First-Line Chemotherapy With Capecitabine and Temozolomide in Patients With Metastatic Pancreatic Endocrine Carcinomas
Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS). Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days. Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events. The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.
First-Line Chemotherapy With Capecitabine
and Temozolomide in Patients With
Metastatic Pancreatic Endocrine Carcinomas
Jonathan R. Strosberg, MD
; Robert L. Fine, MD
; Junsung Choi, MD
; Aejaz Nasir, MD
; Domenico Coppola, MD
Dung-Tsa Chen, PhD
; James Helm, MD
; and Larry Kvols, MD
BACKGROUND. Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indi-
cate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendo-
crine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30
patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS),
and overall survival (OS). METHODS. Patients with metastatic, well, or moderately differentiated pancreatic endocrine
carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m
daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days. RESULTS. Among 30 patients
treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18
months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events.
CONCLUSIONS. The combination of capecitabine and temozolomide is associated with an exceptionally high and
durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response
rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens Cancer 2011;117:268–75.
C2010 American Cancer Society.
KEYWORDS: Pancreatic endocrine tumors, carcinomas, pancreatic neuroendocrine tumors, islet cell tumors,
Pancreatic endocrine carcinomas (PECAs) are rare malignancies originating in neuroendocrine cells of the pan-
creas. Annual incidence is estimated to be 1 per 100,000, and approximately half are metastatic at diagnosis.
characterized by a propensity to secrete a variety of peptide and amine hormones, including insulin, gastrin, glucagon, vas-
oactive intestinal peptide (VIP), and serotonin. Most metastatic cases are unassociated with a hormonal syndrome and are
therefore termed ‘‘nonfunctional.’’
The prognosis of metastatic PECAs is strongly dependent on their histologic grade.
Poorly differentiated (high
grade) tumors bear a histologic resemblance to small cell carcinomas of the lung and are treated similarly with cytotoxic
regimens consisting of a platinum agent combined with etoposide or irinotecan.
The prognosis of low- and intermedi-
ate-grade PECAs is substantially superior, with reported survivals ranging from 2-5.5 years in the metastatic setting.
Cytoreductive surgery has been advocated for patients whose liver metastases can be resected with curative or near-curative
Unfortunately, only a small minority of patients with metastatic tumors are eligible for surgical management.
Locoregional strategies such as hepatic arterial embolization (HAE) or chemoembolization (HACE) have been used in
patients with liver-predominant metastases.
Other emerging treatments include radiolabeled somatostatin analogs
, and inhibitors of the mammalian target of rapamycin (mTOR).
Accumulating evidence supports the notion that PECAs are more sensitive to cytotoxic chemotherapy than other
types of neuroendocrine malignancies, including carcinoid tumors of the small intestine.
One of the first agents to dem-
onstrate clinical effectiveness in PECAs was the nitrosurea streptozocin (STZ).
Subsequent randomized trials conducted
DOI: 10.1002/cncr.25425, Received: December 29, 2009; Revised: February 22, 2010; Accepted: April 8, 2010, Published onlin e September 7, 2010 in Wiley
Online Library (wileyonlinelibrary.com)
Corresponding author: Jonathan R. Strosberg, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia
Drive, Tampa, FL 33612; firstname.lastname@example.org
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida;
Experimental Therapeutics Program, Division of
Medical Oncology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York;
Department of Pathology, H. Lee Moffitt Can-
cer Center and Research Institute, Tampa, Florida;
Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
268 Cancer January 15, 2011
in the 1970s-1980s by the Eastern Cooperative Oncology
Group (ECOG) reported response rates of 63% with
STZ and 5-fluorouracil (5-FU) versus 36% with STZ
Response rates of 69% occurred with the
combination of STZ and doxorubicin versus 45% with
streptozocin and 5-FU.
It is important to note, however,
that these response rates may have been overly optimistic
because of partial reliance on nonradiographic response
criteria, such as clinical assessment of hepatomegaly and
reduction in tumor markers. A more recent retrospective
study investigating the combination of STZ, 5-FU, and
doxorubicin in metastatic PECAs reported a response rate
of 39% by objective radiographic criteria, with a median
response duration of 9.3 months.
is another agent with objective activity in metastatic
PECAs. Ramanathan et al reported a response rate of
33% in an ECOG-sponsored phase II trial.
use of dacarbazine has been limited by its relatively high
rate of toxicity.
In recent years, the oral alkylator temozolomide has
emerged as an active agent in metastatic PECAs. Like
dacarbazine, temozolomide is converted to the active al-
kylating agent MTIC through a spontaneous chemical
conversion process. A phase II trial investigating the com-
bination of temozolomide and thalidomide demonstrated
an objective response rate of 45% in PECAs versus only
7% in metastatic carcinoid tumors.
A response rate of
24% has been reported with the combination of temozo-
lomide with bevacizumab.
The combination of capecitabine, an oral prodrug
for 5-FU, and temozolomide has been studied in vitro,
and found to be synergistic for apoptosis in two neuroen-
docrine tumor cell lines.
The precise mechanism of
synergism is uncertain; however, it requires that temozo-
lomide be administered after exposure of neuroendocrine
tumor cells to capecitabine. One potential rationale for
synergy is depletion of the DNA repair enzyme O
ylguanine DNA methyltransferase (MGMT) by capecita-
bine, thereby potentiating the effect of temozolomide.
Indeed, preclinical evidence supports the hypothesis that
exposure of malignant cells to 5-FU may lead to MGMT
Several preliminary reports have indicated high
objective radiographic response rates among patients with
metastatic neuroendocrine carcinomas using capecitabine
On the basis of this early data, we
have treated 30 chemonaı
¨ve patients consecutively with
metastatic low- and intermediate-grade PECAs, using a
regimen consisting of capecitabine (days 1-14) and temo-
zolomide (days 10-14) every 28 days. In this study, we ret-
rospectively examined the objective radiographic response
rate (ORR), duration of response, progression free sur-
vival (PFS), and overall survival (OS) of the entire cohort
of patients treated consecutively with this regimen.
MATERIALS AND METHODS
Approval for data collection and analysis was obtained
from the University of South Florida (Tampa, FL) institu-
tional review board. The study cohort consisted of all 30
patients with metastatic pancreatic endocrine carcinomas
(PECAs) who received first-line systemic chemotherapy
with capecitabine and temozolomide at the H. Lee Mof-
fitt Cancer Center between September 2005 and January
2009. Patients who had received prior octreotide, inter-
feron-a, or locoregional therapy with hepatic artery
embolization (HAE) were included in this analysis.
Patients who had received prior systemic chemotherapy in
the metastatic setting were excluded. Poorly differentiated
(high-grade) tumors were also excluded from this analysis.
All patients underwent baseline computed tomogra-
phy (CT) or magnetic resonance imaging (MRI) before
initiation of treatment. All had subsequent scans within 3
months of treatment initiation. None of the patients have
been lost to follow-up.
The regimen consisted of oral capecitabine, 750 mg/m
twice daily for 14 days (days 1-14) and oral temozolo-
mide, 200 mg/m
once daily at bedtime for 5 days (days
10-14) every 28 days. Ondansetron 8 mg was prescribed
before each dose of temozolomide. Doses were adjusted to
minimize the number of tablets required. In one patient,
starting doses were reduced by 50% because of baseline re-
nal insufficiency. Thus, the actual average starting doses
of capecitabine and temozolomide in this patient cohort
were 714 mg/m
twice daily (days 1-14) and 175 mg/m
daily (days 10-14), respectively.
Evaluation of Response and Toxicity
All patients had follow-up multiphasic CT or MRI within
three months of treatment initiation. Nearly all had subse-
quent scans on a 3-month schedule until disease progres-
sion. The original films were available and reviewed
independently by a medical oncologist and a radiologist
(JRS and JC). Response to treatment was assessed using
Response Evaluation Criteria in Solid Tumors (RECIST)
Pancreatic Endocrine Carcinoma Treatment/Strosberg et al
Cancer January 15, 2011 269
and toxicity was graded using the National
Cancer Institute Common Terminology Criteria for
Adverse Events (CTCAE), version 3.0 (www.cancer.gov).
Progression-free survival (PFS) was defined as time
from initiation of treatment until disease progression
(PD) or death. Overall survival (OS) was defined as time
from initiation of treatment until death or last known fol-
The primary endpoint was the objective response rate
(ORR). Secondary endpoints included progression-free
survival (time from first dose of chemotherapy until docu-
mentation of tumor progression, initiation of other cancer
treatment, or death), overall survival (time from first dose
of chemotherapy until death from any cause), and dura-
tion of response. PFS, OS, and duration of response were
estimated by the Kaplan-Meier method. The 95% confi-
dence intervals for median PFS and median response du-
ration were derived from the log hazard. Overall survival
rate at 2 years from onset of treatment was also calculated
using the Kaplan-Meier method with 95% confidence
intervals. All statistical calculations were performed using
R software version 2.9 (R Foundation for Statistical Com-
puting, Vienna, Austria).
Demographics and Tumor Characteristics
We identified 30 patients (18 males and 12 females) with
metastatic PECAs (low- and intermediate-grade) who
were treated with capecitabine and temozolomide. Me-
dian age at onset of treatment was 58 years (range, 28-77).
Clinical and pathologic characteristics are listed in Table
1. Sixteen patients had low-grade (well differentiated) car-
cinomas versus 9 patients with intermediate-grade (mod-
erately differentiated) histology. Five patients had
differentiated tumors that were not precisely graded.
Twenty-two patients had tumors that were nonfunction-
ing (lacking a pathologic hormonal syndrome). The
remaining 8 cases included 2 gastrinomas, 2 insulinomas,
2 VIPomas, 1 glucagonoma, and 1 tumor that secreted
both gastrin and glucagon.
Sixteen patients had received prior octreotide either
for control of hormonal syndromes or for its antiprolifera-
tive effect. Four patients underwent prior transarterial
hepatic embolizations (2 bland embolizations, 2 chemo-
embolizations). Five patients underwent surgical resection
of their primary pancreatic tumors, and an additional 7
patients underwent cytoreductive hepatic surgery before
beginning chemotherapy. One patient had received adju-
vant chemotherapy before detection of metastatic disease.
Twelve patients received no prior medical or surgical lines
The median time from diagnosis until onset of treat-
ment with capecitabine and temozolomide was 12
months (range, 1-101 months). Apart from 10 newly
diagnosed cases, all patients had evidence of disease
Table 1. Patient Characteristics
Age, y, median, [range] 58 [28-77]
Male 18 60
Female 12 42
White 23 77
Nonfunctional 22 73
Low 16 53
Yes 20 66
New diagnosis 10 33
Octreotide 16 50
Resection of primary tumor 517
Hepatic cytoreduction 723
Interval diagnosis to
treatment, mo, median [range]
Abdominal pain 15 50
Weight loss 27
GI bleed 13
Peptic ulceration 13
Incidental radiographic finding 723
Transarterial embolization/transarterial chemoembolization.
270 Cancer January 15, 2011
progression before initiation of treatment with capecita-
bine and temozolomide.
The overall radiographic response rate was 70% (95% CI,
54%-86%). Among the entire cohort of 30 patients, 21
patients (70%) achieved an objective partial radiographic
response (PR) to chemotherapy, 8 patients (27%) had sta-
ble disease (SD), and 1 (3%) had disease progression (PD)
as best response (Fig. 1). The pre- and post-treatment CT
scans of 3 patients who achieved an exceptionally favor-
able PR are depicted (Fig. 2).
Only 11 patients continued treatment until disease
progression versus 15 who were treated until either a max-
imal response or chemotherapy break was recommended.
Treatment was discontinued in 1 patient because of toxic-
ity. Three patients remain on treatment. The median du-
ration of treatment was 8 cycles (range 3-23).
Eleven patients had documented elevations of serum
chromogranin A (CgA) before initiation of chemother-
apy. Among these patients, 10 (91%) experienced a major
biochemical response (defined as normalization or >50%
reduction in levels of CgA). Other elevated biomarkers
included gastrin and vasoactive intestinal peptide (VIP).
Two patients with hypergastrinemia had a minor (<50%)
reduction in serum gastrin levels. In one VIPoma patient,
normalization of serum VIP level was achieved with
Only 2 deaths (7%) have occurred, both attributable to
disease progression. The remaining 28 patients are alive at
the time of analysis, with a median follow-up of 20
months (range 4-42 months). Thus, median overall sur-
vival cannot be estimated. At 2 years, estimated rate of OS
from onset of treatment was 92% (95% CI, 72%-98%;
The median PFS was 18 months (95% CI, 9-31
months; Fig. 4). Among responding patients, the median
duration of response was 20 months (95% CI, 14-26
Side Effects and Dose Reductions
Of the entire group of 30 patients, 1 patient was dose-
reduced at the onset of treatment because of severe renal
insufficiency. In subsequent chemotherapy courses, 4
patients required dose reductions: 2 because of grade 2
palmar-plantar erythrodysesthesia (PPE), and 2 because
of hematologic toxicity (pancytopenia in 1 patient and
grade 4 thrombocytopenia in the other). Capecitabine
was interrupted for 2 cycles in 1 patient because of chest
pain (which was unassociated with changes in electrocar-
diogram and did not recur with reintroduction of the
Only 4 patients (12%) experienced grade 3 or 4
adverse events (Table 2). Three of these toxicities were
attributed to the chemotherapy regimen and 1 (elevated
AST) was attributed to alcohol use. There were no treat-
The most common minor adverse events were fa-
tigue, nausea, myelosuppression, and palmar-plantar
erythrodysesthesia. One patient experienced ureteral
bleeding secondary to nephrolithiasis, an event that was
not attributed to chemotherapy. Despite the lack of anti-
microbial prophylaxis, only 3 patients developed minor
infections: 2 cases of herpes zoster and 1 case of herpes
In this study, we have observed an objective radiographic
response rate of 70% among patients with metastatic
PECAs treated with front-line capecitabine and temozolo-
mide. The median progression-free survival was 18
months and the median duration of radiographic response
was 20 months. Only 2 deaths occurred among the 30
patients studied, resulting in a 2-year OS rate of 92%.
Among 18 patients with elevated tumor markers docu-
mented at baseline, 14 (77%) experienced a major bio-
chemical response. There was a 12% rate of grade 3 and 4
toxicities associated with this regimen. Grade 1 and 2
events were also limited; however, minor toxicities may
Figure 1. Waterfall plot illustrating best radiographic response
(percent change) in each patient.
Pancreatic Endocrine Carcinoma Treatment/Strosberg et al
Cancer January 15, 2011 271
have been under-documented because of the retrospective
nature of the data.
These outcomes compare favorably with results of
other recent studies investigating cytotoxic regimens and
targeted agents in metastatic PECAs. A retrospective study
examining the triplet combination of streptozocin, doxor-
ubicin, and 5-fluorouracil reported a response-rate of
39%, with a median response duration of 9.3 months and
a 2-year OS rate of 74%.
The frequency of grade 3 and
4 toxicities was 23%. Earlier studies of streptozocin-based
regimens failed to apply strict radiographic criteria and
were associated with substantially poorer median survival
durations of approximately 2 years.
investigating the targeted agents sunitinib and everolimus
have reported response rates of 17% and 27%, respec-
tively, in patients with advanced PECAs.
Figure 2. CT scans of three patients who had an exceptionally favorable response to chemotherapy. Column A (baseline scan);
Column B (maximal response).
272 Cancer January 15, 2011
rates were higher than those observed with the combina-
tion of capecitabine and temozolomide.
Other studies evaluating temozolomide-based regi-
mens in metastatic PECAs have used a dose-dense temo-
zolomide regimen of 150 mg/m
daily every other
This schedule has been associated with a high
rate of lymphopenia, and requires prophylaxis against
P. carinii pneumonia and herpes simplex virus. Given the
higher response rates and lower toxicity events observed in
our study, we recommend a temozolomide schedule of
every 4 weeks.
Because of the prolonged response durations experi-
enced by most patients in our study, few responders con-
tinued treatment until disease progression. Most were
treated until maximal response or until a chemotherapy
break was deemed appropriate. The high rates of overall
Figure 3. Overall survival from onset of treatment. Figure 4. Progression-free survival.
Table 2. Adverse Events
Grade 1 Grade 2 Grade 3 Grade 4
No. % No. % No. % No. %
Anemia 1326 13
Thrombocytopenia 51526 13
Hand-foot skin reaction 51624
Fatigue 412 13
Elevated AST 13
Elevated ALT 12
Herpes labialis 13
Herpes zoster 24
Vaginal bleeding 12
Pancreatic Endocrine Carcinoma Treatment/Strosberg et al
Cancer January 15, 2011 273
survival and low rates of toxicity in our study appear to
validate this treatment strategy.
The synergistic relationship between capecitabine
and temozolomide is not fully understood. Preliminary
evidence suggests that metastatic PECAs express low levels
which explains the high level of chemosen-
sitivity to temozolomide. We hypothesize the DNA dam-
age induced by capecitabine through incorporation of 5-
FdUTP into DNA and reduction of thymidine pools by
inhibition of thymidylate synthase via 5-FdUMP can
reduce the repair activity of MGMT, thereby potentiating
the effects of temozolomide on DNA replication. In the
future, we plan to investigate whether MGMT expression
in metastatic PECAs correlates with response to capecita-
bine and temozolomide.
In summary, the combination of capecitabine and
temozolomide is associated with an exceptionally promis-
ing objective response rate and overall survival duration in
metastatic PECAs. Toxicity rates are considerably lower
than those observed with streptozocin-based regimens.
Future prospective trials should evaluate temozolomide
monotherapy versus the combination of capecitabine and
temozolomide to clinically test the hypothesized synergy
between these two agents. Randomized clinical trials com-
paring temozolomide versus streptozocin-based regimens
are also necessary to establish a standard of care for this
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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