ARTICLE
Auteur(s) : P Afchain1, B
Chibaudel1, G Lledo2, F Selle3, L
Bengrine-Lefevre1,4, S Nguyen5, J-F
Paitel6, L Mineur7, P Artru2, T
André3,4, C
Louvet1,4
1Service d’oncologie, hôpital Saint-Antoine,
Assistance publique des Hôpitaux de Paris, 75012 Paris, France
2Clinique Saint-Jean, 69008 Lyon, France
3Hôpital Tenon, 75020 Paris, France
4Université Pierre-et-Marie-Curie-Paris-VI, 75005 Paris,
France
5Centre hospitalier de Beauvais, 60000 Beauvais,
France
6Centre hospitalier de La Rochelle, 17000
La Rochelle, France
7Clinique Sainte-Catherine, 84000 Avignon, France
Article reçu le 13 Juin 2008, accepté le 16 Février 2009
Introduction
Pancreatic cancer accounts for 3% of all cancers but is the fifth
leading cause of cancer death in Western countries [1]. The
estimated number of new cases of pancreatic cancer in France is
approximately 5,000 per year [2]. Only 1 to 4% of the patients with
pancreatic cancer are alive 5 years after diagnosis [3]. At
the time of diagnosis about 45% of patients have metastases, and
their median survival does not exceed 6 months, while about
40% diagnosed with locally advanced disease have median survival
ranging between 6 and 9 months [4]. There is a strong need for
active systemic treatments in patients with non-resectable disease.
Some chemotherapeutic agents have a palliative effect [5, 6] and
prolong survival [5-7]. No single-agent drug has achieved
reproducible response rates over 10%, when subjected to independent
expert radiological evaluation. Clinical benefit (improvement in
performance status (PS), decrease of pain or analgesic consumption,
and weight gain [8]) is an alternative method for assessing
efficacy of chemotherapy, but is not commonly recorded.
Since the publication of Burris et al. study [5], gemcitabine
single agent is considered as the standard treatment of
non-resectable pancreatic cancer. Many attempts of
gemcitabine-based doublets have been performed during the past
years. Except for gemcitabine + erlotinib combination [9], all
individual studies failed to demonstrate statistically significant
improvement of survival. However, meta-analysis indicated that
gemcitabine plus fluoropyrimidine, and gemcitabine plus platinum
salts could improved survival as compared to gemcitabine single
agent, particularly in patients with PS: 0-1 [10, 11].
GemOx regimen achieved promising activity in the first phase II
study [12], which was confirmed in the GERCOR-GISCAD phase III
study [13], but without significant difference compared to
gemcitabine single agent. More recently, the ECOG study also failed
to demonstrate a superiority of the GemOx regimen over either
gemcitabine 30-minute infusion or gemcitabine fixed dose rate [14].
However, GemOx regimen remains an alternative option, particularly
in patients with favourable performance status [11].
The GemOx regimen was based on published preclinical in vitro
synergy data [15] between gemcitabine and oxaliplatin, which was
optimal when tumor cells were exposed to oxaliplatin 24 hours
after gemcitabine. Then, in the GemOx regimen, patients received
gemcitabine on day 1 (D1) and oxaliplatin on day 2 (D2). The aim of
the present study was to generate data on a S-GemOx regimen (both
drugs sequentially administered on day 1) in terms of activity as
well as toxicity, and to evaluate whether or not such modification
could impair the results of the original GemOx regimen. In order to
minimize the heterogeneity of successive studies, a randomized
phase II design was chosen.
Patients and methods
Eligibility criteria
Patients with pathologically proven metastatic adenocarcinoma of
the exocrine pancreas, age superior to 18 years, WHO
performance status: 0-2, and measurable disease were eligible for
this study. They should also never received previous chemo- or
radiation-therapy, nor have had clinical CNS involvement, previous
peripheral neuropathy. Adequate biological parameters (neutrophil
count > 1,500/mL, platelet count > 100,000/mL, serum
creatinine < 1.5 × the upper limit of normal value [ULN]),
alkaline phosphatases < 5 × ULN, and
bilirubin < 1.5 × ULN) were required. Pain and biliary
obstruction had to be controlled in all patients before inclusion
in the study. Written informed consent was required from each
patient and the ethic committees of the participating centers
approved the study.
Treatment plan and dose-adaptations
S-GEMOX regimen consisted in a fixed dose rate of gemcitabine
1,000 mg/m2 (10 mg/m2 per minute)
on day 1 immediately followed by a two-hour infusion of
100 mg/m2 oxaliplatin, and then only differed from
the original GemOx by the timing of oxaliplatin administration
(gemcitabine day one, and oxaliplatin day two). Treatment was
repeated every 2 weeks. Dose reductions were made on the basis
of the worst toxicity observed during the previous cycle. In case
of non-neurological toxicity (NCI-CTC version 2) superior to grade
2, the subsequent cycle was administered after recovery with a
gemcitabine dose decreased to 800 mg/m2 (80-minute
infusion), and an oxaliplatin dose decreased to
85 mg/m2 (120-minute infusion). Oxaliplatin dose
was reduced to 85 mg/m2 in case of sensory
peripheral neuropathy of grade 2 and discontinued in case of grade
3. Patients would then continue to receive gemcitabine monotherapy
according to the same biweekly schedule and oxaliplatin could be
re-introduced in case of recovery of the neurological symptoms
(grade 2 or less). In case of laryngopharyngeal dysesthesia,
oxaliplatin infusion was prolonged to 6 hours, and eventually
stopped if further symptoms occurred during the following cycles.
Patients received chemotherapy until evidence of disease
progression, patient’s refusal or unacceptable toxicity.
Treatment evaluations
Baseline assessment involved medical history, physical examination
including evaluation of clinical symptoms, biological analyses
(blood cell count, serum creatinine, bilirubin, ASAT, ALAT,
alkaline phosphatases, and CA 19.9 levels) were performed within
the week proceeding treatment initiation, and tumor measurement
(CT-scan) was performed within 21 days of treatment start.
During the treatment period, blood counts, evaluation of
toxicity and physical examination were to be performed before each
cycle of chemotherapy.
Tumor assessment by the same imaging method throughout the
follow-up period, defined according to the World Health
Organization (WHO), was required every 2 months or earlier if
clinically indicated, in both arms. Toxicity was graded according
to the National Cancer Institute Common Toxicity Criteria (NCI-CTC)
version 2. Progression-free survival (PFS) was calculated from the
day of randomisation until evidence of clinical progression or
tumor progression assessed by CT-scan measurement or death
occurring before progression evidence. Overall survival (OS) was
calculated from the day of randomisation until the date of
death.
Statistical analysis
Assuming a 20% response rate in S-GemOx and a type one error of 5%,
a power of 80%, 37 patients were to be included according to the
single-stage Fleming plan. As efficacy of the classical GemOx
regimen was previously well described, an unbalanced centralised
randomization (2:1) was performed. Minimization method was used to
balance treatment allocation according to center, and performance
status (0/1 versus 2).
Intent-to-treat population consisted in all randomized patients.
Data analyses (efficacy and safety) concerned all patients who
received at least one cycle of treatment and who fit eligibility
criteria (per protocol population).
Quantitative data were expressed as mean ± standard deviation.
Qualitative data were expressed as percentage ± 95% confidence
interval. Survival curves were established according to the
Kaplan-Meier method.
Results
Enrollment and patients characteristics
Sixty patients were included and randomized (GemOx: 20; S-GemOx:
40). Three patients randomized in the S-GemOx arm were excluded
from analysis: one with cholangiocarcinoma, and two who never
received treatment. Therefore, 57 patients were both eligible and
treated, and were included in the per protocol population for both
efficacy and safety analysis. Twenty-two percent of patients had PS
2. Patients’ characteristics (table 1)
were well balanced for age, gender, and location of primary tumor,
metastatic sites, and CA 19.9 level. However, more poorly
differentiated tumors were observed in the GemOx arm as compared to
the S-GemOx arm (36 vs 8%, P = 0.051). No pathological review was
performed.
Table 1 Patients’ characteristics
|
|
|
|
N eligible patients
|
20
|
37
|
|
Gender
|
|
|
|
F
|
7 (35)
|
16 (43)
|
|
M
|
13 (65)
|
21 (57)
|
|
Performance status (PS)
|
|
|
|
0
|
7 (35)
|
10 (27)
|
|
1
|
9 (45)
|
19 (51)
|
|
2
|
4 (20)
|
8 (22)
|
|
Age (mean)
|
66.6
|
64.9
|
|
Range (min-max)
|
49-80
|
47-80
|
|
Tumor location
|
|
|
|
Head
|
10 (50)
|
18 (49)
|
|
Body
|
6 (30)
|
11 (30)
|
|
Tail
|
4 (20)
|
8 (21)
|
|
Metastasis site
|
|
|
|
Liver
|
17 (85)
|
28 (76)
|
|
Peritoneum
|
4 (20)
|
9 (24)
|
|
Lung
|
2 (10)
|
6 (16)
|
|
Lymph node
|
3 (15)
|
5 (14)
|
|
Other
|
1 (5)
|
2 (5)
|
|
Tumor differentiation
|
|
|
|
Well
|
3 (15)
|
17 (46)
|
|
Moderately
|
4 (20)
|
7 (19)
|
|
Poorly
|
4 (20)
|
2 (5)
|
|
Unknown
|
9 (45)
|
11 (30)
|
|
CA 19.9 (UI/L) level
|
|
|
|
Mean
|
163
|
368
|
|
Range (min-max)
|
1-32,000,000
|
1-40,000
|
Efficacy
Response rate (RR)
Two patients out 20 and ten patients out 37 achieved a partial
response, in the GemOx arm and in the S-GemOx arm, respectively
(10% [95% CI: 0-23] vs 27% [95% CI: 12-42], P = 0.18).
PFS and OS
Median PFS was 2.5 and 4.0 months in the GemOx and S-GemOx
arm, respectively.
Median OS was 3.2 and 7.6 months in the GemOx and S-GemOx
arm, respectively. One-year survival probability was 10% in the
GemOx arm and 26.6% in the S-GemOx arm.
Efficacy results for the per-protocol population are summarized
in table 2.
Table 2 Efficacy results
|
|
|
|
Response
|
|
|
|
Partial response
|
2 (10)
|
10 (27)
|
|
Stable disease
|
9 (45)
|
16 (43)
|
|
Progression
|
9 (45)
|
11 (30)
|
|
Progression free survival
|
|
|
|
Median (months)
|
2.5
|
4.0
|
|
Overall Survival
|
|
|
|
Median (months)
|
3.2
|
7.6
|
|
One-year survival
|
13.7%
|
30.3%
|
Safety
The median number of cycles received was 7.6 (± 1.8, range:
1-29). More cycles were administered in S-GemOx arm (8.5 [1-29] as
compared to GemOx arm (5.8 [2-12]). No toxic death occurred.
Table 3 summarized grade 3-4
toxicities observed in both arms. No grade 4-toxicity was observed
in the GemOx arm. Grade 3-4 hematological toxicities were more
frequent in the S-GemOx arm in terms of neutropenia and
thrombocytopenia. As expected, due to the highest median number of
administrated cycles, peripheral neuropathy was highest in the
S-GemOx arm (8 vs 0 patients). Overall, the maximal grades 3-4
toxicity rate in S-GemOx was higher than that observed for the
GemOx arm, even non-statistically significant (57 vs 40%, P =
0.227). Of note, the toxicity profile of the S-GemOx observed in
this study is quite similar as that reported for the GemOx arm of
the Gem-GemOx study [13].
Table 3 Toxicity
|
Grade 3
|
Grade 4
|
|
GemOx
|
S-GemOx
|
GemOx
|
S-GemOx
|
|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
|
PNN
|
–
|
4 (10)
|
–
|
3 (8)
|
|
Platelets
|
2 (10)
|
4 (10)
|
–
|
2 (5)
|
|
Hb
|
1 (5)
|
3 (8)
|
–
|
–
|
|
Nausea
|
2 (10)
|
6 (16)
|
–
|
–
|
|
Vomiting
|
2 (10)
|
5 (13)
|
–
|
–
|
|
Diarrhea
|
2 (10)
|
4 (10)
|
–
|
–
|
|
Mucositis
|
–
|
–
|
–
|
–
|
|
Skin toxicity
|
–
|
–
|
–
|
–
|
|
Neurotoxicity
|
–
|
8 (21)
|
–
|
–
|
|
Alopecia
|
–
|
–
|
–
|
–
|
|
Maximal toxicity
|
8 (40)
|
17 (46)
|
0 (0)
|
4 (11)
|
Discussion
After the negative results of Gem-GemOx and the ECOG studies, GemOx
regimen cannot be considered as a standard of care in advanced
pancreatic cancer [13, 14]. However, the present study was designed
before the ECOG study report. Furthermore, the GemOx combination
could be of interest in other malignancies such as advanced biliary
tract cancers [16], but also for salvage situations in breast
cancer [17, 18], recurrent ovarian cancer [19], germ cell cancer
[20], or lung cancer [21]. Clinical trials using GemOx in
hematological malignancies as well as in pediatric solid tumors are
also in progress.
One of the GemOx regimen disadvantages is the D1-D2
administration, which was defined following previous in vitro
studies [15]. Actually, the antitumor effect of the combined
treatment was superior when tumor cells were exposed to gemcitabine
first and to oxaliplatin 24 hours later, as compared to a
simultaneous exposure. The present study kept the concept of a
sequential exposure, but without any delay between the two drugs,
in order to provide a more convenient treatment for patients. Thus,
the present study was designed to verify whether or not such a
modification would impair efficacy and/or tolerance.
Comparison between GemOx and S-GemOx did not deserve a
randomized phase III. However, since prognosis factors in APC are
often more important than treatments themselves, a 2:1 randomized
phase II designed was chosen to minimize the heterogeneity of
populations. Activity of S-GemOx regimen favorably compares to the
classical GemOx in the present study, and is in the same range as
what was described in the literature [13]. However, the difference
observed between S-GemOx and GemOx antitumor activity in the
present study seems more related to poor results observed in the
GemOx population rather than a higher activity of S-GemOx. The
randomized phase II design, even stratified on center and PS,
failed to achieve a well-balanced population, at least for tumor
differentiation, which was much more poorly differentiated in the
GemOx arm, and which could at least explain the poor results
observed. This study emphasizes one more time the limit of small
simple size of patients studies in advanced pancreatic cancer.
Toxicity profile of S-GemOx is quite acceptable, and seem to be
in the same range as compared to previous reported profile of
classical GemOx [13], with a 57% overall grades 3-4 toxicity rate.
The lower toxicity profile of GemOx in the present study seems to
be related to the low number of administrated cycles. This is
particularly true for the peripheral cumulative neuropathy.
In conclusion, the immediate sequential administration of
gemcitabine and oxaliplatin seems to keep the antitumor activity of
a D1-D2 regimen, without inducing a higher toxicity. Since this
S-GemOx regimen is clearly more convenient for patients, it could
be recommended when a gemcitabine and oxaliplatin combination is
scheduled.
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