ORIGINAL ARTICLE

A phase II study of nedaplatin and 5-fluorouracil in metastaticsquamous cell carcinoma of the esophagus: The Japan ClinicalOncology Group (JCOG) Trial (JCOG 9905-DI)

Ken Kato • Kei Muro • Nobutoshi Ando • Tadashi Nishimaki •

Atsushi Ohtsu • Kenjiro Aogi • Norio Aoyama • Kagami Nagai •

Hoichi Kato • The Japan Esophageal Oncology Group of the Japan Clinical Oncology Group (JCOG)

Received: 3 November 2013 / Accepted: 12 February 2014

� The Japan Esophageal Society and Springer Japan 2014

Abstract

Background This phase II study evaluated the efficacy

and toxicity of combination chemotherapy with nedaplatin

and 5-fluorouracil (5-FU) for metastatic esophageal squa-

mous cell carcinoma.

Methods Eligibility criteria included squamous cell car-

cinoma with organ metastasis, ECOG performance status

(PS) 0–2, B 75 years, measurable disease, and adequate

organ function. Chemotherapy consisted of 5-FU (800 mg/

m2/day) on days 1–5 and a 2-h infusion of nedaplatin

(90 mg/m2) on day 1, repeated every 4 weeks. Therapy

was continued until disease progression or intolerable

adverse events. The primary end point was response rate.

Secondary end points included overall survival, progres-

sion-free survival, and toxicities.

Results Forty-two patients (39 men, 3 women; median

age 59 years; range 44–70 years) were enrolled. Twenty-

one, 21, and 0 patients had PS 0, 1, and 2, respectively. 23,

6, 3, and 18 patients had a history of surgical resection,

radiotherapy, adjuvant chemotherapy, and no therapy,

respectively. Among the 38 eligible patients, 1 and 14

complete and partial responses were observed, respec-

tively; the overall response rate was 39.5 % (90 % confi-

dence interval: 26.1–54.1 %). The median survival time

was 8.8 months. The one-year survival rate was 32.9 %.

Grade 4 neutropenia and thrombocytopenia were observed

in 7 and 2 % of 41 patients, respectively. Grade 3 nausea,

diarrhea, and stomatitis were observed in 12, 2, and 2 %,

respectively.

Conclusion Combination therapy with nedaplatin and

5-FU is highly active and well tolerated in metastatic or

recurrent esophageal squamous cell cancer and is therefore

a chemotherapy option for esophageal squamous cell

carcinoma.

K. Kato (&) � K. Muro

Gastrointestinal Oncology Division, National Cancer Center

Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

e-mail: kenkato@ncc.go.jp

K. Muro

Department of Clinical Oncology, Aichi Cancer Center Hospital,

Nagoya, Aichi, Japan

N. Ando

Department of Surgery, Tokyo Dental College, Ichikawa

General Hospital, Ichikawa, Chiba, Japan

T. Nishimaki

Department of Surgery, Ryukyu University Hospital, Nishihara,

Okinawa, Japan

A. Ohtsu

Division of Gastrointestinal Oncology, National Cancer Center

Hospital East, Kashiwa, Chiba, Japan

K. Aogi

Department of Surgery, National Hospital Organization Shikoku

Cancer Center, Matsuyama, Ehime, Japan

N. Aoyama

Department of Surgery, Kanagawa Cancer Center Hospital,

Yokohama, Kanagawa, Japan

K. Nagai

Department of Surgery, Tokyo Medical and Dental University

School of Medicine, Tokyo, Japan

H. Kato

Esophageal Surgery Division, National Cancer Center Hospital,

Tokyo, Japan

123

Esophagus

DOI 10.1007/s10388-014-0427-7

Keywords Esophageal squamous cell carcinoma �Chemotherapy � 5-FU � Nedaplatin

Introduction

Esophageal cancer, a highly virulent malignancy, was

responsible for 11,182 deaths in Japan in 2005, accounting

for 3.4 % of the country’s total cancer deaths [1];

10–20 % of patients were diagnosed with stage IV disease.

Systemic chemotherapy with cisplatin (CDDP) and 5-flu-

orouracil (5-FU) is the most commonly used first-line

regimen for advanced esophageal squamous cell carci-

noma (ESCC). CDDP and 5-FU are reported to exhibit a

synergistic effect and are also used as a standard treatment

for head and neck squamous cell cancer. However,

response rates are low at 30–55 %, and median survival is

usually shorter than 8 months [2–4]. Therefore, the treat-

ment objective is mainly long-term local tumor control.

Moreover, CDDP-based chemotherapy often induces tox-

icities such as nausea, vomiting, and renal dysfunction,

which could require dose modification or treatment pro-

longation. In general, esophageal cancer patients have

lower performance status and poorer nutrition than other

cancer patients. Therefore, novel combination therapies

are urgently needed to improve the efficacy and to over-

come toxicity in this setting.

Nedaplatin (cis-diammine-glycolatoplatinum), a novel

second-generation platinum compound, combines with

DNA, interfering with its duplication similar to CDDP. It

exhibits superior antitumor activity and less renal toxicity,

and is 10 times as water soluble as CDDP [5, 6]. An in vivo

study revealed that the combination of nedaplatin and 5-FU

is as effective as the combination of CDDP and 5-FU [7]. A

phase I study of monotherapy against various advanced

cancers demonstrates that the maximum tolerated dose and

recommended dose for phase II studies of nedaplatin are

100 mg/m2 every 4 weeks and that the dose-limiting tox-

icity is thrombocytopenia; no severe renal or gastrointes-

tinal toxicities were observed [8]. Nedaplatin produced

promising response rates in phase II trials as a mono-

therapy for the treatment of squamous cell carcinoma of the

head and neck [9], lungs [10], uterine cervix [11], and

esophagus [12]. A phase I/II study of nedaplatin combined

with 5-FU (800 mg/m2 on days 1–5) for ESCC defines a

dose of nedaplatin as 90 mg/m2 on day 1 and the dose-

limiting toxicity as sepsis. This previous study demon-

strates the safety and efficacy of a regimen combining

nedaplatin and 5-FU with a response rate of 50 %. How-

ever, these data were produced by a preliminary study that

included only 16 patients. Moreover, there are few pro-

spective studies of nedaplatin and 5-FU combination

therapy for esophageal cancer in the literature. Therefore,

the present phase II study evaluated the efficacy and tox-

icity of nedaplatin and 5-FU for metastatic ESCC.

Patients and methods

Eligibility

The eligibility criteria were as follows: pathologically con-

firmed thoracic ESCC; measurable distant or recurrent

metastasis; Eastern Cooperative Oncology Group (ECOG)

performance status (PS) 0, 1, or 2; and age, 20–75 years.

Patients who had previously received chemotherapy for

esophageal cancer or chemotherapy/radiotherapy for other

malignancies or had other active malignancies were exclu-

ded. Adjuvant chemotherapy which terminated more than

6months before recurrence was acceptable. All patients were

required to meet the following laboratory criteria within

14 days before registration: white blood cells (WBCs)

C4,000/mm3, platelet count C100,000/mm3, hemoglobin

level C10 g/dL, aspartate aminotransferase (AST)/alanine

aminotransferase (ALT) B2 times the upper normal limit at

the institution, total bilirubin B1.5 mg/dL, serum creatinine

B1.2 mg/dL, creatinine clearance C60 mL/min, and no

major electrocardiogram abnormalities.

The study was performed in accordance with the Dec-

laration of Helsinki. Written informed consent was

obtained from all patients prior to participation. The study

protocol was approved by the JCOG Clinical Trial Review

Committee and the independent ethics committee or

institutional review board at each site.

Chemotherapy

In accordance with the results of a previous study, che-

motherapy comprised 5-FU infusion (800 mg/m2) on days

1–5 and a 2-h infusion of nedaplatin (90 mg/m2) on day 1.

This regimen was repeated every 4–6 weeks for 4 courses.

Administration of both chemotherapeutic agents was dis-

continued if any of the following conditions were met:

WBCs \ 3,000/mm3, platelet count \ 75,000/mm3, total

bilirubin [ 2.0 mg/dL, serum creatinine [ 1.2 mg/dL,

and any other non-hematological toxicity C grade 2.

The doses of both agents were reduced by 30 % in

the subsequent course if at least one of the following tox-

icities was observed: WBCs \ 2,000/mm3 and platelet

count \ 50,000/mm3. The dose of 5-FU was reduced by

30 % in the subsequent course if grade 3/4 stomatitis,

nausea, vomiting, or diarrhea was observed. Treatment was

terminated when disease progression was observed,

patients refused to continue, or recovery from toxicity

delayed the initiation of the next course by more than

6 weeks from the previous nedaplatin administration.

Esophagus

123

Assessments

Esophagoscopy and computed tomography (CT) scanning

were carried out after each course to assess the response.

Primary tumor response was evaluated endoscopically

according to the modified criteria of the Japanese Society

for Esophageal Diseases [13]. The efficacy in terms of

lymph node and organ metastasis was evaluated according

to the World Health Organization (WHO) criteria (1979).

Confirmation of response after 4weeks was not required.

Acute toxicities were assessed weekly during chemother-

apy. Toxicities were evaluated according to the National

Cancer Institute Common Toxicity Criteria (NCI-CTC

version 2.0).

Statistical analysis

On the basis of JCOG 9407 trial results [2], in which the

response rate for metastatic or recurrent esophageal cancer

was 33.3 %, we initially calculated the sample size

expecting a response rate of 40 % with a threshold of

20 %. With both a and b error levels set at 0.1, the

required number of eligible patients was 36 according to

Simon’s minimax design. We finally decided on a sample

size of 40 including some ineligible patients. Therefore,

the accrual had to be stopped if there were less than 4

responses among the first 19 patients, after which an

additional 21 patients were planned to be enrolled. The

planned periods of accrual and follow-up after registration

were 2 years each.

Overall survival was defined as the time from registra-

tion to death from any cause and was censored at the date

of the last follow-up for survivors. Progression-free sur-

vival was defined as the time from registration to disease

progression or death from any cause and was censored at

the date of the last visit for patients without progression.

The time-to-event distribution was estimated using the

Kaplan–Meier method, and confidence intervals (CIs) were

calculated using Greenwood’s formula.

Results

Patient characteristics

Forty-two patients were accrued between December 1999

and June 2002 (Table 1). The median age was 59 years

(range 44–70 years). Twenty-one (50 %) patients each

exhibited ECOG PS 0 and 1. There were 23, 6, 3, and 18

patients with a history of surgical resection, radiotherapy,

adjuvant chemotherapy, and no therapy, respectively.

Major target sites were the lymph nodes, lungs, and liver in

34, 24, and 21 patients, respectively. Of the 42 patients, 1

patient who had a lung lesion after esophagectomy was

diagnosed with tuberculosis after registration and did not

receive the planned treatment. Toxicity was evaluated in 41

patients who received protocol treatment. However, 3 of

these patients were excluded: 2 because of the absence of

distant metastasis, and 1 because of ineligible histology.

Finally, efficacy was evaluated in 38 eligible patients.

Treatment

The 38 eligible patients had median treatment duration of

2.0 months (range 0.7–8.8 months) with a median of 2

treatment courses (range 1–11). Twelve patients completed

the 4 courses of protocol treatment, while 26 terminated

treatment: 20 due to progressive disease, 5 due to toxicities,

and 1 due to death during protocol treatment. After ne-

daplatin and 5-FU discontinuation, 31 patients (78.0 %)

received some type of post-therapy, including 10, 6, and 4

with chemotherapy with taxan-, vindesine-, and irinotecan-

based regimens, respectively; 6 with palliative radiother-

apy; and 2 with palliative surgery. Seven patients received

best supportive care rather than therapy.

Efficacy

Of the 38 eligible patients, 1 complete response and 14

partial responses were observed. The best response rate

was 39.5 % (95 % CI 24.0–56.6 %) (Table 2). The median

Table 1 Patient characteristics (n = 42)

No. of patients

Sex (male/female) 39/3

Median age (range) 59 (44–70)

Performance status (ECOG) 0/1/2 21/21/0

Any prior therapy 24

Surgery 15

Surgery with adjuvant chemotherapy 3

Surgery with radiotherapy 5

Radiotherapy only 1

Location of cancer

Primary site 18

Lymph node 34

Lungs 24

Liver 21

Bone 4

Other 4

None 1a

a A patient with a lung lesion was shown to have tuberculosis after

registration

Esophagus

123

survival time was 8.8 months (95 %CI 7.4–10.2 months)

and the one-year survival rate was 32.9 % (Fig. 1). Median

progression-free survival was 2.5 months (95 %CI

1.6–3.5 months) and the one-year progression-free survival

rate was 18.4 % (Fig. 2).

Toxicity

The major adverse events observed were anemia (90.2 %),

nausea (63.4 %), and neutropenia (58.5 %), which were

mostly grade 1 or 2 (Table 3). The most common grade 4

hematological toxicities were leukopenia, neutropenia, and

thrombocytopenia, which occurred in 4.9, 7.3, and 2.4 % of

the cases, respectively. The most common grade 3/4 non-

hematological toxicities were nausea, diarrhea, and sto-

matitis, which occurred in 14.6, 2.4, and 2.4 % of cases,

respectively. There was 1 treatment-related death due to

septic shock after febrile neutropenia.

Table 2 Best responses of eligible patients (n = 38)

Response No. of patients (%)

Complete response (CR) 1 (2.6)

Partial response (PR) 14 (36.8)

Stable disease 13 (34.2)

Progressive disease 9 (23.7)

Not evaluable 1 (2.6)

CR ? PR 15

Overall response rate 39.5 %; (95 %CI, 24.0–56.6 %)

CI confidence interval

Fig. 1 Overall survival (OS) of

eligible patients (n = 38)

Fig. 2 Progression-free

survival (PFS) of eligible

patients (n = 38)

Esophagus

123

Discussion

Identifying alternatives to platinum compounds is a strategy

for improving treatment outcomes. Nedaplatin has less

gastrointestinal toxicity than CDDP and exhibits anti-tumor

activity in solid tumors, especially squamous cell carcinoma

[12, 14]. The proportion of all grade nausea was reported

about 70–80 % in 5-FU and cisplatin regimen for esopha-

geal cancer, besides this trial showed 60 % of all grade

nausea patients [3, 23]. With regard to nausea, 5-FU and

nedaplatin had a slight advantage when it compared to

5-FU and cisplatin. In the present study, the response rate,

progression-free survival, and overall survival were 39.5 %

(95 %CI, 24.0–56.6 %), 2.5 months (95 %CI, 1.6–3.5

months), and 8.8 months (95 %CI, 7.4–10.2 months),

respectively. Previous studies involving 5-FU and CDDP

regimens report response rates from 33.3–55 % and median

survival times from 6.7–10.6 months [2, 3, 14, 28].

Although these previous studies are limited by small sample

sizes, the efficacy of the present regimen is comparable to

that of 5-FU and CDDP.

Regarding toxicity, the smaller proportion of patients

reporting nausea, vomiting, or renal toxicity might be an

advantage of nedaplatin over CDDP. CDDP is defined as a

high emetic risk agent in the guidelines. From the results of

previous studies, nausea and vomiting were reported

as 47 % and 33 % for all grade [23]. The present results

indicate relatively low frequencies of nausea, vomiting,

and renal dysfunction. On the other hand, the incidence of

hematologic toxicity in the present study is similar to that

of the 5-FU and CDDP regimen. Furthermore, nedaplatin

does not require large-volume hydration, which sometimes

causes severe toxicities for patients with cardiac or pul-

monary dysfunction. The combination of nedaplatin and

5-FU might be acceptable even if patients have poor PS or

are clinically unfit for CDDP administration. Therefore, the

combination of nedaplatin and 5-FU might be considered

an option for fragile patients in clinical practice. In defin-

itive chemoradiotherapy, some studies also report low rates

of nausea, vomiting, and renal dysfunction [15, 16].

Another platinum compound, oxaliplatin, was evaluated in

ESCC and also exhibited less renal and gastrointestinal

toxicities than CDDP. Oxaliplatin can be used even in

fragile patients in outpatient clinics. FOLFOX4 regimen

shows a response rate of 40 % and an overall survival of

7.1 months with a low level of severe toxicity [17].

New drugs were recently developed in attempts to

improve the survival of metastatic esophageal cancer.

Taxanes are one of the new groups of drugs that have

potential to improve outcomes. Paclitaxel exhibits antitu-

mor activity against esophageal cancer as a single agent for

first- or second-line treatment in combination chemother-

apy [18–20]. Docetaxel also exhibits efficacy for esopha-

geal cancer in a first- or second-line setting [21, 22].

Taxane alone or in combination with fluoropyrimidine and

platinum is one of the candidates for first-line treatment for

metastatic esophageal cancer. Moreover, molecular tar-

geted drugs have been enthusiastically investigated for

various malignant diseases [23–25]. Epidermal growth

factor receptor is one of the targets overexpressed in

50–80 % of ESCC cases [26]. Cetuximab, an anti-epider-

mal growth factor receptor antibody, was effective in a

phase III study in patients with head and neck cancer as

well as esophageal cancer when combined with 5-FU and

platinum [27]. Therefore, it seems reasonable to investigate

whether the combination of these agents affects the sur-

vival of esophageal cancer. Compared to these drugs, ne-

daplatin has some disadvantages. The combination of

nedaplatin and 5-FU regimen requires the hospitalization

of patients for infusion and awareness of renal function and

myelosuppression. Moreover, its efficacy is not substan-

tially higher than that of CDDP or other drugs. If we

Table 3 Toxicities (n = 41)

AST aspartate aminotransferase,

ALT alanine aminotransferase,

T-Bil total bilirubin

NCI-CTC ver. 2.0

Grade 1 Grade 2 Grade 3 Grade 4 All grades (%) CGrade 3 (%)

Leukocytopenia 8 9 1 2 48.8 7.3

Neutropenia 7 9 5 3 58.5 19.5

Anemia 22 13 1 1 90.2 4.9

Thrombocytopenia 1 1 1 1 9.8 4.9

Nausea 13 7 6 0 63.4 14.6

Vomiting 2 1 0 0 7.3 0

Diarrhea 6 2 1 0 22.0 2.4

Stomatitis 11 8 1 0 48.8 2.4

AST/ALT 17 2 0 0 46.3 0

T-Bil 4 1 0 0 12.2 0

Creatinine 3 1 0 0 9.8 0

Allergy 2 0 0 0 4.9 0

Esophagus

123

conduct a phase III study comparing nedaplatin and 5-FU

with 5-FU and CDDP, we will select a non-inferior design,

because nedaplatin appears less toxic than CDDP. How-

ever, it would be impossible to complete such a phase III

study because of difficulties recruiting a sufficiently large

sample size.

In conclusion, combination therapy with nedaplatin and

5-FU is highly active and well tolerated in metastatic or

recurrent ESCC. The combination of nedaplatin and 5-FU

is considered a first-line option for ESCC.

Acknowledgments We thank Ms. Makiko Shinogi and Ms. Hiromi

Orita for collecting data. This study was supported by Grants-in-Aid

for Cancer Research from the Ministry of Health, Labour, and Wel-

fare of Japan.

Ethical Statement This work conforms to the guidelines set forth in

the Helsinki Declaration of 1975, as revised in 2000 (5), concerning

Human and Animal Rights. We followed the policy concerning

informed consent as shown on the following sites. http://www.

springer.com/authors/journal?authors/helpdesk?SGWID=0-1723213-

12-995756-0%3Cbr%20/%3E.

Conflict of interest All authors declare that they have no conflicts

of interest regarding this article.

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