|Classification and external resources|
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 cancer cells have the ability to invade or spread to 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 often used to refer only to that type. These adenocarcinomas start within the pancreatic glands which make 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 in every hundred cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormone-producing neuroendocrine 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 suspect 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.
To prevent pancreatic cancer, maintaining a healthy weight and limiting consumption of red or processed meat is recommended. A smoker's chances of developing the disease are reduced if they cease smoking, after which the risk of the disease returns to normal within 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 the disease; it may also be done to try 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 2012 pancreatic cancers of all types were the seventh most common cause of cancer deaths, resulting in 330,000 deaths globally. In the United States, pancreatic cancer is the fourth most common cause of deaths due to cancer. The disease occurs most often in the developed world, the source of about 70% of new cases in 2012. Pancreatic adenocarcinoma typically has a poor prognosis: after diagnosis, 25% of people survive one year and only 5% live for five years, although 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.
- 1 Types
- 2 Signs and symptoms
- 3 Risk factors
- 4 Diagnosis
- 5 Staging
- 6 Mechanism
- 7 Prevention and screening
- 8 Management
- 9 Outcomes
- 10 Distribution
- 11 History
- 12 Research
- 13 See also
- 14 References
- 15 External links
The many types of pancreatic cancer can be divided into two general groups. The vast majority of cases (about 99%) occur in the exocrine component of the pancreas, which produces digestive enzymes. There are several sub-types of exocrine pancreatic cancers, but their diagnosis and treatment have much in common. Most of the remaining 1% of pancreatic cancers arise in the endocrine or hormone-producing tissue of the pancreas and have different symptoms and treatment, although surgery offers the only possibility of curing both groups. Both groups occur mainly (but not exclusively) in people over 40, and are slightly more common in men, but some rare sub-types mainly occur in women or children.
The exocrine group is dominated by pancreatic adenocarcinoma (variations of this name may add "invasive" and "ductal"), which is by far the most common type, representing about 85% of all pancreatic cancers, although the pancreatic ductal epithelium from which it arises represents less than 10% of the pancreas by cell volume. This cancer arises in the ducts that carry certain hormones and enzymes away from the pancreas, and is covered in detail in other sections. The next most common, acinar cell carcinoma of the pancreas, arises in the cells that make these products, and represents 5% of exocrine pancreas cancers. Like the "functioning" endocrine cancers described below, it may cause over-production of pancreatic products, in this case digestive enzymes, which may produce symptoms including skin rashes and joint pain. Cystadenocarcinoma represents 1% and has a better prognosis than other types.
Pancreatoblastoma is a rare form, mostly occurring in childhood, and with a relatively good prognosis. Other exocrine cancers include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Solid pseudopapillary tumor is a rare low-grade neoplasm that mainly affects younger women, and generally has a very good prognosis.
Pancreatic mucinous cystic neoplasms are a broad group of pancreas tumors that have varying malignant potential. They are being detected at a greatly increased rate as CT scans become more powerful and common, and discussion continues as how best to assess and treat them, as many are benign.
The small minority of tumors that arise from elsewhere in the pancreas are mainly pancreatic neuroendocrine tumors (PanNETs). Neuroendocrine tumors (NETs) are a diverse group of benign or malignant tumors that arise from neuroendocrine cells that are responsible for integrating the nervous and endocrine systems. NETs can occur in most organs of the body, including the pancreas, where the various malignant types are all considered to be rare. PanNETs are grouped into "functioning" and "non-functioning" types, depending on their hormonal characteristics. The functioning types secrete hormones such as insulin, gastrin, and glucagon into the bloodstream, often in large quantities, giving rise to serious symptoms such as low blood sugar, but also favoring relatively early detection. The most common functioning PanNETs are insulinomas and gastrinomas, named after the hormones they secrete. The non-functioning types do not secrete hormones in a sufficient quantity to give rise to overt clinical symptoms. For this reason, non-functioning PanNETs are often diagnosed only after the cancer has spread to other parts of the body.
As with other neuroendocrine tumors, the history of the terminology and classification of PanNETs is complex. PanNETs are sometimes still referred to as "islet cell cancers", even though it is now known that they do not actually arise from islet cells as previously thought.
Signs and symptoms
Since early pancreatic cancer usually does not cause recognizable symptoms, 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, whose over-production of hormones is likely to give a range of symptoms according to the type.
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 of 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.
- 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.
- Trousseau's syndrome, in which blood clots form spontaneously in the portal blood vessels, the deep veins of the extremities, or the superficial veins anywhere on the body, may be associated with pancreatic cancer, and is found in about 10% of cases.
- Clinical depression has been reported in association with pancreatic cancer in some 10–20% of cases, and can be a hindrance to optimal management. The depression sometimes appears before the diagnosis of cancer, suggesting that it may be brought on by the biology of the disease.
There may be symptoms of pancreatic cancer metastasis, where the primary pancreatic cancer has spread to other organs. Typically, pancreatic adenocarcinoma, which spreads aggressively, first metastasizes to regional lymph nodes, and later to the liver or to the peritoneal cavity, large intestine or lungs. It is uncommon for it to spread to the bones or brain.
Cancers in the pancreas may also be secondary cancers that have spread from other parts of the body. This is uncommon, found in only about 2% of cases of pancreatic cancer. Kidney cancer is by far the most common cancer to spread to the pancreas, followed by colorectal cancer, and cancer of the skin, breast, and lung. Surgery may be performed on the pancreas in such cases, whether in hope of a cure or for palliative benefit.
- Age, gender and race; the risk of developing pancreatic cancer increases with age. Most cases occur after age 65, while cases before age 40 are uncommon. The disease is slightly more common in men than women, and in the United States is over 1.5 times more common in African Americans, though incidence in Africa is low.
- Cigarette smoking is the best-established avoidable risk factor for pancreatic cancer, approximately doubling risk among long-term smokers, the risk increasing with the number of cigarettes smoked and the years of smoking. The risk declines slowly after smoking cessation, taking some 20 years to return to that of non-smokers.
- Obesity; a BMI greater than 35 is associated with a roughly 1.5-fold increase in relative risk.
- Family history; 5–10% of pancreatic cancer cases have an inherited component, where people have a family history of pancreatic cancer. Most of the genes involved have not been identified. Hereditary pancreatitis gives a greatly increased lifetime risk of pancreatic cancer of 30–40% to the age of 70. Screening for early pancreatic cancer may be offered to individuals with hereditary pancreatitis on a research basis. Some people may choose to have their pancreas surgically removed to prevent cancer developing in the future.
- Pancreatic cancer has been associated with the following other rare hereditary syndromes: Peutz-Jeghers syndrome due to mutations in the STK11 tumor suppressor gene, dysplastic nevus syndrome (or familial atypical multiple mole and melanoma syndrome, FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene, autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene, hereditary non-polyposis colon cancer (Lynch syndrome), and familial adenomatous polyposis. PanNETs have been associated with multiple endocrine neoplasia type 1 and von Hippel Lindau syndrome.
- Chronic pancreatitis appears to be associated with an almost 3-fold increase in risk, and as with diabetes, new-onset pancreatitis may be a symptom of a tumor. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.
- Diabetes mellitus is a risk factor for pancreatic cancer and, as noted in Signs and symptoms, new-onset diabetes may also be an early sign of the disease. People who have been diagnosed with Type 2 diabetes for longer than ten years may have a 1.5-fold increase in risk, as compared with non-diabetics.
- Specific types of food, as opposed to obesity, have not been clearly shown to increase the risk of pancreatic cancer, although some studies have found links with diets high in red meat and processed meat.
While the association between alcohol abuse and pancreatitis is well established, considerable research has failed to firmly establish alcohol consumption as a risk factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have found no association. Although drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, chronic pancreatitis associated with alcohol consumption is less frequently a precursor for pancreatic cancer than other types of chronic pancreatitis.
Pancreatic adenocarcinoma has a number of symptoms, but none that are individually distinctive to it or appear in the early stages of disease. The symptoms at diagnosis vary according to the location of the cancer on the pancreas, which anatomists divide (from left to right on most diagrams) into the thick head, the neck, and the tapering body, ending in the tail. About 60–70% of adenocarcinomas are in the head of the pancreas, and 20–25% in the body or tail. The most common symptom for all locations is unexplained weight loss, which may be considerable. Tumors in the head of the gland typically also cause jaundice, pain, loss of appetite, dark urine, and light-colored stools. Tumors in the body and tail typically also cause pain. For all locations, nausea, vomiting and a feeling of weakness are present in a large minority (between 35% and 47%) of people at diagnosis.
About 80% to 85% of people with locally advanced or advanced metastatic disease experience pain, which is usually felt in the upper abdomen as a dull ache that radiates straight through to the back. It may be intermittent and made worse by eating. Painful jaundice is present in approximately one-half of people for whom curative surgery is not an option, while painless jaundice is present in approximately one-half of people with a cancer that is potentially curable by surgery.
People sometimes have recent onset of atypical diabetes mellitus, a history of recent but unexplained thrombophlebitis (Trousseau sign), or a previous attack of pancreatitis. Courvoisier's sign (jaundice accompanied by a painlessly swollen gallbladder) can raise suspicion and can help differentiate pancreatic cancer from gallstones. Tiredness, irritability and difficulty eating because of pain may be present.
Medical imaging techniques, such as computed tomography (CT scan) and endoscopic ultrasound (EUS) are used both to confirm the diagnosis and to help decide whether surgery can be used (resectability). Magnetic resonance imaging and positron emission tomography may also be used, and magnetic resonance cholangiopancreatography may be useful in some cases. Abdominal ultrasound is less sensitive and will miss small tumors, but can identify metastasis to the liver and build-up of fluid in the peritoneal cavity (ascites). It may be used for a quick and cheap first examination before other techniques.
A biopsy by fine needle aspiration, often guided by endoscopic ultrasound, may be used where there is uncertainty over the diagnosis, but a histologic diagnosis is not usually required for removal of the tumor by surgery to go ahead.
Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity, not least because 5% of people lack the Lewis (a) antigen and cannot produce CA19-9. It has a sensitivity of 80% and specificity of 73% in for detecting pancreatic adenocarcinoma, and is used for following known cases rather than diagnosis.
The most common form of pancreatic cancer (adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. There is typically considerable formation of fibrous tissue (desmoplasia) around the tumor. This creates an environment that is short of blood vessels (hypovascular) and so of oxygen (tumor hypoxia). It is thought that this prevents many chemotherapy drugs from reaching the tumor, as one factor making the cancer especially hard to treat. Pancreatic cancer has an immunohistochemical profile that is similar to hepatobiliary cancers such as cholangiocarcinoma, and some stomach cancers; thus, it may not always be possible to be certain that a tumor found in the pancreas arose from it.
Pancreatic cancer is usually staged using a CT scan. The cancer staging system used internationally for pancreatic cancer is that of the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC). The AJCC-UICC staging system designates four stages, in keeping with the TNM staging system (based on Tumor size, spread to lymph Nodes and Metastasis). Stage I and II tumors are candidates for successful surgical removal or resection. The staging system makes an important distinction within Stage III between tumors that are classed as "borderline resectable" because they do not involve the celiac axis or superior mesenteric artery, and "unresectable". Surgery is likely to be possible for the former, but is not usual for the latter. These are T3 and T4 respectively in the associated TNM staging system. Stage T1 is localized tumors less than 2 cm in size, T2 tumors over that size but still wholly in the pancreas, and the other T stages are defined by the degree of spread beyond. To help decide treatment, the tumors are also divided into groups based on whether surgical removal (resection) seems possible: in this way, tumors are categorized as "resectable", "borderline resectable", and "unresectable" (due to locally advanced or metastatic disease).
Locally advanced adenocarcinomas have spread into neighboring organs, which may be any of the following (in roughly decreasing order of frequency): the duodenum, stomach, transverse colon, spleen, adrenal gland, or kidney. Very often they also spread to the important blood or lymphatic vessels and nerves that run close to the pancreas, making surgery far more difficult. Typical sites for metastasic spread are the liver, peritoneal cavity and lungs, all of which occur in 50% or more of fully advanced cases.
The 2010 WHO classification of tumors of the digestive system grades all the neuroendocrine tumors into three categories, based on their degree of cellular differentiation (from "NET G1" through to the poorly-differentiated "NET G3"). A TNM staging system for PanNETs has been proposed by The European Neuroendocrine Tumor Society.
These cancers are thought to arise from several types of precancerous cysts (cystic lesions) within the pancreas. But by no means do all such lesions progress to cancer, and the increased numbers detected as a by-product of the increasing use of CT scans for other reasons are not all treated.
Besides pancreatic serous cystadenomas (SCNs), which are almost always benign, three types of precancerous lesion are recognized. The first is pancreatic intraepithelial neoplasia. These are microscopic abnormalities in the pancreas, which are often found in autopsies of people with no diagnosed cancer. These may progress from low to high grade and then to a tumor. More than 90% of cases at all grades carry a faulty KRAS gene, while in grades 2 and 3 damage to three further genes – CDKN2A (p16), p53 and SMAD4 – are increasingly often found.
Secondly, intraductal papillary mucinous neoplasms (IPMNs) are macroscopic lesions, which occur in about 2% of all adults, rising to about 10% by age 70. They also very often have KRAS gene mutations, in about 40–65% of cases, and in the GNAS Gs alpha subunit and RNF43, affecting the Wnt signaling pathway. Even if removed surgically, there remains a considerably increased risk of pancreatic cancer developing subsequently.
The last type, pancreatic mucinous cystic neoplasms (MCNs) mainly occur in women, and may remain benign or progess to cancer. If they become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery.
The genetic events that cause ductal adenocarcinoma have been well characterized, and next-generation DNA analysis (usually exome sequencing) has been done for the common types of tumor. The most common alterations are KRAS mutations (95%), CDKN2A mutations/deletions (about 95%), TP53 inactivations (75%), SMAD4 deletions/mutations (50%), the last especially associated with a poor prognosis. SWI/SNF mutations/deletions occur in about 10−15% of the adenocarcinomas. The genetic alterations in several other types of pancreatic cancer and precancerous lesions have also been researched.
The genes often found mutated in PanNETs are typically a different set from those in pancreatic adenocarcinoma. For example KRAS mutation is normally absent. Instead, common mutations affect MEN1, as in the inherited Wermer's syndrome, DAXX, mTOR and ATRX.
Prevention and screening
Apart from not smoking, the American Cancer Society recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains, while decreasing consumption of red and processed meat, although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically.
In the general population, screening of large groups is not effective, although newer techniques are being evaluated. Nevertheless, regular screening with endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics.
The most crucial decision to be made after diagnosis is whether surgical removal of the tumor is possible, as this is the only cure for this cancer. This requires a tumor that has not spread, and depends on its location. In particular the tumor is examined through CT to see how it relates to the major blood vessels passing close to the pancreas. The general health of the person must also be assessed, though age in itself is not an obstacle to surgery.
Chemotherapy and, to a lesser extent, radiotherapy are likely to be offered to most people, whether or not surgery is possible. Management of pancreatic cancer should be in the hands of a multidisciplinary team including specialists in several aspects of oncology, and is therefore best conducted in larger centers.
Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases. Although CT scans help, it can be difficult to determine whether the tumor can be fully removed (its "resectability"), and it may only become apparent during surgery that it is not possible to successfully remove the tumor without damaging other vital tissues. The advisability of surgical resection depends on several factors including the precise extent of local anatomical adjacency to, or involvement of, the venous or arterial blood vessels, as well as surgical expertise and a careful consideration of projected post-operative recovery. Traditionally, an assessment is made of the tumor's proximity to major venous or arterial vessels by "abutment", defined as the tumor touching up to 180° of a blood vessel's circumference, "encasement" by the tumor, defined as the tumor touching more than 180° round the vessel, or actual vessel involvement.:22 Vascular resection may be be considered selectively, particularly if neoadjuvant therapy is feasible, using chemotherapy:36 and radiation.:29–30 Even when the operation appears to have been successful, cancerous cells are often found at the edges of the tissue removed when examined microscopically by a pathologist (this will always be done), indicating the cancer has not been entirely removed, or there may be spread of stem cells, which are usually not evident microscopically and which may continue to develop.
A diagnostic laparoscopy can be performed to enable a much clearer idea of the outcome of a full operation. Surgery can also be performed for palliation, if the cancer is invading or compressing the duodenum or colon. In such cases, bypass surgery might overcome the obstruction and improve quality of life but is not intended as a cure.
For cancers involving the head of the pancreas, the Whipple procedure is the most common attempted curative surgical treatment. This involves removing the pancreatic head and the curve of the duodenum together (pancreato-duodenectomy), making a bypass for food from stomach to jejunum (gastro-jejunostomy) and attaching a loop of jejunum to the cystic duct to drain bile (cholecysto-jejunostomy). It can be performed only if the person is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can therefore be performed only in a minority of cases. Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy, which often includes splenectomy or removal of the spleen. This is today often done using keyhole or laparoscopic surgery.
Although the operations no longer have the very high death rate that characterized them until the 1980s, there is still a high rate, of between 30% and 45%, of post-operative sickness needing treatment, other than the cancer itself. This comes from a variety of consequences and complications of the surgery, of which difficulty in emptying the stomach is the most common.
After surgery, adjuvant chemotherapy with gemcitabine or 5-FU should be offered if the person is sufficiently fit. There are often clinical trials available for novel adjuvant therapies. Adjuvant radiotherapy has been controversial since the 1980s, and the European Society for Medical Oncology recommends that this should only be used for people in clinical trials. However, it is more likely to be used in the USA. Some surgical procedures that may be used in palliative care are discussed in that section.
The role of radiotherapy after potentially curative surgery has been controversial for many years, with a continuing tendency for clinicians in the US to be more ready to use adjuvant radiation therapy than those in Europe. Many clinical trials since the 1980s, testing a variety of treatment regimes, have failed to settle the matter conclusively.
In people not suitable for curative surgery, chemotherapy may be used to extend life or improve its quality. Gemcitabine was approved by the United States Food and Drug Administration in 1997, after a clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in people with advanced pancreatic cancer. This was the first chemotherapy drug approved by the FDA primarily for a nonsurvival clinical trial endpoint.
Chemotherapy using gemcitabine alone was the standard for about a decade, as a number of trials testing it in combination with other drugs failed to demonstrate significantly better outcomes. However, the combination of gemcitabine with erlotinib was found to increase survival modestly, and erlotinib was licensed by the FDA for use in pancreatic cancer in 2005. The FOLFIRINOX chemotherapy regimen using four drugs was found more effective than gemcitabine, but with substantial side effects, and is thus only suitable for people with good performance status. This is also true of protein-bound paclitaxel or nab-paclitaxel, which was licensed by the FDA in 2013 for use with gemcitabine in pancreas cancer. By the end of 2013, both FOLFIRINOX and nab-paclitaxel with gemcitabine were regarded as good choices for those able to tolerate the side-effects, and gemcitabine remained an effective option for those who were not. A head-to-head trial between the two new options is awaited, and trials investigating other variations continue. However, the changes of the last few years have only increased survival times by a few months.
Some small tumors of less than 1 cm. that are identified incidentally, for example on a CT scan performed for other purposes, may be followed by watchful waiting. This depends on the assessed risk of surgery which is influenced by the site of the tumor and the presence of other medical problems. Tumors within the pancreas only (localized tumors), or with limited metastases, for example to the liver, may be removed by surgery. The type of surgery depends on the tumor location, and the degree of spread to lymph nodes. For localized tumors, the surgical procedure may be much less extensive than the types of surgery used to treat pancreatic adenocarcinoma described above, but otherwise surgical procedures are similar to those for exocrine tumors. The range of possible outcomes varies greatly; some types have a very high survival rate after surgery while others have a poor outlook. As all this group are rare, treatment should be undertaken in a specialized center. Use of liver transplantation may be considered in certain cases of liver metastasis.
For functioning tumors, the somatostatin analog class of medications, such as octreotide, can reduce the excessive production of hormones. Lanreotide can slow tumor growth. If the tumor is not amenable to surgical removal and is causing symptoms, targeted therapy with everolimus or sunitinib can reduce symptoms and slow progression of the disease. Standard cytotoxic chemotherapy is generally not very effective for PanNETs, but may be used when other drug treatments fail to prevent the disease from progressing, or in poorly differentiated PanNET cancers.
Radiation therapy is occasionally used if there is pain due to anatomic extension, such as metastasis to bone. Some PanNETs absorb specific peptides or hormones, and these PanNETs may respond to nuclear medicine therapy with radiolabeled peptides or hormones such as iobenguane (iodine-131-MIBG). Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also be used.
Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer, and improving quality of life. Because pancreatic adenocarcinoma is usually diagnosed after it has progressed to an advanced stage, palliative care as a treatment of symptoms is often the only treatment possible.
Palliative care focuses not on treating the underlying cancer, but on treating symptoms such as pain or nausea, and can assist in decision-making, including when or if hospice care will be beneficial. Pain can be managed with medications such as opioids or through procedural intervention, by a nerve block on the celiac plexus (CPB). This alters or, depending on the technique used, destroys the nerves that transmit pain from the abdomen. CPB is a safe and effective way to reduce the pain, which generally reduces the need to use opioid painkillers, which have significant negative side effects. Other symptoms or complications that can be treated with palliative surgery are obstruction by the tumor of the intestines or bile ducts. For the latter, which occurs in well over half of cases, a small metal tube called a stent may be inserted by endoscope to keep the ducts draining. Palliative care can also help treat depression that often comes with diagnosis of pancreatic cancer.
Both surgery and advanced inoperable tumors often lead to digestive system disorders from a lack of the exocrine products of the pancreas (exocrine insufficiency). These can be treated by taking pancreatin which contains manufactured pancreatic enzymes, and is best taken with food. Difficulty in emptying the stomach (delayed gastric emptying) is common and can be a serious problem, involving hospitalization. Treatment may involve a variety of approaches, including draining the stomach by nasogastric aspiration and drugs called proton-pump inhibitors or H2 antagonists, which both reduce production of gastric acid.
|Clinical stage||Five-year survival (%) – U.S., diagnoses 1992–98|
|Exocrine pancreatic cancer||Neuroendocrine treated with surgery|
|IA / I||14||61|
|IIA / II||7||52|
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 greatly varies according to the type.
For locally advanced and metastatic pancreatic adenocarcinoma, 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. Together with lung cancer, pancreatic cancer as a whole has shown the least improvement in US survival rates of all common cancers over the three decades to 2013, although five-year survival has improved from 2% in cases diagnosed in 1975–77, and 4% in 1987–89 diagnoses, to 6% in 2002–08.
In the remaining 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), approximately 20% of Americans survive to five years.
As of 2012, pancreatic cancer resulted in 330,000 deaths globally, up from 310,000 in 2010 and 200,000 in 1990. In 2014, an estimated 46,000 people in the US are expected to be diagnosed with pancreatic cancer and 40,000 to die of it. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year. It is the seventh highest cause of death from cancer worldwide. Deaths from pancreatic cancer have changed little over time.
Globally pancreatic cancer is the 11th most common cancer in women and the 12th most common in men. The majority of cases occur in developed countries. People from the United States have an average lifetime risk of about 1 in 67 (or 1.5%) of developing the disease, slightly higher than the figure for the UK. The disease is more common in men than women, though the difference in rates has narrowed over recent decades, probably reflecting earlier increases in female smoking. In the United States the risk for African Americans is over 50% greater than for whites, but the rates in Africa and East Asia are much lower than those in North America or Europe. The United States, Central and eastern Europe, and Argentina and Uruguay all have high rates.
Pancreatic cancer is the tenth most common cancer in the UK (around 8,800 people were diagnosed with the disease in 2011), and it is the fifth most common cause of cancer death (around 8,700 people died in 2012).
The annual incidence of clinically recognized PanNETs is low (about five per one million person-years), which is dominated by the non-functioning types. These are variously estimated in recent clinical guidelines to form either up to 90% of PanNETs, or alternatively 45–60%. However, studies of autopsies have uncovered small PanNETs much more frequently, suggesting that the prevalence of tumors that remain inert and asymptomatic may be relatively high. Overall PanNETs are thought to account for about 1 to 2% of all pancreatic tumors. The definition and classification of PanNETs has changed over time, affecting what is known about their epidemiology and clinical relevance.
The earliest recognition of pancreatic cancer has been attributed to the 18th-century Italian scientist Giovanni Battista Morgagni, the historical father of modern-day anatomic pathology, who claimed to have traced several cases of cancer in the pancreas. Many 18th and 19th-century physicians were skeptical about the existence of the disease, given the similar appearance of pancreatitis. Some case reports were published in the 1820s and 1830s, and a genuine histopathologic diagnosis was eventually recorded by the American clinician Jacob Mendes Da Costa, who also doubted the reliability of Morgagni's interpretations. By the start of the 20th century, cancer of the head of the pancreas had become a well-established diagnosis.
Regarding the history of the recognition of PanNETs, the possibility of cancer of the islet cells was initially suggested in 1888. The first case of hyperinsulinism due to a tumor of this type was reported in 1927. Recognition of a non-insulin-secreting type of PanNET is generally ascribed to the American surgeons, R.M. Zollinger and E. H. Ellison, who gave their names to Zollinger–Ellison syndrome, after postulating the existence of a gastrin-secreting pancreatic tumor in a report of two cases of unusually severe peptic ulcers published in 1955. In 2010, the WHO recommended that PanNETs be referred to as "neuroendocrine" rather than "endocrine" tumors.
The first reported partial pancreaticoduodenectomy was performed by the Italian surgeon Alessandro Codivilla in 1898, but the patient only survived 18 days before succumbing to complications. Early operations were compromised partly because of mistaken beliefs that it was essential for life to preserve the duodenum and, at first, the flow of pancreatic juices. Later it was thought, also mistakenly, that the pancreatic duct could simply be tied up without serious adverse effects; in fact it will very often leak later on. In 1907-08, after some more unsuccessful operations by other surgeons, experimental procedures were tried on corpses by French surgeons.
In 1912 the German surgeon Walther Kausch was the first to remove large parts of the duodenum and pancreas together (en bloc). This was in Breslau, now Wrocław in Poland. In 1918 it was demonstrated in operations on dogs that total removal of the duodenum is compatible with life, but this was not reported in human surgery until 1935, when the American surgeon Allen Oldfather Whipple published the results of a series of three operations at Columbia Presbyterian Hospital in New York. Only one of the patients had the duodenum totally removed, but he survived for two years before dying of metastasis to the liver. The first operation was unplanned, as cancer was only discovered in the operating theatre. Whipple's success showed the way for the future, but the operation remained a difficult and dangerous one until recent decades. He published several refinements to his procedure, including the first total removal of the duodenum in 1940, but he only performed a total of 37 operations.
The discovery in the late 1930s that vitamin K prevented bleeding with jaundice, and the development of blood transfusion as an everyday process, both improved post-operative survival, but about 25% of people never left hospital alive as late as the 1970s. In the 1970s a group of American surgeons wrote urging that the procedure was too dangerous and should be abandoned. Since then outcomes in larger centers have improved considerably, and mortality from the operation is often less than 4%. In 2006 a report was published of a series of 1,000 consecutive pancreaticoduodenectomies performed by a single surgeon from Johns Hopkins Hospital between 1969 and 2003. The rate of these operations had increased steadily over this period, with only three of them before 1980, and the median operating time reduced from 8.8 hours in the 1970s to 5.5 hours in the 2000s, and mortality within 30 days or in hospital was only 1%. Another series of 2050 operations at the Massachusetts General Hospital between 1941 and 2011 showed a similar picture of improvement.
Small precancerous neoplasms for many pancreatic cancers are being detected at greatly increased rates by modern medical imaging. One type, the intraductal papillary mucinous neoplasm (IPMN) was first described by Japanese researchers in 1982; "For the next decade, little attention was paid to this report; however, over the subsequent 15 years, there has been a virtual explosion in the recognition of this tumor."
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 role played by genes, in particular 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 themselves. Others aim to target cancer stem cells or the tissue surrounding the pancreatic tumor (the stroma or microenvironment). A third research approach uses immunotherapy, such as using oncolytic viruses.
- Gastrointestinal cancer
- Pancreatic Cancer Action (organization in the UK)
- Lustgarten Foundation for Pancreatic Cancer Research (organization in the US)
- "What is Cancer? Defining Cancer". National Cancer Institute. National Institutes of Health. 7 March 2014. Retrieved 5 December 2014.
- Seufferlein, T; Bachet, JB; Van Cutsem, E; Rougier, P (October 2012). "Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 23 Suppl 7: vii33–40. doi:10.1093/annonc/mds224. PMID 22997452.
- "Pancreatic Cancer Treatment (PDQ®) Patient Version". National Cancer Institute. National Institutes of Health. 17 April 2014. Retrieved 8 June 2014.
- Bond-Smith G, Banga N, Hammond TM, Imber CJ (2012). "Pancreatic adenocarcinoma". BMJ (Clinical research ed.) 344: e2476. doi:10.1136/bmj.e2476. PMID 22592847.
- World Cancer Report 2014. World Health Organization. 2014. Chapter 5.7. ISBN 92-832-0429-8.
- Ryan DP, Hong TS, Bardeesy N (September 2014). "Pancreatic adenocarcinoma". N. Engl. J. Med. 371 (11): 1039–49. doi:10.1056/NEJMra1404198. PMID 25207767.
- Wolfgang CL, Herman JM, Laheru DA, et al. (September 2013). "Recent progress in pancreatic cancer". CA: a Cancer Journal for Clinicians 63 (5): 318–48. doi:10.3322/caac.21190. PMC 3769458. PMID 23856911.
- Bussom S, Saif MW (5 March 2010). "Methods and rationale for the early detection of pancreatic cancer. Highlights from the "2010 ASCO Gastrointestinal Cancers Symposium". Orlando, FL, USA. January 22–24, 2010". JOP : Journal of the pancreas 11 (2): 128–30. PMID 20208319.
- "Can pancreatic cancer be prevented?". American Cancer Society. 11 June 2014. Retrieved 13 November 2014.
- Shahrokni A, Saif MW (10 July 2013). "Metastatic pancreatic cancer: the dilemma of quality vs. quantity of life". JOP : Journal of the pancreas 14 (4): 391–4. doi:10.6092/1590-8577/1663. PMID 23846935.
- Bardou M, Le Ray I (December 2013). "Treatment of pancreatic cancer: A narrative review of cost-effectiveness studies". Best practice & research. Clinical gastroenterology 27 (6): 881–92. doi:10.1016/j.bpg.2013.09.006. PMID 24182608.
- Hariharan D, Saied A, Kocher, HM (2008). "Analysis of mortality rates for pancreatic cancer across the world". HPB 10 (1): 58–62. doi:10.1080/13651820701883148. PMC 2504856. PMID 18695761.
- "Lifetime Risk of Developing or Dying From Cancer". American Cancer Society. 1 October 2014. Retrieved 1 December 2014. The top three vary by gender, and include breast cancer for women and prostate cancer for men.
- "Cancer Facts & Figures 2010" (PDF). American Cancer Society. 2010. Retrieved 5 December 2014. See p. 4 for incidence estimates, and p. 19 for survival percentages.
- "Pancreatic Cancer Treatment (PDQ®) Health Professional Version". National Cancer Institute. National Institutes of Health. 21 February 2014. Retrieved 24 November 2014. "The highest cure rate occurs if the tumor is truly localized to the pancreas; however, this stage of disease accounts for less than 20% of cases. In cases with localized disease and small cancers (<2 cm) with no lymph node metastases and no extension beyond the capsule of the pancreas, complete surgical resection is associated with an actuarial five-year survival rate of 18% to 24%."
- Öberg K, Knigge U, Kwekkeboom D, Perren A (ESMO Guidelines Working Group) (October 2012). "Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 23 Suppl 7: vii124–30. doi:10.1093/annonc/mds295. PMID 22997445.
- Govindan R (2011). DeVita, Hellman, and Rosenberg's Cancer: Cancer: Principles & Practice of Oncology (9th ed.). Lippincott Williams & Wilkins. Chapter 35: Cancer of the Pancreas: Surgical Management. ISBN 978-1-4511-0545-2. Online edition, with updates to 2014
- Tobias JS, Hochhauser D (2010). Cancer and its Management (6th ed.). pp. 276–7. ISBN 978-1-1187-1325-9.
- "Types of Pancreas Tumors". The Sol Goldman Pancreas Cancer Research Center. Johns Hopkins Medicine. 2012. Retrieved 18 November 2014.
- Farrell JJ, Fernández-del Castillo C (June 2013). "Pancreatic cystic neoplasms: management and unanswered questions". Gastroenterology 144 (6): 1303–15. doi:10.1053/j.gastro.2013.01.073. PMID 23622140.
- The PanNET denomination is in line with WHO guidelines for the classification of tumors of the digestive system  published in 2010. Historically, PanNETs have also been referred to by a variety of terms, and are still commonly called "pancreatic endocrine tumors". See: Klimstra DS, Modlin IR, Coppola D, et al (August 2010). "The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems". Pancreas 39 (6): 707–12. doi:10.1097/MPA.0b013e3181ec124e. PMID 20664470.
- Burns WR, Edil BH (March 2012). "Neuroendocrine pancreatic tumors: guidelines for management and update". Current treatment options in oncology 13 (1): 24–34. doi:10.1007/s11864-011-0172-2. PMID 22198808.
- The Medical Subject Headings indexing system refers to "islet cell carcinoma", which is subdivided into gastrinoma, glucagonoma, somatostatinoma and VIPoma. See: 2014 MeSH tree at "Pancreatic Neoplasms [C04.588.322.475]" 16 October 2014
- Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (August 2011). "Pancreatic cancer". Lancet 378 (9791): 607–20. doi:10.1016/S0140-6736(10)62307-0. PMID 21620466.
- De La Cruz MS, Young AP, Ruffin MT (April 2014). "Diagnosis and management of pancreatic cancer". Am Fam Physician 89 (8): 626–32. PMID 24784121.
- Pannala R, Basu A, Petersen GM, Chari ST (January 2009). "New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer". The Lancet. Oncology 10 (1): 88–95. doi:10.1016/S1470-2045(08)70337-1. PMC 2795483. PMID 19111249.
- "Chapter 15; Pancreas". Manual for Staging of Cancer (2nd ed.). American Joint Committee on Cancer. pp. 95–8. See page 95 for citation regarding "... lesser degree of involvement of bones and brain and other anatomical sites."
- Sperti C, Moletta L, Patanè G (15 October 2014). "Metastatic tumors to the pancreas: The role of surgery". World journal of gastrointestinal oncology 6 (10): 381–92. PMID 25320654.
- "Causes of pancreatic cancer". NHS Choices. National Health Service, England. 7 October 2014. Retrieved 5 December 2014.
- Bosetti C, Lucenteforte E, Silverman DT, et al (July 2012). "Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4)". Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 23 (7): 1880–8. doi:10.1093/annonc/mdr541. PMID 22104574.
- Reznik R, Hendifar AE, Tuli R (2014). "Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma". Front Physiol 5: 87. doi:10.3389/fphys.2014.00087. PMC 3939680. PMID 24624093.
- Greenhalf W, Grocock C, Harcus M, Neoptolemos J (2009). "Screening of high-risk families for pancreatic cancer". Pancreatology 9 (3): 215–22. doi:10.1159/000210262. PMID 19349734.
- Larsson SC, Wolk A (January 2012). "Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies". Br J Cancer. Online first (3): 603–7. doi:10.1038/bjc.2011.585. PMC 3273353. PMID 22240790.
- "Alcohol and Cancer – Alcohol Alert No. 21-1993" (Press release). National Institute on Alcohol Abuse and Alcoholism. July 1993. Retrieved 5 December 2014.
- Villeneuve PJ, Johnson KC, Hanley AJ, Mao Y (February 2000). "Alcohol, tobacco and coffee consumption and the risk of pancreatic cancer: results from the Canadian Enhanced Surveillance System case-control project. Canadian Cancer Registries Epidemiology Research Group". European Journal of Cancer Prevention 9 (1): 49–58. doi:10.1097/00008469-200002000-00007. PMID 10777010.
- "Pancreatic cancer risks and causes". Cancer Research UK. 17 June 2014. Retrieved 5 December 2014.
- Fitzgerald JE, White MJ, Lobo DN (April 2009). "Courvoisier's gallbladder: law or sign?". World Journal of Surgery 33 (4): 886–91. doi:10.1007/s00268-008-9908-y. PMID 19190960.
- Cascinu S, Falconi M, Valentini V, et al. (May 2010). "Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO. 21 Suppl 5: v55–8. doi:10.1093/annonc/mdq165. PMID 20555103.
- "Pancreatic cancer survival by stage". American Cancer Society. 11 June 2014. Retrieved 29 September 2014.
- Silberman, editors, Howard Silberman, Allan W.; Nakeeb, Attila; Lillemoe, Keith D. (2010). Principles and practice of surgical oncology : multidisciplinary approach to difficult problems (online ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. Chapter 35. ISBN 978-0-7817-6546-6.
- Öberg K, Knigge U, Kwekkeboom D, Perren A (October 2012). "Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO. 23 Suppl 7: vii124–30. doi:10.1093/annonc/mds295. PMID 22997445. (Table 5 outlines the proposed TNM staging system for PanNETs.)
- Delpu Y, Hanoun N, Lulka H, et al (2011). "Genetic and epigenetic alterations in pancreatic carcinogenesis". Curr Genomics 12 (1): 15–24. doi:10.2174/138920211794520132. PMC 3129039. PMID 21886451.
- Lewis MA, Yao JC (2014). "Molecular pathology and genetics of gastrointestinal neuroendocrine tumours". Current Opinion in Endocrinology & Diabetes and Obesity 21 (1): 22–7. doi:10.1097/MED.0000000000000033. PMID 24310147.
- "Diet and activity factors that affect risks for certain cancers: Pancreatic cancer section". American Cancer Society. 20 August 2012. Retrieved 4 November 2014.
- He XY, Yuan YZ (August 2014). "Advances in pancreatic cancer research: moving towards early detection". World J. Gastroenterol. 20 (32): 11241–8. doi:10.3748/wjg.v20.i32.11241. PMC 4145762. PMID 25170208.
- Okano K, Suzuki Y (August 2014). "Strategies for early detection of resectable pancreatic cancer". World J. Gastroenterol. 20 (32): 11230–40. doi:10.3748/wjg.v20.i32.11230. PMC 4145761. PMID 25170207.
- Stoita, A; Penman, ID; Williams, DB (May 2011). "Review of screening for pancreatic cancer in high risk individuals". World J. Gastroenterol. 17 (19): 2365–71. doi:10.3748/wjg.v17.i19.2365. PMC 3103788. PMID 21633635.
- Gurusamy, K. S.; Kumar, S; Davidson, B. R.; Fusai, G (2014). "Cochrane Database of Systematic Reviews". The Cochrane database of systematic reviews 2: CD010244.doi:10.1002/14651858.CD010244.pub2.PMID 24578248.
- Mollberg, N; Rahbari, NN; Koch, M; et al (2011). "Arterial resection during pancreatectomy for pancreatic cancer: A systematic review and meta-analysis". Annals of Surgery 6: 882–93. doi:10.1097/SLA.0b013e31823ac299. PMID 22064622.
- "Pancreatic adenocarcinoma. NCCN Guidelines Version 1.2015". NCCN Guidelines. National Comprehensive Cancer Network, Inc. December 4, 2014. Retrieved December 26, 2014.
- Alamo, J. M.; Marín, L. M.; Suarez, G; Bernal, C; Serrano, J; Barrera, L; Gómez, M. A.; Muntané, J; Padillo, F. J. (2014). "Improving outcomes in pancreatic cancer: Key points in perioperative management". World Journal of Gastroenterology 20 (39): 14237–45.doi:10.3748/wjg.v20.i39.14237. PMC 4202352.PMID 25339810
- Lopez, N. E.; Prendergast, C; Lowy, A. M. (2014)."Borderline resectable pancreatic cancer: Definitions and management". World Journal of Gastroenterology 20 (31): 10740–51. doi:10.3748/wjg.v20.i31.10740.PMC 4138454. PMID 25152577
- Heinemann, V; Haas, M; Boeck, S (2013). "Neoadjuvant treatment of borderline resectable and non-resectable pancreatic cancer". Annals of Oncology 24 (10): 2484–92. doi:10.1093/annonc/mdt239. PMID 23852311.
- Polistina, F; Di Natale, G; Bonciarelli, G; Ambrosino, G; Frego, M (2014). "Neoadjuvant strategies for pancreatic cancer". World journal of gastroenterology : WJG 20 (28): 9374–83. doi:10.3748/wjg.v20.i28.9374 (inactive 2014-12-26). PMC 4110569. PMID 25071332
- Gillen, S; Schuster, T; Meyer Zum Büschenfelde, C; Friess, H; Kleeff, J (2010). "Preoperative/neoadjuvant therapy in pancreatic cancer: A systematic review and meta-analysis of response and resection percentages". PLoS Medicine 7 (4): e1000267. doi:10.1371/journal.pmed.1000267.PMC 2857873. PMID 20422030
- Christians, K. K.; Evans, D. B. (2014). "Additional Support for Neoadjuvant Therapy in the Management of Pancreatic Cancer". Annals of Surgical Oncology. doi:10.1245/s10434-014-4307-0. PMID 25519932
- Tsvetkova, E. V.; Asmis, T. R. (2014). "Role of neoadjuvant therapy in the management of pancreatic cancer: Is the era of biomarker-directed therapy here?". Current Oncology 21(4): e650–7. doi:10.3747/co.21.2006. PMC 4117630.PMID 25089113
- Zhan, H. X.; Xu, J. W.; Wu, D; Zhang, T. P.; Hu, S. Y. (2014). "Pancreatic cancer stem cells: New insight into a stubborn disease". Cancer Letters. doi:10.1016/j.canlet.2014.12.004. PMID 25499079
- Tanase, C. P.; Neagu, A. I.; Necula, L. G.; Mambet, C; Enciu, A. M.; Calenic, B; Cruceru, M. L.; Albulescu, R (2014). "Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics". World Journal of Gastroenterology 20 (31): 10790–801. doi:10.3748/wjg.v20.i31.10790. PMC 4138459. PMID 25152582.
- Allen, VB; Gurusamy, KS; Takwoingi, Y; Kalia, A; Davidson, BR (2013). "Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer". Cochrane Database Syst Rev 11: CD009323. doi:10.1002/14651858.CD009323.pub2. PMID 24272022.
- Thota, R; Pauff, JM; Berlin, JD (January 2014). "Treatment of metastatic pancreatic adenocarcinoma: a review". Oncology (Williston Park, N.Y.) 28 (1): 70–4. PMID 24683721.
- Ryan, DP (8 July 2014). "Chemotherapy for advanced exocrine pancreatic cancer: Topic 2475, Version 46.0" (subscription required). UpToDate. Wolters Kluwer Health. Retrieved 18 November 2014.
- "Cancer Drug Information: FDA Approval for Erlotinib Hydrochloride". National Cancer Institute. National Institutes of Health. 3 July 2013. Retrieved 5 December 2014.
- Borazanci, E; Von Hoff, DD (September 2014). "Nab-paclitaxel and gemcitabine for the treatment of people with metastatic pancreatic cancer". Expert Rev Gastroenterol Hepatol 8 (7): 739–47. doi:10.1586/17474124.2014.925799. PMID 24882381.
- Falconi, M; Bartsch, DK; Eriksson, B; Barcelona Consensus Conference participants (2012). "ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: Well-differentiated pancreatic non-functioning tumors". Neuroendocrinology 95 (2): 120–34. doi:10.1159/000335587. PMID 22261872.
- Jensen, RT; Cadiot, G; Brandi, ML et al; Barcelona Consensus Conference participants (2012). "ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: Functional pancreatic endocrine tumor syndromes". Neuroendocrinology 95 (2): 98–119. doi:10.1159/000335591. PMC 3701449. PMID 22261919.
- Pavel, M; Baudin, E; Couvelard, A; Barcelona Consensus Conference participants (2012). "ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary". Neuroendocrinology 95 (2): 157–76. doi:10.1159/000335597. PMID 22262022.
- "Neuroendocrine tumors, NCCN Guidelines Version 1.2015". NCCN Guidelines. National Comprehensive Cancer Network, Inc. November 11, 2014. Retrieved December 25, 2014.
- Rossi, RE; Massironi, S; Conte, D; Peracchi, M (2014). "Therapy for metastatic pancreatic neuroendocrine tumors". Annals of Translational Medicine 2 (1): 8. doi:10.3978/j.issn.2305-5839.2013.03.01. PMID 25332984.
- Nick Mulcahy (December 17, 2014). "FDA Approves Lanreotide for Neuroendocrine Tumors". Medscape Medical News. WebMD LLC. Retrieved December 25, 2014.
- Everolimus Approved for Pancreatic Neuroendocrine Tumors. The ASCO Post. May 15, 2011, Volume 2, Issue 8 http://ascopost.com/articles/may-15-2011/everolimus-approved-for-pancreatic-neuroendocrine-tumors/
- National Cancer Institute. Cancer Drug Information. FDA Approval for Sunitinib Malate. Pancreatic Neuroendocrine Tumors http://www.cancer.gov/cancertopics/druginfo/fda-sunitinib-malate
- Tejani MA, Saif MW (2014). "Pancreatic neuroendocrine tumors: Does chemotherapy work?". JOP: Journal of the pancreas 15 (2): 132–4. doi:10.6092/1590-8577/2301. PMID 24618436.
- Text is available electronically (but may require free registration) See: Benson AB, Myerson RJ, Sasson AR. "Pancreatic, neuroendocrine GI, and adrenal cancers. Cancer Management: A Multidisciplinary Approach 13th edition 2010.". ISBN 978-0-615-41824-7.
- Gulenchyn, KY; Yao, X; Asa; SL; Singh, S; Law, C (2012). "Radionuclide therapy in neuroendocrine tumours: A systematic review". Clinical Oncology 24 (4): 294–308. doi:10.1016/j.clon.2011.12.003. PMID 22221516.
- Vinik, AI (2014). "Advances in Diagnosis and Treatment of Pancreatic Neuroendocrine Tumors (PNETS)". Endocrine Practice 20 (11): 1–23. doi:10.4158/EP14373.RA. PMID 25297671.
- Kwekkeboom, DJ; De Herder, WW; Van Eijck, CH (2010). "Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors". Seminars in Nuclear Medicine 40 (2): 78–88. doi:10.1053/j.semnuclmed.2009.10.004. PMID 20113677.
- Bodei, L; Cremonesi, M; Kidd, M; Grana, CM; Severi, S; Modlin, IM; Paganelli, G (2014). "Peptide receptor radionuclide therapy for advanced neuroendocrine tumors". Thoracic Surgery Clinics 24 (3): 333–49. doi:10.1016/j.thorsurg.2014.04.005. PMID 25065935.
- Castellano D, Grande E, Valle J, et al (2014). "Expert consensus for the management of advanced or metastatic pancreatic neuroendocrine and carcinoid tumors". Cancer Chemotherapy and Pharmacology. doi:10.1007/s00280-014-2642-2. PMID 25480314.
- Singh S, Dey C, Kennecke H, et al (2014). "Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group". Annals of Surgical Oncology. doi:10.1245/s10434-014-4145-0. PMID 25366583.
- "Palliative or Supportive Care". American Cancer Society. 2014. Retrieved 20 August 2014.
- Buanes TA (14 August 2014). "Pancreatic cancer-improved care achievable". World journal of gastroenterology : WJG 20 (30): 10405–18. doi:10.3748/wjg.v20.i30.10405. PMID 25132756.
- "If treatment for pancreatic cancer stops working". American Cancer Society. 11 June 2014. Retrieved 20 August 2014.
- Arcidiacono PG, Calori G, Carrara S, et al (2011). Arcidiacono, Paolo G, ed. "Celiac plexus block for pancreatic cancer pain in adults". Cochrane Database Syst Rev (3): CD007519. doi:10.1002/14651858.CD007519.pub2. PMID 21412903.
- "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved 11 November 2009.
- Lozano R, Naghavi M, Foreman K, et al (December 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- Jemal A, Siegel R, Ward E, et al (2007). "Cancer statistics, 2007". CA 57 (1): 43–66. doi:10.3322/canjclin.57.1.43. PMID 17237035.
- "What are the key statistics about pancreatic cancer?". American Cancer Society. 11 June 2014. Retrieved 11 November 2014.
- "Pancreatic cancer statistics". Cancer Research UK. Retrieved 18 December 2014.; "In 2010, in the UK, the lifetime risk of developing pancreatic cancer is 1 in 73 for men and 1 in 74 for women", noting "The lifetime risk ... has been calculated ... using the 'Current Probability' method; this is a different method used from most other cancer sites since the possibility of having more than one diagnosis of pancreatic cancer over the course of their lifetime is very low"
- "Pancreatic cancer statistics". Cancer Research UK. Retrieved 28 October 2014.
- Busnardo AC, DiDio LJ, Tidrick RT, et al (1983). "History of the pancreas". American Journal of Surgery 146 (5): 539–50. doi:10.1016/0002-9610(83)90286-6. PMID 6356946.
- Are C, Dhir M, Ravipati L (June 2011). "History of pancreaticoduodenectomy: early misconceptions, initial milestones and the pioneers". HPB : the official journal of the International Hepato Pancreato Biliary Association 13 (6): 377–84. doi:10.1111/j.1477-2574.2011.00305.x. PMID 21609369.
- Cameron JL, Riall, TS, Coleman J, Belcher KA (July 2006). "One thousand consecutive pancreaticoduodenectomies". Annals of surgery 244 (1): 10–5. doi:10.1097/01.sla.0000217673.04165.ea. PMID 16794383.
- Fernández-del Castillo C, Morales-Oyarvide V, McGrath D, et al. (September 2012). "Evolution of the Whipple procedure at the Massachusetts General Hospital". Surgery 152 (3 Suppl 1): S56–63. doi:10.1016/j.surg.2012.05.022. PMC 3806095. PMID 22770961.
- Wolpin BM, Stampfer MJ (July 2009). "Defining determinants of pancreatic cancer risk: are we making progress?". J. Natl. Cancer Inst. 101 (14): 972–3. doi:10.1093/jnci/djp182. PMID 19561317.
- "What's new in pancreatic cancer research and treatment?". American Cancer Society. 11 June 2014. Retrieved 17 July 2014.
- "Pancreatic cancer research". Cancer Research UK. Retrieved 17 July 2014.
- "Australian Pancreatic Genome Initiative". Garvan Institute. Retrieved 17 July 2014.
- Biankin AV, Waddell N, Kassahn KS, et al (November 2012). "Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes". Nature 491 (7424): 399–405. doi:10.1038/nature11547. PMC 3530898. PMID 23103869.
- Pannala R, Basu A, Petersen GM, Chari ST (January 2009). "New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer". Lancet Oncol. 10 (1): 88–95. doi:10.1016/S1470-2045(08)70337-1. PMC 2795483. PMID 19111249.
- Graham JS, Jamieson NB, Rulach R, et al (November 2014). "Pancreatic cancer genomics: where can the science take us?". Clin. Genet. doi:10.1111/cge.12536. PMID 25388820.
- "About EUROPAC". European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). University of Liverpool. Retrieved 17 July 2014.
- Subar D, Gobardhan PD, Gayet B. "Laparoscopic pancreatic surgery". Best Practice & Research Clinical Gastroenterology 28 (1): 123–32. doi:10.1016/j.bpg.2013.11.011.
- Weiss J, Wolfgang CL. "Irreversible electroporation: a novel pancreatic cancer therapy". Current problems in cancer 37 (5): 262–5. PMID 24331180.
- Moir J, White SA, French JJ, et al (December 2014). "Systematic review of irreversible electroporation in the treatment of advanced pancreatic cancer". European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 40 (12): 1598–1604. PMID 25307210.
- Al Haddad AH, Adrian TE (November 2014). "Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma". Expert Opin Investig Drugs 23 (11): 1499–515. doi:10.1517/13543784.2014.933206. PMID 25078674.
- Kleger A, Perkhofer L, Seufferlein T (July 2014). "Smarter drugs emerging in pancreatic cancer therapy". Ann. Oncol. 25 (7): 1260–70. doi:10.1093/annonc/mdu013. PMID 24631947.
- Tang, S. C.; Chen, Y. C. (2014). "Novel therapeutic targets for pancreatic cancer". World Journal of Gastroenterology 20 (31): 10825–44. doi:10.3748/wjg.v20.i31.10825. PMC 4138462. PMID 25152585.
- Schober, M; Jesenofsky, R; Faissner, R; Weidenauer, C; Hagmann, W; Michl, P; Heuchel, R. L.; Haas, S. L.; Löhr, J. M. (2014). "Desmoplasia and chemoresistance in pancreatic cancer". Cancers 6 (4): 2137–54.doi:10.3390/cancers6042137. PMID 25337831
- Rossi, M. L.; Rehman, A. A.; Gondi, C. S. (2014). "Therapeutic options for the management of pancreatic cancer". World Journal of Gastroenterology 20 (32): 11142–59.doi:10.3748/wjg.v20.i32.11142. PMC 4145755. PMID 25170201
- Neesse A, Krug S, Gress TM, et al (2013). "Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma". Onco Targets Ther 7: 33–43. doi:10.2147/OTT.S38111. PMC 3872146. PMID 24379681.
- Heinemann V, Reni M, Ychou M, et al (February 2014). "Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies". Cancer Treat. Rev. 40 (1): 118–28. doi:10.1016/j.ctrv.2013.04.004. PMID 23849556.
- Fong Y, Ady J, Heffner J, Klein E. "Oncolytic viral therapy for pancreatic cancer: current research and future directions". Oncolytic Virotherapy: 35. doi:10.2147/OV.S53858.
- Pavelic J (October 2014). "Editorial: combined cancer therapy". Curr. Pharm. Des. 20 (42): 6511–2. PMID 25341927.
|Wikimedia Commons has media related to Pancreatic cancer.|