Annals of Oncology Advance Access published April 8, 2014

Chronicle: Results of a randomised phase III trial in locally advanced rectal

cancer after neoadjuvant chemoradiation randomising postoperative adjuvant
capecitabine plus oxaliplatin (Xelox) versus control.

R. Glynne-Jones1, N. Counsell2, P. Quirke3, N. Mortensen4, A. Maraveyas5, H.M.

Meadows2, J. Ledermann2, D. Sebag-Montefiore3
1
Mount Vernon Centre for Cancer Treatment, London, UK
2
CRUK & UCL Cancer Trials Centre, London, UK
3
University of Leeds, Leeds, UK
4
University of Oxford, Oxford, UK
5
Castle Hill Hospital, Hull, UK

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Corresponding Author: Dr R Glynne-Jones, Tel: +44 (0) 1923 844767, Fax: +44 (0)
1923 844 138, E-mail: rob.glynnejones@nhs.net

Key Message: "Locally advanced rectal cancer is conventionally treated with 
preoperative chemoradiation, but has a high risk of distant recurrence. The Chronicle 
trial did not detect a significant difference in DFS or OS for adjuvant XELOX compared 
to surgery alone following chemoradiation. The difficulty in recruitment, high acute 
levels of toxicity and poor compliance to adjuvant chemotherapy, all support the 
need for trials that test the role of neoadjuvant chemotherapy."

© The Author 2014. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
 2

Abstract

Background: In stage III colon cancer oxaliplatin/5FU-based adjuvant chemotherapy

(FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal
adenocarcinoma following neoadjuvant chemoradiation (CRT), we examined the
benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX)
chemotherapy.

Methods: Eligible patients were randomly assigned following fluoropyrimidine-based

CRT and curative resection to observation or 6 cycles of XELOX. The primary
endpoint was DFS; secondary endpoints were acute toxicity and OS. 390 patients

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were required in each arm, to detect an improvement in 3-year DFS from 40% to
50.5%, with 85% power and two-sided 5% significance level.

Results: The study closed prematurely in 2008 because of poor accrual. Only 113
patients were randomly assigned to either observation (n=59) or XELOX (n=54).
Compliance was poor, 93% allocated chemotherapy started and 48% completed 6
cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4
toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the
observation arm had relapsed or died compared with 12 patients (22%) in XELOX.
The 3-year DFS rate was 78% with XELOX and 71% with observation (hazard ratio
[HR] for DFS=0.80; 95% CI: 0.38-1.69; p=0.56). The 3-year OS for XELOX and
observation were 89% and 88% respectively (HR for OS=1.18; 95% CI: 0.43-3.26;
p=0.75).

Conclusions: The observed improvement in DFS for adjuvant XELOX and similar
OS were not statistically significant, as expected given the small number of patients
and consequent low power. Our findings support the need for trials that test the role of
neoadjuvant chemotherapy.

Key words: Rectal adenocarcinoma, preoperative chemoradiation, metastatic disease,

adjuvant chemotherapy, capecitabine, oxaliplatin.
 3

Introduction

Postoperative 5-Fluorouracil (5FU)-based adjuvant chemotherapy improves overall

survival (OS) in stage III colon cancer1. Oxaliplatin added to 5FU-based
chemotherapy improves disease-free survival (DFS) and OS2,3, and is considered an
international standard for stage III colon cancer.

Locally advanced rectal cancer (LARC) has a high risk of local and distant

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recurrence. Many oncologists, and the European and National Comprehensive Cancer
Network Guidelines, recommend a FOLFOX regimen as postoperative chemotherapy
in patients with stage III or adverse histology following chemoradiation and
surgery4,5,6,7,8,9. The validity of this strategy has been questioned10. Trials which
directly examined adjuvant 5FU alone after chemoradiation, have provided no
evidence for its efficacy11,12,13,.

The CHRONICLE trial aimed to evaluate postoperative adjuvant chemotherapy

following neoadjuvant chemoradiation (NCRT) in LARC. The trial examined whether
six cycles of capecitabine and oxaliplatin (XELOX) over 4 months would improve
DFS and OS compared to surgical follow-up alone. We report the results of acute
toxicity and compliance in addition to DFS and OS.

Patients and Methods

The Chronicle trial was approved by institutional ethics committees of participating
centres and monitored by an Independent Data Monitoring (IDMC) and Trial Steering
Committee (TSC). Six-monthly review of recruitment was prospectively defined to
assess the feasibility of obtaining a clinically worthwhile result, if accrual was lower
than anticipated.

Eligibility
Eligible patients were aged >18 years, with histologically confirmed rectal
adenocarcinoma, located <15cm from the anal verge, or below the peritoneal
reflection. Surgery was performed before randomisation, to start chemotherapy within
12 weeks of surgery. Before enrolment patients received preoperative
fluoropyrimidine-based chemoradiation, minimum total dose 45Gy. Patients may
 4

have had up to a 12-week maximum of neoadjuvant fluoropyrimidine-based

chemotherapy.

Other eligibility criteria included WHO performance status 0-1, adequate

hematologic, renal, and hepatic function, complete resection of the primary tumour, a
negative circumferential margin (CRM>1mm), and no evidence of metastatic disease.
Definitive histology at surgery required ypT0-T4, N0-N2.

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Patients were excluded in the presence of metastatic disease (M1), R1 or R2
resections, and for significant cardiac disease, CNS disorders, known peripheral
neuropathy, moderate/severe renal impairment, and pregnancy or lactation.

Treatment
Patients were randomised to observation alone (Observation arm) or XELOX -
capecitabine (1000mg/m2 orally twice daily days 1-14) and oxaliplatin (130mg/m2
day 1) as a two-hour infusion (XELOX arm) as indicated in the CONSORT diagram
(FIGURE 1). A total of 6 three-weekly cycles were intended. Dose modifications for
toxicity were defined in the protocol.

Assessments
Pre-treatment evaluation included: CT scans of chest, abdomen and pelvis;
demographic data, medical history, physical examination, ECG, carcino-embryonic
antigen (CEA) determination; height, weight, vital signs, WHO performance status,
haematology, and blood chemistry.

Adverse events were monitored during and for 28 days after study treatment. Toxicity
was graded according to National Cancer Institute Common Toxicity Criteria, version
3.0. Neurotoxicity was monitored up to 3 years post-randomisation.

Follow-up
Patients were evaluated clinically every three weeks following randomisation until 4
months, then three-monthly until the end of the second year, six-monthly until the end
of the fifth year and then annually. Colonoscopy was recommended prior to surgery
or within 3 months after surgery, and thereafter every third year. Abdo-pelvic CT
 5

scans or ultrasound and chest x-ray or thoracic CT were to be performed at 6, 12, 18,
24, 36 and 48 months post-randomisation. CEA levels were measured every 3 months
(starting 6 months post-randomisation) for the first 3 years and every 6 months
thereafter. Assessments were made for local relapse, distant metastases, late toxicity,
second cancers and death. Patients were flagged at the UK Office of National
Statistics to capture death notification.

Statistical Analysis

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Patients were randomly assigned 1:1 between trial arms using permuted blocks,
stratified by surgeon and pathological nodal status.

The primary endpoint was DFS, defined as the time from randomisation to relapse,
development of a new cancer or death, whichever occurred first. 390 patients were
required in each arm to detect an improvement in 3-year DFS from 40% to 50.5%
(equivalent to a hazard ratio of 0.75), with 85% power and two-sided 5% significance
level. With allowance for loss to follow-up, the target sample size was 800 patients in
total, assuming an enrolment and follow-up period of 3 years.

If an advantage was observed for postoperative chemotherapy, it was planned to

explore whether it was consistent across various subgroups described in the statistical
analysis plan. Secondary endpoints were OS, measured from date of randomisation
until death from any cause, incidence rates of acute toxicity and compliance to
treatment.

Hazard ratios with 95% confidence intervals (CIs) were calculated using the Cox
proportional hazards model. Survival curves are presented using the Kaplan-Meier
method. Patients were censored using the date they were last seen if no event had
occurred. Analysis was performed on an intention-to-treat (ITT) basis, unless
otherwise specified, and generated using SAS software version 9.3, (SAS Institute,
Cary NC).
 6

Results

Accrual
Between 2004 and 2008, 113 patients were randomised; TABLE 1 shows the baseline
characteristics. After 4 years of slower-than-anticipated accrual, the trial was
terminated early on the recommendation of the IDMC.

Compliance

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54 patients were randomly assigned to XELOX and 59 to the observation arm. At
least one cycle of study treatment was received by 50 patients (92.6%). The planned
six cycles of chemotherapy were received by only 26 (48.1%). Twenty-one (38.9%)
had a dose reduction and 21 (38.9%) had a dose delay; TABLE 2.

Median total oxaliplatin dose received was 601mg/m2, compared with a per-protocol
six-cycle dose of 780mg/m2. Median total capecitabine dose received was
96,923mg/m2, compared with a per-protocol six-cycle dose of 168,000mg/m2.

Therapy after relapse was received by 9 (16.7%) XELOX and 15 (25.4%) patients in
the observation arm. Post-relapse, in the XELOX and observation arms respectively, 6
(11.1%) and 7 (11.9%) patients received chemotherapy, 4 (7.4%) and 7 (11.9%)
received surgery, 2 (3.7%) and 2 (3.4%) received palliative care, 1 (1.9%) and 1
(1.7%) received radiotherapy, and 1 (1.9%) XELOX patient was offered a different
trial.

Toxicity
Fifty (92.6%) XELOX patients received at least 1 cycle of treatment – defined as the
safety population. Twenty (40.0% of the safety population) reported grade 3 or higher
toxicity; TABLE 3. Three (6.0%) reported a grade 4 toxicity (sensory neuropathy
(n=2) and diarrhoea (n=1)). There was one treatment-related death from diarrhoea.

Nine patients reported a grade 3/4 adverse event during follow-up. Six XELOX
patients reported 8 late toxicities: bowel obstruction (G4, n=1), malignant fistula (G4,
n=1), neuropathy (G3, n=2), impaired bladder function (G3, n=1), pulmonary
embolism (G3, n=1), pain (G3, n=1), and blepharospasm (G3, n=1). Three patients in
 7

the observation arm reported 3 late toxicities: angina (G3, n=1), back pain (G3, n=1),
and poor bowel control (G3, n=1).

Efficacy
The median follow-up was 44.8 months, censoring those who had died. Only two
local recurrences have been observed. There were 16 (27.2%) observation and 12
(22.2%) XELOX patients who had relapsed or died, with 3-year DFS of 71.3% and
77.5% respectively. The hazard ratio (HR) for DFS was 0.80 (95% CI: 0.38-1.69;

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p=0.56), in favour of XELOX (FIGURE 2A). The observed 3-year DFS rates were
higher than expected (40-50% from the sample size calculation), and the hazard ratio
was close to the target value of 0.75. The HR after adjusting for factors that are
imbalanced in Table 1 was 0.84 (95% CI: 0.37-1.93, p=0.69).

Fifteen patients died, 7 observation (11.9%; rectal cancer (n=6), rectal & breast cancer
with brain metastases (n=1)) and 8 XELOX (14.8%; rectal cancer (n=6),
chemotherapy-related (n=1), pharyngeal tumour (n=1)), with 3-year OS of 87.8% and
88.8% respectively. The HR for OS was 1.18 (95% CI: 0.43-3.26; p=0.75) in favour
of observation only (FIGURE 2B). The HR after adjusting for factors that appear
imbalanced in Table 1 was 1.42 (95% CI: 0.44-4.52, p=0.55).

Discussion

The Chronicle trial is unique in comparing XELOX postoperatively against

observation alone in LARC treated with preoperative chemoradiation. Results show
that after a median follow-up of 44.8 months, the 3-year DFS rate was 78% with
XELOX and 71% with observation (HR for DFS, 0.80; 95% CI: 0.38-1.69; p=0.56).
Hence no statistically significant benefit of adjuvant XELOX chemotherapy was
found, but the study was underpowered with only 113 patients reducing the planned
power of 85% to <20% for the primary endpoint.

We did not specify baseline clinical stage as an eligibility criterion; following the
CR07 trial, most patients in the UK with resectable LARC received short course
preoperative radiotherapy (5x5Gy). Chemoradiation tended to be given for fixed or
unresectable cancers.
 8

Based on results of a meta-analysis in colon cancer14, it is assumed chemotherapy

should start as soon as possible following surgery, and not be delayed beyond 3
months. In the Chronicle study, the median time from surgery to randomisation was 8
weeks. Compliance to postoperative chemotherapy was poor. Only 26 patients
(48.1%) received the planned six cycles. This finding is consistent with other studies.

The Chronicle trial benefits from high levels of complete data, pathologic verification,

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and mature follow-up of individuals within the trial.Yet few patients were actually
accrued from a large number of recruiting centres, which meant that patients receiving
XELOX were not well-matched for individual prognostic factors versus those in the
observation arm. In particular, the two study groups differed slightly in the number of
patients achieving a pathological CR, because patients were randomly assigned using
blocked stratification by nodal status and surgeon (82 surgeons, for only 113/800
patients). However, outcomes are similar even after adjusting for these differences.

By restricting eligibilty to patients with a CRM>1mm, we selected patients with more

favourable outcomes because non-responders to CRT were effectively excluded. This
factor might explain the paucity of relevant events such as low local recurrence rate.

The evidence-base for postoperative adjuvant chemotherapy in LARC is scanty. A

phase III Japanese trial of oral UFT15 in 274 patients, suggests an advantage to
postoperative adjuvant chemotherapy in rectal cancer although no NCRT was given
and surgery involved bilateral lateral pelvic lymph node dissection. A recent meta-
analysis16 of 21 randomised controlled trials in 9221 patients, examined postoperative
chemotherapy and showed a significant benefit in terms of DFS (HR=0.75,CI: 0.68-
0.83) and OS (HR=0.83, CI: 0.76-0.91) for patients with rectal cancer administered
postoperative fluoropyrimidine-based chemotherapy (without oxaliplatin) as
compared to observation alone. However, only 3 studies11,17,18 included patients who
had received preoperative radiotherapy. In the largest EORTC 22921 study11,19 in
1011 patients with T3/T4 resectable there was no significant benefit in terms of DFS
or OS from the addition of postoperative FUFA.
 9

A Korean study randomised 320 patients (161 to 5FU, 159 to FOLFOX) with ypstage
II and III rectal cancer following CRT20. After a median follow-up of 22.5 months,
estimated 2-year DFS rate was 82.0% in FOLFOX and 69.4% in the 5FU arm
(HR=0.46; 95% CI, 0.28-0.76, p=0.002).

There is a well-recognised problem of delivery and compliance to chemotherapy

following preoperative CRT and surgery, because of slow recovery and healing, poor
tolerance, marked dose reductions and patient reluctance – affecting at least 40% of

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patients10,11,21. The Chronicle trial demonstrates only 48% of patients allocated
chemotherapy completed 6 cycles.

In contrast, compliance to chemotherapy in the preoperative setting is high22 and

delivered more easily than postoperative23, enabling full systemic doses of
chemotherapy to be delivered at an early stage rather than a delay of up to 18 weeks
associated with CRT.

Unpublished studies
The Eastern Cooperative Oncology Group (E3201) trial closed after 225 patients of
the planned 3150 had been enrolled, when the GI Intergroup developed an alternative
trial with bevacizumab (E5204). An updated analysis24 showed no difference in OS
between patients who received 5FU alone, oxaliplatin-based or irinotecan-based
adjuvant therapy. The follow-on E5204 trial aimed to randomise 2100 patients
between modified FOLFOX 6 with or without bevacizumab but closed in 2009.

The PETACC 6 (1094 patients)25 and the German ARO/CAO/AIO-04 trials (1259
patients)26 may provide further evidence regarding the role of postoperative FOLFOX
(ARO/CAO/AIO-04) or XELOX (PETACC 6) versus adjuvant 5FU/capecitabine
alone.

The Dutch CKTO/2003-16/PROCTOR/SCRIPT study initially randomised patients

after short course preoperative radiotherapy (5x5Gy) to capecitabine or control, but
was amended to include preoperative chemoradiation. Preliminary results in 470 of
the 840 originally intended patients, show the 3-year DFS was 67.4% for
chemotherapy versus 66.1% for observation (HR 0.835, 95% CI: 0.61-1.13 p=0.24)27.
 10

In Chronicle there were sufficient centres open, but the high rate of refusals to take
part reflects lack of equipoise on the part of oncologists and strong preferences by
patients for no further treatment following CRT. This is a well-recognised problem in
non-blinded randomised trials and is unlikely to be due to a specific feature of rectal
cancer.

Conclusion

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The Chronicle trial did not detect a significant difference in DFS or OS for adjuvant
XELOX. No definitive conclusion can be drawn from a trial with inadequate
numbers, poor compliance and insufficient statistical power. We remain unsure of the
advantage of additional adjuvant chemotherapy following CRT, either in terms of
5FU alone or combined with oxaliplatin, and of specific subgroups who might benefit
most/least. Although unable to provide a definitive result, this trial in terms of the
hazard ratio of 0.80 for DFS (95% CI: 0.38-1.69), can contribute to future reviews and
meta-analyses.

The poor compliance to oxaliplatin containing chemotherapy in the postoperative

setting following chemoradiation therefore supports the hypothesis that neoadjuvant
chemotherapy – as piloted in the UK BACCHUS Study (NCT01650428) and the US
NCCTG N1048 PROSPECT trial (NCT01515787) - might prove a more effective
strategy.
 11

Acknowledgements

The Chronicle trial was conducted across the National Cancer Research Network, and

funded by Cancer Research UK - grant award no C10568/A4148. We would like to

acknowledge Wendy Wood and Patricia Henley for trial coordination. Capecitabine

and Oxaliplatin were supplied free of charge by Roche and Sanofi-Aventis

respectively.

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Recruiting hospitals and investigators: Dr Samuel, Aberdeen Royal Infirmary; Dr

Sothi, Alexandra Hospital (Redditch); Dr McDonald, Beatson Oncology Centre; Dr

Geh, Birmingham Heartlands Hospital; Dr Susnerwala, Blackpool Victoria Hospital;

Dr Falk, Bristol Royal Infirmary; Dr Lowdell, Charing Cross Hospital; Dr Myint,

Clatterbridge Hospital; Dr Sebag-Montefiore, Cookridge Hospital; Dr Wadsley,

Doncaster Royal Infirmary; Dr Sizer, Essex County Hospital; Dr Biswas, Furness

General Hospital; Dr Glaholm, Good Hope Hospital; Dr Soomal, Ipswich Hospital;

Dr Churn, Kidderminster Hospital; Dr Hartley, Manor Hospital; Dr Glynne-Jones,

Mount Vernon Hospital; Dr Osborne, North Devon District Hospital; Dr Bridgewater,

Princess Alexandra Hospital; Dr Maraveyas, Princess Royal Hospital; Dr Geh, Queen

Elizabeth Hospital (Birmingham); Dr Dobrowsky, Queen Elizabeth Hospital

(Gateshead); Dr Kulkarni, Queen's Hospital; Dr Whillis, Raigmore Hospital; Dr

Wilson, Royal Albert Edward Infirmary; Dr Osborne, Royal Devon and Exeter

Hospital; Dr Biswas, Royal Lancaster Infirmary; Dr Awwad, Royal Shrewsbury

Hospital; Dr Hamilton, Scarborough Hospital; Dr Hamid, Scunthorpe General

Hospital; Dr Bateman, Southampton General Hospital; Dr Tsang, Southend Hospital;

Dr Myint, Southport and Formby DGH; Dr Cottrill, St Bartholomew's Hospital; Dr

O'Callaghan, St Mary's Hospital (Portsmouth); Dr Pedley, Sunderland Royal Hospital;

 12

Dr Ledermann, UCLH (Middlesex Hospital); Prof Maughan, Velindre Hospital; Dr

Riddle, West Middlesex University Hospital; Dr Wadsley, Weston Park Hospital; Dr

Hochhauser, Whittington Hospital; Dr Weaver, Wycombe Hospital; Dr Falk, Yeovil

Hospital.

RGJ has received honoraria and research funding from Roche, Sanofi-Aventis and

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Merck KgaA. DSM has received research funding from Roche and Sanofi-Aventis.

All remaining authors have declared no conflicts of interest.

 13

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 16

Figure 1. CONSORT diagram

Figure 2. (A) Disease-free and (B) overall survival curves according to treatment
arms in all patients – ITT Population

Table 1. Baseline Characteristics – ITT Population

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Table 2. Compliance to Chemotherapy – ITT Population

Table 3. Reported Grade 3 or 4 Toxicities – Safety Population

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Table 1. Baseline Characteristics – ITT Population

Follow-up only Capecitabine + Oxaliplatin

Variable
(n = 59) (n = 54)

median (IQR) median (IQR)

Age at random assignment, years 58.0 (52.0 – 65.0) 59.0 (55.0 – 66.0)
Time from chemotherapy to surgery, weeks 9.2 (7.4 – 11.4) 8.7 (7.1 – 11.7)
Time from radiotherapy to surgery, weeks 8.9 (7.1 – 10.6) 8.5 (7.1 – 11.9)
Time from surgery to randomisation, weeks 8.7 (7.3 – 10.6) 8.9 (7.0 – 10.6)

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No. (%) No. (%)
Gender
Female 20 (33.9) 10 (18.5)
Male 39 (66.1) 44 (81.5)
WHO performance status
0 37 (62.7) 33 (61.1)
1 22 (37.3) 21 (38.9)
Tumour site
Lower (0 – 4.9cm) 30 (50.9) 25 (46.3)
Middle (5 – 9.9cm 16 (27.1) 17 (31.5)
Upper (10 – 15cm) 13 (22.0) 12 (22.2)
Tumour stage (ypT)
T0 1 (1.7) 8 (14.8)
T1 2 (3.4) 2 (3.7)
T2 14 (23.7) 15 (27.8)
T3 38 (64.4) 27 (50.0)
T4 4 (6.8) 2 (3.7)
Nodal status (ypN)
N0 31 (52.4) 44 (81.5)
N1 23 (39.0) 7 (13.0)
N2 5 (8.5) 3 (5.6)
Surgical technique
Abdomino-perineal resection 21 (36.2) 25 (47.2)
Anterior resection 31 (53.4) 27 (50.9)
Low Hartmann's 3 (5.2) 0 (0.0)
Other 3 (5.2) 1 (1.9)
Missing 1 1

NB: the apparent imbalance for some of the baseline characteristics (e.g. gender) is due to chance:
patients were randomly assigned by blocked stratification using nodal status and surgeon, but with 82
surgeons there were many randomisation ‘cells’, and with only 113 recruited patients out of the target of
800, this method of randomisation can produce chance imbalances.
Table 2. Compliance to Chemotherapy – ITT Population

Capecitabine + Oxaliplatin
Variable Cycle
(n = 54)

No. (%)

Number of cycles received 0 3 (5.6)

1 12 (22.2)
2 3 (5.6)
3 2 (3.7)

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4 5 (9.3)
5 2 (3.7)
6 26 (48.1)
missing 1 (1.9)

Dose delay 1 6 (11.1)

2 1 (1.9)
3 6 (11.1)
4 9 (16.7)
5 9 (16.7)
6 4 (7.4)
Any dose delay 21 (38.9)

Dose reduction 1 8 (14.8)

2 3 (5.6)
3 2 (3.7)
4 6 (11.1)
5 4 (7.4)
6 1 (1.9)
Any dose reduction 21 (38.9)

median (IQR)

Total dose Capecitabine given, mg/m2 96923 (28290, 160000)

Total dose Oxaliplatin given, mg/m2 601 (130, 769)

Table 3. Reported Grade 3 or 4 Toxicities – Safety Population

Capecitabine + Oxaliplatin
Variable
(n = 50)

No. (%)

Any toxicity (each patient counted once) 20* (40.0)

Diarrhoea 8 (16.0)
Fatigue 6 (12.0)
Nausea 4 (8.0)

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Neuropathy:sensory 4 (8.0)
Hand-Foot reaction 3 (6.0)
Vomiting 3 (6.0)
Anorexia 1 (2.0)
Clumsiness 1 (2.0)
Febrile neutropenia 1 (2.0)
Granulocytes 1 (2.0)
Pain - abdomen 1 (2.0)
Paraesthesiae/dyaesthesiae 1 (2.0)

* Grade 4 = 3 patients (6.0%): Diarrhoea (n=1), Neuropathy:sensory (n=2)