I. Introduction
Cancer of the
exocrine pancreas is considered one of the most difficult cancers to treat,
since patients show a five-year overall survival rate lower than 5%. At the
time of diagnosis only 10-15% of patients undergo potentially curative surgery
with a median survival of 10-18 months while the majority of patients have
locally advanced inoperable and/or metastatic disease with a median survival
ranging from 3 to 6 months (Evans et al, 1997).
Single-agent
gemcitabine (GEM) is currently considered as the treatment of choice for
advanced pancreatic cancer (APCa). Collective data gave employing only GEM have
shown an objective overall response rate (ORR) in the range of 5.4-16.6% and a
median survival of 3.9-6.3 months (Casper et al, 1994; Carmichael et al, 1996;
Burris et al, 1997; Crino et al, 1997). In a randomised phase III trial, GEM
obtained a statistically significant advantage in terms of clinical benefit
(CB) rate, based on measurements of pain, functional impairment and weight loss
(23.8% versus 5.4%, p:0.0022), and overall survival (OS; 5.65 versus 4.41
weeks, p:0.0025) when compared to the standard 5-fluorouracil (5-FU) (Burris et
al, 1997). Combination chemotherapy with GEM, therefore, has been studied to
improve the outcome of patients with APCa. 5-FU, the most extensively studied
single drug in the treatment of APCa, yields an ORR of less than 10% with
marginal impact on quality of life and OS (Ahlgren, 1996). In vitro the
combination of 5-FU and GEM have demonstrated to have synergistic activity: GEM
depletes the polls of cellular deoxyuridine monophoshate (dUMP) pools,
decreasing competition with 5-FdUMP at the target enzyme thymidilate synthase:
5-FU metabolites may inhibit deoxycytidine monophosphate deaminase, the enzyme
responsible for inactivation of GEM monophosphate (Kanzawa and Saijo, 1997).
Several phase I-II trials of GEM in combination with 5-FU have been
conducted in patients with APCa. Although the dose and schedule of GEM were
similar in all trials, the administration of 5-FU varied from protracted
continuous infusion, to 24 hours continuous venous infusion (cvi), to weekly
bolus at different dose levels, with or without folinic acid (FA). Four phase
II trials evaluated the combination of GEM and bolus 5-FU administered for 3
consecutive weeks every 4 weeks. The ORR was in the range of 3.7-34.7% and the
OS in the range of 4.4-9.0 months (Cascinu et al, 1998; Berlin et al, 2000;
Murad et al, 2000; Pastorelli et al, 2000). Reported toxicities were mild, with
a low percentage of hematological and gastrointestinal grade 3-4 side effects.
Several other trials of GEM in combination with bolus or cvi 5-FU modulated by
FA have been reported to date: the ORR was in the range of 5-26% and the median
OS was 9 months (Gutzler et al, 1999; Hidalgo et al, 1999; Louvet et al, 1999;
Kurtz et al, 2000; Lencioni et al, 2000; Polyzos et al, 2000; Rauch et al,
2001). Hematological and gastrointestinal side-effects were the main observed
toxicities, whose severity depended on treatment schedule. However, in a recent
phase III trial, the combination of GEM and 5-FU showed no advantage with
respect to only GEM in median OS (6.7 vs 5.4 months, p:0.09) and ORR (6.9 vs
5.6%) (Berlin et al, 2002).
Single-agent
cisplatin (CDDP) has been reported to produce a 21% ORR in APCa patients with a
median OS of 4 months (Wils et al, 1993). The combination of GEM and CDDP has
been shown to be synergistic in vitro, since GEM is able to inhibit DNA repair
after CDDP-induced damage, and CDDP is able to influence GEM catabolism through
the inhibition of ribonucleotide-reductase (Bergman et al, 1996). Several
schedules have been adopted for the combination of the two drugs. In two phase
II trials, the administration of GEM on day 1,8,15 plus CDDP on day 1 and 15
every 4 weeks, obtained a 11.5% and 26.0% ORR, a median time to progression
(TTP) of 4.3 and 5.4 months, and a median OS of 8.2 and 7.1 months,
respectively (Heinemann et al, 2000; Philip et al, 2001; Colucci et al, 2002).
In a previous multicenter randomised phase III trial conducted by our group,
the combination of GEM plus CDDP, administered weekly for 7 weeks, demonstrated
to be more effective than GEM alone in terms of ORR (31% vs 10%, p:0.01), and
median TTP (20 vs 8 weeks, p: 0.048) with a similar CB rate (52% vs 49%). The
median OS showed a trend in favour of the combination arm but it did not
reached the statistical significance (30 vs 20 weeks, p:0.48). Toxicity
recorded in the CDDP plus GEM arm was more acceptable than that reported in
other phase II trials with the same combination (Heinemann et al, 2000). This
difference most likely was related to dosages and schedules employed. A
nationwide confirmatory phase III trial is currently ongoing.
Taking
into account these data, the Gruppo Oncologico Italia Meridionale (GOIM) carried out a phase II trial
with the aim to evaluate the activity of a triplet combination regimen in APCa
patients. The main end-points of the study were the efficacy of the treatment
in terms of ORR and CR rate, and the toxicity of the treatment; median TTP and
OS were also evaluated.
II.
Patients and methods
A. Patient selection and study design
Patients
were enrolled into the study if they satisfied the following inclusion
criteria: a) histological or cytological diagnosis of locally advanced and/or
metastatic pancreatic carcinoma; b) bi-dimensionally measurable disease
according to standard WHO criteria, c) no previous chemotherapy, hormonal
therapy, or radiotherapy; d) age between 18 and 75 years; e) performance status
(PS) >50 according to the Karnofsky Index; f) no evidence of
congestive heart failure, serious arrhythmias or coronary artery disease; g)
absence of severe uncontrolled metabolic, infectious or neurological disease;
h) absence of other malignant neoplasms with the exception of adequately
treated in situ carcinoma of the uterine cervix or non-melanotic skin cancer.
Informed written consent was also requested from all patients before their
inclusion into the study. Besides patients should have an adequate baseline
bone marrow reserve (WBC count >4,000/mm3, neutrophils >
1,500/mm3, platelets > 100,000/mm3 and
hemoglobin level > 10gr/dl), an adequate hepatic function (levels of
bilirubin and transaminases < 2.5 normal values) and an adequate
renal function (defined as serum creatinine concentration < 1.5
mg/dL, and BUN < 50 mg/dL). Patients were excluded from the trial in
the presence of brain metastases or any pre-existing medical condition of
sufficient severity to prevent
full compliance with the study. Geographical accessibility was also
considered as a prerequisite in order to guarantee correct therapy and
follow-up.
B.
Treatment schedule
Patients were centrally registered at the GOIM headquarters at the
Oncology Institute of Bari, Italy. The treatment schedule was as follows: at
the first cycle (8 weeks) GEM was administered as a 30-minute iv infusion at a
dose of 1000 mg/m2 diluted in 250 normal saline solution, once a
week for 7 consecutive weeks; CDDP was administered on day 1, 8, 15, 29, 36 and
42, at a dose of 25 mg/m2 diluted in 500 cc of normal saline
ensuring adequate hydration, one hour before the administration of GEM, while
FA and 5-FU were administered on the same days, immediately after GEM, at a
dose of 100 mg/m2 in 500 cc of normal saline solution in 2 hours, and 300 mg/m2
bolus, respectively. After a 2-week rest, treatment was continued on day 1, 8,
and 15 of a 4-week cycle; treatment was administered until progression or
unacceptable toxicity. Antiemetic therapy consisted of anti-HT3 agent and
dexametasone. G-CSF was not administered routinely in this study.
Toxicities were graded according to the NCI common toxicity criteria. If multiple toxicities were observed, the dose administered was based on the most severe toxicity experienced. The dose adjustment schedule was evaluated at the beginning of a new administration. Dose reductions were performed as follows: if the absolute neutrophil count (ANC) was > 1,000/mm3 and platelets were >100,000/mm3, 100% of the dose was administered; if ANC was in the range of 500-1,000/mm3 and platelets in the range of 50,000-100,000/mm3, 75% of the dose was administered; if ANC was <500/mm3 and platelets <50,000/mm3, treatment was delayed for one week.
C.
Pre-treatment evaluation and follow-up
Staging and clinical
evaluation procedures consisted of complete medical history and physical
examination, EKG, complete peripheral blood cell counts, serum chemistry panel
including serum tumor markers (CEA,Ca19-9). Bidimensionally measurable disease
was determined by chest x-rays, CT and/or NMR as needed. Elevated CEA or Ca
19.9 levels were not considered as measurable disease. Endoscopy was employed
according to patients needs. After withdrawal from the study, patients
underwent follow-up examinations every two months until death.
D. Efficacy assessment
The first evaluation
of disease status and CB was performed after the first cycle (8 weeks).
Objective responses (OR) were determined according to the WHO criteria: a
complete response (CR) was defined as the complete disappearance of all disease
sites and of all disease-related symptoms with no evidence of new lesions for
at least 4 consecutive weeks; a partial response (PR) was defined as a 50% or
more reduction in the sum of the products of the longer perpendicular diameters
of all measurable lesions, without any evidence of new lesions; stable disease (SD) was defined as a less than
50% reduction or a less than 25% increase in the sum of the products of the
measurable lesions, with no evidence of
new lesions; progressive disease (PD) was defined as a > 25%
increase in one or more lesions or the appearance of new lesions. The sum of
CR, PR, and SD was reported as tumor growth control rate (TGCR). Patients with
complete or partial response and those with stable disease continued treatment
and were re-evaluated after two 28-day cycles. TTP was estimated from the date
of first treatment to the first evidence of PD. OS was estimated from the date
of first treatment to the date of death or the last follow-up.
Clinical Benefit
(CB) assessment was based on the measurement of three common signs or symptoms
two of which were defined as primary, i.e. pain and functional impairment, and
one as secondary, i.e. weight loss. Pain was assessed by pain intensity and
analgesic consumption. Pain intensity was determined daily by a visual analogic
scale and the weekly value was defined as the median of the entire recorded daily values; an improvement of
>50% from baseline which was sustained for > 4 weeks was
considered to be a positive response, assuming a baseline pain score of 30.
Analgesic consumption was recorded weekly employing the following scale: 0 = no
analgesic consumption; 1 = administration of non-steroidal anti-inflammatory
drugs; 2 = consumption of codeine phosphate; 3 = oral administration of
morphine sulfate; 4 = parenteral administration of morphine; 5 = neurosurgical
procedures. A change from a higher to a lower level was considered to be a
positive response. When consumption of analgesic drugs was considered within
each level, patients who required an increase in their daily dose were defined
as non-responders.
Functional impairment was assessed by the Karnofsky performance scale. Two different investigators determined baseline values weekly. For patients with a PS of 50, 60 and 70, an improvement of >20 points from baseline which was sustained for > 4 weeks was considered to be a positive response. Weight was measured weekly and a weight gain of >7% (excluding third spaces) sustained for > 4 weeks was considered to be a positive response. Therefore, a patient was classified as a clinical benefit responder if one of the two primary parameters improved without deterioration in the others or if the primary parameters were stable and a weight gain >7% from baseline was observed.
E.
Statistical Analysis
Objective responses were reported as their relative rates with 95% confidence interval (95% CI) accordingly to an intent-to-treat (ITT) analysis and in evaluable patients. Percentages of response or other data were adjusted to the nearest unit. A univariate analysis of TTP and OS according to the Kaplan-Meier product limit estimate was performed. The population sample size was calculated considering a response rate of 20% in previous studies, assuming a minimum difference wished to be significant of 0.2 and estimated response rate of 30% with a type 1 error of 0.05 and a type 1 error of 80%. Therefore 33 patients had to be enrolled into the trial.
III. Results
A. Patients population and disease status
A total
of 33 patients entered the trial; the main characteristics of the enrolled
patients are summarized in Table 1. Overall, there were 20 males and 13 females with a
median age of 65 years (range 42-75) and a median Karnofsky PS of 80 (range
50-100). Few patients (9%) had recurrent disease after radical surgery, while
30 patients (91%) had locally advanced and/or metastatic disease at the time of
diagnosis; 22 patients (67%) had multiple sites of disease while 11 patients
(33%) had only one site of disease. The main disease sites were primary tumor
(30 patients), liver (15 patients), and lymph nodes (12 patients).
B. Objective response, time to
progression, and overall survival
Twenty-eight
patients were available for objective response, while 4 patients withdrew from
treatment, before re-evaluation: 3 patients due to treatment-related toxicity,
and 1 because he refused treatment due to side-effects. ORR, CR rate, median
TTP, and OS are depicted in Table 2. According to an ITT analysis, no CR and 6 PR were
observed for an ORR of 18% (95% CL 7% - 35%), 12 patients (36%) had SD, with a
TGCR of 54%, and 10 patients (30%) had PD. In the evaluable patients the ORR
was 21.4% (95% CL 8%-41%). The duration of objective responses were 12+, 28+,
32, 36, 48 and 52 weeks respectively (median 34 weeks), and were observed at
primary tumor (20% of cases), liver (13%) and lymph nodes (17%). The median TTP
was 16 weeks, while the median OS was 30 weeks. Thirteen patients (39%) were
alive at 6 months and 5 patients (15%) at 1 year. The median survival of
responder patients was 11 months.
Table 1: Patient
characteristics
Enrolled: 33
(100%)
Sex
Male: 20
(61%)
Female: 13
(39%)
Age (yr)
Median: 65
Range: 42-75
Karnofsky PS:
Median: 80
Range: 50-100
Stage
III: 8
(24%)
IV: 25
(76%)
Surgery
Radical: 3
(9%)
Biopsy: 30
(91%)
Sites of disease
Pancreas: 30
(91%)
Liver: 15
(45%)
Lymph nodes: 12
(36%)
Other: 5
(15%)
Sites:
Single: 11
(33%)
multiple: 22
(67%)
Table 2: Objective response
rate, time to progression, overall survival
Enrolled
patients: 33
(100%)
Evaluable patients: 28
( 85%)
CR: 0
(00.0%)
PR: 6
(21.4%)
SD: 12
(36.3%)
PD: 10
(30.3%)
Overall response rate (ORR):
Evaluable pts: 21.4%
ITT analysis: 18.0%
Median time to
progression (weeks): 16
Median overall
survival (weeks): 30
C. Clinical benefit (CB)
Twenty-two (67%) of
33 patients enrolled were evaluable for CB assessment; 11 patients (50%) were
evaluable for both PS and pain; 6 (18%) only for PS and 5 (15%) only for pain.
Both pain and PS improved in one patient, whereas 4 patients showed a decrease
in pain without deterioration of PS and 1 patient an improvement of PS with no
change of pain. Furthermore 2 patients showed a weight increase > 7% with no
change in PS and pain. Therefore 10 patients (40%; 95% CL 24%-68%) were
considered CB responders. Improvement in the CB parameters was observed after
the fourth week of administration (Table 3).
D. Toxicity
The
pattern of toxicity is depicted in Table 4. All patients were evaluable for toxicity. No
toxic-related death has been observed. The main grade 3-4 toxicities were:
neutropenia 18%, thrombocytopenia 21%, diarrhea 21%, anemia 9%, mucositis
(12%), and nausea/emesis 2%. Four patients discontinued treatment for grade 3-4
thrombocytopenia and diarrhea. Grade 1-2 toxicity were: neutropenia 21%,
thrombocytopenia 45%, anemia 30%, nausea/emesis 36%, diarrea 12%, transaminases
15%, fever 12%, asthenia 12%, alopecia 18%.
Table 3: Results on
Clinical Benefit
Evaluable patients: 22/33
(67%)
pain and performance: 11
(50%)
only performance: 6
(27%)
only pain: 5
(23 %)
Responders:
pain and performance: 3
only performance: 1
only pain: 4
weight: 2
Table 4: Toxicity recorded according to NCI criteria
|
Mucositis |
-- |
2 (6) |
4 (12) |
-- |
|
Diarrhea |
1 (3) |
3 (9) |
5 (18) |
1 (3) |
|
Nausea/Vomiting |
8 (24) |
4 (12) |
1 (3) |
-- |
|
Leukopenia |
8 (24) |
9 (27) |
3 (9) |
2 (6) |
|
Neutrophils |
4 (12) |
3 (9) |
3 (9) |
3 (9) |
|
Anemia |
3 (9) |
7 (21) |
3 (9) |
-- |
|
Platelets |
6 (18) |
9 (27) |
4 (12) |
3 (9) |
|
Transaminases |
3 (9) |
2 (6) |
-- |
-- |
|
Asthenia |
4 (12) |
-- |
-- |
-- |
|
Loss of Hair |
4 (12) |
3 (9) |
-- |
-- |
|
Flu-like
syndrome |
2 (6) |
1 (3) |
-- |
-- |
IV. Discussion
To
date, GEM is considered as the standard palliative chemotherapy for patients
with APCa by most oncologists on the basis of the results obtained in phase
II-III trials reporting a CB response in 23-40% of patients. However GEM has
limited antineoplastic activity when used as single-agent: the major objective
responses are in the range of 5.4-16.6% with a median OS of 3.9-6.3 months. The
Investigational New Drug Treatment Program reported a 12% ORR in 982 patients
with APCa treated with single-agent GEM. The survival data from 2380 patients
showed that the median survival was 4.8 months, with a 1-year survival rate of
15% (Storniolo et al, 1999). These data have led to numerous studies with the
aim to evaluate the activity and efficacy of GEM employed in combination with
other drugs that showed to be synergistic in vitro such as 5-FU, docetaxel,
CDDP, and oxaliplatin. In this phase II study we have explored the activity and
the tolerability of the triplet combination of GEM, CDDP and 5-FU/FA employing
the same weekly schedule tested in our previous study aiming to maximize the
potential synergism among the drugs and to reduce toxicity. In the twenty-eight
evaluable patients we observed a 21% of ORR with a 36% of stable disease and a
tumor growth control rate of 54%, a median TTP of 16 weeks and a median OS of
32 weeks. A CB was obtained in 40% of patients. These results are in the range
reported for GEM-based combination chemotherapy regimens in medical literature,
but they do not seem to be better than those observed in our previous
randomised phase III trial with the combination of GEM and CDDP. With regard to
toxicity, the addition of 5FU/FA to CDDP/GEM results in an increase in the
severity of the side effects: we recorded grade 3-4 neutropenia in 18% of
cases, diarrhea in 21%, anemia in 9%, mucositis in 12%, and thrombocytopenia in
21%. Toxicity determined the discontinuation of treatment in four patients
(14%). Therefore the addition of 5-FU/FA to GEM/CDDP on a weekly schedule
results in a significative increase in the severity and the incidence of
toxicity without improving clinical efficacy.
Philip et al,
(2001) considering the results of their previous phase II trial of GEM and
CDDP, recently tested the activity and toxicity of the triplet combination of
GEM administered at 1000 mg/m2 on day 1, 8 and 15 of a 4-week cycle,
CDDP at 50 mg/m2 on days 1 and 15 and 5-FU 175 mg/m2 cvi
for 14 days obtaining analogue results than our trial (El-Rayes et al, 2003).
Among the 47 evaluable patients they observed 11 PR (26%) and 27 SD (57%), with
a median TTP of 5.7 months and a median OS of 8.6 months (El-Rayes et al,
2003). Also the main grade 3-4 toxicities were similar: neutropenia (19%),
thrombocytopenia (38%) and mucositis/ stomatitis (15%).
GEM has also been tested in combination with docetaxel initially with
poor results: less than 10% of ORR has been reported in three clinical
experiences employing TXT at single administration every 3-4 weeks (Kakolyris
et al, 1999; Cascinu et al, 1999; Clark et al, 2000). Different schedules of
treatment have been explored; the weekly administration of both GEM and TXT seems
to gave the better results. Both Schmidt et al, (2002) and Schneider et al, (2002)
recently
reported a 24.0% ORR employing GEM at the dosage of 750-1000 mg/m2/week and
docetaxel at the dosage of 35 mg/m2/week for 3 weeks on a 4-week cycle.
Recently the combination of GEM and CPT-11 revealed to be active with an ORR of
24%, a median TTP of 2.8 months and a median OS of 5.7 months in 45 patients
with a low grade of grade 3-4 toxicities (Rocha-Lima et al, 2002). The GEM and
oxaliplatin regimen was shown to yield 31% ORR, a median TTP of 5.3 months, and
a median OS of 9.2 months and a CB of 40% in 64 eligible patients (Louvet et
al, 2002).
In
conclusion the data of this trial demonstrate that the triplet combination of
GEM, CDDP and bolus 5-FU modulated by FA is an active treatment for patients
affected by APCa. However the results achieved with our weekly schedule are no
better than those observed in our previous randomised phase III trial with GEM
plus CDDP (Colucci et al, 2002). Furthermore, the addition of 5-FU/FA seems to
increase the severity of toxicity reported with weekly GEM/CDDP. Other
schedules or combinations should be tested to increase the results in the
treatment of APCa.
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