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ORIGINAL ARTICLE
Maurizio Cantore Æ Giovanni Serio Æ Paolo Pederzoli
Andrea Mambrini Æ Calogero Iacono
Coriolano Pulica Æ Paola Capelli Æ Mirko Lombardi
Tito Torri Æ Paola Pacetti Æ Mauro Pagani
Giammaria Fiorenti ni
Adjuvant intra-arterial 5-fluoruracil, leucovorin, epirubicin
and carboplatin with or without systemic gemcitabine
after curative resection for pancreatic adenocarcinoma
Received: 7 November 2005 / Accepted: 24 January 2006 / Published online: 22 April 2006
Ó Springer-Verlag 2006
Abstract Background: The role of adjuvant therapy in
pancreatic cancer remains cont roversial. Gemcitabine
given systemically seems to be effective; intra-arterial
chemotherapy (IAC) has a deep rationale. Patients and
methods: The goal was to evaluate the impact of post-
operative IAC followed or not by systemic gemcitabine
in patients after curative resection for pancreatic ade-
nocarcinoma. 5-fluoruracil 750 mg sqm
1
, leucovorin
75 mg sqm
1
, epirubicin 45 mg sqm
1
, carboplatin
225 mg sqm
1
were administered every 3 weeks into
celiac axis for three cycles (FLEC regimen), then gem-
citabine at the dosage of 1 g sqm
1
on days 1, 8 and 15
every 4 weeks for 3 months (FLECG regimen). Results:
Forty-seven patients entered the study. The first 24 re-
ceived only IAC (FLEC regimen), the other 23 received
the same intra-arterial regimen followed by systemic
gemcitabine (FLECG regimen). After a median follow-
up of 16.9 months, 29 patients recurred (61.7%). Med-
ian disease free survival (DFS) was 18 months and
median overall survival (OS) was 29.7 months. One-year
DFS was 59.4% and 1-year OS was 75.5%. Main grade
3 toxicity related to IAC wa s only nausea/vomiting in
4%; regarding gemcitabine, grade 3 toxicities were
anaemia 8%, leukopenia 8%, thrombocitopenia 17%,
nausea/vomiting 4%. Conclusions: FLEC regimen with
or without gemcitabine is active with a very mild toxicity
and results are very encouraging in an adjuvant setting.
Keywords Adjuvant chemotherapy Æ Gemcitabine Æ
Intra-arterial chem otherapy Æ Pancreatic cancer
Introduction
Surgery offers the only chance of cure for pancreatic
adenocarcinoma but only 10–15% of patients are suit-
able for resection due to the presence of locally advanced
or metastatic disease: the majority of patients submitted
to surgery relapses both locally and at distance with
median survival of 13–18 months and with 5-year sur-
vival at best of 15–20% [1, 2]. More radical pancreatic
resections and extended lymphadenectomy have failed
to produce significant survival advantage [3]. In the
United States, adjuvant treatment with fluoruracil-based
chemoradiation is frequently recommended even if these
data have been translated from a study of 43 patients
enrolled over 9 years [4]. In Europe a recent randomised,
widely criticised trial concluded that standard care for
patients with resectable pancreatic cancer should consist
of curative surgery followed by adjuvant systemic che-
motherapy [5 ]. Adjuvant gemcitabine seems to improve
M. Cantore Æ A. Mambrini Æ T. Torri Æ P. Pacetti Æ M. Pagani
Department of Oncology, General City Hospital,
Massa Carrara, Italy
M. Cantore (&)
Department of Oncology, Massa Carrara City Hospital,
Presidio Ospedaliero di Carrara,
Localita
`
Monterosso,
54033 Massa Carrara, Italy
E-mail: maurizio.cantore@usl1.toscana.it
Tel.: +39-0585-7672192021
Fax: +39-0585-76721417
G. Serio Æ C. Iacono
Department of Surgery C, University of Verona, Verona, Italy
P. Pederzoli
Department of Surgery A, University of Verona, Verona, Italy
C. Pulica
Department of Surgery, C. Poma General Hospital, Mantova, Italy
P. Capelli
Department of Pathology, University of Verona, Verona, Italy
M. Lombardi
Department of Surgery, Massa Carrara City Hospital,
Massa Carrara, Italy
G. Fiorentini
Department of Oncology, General City Hospital, Empoli, Italy
Cancer Chemother Pharmacol (2006) 58: 504–508
DOI 10.1007/s00280-006-0200-2
disease free survival (DFS) and even if data are not yet
mature, survival curves have separated [6]. One way of
research is oriented to find new integrated strategies and
new routes of administration able to deliver drug dose to
the tumour in order to overcome the drug resistance.
Regional chemotherapy attempts to maximise the dose
of cytotoxic agent reducing systemic side effects. Intra-
arterial chemotherapy (IAC) has been evaluated in ad-
vanced pancreatic cancer and preliminary results have
demonstrated interesting response rates and survival in
some series [7, 8].
Based on our previous trial about IAC in locally
advanced and metastatic pancreatic carcinoma [9], and
on the encouraging results of some adjuvant intra-arte-
rial phase II trials [10–12], a study of FLEC regimen
infused into celiac axis followed or not by systemic
gemcitabine in patients submitted to curative surgery for
pancreatic adenocarcinoma was started in January 1998.
In this trial we have used drugs with proven efficacy
in pancreatic cancer at conventional dose without he-
mofiltration and with a pharmacologic advantage in
terms of concentration when administered arterially [9].
Patients and methods
Patient population
Patients submitted to curative surg ery for pancreatic
adenocarcinoma entered into the study. Eligibility crite-
ria were Karn ofsky performance status > 70, white
blood cell count > 3,000 mm
3
, platelet count >
120,000 mm
3
, haemoglobin level > 10 g dl
1
; total
bilirubin and serum creatinine level were required to be
<1.5 times the institutional upper limit of normal. Pa-
tients were excluded from the stud y if they had any of the
following: concomitant second malignancy, with the
exception of treated basal cell carcinoma of the skin or
cured cervical cancer; concurrent treatment with other
experimental drugs; another serious illness or medical
condition. All patients gave their informed consent
according to our institutional guidelines and the study has
been carried out with ethical committee approval.
Study design
Three cycles of chemotherapy were administered every 3
weeks through an angiographic catheter (Simmons 2; 5
Fr) introduced via the femoral artery into celiac axis.
Each drug was diluted in 100 ml of normal saline and
then infused by bolus one after the other in the following
order: folinic acid 75 mg sqm
1
; 5-fluoruracil
750 mg sqm
1
; epirubicin 45 mg sqm
1
; carboplatin
225 mg sqm
1
. Supportive antiemetic (granisetron
8 mg) and anti-H2 blocker (famotidine 40 mg) were gi-
ven intravenously (FLEC regimen). Since June 2002 after
three cycles of locoregional therapy, gemcitabine was
infused systemically at the dosage of 1,000 mg sqm
1
weekly for 3 weeks every 4, over 3 months (FLECG
regimen). Pretreatment evaluation included medical his-
tory, a physical examination, complete blood cell count,
biochemical profile, Ca 19-9 value, ECG, and abdominal
CT scan. Blood cell count was evaluated on days 10, 14
and 18 after IAC. Before each subsequent cycle patients
underwent a physical examination, complete blood cell
count, and biochemical profile. CT scan and Ca 19-9
were repeated at the end of IAC and after systemic
gemcitabine, then every 3 months or when there was a
suspicion of recurrence. Toxic ity was graded by the
National Cancer Institute Common Toxicity Criteria
version 2.0 [13].
Statistical analysis
The aim of this prospective trial was the assessment of
feasibility of FLEC regimen given intra-arterially in
adjuvant setting with or without the sequential addition
of systemic gemcitabine (FLECG regimen).
The primary end point of the study was 1-year DFS.
The target enrolment was estimated to be 46 patients,
according to the Simon Two Stage Optimal Design [14]
with the lower proportion of interest of 40% and the
target proportion of interest of 60% (a=0.05 and
b=0.20).
The strategy would be considered to deserve further
analysis if at least 23 patients were disease free at 1 year.
DFS was defined as the interval between surgery and the
first evidence of recurrent disease or death whichever
occurred first. Overall survival (OS) was considered
from surgery to death or to the last follow-up assessment
and survival time was calculated using the Kaplan–
Meier method. Univariate analysis was used to calculate
survival probabilities in relation to clinical variables
(gender, age), tumour related variables (size, site, grad-
ing, nodal status, Ca 19-9 level) and treatment related
variables (lymph nodes dissection, resection margins,
adjuvant treatment): survival curv es were estimated with
the Kaplan–Meier method and compared by use of the
log-rank test.
Results
Since January 1998, 47 patients from four surgical
departments (two in Verona, Mantova, Carrara) were
enrolled onto the study. Patients’ characteristics are
listed in Table 1. The first group (January 1998–May
2002) included 24 patients that received only three cy-
cles of FLEC regimen, the second group (June 2002–
December 2004) included 23 patients that received also
systemic gemcitabine after three cycles of intra-arterial
chemotherapy (FLECG regimen). The median time
from surgery to chemotherapy was 45.5 days (range
29–84). A total of 137 intra-arterial cycles and
505
198 weekly gemcitabine cycles were administered. All
the patients except two completed the IAC scheduled
program: one did not because early progression of
disease and one because refusal. Nine cycles of gem-
citabine were not administered because of thombocy-
topenia in four patients.
Disease free survival and overall survival
Twenty-seven patients (57.4%) were disease free at
1 year from surgery. Median DFS and OS for the whole
series were 18 and 29.7 months, respectively.
In FLEC group, after a median follow-up of
27 months (4.1–65), 18 out of 24 (75%) relapsed and the
sites of the first recurrences were, respectively, local in
six patients, peritoneal in six, hepatic in six and extra-
abdominal in two. Median DFS was 14 months with
1- and 2-year DFS of 54 and 38%, respectively. Median
survival was 24.8 mont hs with 1- and 2-year OS of 67
and 58.3%, respectively.
In FLECG group, after a median follow-up of 14
months (4–39), 11 out 23 (48%) relapsed and the sites of
the first recurrences were, respectively, local in six pa-
tients, peritoneal in five, hepatic in four and extra-
abdominal in one patient. Median DFS was 22 months
with 1- and 2-year DFS of 65 and 47%, respectively.
Median survival was not reached and 1- and 2-year OS
were, respectively, of 88 and 70%.
Toxicity
No side effects related to angiographic technique were
observed. Table 2 shows systemic toxicity related to the
IAC (all 47 patients are evaluable) and to gemcitabine
(all 23 patients are evaluable). IAC was well tolerated,
with only 4% of grade 3 nausea/vomiting and no other
grade 3/4 toxicity. About systemic treatment, we ob-
served a grade 3 anaemia in 8%, a grade 3 leukopenia in
8%, a grade 3 thrombocytopenia in 17% and a grade 3
nausea/vomiting in 4% of patients.
Discussion
Adjuvant treatment’s aim is to improve survival by
treating subclinical residual tumour. There is no globally
accepted standard for adjuvant therapy in pancreatic
cancer and the use of chemotherapy has a strong ratio-
nale, principally because radiotherapy only decreases
loco-regional recurrence without any changes in hepatic,
peritoneal and syste mic progression [15, 16].
Preliminary results of the first adjuvant randomised
trial of gemcitabine are very encouraging showing a
DFS almost twice as long for the treated patients,
14.2 months for the gemcitabine group compared with
7.5 months for the observation group (P<0.001). This
advantage remains regardless of whether margins were
positive or negative or whether nodes were involved. At
the time of presentation OS data were not yet mature,
but the curves had separated [6]. The main aim of re-
gional chemotherapy is delivery of high doses of
chemotherapic agents to the principal focus of recurrent
disease, liver and pancreatic bed and yet minimise sys-
temic toxicity. Celiac axis, portal vein and hepatic artery
have been used to administer different chemotherapic
agents. Ishikawa et al. [11] placed cath eter in hepatic
artery and in portal vein and infused 5-fluoruracil con-
tinuously over 4–5 weeks after radical surgery in 27
patients. There was a significant improvement in 1- and
3-year survival: 62 and 35% for historical control versus
92 and 51% for the treated gro up, with an impres sive
decrease of hepatic recurrence. The group of Papa-
christou treated 31 patients with six cycles of mitoxan-
trone, 5-fluoruracil, folinic acid and cisplatin infused via
celiac axis in 5 days every 5 weeks and achieved a
median survival of 21 months with a liver recurrence
rate of 15% [12]. With regard to treatment sequence
Table 1 Patients’characteristics
Regimen FLEC FLEC-G
Number 24 23
Age (years)
Median 60 62
Range 28–78 33–74
Sex
Male 14 14
Female 10 9
Karnofsky PS
90–100 11 11
70–80 13 12
Tumour site
Head 19 20
Body 3 3
Tail 2
Tumour size (cm)
Median 3.0 (1.2–5) 2.5 (0.5–5)
Histology
Adenocarcinoma 23 23
Acinar cell adenocarcinoma 1 0
Tumour grade
111
21314
3108
Stage
II (T
3
N
0
M
0
)72
III (T
1
T
3
N
1
M
0
)1421
Iva (T
4
N
any
M
0
)30
Lymphoadenectomy
Extended 9 7
Standard 15 16
Number of lymph nodes
Median 15.0 21.0
Range 4–53 5–60
Lymph node
N0 7 2
N1 17 21
Resection margins
R0 15 19
R1 9 4
506
(at first IAC and then systemic gemcitabine), it seems
more rationale to treat subclinical disease that probably
grows into the liver and into pancreatic bed with a
higher drug concentration at first pass. The current
study showed that FLEC regimen with or without
gemcitabine is tolerated without any significant toxicity
after radical surgery for pancreatic adenocarc inoma.
Primary end point of the trial, that was to maintain at
least 23 of 47 patients free of disease at 1 year from
surgery, was completely obtained with 27 patients
(57.4%) without an y recurrence of disease after 1 year.
Regarding OS, when we consider all the patients, we
observed a median of 29.7 months with a 1- and 2-year
survival of 75 and 60%, respectively. It was not possible
to make a statistical comparison between the two groups
because the sample size is inadequate and the FLECG
group follow-up is shorter than FLEC one with a limited
number of events. However 1-year OSs are 67 and 88%
for FLEC and FLECG, respectively (Fig. 1).
This result reflects what happens in advanced pan-
creatic cancer where PEFG regimen has shown a more
favourable outcome in terms of progression free survival
and OS than gemcitabine alone [17]. Also our study
includes an antifolate, an anthracicline, a platinum
compound and gemcitabine, all active drugs in pancre-
atic cancer.
Negative prognostic factors result only in undiffer-
entiated tumour (G3) and nodal involvement (>3
nodes): these data confirm the relevance of the biological
behaviour of the tumour in our study.
Toxicity after intra -arterial administration is mild
with a very good compliance: side effec ts related to the
technique and grade 4 toxicity were not observed: grade
3 nausea/vomiting was seen in 4% of the patients. The
absence of haematological grade 3–4 toxicity compared
with FLEC regimen used in patients with locally ad-
vanced and metastatic pancreatic adenocarcinoma [9]is
due to the dose reduction of 25% that we applied in
adjuvant setting.
Liver metastases have been reported to occur in up to
90% of patients after pancreatic surgery [1]. IAC seems
to reduce the rate of hepatic recurrence also in this trial,
where we observed 10 out of 47 patients (21%) with liver
recurrence as first site of relapse. This is probably related
to the high drug concentration reached in the liver
during the first pass of the drug administered intra-
arterially.
In our series it is not possible to compare the two
different patterns of failure regarding the addition of
systemic gemcitabine (FLEC and FLECG) because the
small number of patients and the different median fol-
low-up. However, it seems that FLECG might have a
better impact on all kinds of recurrence except local one.
Even if to compare with other adjuvant studies is not
appropriate, the median OS obtained with our regimen
is very encouraging and suggests further evaluations.
In conclusion, many paradigms about the treatment
of pancreatic cancer have been changing this year. In
advanced disease the combination of gemcitabine plus
the oral EGFR (epidermal growth factor receptor)
tyrosine kinase inhibitor erlotinib was compared with
gemcitabine plus placebo and has shown a statistical
improvement in survival [18]. This is the first evidence of
the benefits of EGFR tyrosine kinase inhibitors in
combination with chemotherapy. Similar trials assessing
bevacizumab and cetuximab are ongoing. A four-drug
regimen (PEFG) was associated with improvements in
both tumour response rate and progression free survival
Table 2 Toxicity profile
Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%)
Toxicities of intra-arterial chemotherapy (137 cycles in 47 patients)
Anaemia 8 17 0 0
Leukopenia 4 2 0 0
Thrombocytopenia 6 0 0 0
Nausea/vomiting 6 6 4 0
Diarrhoea 4 0 0 0
Alopecia 0 8 0 0
Toxicities of systemic chemotherapy (198 weekly administrations in 23 patients)
Anaemia 17 17 8 0
Leukopenia 17 13 8 0
Thrombocytopenia 13 17 17 0
Nausea/vomiting 8 8 4 0
Diarrhoea 4 4 0 0
0 4 8 12 16 20 24 28 32 36 40 44 48
0
25
50
75
100
FLEC
FLECG
Time (months)
Overall survival (%)
FLEC 24 24 22 16 16 16 14 12 9 8 7 5 5
FLECG 23 23 21 17 14 7 4 4 4 4 2
Fig. 1 Overall survival of patients treated with FLEC (24) and
FLECG (23) regimen
507
when compared with gemcitabine alone with a small but
significant improvement in OS [17]. In adjuvant setting
gemcitabine compared to surgery alone significantly in-
creases DFS [6]. This is the first evidence of a substantial
benefit from chemotherapy in resected patients. Our
study, with its limits of a small sample size (47 patients),
a long time of enrolment (7 years), a not widely accepted
locoregional technique (celiac axis bolus infusion), is in
the direction of a four-drug regimen in the treatment of
pancreatic cancer: it appears feasible without significant
toxicities and results in terms of DFS and OS should not
be ignored.
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