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Erlotinib in Pancreatic Cancer Patients: Do We Need More Information From the NCIC CTG Trial?

Unit of Medical Oncology, Ospedali Riuniti Bergamo, Italy

Gianluigi Ferretti

Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy

To the Editor:

We read with great interest the article by Moore et al.¹ In their excellent article the authors demonstrated that erlotinib added to gemcitabine improved survival in advanced pancreatic cancer patients.¹ We recently demonstrated that the occurrence of venous thromboembolism (VTE) may be associated with a reduced response rate and a shorter progression-free survival and overall survival among patients with nonresectable pancreatic cancer patients treated with a gemcitabine-based chemotherapy.²

Experimental studies in vitro or in animal models support the hypothesis that the inhibition of blood coagulation may interfere with the progression of malignancy. Experimental and clinical data to support the hypothesis that anticoagulation may influence prognosis of cancer patients have been recently reviewed.³

There is some evidence that patients with cancer who develop thromboembolism have poorer survival.⁴ Indeed, many clinical trials in pancreatic cancer published in the past years, including the article by Moore et al,¹ have not reported toxic effects related to VTE. Furthermore, in its initial version, the US National Cancer Institute criteria for common toxicity did not include VTE, suggesting that this type of complication had been underestimated.

This type of complication may be of crucial interest since the development of VTE may reflect the presence of a biologically more aggressive cancer that, in turn, leads to a worse prognosis. Furthermore, the expression of vascular endothelial growth factor, at present regarded as the major proangiogenic factor for most types of human cancer, is strongly induced by epidermal growth factor (EGF) and tumor growth factor-.⁵ Overexpression of EGF, tumor growth factor-, and EGF receptor by human pancreatic tumors has been shown to correlate with rapid progression of the disease.⁶

Coagulation and angiogenesis are linked by at least two key mediators: the enzyme thrombin, whose broad substrate specificity supports a variety of cellular effects relevant to tumor growth and metastasis; and tissue factor, the primary initiator of the coagulation cascade, whose rather ubiquitous presence as a transmembrane receptor on a variety of nucleated cells confers responsibility for the generation of cell-surface thrombin in many pathologic situations. We applaud the authors for their effort to conduct this interesting study, and we think that knowing these data may contribute to better understanding the results of this trial.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. 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 25:1960-1966, 2007[Abstract/Free Full Text]

2. Mandala M, Reni M, Cascinu S, et al: Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Ann Oncol doi:10.1093/annonc/mdm284

3. Zacharski LR, Ornstein DL: Heparin and cancer. Thromb Haemost 80:10-23, 1998[Medline]

4. Sorensen HT, Mellemkjaer L, Olsen JH, et al: Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343:1846-1850, 2000[Abstract/Free Full Text]

5. Goldman CK, Kim J, Wong WL, et al: Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: A model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4:121-133, 1993[Abstract]

6. Schreiber AB, Winkler ME, Derynck R: Transforming growth factor-alpha: a more potent angiogenic mediator than epidermal growth factor. Science 232:1250-1253, 1986[Abstract/Free Full Text]

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