Phase III Randomized Comparison of Gemcitabine Versus Gemcitabine Plus Capecitabine in Patients With Advanced Pancreatic Cancer

Cunningham, David; Chau, Ian; Stocken, Deborah; Valle, Juan W; Smith, David B.; Steward, William P.; Harper, Peter; Dunn, Janet A.; Smith, Catrin Tudur; West, J. H.; Falk, Stephen; Crellin, A.; Adab, F.; Thompson, Joyce; Leonard, Pauline; Ostrowski, J.; Eatock, Martin; Scheithauer, Werner; Herrmann, Richard; Neoptolemos, John P.

doi:10.1200/jco.2009.24.2446

Cited by 713 publications

(449 citation statements)

References 27 publications

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“…In advanced or metastatic pancreatic cancer, combinations of gemcitabine plus 5-fluorouracil (5-FU) [4], cisplatin [5], oxaliplatin [6] and irinotecan [7] have not shown significant benefit in overall survival compared to single-agent gemcitabine. Capecitabine, an orally administered fluoropyrimidine carbamate which converts to active 5-FU in the tumour site demonstrates efficacy in untreated advanced colorectal carcinoma [8] and the combination of gemcitabine and capecitabine in advanced pancreatic cancer improves overall survival, clinical benefit response and quality of life at a statistically significant level compared with standard gemcitabine treatment [9,10]. Reports of expression of the ErbB receptor family, including the epidermal growth factor receptor (EGFR; ErbB1/HER1) and HER2; ErbB2/neu vary widely in PDAC.…”

Section: Introductionmentioning

confidence: 99%

EGFR and HER2 inhibition in pancreatic cancer

et al. 2012

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Summary The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC 50 < 2 μM). Lapatinib also demonstrated some activity in three KRas mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5'deoxy-5'fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma.

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Section: Introductionmentioning

confidence: 99%

EGFR and HER2 inhibition in pancreatic cancer

et al. 2012

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“…Nineteen studies involving 4697 patients were included (Supplementary Table 2) (Berlin et al, 2002;Colucci et al, 2002;Wang et al, 2002;Heinemann et al, 2003;Scheithauer et al, 2003;Li and Chao, 2004;Ohkawa, 2004;Rocha Lima et al, 2004;Viret et al, 2004;Cunningham et al, 2005 Cullinan 1990 Cullinan 1990 Cullinan 1990 …”

Section: Gemcitabine Vs Gemcitabine-based Combination Chemotherapymentioning

confidence: 99%

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses

Sultana¹,

Smith

Cunningham

et al. 2008

Br J Cancer

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In advanced pancreatic cancer, level one evidence has established a significant survival advantage with chemotherapy, compared to best supportive care. The treatment-associated toxicity needs to be evaluated. This study examines the secondary outcome measures for chemotherapy in advanced pancreatic cancer using meta-analyses. A systematic review was undertaken employing Cochrane methodology, with search of databases, conference proceedings and trial registers. The secondary end points were progression-free survival (PFS)/time to progression (TTP) (summarised using the hazard ratio (HR)), response rate and toxicity (summarised using relative risk). There was no significant advantage of 5FU combinations vs 5FU alone for TTP (HR ¼ 1.02; 95% CI ¼ 0.85 -1.23) and toxicity. Progression-free survival (HR 0.78; CI 0.70 -0.88), TTP (HR ¼ 0.85; 95% CI ¼ 0.72 -0.99) and overall response rate (RR ¼ 0.56; 95% CI ¼ 0.46 -0.68) were significantly better for gemcitabine combination chemotherapy, but offset by the greater grade 3/4 toxicity thrombocytopenia (RR ¼ 1.94; 95% CI ¼ 1.32 -2.84), leucopenia (RR ¼ 1.46; 95% CI ¼ 1.15 -1.86), neutropenia (RR ¼ 1.48; 95% CI ¼ 1.07 -2.05), nausea (RR ¼ 1.77; 95% CI ¼ 1.37 -2.29), vomiting (RR ¼ 1.64; 95% CI ¼ 1.24 -2.16) and diarrhoea (RR ¼ 2.73; 95% CI ¼ 1.87 -3.98). There is no significant advantage on secondary end point analyses for administering 5FU in combination over 5FU alone. There is improved PFS/TTP and response rate, with gemcitabine-based combinations, although this comes with greater toxicity.

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“…Recent clinical trials using novel drug combinations have demonstrated some benefit, [2][3][4] but nevertheless, the overall 5-year survival rate for pancreatic cancer patients has remained low [2,3]. These poor outcomes have been attributed to many factors, including extensive fibrosis typically surrounding the pancreatic tumor.…”

Section: Introductionmentioning

confidence: 99%

Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

Heinrich

Arrington

et al. 2013

Cancer Microenvironment

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Chemokine receptors mediate cancer progression and metastasis. We have previously examined chemokine receptor CCR9 expression in pancreatic cancer. Here, our objective was to evaluate pancreatic stellate cells (PSCs) as a source of CCL25, the CCR9 ligand, and as an activator of CCL25-CCR9 signaling in pancreatic cancer cells. CCL25 and CCR9 expression levels in human pancreatic cancer tissues and normal human pancreas were assessed by immunohistochemsitry. In vitro secretion of CCL25 in PSCs and PANC-1 cells was verified by enzyme-linked immunosorbent assay. Pancreatic cancer cell invasion was measured using a modified Boyden chamber assay with CCL25, PSC secreted proteins, and PANC-1 secreted proteins as the chemoattractant. There was immunostaining for CCR9 expression in human pancreatic tumor tissues, but not in normal pancreatic tissue. CCL25 expression was absent in the normal pancreatic tissue sample, but was observed in cancer cells and in the stromal cells surrounding the tumor. In vitro, both PANC-1 cells and PSCs secreted CCL25. In an invasion assay, exposure to CCL25, PSC-and PANC-1-conditioned media significantly increased the invasiveness of PANC-1 cells. Inclusion of a CCR9-neutralizing antibody in the invasion assay blocked the increase in invading cells elicited by the chemoattractants. Our studies show that pancreatic cancer invasiveness is enhanced by autocrine and paracrine stimulation of CCR9. PSCs in the tumor microenvironment appear to contribute to paracrine activation of CCR9. Investigations into CCR9 as a potential therapeutic target in pancreatic cancer must consider cancer cell autocrine signaling and also paracrine signaling from interactions in the tumor microenvironment.

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Phase III Randomized Comparison of Gemcitabine Versus Gemcitabine Plus Capecitabine in Patients With Advanced Pancreatic Cancer

Abstract: On the basis of our trial and the meta-analysis, GEM-CAP should be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.

Cited by 713 publications

References 27 publications

EGFR and HER2 inhibition in pancreatic cancer

EGFR and HER2 inhibition in pancreatic cancer

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses

Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

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