Clinical Study
Received: December 2, 2011
Accepted after revision: May 4, 2012
Published online: July 9, 2012

Oncology 2012;83:101–107
DOI: 10.1159/000339541

Safety Verification Trials of mFOLFIRI and
Sequential Irinotecan + Bevacizumab as First- or
Second-Line Therapies for Metastatic Colorectal
Cancer in Japanese PatientsShunsuke Kato a Hideaki Andoh e Makio Gamoh f Takuhiro Yamaguchi b
Yasuko Murakawa g Hideki Shimodaira a Shin Takahashi a Takahiro Mori c
Hisatsugu Ohori a Shun-ichi Maeda h Takao Suzuki d Satoshi Kato i
Shoko Akiyama a Yuka Sasaki b Takashi Yoshioka j Chikashi Ishioka aon behalf of Tohoku Clinical Oncology Research and EducationaInstitute of Development, Department of Clinical Oncology, Aging and Cancer, Tohoku University,
Department of Biostatistics, Tohoku University School of Medicine, c Tohoku University Hospital Cancer Center,and d Sendai Medical Center, Sendai, e Nakadori General Hospital, Akita, f South Miyagi Medical Center, Shibata-gun,gMiyagi Cancer Center, Medeshima, h Hachinohe City Hospital, Hachinohe, i Iwate Prefecture Central Hospital,
Morioka, and j Department of Clinical Oncology, Faculty of Medicine, Yamagata University, Yamagata, Japanb

Key Words
Advanced colorectal cancer ⴢ Irinotecan ⴢ Bevacizumab ⴢ
S-1 ⴢ Randomized trial

Abstract
Objective: S-1 is effective in sequential combination with irinotecan (IRIS) in treating metastatic colorectal cancer. We
conducted a randomized phase II trial of modified leucovorin, fluorouracil and irinotecan (mFOLFIRI) + bevacizumab
and sequential IRIS + bevacizumab as first- or second-line
therapies. Methods: Sixty metastatic colorectal cancer patients were randomly assigned to receive mFOLFIRI + bevacizumab or sequential IRIS + bevacizumab (7.5 mg/kg of bevacizumab and 150 mg/m2 of irinitecan, and 80 mg/m2/dayof S-1 orally from day 3 until day 16 as a 3-week course). The
primary endpoint was the safety of each method until week
12, with the secondary endpoint being the comparison of
the safety and efficacy of the two methods. Results: The© 2012 S. Karger AG, Basel
0030–2414/12/0832–0101$38.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com

Accessible online at:www.karger.com/ocl

safety of the two treatments was comparable, except that G3
anorexia and diarrhoea were less frequent with sequential
IRIS + bevacizumab. The overall response rate was 62% [95%confidence interval (CI) 40.1–79.8] versus 72% (95% CI 50.6–
86.2), and progression-free survival was 324 days (95% CI
247–475) versus 345 days (95% CI 312–594) with mFOLFIRI +bevacizumab versus IRIS + bevacizumab, respectively. Conclusion: Sequential IRIS + bevacizumab is a safe and effective method of systemic chemotherapy against metastatic
colorectal cancer and is compatible with mFOLFIRI + bevacizumab.
Copyright © 2012 S. Karger AG, Basel

Introduction

Over the past 10 years, as a result of multidisciplinary
therapies including systemic chemotherapy, there has
been a dramatic improvement in the success of treatChikashi Ishioka
4-1 Seiryo-machi
Aoba-ku, Sendai 980–8575 (Japan)
E-Mail chikashi @ idac.tohoku.ac.jp

ments against unresectable and/or recurrent colorectal
cancer [1]. Particularly, based on the results of several
clinical trials, bevacizumab was shown to extend progression-free survival (PFS) when used in combination
with other chemotherapies including irinotecan, fluorouracil and leucovorin [2], leucovorin, fluorouracil andoxaliplatin (FOLFOX) [3], leucovorin, fluorouracil andirinotecan (FOLFIRI) [4], and 5-fluorouracil and leucovorin (5-FU/LV) [5]. These results are further supported
by large-scale observational studies [6, 7]; however, instandard chemotherapy treatments, as often represented
by either FOLFOX or FOLFIRI, placement of a peripherally inserted central venous port (CV port) is required forcontinuous 5-FU infusion. The usage of CV ports cancause complications, including infections and thrombosis, resulting in decreasing the patient’s quality of life
[8, 9].
In consideration of these factors, chemotherapy regimens using oral fluoropyrimidines rather than continuous 5-FU infusion must be developed. The CapeOX regimen, which uses capecitabine, an oral fluoropyrimidine
pro-drug of 5-FU rather than 5-FU/LV, plus oxaliplatin,
has identical therapeutic effects to FOLFOX. Favourable
results were also observed when used in combination
with bevacizumab [10]. However, because of severe gastrointestinal toxicity associated with capecitabine in
combination with irinotecan (CapeIRI or XELIRI), an
effective alternative treatment to FOLFIRI has yet to be
developed [4].
S-1 is a combination of tegafur, a pro-drug of 5-FU
that consists of oral fluoropyrimidines, gimeracil (5-chloro-2,4-dihydoroxypyridine) and oteracil (potassium oxonate) at a molar ratio of 1:0.4:1 [11]. Gimeracil has a reversible competitive inhibitory effect on dihydropyrimidine dehydrogenase, a rate-limiting enzyme involved in
the metabolic degradation of 5-FU. Oteracil reduces gastrointestinal toxicity and is effective against a wide rangeof carcinomas. Against metastatic colorectal cancer, S-1
showed a response rate of 39.5%, a PFS of 5.4 months andan overall survival time of 11.9 months when used as amonotherapy [12]. Because S-1 is expected to replace
5-FU/LV, there have been several prospective clinical trials in Japan using S-1 in combination with oxaliplatin(L-OHP or SOX) [13]. Clinical trials of S-1 combined withirinotecan (IRIS) were also conducted with various
schedules or dosage regimens [14–16]. Among these, Yoshioka et al. [15] conducted phase I/II trials of sequential
IRIS and the combined treatment of staggered irinotecan
and S-1. These clinical trials were performed in order toavoid decreased therapeutic effects and increased toxici102

Oncology 2012;83:101–107

ties caused by the inhibitory effect of 5-FU and its metabolites on the bioactivation of SN-38 from irinotecan[17, 18]. The authors reported on how this treatment regimen effectively avoided toxicity and rivaled the efficacy
of previous FOLFIRI treatments; however, because theintroduction of molecular targeted drugs in Japan was
delayed, no studies were performed on the safety and efficacy of sequential IRIS in combination with bevacizumab. Thus, we report on the respective safety of sequential IRIS + bevacizumab and modified FOLFIRI(mFOLFIRI) + bevacizumab therapies against unresectable colorectal cancer. A secondary comparative study on
the safety and efficacy of both therapies was also performed.

Patients and Methods
Patient Eligibility
The eligibility criteria were as follows: (1) patients histologically diagnosed with colorectal cancer; (2) patients with either anunresectable primary tumour or distal metastatic tumours; (3) an
Eastern Cooperative Oncology Group performance status of 0 or
1; (4) the previous chemotherapy regimen had to be ^1; (5) patients of post-operative adjuvant chemotherapy 1 6 months sincelast administration of drugs; (6) in the case of second-line therapy,
first-line therapy had to be FOLFOX treatment; (7) internal organfunction maintained, i.e. white blood cell count of 3,500–
12,000/␮l, platelet count 6100,000/␮l, aspartate aminotransferase (AST) ^100 IU/l, alanine aminotransferase (ALT) ^100 IU/l,
total bilirubin ^ 1.5 mg/dl, serum creatinine ^1.2 mg/dl, serum
creatinine clearance as estimated by Cockcroft-Gault equation
650 ml/min; (8) survival expected to be at least 63 months; and(9) written informed consent obtained from the patient for trial
participation.
Exclusion criteria were as follows: (1) a history of abdominal
irradiation; (2) any complications, such as intestinal paralysis, intestinal obstruction, poorly controlled diabetes, poorly controlled
hypertension, unstable angina, hepatic cirrhosis, interstitial
pneumonia, pulmonary fibrosis or severe pulmonary emphysema; (3) body cavity fluid retention requiring treatment; (4) poorly controlled peptic ulcerations; (5) concomitant gastrointestinal
perforation or a history of perforation within 1 year prior to registration; (6) brain tumours or cerebral metastases confirmed on
imaging; (7) concomitant symptoms of cerebrovascular nerve
damage or any type of cardiac disease requiring treatment; (8)surgical treatment within 4 weeks prior to registration; (9) ableeding tendency, coagulation disorder or excessive clotting factors; (10) awaiting or on treatment for chronic inflammatory disease such as rheumatoid arthritis, with any drugs that inhibit
platelet function (aspirin or non-steroidal anti-inflammatory
drugs); (11) women who are pregnant, may be pregnant, wish to
become pregnant or are lactating; (12) men who wish their partner to become pregnant; (13) patients using irinotecan as postoperative adjuvant chemotherapy.

Kato et al.

Treatment Methods
In the sequential IRIS + bevacizumab treatment regimen, on
day 1, 7.5 mg/kg of bevacizumab was administered for 130 min,and 150 mg/m2 of irinotecan was administered continuously for
190 min. Then, for the 2-week period from days 3 to 16, divided
doses of S-1 were administered twice daily. The dosage of S-1 was
as follows: body surface area (BSA) !1.25 m2, 80 mg/day; BSA
1.25–1.5 m2, 100 mg/day, and BSA 11.5 m2, 120 mg/day as a
3-week course. Dosage for the mFOLFIRI + bevacizumab treatment regimen was as follows: 5 mg/kg of bevacizumab, 150 mg/
m2 of irinotecan, 200 mg/m2 of L-leucovorin, 400 mg/m2 of 5-FUby rapid intravenous infusion on day 1, and 2,400 mg/m2 of 5-FU
for 46 h by continuous intravenous infusion as a 2-week course.
The treatment protocol period was set at 12 weeks in both groups,
and treatment was continued until the criteria for discontinuationof the trial were met.
The criteria for commencement of treatment in each course
were as follows: white blood cell count 63,000/␮l, platelet count675,000/␮l (mFOLFIRI + bevacizumab) or 6100,000/␮l (IRIS +bevacizumab), AST ^100 IU/l, ALT ^100 IU/l, total bilirubin^1.5 mg/dl, and serum creatinine ^1.2 mg/dl. In addition, diarrhoea of grade 0 and improvement in any other non-haematologic toxicity (excluding constipation, loss of appetite, loss of hair,chromatosis and dysgeusia) of grade ^1 was required. In patientswhere the criteria for commencement of treatment were not met,
treatment was delayed until all necessary requirements were completely satisfied. Treatment was discontinued in those patientswhere the criteria for commencement of treatment were not met
even after a delay of 63 weeks.
The criteria common to both groups for discontinuation of
bevacizumab treatment were as follows: (1) any grade of haemoptysis, gastrointestinal perforation, reversible leucoencephalopathy syndrome; (2) grade 63 thromboembolism, haemorrhage or
hypersensitivity reaction, and (3) grade 4 proteinuria or hypertension. In patients with grade 2 haemorrhage, treatment was withdrawn until improvement to grade 0, and treatment was discontinued in patients where grade 2 haemorrhage recurred. Treatment was discontinued in patients with grade 3 hypertension that
could not be controlled by medication. Treatment was withdrawn
in the following situation: patients with grade 2 or 3 proteinuria
until proteinuria was ^2 g as determined by 24-hour urine collection analyses, with grade 3 or 4 liver dysfunction until improvement to either grade 1 or baseline, and in instances of recurrence.
In the IRIS group, S-1 administration was stopped if any of
the following adverse effects occurred during the course: (1)grade 63 leucopenia or neutropenia in addition to other grade
63 non-haematological toxicity, until patient recovery; (2) grade
62 thrombocytopenia, diarrhoea, stomatitis, nausea or vomiting; (3) serum creatinine 61.5! the upper limit of normal, and(4) AST or ALT 6100 IU/l. Any patients exhibiting grade 64
leucopenia or neutropenia, grade 63 thrombocytopenia, diarrhoea, stomatitis, nausea or vomiting, non-haematological toxicity, or AST or ALT 6200 IU/l during the study were administered a lower dosage of IRIS in the next course of treatment. The
low dosage of S-1 (level 1) was 50 mg/day for BSA !1.25 m2, 80
mg/day for BSA 1.25–1.50 m2, and 100 mg/day for BSA 11.5 m2.
For irinotecan, level 1 was 120 mg/m2 and level 2 was 100 mg/m2;
no increase was made once dosage decreased. Also, in the mFOLFIRI + bevacizumab regimen, dosage was reduced in patients

Safety Verification Trials of mFOLFIRI
and IRIS + Bevacizumab

with grade 64 leucopenia or neutropenia, grade 63 thrombocytopenia, diarrhoea, stomatitis, nausea or vomiting or non-haematological toxicity as follows: 120 mg/m2 of irinotecan and 200
mg/m2 of 5-FU (bolus) for level 1, and 100 mg/m2 of irinotecan,
200 mg/m2 of 5-FU (bolus) and 2,000 mg/m2 of 5-FU (infusion)
for level 2.
With regard to safety data, the patients’ health status was observed and blood samples were tested during weekly medical examinations by the attending physician until 4 weeks after commencing treatment and repeated after the fifth week at the startof each new course of treatment. Adverse events were evaluatedaccording to the Common Terminology Criteria for Adverse
Events version 3.0, and effectiveness was observed according to
the Response Evaluation Criteria in Solid Tumors 1.0. Computed
tomographic scans were performed every 6 weeks. Effectivenesswas judged comprehensively using blinded tests on the treatment
methods by 3 or more physicians not including primary physicians.
Interim Analysis about Safety
After 3 cases have been registered in each group, registration
was stopped to evaluate the safety of the two treatments (step 1).
After the confirmation of the safety of the two treatments by theefficacy and safety evaluation committee, registration was reopened with 60 patients enrolled (30 per group; step 2).
Statistical Analysis
While attempting to detect a frequency of 610% with 95%
probability for the occurrence of adverse events, we determinedthat the sample size would include 30 patients in each experimental group or 60 patients overall in the two experimental groups[19]. Patients’ background, safety and efficacy data were summarized as frequencies and percentages. The ␹2 test was used to compare between groups, while the Kaplan-Meier method was used
to analyse PFS.

Results

Patient Background
From November 2007 to February 2010, 60 patientswere registered from the 12 institutes of the Tohoku
Clinical Oncology Research and Education Society.
These patients were randomly assigned to either themFOLFIRI + bevacizumab or sequential IRIS + bevacizumab groups, with 30 patients in each group. Patient
backgrounds are presented in table 1; the median age was62.5 (range 46–77) and 62 years (range 31–73) in themFOLFIRI + bevacizumab and sequential IRIS + bevacizumab group, respectively. Many patients were receiving first-line treatment (24 patients in the mFOLFIRI +bevacizumab group and 23 patients in the IRIS + bevacizumab group). No significant bias was seen between
the two groups.

Oncology 2012;83:101–107

103

Safety Verification Test (Step 1)
Step 1 of this trial was to register 3 patients at a time
into the two experimental chemotherapy regimen groups
and evaluate the initial safety for 12 weeks. The last patient was registered in April 2008 when patient registration was temporarily suspended and initial safety was assessed. Except for 1 patient in the mFOLFIRI + bevacizumab group with gastrointestinal perforation (G3), noother severe adverse events occurred. Because international phase III and verification trials in combination
with FOLFOX treatment in a Japanese population cite
gastrointestinal perforation as an expected adverse event,the efficacy and safety evaluation committee recommended proceeding to step 2 while maintaining utmost
vigilance with regard to patient safety.
Safety Verification Trial (Step 2)
By February 2010, 60 patients had been registered in
the study, including the 6 patients from step 1 and wererandomly allocated to the two experimental groups (table 1). Although one adverse event of gastrointestinal perforation (G5) was observed in the mFOLFIRI + bevacizumab group, this was determined to be due to progression of an underlying disease (table 2) and not due to theexperimental treatment. With regard to G3/4 haematological toxicities in the mFOLFIRI + bevacizumab andsequential IRIS + bevacizumab treatment groups, neutropenia was seen at a rate of 48 and 38%, respectively.
Although statistical differences were not observed, G3/4
gastrointestinal toxicities were more frequent in themFOLFIRI + bevacizumab group than in the sequential
IRIS + bevacizumab group (anorexia 17.9 and 3.4%, nausea 7.1 and 0%, diarrhoea 14.3 and 6.9%, respectively).
G3/4 severity in hypertension, which is the representative
adverse event of bevacizumab, was confirmed as 3.6% in
the mFOLFIRI + bevacizumab group, whereas it was notobserved in the sequential IRIS + bevacizumab group. No
patient experienced severe proteinurea, thrombosis or
haemorrhage in either group.
Comparison of Efficacy
The treatment methods were blind, and efficacy wascompared by judging the response rate with a 3-person
decision committee. The overall response rate (ORR) in
the mFOLFIRI + bevacizumab group versus the sequential IRIS + bevacizumab group was 61.5% [95% confidence interval (CI) 40–80] and 72.0% (95% CI 51–86),
respectively (table 3). Two patients showed complete response in the sequential IRIS + bevacizumab group. The
median PFS was 324 days (95% CI 247–475) in the mFOL104

Oncology 2012;83:101–107

Table 1. Characteristics of patients

Age, years
MedianRange
Males/females
ECOG performance status01
Primary legion
Colon
RectumBothCancerAdvanced
Recurrent
Histology
WellModerately
Poor
Other
Primary site
Yes
No
Number of metastases
1
2
3
Adjuvant chemotherapy
YesNo
Prior chemotherapy
YesNo

mFOLFIRI +bevacizumab(n = 30)

IRIS +
bevacizumab(n = 30)

62.5
46–77
18/12

62
31–73
17/13

24
6

27
3

17
12
1

17
13
0

22
8

20
10

7
20
2
1

7
22
0
1

5
25

6
24

17
9
4

16
10
4

5
25

7
23

24
6

25
5

ECOG = Eastern Cooperative Oncology Group.

FIRI + bevacizumab group and 345 days (95% CI 312–594) in the sequential IRIS + bevacizumab group (fig. 1).
Statistical significance was not observed between the twogroups (p = 0.71).

Discussion

Systemic chemotherapy against unresectable or recurrent colorectal cancer was developed on the basis of thesuccessful combination therapy of 5-FU and L-leucovorin. Continuous 5-FU infusion and cytotoxic drugs (e.g.
irinotecan and L-OHP, as well as other molecular targetKato et al.

Table 2. Adverse events of the two treatments

Adverse event

mFOLFIRI + bevacizumab
G0

G1

G2

G3

Non-haematological
Anorexia
NauseaVomiting
Diarrhoea
Mucositis
Fatigue
GI perforation
Bleeding
Hypertension
Proteinuria

10
10
20
12
17
14
26
20
20
20

5
7
6
12
10
8

8
9
1

5
2
1
4

7
3
3

1
2
2

1

Haematological
Leucopenia
Neutropenia
Thrombopenia

5
31
23

6

12
11

4
8

1
4

IRIS + bevacizumab
G4

2
1

G5

1

5

4

grade >3, %

G0

G1

G2

G3

17.9
7.1
3.6
14.3
0.0
7.1
7.1
0.0
3.6
0.0

13
16
28
15
23
17
29
21
24
22

10
11

5
2

1

11
6
9

1
3

8
2
2

1
3

14.3
48.1
0.0

12
121
22

3

1
2

9
6

5
7
1

200

300

6

G4 G5

4

grade >3, %p value(␹2 test;
G3,4)

3.4
0.0
3.4
6.9
0.0
0.0
0.0
0.0
0.0
0.0

0.076
0.143
0.980
0.364
(–)
0.143
0.143
(–)
0.304
(–)

17.2
37.9
3.4

0.409
0.598
0.286

GI = Gastrointestinal. 1 Frequency of G0 and G1.

Table 3. Overall response of the two treatments
100

mFOLFIRI +bevacizumab

IRIS +
bevacizumab

CR
PR
SD
PD
NE
Total

0
16
8
2
4
30

2
16
5
2
5
30

RR, %

61.5 (40.1–79.8)

72.0 (CI 50.6–86.2)

Figures in parentheses are 95% CIs.
CR = Complete response; PR = partial response; SD = stabledisease; PD = progressive disease; NE = not evaluated.

ed drugs, such as bevacizumab, cetuximab and panitumumab) are used concomitantly or sequentially to yielda median survival time that exceeds 2 years; however,continuous 5-FU infusion necessitates the insertion of aperipherally inserted central catheter or CV port, which
can increase infection and thromboembolism risks. In
order to circumvent these drawbacks, novel treatment
options with oral fluoropyrimidines are being developed
to replace the need for 5-FU infusions. The oral fluoroSafety Verification Trials of mFOLFIRI
and IRIS + Bevacizumab

PFS (%)

75

50

25

0
0

100

400 500
Time (days)

600

700

800

900

Fig. 1. Kaplan-Meier PFS curves of patients with metastatic
colorectal cancer treated with mFOLFIRI + bevacizumab (dottedline) and IRIS + bevacizumab (solid line).

pyrimidine S-1 exhibits a lower frequency of diarrhoea
and hand-foot syndrome when compared with capecitabine, and S-1 has a higher tolerance level among Japanesepeople. Therefore, treatments such as SOX and IRIS are
being developed in Japan to replace FOLFOX and FOLFIRI therapies, and it has been suggested that S-1 may be
Oncology 2012;83:101–107

105

able to replace 5-FU/LV [12–14]. Furthermore, because
molecular targeted drugs, such as bevacizumab, cetuximab and panitumumab, have been introduced into routine clinical use in Japan, it has become important to evaluate the safety and efficacy of combined therapies on thebasis of these drugs and on the new oral fluoropyrimidines.
Prior to this study, we tested the safety and efficacy of
sequential IRIS therapy, which we found to have a low
toxicity and high efficacy [13]. In this study, among patients with G3 or higher haematological toxicities, no significant differences between the two groups were observed with regard to neutropenia and/or leucopenia, although a lower trend was observed in the sequential IRIS
+ bevacizumab group. Muro et al. [16] performed a phase
II/III trial comparing mFOLFIRI with irinotecan + S-1
therapy as a second line of treatment for patients withunresectable recurrent colorectal cancer. Although theiradministration method differed from our sequential IRIS
therapy, as Muro et al. [16] did not use bevacizumab in
their study, the frequency of G3/4 neutropenia in themFOLFIRI (150 mg/m2/2 weeks of irinotecan) and IRIS
groups showed a similar trend to our data (52.1 and36.2%, respectively), indicating that IRIS exhibits lessneutropenic toxicity.
The incidence of gastrointestinal toxicity observed inthis study in the mFOLFIRI + bevacizumab group wasnearly identical to that in the FOLFIRI group (43.2–
53.6%) as reported by a BICC-C study [4]. As with haematological toxicities, the frequency of non-haematological toxicity was lower in the sequential IRIS + bevacizumab group than in the mFOLFIRI + bevacizumab
group. Furthermore, the frequency of reported gastrointestinal toxicities, such as loss of appetite (11%) and diarrhoea (20.5%), in the sequential IRIS + bevacizumab
group of our study tended to be lower than that in the
IRIS group in the study of Muro et al. [16]. This difference
may be due to the following reasons: (1) all patients in the
study of Muro et al. [16] were undergoing second-line
treatment, and (2) the different administration method
used placed a greater emphasis on irinotecan dose intensity than our sequential IRIS method. Muro et al. [16] alsomentioned that raising the dose intensity of irinotecan
was among the effective strategies for patients resistant tooxaliplatin-based chemotherapy; however, with regard tothese adverse events, we believe that raising the dose intensity of S-1 rather than that of irinotecan is the better
strategy for first-line treatment with regard to safety. Finally, as regards efficacy, the median PFS in both groups
was about nearly a year. Although the number of patients
106

Oncology 2012;83:101–107

in the current study was small, the level of efficacy seems
to be higher than that in previous studies. The data on
overall survival time are currently being analysed in afollow-up study.
Recently, Yamada et al. [20] reported the results of aphase II study on IRIS combined with bevacizumab(SIRB study). In the SIRB regimen, S-1 is administered ondays 1–14 of a 21-day cycle, but the dose intensity of S-1,
irinotecan and bevacizumab was equivalent to that of thesequential IRIS + bevacizumab regimen. Toxicity in the
SIRB regimen was low and manageable (G3/4 neutropenia 26%, G3/4 anorexia 12%, G3/4 diarrhoea 8%). The
ORR was 67% (95% CI 52.1–79.1) and the median PFS was
373 days (95% CI 299–440), which is comparable with oursequential IRIS + bevacizumab therapy.
From these results, we concluded that the combinationof S-1, irinotecan and bevacizumab could be an effective
primary therapy in Japanese patients, compared withmFOLFIRI + bevacizumab. Moreover, this regimen
could reduce the risk of infection because it does not require a CV port. Therefore, sequential IRIS + bevacizumab therapy, a very promising treatment method, should
be developed further in a larger randomized clinical trial.
We are currently in the process of planning a phase III
clinical trial in Japan comparing IRIS + bevacizumab
with CapOX/FOLFOX + bevacizumab.

Acknowledgement
The Tohoku Clinical Oncology Research and Education was
the sponsor of this trial.

Disclosure Statement
Chikashi Ishioka is partly supported by research funding from
Chugai Pharmaceutical Co., Ltd., and Novartis Pharma, Inc.

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