Prognostic Relevance of Perioperative Cancer Cell Dissemination and Systemic Immune Suppression in Resectable Ductal Pancreatic Adenocarcinoma

Prognostic relevance of circulating cancer cells and immunosuppression in resectable pancreatic carcinoma

1. Introduction

Pancreatic adenocarcinoma is the fourth commonest cause of death from cancer in men and women, with 5-year survival for all stages of disease of less than 5%. The case-fatality rate for pancreatic cancer is extremely high and virtually identical to the number of new cases (World Health Organization. World cancer report. Lyon: IACR Press; 2003). Most patients with cancer of the pancreas are diagnosed at an advanced stage and have a median survival of 4 to 10 months, depending on the extent of disease and irrespective the type of treatment modality. Overall, fewer than 5% of the patients have resection with curative intent, though over 80% will develop cancer recurrence (Jemal A, Thomas A, Murray T, Thun M. Cancer Statistics. CA Cancer J Clin 2002; 52: 23-47). The primary site of metastatic disease in patients with pancreatic cancer is the liver and/or the peritoneal cavity.

Cancer recurrence is multifactorial and determined by patient-, tumour-, and surgery-related factors. Any combination of several mechanisms have been proposed by which cancer may recur following potentially curative resection (Coffey JC, Wang JH, Smith MJF, Bouchier-Hayes D, Cotter TG,and Redmond HP. Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol 2003;4:760-68). Surgery may contribute to the overall residual tumor burden by adding disseminated cancer cells during tumor manipulation. Due to post-operative immunosuppression the patient may become more susceptible to tumorigenesis and/or disseminated cancer cells may escape the immune response more easily. Finally, surgical resection may alter biological properties of cancer cells and lead to increased cellular proliferation and reduced cell death. 2. Cancer cell dissemination

Solid markers are lacking to predict cancer recurrence or cancer progression before being measurable with conventional or modern diagnostic imaging. Molecular techniques such as the reverse transcriptase polymerase chain reaction (RT-PCR) technique have proven to be a highly sensitive method and a powerful tool in the study of cancer metastasis (Raj GV, Moreno JG, Gomella LG. Utilization of Polymerase Chain Reaction Technology in the Detection of Solid Tumors. Cancer 1998; 82: 1419-42). The prognostic relevance of circulating cancer cells in patients with pancreatic cancer is hardly studied. In patients with breast cancer the number of circulating cancer cells expressing EpCAM (epithelial cell adhesion molecule) has proven to be an independent predictor of progression-free and overall survival (Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781-91). EpCAM is a marker present on most epithelial cell tumours and frequently overexpressed in primary and metastatic adenocarcinoma including pancreatic cancer (Rao CG, Chianese D, Doyle GV, Miller MC, Russell T, Sanders RA Jr, Terstappen LW. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors. Int J Oncol 2005; 27: 49-57). Also, other markers such as CEA, CK20, K-ras have been used to detect disseminated pancreatic cancer cells. In patients with colorectal carcinoma circulating cancer cells in peripheral or in mesenteric venous blood as detected by RT-PCR, using CEA and CK20 mRNA transcripts, seem to represent a prognostic factor (Yamaguchi K, Takagi Y, Aoki S, Futamura M, Saji S. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann Surg 2000; 232: 58-65. Guller U, Zajac P, Schnider A, Bösch B, Vorburger S, Zuber M, Spagnoli GC, Oertli D, Maurer R, Metzger U, Harder F, Heberer M, Marti WR. Disseminated single tumor cells as detected by real-time quantitative polymerase chain reaction represent a prognostic factor in patients undergoing surgery for colorectal cancer. Ann Surg 2002; 236: 768-76). 3. Molecular characteristics of metastatic cancer cells