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European Journal of Cancer (2013) xxx, xxx– xxx
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A randomised phase III intergroup trial comparing high-dose
infusional 5-fluorouracil with or without folinic acid with
standard bolus 5-fluorouracil/folinic acid in the adjuvant
treatment of stage III colon cancer: The Pan-European Trial
in Adjuvant Colon Cancer 2 study
Claus-Henning Köhne a,⇑, Laurent Bedenne b, Alfredo Carrato c, Olivier Bouché d,
Ivan Popov e, Losa Gaspà f, Manuel Valladares g, Phillipe Rougier h, Christiane Gog i,
Peter Reichardt j, Jacques Wils k, Francesco Pignatti l, Frank Biertz m
a
Department of Oncology and Hematology, Klinikum Oldenburg, European Medical School Oldenburg/Groningen, Carl von Ossietzky University,
Oldenburg, Germany
b
CHU de Dijon – Complexe du Bocage, Faculté de Medecine, 1, Bd Jeanne d’Arc, F-21079 Dijon Cedex, France
c
Hospital General Universitario de Elche, Servicio Oncologia Médica, Huertos y molinos s/n, 3203 Elche (Alicante), Spain
d
University Hospital of Reims, Hôpital Robert Debré, Rue du Général Koënig, 51092 Reims Cedex, France
e
Institute for Oncology and Radiology, Department for Medical Oncology, Pasterova 14, Belgrade, Serbia
f
Consorci Creu Roja a Catalunya, Servicio de Oncologı́a Médica, Barcelona, Spain
g
Complejo Hospitalario Juan Canalejo Marı́timo de Oza, Department of Medical Oncology, Paseo de las Jubias de Arriba, 84, 15006 La Coruña, Spain
h
Hopital Ambroise Paré, Serv. De Hepato-Gastroent. Concologie digestive, 9, Avenue Charles de Gaulle, 92104 Boulogne Cedex, France
i
Klinikum der J.W. Goethe Universität, Klinik für Allgemein- und Gefäßchirurgie, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany
j
Helios-Klinikum Bad Saarow, Pieskower Str. 33, 15526 Bad Saarow, Germany
k
Laurentius Hospital, Mgr. Driessenstraat 6; 6043 CV Roermond, The Netherlands
l
The European Medicines Agency (EMA) 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom
m
Medical School of Hannover, Department of Biomedical Statistics, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
KEYWORDS
Colon cancer
Adjuvant treatment
5-Flurouracil
Abstract Purpose: To investigate whether infusional high-dose 5-flurouracil (HD-FU) provides a significant improvement in recurrence-free survival (RFS) and overall survival (OS)
compared with a standard bolus 5-FU regimen (Mayo Clinic) in patients with curatively
resectable stage III colon cancer.
⇑ Corresponding author: Address: European Medical School Oldenburg/Groningen, Carl von Ossietzky University of Oldenburg, Klinikum
Oldenburg gGmbH, Department of Oncology and Hematology, Rahel-Straus-Str. 10, 26133 Oldenburg, Germany. Tel.: +49 441 403 2611; fax:
+49 441 403 2654.
E-mail address: [email protected] (C.-H. Köhne).
0959-8049/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejca.2013.01.030
Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http://
dx.doi.org/10.1016/j.ejca.2013.01.030
2
C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx
Bolus
Infusional
High-dose
Methods: Patients (n = 1601) were randomised to receive either the Mayo Clinic regimen or
one of the three HD-FU regimens; LV5FU2, the Arbeitsgemeinschaft Internistische Onkologie (AIO) or the Grupo Espaňol para el Tratamiento Digestivos (TTD), the data from which
were combined to provide the HD-FU arm for final analysis.
Results: Patients were evenly balanced for age, TMN, tumor grade and vascular and lymphatic invasion. Median follow-up was approximately 42 months, RFS (hazard ratio
[HR] = 0.997) and OS (HR = 0.96) (primary end-point) were not statistically different
between the two treatment arms. Infusional HD-FU was generally better tolerated than bolus
5-FU regimen.
Conclusions: Infusional HD-FU does not improve RFS and OS in curatively resected stage III
colon cancer patients compared to the Mayo Clinic regimen, but is less toxic.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Colorectal cancer (CRC) is the third most frequent
cancer in women and the fourth in men and accounted
for 500,000 deaths worldwide in 2002.1 Approximately
50% of patients with stage III colon cancer experience
a tumor recurrence following curative surgery, with 5year survival rates of 59.5% having been reported.2 A
study in the late 1980s reported a reduction in the mortality rate of 33% following the administration of an
intravenous (i.v.) bolus of 5-fluorouracil (5-FU) and levamisole in the adjuvant treatment of stage III colon cancer.3 Subsequent investigations confirmed bolus 5-FU
plus either high-dose folinic acid (FA) (weekly Roswell
Park schedule) or low-dose FA (Mayo-Clinic regimen)
administered for 6 months to be the accepted standard
treatment for adjuvant colon cancer.4–8
5-FU is active against cells in S-phase, inhibiting thymidylate synthase a key enzyme involved in DNA synthesis.9 The plasma half-life of the drug is relatively
short (approximately 11-min) thus with bolus injections
only a small proportion of tumor cells can be assumed
to be susceptible.10 This has provided a rationale for
the use of continuous infusion (CI) of 5-FU (usually
delivered over 24 h or 48 h periods) instead of bolus
injections in the treatment of colon cancer. In the adjuvant setting studies investigating CI 5-FU have reported
similar efficacy but reduced toxicity when compared
with standard bolus 5-FU.11,12 An added advantage of
using infusional 5-FU-based therapy over 5-FU delivered as a bolus is that a higher-dose intensity of the drug
can be achieved. It has been suggested that 4–5 times
more 5-FU can be administered and that infusional
high-dose 5-flurouracil (HD-FU) and bolus 5-FU
behave as different drugs with different mechanisms of
cytotoxicity in colon cancer.13 Randomised studies have
reported higher response rates in metastatic CRC
(mCRC) patients receiving HD-FU modulated by FA,
compared to patients receiving standard dose bolus 5FU/FA therapy.14–17 The administration of a HD-FUbased regimen (LV5FU2) in comparison with 5-FU
(15 min infusion) and FA was reported to show no difference in efficacy, but confirmed the value of LV5FU2
as a control arm in multicentre international studies
investigating the efficacy of oxaliplatin and irinotecan
in combination with 5-FU/FA in the adjuvant treatment
of colon cancer.18–20 Indeed the LV5FU2 regimen is the
recommended choice for combination with oxaliplatin
(FOLFOX) for the adjuvant treatment of colon cancer
following data from the MOSAIC trial in which a significant increase in 3-year disease-free survival (DFS) rate
(78.2% versus 72.9%) was first demonstrated with this
combination in patients compared to those receiving
LV5FU2 alone.20 The 5-year DFS rate was maintained
and a significant improvement in overall survival (OS)
reported in patients with a median follow up of 6 years
in an update of this study.21
We describe a large randomised intergroup trial that
compares the efficacy and the toxicity of HD-FU regimens with the standard Mayo bolus 5-FU regimen
(Mayo-Clinic), in the adjuvant treatment of patients
with stage III adenocarcinoma of the colon following
complete resection of their disease. Patients were
recruited and randomised from centres within participating European co-operative groups namely the Arbeitsgemeinschaft Internistische Onkologie (AIO), the
Foundation Francßaise de Cancérologie Digestive
(FFCD), the Grupo Espaňol para el Tratamiento
Digestivos (TTD) and the European Organization for
Research and Treatment of Cancer (EORTC). The
whole study was coordinated within the framework of
the Pan-European Trials in Adjuvant Colon Cancer
(PETACC-2).
2. Patients and methods
2.1. Patient eligibility
Patients eligible for study inclusion were those with
UICC (International Union Against Cancer) stage III,
histologically confirmed adenocarcinoma or mucinous
adenocarcinoma of the colon who had undergone curative radical resection (R0) within the 8 weeks prior to
randomisation. Patients were required to be P18 years,
with a World Health Organization (WHO) performance
status (PS) of 1 or less, with adequate bone marrow
Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http://
dx.doi.org/10.1016/j.ejca.2013.01.030
C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx
(leukocytes P3.5 109/l, platelets P100 109/l,
Hb > 10 g/l), liver and renal function (total bilirubin
62 mg % = 34 lmol/1; serum creatinine 61.5 mg
% = 150 lmol/l). Patients with a history of familial
adenomatous polyposis or other hereditary syndromes
(Gardner’s, Turcot’s Hereditary Non-Polyposis Coli),
Crohn’s disease or ulcerative colitis were excluded.
Patients were also excluded if they had any prior history of malignant disease (excluding adequately treated basal cell carcinoma of the skin and cervical
cancer) within the previous 10-years, prior chemotherapy or radiotherapy for colon cancer, or any other
severe concomitant disease (e.g. coronary heart disease, uncontrolled infection), as were those with
known allergy to FA. Pregnant or lactating patients
and fertile patients who could not ensure adequate
contraception up to 6 months following completion
were also excluded from the study. The study was
conducted in compliance with the ethical principles
of the Declaration of Helsinki (1964) as amended in
South Africa (1996). Written informed consent was
obtained prior to the initiation of protocol procedures
from participating institutions, which granted ethical
approval according to their national legislation.
2.2. Study design
This was a randomised, intergroup phase III trial
to investigate whether infusional HD-FU regimens
were superior to bolus 5-FU and FA in patients with
resectable stage III colon cancer. The main study endpoints were recurrence-free survival (RFS) and OS
and the secondary end-point was to assess safety. Eligible patients were randomised at the National Data
Centers (NDC) of the participating co-operative
groups namely AIO, FFCD, TTD and EORTC.
Patients were randomised to receive either the
Mayo-Clinic regimen; days 1–5 of a 4-week cycle,
DL-FA, 20 mg/m2, 5-FU, 370–425 mg/m2 i.v. bolus
for 6-cycles or one of three HD-FU regimens specific
to the geographical region of the NDC. All patients
within a participating institution that were randomised
to the HD-FU arm received the same HD-FU regimen. HD-FU regimens included, HD-FU alone (the
Spanish TTD regimen); day 1, 5-FU, 3500 mg/m2 continuous infusion for 48 h, given weekly during an 8week cycle for 3-cycles or HD-FU plus FA (the German AIO regimen); day 1, FA, 500 mg/m2 i.v. 2-h
infusion, followed by 5-FU, 2600 mg/m2 i.v. 24-h infusion, given weekly during a 6-week cycle for 3-cycles
or the LV5FU2 schedule (the French de Gramont regimen); day 1–2 of a 2-week cycle, DL-FA, 200 mg/m2
2-h infusion, followed by 5-FU, 400 mg/m2 i.v., bolus,
followed by 5-FU, 600 mg/m2 22-h i.v., for 12-cycles.
Patients randomised through the EORTC received
one of the three HD-FU regimens as predefined by
3
centres. Treatment was administered within 8 days of
randomisation for the number of cycles scheduled
for each regimen and stopped early in cases of unacceptable toxicity, disease recurrence, withdrawal of
consent or the loss of subjects to follow-up.
A single independent data monitoring committee
(IDMC) annually examined data from interim analyses
and safety evaluations from the study and advised the
PETACC-2 coordinating unit of any necessary actions.
2.3. Baseline and response evaluation
Prior (within 2-weeks) to randomisation a complete
patient medical history and blood count were undertaken and an ECG, chest X-ray, abdominal scan and
colonoscopy performed. During treatment, prior to each
cycle, a physical examination, blood count and blood
biochemistry were undertaken and an evaluation of toxicity performed. Patients were evaluated for tumor
recurrence during follow-up, at least every 6 months
until final analysis (3 years after randomisation of the
last patient) and yearly thereafter until death. Tumor
recurrence was assessed primarily on radiological evidence (X-ray, ultrasound). Toxicity in the form of
adverse events (AE) was evaluated according to the
National Cancer Institute of Canada Common Toxicity
Criteria (NCIC-CTC).
2.4. Statistical analysis
Patients were assigned to treatment arms using the
minimisation technique22 and stratified by institution
and regional lymph nodal status N1 (1–3 pericolic
lymph nodes) versus N2 (>3 pericolic lymph nodes).
Patient sample sizes were calculated assuming 5-year
survival in the control arm (5-FU/FA) to be 67%, it
was estimated that an approximate total of 424 events
were required to detect an absolute difference of 7%,
which is equivalent to a 5-year survival of 74% for the
HD-FU arm, with a power of 90% allowing for onesided type I error of 5%. Assuming 3 years of recruitment and 3 years of follow-up (median follow-up of
4.5 years) it was estimated that approximately 1600
patients were required for randomisation between the
treatment arms. The analysis of efficacy (RFS and OS)
was conducted in the intent-to-treat population (all randomised) patients. Safety data were presented for all
patients treated according to the actual treatment
received. Time to event data (RFS and OS) were measured from the date of randomisation; patients not experiencing an event were censored at the most recent date
of analysis. RFS was defined as date from randomisation to recurrence or death, which ever occurred first
and survival time was defined as date from randomisation to death. In the main statistical analysis,
survival curves were estimated using the Kaplan–Meier
Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http://
dx.doi.org/10.1016/j.ejca.2013.01.030
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technique and differences in duration of survival compared using the one-sided log-rank test and the 0.05 level
of significance. For both RFS and survival on treatment
comparison was made between bolus 5-FU/FA versus
all combined HD-FU arms. In exploratory statistical
analysis, the main analysis was performed on eligible
patients only, retrospective stratification and Cox proportional hazard model were used to adjust for confounding variables in all randomised patients and
eligible patients only. Safety data on the different infusional schedules were evaluated and compared using
the Kruskal–Wallis test.
3. Results
3.1. Patient characteristics
A total of 1601 patients were recruited from 169
European centres between March 1999 and March
2004 and randomised to receive bolus 5-FU/FA
(n = 804) or a HD-FU regimen (n = 797). Details of
patient disposition are shown in Fig. 1. Five patients
recruited to receive HD-FU receive bolus 5-FU and four
patients recruited to receive bolus 5-FU/FA received
HD-FU. AIO recruited 669 patients, EORTC 188,
FFCD 417 and TTD 327. Patient and disease characteristics at baseline are summarised in Table 1. Greater
than 50% of patients were male in both treatment arms
and both groups were well balanced with respect to
patient age, tumor stage and tumor grading (Table 1).
Removal and analysis of lymph nodes were balanced
between both arms with greater than 50% of patients
having between 10 and 19 nodes removed and examined.
No difference in lymph node involvement was detected
between the treatment arms with greater than 90% of
patients in both arms demonstrating less than 10
invaded nodes. Vascular and lymphatic vessel invasion
were also balanced between the treatment groups
(Table 1). No differences were observed in these characteristics when patients were stratified by co-operative
group (data not shown).
3.2. Recurrence-free survival and overall survival
The efficacy data for patients receiving bolus 5-FU/
FA or HD-FU regimens are summarised in Table 2.
The median follow-up was similar for both treatment
arms, 41.6 months for patients receiving bolus 5-FU/
FA and 41.8 months for those receiving a HD-FU regimen. Median RFS and OS times were not achieved for
either arm at the time of analysis. No differences were
observed in RFS between the two treatment arms
(HR = 0.997, p = 0.98) (Fig. 2), 3-year and 5-year
RFS rates were also similar (Table 2). No differences
in OS were observed between the two treatment arms
(HR = 0.96, p = 0.74) (Fig. 3), with 5-year survival rates
of 78.9% observed in both arms (Table 2).
3.3. Treatment toxicity
Grade 3/4 AEs are summarised in Table 4. Grade 3/4
leucopenia was significantly more common in patients
receiving bolus 5-FU than in patients receiving HDFU regimens (6.9% versus 2.1%) as was stomatitis
(9.7% versus 3.1%). In contrast grade 3/4 hand–foot
syndrome was significantly more common in patients
receiving a HD-FU regimen than in those patients
receiving bolus 5-FU/FA (4.2% versus 0.4%). The total
serious adverse events were similar between the two
treatment arms (data not shown), 14.5% in patients
receiving bolus 5-FU/FA in which nine patients died
Total number of recruited patients
(intend to treat population)
(N=1601)
Treated patients
Bolus 5-FU/FA
N=804
64 patients did not
receive any
treatment
Randomised by participating
cooperative group
AIO
n=669
FFCD
n=417
TTD
n=327
EORTC
n=188
Treated patients
HD FU
N=797
AIO regimen n= 341
FFCD regimen n=262
TTD regimen n=182
Unknown
n=12
64 patients did not
receive any
treatment
Fig. 1. Disposition of patients. Patient numbers according to randomisation and treatment received are shown. Abbreviations: AIO,
Arbeitsgemeinschaft Internistische Onkologie; EORTC, European Organization for Research and Treatment of Cancer; FFCD, Fédération
Francophone de Cancérologie Digestive; TTD, The Grupo Espaňol para el Tratamiento de Tumores Digestivos.
Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http://
dx.doi.org/10.1016/j.ejca.2013.01.030
C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx
Table 1
Characteristics of randomised patients.
5
Table 2
Efficacy data.
Bolus 5-FU/FA
N = 804
High-dose 5-FU
N = 797
Co-operative group, n
AIO
EORTC
FFCD
TTD
338
96
206
164
331
92
211
163
Age (years)
Median
Range
64
22–90
64
24–83
Gender, n (%)
Male
Female
429 (53.4)
375 (46.6)
434 (54.7)
363 (45.5)
WHO performance statusa
0
307 (65.9)
1
159 (34.1)
312 (67.0)
154 (33.0)
Grading
G1
G2
G3
G4
Low (G1–G2)
High (G3–G4)
Unknown
161 (20.0)
496 (61.7)
125 (15.5)
9 (1.1)
5 (0.6)
0 (0)
8 (1.0)
153 (19.2)
471 (59.1)
147 (18.4)
8 (1.0)
3 (0.4)
2 (0.3)
13 (1.6)
pTMN
T1
T2
T3
T4
Tis/Tx
17 (2.1)
65 (8.1)
583 (72.5)
138 (17.2)
1 (0.1)
10 (1.3)
63 (7.9)
594 (74.5)
129 (16.2)
1 90.1)
Bolus 5-FU/FA
HD-FU
RFSa
3-year RFS, %
5-year RFS, %
Hazard ratio [95% CI]
Log-rank p-value
N = 804
63.0
67.1
N = 797
67.0
62.7
OSa
3-year OS, %
5-year OS, %
Hazard ratio [95% CI]
Log-rank p-value
N = 804
84.5
78.9
0.997 [0.84–1.18]
0.98
N = 797
85.0
78.9
0.96 [0.78–1.20]
0.74
Abbreviations: RFS, recurrence-free survival, OS, overall survival; FU,
5-fluorouracil; FA, folinic acid.
a
Median values not reached.
Recurrencefree survival
(recurrence of death)
1,00
therapy arm
infusional
bolus
0,75
0,50
HR 0.997 [0.84 - 1.18]
Lymph nodes removed
<10
>10
155 (19.3)
647 (80.7)
160 (20.1)
635 (79.9)
Lymph nodes invaded
<10
>10
753 (93.7)
51 (6.3)
745 (93.6)
51 (6.4)
0,00
Lymphatic vessels invaded
No
341 (47.4)
Yes
223 (31.0)
Unknown
156 (21.7)
322 (44.8)
256 (35.6)
141 (19.6)
Vascular invasion
No
Yes
Unknown
444 (55.7)
145 (18.2)
208 (26.1)
446 (55.5)
136 (16.9)
222 (27.6)
0,25
Abbreviations: AIO, Arbeitsgemeinschaft Internistische Onkologie,
EORTC, European Organization for Research and Treatment of Cancer, FFCD, Fédération Francophone de Cancérologie Digestive, TTD,
The Grupo Espaňol para el Tratamiento de Tumores Digestivos; FU, 5fluorouracil, FA, folinic acid; WHO, World Health Organization.
a
Available for EORTC, FFCD and TTD recruited patients only.
(1.1%) and 15.8% in patients receiving a HD-FU regimen in which 11 patients died (1.4%).
3.4. Sub group analysis
An exploratory subgroup analysis was performed of
RFS and OS in patients receiving different HD-FU regimens in comparison to bolus 5-FU/FA (Table 3). No
0
2
4
6
8
10
years
Fig. 2. Kaplan–Meier plots for recurrence-free survival in patients
treated with standard bolus 5-FU/FA and high-dose Infusional 5-FUbased regimen. Abbreviations: FU, fluorouracil; FA, folinic acid.
differences in RFS or OS were observed between
patients recruited in Germany receiving AIO (RFS
HR = 0.84, OS HR = 0.85) or LV5FU2 regimen in
patients recruited from France (RFS HR = 0.88, OS
HR = 0.99) compared with the bolus 5-FU/FA arms
in the corresponding geographical regions. However
RFS and OS for patients receiving high-dose 5-FU
alone (TTD) recruited in Spain was shorter (RFS
HR = 1.38, OS HR = 1.59) than observed in patients
receiving bolus 5-FU in that region, although the difference was not statistically significant (Table 3).
A subgroup analysis was also performed for toxicity
in patients stratified by the treatment regimen they
received compared to bolus 5-FU. Similar patterns of
Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http://
dx.doi.org/10.1016/j.ejca.2013.01.030
6
C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx
recruited in Germany receiving the AIO regimen and
Spain receiving the TTD regimen experienced higher
grade 3/4 diarrhoea (20.1% and 23.3%) than patients
recruited in France who received the LV5FU2 regimen
(3.5%).
Overall Survival
1,00
therapy arm
infusional
bolus
0,75
4. Discussion
0,50
HR 0.96 [0.78 - 1.2]
0,25
0,00
0
2
4
6
8
10
Years
Fig. 3. Kaplan–Meier plots for recurrence-free survival in patients
treated with standard bolus 5-FU/FA and high-dose Infusional 5-FUbased regimen. Abbreviations: FU, fluorouracil; FA, folinic acid.
grade 3/4 AE were observed when comparing specific
HD-FU regimens with bolus regimen to those observed
in the main analysis (Table 4). In comparing treatment
regimens between different geographical regions of
recruitment and randomisation, grade 3/4 leucopenia
was more frequent in patients receiving bolus 5-FU/
FA, treated in Spain (TTD, 13.7%) than in patients treated in Germany (AIO, 3.8%) or France (FFCD, 4.9%).
Stomatitis was found to be higher in patients receiving
bolus 5-FU/FA treated in Germany and diarrhoea was
more frequent in Spanish patients receiving the same
treatment. In patients receiving HD-FU regimens those
In PETACC-2 we found no statistical difference in
RFS and OS in patients with stage III colon cancer
following complete resection, treated with adjuvant
standard bolus 5-FU or one of the three infusional
HD-FU regimens. However significant differences were
demonstrated in toxicity profiles, with CI HD-FU
exhibiting significantly less haematological toxicity than
bolus treatment but significantly more hand–foot
syndrome. Our findings confirm previous randomised
studies which also demonstrated no statistical difference
in DFS and OS but more favourable toxicity with
CI 5-FU compared with a standard bolus 5-FU regimen.11,12,19,23 Furthermore our data substantiate the
findings from investigations that promote LV5FU2 as
the regimen of choice for the control arm in randomised
studies to assess the efficacy of combinations of irinotecan and oxaliplatin in adjuvant colon cancer.11,20
We had the opportunity to compare the efficacy and
the safety of three different HD-FU regimens to bolus
5-FU therapy in a subgroup analysis of patients stratified by randomising institution. The HD-FU regimens
included the weekly 24-h infusion German AIO regimen
that has demonstrated improvement efficacy over bolus
5-FU in mCRC patients16 and has been used in adjuvant
colon cancer although not in direct comparison with
bolus 5-FU.18 The semi-monthly French LV5FU2 regimen and the Spanish high-dose 5-FU were administered
as a 48-h weekly infusion alone, both of which had been
shown to demonstrate efficacy and to be tolerable in the
adjuvant setting.15,23 This analysis should be regarded as
Table 3
Efficacy data in patients stratified by treatment-regimen.
Treatment
RFS
OS
Patient number
HR [95%CI]
p-Value
Patient number
HR [95% CI]
p-Value
AIOa
Bolus FU/FA
HD-FU/FA
338
331
0.84 [0.64–1.11]
0.41
338
331
0.85 [0.59–1.2]
0.36
FFCD
Bolus FU/FAb
LV5FU2a
206
211
0.88 [0.65–1.19]
0.22
206
211
0.9 [0.63–1.30]
0.55
TTDa
Bolus FU/FA
HD-FU
164
163
1.38 [0.94–2.02]
0.09
164
163
1.59 [0.93–2.7]
0.085
Abbreviations: AIO, Arbeitsgemeinschaft Internistische Onkologie; FFCD, Fédération Francophone de Cancérologie Digestive; TTD, The Grupo
Espaňol para el Tratamiento de Tumores Digestivos; FU, 5-fluorouracil; FA, folinic acid; HR, hazard ratio; CI, confidence interval.
a
Median values not reached.
b
Median recurrence-free survival = 5.16 months.
Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http://
dx.doi.org/10.1016/j.ejca.2013.01.030
C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx
Table 4
Grade 3/4 adverse events in treated patients.
Bolus 5-FU/FA
N = 740
High-dose-FU
N = 733
8 (1.1%)
51 (6.9%)
6 (0.8%)
119 (16.1%)
72 (9.7%)
3 (0.4%)
5 (0.7%)
15 (2.1%)
4 (0.6%)
106 (14.5%)
23 (3.1%)
31 (4.2%)
Randomising Centre n (%)
AIO, n (%)
Anaemia
Leucopenia*
Thrombocytopenia
Diarrhoea
Stomatitis*
Hand–foot syndrome*
N = 292 (39.5%)
1 (0.3%)
11 (3.8%)
3 (1.0%)
50 (17.1%)
41 (14.0%)
1 (0.3%)
N = 289 (39.4%)
2 (0.7%)
4 (1.4%)
1 (0.3%)
58 (20.1%)
9 (3.1%)
16 (5.5%)
EORTC, n (%)
Anaemia
Leucopenia*
Thrombocytopenia
Diarrhoea
Stomatitis
Hand–foot syndrome
N = 84 (11.4%)
1 (1.2%)
8 (9.5%)
0 (0.0%)
6 (7.1%)
5 (6.0%)
0 (0.0%)
N = 84 (11.5%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
4 (4.8%)
1 (1.2%)
2 (2.4%)
FFCD, n (%)
Anaemia
Leucopenia*
Thrombocytopenia
Diarrhoea*
Stomatitis*
Hand–foot syndrome*
N = 203 (27.4%)
1 (0.5%)
10 (4.9%)
1 (0.5%)
22 (10.8%)
18 (8.9%)
2 (1.0%)
N = 201 (27.4%)
3 (1.5%)
4 (2.0%)
1 (0.5%)
7 (3.5%)
1 (0.5%)
3 (1.5%)
TTD, n (%)
Anaemia*
Leucopenia*
Thrombocytopenia
Diarrhoea
Stomatitis
Hand–foot syndrome*
N = 161 (21.8%)
5 (3.1%)
22 (13.7%)
2 (1.2%)
41 (25.5%)
8 (5.0%)
0 (0.0%)
N = 159 (21.7%)
0 (0.0%)
7 (4.4%)
2 (1.3%)
37 (23.3%)
12 (7.5%)
10 (6.3%)
Anaemia
Leucopenia*
Thrombocytopenia
Diarrhoea
Stomatitis*
Hand–foot-syndrome*
Abbreviations: HD-FU, high-dose 5-FU regimen; AIO, Arbeitsgemeinschaft Internistische Onkologie; EORTC, European Organization
for Research and Treatment of Cancer; FFCD, Fédération Francophone de Cancérologie Digestive; TTD, the Grupo Espaňol para el
Tratamiento de Tumores Digestivos.
*
p < 0.05.
exploratory as the patients were not randomised to
receive different HD-FU regimens within the same institutions. No significant differences were found for DFS
and OS when comparing each HD-FU regimen to bolus
5-FU/FA, however, although not statistically significant
the TTD regimen compared less favourably for RFS
(HR = 1.38) and OS (1.59) to bolus 5-FU/FA. The patterns of toxicity of each individual HD-FU regimen
compared to standard bolus 5-FU were similar to those
found in the main analysis, and support the general view
that in addition to LV5FU that AIO and TTD are more
tolerable than standard bolus 5-FU. However some different patterns of toxicity between the three HD-FU
regimens were observed with grade 3/4 diarrhoea being
7
more common in the Spanish and the German regimens
than the French treatment which was generally more
tolerable. Thus our exploratory findings support those
of the previous studies suggesting the LV5FU regimen
may be the most suitable HD-FU backbone of choice
for combination with other cytotoxic agents.11,12,19,23
Within the subgroup analysis marked differences in
the toxicity of standard bolus 5-FU/FA were noted in
the different treatment regions. Thus grade 3/4 leucopenia was more frequent in patients receiving bolus 5FU/FA, treated in Spain than in patients treated in Germany or France. Stomatitis was found to be higher in
patients receiving bolus 5-FU/FA treated in Germany
whilst diarrhoea was more frequent in Spanish patients
receiving the same treatment.
Regional differences were also observed for the oral
fluoropyrimidine capecitabine.24 This may reflect differences in the delivery of 5-FU/FA between institutions in
different countries and/or may reflect the pharmocogenetics of 5-FU activation and metabolism in different
populations.25
In summary the large pan European PETACC-2
study has demonstrated that infusional HD-FU regimens were more tolerable than traditional bolus (Mayo
Clinic) regimen but did not provide a statistically significant improvement in RFS or OS in the adjuvant treatment of patients with curatively resected stage III colon
cancer. These findings are in accordance with previous
randomised studies and confirm that infusional HDFU (particularly LVFU2 regimen) remains a treatment
option.
Conflict of interest statement
All authors have no proprietary, financial, professional or other personal interest of any nature or kind
in any product, service and/or company that could be
construed as influencing the position presented in the
manuscript entitled ‘A randomized phase III intergroup
trial comparing high-dose infusional 5-fluorouracil with
or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III
colon cancer: the PETACC-2 study’.
Acknowledgements
We would like to thank the patients who took part in
this study and all investigators who are not co-authors
from the collaborating centres who contributed patients
to this study. The manuscript has been drafted by a
medical writer (Cancer Communications and Consultancy Ltd.).
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