Advanced Pancreatic Carcinoma: Current Treatment and Future Challenges

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Table 1.

Reference or trial	Study design	Study phase	Tumor type	Number of patients	Treatment	Status (estimated end date)
Icli et al. (2007)^[14]	Single arm	II	Pancreas	69	Gemcitabine + cisplatin + nadroparin	Closed
Riess et al. (2008)^[16]	Randomized	II	Pancreas	540	Gemcitabine + cisplatin + 5-FU + leucovorin ± enoxaparin	Closed
NCT00462852*	Randomized	II	Pancreas	120	Gemcitabine ± dalteparin	Ongoing (NR)
NCT00662688*	Randomized; four arms	III	Pancreas	136	Gemcitabine ± capecitabine ± dalteparin	Ongoing (January 2012)
NCT00876915*	Single arm	III	Multiple solid tumors	NR	Dalteparin with chemotherapy	Ongoing (September 2013)
NCT00908960*	Randomized	III	Lung, colon, pancreas	NR	Chemotherapy ± enoxaparin	Ongoing (April 2011)
NCT00031837*	Randomized	III	Multiple solid tumors	400	Gemcitabine ± dalteparin	Closed
NCT00312013*	Single arm	III	Lung, prostate, pancreas	NR	Chemotherapy + nadroparin	Closed
*Trials registered at www.clinicaltrials.gov, the official National Cancer Institute website (last updated August 2009). Abbreviations: 5-FU, 5-fluorouracil; NR, not reported.

Recent and ongoing trials of chemotherapy and prophylactic anticoagualtion in patients with pancreatic cancer

Table 2.

Reference*	Treatment	Number of patients	Median survival (months)
Heinemann et al. (2006)^[28]	Gemcitabine vs gemcitabine + cisplatin	195	6 vs 7.5 (P = 0.15)
Colucci et al. (2002)^[29]	Gemcitabine vs gemcitabine + cisplatin	107	5 vs 7.5 (P = 0.43)
Louvet et al.(2005)^[30]	Gemcitabine vs gemcitabine + oxaliplatin	313	7.1 vs 9 (P = 0.13)
Poplin et al. (2009)^[31]	Gemcitabine vs gemcitabine FDR vs gemcitabine + oxaliplatin	832	4.9 vs 6.2 (P = 0.04) vs 5.7 (P = 0.22)
Berlin et al. (2002)^[32]	Gemcitabine vs gemcitabine + 5-FU	322	5.7 vs 6.5 (P = 0.09)
Herrmann et al. (2007)^[34]	Gemcitabine vs gemcitabine + capecitabine	319	7.2 vs 8.4 (P = 0.234)
Rocha Lima et al. (2004)^[36]	Gemcitabine vs gemcitabine + irinotecan	342	6.3 vs 6.6 (P = 0.789)
Stathopoulos et al. (2006)^[37]	Gemcitabine vs gemcitabine + irinotecan	145	6.4 vs 6.5 (P = 0.970)
Abou-Alfa et al. (2006)^[38]	Gemcitabine vs gemcitabine + exatecan	349	6.2 vs 6.7 (P = 0.52)
Oettle et al. (2005)^[39]	Gemcitabine vs gemcitabine + pemetrexed	565	6.3 vs 6.2 (P = 0.847)
*Articles shown are reported in complete form. Abbreviations: FDR, fixed dose rate; 5-FU, 5-fluorouracil.

Phase III trials of chemotherapy in advanced pancreatic cancer patients

Table 3.

Reference	Treatment	Class of targeted agent	Target of targeted agent	Number of patients
Bramhall et al. (2001)^[54]	Gemcitabine vs marimastat	Broad-spectrum inhibitor of MMP	MMP	414
Bramhall et al. (2002)^[55]	Gemcitabine vs gemcitabine + marimastat	Broad-spectrum inhibitor of MMP	MMP	313
Moore et al. (2003)^[56]	Gemcitabine vs BAY 12-9566	Inhibitor of MMP-2, MMP-3, MMP-9, MMP-13	MMP	277
Van Cutsem et al. (2004)^[51]	Gemcitabine vs gemcitabine+tipifarnib	Inhibitor of FT	FT	688
Moore et al. (2007)^[64]	Gemcitabine vs gemcitabine + erlotinib	Tyrosine kinase inhibitor	EGFR	569
Kindler et al. (2007)^[59]*	Gemcitabine vs gemcitabine + bevacizumab	Monoclonal antibody	VEGF	602
Philip et al. (2007)^[68]*	Gemcitabine vs gemcitabine + cetuximab	Monocolonal antibody	EGFR	766
Vervenne et al. (2008)^[60]*	Gemcitabine + erlotinib vs gemcitabine + erlotinib + bevacizumab	Tyrosine kinase inhibitor/ monoclonal antibody	EGFR/ VEGF	607
*Trials reported in abstract form. Abbreviations: FT, farnesyltransferase; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor.

Phase III trials of targeted agents in advanced pancreatic carcinoma

Table 4.

Trial ID	Treatment	Estimated number of patients	Disease stage
NCT00112658‡	Gemcitabine vs oxaliplatin + irinotecan + 5-FU+folinic acid	348	IV
NCT00113256‡	Gemcitabine vs gemcitabine + rubitecan	NS	II—IV
NCT00051467	TNFerade^TM + 5-FU + radiation	NS	II-III
NCT00425360§	Gemcitabine + capecitabine ± GV1001	1110	III—IV
NCT00440167	Capecitanib + erlotinib followed by gemcitabine if PD vs gemcitabine + erlotinib followed by capecitabine if PD	NS	II—IV
NCT00486460	Gemcitabine + curcumin + celecoxib	NS	II—IV
NCT00498225	Gemcitabine vs TS-1 vs gemcitabine + TS1	NS	II—IV
NCT00486460	Gemcitabine vs gemcitabine + sorafenib	104	II—IV
NCT00574275	Gemcitabine vs gemcitabine + aflibercept	NS
NCT00634725	Gemcitabine ± capecitabine and/or radiotherapy vs gemcitabine ± erlotinib	820	III
NCT00662688	Gemcitabine ± capecitabine ± dalteparin	136	IV
NCT00789633	Gemcitabine vs gemcitabine + masitinib	NS	II—IV
*Data from the National Cancer Institute website (last updated Aug 2009) of ongoing and recently closed trials in patients with locally advanced and metastatic pancreatic cancer. ‡Phase II/III trials. §Three treatment arms: only chemotherapy (gemcitabine plus capecitabine) vs the same chemotherapy regimen for two cycles followed by GV1001 until disease progression and switch to the same chemotherapy, versus the same chemotherapy plus GV1001. Abbreviations: 5-FU, 5-fluorouracil; NS, not specified; PD, progressive disease.

Ongoing phase III trials in patients with pancreatic carcinoma*

Box 1.

Signal transduction pathways via Ras and PI3K/Akt that cause cell proliferation and survival

EGFR
IGF-1R
HGFR
VEGFR

Developmental signaling pathways that can cause tumor progression and resistance to chemotherapy

Hedgehog
Notch
Wnt

Tissue invasion and neovascularization

MMP
Other proteins

DNA damage control and impaired apoptosis

p53
p14 ARF/p16^INK4A
SMAD4/TGF-b

Pathways involved in pancreatic cancer

Box 2.

Rubitecan
Oral topoisomerase I inhibitor that blocks DNA and RNA synthesis in dividing cells.

TNF erade
Replication deficient adenovirus vector containing the gene for TNF-a controlled by a chemoradiation inducible promoter; used in combination with radiation therapy.

GV1001
Telomerase peptide vaccine; stimulates T cells to destroy the cancer cells by targeting the telomerase.

Curcumin
Natural compound with potent anti-inflammatory and antioxidative properties; inhibits cyclooxygenase-2 and blocks several pathways in cancer cells.

Celecoxib
Inhibits the enzyme cyclooxygenase-2 that is produced in response to inflammation and by precancerous and cancerous tissues.

TS-1
Prodrug of 5-fluorouracil (Tegafur) combined with two modulators to inhance its activity and reduce the gastrointestinal side effects of 5-FU.

Sorafenib
Tyrosine kinase inhibitor; blocks pathways involved in cell division and proliferation such as RAF/MEK/ERK; in addition blocks angiogenesis through inhibition of VEGFR-2/PDGFR-ß signaling cascade.

Aflibercept
Fusion protein comprised of segments of the extracellular domains of human vascular endothelial growth factor receptors VEGFR-1 and VEGFR-2 and the constant region of human IgG1; binds to VEGF and prevents it from binding to its receptor.

Masitinib
Tyrosine kinase inhibitor that acts on several proteins in critical pathways, such as KIT, PDGFR, FGFR and, to a lesser extent, focal adhesion kinases.

Agents and their mechanism of action for advanced pancreatic cancer

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Author(s)

Anastasios Stathis, MD

Clinical Research Fellow, Robert and Maggie Bras New Drug Development Program, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Disclosures

Disclosure: Anastasios Stathis, MD, has disclosed no relevant financial relationships.

Malcolm J. Moore, MD

Professor of Medicine and Pharmacology, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Disclosures

Disclosure: Malcolm J. Moore, MD, has disclosed no relevant financial relationships.

Editor(s)

Lisa Hutchinson

Editor, Nature Reviews Clinical Oncology

Disclosures

Disclosure: Lisa Hutchinson has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD

Associate Professor and Residency Director, Department of Family Medicine, University of California-Irvine, Irvine California

Disclosures

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Sarah Fleischman

CME Program Manager, Medscape, LLC

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

CME

Advanced Pancreatic Carcinoma: Current Treatment and Future Challenges

Authors: Anastasios Stathis, MD; Malcolm J. Moore, MD
CME Released: 1/26/2010
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 1/26/2011, 11:59 PM EST

Start Activity

Target Audience and Goal Statement

This activity is intended for primary care physicians, gastroenterologists, oncologists, radiation oncologists, and other physicians who care for patients with pancreatic carcinoma.

The goal of this activity is to describe current and future treatment of advanced pancreatic carcinoma.

Upon completion of this activity, participants will be able to:

Describe the diagnosis and prognosis of pancreatic carcinoma
Identify the first-line treatment for most patients with advanced pancreatic carcinoma
Specify a combination treatment that has improved survival outcomes vs cytotoxic monotherapy among patients with advanced pancreatic carcinoma
Describe the diagnosis and management of locally advanced pancreatic carcinoma

Disclosures

Author(s)

Anastasios Stathis, MD

Clinical Research Fellow, Robert and Maggie Bras New Drug Development Program, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Disclosures

Disclosure: Anastasios Stathis, MD, has disclosed no relevant financial relationships.

Malcolm J. Moore, MD

Professor of Medicine and Pharmacology, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Disclosures

Disclosure: Malcolm J. Moore, MD, has disclosed no relevant financial relationships.

Editor(s)

Lisa Hutchinson

Editor, Nature Reviews Clinical Oncology

Disclosures

Disclosure: Lisa Hutchinson has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD

Associate Professor and Residency Director, Department of Family Medicine, University of California-Irvine, Irvine California

Disclosures

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Sarah Fleischman

CME Program Manager, Medscape, LLC

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Abstract and Introduction

Abstract

Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth leading cause of cancer-related death in North America. Most patients present with locally advanced or metastatic disease that precludes curative resection. These patients have an extremely poor prognosis. In the absence of effective screening methods, considerable efforts have been made during the past decade to identify better systemic treatments. Unfortunately most trials have not shown a survival advantage for most therapies. In tandem with this increased clinical research, there has also been an expansion of preclinical laboratory investigation. These preclinical studies revealed many of the molecular mechanisms involved in pancreatic cancer development, which has provided insights into why current therapies are ineffective. These new discoveries provide some optimism that new agents inhibiting specific targets will improve outcome and overcome the resistance of pancreatic cancer to most standard treatments. We review the current standards of care for patients with locally advanced and metastatic pancreatic carcinoma and outline some future directions for the development of new treatment strategies.

Introduction

Pancreatic carcinoma is one of the most lethal solid malignancies and the fourth leading cause of cancer-related deaths in North America, where over 38,000 cases are diagnosed annually, with a similar number of patients dying from the disease.^[1,2] Pancreatic ductal adenocarcinoma accounts for the majority (>90%) of pancreatic malignancies.^[3] Approximately 60-70% of pancreatic adenocarcinomas arise in the head, neck or uncinate process, whereas presentations in the body (5-10%) or tail (10-15%) of the gland are less common.^[4] At the microscopic level, stroma surrounds the tumor, which is largely composed of fibroblastic and inflammatory cells, and extracellular matrix.^[5] There is a complex interplay between tumor and stromal cells, which leads to the activation of signaling pathways (such as TGF-b/SMAD, HGF/Met, matrix metalloproteinases, Hedgehog, Wnt) through auto-crine and paracrine mechanisms and the establishment of a dynamic microenvironment that promotes tumor growth and invasion.^[6]

Pancreatic adenocarcinoma has a high propensity for local invasion and distant metastases. Perineural, vascular and lymphatic invasion are commonly observed in resected tumor specimens; lymph-node metastases are present in 50-75% of resected cases.^[7-9] The management of patients with pancreatic carcinoma depends on the extent of the disease at diagnosis. Surgical resection followed by adjuvant therapy is the standard of care for patients diagnosed with early-stage disease. The majority of patients, however, present with advanced-stage disease that precludes surgery. Prognosis for these patients is extremely poor and the impact of standard therapy is minimal. Recent advances in the understanding of the molecular alterations that occur in pancreatic cancer have permitted the development of new agents that target components of specific pathways and provide optimism for better treatment strategies in the future.^[10]

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Clinical Presentation

CME Information

References

References

Disclaimer

The material presented here does not necessarily reflect the views of Medscape, LLC or companies that support educational programming on www.medscapecme.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

Table 1.

Table 2.

Table 3.

Table 4.

Box 1.

Box 2.

References

Faculty and Disclosures

Author(s)

Anastasios Stathis, MD

Malcolm J. Moore, MD

Editor(s)

Lisa Hutchinson

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

CME

Advanced Pancreatic Carcinoma: Current Treatment and Future Challenges

Target Audience and Goal Statement

Disclosures

Author(s)

Anastasios Stathis, MD

Malcolm J. Moore, MD

Editor(s)

Lisa Hutchinson

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Advanced Pancreatic Carcinoma: Current Treatment and Future Challenges

Abstract and Introduction

Abstract

Introduction

Table of Contents