Download Pancreatic cancer: Understanding and Overcoming

Pancreatic cancer: Understanding and Overcoming
Li-Tzong Chen, MD, Ph.D.
National Institute of Cancer Research, National Health Research Institutes;
Department of Internal Medicine, National Cheng-Kung University Hospital and
Department of Internal Medicine, Kaohsiung Medical University Hospital
Pancreatic cancer is one of the most detrimental malignancies. Early detection is
uncommon with no more than 15–20% of the patients being amenable for curative
intent surgery at the time of diagnosis. Despite recent data supported that adjuvant
chemotherapy with either 5-FU or gemcitabine could improve the survival of
pancreatic cancer patients underwent curative resection, the median survival of those
patients remained 18 – 24 months. For patients with advanced pancreatic cancer
(APC), gemcitabine either alone or in combination with erlotinib are the only
approved treatments for advanced pancreatic cancer (APC). However, one recent
retrospective study showed gemcitabine/erlotinib combination might not be
detrimental to patients with KRAS mutated advanced pancreatic cancer patients.
Because of the 80-90% of KRAS mutation rate in pancreatic cancer, further study to
confirm the therapeutic effects of gemcitabine/erlotinib in APC is mandatory. On the
other hand, Conroy et al recently showed that a gemcitabine-free triplet
chemotherapy, FOLFIRINOX regimen consisting of oxaliplatin, irinotecan and
infusional 5-FU/leucovorin, could achieve significantly better tumor response rate,
progression-free survival and overall survival than gemcitabine monotherapy in
patients with metastatic pancreatic cancer in a randomization phase III trial. The
encouraging results support the application of an aggressive, triplet chemotherapy is
feasible in APC patients. Recently, Ch’ang et al also showed that 3 months of triplet,
induction chemotherapy followed by concurrent chemo-radiotherapy could achieve a
median time-to-progression and overall survival of 9.3 [95% confidence interval (CI),
5.8-12.8] and 14.5 (95% CI, 11.9-17.1) months, respectively in locally advanced
pancreatic cancer patients, with the one- and two-year survival rates of 68% (95% CI,
55.1-80.9%) and 20.6% (95% CI, 8.7-32.5%), respectively. The results were exciting.
However, further explore the drug resistant mechanisms of pancreatic cancer
including stem cell-like cancer cell phenotype, microenvironment-cancer cell
interaction, drug transporter or metabolic enzyme expression are mandatory to further
1
improve the therapeutic outcome in this difficult tumor.
2
Clonal evolution of pancreatic tumors and metastatic cancer stem cells
Chia-Ning Shen1,2, Chi-Che Hsieh1,2, Wen-Ying Liao3, Yi-Ming Shyr4, Tien-Hua
Chen4, Shian-Ying Sung2,5
1
Stem Cell Program, Genomics Research Center, Academia Sinica, Taipei,
Taiwan;2Program for Cancer Biology and Drug Discovery, China Medical
University, Taichung, Taiwan;3Graduate Institute of Pharmaceutical Chemistry,
China Medical University, Taichung, Taiwan; 4Department of Surgery, Taipei
Veterans General Hospital, Taipei, Taiwan;5Graduate Institute of Cancer Biology,
China Medical University, Taichung, Taiwan
The evolution towards more aggressive form of tumor is often referred to as
cancer progression which is thought to originate from the development of
heterogeneous cancer population combined with the continuous selection toward
more malignant cellular phenotypes. Indeed, metastasis is the major cause of death in
pancreatic cancer patients, where most patients are diagnosed with metastatic disease
and few show a sustained response to chemotherapy or radiation therapy. Recent
identification of cancer stem cells might provide a solution to explain how cancer
heterogeneity can be achieved. However, whether cancer stem cells existed and
contribute to cancer metastasis need to be addressed further. Initially, we
demonstrated that only rare population of pancreatic cancer cells are double-positive
for CD24 and CD44. We further identified CD44+ ABCG2+ (CD24+ or CD24- )
subpopulation not only had self-renewal capability and higher tumorigenicity, but
they also had higher metastatic potentials. And this metastatic behavior was not seen
in the sorted CD44+CD24+ABCG2- subpopulation or unsorted population suggesting
the metastatic subpopulation are derived clonally and suppressed by existence of other
cancer cell population. We also showed that CD44+CD24+ABCG2+ cells displayed
drug resistance, can be maintained constantly in culture, and were able to generate
different subpopulations in vitro. Based on using extracellular flux analyzer, we
revealed that the CD44+CD24+ABCG2+ subpopulation has metabolic plasticity that
produced higher levels of lactate and had higher oxygen consumption rate during
differentiation suggesting this subpopulation can be selectively outgrow under
extreme nutritional conditions. These finding provide novel insights into the
3
metabolic features underlying pancreatic cancer progression and define a clonal
integrity of cancer stem/initiating cell to contribute to pancreatic cancer metastasis.
4
The Impact and Utilization of Pancreatic Stem Cell Concept for Prognosis and
Treatment of Patients with Pancreatic Cancer
Tsann-Long Hwang, Chi-Hong Lo
Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University,
Lin-Kou, Taiwan
The survival of patients with pancreatic cancer is very low. Cancer stem cells (CSCs)
have been identified in pancreatic cancer, which based on the expression of the
surface markers CD24, CD44, CD133, and epithelial specific antigen (ESA). The
prognosis of pancreatic cancer may be related to the presence of tumor with CSCs
surface markers positive or not. In addition, pancreatic cancer is also highly resistance
to various chemotherapeutic agents. Drug resistance of cancer cells may base on the
concept of cancer stem cells. ABCG2 (ATP binding cassette transporter) is an efflux
protein which plays a role on host detoxification of various xenobiotic substrates. The
mechanism of drug resistance based on CSC models and the role of ABCG2 were
investigated.
Cancer stem cells were isolated from Capan-1 and Bx PC-3 pancreatic cancer cell
lines. CD44+ and EpCAM+ CSC markers were confirmed. Different dosages of
Gemcitabine, cisplatin and 5-FU were added on the cultured dishes of CSCs. The
percentages of viable cells among CD+44 cells, EpCAM+cells, and CD44-/EpCAMcells were compared. The expressions of ABCG2 and other related transporter
proteins (NES and NOTCH1) were compared among CD44- ,CD44+, C24+ and
EpiCAM+ CSCs. Seventy one patients (44 male and 27 female) who underwent
surgical treatment at Chang Gung Memorial Hospital - Lin-Kou Medical Center were
included in this study. The patient’ age range from 30 to 84 years. All of their surgical
specimens showed invasive ductal cancer. Immunohistochemical stainings with CD44
antibodies were also performed. The difference of survival rate between patients with
CD44+ and CD44- was compared. 65.2% patients with CD44- survived longer than 3
years, and 24.3% patients with CD44+ survived less than 3 years, the difference was
significance. (p < 0.01). The patients with stage I to III were also compared between
those with CD44+/-. The results showed the patients, all, stage II or III, with CD44all had significantly better three year survival rates than those with CD44+. (p < 0.05)
The differences of viable pancreatic cancer cells to various chemotherapeutic drugs
5
among CD44+ cells, EpCAM+ cells, and CD44-/EpCAM- cells had no significant
difference. The expressions of ABCG2, NES and NOTCH1 were significantly lower
in CD44- than other CSC surfaces markers. (p<0.05)
Our results suggested that CD44 expression in pancreatic cancer were significantly
associated with better longer survival. The transporter protein, such as ABCG2, may
play an important role for chemotherapeutic resistance of CSCs in patients with
pancreatic cancer.
6
4Th International pancreatic cancer conference
Title: The functional heterogeneity of pancreatic cancer cells and surrounding stromal
cells in cancer-stromal interactions
Kenoki Ohuchida,1,2 Kazuhiro Mizumoto,1 and Masao Tanaka1
1Department of Surgery and Oncology, and 2Department of Advanced Medical
Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Abstract
Interactions between cancer cells and surrounding stromal cells play an important role
in aggressive tumor progression. Previously, the functional heterogeneity of cancer
cells, such as cancer stem cells (CSCs), have been reported in pancreatic cancer as
well as other cancers, but the specific role of these cells is unknown. Also, pancreatic
stellate cells (PSCs), which were reported to be important cell population in
surrounding stromal cells, promote the progression of pancreatic cancer. However, the
functional heterogeneity of PSCs has not been identified. Detailed characterization of
the specific
subsets of cancer cells and surrounding stromal cells in human pancreatic cancer
would provide a set of potential targets for specific cell-directed therapy. Recently,
we investigated the relationship between CD133+ cells, one of the putative CSC
candidates, and primary pancreatic stromal cells. And we also investigated the
functional heterogeneity of PSCs derived from pancreatic tumor based on the
presence of cell surface antigen CD10, which is a stromal prognostic marker in
various tumors. In this session, our novel findings regarding the cancer-stromal
interaction will be reported.
Especially, heterogeneity of cancer cells and surrounding stromal cells will be
highlighted.
7
Real effects of venous resection in pancreatoduodenectomy
Masao Tanaka, M.D., Ph.D., F.A.C.S., Department of Surgery and Oncology,
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Although the advent of portal vein resection (PVR) has increased the rate of
resection of ductal adenocarcinoma (DAC) of the head of the pancreas, its real effects
on the outcome, i.e., whether the increase rate of resection improves survival or not
has been questioned. A collective data extracted from the nationwide pancreatic
cancer registry of the Japan Pancreas Society demonstrated no significant difference
when the invasion is histologically positive and even worse prognosis when
histologically negative, suggesting that we should not do PVR only because DAC is
close to the portal vein, but when there is real invasion, PVR does not worsen the
prognosis.
I would briefly introduce our method of pancreatoduodenectomy called “the SMA
first approach” to reduce intraoperative blood loss and to facilitate PVR when
necessary. Dissection of the right side of the SMA is done usually done at the end of
pancreatoduodenectomy; however, if you do this most cumbersome part at the initial
phase of the operation, you can significantly reduce blood loss by preventing venous
congestion in the pancreatic head region (Figure 1 & 2). Moreover, PVR can be
performed with ease in this way. We perform PVR only when the radiological sign of
invasion is unilateral, but not circumferential. When the resected segment of the PV is
more than 5 cm in length, you need to interpose a vein graft, which can be harvested
from the right external iliac vein by the extra-peritoneal approach.
Of 182 pancreatoduodenectomy patients with complete follow-up, 42 or 19%
underwent portal vein or SMV resection in our institution. PVR has been increasing
lately and the rate reached 30% last year. The overall 5-year survival rate was 26.8%.
When divided into two groups in regard with portal vein resection, those who did not
need PVR lived significantly longer than those who needed PVR (Figure 3). When
the patients with PVR were divided into two subgroups according to the presence or
absence of adjuvant gemcitabine chemotherapy, the 5-year survival of patients with
PVR plus chemotherapy was 38.1%, which was similar to 38.4% of those who
underwent adjuvant GEM without PVR. GEM greatly improves survival even in
patients who need PVR to accomplish PD (Figure 4). The prognosis of those with
8
PVR and positive pathological PV invasion was worst in all subgroups. However,
even those with pathological PV invasion showed a 5-year survival rate of 32.1%
after adjuvant GEM.
PVR raises the resection rate and would give a hope for survival to the patient and
his/her family, but does not improve survival by itself. Adjuvant chemotherapy with
gemcitabine improves survival, irrespective of the presence or absence of histological
PV invasion. Adjuvant chemotherapy with gemcitabine is a key to longer survival
even in patients with the need for PVR.
9
What Is A Safe Pancreatic Anastomosis in Pancreaticoduodenectomy?
Yu-Wen Tien, Chin-Yao Yang, Po-Huang Lee
Department of Surgery, National Taiwan University Hospital
Although mortality rates after pancreaticoduodenectomy (PD) has decreased to
less than 5% at high volume centers, operative morbidity has remained high with
recently reported incidence ranging from 20% to 50%. Postoperative pancreatic
fistula (POPF) is the most frequent complication after PD, results in increased
morbidity and mortality, and adversely affects length of stay and costs. Reported rates
of POPF vary from 0% up to more than 30%. Plenty of randomized trials and metaanalyses were published to analyze the ideal procedure, technique of anastomosis, and
perioperative management of patients undergoing PD. However, results are often
discordant and clear evidence on the ideal management and surgical technique to
reduce POPF is not yet provided.
There are many factors that have been considered to influence the development of
POPF. Factors influencing POPF can be classified as patient-related (age, gender,
obesity, cardiovascular diseases, and diabetes mellitus), disease- (histopathological
diagnosis) and pancreas-related (pancreas texture and pancreatic duct size), related to
perioperative treatments (preoperative biliary drainage, neoadjuvant treatment,
prophylactic somatostatin and octreotide, perioperative nutritional support),
intraoperative factors (classical PD vs. pylorus-preserving PD, extended resections,
pancreaticojejunostomy or pancreaticogastrostomy, use of fibrin sealants, pancreatic
duct stenting, intraoperative blood loss and transfusions, operative time, and use of
intraperitoneal drains), and center-related factors (surgeon volume).
Prospectively collected data base of 371 patients having PD at NTUH in last 5
years was analyzed for risk factors related to POPF. Multivariate analyses showed
soft pancreas parenchyma and small pancreatic duct size significantly related to
POPF. However, in spite of high POPF rate (10.8%, 40 in 371 patients), mortality
remained low, 2 (0.53%) in 371 patients. We attributed the low mortality to good
perioperative management.
10
Surgical management of ucinate process pancreatic cancer
Ta-Sen Yeh, MD, PhD
Department of Surgery, Chang Gung memorial Hospital at LinKou, Chang Gung
University
Abstract
Ucinate process pancreatic cancer (UPPC) is traditionally considered to be difficult to
manage because of inconspicuous symptoms/signs, complicated anatomoic location
and proximity to major vessels relevant to the tumor. Until then, few reports have
addressed the clinicopathologic characteristics of UPPC. The aims of this study are to
clarify the predominant symptomatology, resectability, associated surgical
procedures, perioperative complication, and most importantly, the long-term outcome
of patients with UPPC treated in a single institute.
11
Is TS-1 a new agent for advanced pancreatic cancer?
Pancreatic cancer is a highly lethal disease in spite of the recent advances in
diagnostic imaging techniques and multi-modality cancer treatment. The
symptoms and signs of pancreatic cancer are non-specific. Early diagnosis is
very difficult, and curative surgery is suitable for only a minority of patients.
Although radiotherapy and chemotherapy have been incorporated into multimodality treatment in the hope of survival prolongation, the toxicity is significant,
but the efficacy remains unsatisfactory.
Gemcitabine monotherapy has been widely used for the treatment of advanced
pancreatic cancer despite a low response rate (RR) of only 5 to 15% and median
survival time (MST) of 5 to 7 months. Gemcitabine-based combination
chemotherapy has thus been extensively studied, but whether combination
chemotherapy provides additional therapeutic benefit over gemcitabine
monotherapy remains undetermined.
TS-1 is an orally administered drug that is comprised of the 5-FU pro-drug
tegafur and two modulators, gimeracil and oteracil potassium. A phase II study
of advanced pancreatic cancer with distant metastasis demonstrated using TS-1
monotherapy achieved a response rate of 21.1% (4 responders in 19 patients),
time-to-progression (TTP) of 77 days and MST of 169 days 40). Another phase
II study demonstrated a RR of 37.5% (15 responders in 40 patients), TTP of 113
days and MST of 281 days.
In a phase II study, 55 patients were enrolled to receive gemcitabine-TS-1
combination regimen, gemcitabine, 1000 mg/m2 intravenously on days 1 and 8,
and TS-1, 80 mg/m2/day orally from day 1 to 14, every 21 days. Analysis of the
54 evaluable patients showed a response rate of 44%, median progression-free
survival time (PFS) of 5.9 months, MST of 10.1 months, and 1-year survival rate
of 33.0%. Major grade 3/4 toxicities of gemcitabine-TS-1 combination therapy
included neutropenia (80%), leukopenia (59%), thrombocytopenia (22%),
anorexia (17%), increased ALT (7%), rash (7%), nausea (6%) and fatigue (6%).
No treatment-related death was reported. Dose reduction was necessary in 30
patients (56%), and 22 patients (41%) discontinued the study treatment due to
adverse events.
12
A randomized phase III study compare gemcitabine versus TS-1 versus
gemcitabine plus TS-1 in locally advanced or metastatic pancreatic cancer
patients was completed. Total enrolled patient number: Japanese: 768,
Taiwanese: 66. The results will be presented in the conference.
13
A multinational phase II study of PEP02 (liposome irinotecan) for patients with
gemcitabine-refractory metastatic pancreatic cancer.
L.T. Chen,1,2 A.H. Ko,3 M.A. Tempero,3 Y.S. Shan,1 P.W. Lin,1 W.C. Su,1 Y.L. Lin,4
G. Yeh.5
National Cheng Kung University, National Cheng Kung University Hospital, Tainan,
National Institute of Cancer Research, National Health Research Institutes, Tainan,
Taiwan; University of California, San Francisco Comprehensive Cancer Center, San
Francisco, CA; National Taiwan Universiy Hospital, Taipei; PharmaEngine, Inc.,
Taipei, Taiwan
Background: PEP02 is a novel nanoparticle liposome formulation of irinotecan
(CPT-11) with improved pharmacokinetics and tumor biodistribution of both CPT-11
and its active metabolite-SN38 comparing to the free form drug. PEP02 has showed
encouraging safety and efficacy in various tumor types, including significant
antitumor activity in a human pancreatic cancer L3.6pl orthotopic nude mouse
xenograft model. In previous phase I studies, PEP02 either alone or in combination
with 5-FU/LV demonstrated prolonged disease control in 5 of 7 (71%) patients with
gemcitabine-refractory advanced pancreatic cancer (APC).
Objectives: To evaluate the therapeutic efficacy of PEP02 monotherapy as 2nd-line
treatment in patients with metastatic, gemcitabine-refractory APC.
Methods: Patients with histology-proven metastatic pancreatic adenocarcinoma, KPS
≥ 70, and progressed after first-line gemcitabine-based chemotherapy were eligible.
Treatment consisted of intravenous injection of PEP02 120 mg/m2 administration
over 90 minutes, every 3 weeks. A Simon’s two-stage design was used with 16
patients in the first stage and 39 patients in total; primary end-point was 3-month
survival rate (OS3-month). Results: Between March 2009 and September 2010, 41
patients were enrolled at 3 centers in the U.S. and Taiwan. Characteristics for the 40
treated patients were 19 M/21 F; mean (range) age 58.8 (39-82) y/o; 22 Asian/18
Caucasian, KPS 100/90/80/70: 7/16/7/10. Until end of May, 2 patients are still
undergoing PEP02 treatment and 7 patients are still alive. Mean treatment cycles is
5.4 (range, 1-26). Objective response rate is 7.5% and disease control rate (minr
objective response + stable disease > 2 cycles) is 55.0%. Of the 255 patients (20%)
are characterized asevaluable for clinical benefit response (CBR), 5 (20%)ders among
14
the 25 CBR-evaluable pts.achieved CBR. 11 Eleven (34.3%) of 32 patients with
elevated baseline CA19-9 have had > 50% biomarker decline. The OS3-month is 75%,
with median progression free survival (PFS) and OS of 9 and 22.4 weeks,
respectively, with 15 (37.5%) patients still alive after 1 year. Reasons for study
discontinuation: 79.4% progressive disease, 11.8% drug- related toxicity, 8.8% other.
The most common G3/4 toxicities are: neutropenia (30%), leucopenia (22.5%),
anemia (15%), diarrhea (7.5%), and fatigue (7.5%).
Conclusions: This study has already met its primary endpoint (predicted OS3-month
>65%). PEP02 appears to have both activity and tolerable side effects for patients
with metastatic, gemcitabine-refractory APC, and represents a promising option for
this patient population with few standard options.
15
Molecular portraits of structural differentiation predict prognosis of patients
with glandular cancers
Chi-Rong Li,Jimmy J.-M. Su, Patrick Y.-W. Chu, Li-Tzong Chen,Michael T.-L.
Lee,Kelvin K.-C. Tsai
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Department of Nursing, Chung Shan Medical University Hospital, Taichung, Taiwan
Department of Computer Science, Kun Shan University, Tainan, Taiwan
The degree of structural organization is an intrinsic property of glandular cancers and
may critically affect tumor behaviors and clinical outcome. Morphological
characterizations of glandular differentiation, commonly used in pathologic
classification, have only moderate prognostic utility. Here, we simultaneously
modeled structural differentiation of human pancreatic, prostatic, and mammary
epithelia in vitro, thereby identifying a core transcriptional program and a refined
gene signature associated with this developmental process. The expression pattern of
this signature classified early-stage glandular cancers into gland-similar and dissimilar subtypes, and provided useful prognostic information in multiple clinical
data sets. Thus, by exploiting the generic molecular program associated with
structural organization of glandular epithelia, we identified a core regulatory pathway
and improve outcome prediction in human glandular cancers (supported by National
Health Research Institutes Intramural Research Program CA-099-PP-19 and
Department of Health (DOH) of Taiwan DOH100-TD-C-111-004 (to K. Tsai).
16
Which is the best marker for pancreatic NETs?
Chin-Yuan Tzen, MD, PhD
Department of Pathology and Laboratory Medicine
Cathay General Hospital
Taipei, Taiwan
The neuroendocrine cell is a hormonal cell that has receptor for microenvironmental signals. It secretes biological active peptides into the blood circulation
thereby having the capacity to affect distant organs throughout the body. The secreted
peptides can cause various symptoms ranging from sweating, edema, diarrhea,
abdominal pain, gastrointestinal bleeding, cardiac disease, bronchoconstriction and
flushing.
These non-specific presentations could mislead a physician to suspect
other disease as the cause and cause misdiagnosis to food allergy, menopause,
irritable bowel syndrome, alcoholism, neurosis or anxiety attacks. Blood biomarker
tests such as Neuron-Specific Enolase (NSE), Pancreatic Polypeptide (PP) and
Chromogranin A (CgA) become useful in such situations to provide a risk profile for
NETs. A tumor size of 3 mm in diameter will secrete detectable amounts of peptides
in the blood stream for measurement. Of the three biomarkers, NSE provides very low
specificity (33%). PP provides a much higher specificity of 67%. There is limitation
of use due to common false positives occurring in renal insufficiency, diabetes,
inflammation or aging. CgA has high sensitivity (78%-84%) and specificity from
71%-85%. A combination of CgA and PP biomarkers will provide a sensitivity of up
to 95% for NETs. For patients with renal insufficiency, hypertension and on proton
pump inhibitor treatment, false positives occur in CgA；the Chromogranin B（CgB
）biomarker is preferred as it is not affected by this. There is a role for biomarkers
before diagnosis to confirm the suspicion of disease for further tests if needed. Should
the biomarker results be positive, one can then justify sending patients for an MRI or
CT scan to detect the location of the tumors. In addition, biomarkers can also be used
to gauge treatment response.
17
Surgery for Pancreatic Neuroendocrine Tumor (PNETs)
Yan-Shen Shan, Ying-Jui Chao, Hui-Ping Hsu, Pin-Wen Lin
Division of General Surgery, Department of Surgery,
National Cheng Kung University Hospital, Institute of Clinical Medicine,
College of Medicine, National Cheng Kung University
Pancreatic neuroendocrine tumors (PNETs) are a subset of pancreatic tumors.
They exhibit a wide spectrum of clinical behavior that has made diagnosis
difficult. The majority of PNETs are associated with prolonged survival, yet
there can be significant variability in outcomes because of their biological
heterogeneity. An old classification system divides PNETs into functional and
nonfunctional tumors based on excess hormone production. Patients with
functional tumors usually present with syndromes of gastrointestinal hormone
overproduction, whereas patients with nonfunctional tumors usually present
with mass effect or symptoms of metastatic disease. However, new WHO
classification system have been proposed and validated for prognostic
stratification of PNET patients.
Surgery is the only curative modality for PNETs. For its slow growing
and biological indolent, aggressive therapy is warranted. Recent studies have
demonstrated improved survival across all stages of disease, advocating
resection of the primary tumor in localized, regional, and metastatic disease.
With the advent of laparoscopy and advances in surgical technique, minimally
invasive operations are gaining acceptance in the management of various
pancreatic diseases, including PNETs. The purpose of this study was to evaluate
our institution’s surgical experience with PNETs and to demonstrate our
progress in minimally invasive/parenchyma-sparing resections.
18
Chemotherapy for Advanced Pancreatic Neuroendocrine Tumors (NETs)
Kun-Huei Yeh, M.D., Ph.D., Department of Oncology, National Taiwan University
Hospital
In contrast to carcinoid tumors, pancreatic NETs are evidently responsive to
cytotoxic chemotherapy. Historically, streptozocin-based or dacarbazine-based
regimens have been used. In the modern chemotherapy era, temozolomide plus
capecitabine, or oxaliplatin plus infusional 5-fluorouracil (5-FU) is active
combination. Cisplatin plus etoposide is active in patients with poorly differentiated
NETs. Novel targeted therapy plus chemotherapy warrants active investigation in
advanced pancreatic NETs.
Streptozocin-based regimens — Streptozocin has been an historical treatment for
patients with advanced pancreatic NET. In an early randomized trial, streptozocin
plus doxorubicin had a combined biochemical and radiologic response rate of 69
percent and a median survival of 2.2 years.
Dacarbazine (DTIC)-based regimens — Dacarbazine is an alkylating agent with
activity against pancreatic NETs. The objective response rate of 33 percent was
reported in an ECOG phase II trial of dacarbazine in patients with advanced
pancreatic islet cell tumors.
However, the widespread use of streptozocin-based or dacarbazine-based
regimens has been limited by concerns about toxicity.
Temozolomide-based regimens — Temozolomide is a less toxic orally active analog
of dacarbazine that has activity in patients with pancreatic NETs. In prospective
studies, temozolomide has been combined with bevacizumab, everolimus, or
thalidomide with overall response rates of 24 to 45 percent. The most encouraging
response rate was reported in a retrospective study using temozolomide plus
capecitabine combination with a response rate of 70 percent.
Oxaliplatin-based regimens — Oxaliplatin plus infusional 5-fluorouracil (5-FU)
plus leucovorin (FOLFOX) and bevacizumab in patients with advanced progressive
NETs had a partial response in three of five patients with advanced pancreatic NET in
a preliminary phase II trial.
Cisplatin-based regimens for poorly differentiated tumors — Patients with poorly
differentiated gastroenteropancreatic NETs are more responsive to cytotoxic
19
chemotherapy than those with well-differentiated tumors. Cisplatin and etoposide
combination had an overall response rate of 67 percent in patients with poorly
differentiated NETs.
20
Novel agents for advanced pancreatic NETs
The traditional cytotoxic agents are of limited efficacy in the treatment of pancreatic
neuroendocrine tumors (P-NETs). Recent investigations have brought up a number of
biological features in this family of neoplasms that could represent targets for
anticancer treatment. P-NETs seem to have an extraordinary tumor vascularization
with high expression of proangiogenic molecules such as the vascular endothelial
growth factor along with overexpression of certain tyrosine kinase receptors such as
the insulin growth factor receptor (IGFR) and their downstream signaling pathway
components (PI3K/AKT/mTOR). The rationale of an antiangiogenic approach in the
treatment of NETs and the use of mammalian target of rapamycin inhibitors are
discussed. Additionally, the emerging results of recent clinical trials with these
targeted drugs are presented.
21