PDA tumors are rich in stroma
© O. Strobel, University of Heidelberg

The pancreas has endocrine and exocrine functions involving, respectively, the secretion of hormones including insulin and glucagon, and multiple enzymes that assist in digestion of nutrients in the small intestine. The most common type of pancreatic cancer, accounting for approximately 95% of cases, is pancreatic ductal adenocarcinoma (PDA), which arises within the exocrine component of the pancreas.

The main risk factors for PDA are inherited germ line mutations (e.g. in BRCA2), smoking, and chronic pancreatitis, the latter often associated with excessive alcohol consumption.

Typical symptoms that lead to the detection of PDA are abdominal and back pain, obstructive jaundice and weight loss. Once diagnosed, the disease has usually already spread to surrounding tissues. In approximately 80% of cases, the cancer is non-resectable. The 5 year survival rate of these patients is dismal: less than 1%, with most patients dying within 3-6 months after diagnosis. At present, the 5 year survival rate for patients with resectable disease is approximately 20%.

Between 50-80% of the PDA tumor mass is taken up by stroma containing, amongst others, activated fibroblasts and myeloid cells. The abundance of stromal cells bears witness to the fact that the development of PDA is associated with chronic inflammation, and plays an important role in chemotherapy-resistance. Genetic analysis of PDA has pointed at simultaneous defects in multiple growth regulatory pathways, mutations in K-ras being the most prominent (almost 100%).

Surgical treatment

For pancreatic cancer, surgical resection still remains the only chance for cure. As mentioned above, this treatment is only available to approximately 20% of the patients who are diagnosed with resectable disease. Since most cancers arise in the head of the pancreas, pancreaticoduodenectomy (PD, the so-called Kausch-Whipple procedure, named after the surgeons who first described it) is the most commonly applied surgical procedure. It is a radical procedure during which also parts of the intestine and stomach are removed, along with gallbladder and many local lymph nodes. If possible, with respect to spread of the tumor mass, the stomach can be preserved (pylorus-preserving PD). If the tumor has spread throughout the pancreas, total pancreatectomy is performed.

Cytostatic Therapy

The most commonly applied, standard of care (SOC) chemotherapy applied to non-resectable PDA is currently Gemcitabine. Although not highly effective from a therapeutic perspective, treatment with this relatively mild drug suppresses cancer-related symptoms while rarely causing adverse events. Since the establishment of Gemcitabine as SOC, this drug has been tested in clinical trials in conjunction with a variety of other chemotherapeutic and targeted treatments, but none of these combinations were shown to result in significantly improved therapeutic efficacy and/or quality of life. Current emphasis is on small molecule drugs that target the Ras pathway (e.g. MEK inhibitors) as well as on drugs that target the stromal component of PDA (e.g. hedgehog inhibitors and abraxane).

The efficacy of cytostatic therapy is more prominent in the context of adjuvant treatment of resectable PDA, where the aim is to prevent – or at least slow down - the outgrowth of micrometastases. This, and the advancement of surgical techniques, has now increased the 5-year survival rate of patients with resectable pancreatic cancer to approximately 20%. In an attempt to get this number up further, cytostatic therapy is currently also applied during the weeks between diagnosis and surgery (neo-adjuvant treatment). It is evident that development of more effective adjuvant strategies, such as those mobilizing immune effector mechanisms, could further increase the survival rate of these patients.

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