Phase II Study of Trastuzumab/Docetaxel for Gastric Cancer
Tohoku J. Exp. Med., 2021, 254, 49-55

49

Phase II Study of the Reuse of Trastuzumab with Docetaxel
beyond Progression after First-Line Treatment in Second-Line
Treatment for Unresectable, Metastatic Gastric Cancer(T-CORE1203)
Masanobu Takahashi,1,2 Yasuhiro Sakamoto,3 Kazunori Otsuka,4 Mariko Kanbe,5Hisatsugu Ohori,6 Yoshiaki Shindo,7 Hiroshi Honda,8 Ken Saijo,1,2 Kota Ouchi,3
Yasuko Murakawa,4 Hidekazu Takahashi,6 Sadayuki Kawai,3 Yuichi Tanaka,7Takuhiro Yamaguchi,9 Hideki Shimodaira,1,2 Takashi Yoshioka10 and
Chikashi Ishioka1,2,11
Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan
Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai,
Miyagi, Japan3
Department of Medical Oncology, Osaki Citizen Hospital, Osaki, Miyagi, Japan
4
Department of Medical Oncology, Miyagi Cancer Center, Natori, Miyagi, Japan
5
Department of Internal Medicine, Senseki Hospital, Higashimatsushima, Miyagi, Japan
6
Department of Clinical Oncology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Miyagi, Japan
7
Department of Gastroenterological Surgery, Nakadori General Hospital, Akita, Akita, Japan
8
Department of Surgery, Sendai Open Hospital, Sendai, Miyagi, Japan
9
Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan10
Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Yamagata, Japan
11
Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
1
2

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patientswith unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to beelucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective
for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm,
open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education
Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer andwere refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6
mg/kg trastuzumab and 60 mg/m 2 docetaxel every 3 weeks. The primary endpoint was the overall
response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints
were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patientswere enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patientsamong the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, andthe median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The mostfrequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was notachieved. The results support a current consensus that the continuation of trastuzumab in second-line
therapy for gastric cancer is not a recommended option.
Keywords: docetaxel; gastric cancer; HER2; reuse beyond progression; trastuzumab
Tohoku J. Exp. Med., 2021 May, 254 (1), 49-55.

Received February 10, 2021; revised and accepted April 6, 2021. Published online May 29, 2021; doi: 10.1620/tjem.254.49.
Correspondence: Chikashi Ishioka, Department of Clinical Oncology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
e-mail: chikashi@tohoku.ac.jp©2021 Tohoku University Medical Press. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 International License (CC-BY-NC-ND 4.0). Anyone may download, reuse, copy, reprint, or
distribute the article without modifications or adaptations for non-profit purposes if they cite the original authors and source properly.
https://creativecommons.org/licenses/by-nc-nd/4.0/

49

50

M. Takahashi et al.

Introduction
Gastric cancer has been ranked fifth as the most frequently diagnosed cancer and the third leading cause ofdeath worldwide (Bray et al. 2018). Gastric cancer is estimated to be newly diagnosed in 1,030,000 individuals andresponsible for 782,000 deaths (Bray et al. 2018). For
patients with nonresectable, advanced, or metastatic gastriccancer, chemotherapy is the first treatment option. The
combination of fluoropyrimidine and platinum drugs is thefirst-line standard therapy for these patients (Mizrak Kaya
et al. 2017).
The ToGA study showed that adding trastuzumab, ananti-human epidermal growth factor receptor 2 (ant-HER2)
antibody, to capecitabine plus cisplatin or fluorouracil plus
cisplatin as the first-line treatment improved the overall survival (OS) of patients with HER-2-overexpressed advanced
gastric cancer (Bang et al. 2010). The median OS was 13.8
months (95% confidence interval [CI] 12-16) in the trastuzumab plus chemotherapy arm compared with 11.1 months(95% CI 10-13) in the chemotherapy alone arm (hazard
ratio [HR] 0.74, 95% CI 0.60.91, p = 0.0046) (Bang et al.
2010). The median progression-free survival (PFS) was 6.7
months versus 5.5 months (HR 0.71, 95% CI 0.59-0.85, p =0.0002). According to these results, trastuzumab combinedwith fluoropyrimidine and platinum has become the mostrecommended regimen in previously untreated patients withgastric cancer (Boku 2014). As second-line therapy, ramucirumab, an anti-vascular endothelial growth factor receptor
2 (anti-VEGFR2) antibody, plus paclitaxel is a standard
regimen for patients with advanced gastric cancer regardless of HER2 expression status (Wilke et al. 2014). The
RAINBOW trial showed that OS (median 9.6 months vs.
7.4 months, HR 0.807, 95% CI 0.68-0.96) and PFS (median
4.4 months vs. 2.9 months, HR 0.64, 95% CI 0.54-0.75)
were significantly longer in the ramucirumab plus paclitaxelgroup than in the placebo plus paclitaxel group (Wilke et al.
2014). The objective response rate (ORR) was also greaterin the ramucirumab plus paclitaxel group (28% vs. 16%, P= 0.0001) (Wilke et al. 2014).
It is still unclear whether patients with HER2-positive
gastric cancer would benefit from the sequential use of
trastuzumab in second-line therapy beyond progression
after first-line use of trastuzumab. In HER2-positive breast
cancer, second-line use of anti-HER2 therapy, mainly
trastuzumab emtansine (T-DM1), beyond progression on
first-line therapy is a recommended option (Ponde et al.
2018). At the time we planned this study in 2012, there
were no clinical trials that showed the efficacy of continuing anti-HER2 therapy in second-line therapy in gastriccancer patients. In addition, which treatment was best
among taxanes, irinotecan, other drugs, or combinations insecond-line therapy for patients with gastric cancer, regardless of HER2 status, had not been fully established until the
WJOG4007 trial (Hironaka et al. 2013) and the RAINBOW
trial (Wilke et al. 2014) were reported. On the other hand,in HER2-positive breast cancer, a combination of docetaxel
and trastuzumab was regarded as a promising treatment
options (Inoue et al. 2010, Valero et al. 2011).
The aim of the present phase II study was to evaluate
the efficacy and toxicity of trastuzumab plus docetaxel inpatients with HER2-positive advanced gastric cancer who
had previously received trastuzumab, fluoropyrimidine, andcisplatin.

Methods
EthicsThis single-arm, phase II trial (UMIN000010869)
enrolled patients at seven institutions that participate in the
Tohoku Clinical Oncology Research and Education Society(T-CORE) in Japan. The study was conducted in accordance with the Declaration of Helsinki. The protocol wasapproved by institutional ethics committees and/or institutional review boards at all sites that participated. Written
informed consent was obtained from all patients.
Patients
Patients were regarded eligible if they were aged 20
years or older; had histologically confirmed unresectable,
recurrent, or metastatic gastric adenocarcinoma with HER2
overexpression (immunohistochemistry [IHC] score 3+ or
IHC score 2 and fluorescence-in-situ-hybridization-positive[FISH-positive] before first-line treatment) and measurable
lesions according to the Response Evaluation Criteria in
Solid Tumors version 1.1; an Eastern Oncology Group
Performance Status (ECOG-PS) of 0-2; received one chemotherapeutic regimen, including trastuzumab; did notreceive docetaxel; estimated to be alive at least 3 months
since enrollment in the study; and had appropriate bonemarrow and liver functions [white blood count (WBC)
3,000-12,000/mm3, neutrophil ≥ 1,500/mm3, hemoglobin ≥8.0 g/dl, platelet ≥ 7.5 × 104/mm3, aspartate aminotransferase (AST) ≤ 100 U/l, alanine aminotransferase (ALT) ≤ 100
U/l, and creatinine (Cr) ≤ 1.5 mg/dl].
Treatment
Eight mg/kg of trastuzumab was administered intravenously on day 1 for 90 min, and then 6 mg/kg was administered intravenously for 30 min every 3 weeks. Sixty mg/m2
of docetaxel was administered intravenously for 60 min on
day 1 and continuously administered every 3 weeks.
Endpoints
The primary endpoint was ORR. Secondary endpoints
were PFS, 6-month survival rate, OS, and toxicities. PFS
was defined as the time from the initiation of protocol treatment to the first radiologic confirmation of disease progression or death from any cause. OS was defined as the timefrom the initiation of protocol treatment to death from any
cause. Tumor response was evaluated based on investigatorassessment by using computed tomography taken every 6
weeks according to the Response Evaluation Criteria in51Phase II Study of Trastuzumab/Docetaxel for Gastric Cancer

Solid Tumors version 1.1. The ORR was defined as thenumber of patients with a complete response (CR) or partial
response (PR) divided by the number of all patients withmeasurable lesions. The disease control rate (DCR) was
defined as the number of patients with CR, PR, or stabledisease (SD) divided by the number of response-evaluable
patients.
Statistical analysis
In 2012, at the time this study was planned, there wasonly one phase III study that analyzed the efficacy of second-line treatment in gastric cancer (Thuss-Patience et al.
2011). In the AIO study, OS was superior in the irinotecan
arm to the best supportive care arm, but no ORR was
observed in the irinotecan arm (Thuss-Patience et al. 2011).
In contrast, a phase II study showed an ORR of 16% in
patients who received docetaxel in second-line therapy after
failure of fluoropyrimidine and platinum (Lee et al. 2008).
In light of these reports, the threshold ORR was set to 15%,
and the expected ORR was set to 35%. At a one-sided significance of 0.05 and power of 80%, the minimum numberof patients required was estimated to be 28. Considering
ineligible cases, we decided that 30 patients were to beenrolled in this study. Patient registration period wasplanned to be 2 years from Mar 2013, and follow-up period
was planned to be 2 years.

Results
Patient characteristics
A total of 27 patients were enrolled from 7 institutionsin Japan between May 2013 and June 2016. The patient
recruitment period was initially planned to be two years.
However, due to poor accrual, patient registration was
extended to June 2016, and then stopped. The median follow-up period was 11.8 months.
The clinicopathological characteristics of the patientsare shown in Table 1. The median age was 67 (range, 38-79
years). There were 22 men and 5 women. The ECOG-PS
score was 0 in 19 patients and 1 in 8 patients. HER2 status
before first-line treatment was IHC score 3+ in 25 patientsand IHC score 2+/FISH-positive in 2 patients. Previous
chemotherapeutic regimens were capecitabine, cisplatin,
and trastuzumab in 14 patients; S-1, cisplatin, and trastuzumab in 12 patients; and another in 1 patient. Seven
patients had received postoperative adjuvant chemotherapy.
Efficacy
Among the 27 patients enrolled in this study, 1 patient
without measurable lesions was excluded from the analysis
for ORR and PFS. The reason for the cessation of the treatment protocol was disease progression in 23 patients andtoxicities in 4 patients.
PR was obtained in three patients, and no CR was
observed (Table 2). The ORR was 11.5% (90% CI 1.221.8%), which was not statistically significantly superior to
the pre-planned threshold of 15%. SD was observed in 12
patients (46%) (Table 2). One patient was not evaluable
because of disease progression before CT evaluation.
Median PFS was 3.2 months (95% CI 1.8-4.6 months, Fig.
1A). The 6-month survival rate was 85% (95% CI 65-94%,

Table 1. Characteristics of patients enrolled in this study (n = 27).
FactorSex
Age
HER2 status
Recurrent or metastatic site

History of Surgery
Histology
Previous regimens

Men
Women
MedianRange
IHC 3+IHC 2+ and FISH+
Liver
LN
Peritoneum
Lung
Local
OthersYes
No
Intestinal
DiffuseXP + Trastuzumab
SP + Trastuzumab
Others

n

%

22
5
67
38-79
25
2
19
14
6
2
2
2
15
12
17
10
14
12
1

81
19

93
7
70
52
22
7
7
7
56
44
63
37
52
44
4

IHC, immunohistochemistry; LN, lymph node; XP, capecitabine plus cisplatin; SP, S-1 plus
cisplatin.

52

M. Takahashi et al.
Table 2. Best tumor response and overall response rate.

FactornBest tumor response

%

CR

0

0

PR
SD
PD
NE

3
12
10
1

11.5
46.2
38.5
3.8
11.5
57.7

ORR
DCR

CR, complete response; PR, partial response; SD, stabledisease; PD, progressive disease; NE, not evaluable; ORR,
overall response rate; DCR, disease control rate.

Figure 1

Fig. 1B), and the median OS was 11.6 months (95% CI 8.318.5 months, Fig. 1B).
Adverse events
Among the 27 patients, toxicities of all grade by
CTC-AE included anorexia (55.6%), fatigue (55.6%), nausea (33.3%), stomatitis (29.6%), neuropathy (29.6%) andothers (Table 3). Grade 3 or higher toxicities included
anorexia (14.8%), febrile neutropenia (14.8%), fatigue(7.4%), and others (Table 3). No treatment-related death
was observed.

Discussion
This phase II trial did not demonstrate that trastuzumab plus docetaxel therapy was an effective regimen in

A
Median PFS 3
3.2
2M(95% CI 1.8-4.6)

B
Median OS 11.6 M(95% CI 8.3-18.5)
6-month survival rate
85.2% (95% CI 65.2-94.2)

Fig. 1. Clinical outcome of the patients enrolled in this study.
(A) Kaplan-Meyer curve for progression-free survival of patients enrolled in this study.
(B) Kaplan-Meier curve for overall survival of patients enrolled in this study.

53

Phase II Study of Trastuzumab/Docetaxel for Gastric Cancer
Table 3. Adverse events observed in > 5% of all enrolled patients (n = 27).
FactorGrade 1

Grade 2

Grade 3

Grade 4All

Grade 3-4

n

%

n

%

n

%

n

%

n

%

n

%

Hematological

Febrile neutropenia

n.a.

n.a.

n.a.

n.a.

3

11.1

1

3.7

4

14.8

4

14.8

Non-hematological

Anorexia
Fatigue
NauseaStomatitis
Neuropathy
Fever up
Diarrhea
Abdominal pain
Hand-foot syndrome

5
7
5
5
7
4
2
3
1

18.5
25.9
18.5
18.5
25.9
14.8
7.4
11.1
3.7

6
6
3
2
1
1
1
1
1

22.2
22.2
11.1
7.4
3.7
3.7
3.7
3.7
3.7

4
2
1
1
0
0
0
0
0

14.8
7.4
3.7
3.7
0.0
0.0
0.0
0.0
0.0

0
0
0
0
0
0
0
0
0

0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0

15
15
9
8
8
5
3
4
2

55.6
55.6
33.3
29.6
29.6
18.5
11.1
14.8
7.4

4
2
1
1
0
0
0
0
0

14.8
7.4
3.7
3.7
0.0
0.0
0.0
0.0
0.0

evaluated by CTC-AE ver 4.0. n.a., not available.

patients with advanced HER2-positive gastric cancer who
were refractory to trastuzumab, fluoropyrimidine, and cisplatin.
Some recent retrospective and phase II studies havesuggested the potent efficacy of continuing trastuzumab
beyond progression on first-line treatment. Li et al. (2016)
reported in their retrospective analysis that 32 patientstreated with trastuzumab plus second-line chemotherapy
had longer PFS of the second-line therapy compared with
27 patients treated with second-line chemotherapy alone(median 3.1 vs. 2.0 months, P = 0.008) but did not have statistically significantly longer OS after the second-line therapy (median 10.5 vs. 6.5 months, P = 0.172). Palle et al.
(2017) also performed a retrospective study analyzing 104
patients and showed that continuing trastuzumab was statistically significantly associated with longer PFS (median 4.4
vs. 2.3 months, P = 0.002) and OS (median 12.6 vs. 6.1
months, P = 0.01). They also demonstrated that in the multivariate analysis incorporating ECOG-PS, the continuationof trastuzumab remained significantly associated with longer PFS and OS (Palle et al. 2017). Furthermore, Narita etal. (2017) reported in their retrospective analysis that PFS
tended to be longer in the continuation of the trastuzumab
group but with no significance (median 4.0 vs. 2.3 months,
P = 0.14). In a meta-analysis of five reports, including the
aforementioned ones, the addition of trastuzumab to second-line chemotherapy beyond progression at first-line
therapy, including trastuzumab, was not associated withlonger OS or higher ORR but was associated with longer
PFS compared with chemotherapy alone (HR 0.64, 95% CI
0.45-0.91, P < 0.05) (Ter Veer et al. 2018).
More recently, Horita et al. (2019) reported the resultsof their phase II study in which the ORR was 21.4% among
28 patients who received trastuzumab plus weekly paclitaxel as second-line therapy regardless of trastuzumab use
in first-line therapy. Of all patients, the median PFS was 4.6
months, and the median OS was 9.6 months (Horita et al.

2019). However, there were no significant differences in
ORR, PFS, or OS between the 20 patients who received
trastuzumab beyond progression and the 8 patients without
trastuzumab use in first-line therapy (Horita et al. 2019). In
addition, Makiyama et al. (2020) have recently shown intheir randomized phase II study that the PFS of patientswith HER2-positive gastric or gastroesophageal cancer inthe paclitaxel plus trastuzumab arm (median 3.7 vs. 3.2
months, HR 0.91, 80% CI 0.67-1.22) and ORR (33% vs.
32%, P = 1.00) were not superior to those in the paclitaxelarm. In light of the results of their retrospective and phase
II studies, the efficacy of trastuzumab beyond progression
in gastric cancer seems quite modest.
In our single-arm phase II study, the ORR, median
PFS, and OS were 11.5%, 3.3 months, and 11.8 months,
respectively. The primary endpoint ORR was not only
achieved but also observed to be relatively low despite theuse of combination with docetaxel in second-line therapy.
The reason for this is yet to be determined. One speculation is that this may be due to the small sample size of thisstudy. In contrast, PFS and OS were comparable to thoseof other retrospective or phase II studies (Li et al. 2016;
Narita et al. 2017; Palle et al. 2017; Ter Veer et al. 2018;
Horita et al. 2019; Makiyama et al. 2020). The RAINBOW
trial showed that the median PFS and OS of patients treatedwith ramucirumab plus paclitaxel at second-line therapy
were 4.4 and 9.6 months, respectively (vs. 2.9 and 7.4
months of those with placebo plus paclitaxel) (Wilke et al.
2014). The PFS and OS in our study were comparable tothose in the RAINBOW trial, but it cannot be concluded
that trastuzumab beyond progression is an optimal approachin second-line treatment for patients with HER2-positive
gastric cancer.
In HER2-positive gastric cancer, anti-HER2 therapy atsecond-line therapy, other than trastuzumab, has not shownpromising results, either. The phase III Tytan trial showedthat lapatinib plus paclitaxel did not significantly prolong

54

M. Takahashi et al.

the OS or PFS (11.0 vs. 8.9 months, P = 0.10, 5.4 vs. 4.4
months, P = 0.24) of patients with HER2-amplified gastriccancer previously treated with trastuzumab, although lapatinib plus paclitaxel significantly improved the ORR (27%vs. 9%, P < 0.001) (Satoh et al. 2014). The phase II/III
GATSBY trial showed that T-DM1 was not superior to taxane as second-line therapy for patients with previously
treated HER2-positive metastatic gastric cancer, approximately three quarters of whom had received trastuzumab in
the first-line therapy (median OS 7.9 vs. 8.6 months, HR
1.15, 95% CI 0.87-1.51, P = 0.86) (Thuss-Patience et al.
2017). At present, the continuation of anti-HER2 therapy,
not just trastuzumab, in second-line therapy beyond progression on first-line therapy is not an attractive option fortreating patients with HER2-positive gastric cancer.
The reason why anti-HER2-therapy beyond progression is not effective in second-line therapy in gastric cancer
remains to be fully elucidated. Saeki et al. (2018) recently
provided a clue to address this issue. They re-analyzed
HER2 expression status in gastric cancer tissues from 33
patients who showed progression within 3 months after thecompletion of a trastuzumab-containing regimen. Of the 33
patients, 20 patients (60.6%) showed a loss of HER2 (Saeki
et al. 2018). A recent phase II trial has supported theirresult by showing that HER2 positivity in tumor tissues waslost after first-line therapy in 11 of 16 patients (69%)(Makiyama et al. 2020). We did not re-analyze HER2
expression after first-line trastuzumab-containing regimen,
however, the frequency of loss of HER2 expression
reported in the two previous other studies appear higher
than those observed in breast cancer (15-32%) (Ignatov etal. 2019, Oh and Bang 2020), which might be one of thereasons why most patients with gastric cancer are resistantto the continuation of anti-HER2 therapy.
On the other hand, more recently, Shitara et al. (2020)
have shown that trastuzumab deruxtecan, an antibody-drug
conjugate consisting of an anti-HER2 antibody and a topoisomerase inhibitor, is a promising drug in patients with
HER2-positive gastric cancer treated with two or more linesof chemotherapy. In their randomized phase II trial, ORR
was 51% in the trastuzumab deruxtecan group (n = 125),
which was higher than 14% in the physician’s choice chemotherapy group (n = 62, P < 0.001). OS was significantly
longer in the trastuzumab deruxtecan group compared within the chemotherapy group (median, 12.5 vs. 8.4 months,
HR 0.59, 95% CI 0.39-0.88) (Shitara et al. 2020). Although
trastuzumab deruxtecan was used in third-line or later setting, not soon after PD by trastuzumab therapy (Shitara etal. 2020), this drug is currently an only drug that has shown
meaningful efficacy after PD by trastuzumab in HER2positive gastric cancer.
Our study has several limitations. First, this study is asingle-arm setting. Second, the planned sample size was30, but the enrollment had to be terminated when 27
patients were enrolled since the pace of enrollment was
slower than initially expected. Nevertheless, we consider

less likely the possibility that the main interpretation waschanged because we set the minimal sample size to 28 witha threshold ORR of 15% at a one-sided significance of 0.05
and power of 80%. Therefore, just one sample was missing, and even if one more patient was enrolled and PR was
obtained, the ORR would be 14.8%, which would meanthat ORR was not significantly superior to the pre-planned
threshold of 15%.
In conclusion, our phase II study did not demonstrate
the efficacy of trastuzumab plus docetaxel therapy beyond
trastuzumab-resistant HER2-positive gastric cancer. The
results support a current consensus that the continuation of
trastuzumab in second-line therapy for gastric cancer is nota recommended option.

Acknowledgments
The authors thank Toru Ishikawa at T-CORE, andNoriko Takenaga at Department of Medical Oncology,
Tohoku University Hospital, for their technical assistance tomanagement of data. The authors also thank Enago (https://www.enago.jp) for the English language review. This study
was supported by Tohoku Clinical Oncology Research and
Education Society (T-CORE).

Author Contributions
M.T., H.S., T. Yoshioka, and C.I. conceived the designof this study. M.T., Y.S., K.O., M.K., H.O., Y.S., H.H.,
K.S., K.O., Y.M., H.T., S.K., T. Yoshioka, and H.S. obtained
informed consent from the patients. T. Yamaguchi performed the data analysis. M.T., T. Yoshioka, and C.I. wrote
the manuscript.

Conflict of Interest
Masanobu Takahashi reports receiving research funding from Ono Pharmaceutical Company. Chikashi Ishioka
reports receiving lecture fees from Taiho, Chugai, Takeda,
Bayer, Pfizer, Mochida, Asahi Kasei, Bristol-Myers Squibb,
Daiichi-Sankyo, Merck Serono, and Novartis, and researchfunding from Chugai, Taiho, Bristol-Myers Squibb,
Daiichi-Sankyo, Merck Serono, Yakult, Ono, and Novartis.
The other authors have no conflict of interest.

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