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Published OnlineFirst August 3, 2010; DOI: 10.1158/1535-7163.MCT-09-0854
Phase II Trial to Evaluate Gemcitabine and Etoposide for
Locally Advanced or Metastatic Pancreatic Cancer
Marianne K. Melnik, Craig P. Webb, Patrick J. Richardson, et al.
Mol Cancer Ther 2010;9:2423-2429. Published OnlineFirst August 3, 2010.
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Published OnlineFirst August 3, 2010; DOI: 10.1158/1535-7163.MCT-09-0854
Molecular
Cancer
Therapeutics
Molecular Medicine in Practice
Phase II Trial to Evaluate Gemcitabine and Etoposide for
Locally Advanced or Metastatic Pancreatic Cancer
Marianne K. Melnik1,2,3, Craig P. Webb4, Patrick J. Richardson4, Charles R. Luttenton1,2, Alan D. Campbell1,2,
Thomas J. Monroe2, Timothy J. O'Rourke1,2, Kathleen J. Yost1,2, Connie M. Szczepanek1, Michelle R. Bassett4,
Kimberly J. Truszkowski3, Phyllis Stein1, Matthew W. Van Brocklin4, Alan T. Davis3, Gabriela Bedolla2,
George F. Vande Woude4, and Han-Mo Koo4 †
Abstract
Prior studies suggest that tumor cell lines harboring RAS mutations display remarkable sensitivity to gemcitabine and etoposide. In a phase II clinical trial of patients with locally advanced or metastatic pancreatic cancer,
we evaluated the response rate to a combination of these drugs. Forty chemo-naïve patients with nonresectable
and histologically confirmed pancreatic cancer were accrued. Patients received gemcitabine 1,000 mg/m2 (days
1 and 8) and etoposide 80 mg/m2 (days 8, 9, and 10; 21-day cycle). The primary end point was radiological
response rate. Secondary objectives were determination of overall survival, response duration (time to progression), quality of life, toxicity, and CA 19-9 biomarker response. In 35 evaluable patients, 10 exhibited a radiological partial response and 12 had stable disease in response to treatment. Twenty patients exhibited a >20%
decrease in CA 19-9 biomarker levels. Median overall survival was 6.7 months for all patients (40) and 7.2
months for evaluable patients (35). Notably, four patients survived for longer than 1 year, with two patients
surviving for more than 2 years. Median time to progression for evaluable patients was 3.1 months. The median
overall survival for locally advanced patients was 8.8 months and 6.75 months for metastatic patients. One-year
survival was 10% for all patients and 11.4% for evaluable patients. Quality of life improved in 12 patients and
remained stable in 3 of the evaluable patients. The primary dose-limiting toxicities were hematologic toxicity
and fatigue. These results show that the gemcitabine and etoposide combination is generally well-tolerated and
exhibits a response rate similar to other published studies. Mol Cancer Ther; 9(8); 2423–9. ©2010 AACR.
Introduction
Although pancreatic cancer accounts for just 3% of
new cancer cases in the United States, it is the fourth
leading cause of all cancer deaths (1). The American Cancer Society predicted that in 2009, ∼42,470 people in the
United States would be diagnosed with pancreatic cancer
and about 35,240 would succumb (1). At the time of diagnosis, 96% to 99% of the patients have incurable disease with a median survival of less than 1 year (1).
Despite multiple clinical trials with new chemotherapeutic approaches and more aggressive surgery, the 5-year
survival rate remains a dismal 5%, with only ∼25% of
Authors' Affiliations: 1 Grand Rapids Clinical Oncology Program,
2Spectrum Health, 3Michigan State University, East Lansing, Michigan;
and 4Van Andel Research Institute, Grand Rapids, Michigan
Note: Supplementary material for this article is available at Molecular
Cancer Therapeutics Online (http://mct.aacrjournals.org/).
M.K. Melnik and C.P. Webb contributed equally to this work.
†
Deceased.
Corresponding Author: Marianne K. Melnik, 100 Michigan Northeast,
no. 012, Grand Rapids, MI 49503. Phone: 616-486-6333; Fax: 616486-6399. E-mail: [email protected]
doi: 10.1158/1535-7163.MCT-09-0854
©2010 American Association for Cancer Research.
all cases being potentially surgically resectable. Of the resectable cancers, the 5-year survival rate remains low at
only 5% to 20%. Treatment with single-agent gemcitabine
for pancreatic cancer has shown a marginal survival benefit, but notably, has exhibited improvement in diseaserelated symptoms (2–4). 5-Fluorouracil (5-FU)–based
therapies combined with other chemotherapeutic agents
or radiation therapy have shown a potential minimal survival benefit as adjuvant therapy after surgical resection
(5). A number of other trials have been conducted with
variable response and overall survival rates, with none
resulting in a significant, complete response rate (6–29).
Recently, the Food and Drug Administration approved
erlotinib in combination with gemcitabine chemotherapy
for the treatment of locally advanced, inoperable, or metastatic pancreatic cancer due to its ability to improve
overall survival by 23% (hazard ratio, 0.81; ref. 30). However, the long-term survival for advanced disease remains extremely poor.
It is well established that certain molecular features of
neoplastic cells correlate with their sensitivity to chemotherapeutic agents and could therefore be used as a basis
for drug selection and therapeutic design. In relation to
the current study, Koo and colleagues observed a correlation between activating RAS mutations in cancer cell lines
and enhanced sensitivity to the cytotoxic agents, cytosine
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Melnik et al.
cytarabine and gemcitabine (an analogue of cytarabine;
ref. 31). Similarly, they found that tumor cell lines harboring RAS oncogenes are more sensitive to topoisomerase II
inhibitors, particularly to epipodophyllotoxin-derived inhibitors such as etoposide and teniposide (31–33). These
studies suggested that tumors harboring activating RAS
mutations (such as carcinoma of the pancreas, colon, and
lung) might be particularly sensitive to these chemotherapeutic agents. In support of this hypothesis, the presence
of oncogenic RAS in acute myeloid leukemic cells was associated with an increased rate of complete remission,
prolonged duration of complete remission, and improved
overall survival of patients in response to treatment with
high-dose cytarabine (34, 35).
Activating RAS mutations are one of the most common
gain-of-function mutations found in human cancer, and
are present in over 90% of pancreatic cancers (36). Based
on the high frequency of activating RAS mutations found in
pancreatic cancers and the preferential sensitivity of RAStransformed cells to gemcitabine and etoposide, we designed a phase II trial to evaluate the response/efficacy
and toxicity of gemcitabine and etoposide combination
therapy in the treatment of locally advanced and metastatic pancreatic cancer. Secondary objectives included
the evaluation of the duration of response (time to progression), CA 19-9 biomarker response, overall survival,
and quality of life (QOL), as well as the toxicity profile of
this two-drug regimen. KRAS codon 12 and 13 mutation
analysis was done on a subset of patient tumors to determine any association between the presence and prevalence of KRAS mutations and tumor response.
Materials and Methods
Patient enrollment
To evaluate the stated objectives of the study, the
Grand Rapids Clinical Oncology Program was engaged
to provide clinical management and oversight for this trial. After obtaining institutional review board approval,
patients were enrolled in this study beginning in March
2002, and continuing through October 2005. For our analysis, 40 patients were enrolled at four of the Grand
Rapids Clinical Oncology Program member sites:
Spectrum Health (Grand Rapids), Saint Mary's Health
Care, Munson Medical Center, and Battle Creek Health
System (see Table 1 for general patient demographics).
A clinical diagnosis of pancreatic cancer was confirmed
by cytologic or histologic analysis from biopsy material.
All patients enrolled had unresectable tumors and were
chemo-naïve. Five patients received 5-FU as a radiation
sensitizer. No other patients received therapeutic radiation. Pretreatment evaluation required uni-dimensional
computerized tomography measurements of target lesions (as per Response Evaluation Criteria in Solid Tumors standards), baseline CA 19-9 values and a QOL
assessment as measured by the “quality of life” form,
BRE 43 (adapted with permission from the Sarah Cannon
Cancer Center, Nashville, TN). Although unverified, the
2424
Mol Cancer Ther; 9(8) August 2010
Table 1. Patient demographics (all patients)
Age
Median (range)
Gender
Male
Female
Karnofsky performance status
90–100%
70–89%
50–69%
Disease state
Locally advanced
Metastatic
61.4 (28.2–78.7)
19
21
19
20
1
7
33
BRE 43 QOL form is similar to the verified European
Organization for Research and Treatment of Cancer
QLQ-C30 QOL questionnaire (Supplementary Form 1).
Questions asked included basic performance status questions, associated health issues, pain level, mental status
questions, and treatment effect on family and social life.
QOL was determined to be an important measure to include, to ascertain whether adding etoposide in combination with gemcitabine diminished the QOL in this patient
population. A Karnofsky performance status of ≥50%
was required to be eligible for the study.
A total of eight cycles (21 days per cycle) were to be
administered to each patient (Table 2). When gemcitabine and etoposide were administered sequentially on
the same day (day 8), gemcitabine was infused first.
Toxicity was assessed on days 1 and 8 of every cycle,
using the National Cancer Institute Common Toxicity
Criteria v2.0. Clinical response was based on the Response Evaluation Criteria in Solid Tumors standards
obtained through two independent radiological interpretations. All responses were confirmed by independent radiologic review (evaluations were conducted
every two cycles by computerized tomography scan
measurements of target lesions). Responders were identified as those patients achieving complete response or
partial response (PR) during the course of the trial.
Blood serum CA 19-9 levels were measured following
every cycle. Patients who exhibited a response were allowed to continue treatment beyond the eight cycles until disease progression occurred or patients elected to
discontinue treatment.
KRAS codon 12 and 13 analysis
Codons 12 and 13 of the KRAS (v-Ki-ras2 Kirsten rat
sarcoma viral oncogene homologue) gene were examined
by pyrosequencing on a PyroMarkQ24 instrument (Qiagen). H&E-stained slides were reviewed by a pathologist
and areas containing high tumor content were selected
for DNA extraction from the corresponding paraffinembedded tissue. To increase the sensitivity of the mutant RAS assay, cold PCR was used as described by
Molecular Cancer Therapeutics
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Published OnlineFirst August 3, 2010; DOI: 10.1158/1535-7163.MCT-09-0854
Gemcitabine and Etoposide for Pancreatic Cancer
Zuo et al. (37) using PyroMark KRAS v2.0 reagents
(Qiagen) followed by pyrosequencing as specified by
the manufacturer.
Statistical analysis
The data were analyzed using SAS/STAT software,
version 9.2 (SAS Institute). Kaplan-Meier survival curves
along with median survival times and their corresponding confidence intervals were analyzed using the
LIFETEST procedure. The log rank test was used to calculate survival differences. Demographic data were
analyzed using the means and univariate procedures.
Proportions for the toxicity data, as well as their
corresponding confidence intervals, were analyzed using
the FREQ procedure. CA 19-9 levels and their predictive
ability on radiologic response were analyzed using the
LOGISTIC procedure. A two-sided P value of 0.05 was
used for all statistical hypotheses.
Results
Of the 40 patients accrued to this clinical trial, 7 had
locally advanced disease, whereas 33 had metastatic disease. Five patients were unevaluable due to progression
of disease before cycle 2, with one death occurring from
an unrelated cause, thus providing 35 evaluable patients
(Table 3). Median overall survival for all patients was 6.7
months (4.5–8.1), and 7.2 months (5.5–8.8) for the evaluable patients. The 1-year overall survival was 10% (3.2–
21.5) for all patients and 11.4% (3.6–24) in the evaluable
patients (Table 3). Of the 35 evaluable patients, 10 (28.6%)
exhibited a PR, 12 (34.3%) had stable disease (SD) and 13
(37.1%) had progressive disease (PD; Table 3). Survival
curves were significantly different for patients based on
their radiological best-observed response by log rank test
(P = 0.0012). For those evaluable patients classified as
partial responders, the median time to progression was
3.1 months (1.4–9.3; Fig. 1). Within individual response
categories, it was shown that survival times for PR patients were significantly improved relative to patients exhibiting PD (P = 0.0007, Fig. 1). Notably, two patients
survived over 2 years, the longest surviving 32.8 months,
and 2 patients survived over 1 year. The median overall
survival for the locally advanced patients was 8.8 months
(6–14.8), and 6.75 months (4.5–8.1) for the metastatic patients (P = 0.09). One-year survival differences between
metastatic and locally advanced groups were not significantly different (P = 0.4995). No significant survival difference was observed between patients exhibiting PR and
those with SD (P = 0.0748). Additionally, there was no
significant difference between the number of patients
achieving PR or SD between locally advanced and metastatic disease subsets (P = 0.62).
Using the LOGISTIC procedure in SAS/STAT 9.2, the
predictive ability of CA 19-9 levels on radiologic response was investigated. CA 19-9 levels were recorded
at baseline and immediately after every cycle (every
21 days). A >20% drop in CA 19-9 from baseline was
used as the threshold of response (38, 39). We observed
a >20% decrease in the CA 19-9 level relative to baseline
in 20 (57%) evaluable patients. In general, there was a
more robust CA 19-9 response in patients exhibiting either PR or SD (data not shown). We found that the overall change in CA 19-9 from baseline level to end of study
was a significant predictor of radiologic response (P =
0.048). Additionally, patients showing a >20% decrease
in CA 19-9 levels from baseline to end point had approximately five times higher odds of showing radiologic
response than patients who did not experience such a decrease (odds ratio, 4.9). Patients who experienced a >20%
drop at any point during the study relative to baseline
had ∼11 times higher odds of showing radiological response (odds ratio, 11.4). This was also shown to be a significant predictor of radiologic response (P = 0.03).
QOL improved in 12 (35%) of the evaluable patients
and remained stable in 3 (8.8%; Table 3). The two most
commonly observed dose-limiting toxicities were hematologic toxicity and fatigue (Table 4). Grade 3/4 hematologic toxicity was seen in 26 (74%) of the evaluable
patients. Grade 2/3 fatigue was observed in 21 patients
(60%). Nine patients died during study treatment or
within 30 days of discontinuing treatment because of
PD or disease-related complications. Of these nine patients, all were discontinued due to PD, with three patients having associated complications including pleural
effusion, recurring strokes, and pain control issues,
respectively. Of the remaining evaluable patients, 20 patients were eventually discontinued due to PD.
The results of our trial showed an overall response
rate of 28%, which compares well with response rates
reported in other clinical studies ranging from 4.1% to
33% (Table 5).
Table 2. Treatment plan
Dose schedule
Gemcitabine
Etoposide
Premedication
Growth factor support
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2-wk treatment and 1-wk rest schedule (21-d cycle)
1,000 mg/m2 over 30 min in 250 mL normal saline on days 1 and 8 of a 21-d cycle
80 mg/m2 i.v. over 1 h in 250 mL normal saline on days 8, 9, and 10 of a 21-d cycle
Dexamethasone 10 mg i.v. and a serotonin uptake inhibitor (granisetron, ondansetron, dolasetron)
prior to each chemotherapy treatment. Other premedications at the discretion of the investigator
Discretion of the treatment physician
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Melnik et al.
Table 3. Response and survival data of the study population
Characteristic
Chemo-naïve patients*
Median survival†
1-y survival
Evaluable patients
PR
SD
PD
1-y survival
Median time to progression
CA 19-9 >20% decrease
Survival (months)
Median
Minimum
Maximum
QOL improved††
QOL stable
Overall
Metastatic
Locally advanced
40
6.7 (4.5–8.1) mo
10% (3.2–21.5)
35
28.6% (14.6–46.3)
34.3% (19-52)
37.1% (21.5–55.1)
11.4% (3.6–24)
3.1 (1.4–9.3)
20 (57.1%)
33
5.5 (3.2–7.7)
6% (1–17.6)
28
25% (11-45)
35.7% (18.6–56)
39.3% (21.5–59.4)
7% (1-20)
2.8 (1.2–15)
15 (53.6%)
7
8.8 (6–14.8)‡
14.3% (1-46)§
7
43% (10-82)
28.6% (3.6–71)
28.4% (3.7–70.1)
14.3% (1-46)∥
4.2 (1.4–9.3)¶
5 (71.4%)
7.2 (5.5–8.8)
2.0
32.8
12 (35%)
3 (8.8%)
6.75 (4.5–8.1)
2.0
28
11 (40.7%)
2 (7.4%)
8.8 (6–14.8)**
6.0
32.8
1 (14.3%)
1 (14.3%)
*Except 5-FU as a radiosensitizer.
95% confidence intervals shown in parentheses.
‡
Log rank test (P = 0.09).
§
Fishers exact test (P = 0.4478).
∥
Fishers exact test (P = 0.4995).
¶
Log rank test (P = 0.7016).
**Log rank test (P = 0.1577).
††
Based on patient survey.
†
To further characterize the potential association between the presence of an activating RAS mutation and
clinical response to gemcitabine/etoposide, archival tissue available from 17 patients was screened for KRAS
mutations by pyrosequencing as described in Materials
and Methods. Fifteen patient tumors were shown to carry exclusive single base substitutions in either position 1
or position 2 of codon 12 (Supplementary Table S1).
KRAS mutations were not identified in either codon 12
or 13 in two patients (both classified as nonresponders;
PD). The relative percentage of mutation burden varied
greatly (6–95%) in KRAS-positive tumors (Supplementary Table S1). Interestingly, although not statistically
significant [P = 0.06 (PR-PD), P = 0.14 (SD-PD),
P = 0.57 (SD-PR), pairwise Wilcoxon tests], there was a
general positive trend between tumors harboring a
Figure 1. Response and survival rates for all 35
evaluable patients. Overall survival rates over
time for each response category; difference
in survival time of PR versus PD was statistically
significant (P = 0.0007).
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Mol Cancer Ther; 9(8) August 2010
Molecular Cancer Therapeutics
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Published OnlineFirst August 3, 2010; DOI: 10.1158/1535-7163.MCT-09-0854
Gemcitabine and Etoposide for Pancreatic Cancer
Table 4. Most commonly occurring toxicities as reported by patient population
Adverse event
Alopecia
Constipation
Fatigue
Hematologic
Nausea
Sensory neuropathy
Vomiting
Grade 1
Grade 2
Grade 3
Grade 4
Overall
MET
LA
Overall
MET
LA
Overall
MET
LA
Overall
MET
LA
22.9
17.1
22.9
8.6
45.7
8.6
14.3
25.0
21.4
21.4
10.7
50.0
10.7
14.3
14.3
0
28.6
0
28.6
0
14.3
57.1
17.1
37.1
14.3
17.1
0
11.4
57.1
21.4
39.3
17.9
14.3
0
14.3
57.1
0
28.6
0
28.6
0
0
—
11.4
22.9
28.6
8.6
0
5.7
—
7.1
21.4
25
7.1
0
3.6
—
28.6
28.6
42.9
14.3
0
14.3
—
0
0
45.7
0
0
0
—
0
0
42.9
0
0
0
—
0
0
57.1
0
0
0
NOTE: Values given are percentages of patients.
Abbreviations: LA, locally advanced; MET, metastatic.
higher percentage of KRAS-positive cells and radiological
tumor response [mean values for PR (70.1), SD (51.2), and
PD (21.8)].
Discussion
RAS mutations are found in >90% of pancreatic cancers
(36). Koo et al. (31, 32) observed a striking correlation
between activating RAS mutations in human tumor cells
and enhanced sensitivity to deoxycytidine analogues as
well as to topoisomerase II inhibitors. Thus, human cell
lines harboring activated RAS oncogenes display
enhanced cytotoxicity to deoxycytidine analogues, including 1-β-D-arabinofuranosylcytosine (cytarabine) and
gemcitabine, and especially to topoisomerase II
inhibitors.
The presence of RAS oncogenes in acute myeloid leukemia is associated with increased complete remission
rate, longer complete remission duration, and improved
overall survival in patients treated with cytarabine or the
Table 5. Comparative studies using chemotherapy for unresectable pancreatic cancer
Drugs
Gemcitabine + cisplatin
Gemcitabine
Gemcitabine
5-FU + strep + cisplat + LV/5-FU
Docetaxel
Gemcitabine + docetaxel
Gemcitabine
Cetuximab + gemcitabine
Gemcitabine + oxaliplatin
Gemcitabine + 5-FU
Gemcitabine + 5-FU
5-FU + trimetrexate + leucovorin (NFL)
Gemcitabine
Irinotecan + gemcitabine phase 2
Irinotecan + gemcitabine phase 3
Gemcitabine + docetaxel
Gemcitabine + oxaliplatin
Erlotinib + gemcitabine
Rubitecan
Bevacizumab + gemcitabine
Gemcitabine + capecitabine
Gemcitabine + capecitabine
Gemcitabine + etoposide
www.aacrjournals.org
Response rate (%)
26
27
24
33
15
27
12
12
30.6
19
7
4.1
11
24
16
27
27
8.6
7
21
18.9
25
28.6
Author
Reference
Phillip et al.
Rothenberg et al.
Burris et al.
Martin et al.
Rougier et al.
Sherman et al.
Crino et al.
Xiong et al.
Louvet et al.
Kanat et al.
Oliani et al.
Garcia et al.
Moriwaki et al.
Rocha Lima et al.
Rocha Lima
Schneider et al.
Louvet et al.
Zuo et al.
Burris et al.
Kindler et al.
Stathopoulos et al.
Heinemann
Melnik
(18)
(22)
(7)
(15)
(23)
(25)
(9)
(28, 29)
(13, 14)
(11)
(17)
(10)
(16)
(21)
(20)
(24)
(13, 14)
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Reported herein
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Melnik et al.
combination of cytarabine and a topoisomerase II inhibitor (34, 40). Collectively, the Koo et al. (31, 32) and
Neubauer et al. (34, 35) studies provide a rationale for
the combination therapy of gemcitabine and etoposide
in the pancreatic cancer study that we describe here.
We tested the efficacy and toxicity of this combination
in patients who presented with nonresectable pancreatic
cancer (41) and are particularly encouraged, both by the
trend in patient response (Supplementary Table S1), as
well as by the studies of Neubauer et al. (34, 35), showing
a more favorable response in patients with acute myeloid
leukemia harboring RAS-activating mutations. This combination has shown significant activity against non–small
cell lung cancers (42), which also displays frequent RAS
mutations (41). None of the studies thus far provide an
explanation for why oncogenic RAS enhances sensitivity
to cytarabine/gemcitabine and anthracycline/etoposide.
In the pancreatic cancer patient group for which tissue
was available for KRAS mutation analysis, a trend was
found between radiologic response and degree of KRAS
expression. Moreover, in this group, the longest survivor
(28 months) showed the highest degree of KRAS mutation (95%). These findings provide intriguing support
for the earlier data of Koo et al. (32), linking mutant
KRAS expression with increased sensitivity to gemcitabine and etoposide in vitro. It further suggests that future
clinical investigation in this area should include, in addition to more detailed study of KRAS expression as it relates to clinical response and survival, a comparison of
this regimen with standard gemcitabine. It seems possible that greater KRAS expression could identify patient
subpopulations with significant sensitivity to this regimen. It would be desirable to include a gene-targeting
drug such as erlotinib, which was recently approved
for pancreatic cancer (30), with gemcitabine plus an additional agent such as etoposide or cisplatin, anticipating
that the loss of receptor tyrosine kinase activity would
enhance the tumor sensitivity to chemotherapy agents.
Our clinical trial showed a response rate of 28%, which
compares well with the response rates reported in other
clinical studies ranging from 4.1% to 33% (Table 5). In our
clinical trial, the 1-year survival rate was 11.4% (Table 3).
Notably, two patients survived for more than 2 years and
a total of four patients (11.4%) survived for more than
1 year. As in most other studies, dose-limiting toxicities
were primarily hematologic toxicity and fatigue, but
were manageable (Table 4). On the basis of observed toxicities, especially neutropenia, growth factor support was
added at the discretion of the clinician and should be
strongly considered when this combination therapy is
used. QOL was generally described as favorable, with
improvements reported in 35% of evaluable patients.
This compares favorably with early studies of gemcitabine that showed improvement in clinical benefit response in 28% of patients treated with gemcitabine
alone (43). Thus, the combination of gemcitabine and etoposide is generally well-tolerated and exhibits a response
rate similar to other published studies (Table 5). Based on
the results of this study, follow-up phase II clinical trials
comparing or combining this combination with new
agents targeting molecular vulnerabilities identified in
pancreatic cancer (44) are warranted. An interesting finding in this study is the remarkable overall survival seen
in four patients, with two surviving more than 2 years,
suggesting that specific molecular subsets might exist
that are particularly sensitive to this regimen. Thus,
follow-up trials should include correlative studies to determine whether the molecular traits of individual patients and/or their tumors, including the RAS mutation
status, could be associated with differential therapeutic
responses and outcomes.
Disclosure of Potential Conflicts of Interest
G.F. Vande Woude: Consultant/advisory board. No other potential
conflicts of interest were disclosed.
Acknowledgments
Han-Mo Koo, Ph.D., a brilliant scientist responsible for the preclinical
data and instrumental in the development of this protocol, sadly suffered
an untimely death in the midst of this study, succumbing to an aggressive
NK T-cell lymphoma. He remains sorrowfully missed.
Grant Support
This study was supported entirely by a generous grant (B9E-US-X360)
through Eli Lilly and Company.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
this fact.
Received 09/11/2009; revised 05/21/2010; accepted 05/21/2010;
published OnlineFirst 08/03/2010.
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