Feasibility and Efficacy of Combined Cisplatin and Irinotecan
Chemotherapy for Poorly Differentiated Neuroendocrine
Kenji Nakano1, Shunji Takahashi1,*, Takeshi Yuasa1,2, Noriko Nishimura1, Yuko Mishima1, Sakura Sakajiri1,
Masahiro Yokoyama1, Naoko Tsuyama3, Yuichi Ishikawa3and Kiyohiko Hatake1
1Department of Hematology and Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research,
Ariake,2Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake and
3Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
*For reprints and all correspondence: Shunji Takahashi, Department of Medical Oncology, Cancer Institute Hospital,
Japanese Foundation for Cancer Research, Ariake, Tokyo 135-8550, Japan. E-mail; firstname.lastname@example.org
Received March 8, 2012; accepted May 11, 2012
Objective: No standard treatment has been established for poorly differentiated neuroendo-
crine carcinoma; the usual recommended treatment is based on the strategy for small cell
lung carcinoma. The aim of this study was to evaluate the response of poorly differentiated
neuroendocrine carcinoma to the combination of irinotecan and cisplatin in one institution.
Methods: We retrospectively reviewed 50 poorly differentiated neuroendocrine carcinoma
patients treated from September 2005 to April 2011 in our institution. Patients were divided
into two stages: limited disease or extensive disease. Forty-four patients received the combin-
ation chemotherapy of irinotecan and cisplatin, consisting of 4-week cycles of 60 mg/m2irino-
tecan on days 1, 8, 15 and 60 mg/m2cisplatin on day 1.
Results and conclusion: Median age was 60 years. Median follow-up time was 11.4 months.
Overall survival did not reach the median, and 1-year overall survival was 67%. The response
rate was 50% (64% at first line), and progression-free survival was 4.8 months (7.3 months at
first line). Grade 3–4 hematologic adverse events were seen in 29 patients (66%) and Grade
3–4 non-hematologic adverse events were seen in 20 patients (45%), but no patients died of
adverse events. Multivariate analysis showed a statistically significant relationship with neuron-
specific enolase elevation and poor overall survival (P ¼ 0.016, hazard ratio 6.261, 95% confi-
dence interval). The combination chemotherapy of irinotecan and cisplatin is moderately ef-
fective and feasible, and it should be considered as a treatment option for poorly differentiated
Key words: neuroendocrine carcinoma – extrapulmonary small cell carcinoma – irinotecan –
Neuroendocrine carcinomas are components of neoplasms
that have immunohistochemical staining characteristics
(chromogranin A, synaptophysin and CD56/NCAM) or ultra-
structural features (neurosecretory granules). Prognoses of
neuroendocrine carcinoma patients are various, and for some
of them, especially poorly differentiated neuroendocrine
carcinoma (PDNEC) patients, it is poor. PDNEC arises from
almost all organs and some components are similar to small
cell lung carcinoma (SCLC) in morphology and are called
extrapulmonary small cell carcinoma (EPSCC). EPSCC was
first described in 1930 by Duguid and Kennedy (1) and
accounts for 0.1–0.4% of all malignancies, and 5% of all
small cell carcinomas (2,3). In lung carcinoma, large cell
carcinomas with neuroendocrine characteristics are called
# The Author 2012. Published by Oxford University Press. All rights reserved.
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Jpn J Clin Oncol 2012;42(8)697–703
Advance Access Publication 13 June 2012
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large cell neuroendocrine carcinoma (LCNEC) and LCNEC
patients have recently been known to have as poor prognoses
as SCLC patients (4). Other than lung carcinoma, in clinical
practice, PDNEC and EPSCC are usually treated in the same
way. Because of their rarity, however, there has not been
enough clinical data to establish a treatment strategy for
PDNEC patients. The usual recommendation is to use the
same treatment strategy as for SCLC.
For a long time, the standard systemic chemotherapy for
advanced SCLC has been a combination of cisplatin
(CDDP) and etoposide (EP regimen) (5,6). Recently, com-
bined cisplatin and irinotecan (IP regimen) was reported to
be as effective as the EP regimen for SCLC. The aim of this
study was to evaluate the response of PDNEC to the combin-
ation of IP regimen in one institution.
PATIENTS AND METHODS
We retrospectively evaluated the clinical courses of PDNEC
patients diagnosed and treated between September 2005 and
April 2011 in the Cancer Institute Hospital of Japanese
Foundation for Cancer Research, Tokyo.
All patients were diagnosed pathologically. Pathological
diagnosis of PDNEC was based on the 2004 World Health
Organization criteria for lung cancer (7), including criteria
for SCLC and LCNEC. In order to assist the pathological
diagnosis, immunohistochemistry was performed using the
antibodies for neuroendocrine markers including synapto-
physin, chromogranin A and NCAM/CD56. At least one of
the neuroendocrine markers had to be positive in diagnosing
PDNEC. Patients with well-differentiated neuroendocrine
tumors (or carcinoids), Merkel cell tumors, or patients diag-
nosed with a lung primary (SCLC or LCNEC) clinically
were excluded in the current analysis. The primary organ
was evaluated based on both radiological imaging and
immunohistochemistry. Patients with a lung lesion on chest
computed tomography (CT) at diagnosis and positive thyroid
transcription factor-1 (TTF-1) in the specimens who were
diagnosed as lung primary were excluded.
Patients were staged by utilizing a two-stage system based
on that of SCLC (8). Limited disease (LD) was defined as a
tumor localized to the organ of origin and the locoregional
lymph nodes that could easily be encompassed within one
radiation therapy (RT) treatment portal. Extensive disease
(ED) was defined as a tumor spreading beyond one radiation
portal or with any metastatic lesion.
The CDDP/ IP regimen consisted of 60 mg/m2IP on days 1,
8, 15 and 60 mg/m2CDDP on day 1 every 4 weeks, with ad-
equate hydration and antiemetic drugs as for SCLC studies
(4). On day 8 or 15, if severe hematologic or non-
hematologic toxicities were present, IP was not administered.
If the leukocyte level fell below 2000/mm2or the neutrophil
level fell below 1000/mm2, recombinant human granulocyte
colony-stimulating factor was administered until the leuko-
cyte or neutrophil count was restored.
The IP regimen was repeated until disease progression,
patient refusal or unacceptable toxicity occurred. If Grade
3–4 non-hematological toxicity or prolonged Grade 4 hema-
tological toxicity occurred, the dose of CDDP and IP was
reduced to 80%. After completion, additional locoregional
therapy or palliative therapies were performed if appropriate.
Prophylactic cranial irradiation was not performed.
For measurable disease, responses were evaluated using CT
and magnetic resonance imaging according to the response
evaluation criteria in solid tumors, version 1.1. The National
Center Institute Common Terminology Criteria for Adverse
Events (version 4.0) was used to evaluate toxicity. Using the
Kaplan–Meier method, the progression-free survival (PFS)
and overall survival (OS) were calculated from the start of
the IP regimen to the disease progression and death, respect-
ively. Prognostic factors for OS were compared using a
log-rank test and the Cox proportional hazards model (9,10).
All statistical tests were two sided.
Between September 2005 and April 2011, 50 patients were
diagnosed with PDNEC in the study institution and 44 were
treated with the IP regimen. Six patients never received IP
chemotherapy in their clinical courses. Of those, two patients
with LD stage of head and neck origin were treated with
concurrent chemoradiotherapy with CDDP, according to the
treatment strategy for squamous cell head and neck carcin-
oma (11). Two patients were treated with multimodal
therapy including surgery, radiotherapy and chemotherapy
other than the IP regimen. The remaining two patients died
without receiving any therapy because of aggressive
There were 26 males and 18 females. The median age at
diagnosis was 60 years (range: 26–80). The primary sites
were as follows: 9 gastrointestinal, 18 head and neck, 4
urinary tract, 1 gynecologic organ and 12 unknown primary
origins. Eight patients had lung metastases, 15 patients had
bone metastases and 13 patients had liver metastases at diag-
nosis. Fourteen patients had LD, whereas 30 had ED.
Although these 14 LD patients were considered for locore-
gional therapy before the IP regimen, neither the surgical
treatment nor the curative radiation therapy was performed
because of local invasion. All these patient characteristics
are summarized in Table 1.
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IMMUNOHISTOCHEMICAL RESULTS FOR PDNEC
Synaptophysin was evaluated in 43 patients and shown to be
positive in 39 patients (91%), chromogranin A was positive
in 30 patients out of 41 patients evaluated (73%) and CD56/
NCAM was positive in 37 patients out of 42 patients evalu-
ated (88%). TTF-1 was also evaluated in 36 patients and
tumors of 8 patients were positive. TTF-1 is usually used for
a pathological marker of primary lung cancer, but all of the
eight patients with TTF-1 immunoreactivity proved to have
no lung lesions closely examined by chest CT at diagnosis.
Therefore, they were regarded as extrapulmonary tumors
Forty-four patients received chemotherapy with the IP
regimen. Among these patients, 28 patients were treated
with IP as a first-line therapy, whereas 16 patients
received one or more therapies (surgery, radiation therapy
and/or other chemotherapy regimens) before IP. As for
chemotherapy, 35 patients were chemo-naı ¨ve and 9
patients had a history of systemic chemotherapy. After the
IP regimen, 30 patients received other curative or pallia-
tive therapies, including radiotherapy for 15 patients, sur-
gical operation for 5 and salvage chemotherapy for 18.
There were 16 patients who received therapies with cura-
tive intent after the IP regimen, radiotherapy for 11, sur-
gical operation for 3 and other chemotherapy for 3
patients; 5 patients relapsed after curative therapies. In 14
LD patients, 8 patients received curative therapies and 3
patients relapsed. The other 14 patients received palliative
therapies after progression. Salvage chemotherapy regi-
mens consisted of IP monotherapy, amrubicin, S-1, com-
bined carboplatin and paclitaxel, and combined cisplatin
Table 1. Patient characteristics
Extensive disease30 68
1 11 25
Gastrointestinal tract9 20
Head and neck1841
Unknown origin 1228
Serum tumor marker
Pro-GRP (.UNL) 1227
Table 1. Continued
Chromogranin A þ
Chromogranin A 2
NSE, neuron-specific enolase; TTF-1, thyroid transcription factor-1.
Jpn J Clin Oncol 2012;42(8)699
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THE RESPONSE AND OUTCOME OF THE PATIENTS WHO UNDERWENT
At the time of analysis, 30 patients had progressed after the
IP regimen and 19 patients had died of disease. Median
treatment cycles of IP regimen were 3 (range: 1–8). The
overall response rate to the IP regimen was 50%, with 3
patients (7%) achieving complete response (CR; Table 2). In
patients receiving the IP regimen as first-line therapy, the re-
sponse rate was 64%, whereas in patients receiving other
therapies before IP regimen, the response rate was 25%.
The median follow-up time was 11.4 months (range: 1.2–
46.9 months). The median PFS of the IP regimen chemotherapy
was 4.8, and median OS was not reached (Fig. 1A and B). The
1-year, 2-year and 3-year survival rates were 67, 42 and 21%, re-
spectively. Although LD patients tended to have a better PFS
and OS, there was no statistical significance for either of them
(Fig. 1C and D). Median PFS for patients receiving the IP
regimen as first-line chemotherapy was 7.3 months, whereas the
median PFS was 3.6 months for patients who had already
received any other chemotherapy before the IP regimen; there
was a significant difference (P ¼ 0.003). However, no statistical
significance was shown for the OS by the log-rank test
(P ¼ 0.848; Fig. 2A and B). No significant difference was seen
among the primary organs of PDNEC.
The major adverse events of IP therapy are shown in
Table 3. Grade 3 or 4 hematological adverse events were
seen in 29 patients (66%), most of them being leukocyto-
penia or neutropenia. Grade 3 or 4 non-hematological
Hyponatremia was the most frequently seen severe non-
hematological adverse event (18%). Although 18 patients
(41%) needed to reduce the treatment dose and 2 patients
had to discontinue the IP due to adverse events, no
therapy-related death was seen in this treatment period.
One patient discontinued the IP regimen because of a
Grade 2 skin eruption that occurred after every infusion
of IP. The other patient suffered from febrile neutropenia
and septic shock during the first course of the IP
in 20 patients(45%).
Finally, we examined the prognostic factors of the IP
regimen for these patients. Old age (.60 year old), poor
ECOG PS (.1), ED stage, presence of prior chemotherapy,
post-chemotherapy, presence of particular lesions (lung, liver
and bone) and elevation of serum tumor markers [neuron-
specific enolase (NSE) and Pro-GRP] were evaluated in the
univariate analysis. Of them, old age and NSE elevation
were shown to be prognostic factors for poor OS (P ¼ 0.031
and 0.012, respectively, Fig. 2C and D). Multivariate ana-
lysis also showed a statistically significant relationship with
elevation of serum NSE level and poor OS (P ¼ 0.016,
hazard ratio, 6.261, 95% CI: 1.400–27.998).
Table 2. Response of the irinotecan (IP) regimen
OR (%)CR (%) PR (%)
All patients4416 4.8 22 (50)3 (7) 19 (43)
Limited disease 14 Not reached10.78 (57) 3 (21)5 (36)
Extensive disease30 14.34.5 14 (46)0 (0)14 (46)
P value (log-rank)0.2370.185
Previous therapy 2
28166.4 18 (64)2 (7)16 (57)
Previous therapy þ
P value (log-rank)
1614.6 4.2 4 (25)1 (6) 3 (19)
Gastrointestinal tract9 Not reached 5.14 (44) 1 (11)3 (33)
Head and neck 18Not reached 4.28 (44) 1 (6)7 (39)
Urinary tract4 12.5 1.41 (25)0 (0) 1 (25)
Gynecologic organ1 166.4 0 (0)0 (0) 0 (0)
Unknown origin 12 14.310.6 9 (75) 1 (8)8 (67)
P value (log-rank) 0.8120.055
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Figure 2. Prognostic factors.
Figure 1. Prognoses of patients.
Jpn J Clin Oncol 2012;42(8)701
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Until now, no standard chemotherapeutic regimen has been
established for PDNEC. In this study, our retrospective ana-
lysis demonstrated that the IP regimen was moderately ef-
fective and feasible, suggesting that the IP regimen could be
considered as a treatment option for PDNEC. Noda et al. (5)
reported from the prospective clinical trial for the ED SCLC
patients that the IP regimen showed a better response rate
and a more improved prognosis than the EP regimen.
However, after that, Hanna et al. (6) again compared the IP
regimen with EP in a randomized phase 3 study, which
showed that the IP regimen and EP regimens had almost the
same response, although the doses and schedules used were
different from the previous study. Recently, Jin et al. (12)
reported their clinical experience with cisplatin and IP for 15
EPSCC patients, although the treatment schedule was differ-
ent. In our study, the treatment schedule was the same as
that of Noda’s study.
In general, ED-stage patients have a very poor prognosis.
Haider et al. (13) reported on the prognoses of 101 EPSCC
patients diagnosed in Saskatchewan, Canada, from 1971 to
2002. In their study, the median OS of LD patients was
34 months, much longer than the median OS of ED patients,
which was only 2 months. Moreover, ED-stage PDNEC
patients with unknown primary origin have very poor prog-
noses. Though some case reports showed a long survival of
LD-stage PDNEC patients with unknown primary origin,
median survivals of ED-stage patients with unknown
primary have been less than 1 year (14).
In retrospective studies, a platinum-based regimen and a
doxorubicin-based regimen were used for PDNEC patients
and they showed moderate responses, but long-term progno-
ses are poor (12,15–17). Hainsworth et al. (17) reported
moderate response and OS with a three-drug chemotherapy
regimen (paclitaxel, carboplatin and EP), and our study has
as same response and survival rate as Hainsworth’s study
with a two-drug regimen. In our study, two-thirds of our
patients were ED stage, and PDNEC patients with unknown
primary origin accounted for 24%. The IP regimen is useful
for the ED stage, and/or unknown primary PDNEC patients.
In our study, high serum NSE was shown to be a prognos-
tic factor of poor OS in PDNEC patients receiving the IP
regimen. Serum NSE is known to be a tumor marker of
SCLC, and some investigators have suggested that NSE is
related to the prognosis for SCLC. Shibayama et al. (18)
evaluated the usefulness of Pro-GRP and NSE for the diag-
nosis and prognosis of SCLC and in the SCLC patients re-
ceiving chemotherapy. CR rate in patients with elevated
NSE levels was significantly lower than in patients with
normal levels of NSE (18.5% vs. 61.7%, P , 0.001).
However, whether NSE is related to the prognosis of
PDNEC patients has not yet been evaluated. In earlier
studies, Lin et al. (19) reported favorable prognostic factors
of PDNEC, based on a retrospective analysis of 90 PDNEC
patients; female gender, LD and combined modality treat-
ment are discussed in the article. We found no significant
difference in the prognoses of patients based on gender or
stage. We need to collect and compare more information
about the clinical features and prognoses of PDNEC patients
to identify the best prognostic factors.
In conclusion, the IP regimen can be considered as a good
treatment option for PDNEC patients, especially patients
with unknown primary and ED stage. However, we note that
the response rate and PFS were relatively poor in previously
treated patients. We should pursue a new salvage treatment
option for refractory and relapsed PDNEC in the future.
This work was partly supported by the Takeda Science
Foundation, and Grants-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and
Conflict of interest statement
Table 3. Toxicities of the IP regimen
Adverse eventsAll gradeGrade 3 Grade 4
No.% No.% No.%
Hematologic adverse events
Leukocytopenia39 8914 325 11
Neutropenia 3886 1534 11 25
Anemia 40918 1837
Non-hematologic adverse events
Nausea 33 752500
Infection9 206 1400
AST elevation25 571200
ALT elevation21 481200
T-Bil elevation9 201200
Creatinine elevation14 320000
Peripheral neuropathy6 140000
Other non-hematologic AEa
aOther non-hematologic AE: tumor lysis syndrome G3 (1), vertigo G3 (1),
sick sinus syndrome G3 (1).
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