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The Oncologist, Vol. 13, No. 3, 289-298, March 2008; doi:10.1634/theoncologist.2007-0134
© 2008 AlphaMed Press

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Gastrointestinal Cancer

New Therapeutic Directions for Advanced Pancreatic Cancer: Targeting the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways

Howard Burris, IIIa, Caio Rocha-Limab

aThe Sarah Cannon Research Institute, Nashville, Tennessee, USA; bUniversity of Miami Miller School of Medicine & Sylvester Comprehensive Cancer Center, Miami, Florida, USA

Key Words. Pancreatic cancer • Erlotinib • Cetuximab • Bevacizumab • Sorafenib • Chemotherapy

Correspondence: Howard A. Burris, III, M.D., The Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, Tennessee 37203, USA. Telephone: 615-329-7274; Fax: 615-329-7548; e-mail: hburris{at}tnonc.com

Received August 2, 2007; accepted for publication January 15, 2008.

Disclosure: H.B. has acted as a consultant to Genentech, Roche, OSI, and Lilly. C.R.-L. is on the speakers bureau for Genentech and Lilly. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. This article discusses unlabeled, investigational, or alternative use of bevacizumab, erlotinib, and gemcitabine.


   Learning Objectives
Top
 Footnotes
 Learning Objectives
Abstract
 Introduction
 Gemcitabine Combinations for...
 Advances in Molecular-Targeted...
 Considerations for Selecting...
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Evaluate the existing chemotherapeutic options for advanced pancreatic cancer.
  2. Interpret data from trials of HER-1/EGFR- and VEGFR-targeted agents in advanced pancreatic cancer.
  3. Take advantage of the potential of biomarkers in selecting optimal molecular-targeted therapies for advanced pancreatic cancer.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Footnotes
 Learning Objectives
 Abstract
Introduction
 Gemcitabine Combinations for...
 Advances in Molecular-Targeted...
 Considerations for Selecting...
 Acknowledgments
 References
 
In advanced pancreatic cancer, single-agent gemcitabine became the standard therapy approximately 10 years ago. Subsequently, combinations of gemcitabine with fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Among the newer approaches, targeting human epidermal growth factor receptor (HER-1/EGFR) shows promise. The U.S. Food and Drug Administration recently approved erlotinib (a HER-1/EGFR tyrosine kinase inhibitor) combined with gemcitabine for the first-line treatment of advanced pancreatic cancer. This combination showed a statistically significant survival benefit over gemcitabine alone in locally advanced or metastatic disease (the median overall survival time was 6.24 months versus 5.91 months; hazard ratio, 0.82; p = .038); however, the clinical significance of this survival difference has been questioned. Additionally, a large phase III trial where the addition of cetuximab (an anti–HER-1/EGFR monoclonal antibody [mAb]) to gemcitabine failed to result in a longer overall survival time than with gemcitabine alone has been reported. Targeting vascular endothelial growth factor (VEGF) with bevacizumab (a recombinant, humanized IgG1 mAb that binds to VEGF) in combination with gemcitabine was investigated in a phase II trial, with promising outcomes that were unfortunately not supported by a subsequent phase III study. While the future treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to molecular-targeted therapies, allowing individualization of patient therapy, there are currently no clear candidates, and this remains an interesting area for further investigation.


   INTRODUCTION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
Gemcitabine Combinations for...
 Advances in Molecular-Targeted...
 Considerations for Selecting...
 Acknowledgments
 References
 
Pancreatic cancer is the thirteenth most common cancer and the eighth leading cause of cancer death worldwide [1]. In the U.S. it is the fourth leading cause of cancer-related deaths in males and females [2]. The prognosis for pancreatic cancer is extremely poor, with 98% of patients expected to die from the disease [3]. Progress in the management and early detection of pancreatic cancer has been slow. Because of inherent difficulties in early detection and a high risk for metastases, few patients with pancreatic cancer (15%–20%) present with resectable disease, where surgery offers a chance of a cure [4].

In locally advanced, unresectable disease, patients typically receive 5-fluorouracil (5-FU)-based chemoradiation or chemotherapy alone [4]. The benefits of chemoradiation over chemotherapy alone in locally advanced disease have not been well established [5]. For patients with advanced, metastatic pancreatic cancer, the median survival time is just 4–6 months [6, 7]. The common symptoms of progressive disease are severe pain, nausea, weight loss, and weakness, and treatment is generally palliative at best. Since single-agent gemcitabine became the standard treatment for advanced pancreatic cancer approximately 10 years ago [8], most strategies to improve the management of this disease have been unsuccessful, and it is only recently that some progress has been made.

Our understanding of the underlying genetic and molecular abnormalities that drive the development of pancreatic cancer has expanded significantly over the last decade. Alterations to oncogenes and tumor suppressor genes, such as K-Ras, TP53, and p16INK4 are thought to play a critical role in the development of pancreatic cancer, as are changes in the expression of a range of proteins involved in the control of the cell cycle, proliferation, apoptosis, and invasiveness, such as Bcl-2, and the human epidermal growth factor receptor (HER-1/EGFR) [9, 10]. In addition, a number of growth factors, such as vascular endothelial growth factor (VEGF), transforming growth factor β, fibroblast growth factors, and nerve growth factor, are known to be expressed at higher levels in chronic pancreatitis and pancreatic cancer [9]. These observations have allowed for the rational development of targeted therapies for this hard-to-treat disease.


   GEMCITABINE COMBINATIONS FOR ADVANCED DISEASE
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 Learning Objectives
 Abstract
 Introduction
 Gemcitabine Combinations for...
Advances in Molecular-Targeted...
 Considerations for Selecting...
 Acknowledgments
 References
 
Between 1997 and 2005, gemcitabine was combined with several agents in investigational clinical studies (Table 1). Trials were undertaken with gemcitabine plus either 5-FU, cisplatin, irinotecan, oxaliplatin, pemetrexed, or exatecan [11–17]. Disappointingly, while tumor response and time to cancer progression were greater with some of these regimens, no clear survival benefit has been reported. Higher rates of grade 3 or 4 toxicities were also observed with chemotherapeutic additions.


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  		Table 1. Key phase III trials of cytotoxic agents in advanced pancreatic cancer

 
One exception might have been the addition of capecitabine to gemcitabine. In 2005, preliminary survival data from a phase III study were reported for gemcitabine plus capecitabine, an oral fluoropyrimidine that is metabolized to 5-FU in tumor cells. The hazard ratio (HR) for overall survival (OS) was 0.80 (p = .026). The median survival time was 6 weeks longer in the combination arm [17]. The final results of that trial are awaited; however, it should be noted that the addition of 5-FU to gemcitabine [11, 18] failed to produce longer survival than with gemcitabine alone in previous randomized trials.

An alternative strategy to improve the efficacy of gemcitabine was to prolong its infusion time. Fixed dose rate (FDR) infusion gemcitabine (10 mg/m2 per minute) is based on the observation that the triphosphate form of gemcitabine, one of gemcitabine's active metabolites, was greater in leukemia cell lines with a longer incubation time [19]. The clinical benefit of this approach has been postulated but not clearly proved [20]. Higher 1-year and 2-year survival rates were reported with FDR versus standard delivery in a small randomized phase II trial, supporting further evaluation [21]. In a subsequent phase II study, combining FDR gemcitabine with cisplatin for metastatic pancreatic cancer was well tolerated but did not appear to be superior to other gemcitabine/platinum-based regimens [22]. A recently reported phase III trial compared standard gemcitabine by 30-minute infusion (1,000 mg/m2) with FDR gemcitabine (1,500 mg/m2 over 150 minutes) and with FDR gemcitabine (1,000 mg/m2 over 100 minutes) plus oxaliplatin (100 mg/m2) (GEMOX) [23]. The complete/partial tumor response rates were 5% with gemcitabine 1,000 mg/m2 over 30 minutes, 10% with FDR gemcitabine, and 9% with GEMOX. The median survival times for patients in these arms were 4.9, 6.0, and 5.9 months, respectively, with 1-year survival rates of 17%, 21%, and 21%, respectively. However, neither the HR nor p-value targets for significance (≥0.75; p = .025) were met with FDR or GEMOX versus standard gemcitabine. Grade 3 or 4 toxicity (myelosuppression) was highest in the FDR arm, and GEMOX was associated with treatment-related neuropathy. The investigators concluded that there was no significant benefit of either experimental regimen over gemcitabine by 30-minute infusion.


   ADVANCES IN MOLECULAR-TARGETED THERAPIES
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 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Gemcitabine Combinations for...
 Advances in Molecular-Targeted...
Considerations for Selecting...
 Acknowledgments
 References
 
Initial experiences of combining gemcitabine with molecular-targeted agents were also disappointing (Table 2). Adding the matrix metalloproteinase inhibitor marimastat to gemcitabine failed to result in greater efficacy, and talomastat was associated with a worse outcome than with gemcitabine alone [24–27]. Other molecular-targeted therapies include tipifarnib, a farnesyl-transferase inhibitor (which is implicated in K-Ras regulation), G17 DT (a novel immunoconjugate that targets gastrointestinal-tumor growth factor G17 gastrin), and HER-1/EGFR and VEGF inhibitors, all of which failed to produce longer survival times [28–32].


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  		Table 2. Key phase III trials of molecular-targeted agents in advanced pancreatic cancer

 
Despite such setbacks, new approaches to pancreatic cancer treatment are emerging, driven by increased knowledge of the underlying molecular biology of this disease. HER-1/EGFR has a role in carcinogenesis across many types of cancer, and greater coexpression of HER-1/EGFR and its ligand is common in pancreatic tumors [33–38]. This coexpression has been shown to stimulate tumor cell proliferation, and elevated HER-1/EGFR levels are linked to poor disease outcomes and lower sensitivity to chemotherapy [39, 40]. Blocking HER-1/EGFR should therefore help to stabilize tumor growth and improve prognosis via the inhibition of multiple HER-1/EGFR downstream signaling pathways [33, 40].

Erlotinib
Erlotinib (Tarceva®; Genentech, Inc., South San Francisco, CA), a small-molecule HER-1/EGFR tyrosine kinase inhibitor (TKI), acts on the intracellular domain of this receptor, preventing receptor activation and inhibiting downstream signal transduction and cell proliferation [41]. Erlotinib received U.S. Food and Drug Administration approval when combined with gemcitabine as first-line therapy in locally advanced or metastatic pancreatic cancer based on a statistically significant survival benefit over gemcitabine alone [29, 42]. In the pivotal phase III trial (National Cancer Institute of Canada PA.3), patients receiving erlotinib (100 mg/day) plus gemcitabine (1,000 mg/m2 weekly) had a median survival time of 6.24 months, compared with 5.91 months in the gemcitabine plus placebo arm. The HR for risk of death was 0.82 in favor of the gemcitabine plus erlotinib arm, representing an 18% relatively longer OS time (p = .038) [29]. Secondary endpoint results from the PA.3 trial showed a 1-year survival rate of 23% in the erlotinib plus gemcitabine arm, versus 17% with gemcitabine monotherapy (p = .023). The progression-free survival (PFS) duration was also significantly longer with the combination regimen (3.75 versus 3.55 months; HR, 0.77; p = .004).

The clinical significance of these efficacy results has been questioned by several investigators and treating physicians. The benefit derived from the addition of erlotinib to gemcitabine cannot be predicted based on patient characteristics as assessed by the standard processes performed in advanced and metastatic pancreatic cancer. The treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to molecular-targeted therapies (as seen in non-small cell lung cancer [NSCLC] with erlotinib and another HER-1/EGFR TKI gefitinib; also in colorectal cancer with cetuximab) [43–51]. The advantage of individualizing therapy to patients could be possible if we could better understand which factors predict response to treatment. Research into predictive markers in pancreatic cancer is in its infancy. The investigation of HER-1/EGFR expression in tumor samples from patients in PA.3 did not find a correlation with response. However, this remains an interesting area for further research, as any biomarker would help simplify drug choice, should the portfolio of options for advanced pancreatic cancer continue to widen.

The combination of gemcitabine and erlotinib was well tolerated; grade 3 or 4 toxicities were similar, except for diarrhea and cutaneous rash, which were more frequent with the two-drug combination (6% each). Patients with advanced pancreatic cancer who experienced grade 2 rash or higher (n = 102) had a reported median survival time of 10.5 months and a 1-year survival rate of 43%. A similar observation has been reported in patients with NSCLC treated with erlotinib or gefitinib (Iressa®; AstraZeneca Pharmaceuticals, LP, Macclesfield, UK) and in colon cancer patients treated with cetuximab (Erbitux®; ImClone Systems, Inc., New York) [52–54]. This cannot be explained by patients who stay on treatment longer being at greater risk for rash, but may be an indication of interpatient variability in drug absorption or metabolism, or the strength of the immune system [29]. This observation can only be validated and confirmed by a well-designed randomized clinical trial in which the efficacy of a HER-1/EGFR inhibitor "dosed to rash" (i.e., dose increased until rash is experienced) is compared with the same HER-1/EGFR inhibitor at standard doses. However, regardless of the cause, it may be advantageous to continue treatment of pancreatic cancer patients exhibiting HER-1/EGFR inhibitor–related rash, and provide the appropriate management for the rash based on its severity [55].

The possibility of building on the efficacy provided by erlotinib and gemcitabine has been evaluated. A phase I study of erlotinib plus gemcitabine and paclitaxel plus radiation, followed by maintenance with erlotinib, for locally advanced pancreatic cancer resulted in a partial response rate of 46% and median survival time of 14 months [56]. These results are supported by a second phase I trial of erlotinib plus gemcitabine and radiation for patients with locally advanced, unresectable pancreatic cancer [57].

Erlotinib has been investigated as second-line therapy in pancreatic cancer patients previously treated with gemcitabine. Disappointing results were reported in a retrospective analysis of 13 patients treated with single-agent erlotinib. No responses and a median time to progression (TTP) of only 1 month were observed [58]. A phase II study of erlotinib combined with capecitabine for gemcitabine-refractory pancreatic cancer demonstrated a median survival time of 5.7 months. Erlotinib plus capecitabine combination therapy had a reasonable safety profile, with the most common grade 3 or 4 toxicities including diarrhea (14%), rash (14%), hand–foot syndrome (11%), stomatitis (7%), and thrombosis (7%) [59]. The clinical application of this two-drug combination awaits a prospective comparative trial.

Cetuximab
Cetuximab, an anti–HER-1/EGFR monoclonal antibody (mAb), has also been evaluated as a treatment for pancreatic carcinoma. This agent blocks the extracellular domain of HER-1/EGFR to prevent receptor activation (either ligand dependent or independent) and signaling [60, 61]. Cetuximab given alone or combined with radiation was recently approved in the U.S. and the European Union for head and neck squamous cell carcinoma in patients expressing HER-1/EGFR. Cetuximab was previously approved for HER-1/EGFR-positive metastatic colorectal cancer (either as a single agent or in combination with irinotecan, in patients who can tolerate this chemotherapy).

Adding gemcitabine to cetuximab in pancreatic xenograft models increased the inhibition of tumor regression, growth, or metastasis [62]. Phase I studies suggested that cetuximab alone and in combination with chemotherapy was tolerable, with HER-1/EGFR inhibitor–related rash as the most frequent side effect [40]. In a phase II study, patients screening positively for HER-1/EGFR were treated with cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2 weekly for 7 weeks. Gemcitabine was administered at 1,000 mg/m2 for 7 weeks, followed by 1 week of rest; in subsequent cycles, cetuximab was administered weekly, and gemcitabine was administered weekly for 3 weeks at 4-week intervals [63]. The median OS time for patients treated with this regimen was 7.1 months, the median TTP was 3.8 months, and the 1-year PFS and OS rates were 12% and 31.7%, respectively. Twelve percent of patients achieved a partial response, and 63.4% had stable disease. The most frequently reported grade 3 or 4 adverse events were neutropenia (39%), asthenia (22%), abdominal pain (22%), and thrombocytopenia (17%) [63].

An open-label, randomized phase III trial of gemcitabine monotherapy or gemcitabine plus cetuximab first line for patients with locally advanced, unresectable or metastatic pancreatic cancer was subsequently initiated (Southwest Oncology Group S0205) [64]. More than 700 patients were enrolled in centers throughout the U.S. and Canada. Unfortunately, preliminary reports indicate that this trial failed to meet its primary study endpoint of a statistically longer OS time [30]. The median OS time for gemcitabine plus cetuximab was 6.5 months versus 6 months for gemcitabine alone (HR, 1.09; p = .14). The median PFS time was 3.5 months for gemcitabine plus cetuximab versus 3.0 months for gemcitabine alone (HR, 1.13; p = .58). The therapeutic value of cetuximab for treating advanced pancreatic cancer remains unclear.

Data have recently been reported for a randomized phase II trial of the nongemcitabine combination of irinotecan plus docetaxel with or without cetuximab, as first-line therapy in patients with advanced pancreatic cancer. In total, 47 patients received chemotherapy alone, 45 received chemotherapy plus cetuximab. The efficacy results (including the response rate and PFS and OS times) were slightly better for the cetuximab arm (7% versus 2.3%, 4.5 months versus 2.8 months, and 7.4 months versus 6.5 months, respectively) but not historically different from what has been observed with gemcitabine. However, high toxicity was observed with both regimens, with high rates of grade 3 or 4 neutropenia and diarrhea observed in the cetuximab arm [65].

Bevacizumab
As the overexpression of VEGF and its receptors VEGFR-1, VEGFR-2, and VEGFR-3 promote tumor growth via paracrine angiogenic and autocrine mitogenic pathways [66], targeting the VEGF pathway holds promise for the treatment of advanced pancreatic cancer. Bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA) is a recombinant, humanized IgG1 mAb that binds to VEGF, disrupting its interactions with VEGFR-1 and VEGFR-2. It is approved in combination with i.v. 5-FU–based chemotherapy for the first-line treatment of patients with metastatic colorectal cancer, and in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC [67]. Bevacizumab was investigated in combination with gemcitabine in a phase II trial of patients with advanced pancreatic tumors [68]. Fifty-two patients were enrolled and received gemcitabine (1,000 mg/m2 i.v. over 30 minutes) on days 1, 8, and 15 every 28 days. Bevacizumab (10 mg/kg) was administered after gemcitabine on days 1 and 15. Eleven patients (21%) had confirmed partial responses, and 24 (46%) had stable disease. The median survival time was 8.8 months, the median PFS time was 5.4 months, and the 6-month survival rate was 77% [68]. These results supported the initiation of a phase III study (Cancer and Leukemia Group B 8030) [64]. However, an interim analysis on 64% of the acquired information for OS led to early termination of the trial [31]. Analysis of the acquired data showed no significant differences between the OS times (HR, 1.03; p = .78) or PFS times (HR, 1.0; p = .99) for the gemcitabine (OS, 6.1 months; PFS, 4.9 months) or gemcitabine plus bevacizumab (OS, 5.8 months; PFS, 4.7 months) arms [31]. The discrepancies in the results of the phase II and III trials are probably related to patient selection in the phase II trial. Other VEGF inhibitors are being studied in this disease and may help to better understand the value of targeting this pathway in this disease.

Other HER-1/EGFR- and VEGF(R)-Targeted Agents in Clinical Development for Advanced Pancreatic Cancer
Sorafenib (Nexavar®; Bayer Pharmaceuticals Corporation, West Haven, CT) is a multikinase inhibitor targeting VEGFR, platelet-derived growth factor receptor (PDGFR), Kit, and Flt-3 that is indicated for the treatment of patients with advanced renal cell carcinoma [69]. A recent phase II trial enrolled 17 patients with unresectable pancreatic cancer who had received no prior chemotherapy. All patients had good organ function and a performance status score of 0–1. Patients received gemcitabine (1,000 mg/m2) i.v. over 30 minutes on days 1, 8, and 15 of a 28-day cycle plus sorafenib (400 mg orally twice a day on days 1–28). No responses were observed; three patients (23%) had stable disease and the median survival time was only 4 months. The authors concluded that sorafenib plus gemcitabine was well tolerated but inactive in patients with advanced pancreatic cancer [70]. Despite these negative results, a phase II randomized trial of sorafenib with gemcitabine is under way in patients with pancreatic cancer [64].

Another VEGFR-targeted agent, the small-molecule TKI axitinib (Pfizer Inc., New York), is also being studied in patients with advance pancreatic cancer. Data from a randomized phase II trial have recently been reported for this agent in combination with gemcitabine [71]. In total, 103 patients were enrolled and 69 received axitinib plus gemcitabine. The response rate was 7% in the experimental arm, compared with 0% in the gemcitabine control arm. In addition, the combination regimen demonstrated good tolerability and reduced the likelihood of death by 26% (HR, 0.74) compared with gemcitabine alone. A randomized, controlled, phase III trial of axitinib plus gemcitabine for locally advanced and metastatic pancreatic cancer is planned.

Other agents that target HER-1/EGFR or VEGFR are in clinical development. Phase II trials are under way for sunitinib (Sutent®; Pfizer Inc., New York), a VEGFR- and PDGFR-targeted small-molecule TKI, valatinib (Pfizer Inc., New York), a VEGFR-targeted small-molecule TKI, and lapatinib (Tykerb®; GlaxoSmithKline plc., London, UK), a HER-1/EGFR- and HER-2–targeted small-molecule TKI [64].


   CONSIDERATIONS FOR SELECTING MOLECULAR-TARGETED AGENTS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Gemcitabine Combinations for...
 Advances in Molecular-Targeted...
 Considerations for Selecting...
Acknowledgments
 References
 
As a result of pioneering clinical trial research and advances in molecular biology, it appears that treatment options for pancreatic cancer are finally beginning to expand. Agents that target the HER-1/EGFR or VEGF pathway are at the forefront of development, and a significant number of ongoing trials continue to explore the potential of these therapies for this disease (Table 3 [64]). In addition, a wide range of other targeted agents is also in clinical development for advanced pancreatic cancer; their targets include Src/Abl, histone deacetylase, and mammalian target of rapamycin (Table 4).


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  		Table 3. Ongoing clinical trials with HER-1/EGFR- and VEGF(R)-targeted agents in patients with advanced pancreatic cancer [64]

 


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  		Table 4. Ongoing phase I and II clinical trials of other molecular-targeted agents for advanced or metastatic pancreatic cancer [64]

 
The key to taking the management of pancreatic cancer to the next level resides in identifying the pathway or pathways that drive this challenging cancer. Clinical research into molecular-targeted agents, alongside the routine acquisition of tumor samples and surrogate tissues for correlative studies, may soon unveil better ways to treat this devastating disease.


   ACKNOWLEDGMENTS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Gemcitabine Combinations for...
 Advances in Molecular-Targeted...
 Considerations for Selecting...
 Acknowledgments
References
 
Third-party medical writing support was provided by Genentech, Inc., OSI Pharmaceuticals, Inc., and F. Hoffmann-La Roche Ltd.


   FOOTNOTES
 
Conception/design: Howard Burris III, Caio Rocha-Lima

Collection/assembly of data: Caio Rocha-Lima

Data analysis and interpretation: Howard Burris III

Manuscript writing: Howard Burris III, Caio Rocha-Lima

Final approval of manuscript: Howard Burris III


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Gemcitabine Combinations for...
 Advances in Molecular-Targeted...
 Considerations for Selecting...
 Acknowledgments
 References
 

  1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.[Abstract/Free Full Text]
  2. Cancer Facts & Figures 2006. Atlanta, GA: American Cancer Society Inc, Available at http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed June 21, 2007.
  3. Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
  4. Li D, Xie K, Wolff R et al. Pancreatic cancer. Lancet 2004;363:1049–1057.[CrossRef][Medline]
  5. Chauffert B, Mornex F, Bonnetain F et al. Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study. J Clin Oncol 2006;23:180s.
  6. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.[Abstract/Free Full Text]
  7. Nitecki SS, Sarr MG, Colby TV et al. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 1995;221:59–66.
  8. Burris HA 3rd, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403–2413.[Abstract/Free Full Text]
  9. Talar-Wojnarowska R, Malecka-Panas E. Molecular pathogenesis of pancreatic adenocarcinoma: Potential clinical implications. Med Sci Monit 2006;12:RA186–RA193.[Medline]
  10. Giovannetti E, Mey V, Nannizzi S et al. Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer. Mol Cancer Ther 2006;5:1387–1395.[Abstract/Free Full Text]
  11. Berlin JD, Catalano P, Thomas JP et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002;20:3270–3275.[Abstract/Free Full Text]
  12. Rocha Lima CM, Green MR, Rotche R et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004;22:3776–3783.[Abstract/Free Full Text]
  13. Heinemann V, Quietzsch D, Gieseler F et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006;24:3946–3952.[Abstract/Free Full Text]
  14. Louvet C, Labianca R, Hammel P et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005;23:3509–3516.[Abstract/Free Full Text]
  15. Oettle H, Richards D, Ramanathan RK et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005;16:1639–1645.[Abstract/Free Full Text]
  16. Abou-Alfa GK, Letourneau R, Harker G et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 2006;24:4441–4447.[Abstract/Free Full Text]
  17. Cunningham D, Chau I, Stocken D et al. Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer 2005;3(Suppl):4.
  18. Oettle H, Riess H. Gemcitabine in combination with 5-fluorouracil with or without folinic acid in the treatment of pancreatic cancer. Cancer 2002;95:912–922.[CrossRef][Medline]
  19. Gandhi V, Mineishi S, Huang P et al. Difluorodeoxyguanosine: Cytotoxicity, metabolism, and actions on DNA synthesis in human leukemia cells. Semin Oncol 1995;22(suppl 11):61–67.[Medline]
  20. Hochster HS. Newer approaches to gemcitabine-based therapy of pancreatic cancer: Fixed-dose-rate infusion and novel agents. Int J Radiat Oncol Biol Phys 2003;56;(45) (suppl):24–30.[CrossRef][Medline]
  21. Tempero M, Plunkett W, Ruiz Van Haperen V et al. Randomized phase II comparison of dose-intense gemcitabine: Thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003;21:3402–3408.[Abstract/Free Full Text]
  22. Ko AH, Dito E, Schillinger B et al. Phase II study of fixed dose rate gemcitabine with cisplatin for metastatic adenocarcinoma of the pancreas. J Clin Oncol 2006;24:379–385.[Abstract/Free Full Text]
  23. Poplin E, Levy DE, Berlin J et al. Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion[FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201). J Clin Oncol 2006;24(suppl 18):LBA4004.
  24. Bramhall SR, Rosemurgy A, Brown PD et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: A randomized trial. J Clin Oncol 2001;19:3447–3455.[Abstract/Free Full Text]
  25. Bramhall SR, Schulz J, Nemunaitis J et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87:161–167.[CrossRef][Medline]
  26. Moore MJ, Hamm J, Dancey J et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12–9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:3296–3302.[Abstract/Free Full Text]
  27. Chau I, Rigg A, Cunningham D. Matrix metalloproteinase inhibitors—an emphasis on gastrointestinal malignancies. Crit Rev Oncol Hematol 2003;45:151–176.[CrossRef][Medline]
  28. Van Cutsem E, van de Velde H, Karasek P et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22:1430–1438.[Abstract/Free Full Text]
  29. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960–1966.[Abstract/Free Full Text]
  30. Philip PA, Benedetti J, Fenoglio-Preiser C et al. Phase III study of gemcitabine (G) plus cetuximab (C) versus gemcitabine in patients (pts) with locally advanced or metastatic pancreatic adenocarcinoma (PC): SWOG S0205 study. J Clin Oncol 2007;25:199s.
  31. Kindler HL, Niedzwiecki D, Hollis D et al. A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB). J Clin Oncol 2007;25:199s.
  32. He A, Marshall J. Clinical experiences with G17DT in gastrointestinal malignancies. Future Drugs 2006;6:487–492.
  33. Prenzel N, Fischer O, Streit S et al. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 2001;8:11–31.[Abstract]
  34. Salomon DS, Brandt R, Ciardiello F et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.[Medline]
  35. Tobita K, Kijima H, Dowaki S et al. Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis. Int J Mol Med 2003;11:305–309.[Medline]
  36. Fjallskog ML, Lejonklou MH, Oberg KE et al. Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 2003;9:1469–1473.[Abstract/Free Full Text]
  37. Srivastava A, Alexander J, Lomakin I et al. Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in pancreatic endocrine tumors. Hum Pathol 2001;32:1184–1189.[CrossRef][Medline]
  38. Birk D, Gansauge F, Gansauge S et al. Serum and correspondent tissue measurements of epidermal growth factor (EGF) and epidermal growth factor receptor (EGF-R). Clinical relevance in pancreatic cancer and chronic pancreatitis. Int J Pancreatol 1999;25:89–96.[Medline]
  39. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37(suppl 4):S9–S15.[Medline]
  40. Xiong HQ, Abbruzzese JL. Epidermal growth factor receptor-targeted therapy for pancreatic cancer. Semin Oncol 2002;29(suppl 14):31–37.[Medline]
  41. Ng SS, Tsao MS, Nicklee T et al. Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol Cancer Ther 2002;1:777–783.[Abstract/Free Full Text]
  42. Tarceva® (erlotinib) [prescribing information]. South San Francisco, CA: Genentech Inc, 5 2007.
  43. Tsao M, Sakurada A, Cutz JC et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144.[Abstract/Free Full Text]
  44. Gatzemeier U, Heller A, Foernzler D et al. Exploratory analyses EGFR, kRAS mutations and other molecular markers in tumors of NSCLC patients (pts) treated with chemotherapy +/- erlotinib (TALENT). J Clin Oncol 2005;23:627s.
  45. Miller VA, Herbst R, Prager D et al. Long survival of never smoking non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib HCl (OSI-774) and chemotherapy: Sub-group analysis of TRIBUTE. J Clin Oncol 2004;22:628.
  46. Bailey R, Kris M, Wolf M et al. Gefitinib (Iressa, ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer in IDEAL1 and 2: Tumor response is not clinically relevantly predictable from tumor EGFR membrane staining alone. Lung Cancer 2003;41:S71.
  47. Cappuzzo F, Ligorio C, Jänne PA et al. Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: The ONCOBELL trial. J Clin Oncol 2007;25:2248–2255.[Abstract/Free Full Text]
  48. Cappuzzo F, Magrini E, Ceresoli GL et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2004;96:1133–1141.[Abstract/Free Full Text]
  49. Gandara DR, West H, Chansky K et al. Bronchioloalveolar carcinoma: A model for investigating the biology of epidermal growth factor receptor inhibition. Clin Cancer Res 2004;10:4205s–4209s.[CrossRef][Medline]
  50. Guix M, Kelley MS, Reyzer ML et al. Short course of EGF receptor tyrosine kinase inhibitor erlotinib (OSI-774, ‘Tarceva’) reduces tumor cell proliferation and active MAP kinase in situ in untreated operable breast cancers: A strategy for patient selection into phase II trials with signaling inhibitors. J Clin Oncol 2005;23:194s.
  51. Crews KR. Individualizing chemotherapeutic treatment of colorectal cancer. Am J Health Syst Pharm 2006;63(suppl 2):S12–S17.[Abstract/Free Full Text]
  52. Perez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer 2006;8(suppl 1):S7–S14.[Medline]
  53. West HL, Franklin WA, McCoy J et al. Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126. J Clin Oncol 2006;24:1807–1813.[Abstract/Free Full Text]
  54. Saltz L, Rubin MS, Hochster H et al. Acne-like rash predicts response in patients treated with cetuximab (IMC-225) plus irinotecan (CPT-11) in CPT-11 refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Clin Cancer Res 2001;7:3766s.
  55. Lynch TJ Jr, Kim ES, Eaby B et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: An evolving paradigm in clinical management. The Oncologist 2007;12:610–621.[Abstract/Free Full Text]
  56. Iannitti D, Dipetrillo T, Akerman P et al. Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: A phase I study. Am J Clin Oncol 2005;28:570–575.[CrossRef][Medline]
  57. Kortmansky JS, O'Reilly EM, Minsky BD et al. A phase I trial of erlotinib, gemcitabine and radiation for patients with locally-advanced, unresectable pancreatic cancer. Proc Am Soc Clin Oncol 2005;23:133.
  58. Epelbaum R, Schnaider J, Gluzman A et al. Erlotinib as a single-agent therapy in patients with advanced pancreatic cancer. the ASCO Gastrointestinal Cancer Symposium; January 19–21, 2007; Orlando, FL, Presented at.
  59. Blaszkowsky L, Kulke M, Ryan D et al. A phase II study of erlotinib (Tarceva) in combination with capecitabine in previously treated patients with metastatic pancreatic cancer. J Clin Oncol 2005;23:332s.
  60. Hudziak RM, Lewis GD, Winget M et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 1989;9:1165–1172.[Abstract/Free Full Text]
  61. Kawamoto T, Sato JD, Le A et al. Growth stimulation of A431 cells by epidermal growth factor: Identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A 1983;80:1337–1341.[Abstract/Free Full Text]
  62. Bruns CJ, Harbison MT, Davis DW et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000;6:1936–1948.[Abstract/Free Full Text]
  63. Xiong HQ, Rosenberg A, LoBuglio A et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: A multicenter phase II trial. J Clin Oncol 2004;22:2610–2616.[Abstract/Free Full Text]
  64. ClinicalTrials.gov Bethesda, MD: National Library of Medicine, National Institutes of Health, Available at http://www.clinicaltrials.gov/ct2/results?term=pancreatic+cancer. Accessed June 21, 2007.
  65. Burtness BA, Powell M, Berlin J et al. Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor receptor (EGF-r): Eastern Cooperative Oncology Group. J Clin Oncol 2007;25:202s.
  66. Seo Y, Baba H, Fukuda T et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000;88:2239–2245.[CrossRef][Medline]
  67. Avastin® (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech Inc, 10 2006.
  68. Kindler HL, Friberg G, Singh DA et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005;23:8033–8040.[Abstract/Free Full Text]
  69. Nexavar® (sorafenib) [prescribing information]. West Haven, CT: Bayer Pharmaceuticals Corp, 2 2007.
  70. Wallace JA, Locker G, Nattam S et al. Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium. J Clin Oncol 2007;25:224s.
  71. Spano J, Chodkiewicz C, Maurel J et al. A randomized phase II study of axitinib (AG-013736) and gemcitabine versus gemcitabine in advanced pancreatic cancer, preceded by a phase I component. J Clin Oncol 2007;25:210s.




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