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Adjuvant intra-arterial 5-fluoruracil, leucovorin, epirubicin and carboplatin with or without systemic gemcitabine after curative resection for pancreatic adenocarcinoma

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Background: The role of adjuvant therapy in pancreatic cancer remains controversial. 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 postoperative IAC followed or not by systemic gemcitabine in patients after curative resection for pancreatic adenocarcinoma. 5-fluoruracil 750 mg sq m(-1), leucovorin 75 mg sq m(-1), epirubicin 45 mg sq m(-1), carboplatin 225 mg sq m(-1) were administered every 3 weeks into celiac axis for three cycles (FLEC regimen), then gemcitabine at the dosage of 1 g sq m(-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 received 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%). Median 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 was 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.
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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 [1012], 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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... Several successful clinical trials of adjuvant chemotherapy based on 5FU and/or GEM for pancreatic cancer have been published [15][16][17][18][19][20][21][22][23][24][25]. Moreover, recent prospective, randomized studies of adjuvant GEM chemotherapy suggested an improvement in DFS and/or OS of pancreatic cancer patients [26][27][28][29][30][31], except for the ESPAC-3 trial [32]. ...
Article
Full-text available
Background Although adjuvant gemcitabine (GEM) chemotherapy for pancreatic cancer is standard, the quality of life (QOL) in those patients is still impaired by the standard regimen of GEM. Therefore, we studied whether mild dose-intensity adjuvant chemotherapy with bi-weekly GEM administration could provide a survival benefit with acceptable QOL to the patients with pancreatic cancer. Methods After a phase I trial, an adjuvant bi-weekly 1,000 mg/m2 of GEM chemotherapy was performed in 58 patients with pancreatic cancer for at least 12 courses (Group A). In contrast, 36 patients who declined the adjuvant bi-weekly GEM chemotherapy underwent traditional adjuvant 5FU-based chemotherapy (Group B). Careful periodical follow-ups for side effects of GEM and disease recurrence, and assessment of patients’ QOL using the EORTC QOL questionnaire (QLQ-C30) and pancreatic cancer-specific supplemental module (QLQ-PAN26) were performed. Retrospectively, the degree of side effects, patients’ QOL, compliance rate, disease-free survival (DFS), and overall survival (OS) in Group A were compared with those in Group B. Results No severe side effects (higher than Grade 2 according to the common toxicity criteria of ECOG) were observed, except for patients in Group B, who were switched to the standard GEM chemotherapy. Patients’ QOL was better in Group A than B (fatigue: 48.9 ± 32.1 versus 68.1 ± 36.3, nausea and vomiting: 26.8 ± 20.4 versus 53.7 ± 32.6, diarrhea: 21.0 ± 22.6 versus 53.9 ± 38.5, difficulty gaining weight: 49.5 ± 34.4 versus 67.7 ± 40.5, P < 0.05). Compliance rates in Groups A and B were 93% and 47%. There was a significant difference in the median DFS between both groups (Group A : B =12.5 : 6.6 months, P < 0.001). The median OS of Group A was prolonged markedly compared with Group B (20.2 versus 11.9 months, P < 0.005). For OS between both groups, univariate analysis revealed no statistical difference in 69-year-old or under females, and T1–2 factors, moreover, multivariate analysis indicated three factors, such as bi-weekly adjuvant GEM chemotherapy, T2 or less, and R0. Conclusions Adjuvant chemotherapy with bi-weekly GEM offered not only the advantage of survival benefits but the excellent compliance with acceptable QOL for postoperative pancreatic cancer patients.
... 10 Radio-chemotherapy (RCT) can increase local control of the disease and intra-arterial chemotherapy has been considered to reduce progression in the liver. [11][12][13][14] The primary aim of the study was to test different treatments associated with RFA in locally advanced pancreatic cancer patients to determine whether this is an effective multimodal approach. The secondary aim was to investigate the role of intraarterial and systemic chemotherapy (IASC) combined with ablative debulking by RFA. ...
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Background: Radiofrequency ablation (RFA) is a relatively new technique, applied to metastatic solid tumours which, in recent studies, has been shown to be feasible and safe on locally advanced pancreatic carcinoma (LAPC). RFA can be combined with radio-chemotherapy (RCT) and intra-arterial plus systemic chemotherapy (IASC). The aim of this study was to investigate the impact on the prognosis of a multimodal approach to LAPC and define the best timing of RFA. Methods: This is a retrospective observational study of patients who have consecutively undergone RFA associated with multiple adjuvant approaches. Results: Between February 2007 and December 2011, 168 consecutive patients were treated by RFA, of which 107 were eligible for at least 18 months of follow-up. Forty-seven patients (group 1) underwent RFA as an up-front treatment and 60 patients as second treatment (group 2) depending on clinician choice. The median overall survival (OS) of the whole series was 25.6 months: 14.7 months in the group 1 and 25.6 months in the group 2 (P = 0.004). Those patients who received the multimodal treatment (RFA, RCT and IASC-triple approach strategy) had an OS of 34.0 months. Conclusions: The multimodal approach seems to be feasible and associated with an improved longer survival rate.
Chapter
Pancreatic cancer is one of the major causes of cancer death. Most patientspresent with advanced disease, and only 10-15% of patients can undergo resection. Survival after curative surgery is poor, as recurrences occur either locally ordistantly. Adjuvant therapy has been employed in large randomized trials to treatsystemic disease and hopefully improve the poor prognosis. Chemoradiation, chemotherapy using 5-fluorouracil/folinic acid (5FU/FA), S-1, gemcitabine orgemcitabine plus capecitabine, and combination therapy have all been used in theadjuvant setting. The results of the EORTC and ESPAC-1 trials have revealed that there is nosurvival advantage associated with adjuvant chemoradiation following resectionfor pancreatic cancer compared to no chemoradiation. There is no level 1 evidence, as yet that chemoradiation is superior to chemotherapy alone followingsurgery. Justification for the use of combination chemoradiation with follow-onchemotherapy is based on the results of an underpowered 1987 GITSG study, which closed prematurely and compared intervention to observation. The RTOG9704 combination study did not demonstrate a survival difference between a5FU-based regimen compared with a gemcitabine-based chemoradiation regimen. There is no completed randomized study comparing chemotherapy versuscombination therapy. There is a clear survival advantage with adjuvant 5FU/FA and single-agentgemcitabine based on the results from the ESPAC-1 and CONKO-001 study, respectively. The ESPAC-3 trial showed that these adjuvant regimens are equallyeffective, but gemcitabine has a better toxicity profile. In contrast, in a Japanesepopulation, the JASPAC-01 trial demonstrated the superiority of S1 overgemcitabine. Adjuvant combination chemotherapy with gemcitabine plus capecitabinehas been recently shown to provide a survival advantage compared withgemcitabine alone in Western patients in the ESPAC-4 trial. Phase III studiesinvestigating other combination chemotherapy regimens are ongoing and willpossibly increase the number of treatment options in this setting. © Springer Science+Business Media, LLC, part of Springer Nature 2018.
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Locoregional treatment of liver metastases has been developed especially for tumors that give liver-limited metastases. For all the tumor types and especially for less usual that are presented in this chapter, the aim is to increase the amount of the drug delivered to the tumor and to decrease systemic toxicity.
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Pancreatic cancer is one of the major causes of cancer death. Most patients present with advanced disease, and only 10–15% of patients can undergo resection. Survival after curative surgery is poor, as recurrences occur either locally or distantly. Adjuvant therapy has been employed in large randomized trials to treat systemic disease and hopefully improve the poor prognosis. Chemoradiation, chemotherapy using 5-fluorouracil/folinic acid (5FU/FA), S-1, gemcitabine or gemcitabine plus capecitabine, and combination therapy have all been used in the adjuvant setting. The results of the EORTC and ESPAC-1 trials have revealed that there is no survival advantage associated with adjuvant chemoradiation following resection for pancreatic cancer compared to no chemoradiation. There is no level 1 evidence, as yet that chemoradiation is superior to chemotherapy alone following surgery. Justification for the use of combination chemoradiation with follow-on chemotherapy is based on the results of an underpowered 1987 GITSG study, which closed prematurely and compared intervention to observation. The RTOG 9704 combination study did not demonstrate a survival difference between a 5FU-based regimen compared with a gemcitabine-based chemoradiation regimen. There is no completed randomized study comparing chemotherapy versus combination therapy. There is a clear survival advantage with adjuvant 5FU/FA and single-agent gemcitabine based on the results from the ESPAC-1 and CONKO-001 study, respectively. The ESPAC-3 trial showed that these adjuvant regimens are equally effective, but gemcitabine has a better toxicity profile. In contrast, in a Japanese population, the JASPAC-01 trial demonstrated the superiority of S1 over gemcitabine. Adjuvant combination chemotherapy with gemcitabine plus capecitabine has been recently shown to provide a survival advantage compared with gemcitabine alone in Western patients in the ESPAC-4 trial. Phase III studies investigating other combination chemotherapy regimens are ongoing and will possibly increase the number of treatment options in this setting.
Article
Pancreatic cancer is one of the major causes of cancer death. Most patients present with advanced disease and only 10–15% of patients can undergo resection. Survival after curative surgery is poor, as recurrences occur either locally or in the liver. Adjuvant therapy has been employed in large randomized trials to treat systemic disease and hopefully improve the poor prognosis. Chemoradiation, chemotherapy using either 5-fluorouracil/folinic acid (5FU/FA) or gemcitabine and combination therapy have all been used in the adjuvant setting.
Article
Locoregional treatment of liver metastases has been developed especially for tumors that give liver-limited metastases. For all the tumors types and especially for the less usual that are presented in this chapter, the aim is to increase the amount of the drug delivered to the tumor and to decrease systemic toxicity. On the other hand, locoregional treatment in these specific settings may help to increase the activity of the drug especially for rather orphan tumors such as melanoma and pancreatic cancer for instance. Another aim is to fight against the appearance of resistance to systemic treatment (pancreatic carcinoma, breast cancer). In aggressive diseases such as pancreatic carcinoma and melanoma, it is obvious that the indications of locoregional treatment directed to the liver should not be proposed if there is any suspicion of extrahepatic disease. This requirement is not mandatory in tumors such as breast carcinoma in which the prognosis may be linked to liver involvement. In these tumors, liver locoregional treatment could be at least considered even if there is extrahepatic disease when the liver metastases are able to rapidly shorten the survival of the patients.
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The overwhelming majority of head and neck malignancies are squamous cell carcinomas of the oral cavity, pharynx, and larynx. In recent years, systemic chemoradiation has become an accepted alternative to surgery and postoperative radiation therapy in advanced cancers. While systemic induction chemotherapy has proven an advantage in large trials for unresectable head and neck cancer and in case of larynx preservation, locoregional chemotherapy should have an even greater potential but this has not yet been proven (neither for intra-arterial chemoradiation nor for intra-arterial induction). However, besides of palliation of advanced and recurrent cancers, available data indicate that locoregional chemotherapy should now be considered for induction of resectable cancers of the oral cavity and anterior oropharynx. As an important and carefully examined part in the armamentarium of anticancer tools, it should be used in daily routine and considered for future trials.
Article
Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)- I trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraciperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charit6 Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gerneitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median diseasefree survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii)chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.
Article
Radiofrequency ablation (RFA) is an emerging treatment for patients with locally advanced pancreatic carcinoma, and can be combined with radiochemotherapy and intra-arterial plus systemic chemotherapy. This observational study compared two groups of patients with locally advanced pancreatic carcinoma treated with either primary RFA (group 1) or RFA following any other primary treatment (group 2). Between February 2007 and May 2010, 107 consecutive patients were treated with RFA. There were 47 patients in group 1 and 60 in group 2. Median overall survival was 25·6 months. Median overall survival was significantly shorter in group 1 than in group 2 (14·7 versus 25·6 months; P = 0·004) Patients treated with RFA, radiochemotherapy and intra-arterial plus systemic chemotherapy (triple-approach strategy) had a median overall survival of 34·0 months. RFA after alternative primary treatment was associated with prolonged survival. This was further extended by use of a triple-approach strategy in selected patients. Further evaluation of this approach seems warranted.
Article
LBA4504 Background: Prognosis of patients (pts) with PC is dismal, even after curatively intended resection. Whereas gemcitabine-based chemotherapy is standard in advanced PC, the role of adjuvant chemotherapy is still under discussion. Methods: CONKO-001, a prospective, open, multicenter, controlled phase 3 study was designed to evaluate the efficacy and toxicity of gemcitabine in PC pts after complete (R0 or R1) resection. After stratification for R0/R1, nodal tumour involvement and tumour stage pts were randomized to receive either gemcitabine (G) (1g/m2 d 1, 8 and 15 every 4 weeks) for 6 months or observation (O). Pts in the observation group received no specific anticancer treatment. Primary study endpoint was disease free survival (DFS), secondary endpoints included OS and toxicity. The study was powered to detect a significant difference in DFS with 90% probability at a significance level of .05 on all eligible patients. Results: Between July 1998 and December 2004 368 pts were randomized and 354 w...
Article
Over ninety percent of patients with pancreatic cancer come to diagnosis with an unresectable pancreatic neoplasm. Regional chemotherapy appears to improve the response rate over that of systemic therapies. Since 1989 eighteen patients with advanced, intra-abdominal pancreatic cancer have been treated with regional chemotherapy in combination with extracorporeal hemofiltration. Ten patients had locally advanced, unresectable cancer, and six had advanced disease with liver metastases. One patient had developed liver metastases following a radical resection. One patient had an incomplete resection with local residual disease. The patients underwent 51 treatments with regional chemotherapy plus hemofiltration, an average of 2.8 treatments per patient. There were two complete responses (11%) and seven partial responses (39%), an overall total response rate of 50%. The average survival for patients with unresectable disease and liver metastases is 9 months and that for localized, unresectable disease is 13 months.
Article
Thirty-six patients underwent curative resection of a primary pancreatic carcinoma from January 1977 to September 1987; 26 had Whipple resections, seven had total pancreatectomies, and three had distal pancreatectomies. Twenty-six patients manifested recurrent disease, four died of intercurrent disease, and six were apparently cured. Median survival was 11.5 months with actuarial survival at 2 and 5 years of 32% and 17%, respectively. of the eventual recurrences, 19% were local only (pancreatic bed, regional nodes, adjacent organs, and immediately adjacent peritoneum) and 73% had a component of local failure. All patients failing did so with a component in the intraabdominal cavity. Peritoneal (42%) and hepatic failures (62%) were common. Extraabdominal metastases were documented in only 27%, but never as a sole site. Fourteen patient and tumor characteristics were evaluated for any relationships with failure or survival. No single variable independently predicted for local failure. However, a group of three (age > 60 years, T2 or T3 stage, and location of tumor in the body or tail) was associated with a substantial local failure risk (85% of all patients with local failure). Multivariate analysis showed that low tumor grade (P = 0.002), female sex (P = 0.002), and adjuvant radiation (P = 0.02) were all independent predictors of prolonged survival. Ten patients were treated in an adjacent setting. Those given 55 Gy or greater had improved local control (50% versus 25%) and cure (33% versus none) when compared with patients treated to lower doses. The authors conclude that local failure after curative resection remains a significant problem and further efforts to improve local control are warranted. However, peritoneal and hepatic relapses occur frequently. Thus, adjuvant treatment strategies using wide-field radiation techniques or intraperitoneal therapy, in combination with local tumor bed irradiation and chemotherapy, should be explored.
Article
Methods of assessing and reporting toxic reactions induced by therapy, particularly chemotherapy, need improvements. Accurate and reliable reporting of therapy-induced toxicity will be necessary for quality clinical research including drug development and for implementation of complex multimodality treatments, currently, however, the extent and quality of reporting of toxic reactions vary widely. Whereas standard and widely accepted criteria have been established for assessing and reporting therapeutic response, no such criteria exist for toxicity. We have developed comprehensive criteria for assessing and reliably reporting toxic reactions. We have reduced the degree of subjectivity in assigning grades by using primarily objective methods. An attempt has been made to standardize the "morbidity impact" of each toxicity grade irrespective of the organ system involved.
Article
The primary objective of a phase II clinical trial of a new drug or regimen is to determine whether it has sufficient biological activity against the disease under study to warrant more extensive development. Such trials are often conducted in a multi-institution setting where designs of more than two stages are difficult to manage. This paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the regimen has low activity subject to constraints upon the size of the type 1 and type 2 errors. Two-stage designs which minimize the maximum sample size are also determined. Optimum and "minimax" designs for a range of design parameters are tabulated. These designs can also be used for pilot studies of new regimens where toxicity is the endpoint of interest.
Article
The efficacy of combined radiation and fluorouracil as adjuvant therapy for pancreatic cancer is suggested by a prospective randomized study conducted by the Gastrointestinal Tumor Study Group (GITSG). Twenty-two patients randomized to no adjuvant treatment and 21 to combined therapy were analyzed. Neither life-threatening toxic reaction nor death due to toxic effect was encountered. The study was terminated prematurely because of an unacceptably low rate of accrual combined with the observation of increasingly large survival differences between the study arms. Median survival for the treatment group (20 months) was significantly longer than that observed for the control group (11 months). Four patients, three in the treated and one in the control group, have survived five years or longer following surgery. The extent of the tumor and initial performance status were significantly and independently related to survival.