ORIGINAL ARTICLE

Combination of irinotecan (CPT-11) and nedaplatin (NDP)for recurrent patients with uterine cervical cancer

Tatsuru Ohara • Yoichi Kobayashi • Ayako Yoshida •

Norihito Yoshioka • Namiko Yahagi • Haruhiro Kondo •

Akiko Tozawa • Kazushige Kiguchi • Nao Suzuki

Received: 27 July 2012 / Accepted: 3 October 2012 / Published online: 25 October 2012

� Japan Society of Clinical Oncology 2012

Abstract

Background The clinical activity of combination of iri-

notecan (CPT-11) and nedaplatin (NDP) for recurrent

patients with uterine cervical cancer was evaluated

retrospectively.

Methods Intravenous CPT-11 was given at 60 mg/m2

(days 1, 8, 15), followed by NDP 80 mg/m2 (day 1), every

4 weeks.

Results According to the medical records, 29 cases have

received this regimen since 2000. Median age was 57 years

(range, 29–80), and performance status (PS) of the patients

was 18 cases with PS 0, 10 cases with PS 1, and 1 case with

PS 2, respectively. Clinical stage was as follows: 3 cases of

stage Ib1, 2 cases of Ib2, 2 cases of IIa, 10 cases of IIb, 8

cases of IIIb, and 4 cases of IVb. There were 27 cases of

squamous cell carcinoma and 2 cases of adenocarcinoma.

Concerning hematological toxicity of grade 3 or more,

neutropenia, leukopenia, and febrile neutropenia were

observed in 79.3 %, 96.6 %, and 13.8 % of cases, respec-

tively. For nonhematological toxicity, nausea, anorexia,

joint pain, and confusion were observed in only 1 case,

respectively, and as a result, in 7 cases chemotherapy was

not completed. Among 26 cases with clinically evaluable

lesions, there were 7 complete responses, 3 partial

responses, 7 stable disease, and 9 progressive disease; the

clinical response rate was 38.5 %. Median progression-free

survival was 7 months (range, 0–38 months).

Conclusion The combination of CPT-11 and NDP seems

to be active for patients with recurrent uterine cervical

cancer.

Keywords Recurrent cervical cancer � Combination

chemotherapy � Irinotecan � Nedaplatin

Introduction

In the Japanese Treatment Guidelines for Cervical Cancer,

2011 edition, single or combined chemotherapy including

cisplatin (CDDP) is recommended as well as other kinds of

platinum drugs [1]. Monk et al. [2] reported a phase III trial

of combination chemotherapy with CDDP paclitaxel plus

CDDP (PC), vinorelbine plus CDDP (VC), gemcitabine

plus CDDP (GC), and topotecan plus CDDP (TC) for stage

IVb or recurrent cervical cancer patients, and they con-

cluded that for overall survival no regimen was superior to

PC. On the other hand, irinotecan (CPT-11) is a topoiso-

merase I inhibitor similar to topotecan. CPT-11 is a drug

that was developed in Japan and has been evaluated in

many trials in this country. It is one of the few anticancer

drugs for cervical cancer covered by Japanese insurance.

The response rate is good at 59 % for cisplatin plus CPT-

11 combination therapy, with a manageable level of

toxicity in advanced or recurrent cervical cancer [3].

Hydronephrosis and hydroureter are commonly seen in

patients with recurrent cancer and often cause postrenal

renal failure. In such cases, use of cisplatin is difficult

because it requires diuresis before and after administration

to prevent renal toxicity. Nedaplatin (NDP) is another

platinum-based drug that was developed in Japan. The

T. Ohara � A. Yoshida � N. Yoshioka � N. Yahagi � H. Kondo �A. Tozawa � K. Kiguchi � N. Suzuki (&)

Department of Obstetrics and Gynecology, School of Medicine,

St. Marianna University, 2-16-1 Sugao, Miyamae,

Kawasaki, Kanagawa 216-8511, Japan

e-mail: nao@marianna-u.ac.jp

Y. Kobayashi

Department of Obstetrics and Gynecology,

School of Medicine, Kyorin University, 6-20-2 Shinkawa,

Mitaka, Tokyo 181-8611, Japan

123

Int J Clin Oncol (2013) 18:1102–1106

DOI 10.1007/s10147-012-0487-4

response rate to NDP monotherapy is high at 34–41 % for

cervical cancer [4]. NDP is considered a useful alternative

for patients with renal dysfunction [5]. We analyze and

report the effectiveness of the combination of CPT-11 and

NDP for patients with recurrent uterine cervical cancer,

retrospectively.

Patients and methods

From 2000, recurrent cervical cancer patients were given

chemotherapy consisting of CPT-11 plus NDP, and their

medical records were examined retrospectively. Intrave-

nous CPT-11 was given at 60 mg/m2 (days 1, 8, 15), fol-

lowed by NDP 80 mg/m2 (day 1) every 4 weeks.

Progression-free survival (PFS) was evaluated as a primary

endpoint, and toxicity, i.e., the percentage who could

complete more than three courses, response rate, and

overall survival (OS) were evaluated as secondary end-

points. Toxicity was evaluated according to NCI-Common

Terminology Criteria for Adverse Events (CTCAE version

3.0). The effectiveness was evaluated according to

response evaluation criteria in solid tumors (RECIST).

Statistical analysis was made by v2 analysis.

Results

Patient characteristics

Overall, 29 cases were enrolled. Observation time ranged

from 3 to 48 months (median, 15 months). Median age of

the patients was 57 years (range 29–80 years): there were

27 patients with squamous cell carcinoma and 2 cases of

adenocarcinoma. Performance status (PS) of the patients

was as follows: 18 cases of PS 0, 10 cases of PS 1, and 1

case of PS2. International Federation of Gynecology and

Obstetrics (FIGO) stage of the patients was as follows: 3

cases of Ib1, 2 cases of Ib2, 2 cases of IIa, 10 cases of IIb, 8

cases of IIIb, and 4 cases of IVb. Ten cases recurred in the

pelvis and 19 cases recurred outside the pelvis (Table 1).

For previous treatment, 12 cases had received chemora-

diotherapy and 17 cases underwent radical hysterectomy

followed by chemoradiotherapy. Of 29 cases, 22 cases

(75.9 %) could complete more than three courses (12

cases, three courses; 2 cases, four courses; 3 cases, five

courses; and 5 cases, six courses, respectively). There were

7 cases who could not continue this regimen for reasons of

febrile neutropenia (grade 3, 1 case; grade 4, 2 cases),

grade 3 of distraction (1 case), and progression of the

disease (3 cases), respectively.

Median values of PFS and OS were 7 and 11 months

(Figs. 1, 2), respectively. In 26 cases with evaluable

lesions, there were 7 of complete response (CR), 3 of

partial response (PR), 7 of stable disease (SD), and 9 of

progressive disease (PD); the overall response rate (RR)

was 38.5 % (10/26). The RR was significantly better in the

cases of recurrence outside the irradiated field compared to

those of recurrence within the irradiated field (50.0 % vs.

12.5 %; p \ 0.05) (Table 2). However, PFS and OS of 18

cases with recurrence outside and inside the irradiated field

were 5.5 and 11 months, and 8 and 12.5 months,

Table 1 Characteristics of the eligible patients (n = 29)

Age (years) Median (range) 57 (29–80)

PS 0/1/2 18/10/1

FIGO stage Ib1/Ib2/IIa/IIb/IIIb/IVb 3/2/2/10/8/4

Histology Squamous cell carcinoma/

adenocarcinoma

27/2

Site of recurrence Inside radiation field/outside

radiation field

10/19

Prior therapy Chemoradiation/surgery plus

chemoradiation

12/17

0

0.2

0.4

0.6

0.8

1

0 10 20 30 40

Surv

ival

rat

e (%

)

Time (month)

Fig. 1 Kaplan–Meier curve of progression-free survival. Median

duration was 7 months

Time (month)

Surv

ival

rat

e (%

)

0

0.2

0.4

0.6

0.8

1

0 10 20 30 40 50

Fig. 2 Kaplan–Meier curve of overall survival. Median duration was

11 months

Int J Clin Oncol (2013) 18:1102–1106 1103

123

respectively; there was no significant difference between

two groups (Figs. 3, 4).

As to hematological toxicities greater than grade 3, there

were 23 cases of neutropenia (79.3 %), 28 cases of leu-

kopenia (96.6 %), 14 cases of anemia (48.3 %), 13 cases of

thrombocytopenia (44.8 %), and 4 cases of febrile neu-

tropenia (13.8 %) (Table 3). As to nonhematological tox-

icities greater than grade 3, there was 1 case each of

nausea, anorexia, joint pain, and confusion; there was no

grade 3 or greater of diarrhea (Table 4).

Discussion

Median duration of survival and 3-year survival rate of

recurrent cervical cancer patients have been reported as

about 1 year and 6 %, respectively [11]. Especially, the

prognosis of those who are not indicated for debulking

surgery or radiation therapy is very poor. Because systemic

chemotherapy could not achieve complete remission as

with other solid tumors, best supportive care (BSC) could

be the first choice for these patients to achieve maintain

their quality of life and to improve overall survival time.

Several factors such as patient age [7], good performance

status, and long duration from initial therapy to recurrence

[12] have been reported to influence the effect of

chemotherapy.

When performing systemic chemotherapy in recurrent

cervical cancer patients, the possibility of surgical or

0

0.2

0.4

0.6

0.8

1

0 10 20 30 40 50

Outside radiation field

inside radiation field

Surv

ival

rat

e (%

)

Time (month)

Fig. 4 Overall survival curve of recurrence inside or outside

radiation field. There was no statistical difference between the two

groups

Table 2 Outcome of treatment

PFS progression-free survival,

OS overall survival, CR

complete response, PR partial

response, SD stable disease, PD

progressive diseasea Evaluable cases (n = 26)

Total (n = 29) Inside radiation

field (n = 10)

Outside radiation

field (n = 19)

PFS (range) 7 months (range 0–38) – –

OS (range) 11 months (range 3–40) – –

CR/PR/SD/PD 7/3/7/9a 1/0/4/3 6/3/3/6

Response rate (%) 38.5 %a 12.5 % 50.0 %

p value – \0.05

0

0.2

0.4

0.6

0.8

1

0 10 20 30 40

Outside radiation field

Inside radiation field

Time (month)

Surv

ival

rat

e (%

)

Fig. 3 Progression-free survival curve of recurrence inside or outside

radiation field. There was no statistical difference between the two

groups

Table 4 Nonhematological toxicity (n = 29) (CTCAE version 3.0)

Grade 3/4 toxicity (%)

Nausea 1 (3.4 %)

Vomiting 0

Anorexia 1 (3.4 %)

Diarrhea 0

Stomatitis 0

Fever 0

Allergic reaction 0

Edema 0

Joint pain 1 (3.4 %)

Confusion 1 (3.4 %)

Table 3 Hematological toxicity (n = 29) [Common Terminology

Criteria for Adverse Events (CTCAE) version 3.0]

Grade 3/4 toxicity (%)

Neutropenia 23 (79.3)

Febrile neutropenia 4 (13.7)

Leukopenia 28 (96.5)

Anemia 14 (38.9)

Thrombocytopenia 13 (44.8)

1104 Int J Clin Oncol (2013) 18:1102–1106

123

radiation treatment should be ruled out, and then patient

age, performance status, function of the other organs, past

history of irradiation, and disease-free interval should be

totally evaluated. Before starting systemic chemotherapy,

the patients should be informed about BSC, and chemo-

therapy could be performed for those who desire this

treatment.

Many of those patients might have hydronephrosis or

hydroureter resulting in postrenal failure in recurrent cer-

vical cancer. In these cases, cisplatin, which requires pre-

or posthydration, might be difficult to use. On the other

hand, NDP, one of the platinum agents, available even for

patients with renal failure, showed a high response rate

(34–41 %) for cervical cancer [4, 13]. CPT-11, developed

in Japan, is one of the inhibitors of topo-isomerase, and the

combination therapy of CPT-11 and CDDP showed a high

response rate (59 %) with tolerable adverse effects [3]. For

these reasons, we used CPT-11 with NDP for recurrent

cervical cancer patients.

In this regimen, the median value of PFS as primary

endpoint was 7 months, which is better than the survival

rates of a randomized trial for stage IVb or recurrent cer-

vical cancer patients (Table 5). This regimen also showed

longer OS (11 months). Of 26 evaluable cases, there were 7

cases of CR and 3 cases of PR, with an overall response

rate of 8.5 %. All the previous reports shown in Table 5

were stage IVb, refractory, or persistent squamous cell

carcinoma (SCC) cases, except that of Long et al. [10]. Our

study included two cases of adenocarcinoma among our

patients, and if focusing only on SCC cases, the overall

response rate was 38.5 %. Moreover, all our cases previ-

ously received platinum-based chemoradiation. For these

reasons, our cases could be more difficult to manage.

Because our cases had such disadvantageous conditions,

our results should be satisfactory. Although it was not

superior to the phase II trial using CPT-11 plus cisplatin for

advanced or recurrent cervical cancer patients (response

rate, 59 %) [3], this regimen was considered to have

modest activity, as already described.

Concerning hematological toxicity, grade 3 or more

neutropenia was seen in 79.3 % of cases. Although this

result was slightly higher than previously reported

(60.3 %) [5], in our cases, more than three courses could be

completed in 75.9 %, so it was considered as tolerable. In

our cases, this regimen showed 50.0 % response rate for

recurrence outside the irradiated field, whereas it showed

only 12.5 % response rate for recurrence inside the irra-

diated field. This finding suggested that the therapeutic plan

should be considered according to the recurrent sites.

Those cases recurrent inside the irradiated field have also

been shown a worse response rate and poor prognosis [14,

15]. Nevertheless, there was no significant difference of

PFS and OS in these two groups in our study. So, more

cases should be accumulated to obtain some definitive

conclusion about these issues.

Generally, in patients with recurrent cervical cancer the

path of therapy should be selected individually according

to recurrent location and number, previous therapy, and

prognostic factors. Because excellent new reagents are not

now available, as we indicated in this retrospective study,

the combination of CPT-11 and NDP could be an effective

and feasible regimen for patients with recurrent cervical

cancer.

Conflict of interest The authors declare that they have no conflict

of interest.

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