A phase II study of gemcitabine (gemzar, LY188011) in the treatment of recurrent or
persistent endometrial carcinoma: A gynecologic oncology group study☆
David L. Taita,⁎, John A. Blessingb, James S. Hoffmanc, Kathleen N. Moored, Nick M. Spirtose,
Jason A. Lachancef, Jacob Rotmenschg, David S. Millerh
aCarolinas Medical Center, Blumenthal Cancer Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA
bGynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA
cThe Hospital of Central Connecticut, New Britain, CT, USA
dOklahoma University Health Science Center, Oklahoma City, OK, USA
eWomen's Cancer Center of Nevada, Las Vegas, NV, USA
fMaine Medical Center, Portland, ME, USA
gRush-Presbyterian St. Luke's Medical Center, Chicago IL, USA
hUT Southwestern Medical Center at Dallas, Dallas TX, USA
a b s t r a c ta r t i c l ei n f o
Received 22 September 2010
Available online 14 December 2010
Gynecologic Oncology Group
Objective. The study aims to evaluate the anti-tumor activity and toxicity of gemcitabine in patients with
persistent or recurrent endometrial carcinoma.
Methods. Patients with advanced or recurrent carcinoma of the endometrium previously treated with one
chemotherapy regimen were treated on a phase II trial conducted by the Gynecologic Oncology Group (GOG).
Gemcitabine was administered as an intravenous infusion at a dose of 800 mg/m2over 30 min on days 1 and
8 every 21 days.
Results. Twenty-four patients were entered by 11 GOG member institutions. One patient was ineligible
due to wrong primary tumor. A total of ninety 21-day cycles of therapy were administered with 35% of
patients receiving four or more cycles. All patients had been previously treated with a platinum-based
regimen. One patient had a partial response (4%), nine had stable disease (39%), and twelve had increasing
disease (52%). The median progression-free survival was 1.7 months. Treatment was generally well tolerated
with only 22% of patients experiencing grade 3 or grade 4 hematologic toxicity. There was one treated-related
death due to pulmonary toxicity.
Conclusion. Gemcitabine has minimal activity in the treatment of recurrent or persistent endometrial
carcinoma at the dose and schedule tested.
© 2010 Elsevier Inc. All rights reserved.
Carcinoma of the endometrium is the most common gynecologic
malignancy in the United States and typically presents as an early stage
amenable to curative local therapy. Unfortunately, patients with
metastatic disease have poor outcomes. Cytotoxic agents have shown
only temporary effectiveness in the treatment of advanced or recurrent
endometrial carcinoma. To date, only three drugs with definite activity
against endometrial carcinoma have been identified: doxorubicin,
cisplatin, and paclitaxel [1–7]. Other less active agents against
endometrial carcinoma have been reported and include 5-fluorouracil,
vincristine, Ifosfamide, and ixabepilone [8–11]. The Gynecologic
Oncology Group (GOG) has evaluated manyadditional cytotoxic agents
in phase II trials treating metastatic endometrial carcinoma and none of
these have demonstrated significant activity .
Gemcitabine (Gemzar, LY188011, Eli Lilly and Company, Indiana-
polis, Indiana) interferes with malignant cells undergoing DNA
synthesis (S-phase) and blocks G1/S progression through the
formation of active diphosphate and triphosphate metabolites. The
cytotoxic effect of gemcitabine is through actions of both diphosphate
and triphosphate metabolites. Gemcitabine diphosphate inhibits
ribonucleotide reductase blocking the production of deoxynucleoside
triphosphates for DNA synthesis. Gemcitabine triphosphate competes
with dCTP incorporation into DNA. After incorporation of the
gemcitabine nucleotide into the DNA, only one additional nucleotide
Gynecologic Oncology 121 (2011) 118–121
☆ This study was supported by National Cancer Institute grants to the Gynecologic
Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology
Group Statistical and Data Center (CA 37517). The following Gynecologic Oncology
Group member institutions participated in this study: University of Mississippi Medical
Center, University of North Carolina School of Medicine, Rush-Presbyterian St. Luke's
Medical Center, Washington University School of Medicine, Women's Cancer Center,
University of Oklahoma, Case Western Reserve University, University of Wisconsin,
Women and Infants Hospital, The Hospital of Central Connecticut and Community
Clinical Oncology Program.
⁎ Corresponding author. Fax: +1 704 355 2779.
E-mail address: firstname.lastname@example.org (D.L. Tait).
0090-8258/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/ygyno
can be added to the growing DNA strand, halting DNA synthesis. A
“masked chain termination” occurs when DNA polymerase epsilon is
unable to remove the gemcitabine nucleotide .
Gemcitabine has activity in multiple malignancies including
pancreas, non-small cell lung carcinoma, biliary, breast, ovarian,
cervical, and leiomyosarcoma of the uterus [14–20]. Gemcitabine is
the single most active cytotoxic agent in the treatment of pancreatic
carcinoma, characterized as an aggressive, chemotherapy-resistant
malignancy. The GOG has evaluated gemcitabine in multiple tumor
types and was included in phase III trials of ovarian and cervical
cancer treatment as well as phase II studies in leiomyosarcoma of the
uterus. No clinical trials of gemcitabine treatment of endometrial
carcinoma have been reported. The diverse activity of gemcitabine
to evaluate in patients with advanced or recurrent carcinoma of the
endometrium. The purpose of this study (GOG 129-Q) is to determine
the anti-neoplastic activity of gemcitabine in patients with advanced
or recurrent endometrial carcinoma who failed treatment with other
cytotoxic agents and to determine the nature and degree of toxicity in
this cohort of patients.
Patients had to have recurrent or persistent endometrial adenocar-
to beeligible for this protocol. Histologic confirmationthrougha central
have had measurable disease, defined as at last one lesion that can be
accurately measured in at least one dimension. Each lesion had to be
≥20 mm when measured by conventional techniques, including
palpation, plain X-ray, computerized tomography (CT), and magnetic
resonance imaging (MRI), or ≥10 mm when measured by spiral CT.
Patients were required to have at least one “target lesion” to be used to
assess response on this protocol as defined by Response Evaluation
Criteria in Solid Tumors (RECIST) . Tumors within a previously
radiated field were designated as “non-target” lesions unless progres-
sion was documented, or a biopsy was obtained, to confirm persistence
at least 90 days following completion of radiation therapy. Patients
could not be eligible for a higher priority GOG protocol. In general, this
would refer to any active GOG phase III protocol for the same patient
population. GOG performance status of 0, 1, or 2 was required of all
Patients must have had only one prior chemotherapeutic regimen
for management of endometrial carcinoma. Initial treatment could
include high-dose therapy, consolidation, or extended therapy
administered after surgical or non-surgical assessment. Patients
could not have received more than one previous cytotoxic chemo-
therapy regimen (either with single or combination cytotoxic drug
therapy). Patients were allowed, but not required to receive, one
additional noncytotoxic regime for the management of persistent or
recurrent disease according to the following definition: noncytotoxic
(biologic or cytostatic) agents include (but are not limited to)
hormones, monoclonal antibodies, cytokines, and small-molecule
inhibitors of signal transduction. All patients provided written
informed consent and participating institutions obtained annual
Institutional Review Board (IRB) approval for GOG 129-Q in
accordance with federal, state, local, and institutional requirements
Gemcitabine at a dose of 800 mg/m2was to be administered as an
intravenous (IV) infusion over 30 min on days 1 and 8 every 21 days.
Patients who had been previously treated with radiotherapy were
treated at a one dose level reduction of 600 mg/m2. Gemcitabine was
to be administered on day 1 of each cycle with confirmation of an
absolute neutrophil count (ANC) ≥1500/mcl and a platelet count
≥100,000/mcl and resolution of any non-hematologic toxicity. Day
8 gemcitabine was to be administered with day 8 blood counts of ANC
≥1000/mcl and platelet count ≥75,000/mcl. Patients were removed
from study for a treatment delay N3 weeks. This study utilized the
Common Terminology Criteria for Adverse Events version 3.0 (CTCAE
v3.0) for defining and grading any adverse events. Dose reduction was
required for a 2-week delay beyond the scheduled cycle start day
secondary to hematologic toxicity, hospitalization for grade 3 or grade
4 neutropenic fever, or ANC b1000/mcl or platelet count b75,000/mcl
on day 8 of the cycle. Prophylactic white blood cell growth factors
were not allowed unless patients experienced recurrent neutropenic
complications after prescribed treatment delays and dose modifica-
tions. Patients were treated until disease progression or unacceptable
toxicity precluded further treatment.
This study employed an optimal but flexible two-stage design with
an early stopping rule intended to limit patient accrual to inactive
treatments . During the first stage targeted accrual was 19–26
patients due to administrative coordination. If more than 2 out of 25
or more than 3 out of 26 patients responded and medical judgment
indicated, accrual to the second stage was to be initiated. Otherwise,
the study would be stopped and the treatment regimen classified as
uninteresting. If opened to the second stage, the overall study accrual
would include48 eligible andevaluablepatients,butwaspermittedto
range from 44 to 51 for administrative reasons. If more than 6 out of
44–45 or more than 7 out of 46–51 patients responded, then the
regimen would be considered worthy of additional investigation.
If the true probability of responding is only 10%, the study design
provides a 90% chance of correctly classifying the treatment as
inactive. Conversely, if the true response rate is 25%, then the average
probability of correctly classifying the treatment as active is 90% .
From February 2, 2009 to July 27, 2009, 24 patients were entered
by 11 member institutions of the GOG. Pathology review deemed one
CharacteristicNumber of cases
Prior hormonal therapy
D.L. Tait et al. / Gynecologic Oncology 121 (2011) 118–121
patient ineligible for incorrect tumor type. Table 1 represents the
characteristics of the 23 eligible and evaluable patients. The median
age was 64 years (range 48–79). Endometrioid carcinoma was the
most common histology occurring in 52% of patients. All 23 patients
had received previous treatment with a platinum-based chemother-
apy regimen with 16 patients receiving Carboplatin and paclitaxel.
Nine patients (39%) had received prior radiation, and four patients
(17%) had been treated with hormonal therapy. A total of 90 cycles
(range 1–16) of chemotherapy was administered with 35% of patients
receiving four or more cycles.
Toxicity data is shown in Table 2. Grades 3 and 4 toxicities were
confined predominantly to hematologic toxicities with neutropenia in
22%, anemia in 22%, leukopenia in 13% and thrombocytopenia in 9%.
There was no difference in grades 3 and 4 neutropenia and
thrombocytopenia between patients treated with prior radiation
and those who received no previous radiation. Grades 4 and 5
pulmonary toxicity was seen in 13% of patients and one death from
pulmonary complications was considered to be treatment-related.
One additional patient died from pulmonary complications that were
There were no complete responses observed. One partial response
(4%, 95% confidence interval 0.1–21.9%) occurred with a duration of
response of 11 months. Thirty-nine percent of treated patients had
stable disease for a median of 4.0 months (range 2.1–8.1). Increasing
disease was seen in 52% of patients. Response could not be assessed in
one (4%). The median progression-free survival was 1.7 months. The
median survival has not been reached.
The search for effective treatment of metastatic endometrial
cancer untreatable by surgery or radiation has been disappointing.
Choices for treatment of these patients are limited to chemotherapy
or endocrine therapy. To date, only doxorubicin, cisplatin, and
paclitaxel have demonstrated definitive cytotoxic activity against
carcinoma of the endometrium [2,4,5,7]. Other data has suggested
possible activity of ifosfamide, 5-fluorouracil, vincristine, and ixabe-
pilone [8–11]. The GOG has evaluated 24 additional agents which
have demonstrated no statistically significant activity against endo-
metrial carcinoma. These agents have been referenced previously
. The continued evaluation of chemotherapeutic agents effective
against endometrial cancer is indicated.
Gemcitabine acts against malignant cells undergoing DNA synthe-
sis (S-phase) blocking G1/S progression through the formation of
diphosphate and triphosphate metabolites. Gemcitabine diphosphate
inhibits ribonucleotide reductase blocking production of deoxynu-
cleoside triphosphates required for DNA synthesis and gemcitabine
triphosphate competes with dCTP for incorporation into DNA.
Incorporation of the gemcitabine nucleotide into the replicating
DNA halts DNA synthesis. The subsequent inability of DNA polymer-
ase epsilon to remove the gemcitabine nucleotide results in a “masked
chain termination” .
Since Food and Drug Administration (FDA) approval in 1995,
gemcitabine has shown activity in multiple tumor types, particularly
carcinomas. Gemcitabine is the most active agent against pancreatic
adenocarcinoma and is also used to treat non-small cell lung cancer,
biliary carcinomas, and breast carcinoma [14–17]. Currently no
clinical trials of gemcitabine for the treatment of endometrial
carcinoma have been reported; however, preclinical in vitro data
has demonstrated a cytotoxic effect of gemcitabine in endometrial
carcinoma cell lines . Additionally, gemcitabine is active in several
gynecologic malignancies to include ovarian, cervical, and uterine
leiomyosarcomas [18–20]. Evaluation of gemcitabine by the GOG in
gynecologic malignancy has occurred in several phase III trials.
Gemcitabine in combination with cisplatin showed activity in both
GOG 182 (ovarian) and GOG 204 (cervical) trials [24,25]. Gemcitabine
combined with docetaxel is a highly active combination of agents in
leiomyosarcoma of the uterus and has demonstrated prolonged
progression-free survival in completely resected patients .
This study of gemcitabine in patients with endometrial carcinoma
demonstrated a partial response in 4% of patients and stable disease in
an additional 9 patients (39%). Toxicity was predominantly hemato-
logic with 22% of patients experiencing grade 3 or grade 4 toxicity.
One patient death was possibly attributed to gemcitabine-induced
pulmonary toxicity. This patient had other confounding variables that
possibly contributed to her death to include renal failure, fluid
overload, and morbid obesity.
In summary, gemcitabine showed minimal activity in patients
with persistent or metastatic endometrial carcinoma. Continued
evaluation of cytotoxic agents for this disease is warranted.
Conflict of interest statement
Dr. David Tait is a speaker with Merck. All other co-authors have no conflicts of interest
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