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75 Tue, 25 Nov 2014, 03:41:42

Tumori, 95: 43-47, 2009

Feasibility study of biweekly capecitabine,

oxaliplatin, and irinotecan in patients
with untreated advanced gastric cancer
Emilio Bajetta, Elena Verzoni, Erminia Ferrario, Katia Dotti,
Arpine Gevorgyan, and Luigi Celio
Medical Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

ABSTRACT

Background. Capecitabine in combination with oxaliplatin and irinotecan (COI regimen) is active and well tolerated in metastatic colorectal cancer. Since there is no internationally adopted standard regimen, we have conducted a pilot study of COI in
untreated advanced gastric cancer.
Methods. Patients received irinotecan, 180 mg/m2 infused over 90 min on day 1, followed by oxaliplatin, 85 mg/m2 in a 3-hr infusion on day 2, and capecitabine, 1000
mg/m2/day orally twice daily from days 2 to 6 of a biweekly schedule. Treatment was
continued up to 8 cycles or until progression of disease occurred. Response (RECIST
criteria) was assessed after the first three cycles and was to be confirmed at least 4
weeks following the first response.
Results. A total of 12 patients (5 men and 7 women) with a median age of 54 years
(range, 42-65) was prospectively enrolled. Most of the patients (83%) had metastatic
disease. Three complete responses, four partial responses and two disease stabilizations occurred in the intention-to-treat cohort, with an overall response rate of 58%
(95% confidence interval, 28-85%). Median time to progressive disease and overall
survival were 6.4 and 12 months, respectively. A total of 68 cycles was administered,
with a median of 6 cycles per patient (range, 1-8). Grade 3 neutropenia occurred in
two patients. The most common non-hematologic grade 3 toxicities were nausea (3
patients) and diarrhea (2 patients).
Conclusions. These preliminary findings suggest that biweekly COI is a feasible and
promising triplet for the first-line treatment of advanced gastric cancer. A large multi-institutional phase II study of the combination has already been planned in this
setting.

Introduction
Gastric cancer is one of the most common cancers worldwide with almost one million new cases and 700,000 deaths annually1. In Italy, approximately 13,000 new cases and 8,000 related deaths are estimated to have occurred in 20052.
The prognosis for inoperable or metastatic disease is poor. Patients who have undergone potentially curative resection also have a poor prognosis due to high rates of
local recurrences as well as distant metastases. Systemic chemotherapy is of importance for controlling tumor-related symptoms, improving quality of life, and prolonging survival3. At present, there is no single, common, standard regimen for the
first-line treatment of advanced gastric cancer, and the median survival is still less
than 12 months.
Chemotherapy relies heavily upon fluorouracil (5FU) and/or cisplatin, with
5FU/cisplatin (CF) and epirubicin-cisplatin-5FU (ECF) being currently regarded as
reference regimens4. However, drawbacks of the existing regimens are the inconven-

Key words: advanced, chemotherapy, gastric cancer, triplet.

Correspondence to: Emilio Bajetta,
MD, Medical Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan,
Italy.
Tel +39-02-23902500;
fax +39-02-23902149;
e-mail
emilio.bajetta@istitutotumori.mi.it
Received December 12, 2008;
accepted December 22, 2008.

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44

ience of the 5FU dosing schedule and the requirement

for central venous access catheter and infusion device.
Cisplatin-containing combinations are also difficult to
administer in this often debilitated population and have
the potential for severe toxicity. A recent phase III study
comparing docetaxel/cisplatin/5FU (DCF) to the reference arm of CF showed that DCF significantly improved
survival compared with that seen in the cohort treated
with CF alone5. However, the modest gains in this trial
occurred at the cost of increasing toxicity.
Therefore, there is a great interest in new effective
treatment regimens with acceptable toxicity profiles as
well as increasing attention towards patient convenience and quality of life. In the past decade, several new
cytotoxic agents including irinotecan, oxaliplatin, and
capecitabine have been tested in patients with gastric
cancer6-8.
We previously conducted a phase I/II study of
capecitabine in combination with oxaliplatin and
irinotecan (COI regimen) to find the maximum tolerated dose and to evaluate the activity of the triplet in patients with advanced colorectal cancer9. The COI regimen was administered every other week and was designed to maximize the dose of irinotecan and sequence-dependent synergistic interactions among the
three drugs, while giving capecitabine and oxaliplatin at
fixed clinically relevant doses. The confirmed tumor-regression rate was 63% at the recommended dose in 27
assessable patients. The overall tolerability of COI was
also highly satisfactory, with only a few hematologic
events.
On the basis of our phase I/II data, a preliminary
study was conducted to explore the feasibility and activity of COI in patients with previously untreated advanced gastric cancer.

Patients and methods

The investigation was conducted as a mono-institutional, prospective collection of patients who were
treated by irinotecan (180 mg/m2 infused over 90 min
on day 1), followed by oxaliplatin (85 mg/m2 in a 3-hr infusion on day 2) and capecitabine (1000 mg/m2/day
orally twice daily from days 2 to 6 of a biweekly schedule). Treatment was continued up to a maximum of 8
cycles, until disease progression or unacceptable toxicity. Each patient provided a written informed consent
before being enrolled in the study.
Eligible patients had histologically confirmed inoperable or metastatic adenocarcinoma of the stomach or
gastro-esophageal junction, age between 18 and 70
years, an Eastern Cooperative Oncology Group (ECOG)
performance status score of 0 to 1, and a life expectancy
of at least 3 months. Other inclusion criteria were measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) and adequate hematolog-

E BAJETTA, E VERZONI, E FERRARIO ET AL

ic (absolute neutrophil count 1500/mm3, platelet

count 100,000/mm3 and hemoglobin 9 g/dL), renal
(serum creatinine 1.3 mg/dL) and hepatic functions
(serum bilirubin 1.25 times the institutional upper
limit of normal, and serum transaminases less than or
equal to five times the upper limit of normal). No prior
chemotherapy was allowed, except adjuvant
chemotherapy, which had to be completed at least 6
months before registration.
Patients were excluded from study if they had any other active malignancy with the exception of nonmelanoma skin cancer or in situ cervical cancer, had
documented brain metastases, uncontrolled cardiac
disease, or other clinically significant, uncontrolled coexisting illness.
Baseline evaluations included history and physical
examination, blood chemistry, complete blood count
with differentials, and assessment of ECOG performance status. In addition, imaging studies were completed within 3 weeks before registration. Blood cell
counts were performed weekly and blood chemistry at
the beginning of each cycle. Adverse events were assessed before each cycle using National Cancer Institute Common Toxicity Criteria (version 2.0; NCI-CTC
1999). Peripheral neuropathy was graded according to
the oxaliplatin-specific scale10. Patients were evaluated
for response according to the RECIST criteria after
three cycles (6 weeks) unless clinically otherwise indicated. Objective responses had to be confirmed at
least 4 weeks after the first time the response was observed. Recommended follow-up was at 3-month intervals to collect survival data and to check whether
other chemotherapy (second-line) had been performed.
All patients received antiemetic prophylaxis with
5HT3 receptor antagonists and corticosteroids before
the irinotecan and oxaliplatin infusions. Atropine sulphate, 0.25 mg, was administered subcutaneously as the
prophylactic against irinotecan-induced acute cholinergic-like syndrome. Loperamide and oral rehydration
were prescribed in the event of delayed diarrhea. No
prophylactic treatment with granulocyte colony stimulating factors was recommended.
Treatment was interrupted in the presence of grade 2
or higher events (with the exception of alopecia (grade
2), nausea or vomiting, and anemia) and was not resumed until the adverse event resolved or improved to
grade 1 or less. If treatment had to be delayed for more
than 2 weeks, or any drug discontinued permanently, all
affected patients were withdrawn from the study. In cases of severe toxicity, continuation of treatment required
reduction of doses of all cytotoxic agents reduced by
25% for all the subsequent cycles, except for grade 3 or 4
diarrhea, in which case only irinotecan and
capecitabine doses were reduced by 25%. Capecitabine
dose was reduced by 25% in case of grade 3 or 4 stomatitis and/or hand-foot syndrome. For neurological tox-

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COI REGIMEN IN ADVANCED GASTRIC CANCER

45

icity lasting longer than 7 days, the dose of oxaliplatin

only was reduced by 25% or 50% in patients with grade
2 and grade 3 peripheral neuropathy, respectively. Oxaliplatin was to be discontinued if grade 2 peripheral
neuropathy persisted between courses of treatment.
The goal of the study was a preliminary assessment of
the feasibility and activity of the COI regimen as a firstline treatment for advanced gastric cancer. Descriptive
statistical methodology was used to analyze the results.
All patients who had received at least one cycle of the
study treatment were included in analyses of response,
safety and survival on an intention-to-treat basis. Results were reported with 95% confidence intervals (CI).
Time to tumor progression (TTP) was measured from
the date of the first cycle to the first observation of progressive disease, and survival from the date of starting
treatment to the time of death from any cause. Time-related efficacy parameters for all patients were updated
up to November 15, 2008. TTP and survival were estimated using the Kaplan-Meier method.

Results
Between January 2005 and September 2006, a total of
12 consecutive patients with advanced gastric cancer
was treated at our institution. Baseline patient characteristics are summarized in Table 1. The median age was
54 years (range, 42-65). No patient had a primary tumor

Table 1 - Baseline patient characteristics (n = 12)

Characteristic
Age, years
Median (range)
Gender
Male
Female
ECOG performance status
0
1
Treatment of primary tumor
None
Surgery
Surgery & adjuvant chemotherapy
Disease status
Locally advanced
Metastatic
Recurrent
Number of organs involved
1
2
Organs involved
Lymph nodes
Peritoneum*
Liver
Stomach

No. of patients (%)

54 (42-65)
5 (42)
7 (58)
12
0
4 (33)
5 (42)
3 (25)
2 (17)
2 (17)
8 (66)
6 (50)
6 (50)
6 (50)
5 (42)
3 (36)
2 (17)

ECOG, Eastern Cooperative Oncology Group.

*Including one patient with non-measurable metastatic disease to
the peritoneum.

of the gastro-esophageal junction, and most (67%) of

the patients had undergone curative gastric resection.
The sites of metastatic involvement were liver (3 patients), lymph nodes (6 patients), and peritoneum (5 patients). One patient had only a non-measurable
metastatic disease to the peritoneum. Two patients with
newly diagnosed gastric adenocarcinoma had local-regional advanced disease confirmed by laparoscopic
staging.
Safety
All 12 patients were evaluated for toxicity. A total of
68 cycles were administered, with a median of 6 cycles
per patient (range, 1-8). No toxicity-related death occurred in the study cohort. Treatment-related adverse
effects are summarized in Table 2. Most adverse effects
were mild to moderate in intensity. Hematologic toxicity was rare, with grade 3 neutropenia occurring in 2
(17%) patients. Treatment-induced diarrhea was observed in most of the patients (83%), but only 2 (17%)
cases experienced grade 3 diarrhea. One patient withdrew consent because of gastrointestinal toxicity
(grade 3 nausea and diarrhea) that occurred soon after
the first cycle of therapy.
Treatment was delayed during 5 cycles (7% of cycles
administered) and in 4 (33%) patients due to adverse effects. Eleven patients received more than one cycle,
with 4 (36%) of them having a dose reduction in a total
of four cycles (6% of cycles). Two patients required a
dose reduction of all the drugs because of nausea or
neutropenia. Two patients needed a dose reduction of
capecitabine and irinotecan due to diarrhea.
Anti-tumor activity
One patient had non-measurable disease. Another
patient who dropped out of the study because of toxicity was not assessable due to failure to obtain a followup tumor assessment. The details of treatment efficacy
are shown in Table 3. Confirmed response was documented in 7 of 12 patients (response rate, 58%; 95% CI,
28-85%). A complete response occurred in 2 patients

Table 2 - Worst grade toxicity per patient (n = 12)

Event

Neutropenia
Anemia
Diarrhea
Nausea
Vomiting
Peripheral neuropathy
Hand-foot syndrome
AST/ALT elevation

No. of
patients

Grade 1
No. (%)

Grade 2
No. (%)

Grade 3
No. (%)

5
1
10
8
1
1
1
1

1 (20)
0
5 (50)
2 (25)
0
1 (100)
1 (100)
0

2 (40)
0
3 (30)
3 (37.5)
0
0
0
1 (100)

2 (40)
1 (100)
2 (20)
3 (37.5)
1 (100)
0
0
0

National Cancer Institute Common Toxicity Criteria version 2.0.

AST, aspartate aminotransferase; ALT, alanine aminotransferase.

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46

E BAJETTA, E VERZONI, E FERRARIO ET AL

Table 3 - Best response and survival in the study cohort (intention-to-treat analysis)
Type of response
(RECIST criteria)
Complete response
Partial response
Stable disease
Progressive disease
Unknown
Not evaluable
Overall response rate (%)
95% CI
Median TTP (mo)
95% CI
% patients censored
6-mo TTP rate*
12-mo TTP rate*
Median survival (mo)
95% CI
% patients censored
12-mo survival rate*

No. of patients (%)

3
4
2
1
1
1

(25)
(33)
(17)
(8)
(8)
(8)

58
28-85
6.4
2.6-21
42
62
31
12
9.1-29
42
46%

RECIST, Response Evaluation Criteria in Solid Tumors; CI, confidence

interval; TTP, time to tumor progression.
*Kaplan-Meier estimates.

with liver metastases and in 1 patient with locally advanced disease. Disease stabilization as best response
was observed in 2 patients. As shown in Table 4, sites of
response included liver, lymph nodes, and stomach.
With a median follow-up of 11.5 months (range, 343.5+), the median TTP was 6.4 months (95% CI, 2.6-21).
Median survival was 12 months (95% CI, 9.1-29). Four
patients were still alive at the time of last follow-up. The
estimated 1-year survival rate was 46%.
After completion of the trial, 4 (33%) patients with disease progression received second-line chemotherapy
that included a docetaxel-containing regimen (2 patients) or 5FU in combination with mitomycin (2 patients). Two responsive patients with locally advanced
disease underwent curative surgery. One of them had
achieved a complete response confirmed by pathological examination of the surgical specimen.

Table 4 - Response according to extension and site of disease

Type of extension or site

Assessable patients, n = 11
One organ involved, n = 5
Two organs involved, n = 6
Liver, n = 3
Lymph nodes, n = 6
Stomach, n = 2

Tumor response
CR + PR
No. (%)

SD
No. (%)

PD
No. (%)

7 (64)
4 (80)
3 (50)
3 (100)
2 (33)
2 (100)

2 (18)
2 (33)
2 (33)
-

2 (18)
1 (20)
1 (17)
2 (33)
-

CR, complete response; PR, partial response; SD, stable disease; PD,
progressive disease.

Discussion
The study aimed to explore the feasibility and antitumor activity of the COI regimen in patients with untreated advanced gastric cancer. Current preliminary
results suggest that the triplet regimen administered
every other week on an outpatient basis is feasible and
well tolerated. Hematologic toxicity was rare. No patient
experienced febrile neutropenia. The most common
non-hematologic toxicity was diarrhea and nausea. Only one patient discontinued treatment because of grade
3 gastrointestinal toxicity consisting of nausea and diarrhea. The COI regimen also demonstrated promising
activity, with a response rate of 58%, a median TTP of 6.4
months, and a median survival of 12 months.
Although a number of effective chemotherapy regimens have been established worldwide, no combination therapy has yet emerged as a standard of care for
gastric cancer. The benefit of adding docetaxel to CF
(DCF) compared with CF alone was shown in a multinational trial that enrolled patients with chemotherapynave advanced gastric cancer5. A significantly increased response rate was seen for DCF compared with
CF (37% vs 25%, respectively), as well as an improved
TTP (5.6 vs 3.7 months, respectively) and increased
overall survival (9.2 vs 8.6 months, respectively). However, DCF had a significant potential to expose patients to
toxic effects. The rates of grade 3 to 4 stomatitis ranged
from 21% to 27%, diarrhea from 8% to 18%, neutropenia
from 57% to 82%, and febrile neutropenia from 27% to
29%.
A recent meta-analysis that addressed the issue of
comparing a CF doublet versus triplet in which an anthracycline was added demonstrated a statistically significant benefit in overall survival for three-drug combinations11. Among three-drug combinations, the ECF
regimen seems to be better tolerated. It is noteworthy
that ECF combination therapy improved response rate
and survival compared with 5FU, doxorubicin and
methotrexate, which was considered to be a standard
regimen a decade ago12. In addition, the major disadvantages of ECF are inconvenience of protracted venous
infusion of 5FU and the need for intravenous hydration
to prevent cisplatin-induced renal toxicity.
A four-arm randomized study was conducted to investigate capecitabine and oxaliplatin as alternatives to
infusion of 5FU and cisplatin for patients with untreated advanced esophagogastric cancer13. The hazard ratio
for death was consistent with non-inferiority for the use
of capecitabine and oxaliplatin. In the secondary analysis, overall survival (11.2 months) favored epirubicin,
oxaliplatin, and capecitabine use over ECF (9.9 months)
(hazard ratio, 0.80; P = 0.02). These findings are also
supported by additional data obtained from phase III
trials. A randomized study involving patients with advanced gastric cancer showed that capecitabine was not
inferior to 5FU when substituted in the CF regimen14.

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COI REGIMEN IN ADVANCED GASTRIC CANCER

Moreover, a randomized comparative trial between infused 5FU and leucovorin combined with oxaliplatin or
cisplatin in patients suffering from advanced disease
showed a non-significant trend toward improved progression-free survival in the oxaliplatin group in comparison with the cisplatin group15.
A recent phase II trial combining irinotecan, oxaliplatin and 5FU/leucovorin administered every other
week demonstrated a very promising activity in previously untreated metastatic gastric cancer, achieving a
response rate of 68% (in 33 of 48 patients), a median
TTP of 9.6 months, and a median survival of 14.8
months16. However, this three-drug regimen produced a
high incidence of grade 3 or 4 neutropenia (52% of patients) and retained the inconvenience of protracted venous-infusion 5FU. More recently, we have shown that
COI, a new combination of capecitabine, oxaliplatin
and irinotecan administered on a biweekly schedule, is
a manageable and very active regimen in advanced colorectal cancer9.
Based on this background, it is reasonable to investigate the efficacy and tolerability of such a triplet combination in patients with gastric cancer. The current preliminary findings suggest that COI is a convenient regimen with promising activity in the front-line treatment
of advanced disease. Therefore, the efficacy of the investigational regimen will be assessed in a multi-institutional phase II study that has already been planned.

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