeon’s discretion (nodal
groups 107, 109).
7. The extent of lymphadenectomy for the upper thoracic para-oesophageal nodes (group
105), will be determined by the site of oesophageal transection. This must be above the
aortic arch and preferably within 5 cm of the thoracic inlet.
8. Enlarged nodes in the para-tracheal group (group 106), should be removed for sampling
purposes. NB – complete dissection of the left sided recurrent laryngeal nerve nodal
chain is not mandatory.
9. The anastomotic technique and method of chest drainage is at the surgeon’s discretion.
Lymph node numbers referred to are those used in the Japanese classifications for
oesophageal and gastric carcinoma [18, 19].
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9 Duration of Trial
The trial will end on the date of the last patient receiving their postoperative assessment
(scheduled for 6 weeks after surgery). This will be followed by the non-interventional phase of
long-term follow up, which will continue for a minimum of 5 years.
10 Safety Reporting
ICH GCP requires that both investigators and sponsors follow specific procedures when
reporting adverse events/reactions in clinical trials. These procedures are described in this
section of the protocol.
Section 10.1 lists definitions, section 10.2 gives details of the
institution/investigator responsibilities and section 10.3 provides information on MRC CTU
responsibilities.
10.1 Definitions
EU Countries only:
The definitions of the EU Directive 2001/20/EC Article 2 based on ICH GCP apply in this trial
protocol. These definitions are given in table 10.
10.1.1 Clarifications and Exceptions
*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.
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the
hospitalisation is a precautionary measure for continued observation. Hospitalisations for a preexisting condition (including elective procedures that have not worsened) do not constitute an
SAE.
Medical judgement should be exercised in deciding whether an AE/AR is serious in other
situations. Important AE/ARs that are not immediately life-threatening or do not result in death
or hospitalisation but may jeopardise the subject or may require intervention to prevent one of
the other outcomes listed in the definition above, should also be considered serious.
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Table 10. Definitions
Term
Definition
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical trial
subject to whom a medicinal product has been administered
including occurrences which are not necessarily caused by or
related to that product.
Adverse Reaction (AR)
Any untoward and unintended response to an investigational
medicinal product related to any dose administered.
Unexpected Adverse
Reaction (UAR)
An adverse reaction, the nature or severity of which is not
consistent with the information about the medicinal product in
question set out in the summary of product characteristics (or
Investigator brochure) for that product.
Serious Adverse Event
Respectively any adverse event, adverse reaction or
(SAE) or Serious Adverse unexpected adverse reaction that:
Reaction (SAR) or
results in death
Suspected Unexpected
Serious Adverse Reaction
is life-threatening*
(SUSAR)
requires hospitalisation or prolongation of existing
hospitalisation**
results in persistent or significant disability or incapacity
consists of a congenital anomaly or birth defect
10.1.2 Trial-Specific Exceptions
Disease progression or death as a result of disease progression are not considered to be SAEs
and should be reported on relevant CRF, either the Follow Up form (OE05/8) or Death Form
(OE05/9).
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10.1.3 SAE Excluded from Expedited Notification
The following situations that fulfil the definition of an SAE are excluded from expedited
notification on an SAE form. Nausea, vomiting, diarrhoea and neutropenia should be reported
on the Chemotherapy Form (OE05/3).
i.
Elective hospitalisation and surgery for treatment of oesophageal cancer or its
complications.
ii.
Elective hospitalisation to simplify treatment or procedures.
iii.
Elective hospitalisation for pre-existing conditions that have not been exacerbated by trial
treatment
iv.
Nausea and vomiting
v.
Diarrhoea caused by Capecitbine or 5FU
vi.
Neutropenia
10.2 Institution/Investigator Responsibilities
All non-serious AEs/ARs, whether expected or not, should be recorded in the toxicity
(symptoms) section of the Chemotherapy form (OE05/3) and sent to the MRC CTU within one
month of the form being due. SAEs/SARs should be notified to the MRC CTU as described
below.
The severity (i.e. intensity) of all AEs/ARs (serious and non-serious) in this trial should be should
be graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0
(http://ctep.cancer.gov/reporting/index.html), please refer to Appendix VIII. A flowchart is given
in Appendix VII to help explain the notification procedures. Any questions concerning this
process should be directed to the MRC CTU in the first instance.
10.2.1 Investigator Assessment
(a) Seriousness
When an AE/AR occurs the investigator responsible for the care of the patient must first assess
whether the event is serious using the definitions given in Table 10. If the event is serious and
not exempt from expedited reporting, then an SAE form must be completed and the MRC CTU
notified.
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(b) Causality
The Investigator must assess the causality of all serious events/reactions in relation to the trial
therapy using the definitions in Table 11. There are 5 categories: unrelated, unlikely, possible,
probable and definitely related. If the causality assessment is unrelated or unlikely to be related
the event is classified as a SAE. If the causality is assessed as either possible, probable or
definitely related then the event is classified as a SAR.
Table 11. Definitions of causality
Relationship
Description
Event Type
Unrelated
There is no evidence of any causal relationship
SAE
Unlikely
There is little evidence to suggest there is a causal SAE
relationship (e.g. the event did not occur within a reasonable
time after administration of the trial medication).
There is
another reasonable explanation for the event (e.g. the
patient’s clinical condition, other concomitant treatment).
Possible
There is some evidence to suggest a causal relationship (e.g. SAR
because the event occurs within a reasonable time after
administration of the trial medication). However, the influence
of other factors may have contributed to the event (e.g. the
patient’s clinical condition, other concomitant treatments).
Probable
There is evidence to suggest a causal relationship and the SAR
influence of other factors is unlikely.
Definitely
There is clear evidence to suggest a causal relationship and SAR
other possible contributing factors can be ruled out.
(c) Expectedness
If the event is a SAR the Investigator must assess the expectedness of the event. Please see
Appendix IX for a list of expected toxicities associated with the drugs being used in this trial. If a
SAR is assessed as being unexpected it becomes a SUSAR.
(d) Notification
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Investigators must notify the MRC CTU of all SAEs occurring from the time of randomisation
until 30 days after the last protocol treatment administration. SARs and SUSARs must be
notified to the MRC CTU indefinitely (i.e. no matter when they occur after randomisation).
Notification Procedure:
1. The SAE form must be completed by the Investigator (consultant named on the signature
list and delegation of responsibilities log who is responsible for the patient’s care), with
due care being paid to the grading, causality and expectedness of the event as outlined
above. In the absence of the responsible investigator the form should be completed and
signed by a member of the site trial team.
The responsible investigator should
subsequently check the SAE form, make changes as appropriate, sign and then re-fax to
the MRC CTU as soon as possible. The initial report shall be followed by detailed,
written reports as appropriate.
2. Send the SAE form by fax to the MRC CTU
Fax Number: + 44 (0) 20 7670 4818
3. Follow-up: Patients must be followed-up until clinical recovery is complete and
laboratory results have returned to normal or baseline, or until the event has stabilised.
Follow-up should continue after completion of protocol treatment if necessary. Follow-up
information should be noted on a further SAE form by ticking the box marked ‘follow-up’
and faxing to the MRC CTU as information becomes available.
Extra, annotated
information and/or copies of test results may be provided separately. The patient must
be identified by trial number, date of birth and initials only. The patient’s name should not
be used on any correspondence.
4. Staff at the institution must notify their local research ethics committee (LREC) of the
event (as per the institutions standard local procedure).
10.3 MRC CTU Responsibilities
Medically qualified staff at the MRC CTU and/or the Chief Investigator (or a medically qualified
delegate) will review all SAE reports received. The causality assessment given by the local
Investigator at the hospital cannot be overruled and in the case of disagreement, both opinions
will be provided in any subsequent reports.
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The MRC CTU is undertaking the duties of trial sponsor and is responsible for the reporting of
SUSARs and other SARs to the regulatory authorities (MHRA and competent authorities of other
European member states and any other countries in which the trial is taking place) and the
research ethics committees as appropriate.
The MRC CTU will also keep all investigators informed of any safety issues that arise during the
course of the trial.
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11 Ancillary Studies
11.1 Quality of Life (in selected centres)
The primary outcome in this trial is survival. Nevertheless, patient based assessments of
outcome such as side-effects of treatment, symptom relief and quality of life (QL) issues are
relevant secondary measures. Evidence from prospective observational studies over the past
decade has shown surgery alone has a severe negative impact on many aspects of QL and
there are no published data describing QL experienced during neoadjuvant treatment for
carcinoma of the oesophagus [20]. This may lead to adverse effects and diminish QL even when
survival is extended. The acceptance of new neoadjuvant therapies may sometimes be critically
dependent on their QL consequences.
The main objective of QL assessment within this clinical trial is to determine the impact of both
standard chemotherapy (CF) and ECX chemotherapy on QL. Describing and comparing the
impact of the two chemotherapeutic regimens on QL will lead to a better understanding, from the
patients’ perspective, of the frequency and degree of treatment related side-effects. This will
provide data to help define future treatment options for these patients.
The QL issues that will be considered include general functional aspects: physical, role, social,
cognitive and emotional function. It is known that oesophagectomy has a major impact on these
domains. There are currently no published data describing the impact of neoadjuvant
chemotherapy on QL either during the neoadjuvant stage of treatment or after resection.
Symptoms related to chemotherapy, surgery and carcinoma of the oesophagus will also be
assessed (emesis, appetite loss, mucositis, hoarse voice, psychological impact of weight loss,
dysphagia, reflux and social aspects of eating etc.)
11.1.1 Module and Assessments
Quality of life will be assessed using the EORTC QLQ-C30 [21, 22] questionnaire with its
validated site specific oesophageal module, QLQ-OES18 [23]. The oesophageal cancer module
has undergone detailed development and international field testing for reliability and validity. The
psychometric data to support its high reliability and validity are currently under submission for
publication. It assesses dysphagia, eating issues, reflux, symptoms related to post operative
complications and chemotherapy as well as specific symptoms related to carcinoma of the
oesophagus.
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Quality of life will be assessed at the following time points (see Table 2, section 7.4):
1. Before randomisation, prior to the patient being informed of the treatment they are
allocated to receive (up to three weeks before randomisation).
2. During chemotherapy: day 14 of cycles 2 and 4 in the ECX arm or day 14 of cycle 2 in
the standard arm, when differences between treatments are likely to be greatest.
Patients should be given the QL questionnaire at start of cycle, to be completed on day
14 of that cycle.
3. Before surgery to assess how much the patient’s QL has recovered from neoadjuvant
treatment prior to surgery (within 3 weeks before surgery).
4. 3 months after surgery (+/- 3 weeks).
5. At 6, 9, 12, 18 and 24 months post-date of surgery (+/- 3 weeks)
11.1.2 Completion of Questionnaires
A patient’s guide to self-completion of their questionnaires is detailed in Appendix II(b). The
questionnaires should be completed without conferring with friends or relatives and all questions
should be answered. If the patient feels them to be irrelevant they can answer "not applicable".
The responsible research nurse should check each questionnaire for its completeness, ensuring
that the correct date of completion and patient identifiers are present. The research nurse
should approach patients at appropriate clinical visits to complete a questionnaire. If no clinical
visit is scheduled for the patient at the set time point for the QL assessment or if the patient fails
to attend, the nurse should phone the patient and arrange postal distribution of the
questionnaire. If the patient does not return the questionnaire one further reminder should be
made by telephone.
11.1.3 Centres
In order to ensure good accrual and compliance with QL data collection only centres able to
identify dedicated research staff for QL data collection will participate in this part of the trial. All
patients from these centres are required to complete the QL forms. Furthermore, after six
months of entering the first patient each centre will be reviewed to check the completeness of
QL data collection. Centres with less than 80% baseline accrual and follow up less than 70% will
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be considered for withdrawal from the QL part of the study. All patients recruited at that time will
continue to complete QL assessments, as per protocol.
Patients entered from non-participating centres will not need to be shown documentation
relevant to the quality of life study, nor be asked to complete a questionnaire at any time.
11.1.4 Nutrition assessment
Patients with oesophageal cancer experience difficulties eating which may increase during
neoadjuvant treatment. Nutritional support may, therefore, be required to ensure completion of
treatment without excessive loss of weight. Nutritional support may be simple addition of liquid
supplements, insertion of a naso-gastric or naso-jejunal feeding tube or patients may require
surgical insertion of a feeding jejunostomy. This will have an impact on QL and possible
outcomes of treatment. Patients on the study will be assessed for nutritional support.
11.2 Health Economics
We will not be examining Heath Economics in this trial.
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11.3 Central Pathology Review
Accurate, standardised and complete pathology data are crucial for all data analyses related to
clinicopathological variables within this clinical trial. Two recent audits into the reporting of
oesophageal and gastric cancer pathology in the UK have demonstrated that pathology reports
were often incomplete despite the introduction of the Royal College of Pathologists reporting
proforma [1,2].
Central pathology review of all pre-treatment biopsies and all resections specimens will enable
us to comprehensively quality control the pathology reporting within the OE05 trial and to ensure
that high quality pathology data are available for all analyses. Central pathology review within a
large clinical trial such as the OE05 trial will also enable us to provide the evidence for the
prognostic value of circumferential resection margin involvement, number of positive lymph
nodes and tumour regression grade in oesophageal cancer, issues which are still under debate
in the current literature.
The OE05 central pathology review panel consists of experienced Consultant Histopathologists,
specialised in gastrointestinal pathology and is coordinated by Dr Heike Grabsch, Senior Clinical
Lecturer in GI Pathology and Honorary Consultant Histopathologist in Leeds, (OE05 CoInvestigator).
1. Burroughs, S. H. et al. J Clin Pathol 52: 435-9, 1999.
2. King, P. M. et al. J Clin Pathol 57: 702-5, 2004.
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The central pathology review panel wish to review all Haematoxylin/Eosin (HE) stained slides
from the pre-treatment biopsy and the resection specimen, macroscopic images (if available)
and pathology reports from all participating pathology departments. Slides will be scanned at the
Leeds Aperio Scanning Facility and will be viewable via the internet for all participating centres.
Patient identifiers will not be disclosed via the internet and access to the virtual slides will be
password protected.
If there are major discrepancies between the local pathologist and the pathology review panel
that might result in changes to the patient’s prognosis, the case will first be discussed between
the reviewers and the local pathologist and the MRC CTU will be informed about the outcome of
this discussion. If any major discrepancies are confirmed, the local pathologist should inform the
recruiting clinician and the case should be re-discussed at the local Multi-disciplinary Team
Meeting. On a 6 monthly basis the pathology Review panel will report the number of minor or
major discrepancies in pathology reporting of oesophageal cancer to the TMG.
National
educational events for all participating pathologists may be organised in order to improve
reporting of oesophageal cancer.
11.3.1 Collection and transportation of material for pathology review
The OE05 central pathology review panel wish to review the pathology specimens for all OE05
patients. For each patient, around 4 weeks after surgery or immediately if the patient had
surgery >4 weeks ago, the trial nurse should complete the relevant OE05 Pathology Request
Letter (i.e. depending on whether the patient is participating in Trans-OE05) and send this along
with a copy of the OE05 Pathology Sample form to the local pathologist to request slides,
images and pathology reports for review..
The local pathologist or research staff should complete the relevant sections of the OE05
Pathology Sample form (as indicated on the OE05 Pathology Request Letter) and return this to
the Pathology team in Leeds along with the anonymised pathology samples. This request will
usually coincide with the request for paraffin blocks for the OE05 translational research studies
(i.e. Trans-OE05).
Before returning the samples and OE05 Pathology Sample form, the local pathologist should
ensure that the form is fully completed and signed and the slides, images and pathology reports
are anonymised and labelled with the Trial Name (i.e. OE05), Patient Trial ID, Patient initials and
Hospital Name. The material should be sent in appropriate packaging to the Leeds laboratory.
Address labels will be provided to centres by the MRC CTU. The original OE05 Pathology
Sample form should be enclosed with the pathology samples. One copy of the form should be
retained by the local pathologist along with the pathology request letter, a second copy should
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be returned to the Trial Nurse at the site to be filed in the patient file and a third copy sent to the
MRC CTU as confirmation that the pathology samples have been sent for review. The package
should be sent directly to the OE05 pathology review panel at the following address:
OE05 Pathology Research
c/o Dr Heike Grabsch,
Pathology and Tumour Biology, Leeds Institute of Molecular Medicine
Wellcome Trust Brenner Building, St James's University Hospital
Beckett Street, Leeds, LS9 7TF
11.4 Trans-OE05: Tissue and Blood Collection for Translational Research
The TRANS-OE05 study is the collection and storage of pathology and blood samples from
patients who have been recruited to the OE05 trial. Tissue` samples will be stored in the Section
of Pathology and Tumour Biology, at the Leeds Institute of Molecular Medicine for use in future
oesophageal cancer research.
The aim of the OE05 translational research studies is to identify biomarkers which can be used
in clinical practice in the future to predict which patients will benefit most from which treatment
and/or is least likely to experience severe toxicity. In addition, the identification of proteins or
genes predicting clinical drug effects will provide useful information for future drug development
and thus development of new, hopefully more effective treatment.
11.4.1 Patient Consent for Translational Research
i. Prospective Patients
In order to collect the samples for translational research, patients will be required to sign the
Trans-OE05 consent form prior to any blood samples being taken. The Trans-OE05 study
should be discussed in full with the patient at the same time as the OE05 trial is explained. The
patient information sheet has been updated to include information about the Trans-OE05 trial.
The site will be asked at time of randomisation whether that patient has given consent to
participate in the Trans-OE05 study.
Although most patients are expected to consent to
participate in the translational research programme, the wishes of patients who do not want to
be involved in the translational sample collection will be respected and they will be allowed to
enter the clinical trial without contributing samples to the translational research component.
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ii. Patients already recruited into the OE05 trial
Patients that were entered into the OE05 trial prior to the commencement of the Trans-OE05
study will not be able to contribute a pre-treatment blood sample to the study. However they will
still be able to contribute their biopsy and resection samples without additional consent being
required. (See 11.4.6 for more details).
11.4.2 Storage of tissue and blood samples
All collected material will be stored in the Section of the Pathology and Tumour Biology at the
Leeds Institute of Molecular Medicine, University of Leeds. Translational research studies will be
performed by the Gastrointestinal Cancer Research Group, led by Dr H Grabsch, in the Section
of Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, University of Leeds,
UK and collaborators in the first instance. A Sample Access Committee will be set up according
to the existing guidelines published by Cancer Research UK, UK Biobank and OnCore in order
to review any requests of external researcher for material in the future. Only projects that have
been peer reviewed and approved by an ethics committee will be considered.
11.4.3 Collection and transportation of blood samples
Blood samples should be collected by the trial nurse once consent has been given and prior to
starting treatment. It is recommended that the blood samples are taken at the same time as the
routine bloods as far as possible so that the patient does not have to undergo an additional
venepucture. Venepucture is recommended to be performed in the morning according to the
common standard procedures in supine position. Free flow with mild aspiration has to be
assured to avoid haemolysis. Blood (20ml in total) is drawn from a cubital vein into EDTA
containing collection tubes without gel separator. After filling the collection tube, each tube has
to be inverted five times to facilitate the mixing of blood and anticoagulant. Local procedures for
the safe use of vacutainers should be followed.
Each tube needs to be clearly labelled with:
Trial Name (i.e. OE05)
Patient Trial ID (if available)
Patient initials
Patient Hospital number
Hospital Name
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Date and time of collection
Tubes should be placed in a Royal Mail 'Safebox' supplied to your centre at the time of centre
set up by the MRC CTU. These boxes are pre-paid and the MRC CTU will supply address
labels.
The Trans-OE05 Blood Sample form should be completed and placed inside the
‘Safebox’ with the tubes. A copy of the form should be retained in the patient file as confirmation
that the blood sample has been sent to the Leeds Laboratory. The 'Safebox' should be placed in
the post as soon as possible on the day of blood collection.
11.4.4 Collection and transportation of tissue samples
The project leader of the tissue collection, and Co-Investigator, Dr Heike Grabsch, is a
Consultant Histopathologist specialising in gastrointestinal pathology. Dr Grabsch will ensure
that blocks will never be sectioned to exhaustion and that diagnostic material will always remain
in the paraffin block.
Pre-treatment biopsies
Paraffin embedded diagnostic biopsies may be very small. However, these biopsies will be an
invaluable resource to validate whether molecular markers, identified during investigations
performed on the material from the resection, are truly able to predict response to therapy.
Ideally, all blocks from pre-treatment biopsies will be collected and transported to the Leeds
laboratory as described below.
Resection specimen
In order to keep the procedure as simple as possible and reduce the workload of the local
histopathologist, the Leeds laboratory offers to select the most appropriate blocks. If the local
pathologist is happy with this approach, he/she should send all blocks to Leeds at the same time
as sending the HE stained slides for central pathology review.
Upon arrival, the Leeds
laboratory will select three blocks containing primary tumour OR three blocks containing areas
with evidence of tumour regression, three blocks from non-involved oesophageal mucosa and
blocks from lymph node metastases or other metastases if present. All other blocks will be
returned to the submitting pathology department immediately.
However, if local histopathologists do not feel comfortable with this approach and would prefer to
select blocks themselves, they will be asked to submit three paraffin blocks containing viable
primary tumour OR three paraffin blocks with areas with evidence of tumour regression (as
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appropriate), three blocks with non-involved oesophageal mucosa furthest away from the tumour
as possible and blocks from lymph node metastases or other metastasis if present.
11.4.5 Timing of tissue collection and transportation
Four weeks after surgery, the trial nurse should complete the relevant OE05 Pathology Request
Letter and send this along with a copy of the OE05 Pathology Sample form to the local
pathologist to request the patient’s stored formalin-fixed, paraffin-embedded material (pretreatment biopsy and resection specimen as outlined above) and the related pathology reports.
The local pathologist or research staff should complete the relevant sections of the OE05
Pathology Sample form (as indicated on the OE05 Pathology Request Letter) and return this to
the Pathology team in Leeds along with the anonymised pathology samples. This request will
usually coincide with the request for slides, macroscopic images and pathology report for the
central pathology review.
Before returning the samples and OE05 Pathology Sample form, the local pathologist should
ensure that the form is fully completed and signed and the pathology reports, slides and tissue
blocks are anonymised and labeled with the trial name (i.e. OE05) and Patient Trial ID number.
The material should be sent in appropriate packaging to the Leeds laboratory. Address labels
will be provided to centres by the MRC CTU. The original OE05 Pathology Sample form should
be enclosed with the pathology samples. One copy of the form should be retained by the local
pathologist along with the pathology request letter, a second copy should be returned to the Trial
Nurse at the site to be filed in the patient file and a third copy sent to the MRC CTU as
confirmation that the pathology samples have been sent for review.
The package should be
sent directly to the OE05 pathology review panel at the following address:
OE05 Pathology Research
C/o Dr H Grabsch
Pathology and Tumour Biology
Leeds Institute of Molecular Medicine
Wellcome Trust Brenner Building
St James's University Hospital
Beckett Street
Leeds LS9 7TF
Phone: 0113 3438626 Email: [email protected]
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11.4.6
Procedures
for
sample
collection
in
patients
already
recruited
prior
commencement of Trans-OE05 (consent not required)
The MRC will provide Dr. Grabsch with a list of details (pathology specimen number OR if
pathology number not available the patient name, date of birth, date of surgery, name and
address of the hospital and local pathologist (if available) for those patients recruited prior to
commencement of Trans-OE05.
Dr. Grabsch will contact the pathology departments directly and request slides, blocks and
copies of the pathology reports emphasizing that the material needs to be anonymised before
sending to Leeds by appropriate means. Leeds will co-ordinate the responses and update the
MRC regularly about progress.
11.4.7 Funding
The principal investigator of Trans-OE05, Dr H Grabsch, has received funding from Cancer
Research UK for the collection of blood samples and paraffin blocks. All participating pathology
departments will receive an administrative fee of £15 for the pre-treatment biopsy block and
additional £15 for the blocks from the resection specimen.
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11.5 Radiology Review
Once we have completed our target recruitment, a reference radiologist may review
approximately 10% of pre-treatment CT scans as an indicator for quality control. Scans for those
patients selected would be requested by the CTU and sent to the reviewer.
Dr Bhupinder Sharma
Consultant Radiologist
Radiology Department
The Royal Marsden Hospital
Fulham Road
London SW3 6JJ
If there are major discrepancies between the local radiologist and reference radiologist, that
might result in changes to the patient’s prognosis, the case will be first be discussed by the
reviewers and local radiologist. If confirmed, a letter will be sent to the recruiting clinician and
the case should be re-discussed at the local Multi-disciplinary Team Meeting
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12 Statistical Considerations
Patients will be randomly allocated to a treatment arm using a minimisation procedure with a
random element and stratifying for a number of clinically important factors. To further decrease
determinability, these are not listed here.
12.1 Outcome measures
Primary endpoint:
Overall survival
Secondary endpoints:
Disease-free survival
Local control
Quality of life
Morbidity from surgery and chemotherapy
12.2 Sample size
The standard chemotherapy regimen (OE02 regimen) improved 3-year survival by an absolute
difference of approximately 10% over surgery alone; it is probably unrealistic to expect the
difference between two arms which both involve neoadjuvant therapy to exceed this.
Assuming a 6-year total recruitment period, approximate numbers of patients (events in
brackets) required to detect the following differences (2α=0.05, baseline survival rate at 3
years=30%) between the two arms are shown below:
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Absolute
difference at
3 years
Duration of
Follow-up
Patients
Events
power
8%
6 months
1300
860
90%
7%
6 months
1300
860
80%
8%
2 years
1058
860
90%
7%
2 years
1058
860
80%
8%
2 years
842
677
82%
7%
2 years
842
677
70%
It is proposed to randomise a minimum of 842 patients (maximum of 1300 patients) over 6 years
in equal proportions between the two arms, and to follow-up patients for a minimum of 2 years
prior to analysis. This would provide at least 82% power to detect an 8% difference or 70%
power to detect a 7% difference between the trial arms with a 2-sided significance level of 5%.
12.3 Planned analyses
12.3.1 Clinical outcomes
The primary outcome of survival and secondary outcome disease-free survival will be compared
across the two arms using a Logrank χ2 test. All analyses will be performed on an intention-totreat basis. The comparison of the toxicity/morbidity grades between treatment groups, at each
of the time points, will be performed a using Chi-squared test (or Fisher’s exact test, where
appropriate).
12.3.2 Quality of Life
Data will be scored according to the algorithm described in the EORTC QLQ-C30 scoring
manual [22]. All scales and single items are scored on categorical scales and linearly
transformed to 0-100 scales. A high score for a symptom scale or item represents a high level of
symptoms or problems. A high score for a functional scale represents a high or healthy level of
functioning. A high score for the global health status/QL represents high QL.
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The exact type of analyses performed will depend on the quantity and pattern of missing data,
but we anticipate this being minimal in view of the data monitoring of data quality planned for this
trial.
Using a group-based approach, we will provide cross-sectional descriptions and plots of the
mean scores by treatment arm at each assessment timepoint together with confidence intervals.
Overall patterns of change will be assessed using a longitudinal mixed effects model. Using a
subject-specific approach, the proportion of patients experiencing a score change of 10 points or
more from baseline to the timepoints of interest will be described and compared. While data on
all function and symptom scales will be described, formal comparisons will focus on global QL
and symptoms related to the impact of chemotherapy and surgery on carcinoma of the
oesophagus specifically (appetite loss, dysphagia, reflux and social aspects of eating).
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13 Monitoring and Quality Assurance
13.1 Interim Analysis
The data will be reviewed and formal interim analyses presented at regular intervals
(approximately annually) to an independent Data Monitoring Committee (IDMC). They will be
asked to give advice on whether the accumulated data from the trial, together with results from
other relevant trials, justifies continuing recruitment of further patients. A decision to discontinue
recruitment, in all patients or in selected subgroups will be made only if the result is likely to
convince a broad range of clinicians including participants in the trial and the general clinical
community. If a decision is made to continue, the IDMC will advise on the frequency of future
reviews of the data on the basis of accrual and event rates. The IDMC will make
recommendations to the Trial Steering Committee (TSC) as to the continuation of the trial. The
role of the TSC is to provide overall supervision for the trial and provide advice through its
independent Chairman. The ultimate decision for the continuation of the trial lies with the TSC.
13.2 Site visits
A member of staff from the MRC CTU and/or a clinical member of the TMG may visit a clinical
centre during the trial either if indicated or if a quality assurance exercise is deemed necessary.
It would be expected that these individuals have access to all medical records for patients
entered into the trial so as to ensure:
i.
Completion of all out-standing CRFs
ii.
Resolution of all out-standing queries
A monitoring visit may be made during the trial to:
Larger participating centres, who have randomised a minimum of 30 patients
A random sample of smaller participating centres
Centres found to have poor compliance (e.g. poor quality data, repeatedly late
data return)
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14 Ethical Considerations
The protocol has Multi-Centre Research Ethics Committee (MREC) approval but the Local
Research Ethics Committee (LREC) must approve each centre by a site specific assessment
(SSA) before patients are entered. The patient’s consent to participate in the trial should be
obtained after a full explanation has been given of the treatment options, including the
conventional and generally accepted methods of treatment. The patient information sheet,
consent form and GP letter are provided separately to the protocol.
The right of the patient to refuse to participate in the trial without giving reasons must be
respected. After the patient has entered the trial, the clinician must remain free to give
alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the
best interest of the patient. However, the reason for doing so should be recorded and the patient
will remain within the trial for the purpose of follow up and data analysis according to the
treatment option to which he/she has been allocated. Similarly, the patient must remain free to
withdraw at any time from the protocol treatment without giving reasons and without prejudicing
his/her further treatment.
15 Sponsorship
The sponsor of the OE05 trial is the Medical Research Council. Please contact David Harrop,
Head, MRC Centre London, second Floor, Stephenson House, 158-160 North Gower Street,
London, NW1 2ND
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16 Indemnity
Cancer Research UK does not provide indemnity cover for participants in Cancer Research UK
funded phase III trials. The MRC and NHS are not allowed to purchase advance insurance to
cover indemnity because they are publicly funded bodies. However, MRC Head Office has
issued this statement: “MRC will give sympathetic consideration to claims for non-negligent harm
suffered by a person as a result of trial or other work supported by MRC. This does not extend to
liability for non-negligent harm arising from conventional treatment where this is one arm of a
trial. MRC acts as its own insurer and does not provide cover for non-negligent harm in advance
for participants in MRC-funded studies. Where studies are carried out in a hospital, the hospital
continues to have a duty of care to a patient being treated within the hospital, whether or not the
patient is participating in an MRC-supported study. MRC does not accept liability for any breach
in the hospital’s duty of care, or any negligence on the part of employees of hospitals. This
applies whether the hospital is a NHS Trust or not.”
If patients have any complaints or concerns about any aspect of the way they are approached or
treated during the course of this study, the normal NHS complaints mechanisms should be
available to them.
17 Finance
OE05 is coordinated by the MRC Clinical Trials Unit in London. Financial support for the trial
has been supplied by Cancer Research UK, grant number: C1495/A3005
Roche Products Ltd has agreed to support this trial by providing free capecitabine for up to 650
patients on the trial on the basis that the MRC CTU is responsible for co-ordinating the study.
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18 Trial Committees
In accordance with MRC guidelines on GCP in clinical trials, the day-to-day running of the trial
will be the responsibility of the Chief Investigator, the co-investigators, and the relevant MRC
CTU staff, who together form the TMG.
The IDMC will meet regularly to review the accumulating data on treatment compliance, toxicity
and efficacy. They will make recommendations to the TSC concerning modifying or stopping the
trial. The TSC will meet at least annually with representatives from the TMG to review the overall
progress of the trial and to discuss the IDMC recommendations.
For further information regarding the trial committees, please refer to Appendix I.
19 Publication Policy
The results from different centres will be analysed together and published as soon as possible.
Individual clinicians must not publish any data concerning their patients before the main trial is
published. The TMG will form the basis of the writing committee for publications concerning the
trial. The publications will be in the name of the collaborative group with the writing committee,
participants and all collaborators listed in the report.
The main publications on this trial will be published as from the “NCRI Upper GI Clinical Studies
Group”; those members who planned and conducted the trial will be listed. The authors of the
report, the Chief Investigators, all expert advisors, statistician(s), clinical trials manager(s), local
co-ordinators and all the consultants contributing patients will be named. The number of patients
entered from each centre will be indicated.
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20 References
[1]
Clark P. Surgical resection with or without pre-operative chemotherapy in oesophageal
cancer: an updated analysis of a randomised controlled trial conducted by the UK Medical
Research Council Upper GI Tract Cancer Group. Lancet 2002; 359: 1727-33.
[2]
Vanhoefer U, Rougier P, Wilke H, et al. Final results of a randomized phase III trial of
sequential high-dose methotrexate, fluorouracil and doxorubicin versus etoposide, leucovorin
and fluorouracil versus infusional fluorouacil and cisplatin in advanced gastric cancer: a trial of
the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer
Cooperative Group. J Clin Onc 2000; 18: 2648-2657.
[3]
Webb A, Cunningham D, Scarffe JH, et al. Randomized trial comparing epirubicin,
cisplatin and fluorouacil versus fluorouracil, doxorubicin and methotrexate in advanced
esophagogastric cancer. J Clin Onc 1997; 15: 261-267.
[4]
Ross P, Cunningham D, Scarffe H, et al. Results of a randomised trial comparing ECF
with MCF in advanced oesophago-gastric cancer. Proc ASCO 1999; 18: 272a, abstract 1042.
[5]
Cunningham D, Allum W, Weeden S. Perioperative chemotherapy in operable gastric
and lower oesophageal cancer: A randomised, controlled trial of the NCRI Upper GI Clinical
Studies Group (the MAGIC trial, ISRCTN 93793971). Proc ASCO 2005, abstract 4001[6] Walsh
TN, Noonan N, Hollowood D et al. A comparison of multimodal therapy and surgery for
esophageal adenocarcinoma. N Engl J Med 1996; 335: 462-467.
[7]
Forastiere AA, Heitmiller RF, Lee DJ et al. Intensive chemoradiation followed by
esophagectomy for squamous cell and adenocarcinoma of the esophagus. Cancer J Sci Am
1997; 3:144-152.
[8]
Smith TJ, Ryan LM, Douglass HO et al. Combined chemoradiotherapy versus
radiotherapy alone for early stage squamous cell carcinoma of the oesophagus: a study of the
Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys 1998; 42: 269-276.
[9]
al-Sarraf M, Martz K, Herskovic A et al. Progress report of combined chemoradiotherapy
versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol
1997; 15: 277-284.
[10]
Schuller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor
following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000;
45(4): 291-297.
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[11]
Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous
fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal
cancer: Results of a randomized phase III study. J Clin Oncol 2001; 19(8): 2282-2292.
[12]
Van Cutsem E, Twelves C, Cassidy J et al. Oral capecitabine compared with intravenous
fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase
III study. J Clin Oncol 2001; 19(21): 4097-4106.
[13]
Twelves C. Capecitabine as first-line treatment in colorectal cancer. Pooled data from
two large, phase III trials. Eur J Cancer 2002; 38 Suppl 2:15-20.
[14]
Twelves C, Boyer M, Findlay M et al. Capecitabine (Xeloda) improves medical resource
use compared with 5- fluorouracil plus leucovorin in a phase III trial conducted in patients with
advanced colorectal carcinoma. Eur J Cancer 2001; 37(5): 597-604.
[15]
Tebbutt N, Norman A, Cunningham D et al. Randomised, multicentre phase III study
comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced
oesophago-gastric cancer; interim analysis. Proc Am Soc Clin Oncol 2002; 21: 131a.
[16]
Sumpter KA, Harper-Whynne C, Cunningham D, et al: Randomised multicentre phase III
study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with
advanced oesophagogastric cancer: Confirmation of dose escalation. Br J Cancer. 2005 Jun
6;92(11):1976-83
[17]
Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction.
Br J Surg 1998; 85(11):1457-9.
[18]
Japanese Society for Esophageal Diseases. Guidelines for clinical and pathologic
studies on carcinoma of the esophagus. Jpn J Surg 1976; 6: 70-86.
[19]
Japanese Research Society for gastric Cancer. Japanese Classification of Gastric
Carcinoma. 1st English Edition. Tokyo: Kanehara, 1995.
[20]
Blazeby JM, Farndon JR, Donovan JL, et al. A prospective longitudinal study examining
the quality of life of patients with esophageal cancer. Cancer, 2000; 88: 1781-1787.
[21]
Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research
and Treatment of Cancer QLQ-C30: A Quality of Life Instrument for use in International Clinical
Trials in Oncology. JNCI, 1993; 85: 365-376.
[22]
Fayers PM, Aaronson NK, Bjordal K, et al. on behalf of EORTC Quality of Life Study
Group. EORTC QLQ-C30 Scoring Manual. EORTC Study Group on Quality of Life (1995).
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[23]
Blazeby JM, Conroy T, Hammerlid E, et al. on behalf of the EORTC Gastro-intestinal and
Quality of Life Groups. Clinical and psychometric validation of an EORTC questionnaire module,
the EORTC QLQ-OES18, to assess quality of life in patients with oesophageal cancer. Eur J
Cancer, 2003; 39: 1384-1394.
[24]
Burroughs, S. H. et al. Oesophageal and Gastric Cancer Pathology Reporting: A regional
audit. J Clin Pathol, 1999, 52: 435-9.
[25]
King, P. M, Blazeby, J.M, Gupta, J, Alderson, D. et al. Upper gastrointestinal cancer
pathology reporting: a regional audit to compare standards with minimum datasets. J Clin
Pathol, 2004, 57: 702-5.
[26]
Scottish Executive Health Department. Scottish Audit of Gastric and Oseophageal
Cancer, Edinburgh 2002 http://www.crag.scot.nhs.uk/committees/CEPS/reports/0_prelims.pdf
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APPENDIX A: WHO PERFORMANCE STATUS
Grade
Performance Status
0
Able to carry out all normal activity without restriction.
1
Restricted in strenuous physical activity but ambulatory and able to carry out
light work.
2
Ambulatory and capable of all self-care but unable to carry out any work; up
and about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of
waking hours.
4
Completely disabled; cannot carry on any self-care; totally confined to bed or
chair.
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APPENDIX B: SURFACE AREA NOMOGRAM
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APPENDIX C: The Chemotherapy Regimens
1) The Cisplatin & 5FU Regimen
Cisplatin
80mg/m2 IV D1
5-Fluorouracil
1g/m2/day IV continuous infusion D1-4 (repeated every 21 days)
Patients will be treated every 21 days (3 weeks) for 2 cycles.
On day 1 of each cycle:
1 hour before administration of IV chemotherapy (T=-1hr), patients will receive frusemide
40mg IV bolus or PO and sodium chloride 0.9% (normal saline) 1 litre + 20mmol KCl over
1 hour.
Prior to administration of IV chemotherapy (T=0hr), patients should receive as antiemetics Granisetron 1mg IV bolus (2mg if >100kg) and dexamethasone 8mg IV bolus.
(T=0hr): Cisplatin 80mg/m2 will be administered in 1 litre of sodium chloride 0.9%
(normal saline) over 4 hours.
(T=0hr): Mannitol 10% 200ml should be administered IV over 30 minutes.
(T=+4hr): Sodium chloride 0.9% (normal saline) 1 litre + 20 mmol KCl + 10mmol MgCl2
should be administered IV over 2 hours.
(T=+6hr): Sodium chloride 0.9% (normal saline) 1 litre + 20 mmol KCl + 10mmol MgCl2
should be administered IV over 1 hours.
5-Fluouracil infusion:
5-FU to a total dose of 4g/m2 per cycle should be administered at a rate of 1g/m2/day in
1 litre sodium chloride 0.9% (normal saline) per day from days 1 to 4 by continuous
infusion.
Oral anti-emetics:
Patients should be provided with oral anti-emetics as follows:
Dexamethasone 4mg PO TDS D1-2
Metoclopramide 10mg PO TDS D1-3
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2) The ECX Regimen
Epirubicin
50mg/m2 IV D1
Cisplatin
60mg/m2 IV D1
Capecitabine 1250mg/m2/day PO in 2 divided doses D1-21 (repeated every 21 days)
Patients will be treated every 21 days (3 weeks) for 4 cycles.
On day 1 of each cycle:
1 hour before administration of IV chemotherapy (T=-1hr), patients will receive frusemide
40mg IV bolus or PO and sodium chloride 0.9% (normal saline) 1 litre + 20mmol KCl +
10mmol MgCl2 IV over 1 hour.
Prior to administration of IV chemotherapy (T=0hr), patients should receive as antiemetics Granisetron 1mg IV bolus (2mg if >100kg) and dexamethasone 8mg IV bolus.
(T=0hr): Epirubicin 50mg/m2 will be administered as an IV bolus via fast running drip.
(T=0hr): Cisplatin 60mg/m2 will be administered in of sodium chloride 0.9% (normal
saline) 1 litre + 20mmol KCl over 4 hours.
(T=0hr): Mannitol 20% 100ml should be administered IV over 4 hours.
(T=+4hr): Sodium chloride 0.9% (normal saline) 1 litre + 20 mmol KCl + 10mmol MgCl2
should be administered IV over 2 hours.
(T=+6hr): Sodium chloride 0.9% (normal saline) 500mls + 10 mmol KCl should be
administered IV over 1 hours.
Oral anti-emetics:
Patients should be provided with oral anti-emetics as follows:
Dexamethasone 4mg PO TDS D1-2
Metoclopramide 10mg PO TDS D1-3
Capecitabine:
Capecitabine 1250mg/m2/day will be administered PO in 2 divided doses continuously
for the 12 weeks of neoadjuvant treatment. Capecitabine tablets should be administered
morning and evening and swallowed with water. Administration within 30 minutes after a
meal is suggested if patients are at risk of gastric irritation.
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APPENDIX D: Safety Reporting Flowchart
Adverse Event/Adverse Reaction
Was the event serious?
-Resulted in death
-Life-threatening
-Required inpatient hospitalisation or prolongation of existing hospitalisation
-Persistent or significant disability/incapacity
-Congenital anomaly/birth defect
No
Yes
Was the SAE specified in the protocol as being exempt from
expedited reporting?
Unlikely
Not
related
No
1.1.1.1.1
Yes
Causal relationship to protocol medication?
AE/AR
Record on the
Chemotherapy Form
(OE05/3) and send to
the MRC CTU within
one month of the CRF
due date
SAE
Record on the
Chemotherapy Form
(OE05/3) and send to
the MRC CTU within
one month of the CRF
due date
SAE
Record on an SAE
form. Notify MRC CTU
within 24-48 hours of
becoming aware of the
event
Definitely, Probably, Possibly
Was the SAE one of the recognised undesirable effects of the
trial medication?
Expected
Unexpected
CRF: Case report form
SAE: Serious adverse event
SPC: Summary of product characteristics
IB: Investigator’s brochure
SAR: Serious adverse reaction
SUSAR: Suspected unexpected serious adverse reaction
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SAR
Record on an SAE
form. Notify MRC CTU
within 24-48 hours of
becoming aware of the
event
SUSAR
Record on an SAE
form. Notify MRC CTU
within 24-48 hours of
becoming aware of the
event
MRC OE05
APPENDIX E: OE05 Common Toxicity Criteria based on CTCAE Version 3.0
GRADE
Short Name
1
2
3
4
5
AUDITORY/EAR
Hearing (without
-
monitoring program)
Hearing loss not
Hearing loss
Profound bilateral
requiring hearing aid
requiring hearing
hearing loss
or intervention (i.e.
aid or intervention
not interfering with
(i.e. interfering with
activities of daily
ADL)
(>90 dB)
-
living (ADL)
BLOOD/BONE MARROW
Neutrophils
< LLN-
< 1500 – 1000mm3
< 1000 – 500mm3
< 500mm3
< 1.5 – 1.0 x 109/L
<1.0 – 0.5 x 109/L
<0.5 x 109/L
< LLN-
< 75,000 –
< 50,000 –
< 25,000/mm3
75,000/mm3
50,000mm3
25,000mm3
Death
1500/mm3
< LLN-1.5 x
109/L
Platelets
Death
<25.0 x 109/L
< LLN-75.0 x
< 75.0 – 50.0 x 109/L
109/L
<50.0 – 25.0 x
109/L
CARDIAC GENERAL
Left ventricular systolic
Asymptomatic,
Asymptomatic,
Symptomatic
dysfunction
resting ejection
resting EF <50-40%
congestive heart
failure (CHF)
fraction (EF)
<60-50%;
SF <24-15%
shortening
responsive to
intervention.
Refractory CHF
Death
or poorly
controlled; EF
<20%; intervention
such as ventricular
fraction (SF)
<30-24%
EF <4—20% SF
assist device,
<15%
ventricular
reduction surgery
or heart transplant
indicated
DERMATOLOGY/SKIN
Alopecia
Thinning or
Complete
patchy
-
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Hand-foot
Minimal skin
Skin changes (e.g.
Ulcerative
changes or
peeling, blisters,
dermatitis or skin
dermatitis
bleeding, edema) or
changes with pain
(e.g., erythema
pain, not interfering
interfering with
without pain)
with function
function
Increase of <4
Increase of 4-6 stools
Increase of ≥ 7
Life-threatening
stools per day
per day over
stools per day over
consequences
over baseline;
baseline; IV fluids
baseline;
(e.g.
mild increase
indicated <24 hrs;
incontinence; IV
hemodynamic
in
moderate increase in
fluids <24 hrs;
collapse)
ostomy output
Hospitalisation;
compared to
severe increase in
baseline; not
ostomy output
interfering with ADL
compare to
GASTROINTESTINAL
Diarrhoea
ostomy output
compared to
baseline
Death
baseline; interfering
with ADL
Nausea
Loss of
Oral intake
Inadequate oral
Life-threatening
appetite
decreased without
caloric or fluid
consequences
without
significant weight
intake; IV fluids,
alteration in
loss, dehydration or
tube feedings or
eating habits
malnutrition; IV fluids
total parenteral
indicated <24hrs
nutrition (TPN)
Death
indicated ≥24 hrs
Mucositis
Erythema of
Patchy ulcerations or
Confluent
the mucosa
pseudomemdranes
ulcerations or
(clinical exam)
pseudomembranes;
bleeding with minor
Select:
trauma
Tissue necrosis;
Death
Significant
spontaneous
bleeding; life
threatening
-Oral cavity
consequences
-Pharynx
Mucositis
(Functional/symptomatic)
Select:
-Oral cavity
-Pharynx
Minimal
Symptomatic but can
Symptomatic and
Symptoms
symptoms,
eat and swallow
unable to
associated with
normal diet;
modified diet;
adequately aliment
life-threatening
minimal
respiratory symptoms
or hydrate orally;
consequences
respiratory
interfering with
respiratory
symptoms but
function but not
symptoms
not interfering
interfering with ADL
interfering with ADL
with function
Taste alteration
Altered taste
Altered taste with a
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but no change
change in diet (e.g.
in diet
oral supplements);
-
-
Life threatening
-
noxious or
unpleasant taste;
loss of taste.
Vomiting
1 episode in 24
2-5 episodes in 24
XXXXX 6 episodes
hrs
hrs; IV fluids
in 24hrs; IV fluids,
indicated <24hrs
or TPN indicated
Death
XXX 24 hrs
INFECTION
Febrile neutropenia
Present
Life threatening
consequences
(e.g. septic shock,
-
Death
hypotension,
-
acidosis, necrosis)
Infection (documented
Localised, local
IV antibiotic,
Life threatening
clinically)
intervention indicated
antifungal or
consequences
antiviral
(e.g. septic shock,
intervention
hypotension,
indicated;
acidosis, necrosis)
Death
interventional
radiology or
-
operative
intervention
indicated
NEUROLOGY
Neuropathy-sensory
Asymptomatic;
Sensory alteration or
Sensory alteration
loss of deep
paresthesia
or paresthesia
tendon reflexes
(including tingling),
interfering with ADL
or parasthesia
interfering with
(including
function, but not
tingling) but not
interfering with ADL
Disabling
Death
interfering with
function
METABOLIC/LABORATORY
Bilirubin
>ULN – 1.5 x
>1.5 – 3.0 x ULN
>3.0 – 10.0 x ULN
>10.0 x ULN
-
>1.5 – 3.0 x ULN
>3.0 – 10.0 x ULN
>6.0 x ULN
Death
ULN
Creatinine
>ULN – 1.5 x
ULN
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NB: These are selected categories. For full list see http://ctep.cancer.gov/reporting/ctc.html
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APPENDIX F: Summary of Product Characteristics
This appendix lists an edited version of the Contraindications, Special warnings and Special
Precautions for Use and the Undesirable Effects for the drugs in the ECX and CF arm. For the
full details of the Summary of Product Characteristics please refer to www.medicines.org.uk
CAPECITABINE [Reference: Roche Products Ltd Xeloda, 27 March 2008]
Contraindications
History of severe and unexpected reactions to fluoropyrimidine therapy,
Known hypersensitivity to capecitabine, fluorouracil or any of the excipients,
In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency,
During pregnancy and lactation,
In patients with severe leucopenia, neutropenia, or thrombocytopenia,
In patients with severe hepatic impairment,
In patients with severe renal impairment (creatinine clearance below 30 ml/min),
Treatment with sorivudine or its chemically related analogues, such as brivudine.
Capecitabine - Special warnings and special precautions for use
Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot
syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse events are
reversible and do not require permanent discontinuation of therapy, although doses may need to
be withheld or reduced.
Diarrhoea. Capecitabine can induce the occurrence of diarrhoea, which has been observed in
50% of patients. Patients with severe diarrhoea should be carefully monitored and given fluid
and electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g.
loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6
stools/day or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or
incontinence and malabsorption. Grade 4 diarrhoea is an increase of
10 stools/day or grossly
bloody diarrhoea or the need for parenteral support. If grade 2, 3 or 4 diarrhoea occurs,
administration of Capecitabine should be immediately interrupted until the diarrhoea resolves or
decreases in intensity to grade 1. Following grade 3 or 4 diarrhoea, subsequent doses of
Capecitabine should be decreased or treatment discontinued permanently (grade 4).
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Dehydration. Dehydration should be prevented or corrected at the onset. Patients with
anorexia, asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. If Grade 2
(or higher) dehydration occurs, Xeloda treatment should be immediately interrupted and the
dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any
precipitating causes have been corrected or controlled. If grade 2, 3 or 4 dehydration occurs,
administration of Capecitabine should be immediately interrupted until the dehydration resolves
or decreases in intensity to grade 1. Following grade 3 or 4 dehydration, subsequent doses of
Capecitabine should be decreased or treatment discontinued permanently (grade 4).
Hand-foot
syndrome
(also
known
as
hand-foot
skin
reaction
or
palmar-plantar
erythrodysesthesia or chemotherapy induced acral erythema). Grade 1 hand- foot syndrome is
defined as numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the
hands and/or feet and/or discomfort which does not disrupt the patient's normal activities.
Grade 2 hand- foot syndrome is painful erythema and swelling of the hands and/or feet and/or
discomfort affecting the patient's activities of daily living.
Grade 3 hand- foot syndrome is moist desquamation, ulceration, blistering and severe pain of
the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or
perform activities of daily living. If grade 2 or 3 hand- foot syndrome occurs, administration of
Capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1.
Following grade 3 hand- foot syndrome, subsequent doses of Capecitabine should be
decreased. When Xeloda and cisplatin are used in combination, the use of vitamin B6
(pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand-foot
syndrome, because of published reports that it may decrease the efficacy of cisplatin.
Cardiotoxicity. Cardiotoxicity has been associated with fluoropyrimidine therapy, including
myocardial
infarction,
angina,
dysrhythmias,
cardiogenic
shock,
sudden
death
and
electrocardiographic changes. These adverse events may be more common in patients with a
prior history of coronary artery disease. Cardiac arrhythmias, angina pectoris, myocardial
infarction, heart failure and cardiomyopathy have been reported in patients receiving
Capecitabine. Caution must be exercised in patients with history of significant cardiac disease,
arrhythmias and angina pectoris (see undesirable effects).
Hypo- or hypercalcaemia. Hypo- or hypercalcaemia has been reported during Capecitabine
treatment. Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia (see
undesirable effects).
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Central or peripheral nervous system disease. Caution must be exercised in patients with
central or peripheral nervous system disease, e.g. brain metastasis or neuropathy (see
undesirable effects).
Diabetes Mellitus or electrolyte disturbances. Caution must be exercised in patients with
diabetes mellitus or electrolyte disturbances, as these may be aggravated during Capecitabine
treatment.
Coumarin-derivative anticoagulation. In a drug interaction study with single-dose warfarin
administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These
results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9
isoenzyme system by capecitabine. Patients receiving concomitant Capecitabine and oral
coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or
prothrombin time) monitored closely and the anticoagulant dose adjusted accordingly (see
undesirable effects).
Hepatic impairment. In the absence of safety and efficacy data in patients with hepatic
impairment, Capecitabine use should be carefully monitored in patients with mild to moderate
liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of
Capecitabine should be interrupted if treatment-related elevations in bilirubin of>3.0 x ULN or
treatment-related elevations in hepatic aminotransferases (ALT, AST) of>2.5 x ULN occur.
Treatment with Capecitabine monotherapy may be resumed when bilirubin decreases to
ULN or hepatic aminotransferases decrease to
3.0 x
2.5 x ULN. For combination treatment with
Capecitabine and docetaxel (see undesirable effects).
Renal impairment. The incidence of grade 3 or 4 adverse events in patients with moderate
renal impairment (creatinine clearance 30-50 ml/min) is increased compared to the overall
population.
As this medicinal product contains anhydrous lactose as an excipient, patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
Capecitabine Undesirable Effects
The adverse reactions considered to be possibly, probably, or remotely related to the
administration of Capecitabine have been obtained from clinical studies conducted with
Capecitabine monotherapy (in adjuvant therapy of colon cancer, in metastatic colorectal cancer
and metastatic breast cancer) and Capecitabine in combination with docetaxel in metastatic
breast cancer after failure of cytotoxic chemotherapy, Capecitabine in combination with
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oxaliplatin with or without bevacizumab in metastatic colorectal cancer and Capecitabine in
combination with various agents in advanced gastric cancer.. The most commonly reported
treatment-related adverse events were gastrointestinal disorders (especially diarrhoea, nausea,
vomiting, abdominal pain, stomatitis), fatigue and hand-foot syndrome (palmar-plantar
erythrodysesthesia).
Safety data for Capecitabine monotherapy has been obtained from >1900 patients in three major
clinical trials in adjuvant treatment for colon cancer and for metastatic colorectal cancer (Table
6).
The most frequently reported treatment-related adverse reactions in these trials were
gastrointestinal disorders, especially diarrhoea, nausea, vomiting, stomatitis, and hand-foot
syndrome (palmar-plantar erythrodysesthesia). The safety profile of Capecitabine monotherapy
for the metastatic breast cancer , metastatic colorectal cancer and adjuvant colon cancer
populations are comparable.
The following headings are used to rank the undesirable effects by frequency: Very common
(≥1/10), common (≥1/100, < 1/10) and uncommon (≥1/1,000, < 1/100 ). Within each frequency
grouping, undesirable effects adverse drug reactions are presented in order of decreasing
seriousness.
Table 6: Summary of related adverse events reported in patients treated with Capecitabine
monotherapy in adjuvant treatment for colon cancer and metastatic colorectal cancer .
Body System
Adverse event
Very Common
Common
Uncommon
(
(
(
1/10)
ALL GRADES
1/100 - < 1/10)
ALL GRADES
1/1,000 - < 1/100)
SEVERE AND/OR LIFETHREATENING (GRADE 3-4)
OR CONSIDERED MEDICALLY
RELEVANT
Infections and
infestations
(none)
Herpes simplex
Sepsis
Nasopharyngitis
Urinary tract infection
Lower respiratory tract
infection
Cellulitis
Tonsillitis
Pharyngitis
Oral candidiasis
Influenza
Gastroenteritis
Fungal infection
Herpes infection
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Infection
Tooth abscess
Body System
Adverse event
Very Common
Common
Uncommon
(
(
(
1/10)
ALL GRADES
1/100 - < 1/10)
ALL GRADES
1/1,000 - < 1/100)
SEVERE AND/OR LIFETHREATENING (GRADE 3-4)
OR CONSIDERED MEDICALLY
RELEVANT
Neoplasm benign,
malignant and
unspecified
(none)
(none)
Lipoma
Blood and
lymphatic system
disorders
(none)
Neutropenia
Febrile neutropenia
Anaemia
Pancytopenia
Granulocytopenia
Thrombocytopenia
Leucopenia
Haemolytic anaemia
Immune system
disorders
(none)
(none)
Hypersensitivity
Metabolism and
nutrition disorders
Anorexia
Dehydration
Diabetes
Decreased appetite
Hypokalaemia
Appetite disorder
Malnutrition
Hypertriglyceridaemia
Psychiatric
disorders
(none)
Insomnia
Confusional state
Depression
Panic attack
Depressed mood
Libido decreased
Nervous system
disorders
(none)
Headache
Aphasia
Lethargy
Memory impairment
Dizziness
Ataxia
Paraesthesia
Syncope
Dysgeusia
Balance disorder
Sensory disorder
Neuropathy peripheral
Eye disorders
(none)
Lacrimation increased
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Visual acuity reduced
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Conjunctivitis
Eye irritation
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Diplopia
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Body System
Adverse event
Very Common
Common
Uncommon
(
(
(
1/10)
ALL GRADES
1/100 - < 1/10)
ALL GRADES
1/1,000 - < 1/100)
SEVERE AND/OR LIFETHREATENING (GRADE 3-4)
OR CONSIDERED MEDICALLY
RELEVANT
Ear and labyrinth
disorders
(none)
(none)
Vertigo
Ear pain
Cardiac disorders
(none)
(none)
Angina unstable
Angina pectoris
Myocardial ischaemia
Atrial fibrillation
Arrhythmia
Tachycardia
Sinus tachycardia
Palpitations
Vascular
disorders
(none)
Thrombophlebitis
Deep vein thrombosis
Hypertension
Petechiae
Hypotension
Hot flush
Peripheral coldness
Respiratory,
thoracic and
mediastinal
disorders
(none)
Dyspnoea
Pulmonary embolism
Epistaxis
Pneumothorax
Cough
Haemoptysis
Rhinorrhoea
Asthma
Dyspnoea exertional
Gastrointestinal
disorders
Diarrhoea
Vomiting
Gastrointestinal
haemorrhage
Constipation
Nausea
Upper abdominal pain
Stomatitis
Dyspepsia
Abdominal pain
Flatulence
Dry mouth
Loose stools
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Intestinal obstruction
Ascites
Enteritis
Gastritis
Dysphagia
Abdominal pain lower
Oesophagitis
Abdominal discomfort
Gastro-oesophageal reflux
disease
Colitis
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Body System
Adverse event
Very Common
Common
Uncommon
(
(
(
1/10)
ALL GRADES
1/100 - < 1/10)
ALL GRADES
1/1,000 - < 1/100)
SEVERE AND/OR LIFETHREATENING (GRADE 3-4)
OR CONSIDERED MEDICALLY
RELEVANT
Hepatobiliary
Disorders
(none)
Hyperbilirubinaemia
/blood bilirubin/ blood
bilirubin increased
Jaundice
Skin and
subcutaneous
tissue disorders
Palmar-plantar
erythrodysaesthesia
syndrome
Rash
Skin ulcer
Alopecia
Rash
Erythema
Urticaria
Dry skin
Photosensitivity reaction
Pruritus
Palmar erythema
Skin hyper-pigmentation
Swelling face
Rash macular
Purpura
Skin desquamation
Dermatitis
Pigmentation disorder
Nail disorder
Musculoskeletal
and connective
tissue disorders
(none)
Pain in extremity
Joint swelling
Back pain
Bone pain
Arthralgia
Facial pain
Musculoskeletal stiffness
Muscular weakness
Renal and urinary
disorders
(none)
(none)
Hydronephrosis
Urinary incontinence
Haematuria
Nocturia
Reproductive
system and
breast disorders
(none)
(none)
Vaginal haemorrhage
General disorders
and
administration site
conditions
Fatigue
Pyrexia
Oedema
Asthenia
Lethargy
Chills
Oedema peripheral
Influenza like illness
Malaise
Rigors
Non-cardiac chest pain
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Body System
Adverse event
Very Common
Common
Uncommon
(
(
(
1/10)
ALL GRADES
1/100 - < 1/10)
ALL GRADES
1/1,000 - < 1/100)
SEVERE AND/OR LIFETHREATENING (GRADE 3-4)
OR CONSIDERED MEDICALLY
RELEVANT
Investigations
(none)
Weight decreased
Blood in stool
Liver function test
abnormalities
International normalised ratio
increased
Blood creatinine increased
Body temperature increased
Injury, poisoning
and procedural
complications
(none)
(none)
Blister
Overdose
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Fluorauracil 25mg/ml Injection [Ref Hospira, 27 January 2005]
Contraindications
Fluorouracil is contraindicated in seriously debilitated patients or those with bone marrow
depression after radiotherapy or treatment with other antineoplastic agents.
Fluorouracil is strictly contraindicated in pregnant or breast feeding women.
Fluorouracil should not be used in the management of non-malignant disease.
Fluorauracil Special warnings and special precautions for use
It is recommended that fluorouracil be given only by, or under the strict supervision of a qualified
physician who is conversant with the use of potent antimetabolites.
All patients should be
admitted to hospital for initial treatment.
Adequate treatment with fluorouracil is usually followed by leucopenia, the lowest white blood
cell (WBC) count commonly being observed between the 7th and 14th day of the first course,
but occasionally being delayed for as long as 20 days. The count usually returns to normal by
the 30th day. Daily monitoring of platelet and WBC count is recommended and treatment should
be stopped if platelets fall 100,000 per mm3 or the WBC count falls below 3,500 per mm3. If the
total count is less than 2000 per mm3, and especially if there is granulocytopenia, it is
recommended that the patient be placed in protective isolation in the hospital and treated with
appropriate measures to prevent systemic infection.
Treatment should also be stopped at the first sign of oral ulceration or if there is evidence of
gastrointestinal side effects such as stomatitis, diarrhoea or bleeding from the gastrointestinal
tract or haemorrhage at any site. The ratio between effective and toxic dose is small and
therapeutic response is unlikely without some degree of toxicity. Care must be taken therefore,
in the selection of patients and adjustment of dosage.
Fluorouracil should be used with caution in patients with reduced renal or liver function or
jaundice. Isolated cases of angina, ECG abnormalities and rarely, myocardial infarction have
been reported following administration of Fluorouracil. Caution should therefore be exercised in
treating patients who experience chest pain during courses of treatment, or patients with a
history of heart disease.
There have been reports of increased toxicity in patients who have reduced activity/deficiency of
the enzyme dihydropyrimidine dehydrogenase (DPD).
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Fluorauracil Undesirable effects
Diarrhoea, nausea and vomiting are observed quite commonly during therapy and may be
treated symptomatically. An anti-emetic may be given for nausea and vomiting.
Alopecia may be seen in a substantial number of cases particularly in females, but is reversible.
Other side effects Include dermatitis, pigmentation, changes in the nails , ataxia and fever.
There have been reports of chest pain, tachycardia ,breathlessness and ECG changes after
administration of fluorouracil. Special attention is therefore advisable in treating patients with a
history of heart disease or those who develop chest pain during treatment.
Systemic fluorouracil treatment has been associated with various types of ocular toxicity.
A transient reversible cerebellar syndrome has been reported following fluorouracil treatment.
Rarely, a reversible confusional state may occur. Cases of leucoencephalopathy have also been
reported.
Additionally several other reports have been noted including:
Incidences of excessive lacrimation, dacryostenosis, visual changes and photophobia.
Palmar-plantar erythrodysesthesia syndrome has been reported as an unusual complication of
high dose bolus or protracted continuous therapy for 5-fluorouracil.
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Epirubicin [Pharmorubicin Last Updated September 2004]
Contraindications
Epirubicin is contraindicated in patients with marked myelosuppression induced by previous
treatment with other antitumour agents or by radiotherapy and in patients already treated with
maximal cumulative doses of other anthracyclines such as Doxorubicin or Daunorubicin.
The drug is contraindicated in patients with current or previous history of cardiac impairment.
Special warnings and special precautions for use
Epirubicin should be administered only under the supervision of qualified physicians experienced
in antiblastic and cytotoxic therapy. Treatment with high dose Epirubicin in particular requires the
availability of facilities for the care of possible clinical complications due to myelosuppression.
Initial treatment calls for a careful baseline monitoring of various laboratory parameters and
cardiac function.
During each cycle of treatment with Epirubicin, patients must be carefully and frequently
monitored. Red and white blood cells, neutrophils and platelet counts should be carefully
assessed both before and during each cycle of therapy. Leukopenia and neutropenia are usually
transient with conventional and high-dose schedules, reaching a nadir between the 10th and
14th day and returning to normal values by the 21st day; they are more severe with high dose
schedules. Very few patients, even receiving high doses, experience thrombocytopenia (<
100,000 platelets/mm3).
Before starting therapy and if possible during treatment, liver function should be evaluated
(SGOT, SGPT, alkaline phosphatase, bilirubin). A cumulative dose of 900-1000 mg/m2 should
only be exceeded with extreme caution with both conventional and high doses.
Above this level the risk of irreversible congestive cardiac failure increases greatly. There is
objective evidence that the cardiac toxicity may occur rarely below this range. However, cardiac
function must be carefully monitored during treatment to minimise the risk of cardiac failure of
the type described for other anthracyclines.
Heart failure can appear even several weeks after discontinuing treatment, and may prove
unresponsive to specific medical treatment. The potential risk of cardiotoxicity may increase in
patients who have received concomitant, or prior, radiotherapy to the mediastinal pericardial
area.
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Undesirable Effects
Apart from myelosuppression and cardiotoxicity, the following adverse reactions have been
described:
Alopecia, normally reversible, appears in 60-90% of treated cases; it is accompanied by lack of
beard growth in males.
Mucositis may appear 5-10 days after the start of treatment, and usually involves stomatitis with
areas of painful erosions, mainly along the side of the tongue and the sublingual mucosa.
Gastro-intestinal disturbances, such as nausea, vomiting and diarrhoea.
Hyperpyrexia.
Fever, chills and urticaria have been rarely reported; anaphylaxis may occur.
High doses of Epirubicin have been safely administered in a large number of untreated patients
having various solid tumours and has caused adverse events which are no different from those
seen at conventional doses with the exception of reversible severe neutropenia (< 500
neutrophils/mm3 for < 7 days) which occurred in the majority of patients. Only a few patients
required hospitalisation and supportive therapy for severe infectious complications at high
doses.
During intravesical administration, as drug absorption is minimal, systemic side effects are rare;
more frequently chemical cystitis, sometimes haemorrhagic, has been observed.
Haematological
The occurrence of secondary acute myeloid leukaemia with or without a pre-leukaemic phase
has been reported rarely in patients concurrently treated with epirubicin in association with DNAdamaging antineoplastic agents. Such cases could have a short (1-3 year) latency period.
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Cisplatin [Reference: Hospira, 26 April 2004]
ContraIndications
Cisplatin may give allergic reactions in some patients. Use is contraindicated in those patients
with a history of allergic reaction to cisplatin or other platinum containing compounds. Cisplatin
induces nephrotoxicity which is cumulative. It is therefore contraindicated in patients with renal
impairment.
Cisplatin has been shown to be cumulatively ototoxic and should not be given to patients with
hearing impairment. Cisplatin is also contraindicated in myelosuppressed patients.
Cisplatin - WARNINGS AND PRECAUTIONS
This agent should only be administered under the direction of oncologists in specialist units
under conditions permitting adequate monitoring and surveillance. Supportive equipment should
be available to control anaphylactic reactions.
Cisplatin reacts with metallic aluminium to form a black precipitate of platinum. All aluminium
containing IV sets, needles, catheters and syringes should be avoided.
The solution for infusion should not be mixed with other drugs or additives.
Cisplatin produces cumulative nephrotoxicity which may be potentiated by aminoglycoside
antibiotics. The serum creatinine, plasma urea or creatinine clearance and magnesium, sodium
potassium, and calcium levels should be measured prior to initiating therapy, and prior to each
subsequent course. Cisplatin should not be given more frequently than once every 3-4 weeks
(see Undesirable Effects).
Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred
within minutes of administration to patients with prior exposure to cisplatin and have been
alleviated by administration of adrenaline, steroids and antihistamines.
Neurotoxicity appears to be cumulative. Prior to each course, the absence of symptoms of
peripheral neuropathy should be established. Neurological examination should also be
performed regularly (see Undesirable Effects).
Since ototoxicity of cisplatin is cumulative, audiometric testing should be performed prior to
initiating therapy and prior to each subsequent course of the drug (see Undesirable Effects).
Peripheral blood counts should be monitored weekly. Liver function should be monitored
periodically (see Undesirable Effects).
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Adequate pre-treatment and 'during treatment' hydration should be ensured and such agents as
mannitol given to minimise hazards of renal toxicity. In addition, adequate post-treatment
hydration and urinary output should be monitored.
During, and for at least three months after therapy, both male and female patients should take
contraceptive measures. As is the case with all anticancer drugs, in men this drug may cause
transitional or permanent sterility. Preservation of sperm may be considered for the purpose of
later fatherhood (see section 4.6, Pregnancy and lactation).
Cisplatin Undesirable Effects
Nephrotoxicity: Renal toxicity has been noted in about one third of patients given a single dose
of cisplatin when prior hydration has not been employed. It is first noted during the second week
after a dose and is manifested by elevations in plasma urea and serum creatinine, serum uric
acid and/or decrease in creatinine clearance.
Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal
function must return to acceptable levels before another dose of cisplatin can be given.
Renal function impairment has been associated with renal tubular damage. The administration of
cisplatin using a 6-8 hour infusion with intravenous hydration and mannitol has been used to
reduce nephrotoxicity. However renal toxicity still can occur after utilisation of these procedures.
Gastrointestinal toxicity: Nausea and vomiting occur in the majority of patients, usually starting
within 1 hour of treatment and lasting up to 24 hours. Anorexia, nausea and occasional vomiting
may persist for up to a week.
Ocular Toxicity: There have been reports of optic neuritis, papilloedema and cerebral blindness
following treatment with cisplatin. Improvement and/or total recovery usually occurs following
immediate discontinuation. Blurred vision and altered colour perception have been reported after
the use of regimens with higher doses of cisplatin or greater dose frequencies than those
recommended.
Ototoxicity: Ototoxicity has occurred in up to 31% of patients treated with a single dose of
cisplatin 50 mg/m2. Ototoxicity may be more severe in children and more frequent and severe
with repeated doses.
Careful monitoring should be performed prior to initiation of therapy and prior to subsequent
doses of cisplatin.
Unilateral or bilateral tinnitus, which is usually reversible, and/or hearing loss in the high
frequency range may occur.
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The overall incidence of audiogram abnormalities is 24%, but large variations exist. These
abnormalities usually appear within 4 days after drug administration and consist of at least a 15
decibel loss in pure tone threshold. The damage seems to be cumulative and is not reversible.
The audiogram abnormalities are most common in the 4000-8000 Hz frequencies.
Haemotoxicity: Myelosuppression is observed in about 30% of patients treated with cisplatin.
Leucopenia and thrombocytopenia are more pronounced at higher doses. The nadirs in
circulating platelets and leucocytes generally occur between days 18-23 (range 7.3 to 45) with
most patients recovering by day 39 (range 13 to 62). Leucopenia and thrombocytopenia are
more pronounced at doses greater than 50 mg/m2. Anaemia (decreases of greater than 2 g%
haemoglobin) occurs at approximately the same frequency, but generally with a later onset than
leucopenia and thrombocytopenia. Subsequent courses of cisplatin should not be instituted until
platelets are present at levels greater than 100,000/mm2 and white cells greater than
4,000/mm2. A high incidence of severe anaemia requiring transfusion of packed red cells has
been observed in patients receiving combination chemotherapy including cisplatin.
Anaphylaxis: Reactions possibly secondary to cisplatin therapy have been occasionally
reported in patients who were previously exposed to cisplatin. Patients who are particularly at
risk are those with a prior history or family history of atopy. Facial oedema, wheezing,
tachycardia, hypotension and skin rashes of urticarial non-specific maculopapular type can occur
within a few minutes of administration. Serious reactions seem to be controlled by IV adrenaline,
corticosteroids or antihistamines.
Serum
Electrolyte
Disturbances:
Hypomagnesaemia,
hypocalcaemia,
hyponatraemia,
hypokalaemia and hypophosphataemia have been reported to occur in patients treated with
cisplatin and are probably related to renal tubular damage. Hypomagnesaemia and
hypocalcaemia may result in tetany. Generally, normal serum electrolyte levels are restored by
administering supplemental electrolytes and discontinuing cisplatin. Inappropriate antidiuretic
hormone syndrome has also been reported.
Neurotoxicity: Usually characterised by peripheral neuropathies and paresthesia in both upper
and lower extremities. Peripheral neuropathy, while reversible, may take a year or more to
recover. Loss of taste and seizures have also been reported. Neuropathies resulting from
cisplatin treatment may occur after prolonged therapy; however, neurological symptoms have
been reported to occur after a single dose. The neuropathy may progress after stopping
treatment.
Hyperuricaemia: Hyperuricaemia occurring with cisplatin is more pronounced with doses
greater than 50 mg/m2. Allopurinol effectively reduces uric acid levels.
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Other Toxicities: Vascular toxicities coincident with the use of cisplatin in combination with
other antineoplastic agents have been reported rarely. These events may include myocardial
infarction,
cerebrovascular
accident,
thrombotic
microangiopathy
(haemolytic
uraemic
syndrome) or cerebral arteritis. There are also reports of Raynaud's phenomenon occurring in
patients treated with the combination of bleomycin, vinblastine with or without cisplatin. It has
been suggested that hypomagnesaemia developing coincident with the use of cisplatin may be
an added, although not essential factor, associated with this event. However the cause of this
Raynaud's phenomenon is currently unknown.
Other toxicities reported to occur infrequently are cardiac abnormalities including tachycardia
and arrhythmia.
Local soft tissue toxicity has been reported rarely following extravasation of cisplatin. Infiltration
of solutions of cisplatin may result in tissue cellulitis, fibrosis and necrosis.
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Appendix G: Cockcroft and Gault Formula
The estimated GFR is given by:
Males:
1.25 x (140 - age) x weight (kg)
serum creatinine (µmol/l)
Females:
1.05 x (140 - age) x weight (kg)
serum creatinine (µmol/l)
This formula usually under-estimates GFR by 10-30% compared with EDTA or measured
24-hour creatinine clearance, so is used in this trial as a screening test.
A Cockcroft/Gault estimate of ≥ 60 ml/min is accepted as evidence of adequate renal
function.
Patients with a Cockcroft/Gault estimate of < 60 ml/min prior to randomisation should
have formal GFR measurement with EDTA or 24 urinary creatinine, which must be within
the normal range. The uncorrected EDTA clearance should be ≥60ml/min.
After the start of treatment, if the Cockcroft/Gault estimate falls by >25% from baseline, to
below 60 ml/min, the EDTA measurement should be re-checked.
Centres may follow their standard practice for estimating creatinine clearance
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Appendix H: How to calculate the number of capecitabine tablets to dispense
following a dose reduction
Capecitabine is dose banded according to 3 BSA levels as shown in table 8.1. Depending on
the type of toxicity patients may require 1 of 4 possible dose reductions. The table below shows
the percentage dose reduction based on the initial dose given at start of cycle 1.
Table 1: Daily dose after a dose reduction
Initial daily
dose given at
cycle 1
according to
BSA
15% dose
reduction
25% dose
reduction
30% dose
reduction
50% dose
reduction
(daily dose)
(daily dose)
(daily dose)
(daily dose)
1800 mg
1530
1350
1260
900
2150 mg
1828
1613
1505
1075
2500 mg
2125
1875
1750
1250
To assist you in working out the rounded total daily dose and the number of capecitabine tablets
to dispense, please use the table below.
Table 2: Rounded total Daily Dose and No. of Tablet to dispense
Daily dose
after
reduction
Rounded
total daily
dose
Number of tablets to be
taken in the morning
Number of tablets to be
taken in the evening
150mg
500mg
150mg
500mg
776 – 900
800mg
2
0
0
1
901 – 1075
1000mg
0
1
0
1
1226 – 1375
1300mg
1
1
1
1
1376 – 1525
1450mg
1
1
2
1
1526 – 1700
1600mg
2
1
2
1
1701 – 1900
1800mg
2
1
0
2
1901 – 2075
2000mg
0
2
0
2
2076 – 2225
2150mg
0
2
1
2
Example:
If a patient who received 2150mg as their total daily dose during cycle 1, required a 30% dose
reduction, their total daily dose would be reduced to 1505 mg per day as shown in table 1. The
actual rounded total daily dose prescribed would be 1450mg and administered as shown in
Table 2.
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APPENDIX I:
TRIAL COMMITTEES
Trial Management Group Members:
Surgical Chief Investigator
Professor Derek Alderson
Barling Professor of Surgery
Academic Department of Surgery
Room 29, 4th Floor
Queen Elizabeth Hospital
Edgbaston
Birmingham B15 2TH
Tel: 0121 627 2276
Fax: 0121 472 1230
Email: [email protected]
Oncological Chief Investigator
Professor David Cunningham
Dept of Oncology
Marsden Hospital
Downs Road,
Sutton
Surrey SM2 5PT
Tel: 020 8661 3156
Fax: 020 8643 9414
Email: [email protected]
QL Advisor
Miss Jane Blazeby
University Dept of Surgery, Level 7
Bristol Royal Infirmary
Marlborough St
Bristol BS2 8HW
Tel: 0117 928 3512
Fax: 0117 925 2736
Email: [email protected]
Professor Michael Griffin
Northern Oesophago-Gastric Cancer Unit
Ward 36 Office
Royal Victoria Infirmary
Newcastle upon Tyne, NE1 4LP
Tel: 0191 282 0234
Fax: 0191 282 0237
Email: [email protected]
Dr Adrian Crellin
Cookridge Hospital
Leeds Cancer Centre
Leeds, LS16 6QB
Tel: 0113 392 4257
Fax: 0113 392 4188
Email:[email protected]
Dr Heike Grabsch
Pathology and Tumour Biology,
Leeds Institute of Molecular Medicine
Wellcome Trust Brenner Building,
St James's University Hospital
Beckett Street, Leeds, LS9 7TF
Phone: 0113 3438626
Email: [email protected]
OE05 MRC CTU Team:
Project Leader
Dr Ruth Langley
Tel: 020 7670 4718
Email: [email protected]
Senior Medical Statistician
Sally Stenning
Tel: 020 7670 4707
Email:[email protected]
Trial Statistician
Matthew Nankivell
Tel: 020 7670 4717
Email: [email protected]
Trial Manager
Paul Cortissos
Tel: 020 7670 4795
Email: [email protected]
Data Manager
Dipa Noor
Tel: 020 7670 4804
Email: [email protected]
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Trial Overseeing Committees
Trial Steering Committee (TSC):
The role of the TSC is to provide overall supervision of the trial and ensure that the trial is
conducted according to the MRC guidelines for Good Clinical Practice. It also provides advice,
through its independent Chairman, on all aspects of the trial. The TSC reviews the progress of
the trial, adherence to the protocol and patient safety. It also considers any new information
relevant to the trial and any results from other trials that may have a direct bearing on the future
conduct of the trial. The GI/Gynaecology TSC, chaired by Professor Malcolm Mason will oversee
this trial.
Independent Data Monitoring Committee (IDMC):
The role of the IDMC is to monitor the data during the trial and to make recommendations to the
TSC on whether there are any ethical or safety reasons why the trial should be modified or
discontinued. It will also consider any reported adverse events and any data emerging from
other related studies. The IDMC is the only body involved in the trial that has access to
unblinded data. Members of this committee include:
John Bancewitz (Chairman)
Oncologist (Retired)
Janet Dunn
Statistician
Pippa Corrie
Oncologist
OE05 Sample Access Committee (SAC):
Proposals for translational research projects involving the OE05 material will be considered for
approval by the OE05 Sample Access Committee and Independent Trial Steering Committee
(TSC). The OE05 sample Access committee includes:
Dr. Heike Grabsch
Leeds Teaching Hospital NHS Trust
Prof. David Cunningham
Royal Marsden Hospital NHS Trust
Dr Olorunda Rotimi
Leeds Teaching Hospital NHS Trust
Dr Ruth Langley
MRC CTU
Dr Andrew Wotherspoon
Royal Marsden Hospital NHS Trust
Gastric Intestinal /Gynaecology TSC
rd
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Appendix J: Summary of Protocol Amendments
Please check with the MRC CTU that you are using the most recent version of the OE05 clinical
protocol. For the full details of the amendments submitted to the South West MREC by the MRC
CTU, please refer to your sites OE05 Master File Documents.
OE05 Protocol Version 1, 22nd January 2004
Approved by MREC on 10th February 2004
Summary of Product Characteristics Capecitabine
Summary of Product Characteristics Cisplatin 50
Summary of Product Characteristics Fluorouracil injection
GP Letter (version 1 24th November 2003)
Patient Information Sheet (version 1 22nd January 2004)
QL questionnaire An Explantation (version 1 22nd January 2004)
Consent Form (version 1 22nd January 2004)
Version 1, 22nd January 2004 - Administrative Amendments
Approved by MREC on 30th April 2004
Front Cover & inside cover
Summary Trial Outline
Section 4 Design
Selection of Patients
Randomising Patients
Table 1 Trial Assessments
Table 2 Time Points for forms
7.4 Time Point points for forms
Appendix VIII Trial Committees
11.3.2 Quality of Life
Version 2, 16th June 2004 - Substantial Amendment
Approved by MREC on 19th July 2004
The main changes concerned the administration of chemotherapy and Safety reporting section
to comply with the EU Directive on Clinical Trials
Version 3, 19th September 2005 - Substantial Amendment
Approved by MREC on 2nd November 2005
The main changes included further clarification to the protocol
Pre-randomisation Investigations
Inclusion criteria
Exclusion criteria
Centre Accreditation Process
MHRA CTA approval for Investigators
Drug Supply
Withdrawal of patients from treatment & Trial
Table of trial assessments
Chemotherapy Regimes
ADDED: Management of chest pain whilst receiving fluorpyrimidines
Toxicities
Pathology Review
Radiology Review
Site visits
Safety Reporting
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Ethical Approval
Sponsorship
Patient Information Sheet
Consent Form
Safety Reporting Flow Chart
Common Toxicity Criteria (version 3)
Summary of Product Characteristics
Version 4, 21st November 2006 - Substantial Amendment
Approved by MREC on 7th December 2006
The main changes included further clarification to the protocol
Amendment to the surgery procedure
Contact details for new data manager
Appendix VII CTCAE has been updated with the hand-foot grading description
Version 5, 31st July 2008 – Substantial Amendment
Approved by MREC on 5th September 2008
The main changes included further clarification to the protocol
Update staging investigations to allow laparoscopy to be included as staging
investigation (within the 28 days of randomisation)
Surgical procedure updated
Sample size updated
Pathology review updated
Trans-OE05 added
Consent form updated to allow collection of blood samples. New consent form for TransOE05
Summary of Product Characteristics updated for Capecitabine
Clarification of GFR criteria. Cockcroft and Gault Formula added to Appendix.
Patient diary card has been introduced to assess patient’s compliance in taking the full
prescribed dose of capecitabine per cycle
Appenidx G Cockcroft and Gault Formula
Appendix H How to calculate the number of capecitabine tablets to dispense following a
dose reduction.
Version 6, 23rd December 2009 – Substantial Amendment
Aprroved by MREC on
The main changes included further clarification to the protocol
▪
Changes to Inclusion/Exclusion criteria
▪
Further information on eligibility
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▪ Clarification of dosing
▪ Clarification of Trans-OE05 procedures and consent issues
Current version of the OE05 clinical protocol is Version 6, 23rd December 2009
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Glossary and Abbreviations
5FU……………………………………………………………………………………………5-Flurouracil
AUC………………………………………………………………………….……..Area Under the Curve
CT.……………………………………………………………………………….Computed Tomography
CTA………………………………………………………………….………...Clinical Trial Authorisation
CTU…………………………………………………………………………………….Clinical Trials Unit
ICH GCP………………….. ….International Conference on Harmonisation Good Clinical Practice
IDMC………………………………………………………...Independent Data Monitoring Committee
ECF……………………………………….Epirubicin, Cisplatin and 5FU chemotherapy combination
ECX……………………………..Epirubicin, Cisplatin and capecitabine chemotherapy combination
EDTA……………………………………………………………….Ethylene Diamine Tetra Acetic acid
EORTC…………………………….European Organisation for Research and Treatment of Cancer
EUS……………………………………………………………………………….Endoscopic Ultrasound
FBC……………………………………………………………………………………….Full Blood Count
FAMTX…………………………….5FU, doxorubicin and methotrexate chemotherapy combination
FEV…………………………………………………………………………….Forced Expiratory Volume
GI…………………………………………………………………………………………..Gastrointestinal
Hb…………………………………………………………………………………………….Haemoglobin
IV……………………………………………………………………………………………….Intravenous
KCl…………………………………………………………………………………….Potassium Chloride
LLN…………………………………………………………………………………Lower Limit of Normal
LREC…………………………………………………………………Local Research Ethics Committee
MDT………………………………………………………………………………..Multi Disciplinary
Team
MRC…………………………………………………………………………..Medical Research Council
MREC………………………………………………………...Multi-centre Research Ethics Committee
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MUGA………………………………………………………………………..Multiple Gated Acquisition
NaCl……………………………………………………………………………………..Sodium Chloride
ONS…………………………………………………………………………Office of National Statistics
PO………………………………………………………………………………………………...Per Oral
QL…………………………………………………………………………………………...Quality of Life
SpC ……………………………………………………………...Summary of Product Characteristics
SAE……………………………………………………………………………...Serious Adverse Event
SAR………………………………………………………………………….Serious Adverse Reaction
SSA ………………………………………………………………………….Site Specific Assessment
SUSAR …………………………………………Suspected Unexpected Serious Adverse Reaction
TDS …………………………………………………………………………………..Three times a day
TMG…………………………………………………………………………..Trial Management Group
TSC…………………………………………………………………………..Trial Steering Committee
ULN………………………………………………………………………………Upper Limit of Normal
WBC…………………………………………………………………………………White Blood Count
WHO………………………………………………………………………...World Heath Organisation
WNL……………………………………………………………………………….Within Normal Limits
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