Pancreatic Cancer

 Pancreatic Cancer 

Andrew Siegel, M.D.  Blog #124

The pancreas is a vitally important organ that serves dual roles: as an endocrine organ that produces hormones including insulin and glucagon and as an exocrine organ that secretes digestive enzymes that help the process of fat, protein and carbohydrate breakdown and digestion.  It is located deep within the upper abdomen and is divided into a head, body and tail.  The head lies within the concavity of the duodenum (the first part of the intestine).  The body runs behind the stomach and the tail touches the spleen.  The fact that it is such a deep-seated organ makes it virtually impossible to examine on a physical exam (unlike superficial organs such as the breasts or testicles) and pathological problems of the pancreas are identifiable only on sophisticated imaging studies of the abdomen.

Cancer of the pancreas is an incredibly lethal malignant tumor.  Approximately 45,000 Americans will be diagnosed with pancreatic cancer in 2013 and more than 38,000 will die from the disease, with a five-year survival rate of only about 5%.   The greatest challenge is that there are no early detection tests and, unfortunately, most patients who have early and localized disease have no recognizable symptoms such that most are not diagnosed until late in the disease—after the cancer has spread (metastasized).

In spite of the dismal prognosis, there has been recent progress in pancreatic cancer with surgery becoming safer and less invasive, the availability of new drug combinations that have been shown to improve survival, and advances in radiation that have resulted in less side effects. Significant strides forward have been made in the understanding of the genetics of pancreatic cancer, and unlocking the molecular basis of this horrific disease hopefully will translate into better treatment options.

The most common form of pancreatic cancer is invasive ductal adenocarcinoma.  The second most common type is a pancreatic neuroendocrine tumor; this is less aggressive than the ductal carcinomas, but still has a 10-year survival rate of only 45%. Some of the neuroendocrine tumors manufacture hormones such as insulin that produce clinical syndromes.

A combination of inherited and environmental factors contributes to the development of pancreatic cancer. The most common environmental risk factor is tobacco; smokers having a more than double the risk of pancreatic cancer as compared to non-smokers.  The good news is that smoking cessation will substantially reduce the risk.  Other risk factors are long-standing type II diabetes, increased body mass index, heavy alcohol consumption, and chronic pancreatitis.   A strong family history of pancreatic cancer puts an individual at significant risk.  BRCA2 gene mutations also increase the risk. Additionally, patients who have hereditary pancreatitis have a 60-fold increased risk; this is so substantial that some patients with this disease opt for a prophylactic removal of the pancreas.

Now for Molecular Biology 101:  Genes are inherited bits of information that code for proteins.  When genes become mutated, the proteins that the genes code for become dysfunctional.  One can think of genes as the written recipe for a particular meal and their product as the meal itself—when the recipe is changed (mutated) the resultant meal is defective.  In the case of the human body, the altered genes code for altered proteins that damage cellular function and replication in such a way as to alter the normal orderly process of cellular reproduction, resulting in unrestrained, disorderly cell replication, aka cancer.  Scientists have identified numerous genetic mutations responsible for cancers and they are named with bizarre combinations of letters and numbers—do not be daunted by their names as follow.

So, on a molecular level, cancer is caused by inherited and acquired mutations in genes. The sequencing of the genetic material of the pancreatic ductal adenocarcinomas has demonstrated that four specific genes are each altered in more than 50% of these cancers.  KRAS, an oncogene (a gene with the potential to cause cancer), becomes activated in 95% of pancreatic cancers—the protein coded for by this gene plays an important role in cell signaling, a complex system of communication that governs basic cellular activities and coordinates cell actions. The p16/CDKN2A gene, a tumor suppressor gene (a gene that protects a cell from cancer that, when mutated, would allow the cell to progress to cancer), becomes inactivated in 95% of pancreatic cancers.  The protein product of this gene plays an important role in the regulation of the cell cycle and its loss promotes unrestricted cell growth. The TP53 tumor suppressor gene is inactivated in 75% of pancreatic cancers. Loss of its function through mutation promotes pancreatic cancer through the loss of a number of critical cell functions.  The SMAD4 tumor suppressor gene has a protein product in the cell signaling pathway that when interfered with is associated with a very poor prognosis and widely metastatic disease. In addition to these 4 major genes, there are numerous other genes that are mutated in pancreatic cancer at lower frequencies.

Unfortunately, most pancreatic cancers do not cause specific symptoms and are not diagnosed in a timely manner. Typical non-specific symptoms include upper abdominal pain radiating to the back; unexplained weight loss; nausea; jaundice; clay colored stools; and in a small percentage of people, migratory thrombophlebitis (multiple blood clots appearing in a variety of veins). At times, it can present with diabetes, symptoms of pancreatitis, or depression. Diagnosis is predicated upon imaging tests including CT, MRI, and endoscopic ultrasound.  Standard cancer staging is stage I through stage IV, with stages I an II being localized, III being locally advanced, and IV being metastatic. In the absence of metastatic disease, the ability to surgically remove the cancer is predicated on the relationship of the tumor to the adjacent major blood vessels.

Pancreatic cancer is a complex disease and is best treated by a multidisciplinary team including a surgeon, medical oncologist, and radiation oncologist. In general, patients with stage I/II disease should undergo surgery followed by adjuvant therapy (chemotherapy and/or radiation).  Patients with stage III locally advanced disease should be treated with chemotherapy and/or chemo-radiation.  Patients with stage IV and good performance status may receive systemic therapy and those with poor health should be given supportive therapy.

The best chance of long-term survival of a patient with localized pancreatic cancer is surgical removal. However, because pancreatic cancer is often beyond the confines of the pancreas at presentation and due to the potentially negative impact of surgery on quality of life as well as the low chance of long-term survival, surgery is often non-curative. Certainly, the risk of local and systemic recurrence after surgery is very high.

Bottom Line: Pancreatic cancer is a wickedly lethal cancer.  In terms of minimizing one’s risk, avoid tobacco, obesity and heavy alcohol consumption. So, don’t smoke, eat a healthy diet, maintain a good weight, and be moderate with alcohol.  Despite the dismal prognosis, there have been recent advances on many fronts, particularly in terms of the genetics of the cancer, wherein the key to treating this miserable cancer most likely lies.

“Sometimes life hits you in the head with a brick. Don’t lose faith. I’m convinced that the only thing that kept me going was that I loved what I did. You’ve got to find what you love. And that is as true for your work as it is for your lovers. Your work is going to fill a large part of your life, and the only way to be truly satisfied is to do what you believe is great work. And the only way to do great work is to love what you do. If you haven’t found it yet, keep looking. Don’t settle. As with all matters of the heart, you’ll know when you find it. And, like any great relationship, it just gets better and better as the years roll on. So keep looking until you find it. Don’t settle.” 

Steve Jobs, who died of neuroendocrine cancer of the pancreas

Reference: Recent Progress in Pancreatic Cancer, Wolfgang, Herman, Laheru, Klein, Erdek, Fishman and Hruban

CA CANCER J CLIN 2013;63:318-348 September/October 2013

Andrew Siegel, M.D.

Author of Promiscuous Eating: Understanding and Ending Our Self-Destructive Relationship with Food: www.promiscuouseating.com

Available on Amazon in Kindle edition

Author of: Male Pelvic Fitness: Optimizing Sexual and Urinary Health; in press and available in e-book and paperback formats in January 2014.

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