Pancreatic Cancer

Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. There are a number of types of pancreatic cancer.The most common, pancreatic adenocarcinoma, accounts for about 85% of cases, and the term “pancreatic cancer” is sometimes used to refer only to that type.These adenocarcinomas start within the part of the pancreas which makes digestive enzymes. Several other types of cancer, which collectively represent the majority of the non-adenocarcinomas, can also arise from these cells, One to two percent of cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormone-producing cells of the pancreas.These are generally less aggressive than pancreatic adenocarcinoma.

Signs and symptoms of the most common form of pancreatic cancer may include yellow skin, abdominal or back pain, unexplained weight loss, light-colored stools, dark urine and loss of appetite.There are usually no symptoms in the disease’s early stages, and symptoms that are specific enough to suggest pancreatic cancer typically do not develop until the disease has reached an advanced stage.By the time of diagnosis, pancreatic cancer has often spread to other parts of the body.

Pancreatic cancer rarely occurs before the age of 40, and more than half of cases of pancreatic adenocarcinoma occur in those over 70.Risk factors for pancreatic cancer include tobacco smoking, obesity, diabetes, and certain rare genetic conditions.About 25% of cases are linked to smoking,and 5–10% are linked to inherited genes.Pancreatic cancer is usually diagnosed by a combination of medical imaging techniques such as ultrasound or computed tomography, blood tests, and examination of tissue samples (biopsy).The disease is divided into stages, from early (stage I) to late (stage IV).Screening the general population has not been found to be effective.

The risk of developing pancreatic cancer is lower among non-smokers, and people who maintain a healthy weight and limit their consumption of red or processed meat. A smoker’s chance of developing the disease decreases if they stop smoking, and almost returns to that of the rest of the population after 20 years.Pancreatic cancer can be treated with surgery, radiotherapy, chemotherapy, palliative care, or a combination of these.Treatment options are partly based on the cancer stage.Surgery is the only treatment that can cure pancreatic adenocarcinoma,and may also be done to improve quality of life without the potential for cure.Pain management and medications to improve digestion are sometimes needed.Early palliative care is recommended even for those receiving treatment that aims for a cure.

In 2015, pancreatic cancers of all types resulted in 411,600 deaths globally.Pancreatic cancer is the fifth most common cause of death from cancer in the United Kingdom,and the fourth most common in the United States.The disease occurs most often in the developed world, where about 70% of the new cases in 2012 originated.Pancreatic adenocarcinoma typically has a very poor prognosis: after diagnosis, 25% of people survive one year and 5% live for five years.For cancers diagnosed early, the five-year survival rate rises to about 20%.Neuroendocrine cancers have better outcomes; at five years from diagnosis, 65% of those diagnosed are living, though survival varies considerably depending on the type of tumor.

Signs and symptoms

Jaundice can be a symptom, due to biliary obstruction from a pancreatic tumor.
Since pancreatic cancer usually does not cause recognizable symptoms in its early stages, the disease is typically not diagnosed until it has spread beyond the pancreas itself.This is one of the main reasons for the generally poor survival rates. Exceptions to this are the functioning PanNETs, where over-production of various active hormones can give rise to symptoms (which depend on the type of hormone).

Bearing in mind that the disease is rarely diagnosed before the age of 40, common symptoms of pancreatic adenocarcinoma occurring before diagnosis include:

Pain in the upper abdomen or back, often spreading from around the stomach to the back. The location of the pain can indicate the part of the pancreas where a tumor is located. The pain may be worse at night and may increase over time to become severe and unremitting.It may be slightly relieved by bending forward. In the UK, about half of new cases of pancreatic cancer are diagnosed following a visit to a hospital emergency department for pain or jaundice. In up to two-thirds of people abdominal pain is the main symptom, for 46% of the total accompanied by jaundice, with 13% having jaundice without pain.
Jaundice, a yellow tint to the whites of the eyes or skin, with or without pain, and possibly in combination with darkened urine. This results when a cancer in the head of the pancreas obstructs the common bile duct as it runs through the pancreas.
Unexplained weight loss, either from loss of appetite, or loss of exocrine function resulting in poor digestion.
The tumor may compress neighboring organs, disrupting digestive processes and making it difficult for the stomach to empty, which may cause nausea and a feeling of fullness. The undigested fat leads to foul-smelling, fatty feces that are difficult to flush away.Constipation is common.
At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis.While long-standing diabetes is a known risk factor for pancreatic cancer (see Risk factors), the cancer can itself cause diabetes, in which case recent onset of diabetes could be considered an early sign of the disease.People over 50 who develop diabetes have eight times the usual risk of developing pancreatic adenocarcinoma within three years, after which the relative risk declines.

Outcomes
Outcomes in pancreatic cancers according to clinical stage
Clinical stage Five-year survival (%) – U.S., diagnoses 1992–98
Pancreatic adenocarcinoma and the other less common exocrine cancers have a very poor prognosis, as they are normally diagnosed at a late stage when the cancer is already locally advanced or has spread to other parts of the body.Outcomes are much better for PanNETs: many are benign and completely without clinical symptoms, and even those cases not treatable with surgery have an average five-year survival rate of 16%,although the outlook varies considerably according to the type.

For locally advanced and metastatic pancreatic adenocarcinomas, which together represent over 80% of cases, numerous recent trials comparing chemotherapy regimes have shown increased survival times, but not to more than one year.Overall five-year survival for pancreatic cancer in the US has improved from 2% in cases diagnosed in 1975–77, and 4% in 1987–89 diagnoses, to 6% in 2003–09.In the less than 20% of cases of pancreatic adenocarcinoma with a diagnosis of a localized and small cancerous growth (less than 2 cm in Stage T1), about 20% of Americans survive to five years.

About 1500 genes are linked to outcomes in pancreatic adenocarcinoma. These include both unfavorable genes, where high expression is related to poor outcome, for example C-Met and MUC-1, and favorable genes where high expression is associated with better survival, for example the transcription factor PELP1.

Research directions
Worldwide efforts on many levels are underway to understand pancreatic cancer, but progress has been slow, particularly into understanding the disease’s causes.There are several fundamental unanswered questions.The nature of the changes that lead to the disease are being intensely investigated, such as the roles played by genes such as KRAS and p53.A key question is the timing of events as the disease develops and progresses – particularly the role of diabetes,and how and when the disease spreads.

Research on early detection is ongoing.For instance, the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) trial is aiming to determine whether regular screening is appropriate for people with a family history of the disease, or who have hereditary pancreatitis.The knowledge that new onset of diabetes can be an early sign of the disease could facilitate timely diagnosis and prevention if a workable screening strategy can be developed.

Another area of interest is in assessing whether keyhole surgery (laparoscopy) would be better than Whipple’s procedure in treating the disease surgically, particularly in terms of recovery time.Irreversible electroporation is a relatively novel ablation technique that has shown promise in downstaging and prolonging survival in persons with locally advanced disease. It is especially suitable for treatment of tumors that are in proximity to peri-pancreatic vessels without risk of vascular trauma.The limited success of outcomes after surgery has led to a number of trials that were running in 2014 to test outcomes using chemotherapy or radiochemotherapy before surgery. This had previously not been found to be helpful, but is being trialed again, using drug combinations which have emerged from the many trials of post-operative therapies, such as FOLFIRINOX.

Efforts are underway to develop new drugs.Some of these involve targeted therapies against the cancer cells’ molecular mechanisms.Others aim to target the highly resistant cancer stem cells.Still others aim to affect the non-neoplastic stroma and microenvironment of the tumor, which is known to influence cell proliferation and metastasis.A further approach involves the use of immunotherapy, such as oncolytic viruses.

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