Pancreatic cancer

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Pancreatic cancer
Classification and external resources
Illu pancrease.svg
ICD-10 C25
ICD-9 157
OMIM 260350
DiseasesDB 9510
MedlinePlus 000236
eMedicine med/1712
MeSH D010190

Pancreatic cancer arises when there is uncontrolled growth of the cells that make up the pancreas – a glandular organ located behind the stomach. These cancer cells have the ability to invade or spread to other parts of the body.[1] There are a number of different types of pancreatic cancer, but pancreatic adenocarcinoma accounts for about 85% of cases.[2] References to pancreatic cancer often refer only to that type. Adenocarcinomas start within the part of the pancreas that makes digestive enzymes, known as the exocrine pancreas. One to two in every hundred cases are neuroendocrine tumors, and arise from the hormone-producing islet cells in the pancreas. 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. However, there are usually no symptoms in the disease's early stages, and symptoms that are specific enough to suspect pancreatic cancer typically do not start until the disease is already in an advanced stage.[3] By the time of diagnosis the cancer has often spread to other parts of the body.[4][5]

Pancreatic cancer is rare in those younger than 40, and more than half of cases occur in people over the age of 70.[6] The disease is more common among people who smoke, are obese, have diabetes, or who have certain rare genetic conditions.[6] About 25% of cases are linked to tobacco smoking,[7] while 5–10% are linked to inherited genes.[6] Pancreatic cancer is usually diagnosed by a combination of medical imaging (such as ultrasound and computed tomography), blood tests (such as CEA and CA 19-9) and examination of tissue samples (biopsy).[3] This allows the disease to be divided into stages, from early (stage I) to late (stage IV).[4] Screening the general population has not been found to be effective.[8]

To prevent pancreatic cancer, maintaining a healthy weight and limiting one's consumption of red and processed meat is recommended.[9] 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.[5] The disease can be treated with surgery, radiotherapy, chemotherapy, or a combination of these. Recommendations are partly based on the cancer stage. Surgery is the only treatment that can cure the disease, but may also be done to try to improve quality of life without trying to cure.[3] Pain management and medications to improve digestion are sometimes needed.[4] Early palliative care is recommended even in those who are receiving treatment that aims for a cure.[10][11]

In 2012 pancreatic cancers of all types caused 330,000 deaths globally, the 7th most common cause of deaths due to cancer.[5] In the United States it is the 4th most common cause of deaths due to cancer.[12] The disease occurs more often in the developed world, which had about 70% of new cases in 2012.[5] Pancreatic adenocarcinoma typically has poor outcomes: after diagnosis, 25% survive one year and only 5% live five years,[5][13] although for cancers diagnosed early this rises around 20%.[14] Neuroendocrine cancers have better outcomes. After 5 years, 65% of people are living, though survival varies considerably depending on the tumor type.[5]

Classification[edit]

The many different types of cancer that can affect the pancreas can be divided into two groups. The vast majority of cases (about 99%) occur in the exocrine component of the pancreas that produces digestive enzymes. There are several types of these, but their diagnosis and treatment have much in common. Most of the remaining 1% or so of pancreatic cancers arise in the endocrine (i.e. hormone-producing) tissue of the pancreas, and often have different symptoms and treatment from those of the exocrine types, although surgery offers the only possibility of curing both groups. Both groups mainly (but not exclusively) occur in people over 40, and are slightly more common in men, but some rare sub-types mainly occur in women or children.[15] For all types the only curative treatment is surgery, and for most sub-types the outcomes are typically poor.

Exocrine[edit]

The exocrine group is dominated by pancreatic adenocarcinoma ("invasive" and "ductal" may be added to this term), which is by far the most common type, representing about 85% of all pancreatic cancers,[6] although the pancreatic ductal epithelium from which it arises represents less than 10% of the pancreas by cell volume.[16] This cancer arises in the tiny 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 "functioning" endocrine cancers (see next section), 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.[17] 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.[6][18]

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.[19]

Endocrine[edit]

Further information: Neuroendocrine tumor

The small minority of tumors that arise from elsewhere in the pancreas are mainly pancreatic neuroendocrine tumors (called PanNETs or PNETs).[20] Neuroendocrine tumors ("NETs") are a diverse group of benign or malignant tumors that all arise from neuroendocrine cells (i.e. cells 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.[21] 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 only diagnosed after the cancer has spread to other parts of the body.[22]

As with other neuroendocrine tumors, the history of the terminology and classification of PanNETs is complex.[20] 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.[22][23]

Signs and symptoms[edit]

Diagram showing anatomy and functions of the pancreas.
The pancreas and some surrounding structures (duodenum, aorta, spleen, bile duct) showing important structural features, as well as some physiological functions. (Histology of pancreatic islet in zoom window.)
The pancreas produces a number of enzymes involved in digestion, as well as several hormones (from pancreatic islets) involved in regulation of digestion and metabolism. Pancreatic cancer may lead to loss of any of these functions.

Since early pancreatic cancer usually does not cause recognizable symptoms, the disease is typically not diagnosed until it has spread beyond the pancreas itself.[24] 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.

Common symptoms of pancreatic adenocarcinoma occurring before diagnosis, bearing in mind that the disease is rarely diagnosed before the age of 40, 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 forwards.[25] 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, or both. Up to two-thirds of people have abdominal pain, 46% accompanied by jaundice, with 13% having jaundice without pain.[4]
  • Painless jaundice (a yellow tint to the whites of the eyes or skin, possibly in combination with darkened urine) when a cancer of the head of the pancreas obstructs the common bile duct as it runs through the pancreas.[26]
  • Unexplained weight loss, either from loss of appetite, or loss of exocrine function resulting in poor digestion.[4]
  • The tumor may compress neighbouring organs, disrupting digestive processes and making it difficult for the stomach to empty, which may cause nausea and a feeling of fullness. As the undigested fat completes its journey, people describe bad smelling stools that float and are difficult to flush away.[4]
  • At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis.[6] While long-standing diabetes is a known risk factor for pancreatic cancer (see below), the cancer can itself cause diabetes, in which case recent onset of diabetes could be considered an early sign of the disease.[27] (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.[4])

Other signs and symptoms[edit]

  • 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.[7]
  • 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 may be there before the cancer is diagnosed, and is perhaps caused by the cancer. But the mechanism for this association is not known.[4][7]

Metastasis[edit]

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;[7] it uncommonly metastasizes to bone or brain.[28]

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, and kidney cancer is by far the most common cancer to spread to the pancreas, followed by colorectal cancer, and those 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.[29]

Risk factors[edit]

Risk factors for pancreatic adenocarcinoma include:[4][5][6][30]

  • Age, gender and race. The risk of developing pancreatic cancer increases with age. Most cases occur after age 65,[5] 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.[5]
  • Cigarette smoking is the best established avoidable risk factor for pancreatic cancer, approximately doubling risk among long-term smokers, with 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.[31]
  • Obesity; a BMI greater than 35 is associated with a roughly 1.5-fold increase in relative risk.[4]
  • Family history: 5–10% of pancreatic cancer cases have an inherited component, where people have a family history of pancreatic cancer.[6] Most of the genes involved have not been identified.[6][32] Hereditary pancreatitis gives a greatly increased lifetime risk of pancreatic cancer, of 30–40% to the age of 70.[7] Screening for early pancreatic cancer may be offered to individuals with hereditary pancreatitis on a research basis.[33] Some people may choose to have their pancreas surgically removed to prevent cancer developing in the future.[7]

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), familial adenomatous polyposis, multiple endocrine neoplasia type 1.[6][7][24]

  • A clinical history of 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.[7] The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.[7][32]
  • Diabetes mellitus is a risk factor for pancreatic cancer (and, as noted above, new-onset diabetes may also be an early sign of the disease). People who have been diagnosed with Type 2 diabetes for longer than 10 years may have a 1.5-fold increase in risk, as compared with non-diabetics.[7]
  • Evidence for specific dietary factors is poor (though see the sections on obesity and alcohol).[6][34] Some studies have found links with diets high in red meat, processed meat,[34] and sugar-sweetened drinks (soft drinks).[35]

Alcohol[edit]

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.[36][37] 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.[38]

Diagnosis[edit]

The head, body and tail of the pancreas
Axial CT image with i.v. contrast. Macrocystic adenocarcinoma of the pancreatic head.

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 (going 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.[6] 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.[26]

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.

Patients 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 is the presence of jaundice with a painlessly swollen gallbladder and is strongly indicative of pancreatic cancer. It can be used to distinguish 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).[4] Magnetic resonance imaging and positron emission tomography may also be used,[6] and magnetic resonance cholangiopancreatography may be useful in some cases.[26] Abdominal ultrasound is less sensitive and will miss small tumors, but can identify metastisis to the liver and the build-up of fluid in the peritoneal cavity (ascites).[4] It may be used for a quick and cheap first examination before other techniques.[2]

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.[4] Pancreatic cancer is usually staged using a CT scan.

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.[4][6]

The most common form of pancreatic cancer (ductal 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).[6] It is thought that this prevents many chemotherapy drugs from reaching the tumor, as one factor making the cancer especially hard to treat.[7] Pancreatic cancer has an immunohistochemical profile that is similar to hepatobiliary cancers (e.g. 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.

Staging[edit]

The cancer staging system used internationally for pancreatic cancer is that of the American Joint Committee on Cancer and Union for International Cancer Control, referred to as AJCC-UICC. The staging system makes an important distinction within Stage II 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 for the latter. These are T3 and T4 respectively in the associated TNM staging system,[7] which builds up an overall stage by assessing the Tumor size, spread to lymph Nodes and Metastasis. Stage T1 is localized tumors less than 2cm 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. A simpler practical classification groups the tumors as "resectable", "borderline resectable", and "unresectable" because of locally advanced or metastatic disease.[39]

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.[40]

Mechanism[edit]

Micrograph of pancreatic ductal adenocarcinoma (the most common type of pancreatic cancer). H&E stain.

Exocrine pancreas cancers[edit]

Micrographs of normal pancreas, pancreatic intraepithelial neoplasia (precursors to pancreatic carcinoma) and pancreatic carcinoma. H&E stain.

These cancers are thought to arise from several types of precancerous cysts (cystic lesions) within the pancreas. But by no means 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.[7]

Three types of precancerous lesion are recognized, in addition to pancreatic serous cystadenomas (SCNs), which are almost always benign.

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 all grades carry a faulty KRAS gene, while in grades 2 and 3 damage to three further genes – CDKN2A, p53 and SMAD4 (the so-called "Mothers against decapentaplegic homolog 4") are increasingly often found.[6]

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.[6] Even if removed surgically, there remains is a considerably increased risk of pancreatic cancer developing subsequently.[7]

The last type, pancreatic mucinous cystic neoplasms (MCNs) mainly occur in women, and may remain benign or progess to cancer.[41] If they become large or cause symptoms they can usually be successfully removed by surgery.[7]

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.[7] SWI/SNF mutations/deletions occur in 35% of tumors.[42][43] The genetic alterations in several other types of pancreatic cancer and precancerous lesions have also been researched.[7]

Cross section of a human liver, taken at autopsy examination, showing multiple large pale tumor deposits. The tumor is an adenocarcinoma derived from a primary lesion in the body of the pancreas.

Pancreatic neuroendocrine tumors[edit]

The genes often found mutated in PanNETs are typically a different set from those in pancreatic adenocarcinoma, and for example KRAS mutation is normally absent. Instead, common mutations affect MEN1, as in the inherited Wermer's syndrome, DAXX, mTOR and ATRX.[22]

Prevention[edit]

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.[44]

Taking a daily low-dose aspirin regimen for more than five years may decrease the risk of developing pancreatic adenocarcinoma (ductal pancreatic cancer) by as much as 75%.[45]

Screening[edit]

In the general population, screening of large groups is not effective, although newer techniques are being evaluated.[46][47] However, regular screening with endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics.[2][24][47][48]

Management[edit]

Exocrine cancer[edit]

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 will require a tumor that has not spread, and will then depend on the location of the tumor. In particular the tumor will be examined through CT to see how it relates to the major blood vessels passing close to the pancreas. An 'abutment' of the tumor is defined as the tumor touching up to 180° of a blood vessel's circumference, and may be operable, but 'encasement', defined as more 180° engaged, is not. The general health of the people must also be assessed, though age in itself is not an obstacle to surgery.[7]

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.[6][7]

Surgery[edit]

Anatomy of parts removed with Whipple's operation

Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases.[4] Although CT scans help, it can be difficult to determine whether the tumor can be fully removed (it's 'resectability'), and can become apparent during surgery that it is not possible to successfully remove the tumor without damaging other vital tissues. Even when the operation appears to have been successful, cancerous cells can sometimes be 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, and will continue to develop.[6]

How the pancreas and bowel are joined back together after a Whipple's operation

A diagnostic laparoscopy can be performed to enable a much clearer idea of the outcome of a full operation.[49] 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.[4]

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.[6][7] This is today often done using keyhole or laparoscopic surgery.[6][7]

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.[7]

After surgery, adjuvant chemotherapy with gemcitabine or 5-FU should be offered if the person is sufficiently fit.[2] Adjuvant radiotherapy has been controversial since the 1980s,[7] and the European Society for Medical Oncology recommends that this should only be used for people in clinical trials.[2] However, it is more likely to be used in the USA.[24] Some surgical procedures that may be used in palliative care are discussed in that section.

Radiotherapy[edit]

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.[6][7]

Chemotherapy[edit]

In people not suitable for curative surgery, palliative chemotherapy may be used to improve quality of life and extend life. 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.[50] This was the first chemotherapy drug approved by the FDA primarily for a nonsurvival clinical trial endpoint.[51] Gemcitabine is administered intravenously on a weekly basis.

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.[52] 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 this purpose.[53] By the end of 2013, both FOLFIRINOX and nab-paclitaxel were regarded as good choices for those able to tolerate the side-effects, with gemcitabine remaining 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 average survival times by a few months.[50]

Neuroendocrine tumors[edit]

Main article: Neuroendocrine tumor

Treatment of pancreatic endocrine tumors, including the less common malignant tumors, may include a number of approaches. Watchful waiting of small tumors identified incidentally, for example on a computed tomography (CT) scan performed for other purposes, may not ultimately need treatment, but the criteria for watchful waiting are unclear.

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.[15] 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.[22]

Standard cytotoxic chemotherapy is generally not very effective for PanNETs, but may be used when other drug treatments fail to prevent the disease progressing.[22] If the tumor is not amenable to surgical removal and is causing symptoms by secreting functional hormones, targeted medication for PanNETs can be effective, both in reducing symptoms and slowing the progression of the disease. These are covered in more detail in the relevant section of the main article on neuroendocrine tumors.

For functioning tumors, a class of drugs called somatostatin analogs are effective in reducing the excessive production of hormones and the associated problems.[15] One of these, octreotide, is often used to lessen the symptoms, and sometimes also slows tumor growth. Everolimus and sunitinib are both licensed for such cases, and trials are exploring their combination with octreotide.[16][22]

Radiation therapy is occasionally used if there is pain due to anatomic extension, such as metastasis to bone. Radiolabeled hormone: some PanNETs absorb a hormone called norepinephrine and these may respond to nuclear medicine medication, radiolabeled MIBG therapy (or, experimentally, other hormones), given intravenously. Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also be used.

Palliative care[edit]

Palliative care is medical care which focuses on treatment of symptoms from serious illness, like cancer, and improving quality of life.[54] 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.[55]

Palliative care focuses not on treating the underlying cancer, but on treating symptoms such as pain or nausea, and can assist in decision making such as when or if hospice care will be beneficial.[56] Pain can be managed with medications such as opioids or through procedural intervention such as 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.[7][57] Other symptoms/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.[26] Palliative care can also help treat depression that often comes with diagnosis of pancreatic cancer.[7]

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.[4] Difficulty in emptying the stomach (delayed gastric emptying) is common and can be a serious problem, involving time in hospital. 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.[4]

Outcomes[edit]

Outcomes in pancreatic cancers according to clinical stage[39]
Clinical stage Five-year survival (%) – U.S., diagnoses 1992–98
Exocrine pancreatic cancer Neuroendocrine treated with surgery
IA / I 14 61
IB 12
IIA / II 7 52
IIB 5
III 3 41
IV 1 16

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.[6] Outcomes with pancreatic endocrine tumors, many of which are benign and completely without clinical symptoms, are much better, and even those cases not able to be treated by surgery have a 5-year survival rate of 16%,[39] although the outlook greatly varies according to the type.

For locally advanced and metastatic pancreatic adenocarcinoma, which together represent over 80%[14] of cases, numerous recent trials comparing chemotherapy regimes have shown increased average survival rates, but not to above one year.[6][50] 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 5-year survival has improved from 2% in cases diagnosed in 1975–77, and 4% in 1987–89 diagnoses, to 6% in 2002–08.[14]

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, this is Stage T1), approximately 20% of American people survive to five years.[58]

Distribution[edit]

Age-standardized death from pancreatic cancer per 100,000 inhabitants in 2004.[59]
  no data
  <1
  1
  2
  3
  4
  5
  6
  7
  8
  9
  10
  >10

Globally, as of 2012, pancreatic cancer resulted in 330,000 deaths,[5] up from 310,000 in 2010 and 200,000 in 1990.[60] 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.[6] Pancreatic cancer has one of the highest fatality rates of all cancers, and is the fourth-highest cancer killer among both men and women worldwide.[61] Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.[62]

Incidence rates vary greatly, with those in the developed world generally being higher. Americans have an average lifetime risk of about 1/67 (or 1.5%) of developing the disease,[63] slightly higher than the figure for the UK.[64] The disease is more common in men than women,[5][6] 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, like 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 of incidence.[5]

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).[65]

PanNETs[edit]

The annual clinically recognized incidence of PanNETs is low (about five per one million person-years).[18] However, PanNETs can be found incidentally in up to 1.5% of autopsies, and most of these tumors would be likely to remain inert and asymptomatic.[66] A problem with these figures is that the majority of PanNETs are usually categorized as benign, but the definition and recognition of malignancy in pancreas endocrine tumors has been ambiguous.[67][68][69] A small subset of endocrine pancreatic tumors are incontrovertible pancreatic endocrine cancers, that make up about 1% of pancreas cancers.[18][70] Definitional migration has caused some complexity of PanNET classification,[70] which has adversely affected what is known about the epidemiology and natural history of these tumors.[70]

The non-functioning types of PanNET are variously estimated in recent clinical guidelines to form either up to 90% of PanNETs,[22] or alternatively 45–60%.[15]

History[edit]

The first reported partial pancreaticoduodenectomy was performed by the Italian surgeon Alessandro Codivilla in 1898, but the person 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 burst under pressure from the juices later on. In the 1900s, after some more unsuccessful operations by other surgeons, experimental procedures were tried on corpses by French surgeons.[71]

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 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.[71]

The discovery of vitamin K in 1940 and the development of blood transfusion as an everyday process both improved post-operative survival,[71] but about 25% of people never left hospital alive as late as the 1970s.[72] 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%.[16] In 2006 a series of One Thousand Consecutive Pancreaticoduodenectomies by a single surgeon from Johns Hopkins Hospital was published, performed 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%.[72] Another series of 2050 operations at the Massachusetts General Hospital between 1941 and 2011 showed a similar picture of improvement.[73]

As described above, the very 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".[40]

Research[edit]

Worldwide efforts are under way to understand pancreatic cancer on many levels, but progress has been slow, particularly into understanding the disease's causes.[74] There are several fundamental unanswered questions.[75][76]

The nature of the changes that lead to the disease are being intensely scrutinized, such as the role played by genes such as KRAS and p53.[32][77][78] A key question is the timing of events as the disease develops and progresses – particularly the role of diabetes,[79] and how and when the disease spreads (metastasizes).[80]

Research on early detection is ongoing.[46][47] For example 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.[81] 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.[79]

Another area of interest is in assessing whether keyhole surgery (laparoscopy) would be better than Whipple’s procedure (pancreaticoduodenectomy) in treating the disease surgically, particularly in terms of recovery time.[82] 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.[6]

Efforts are underway to develop new drugs.[32][83] Some of these involve targeted therapies against the cancer cells themselves.[84] Others aim to target the tissue surrounding the pancreatic tumor (the stroma or microenvironment).[83][85][86] A third research approach uses immunotherapy, such as using oncolytic viruses.[87][88]

See also[edit]


References[edit]

  1. ^ "Defining Cancer". National Cancer Institute. Retrieved 10 June 2014. 
  2. ^ a b c d e Seufferlein, T; Bachet, JB; Van Cutsem, E; Rougier, P; ESMO Guidelines Working, Group (Oct 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. 
  3. ^ a b c "Pancreatic Cancer Treatment (PDQ®) Patient Version". National Cancer Institute. 2014-04-17. Retrieved 8 June 2014. 
  4. ^ a b c d e f g h i j k l m n o p q r Bond-Smith, G; Banga, N; Hammond, TM; Imber, CJ (16 May 2012). "Pancreatic adenocarcinoma.". BMJ (Clinical research ed.) 344: e2476. doi:10.1136/bmj.e2476. PMID 22592847. 
  5. ^ a b c d e f g h i j k l World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 5.7. ISBN 9283204298. 
  6. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Ryan DP, Hong TS, Bardeesy N (September 2014). "Pancreatic adenocarcinoma". N. Engl. J. Med. 371 (11): 1039–49. doi:10.1056/NEJMra1404198. PMID 25207767. 
  7. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z 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. 
  8. ^ Bussom S, Saif MW (5 Mar 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. 
  9. ^ "Can pancreatic cancer be prevented?". American Cancer Society. Retrieved 13 November 2014. 
  10. ^ 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. PMID 23846935. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ "American Cancer Society: Cancer Facts & Figures 2010: see page 4 for incidence estimates, and page 19 for survival percentages". 
  14. ^ a b c "Pancreatic Cancer Treatment (PDQ®) Health Professional Version". NCI. 2014-02-21. Retrieved 24 November 2014. 
  15. ^ a b c d 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. 
  16. ^ a b c "35: Cancer of the Pancreas: Surgical Management". DeVita, Hellman, and Rosenberg's Cancer: Cancer: Principles & Practice of Oncology (9th ed.). Lippincott Williams & Wilkins. 2011. ISBN 9781451105452.  Online edition, with updates to 2014
  17. ^ Tobias Jeffrey S., Hochhauser, Daniel, Cancer and its Management, p. 276, 2010 (6th edn), ISBN 1118713257, 9781118713259
  18. ^ a b c Johns Hopkins Medicine; The Sol Goldman Pancreas Cancer Research Center, Types of Pancreas Tumors, accessed 18 November 2014
  19. ^ Farrell, JJ; Fernández-del Castillo, C (Jun 2013). "Pancreatic cystic neoplasms: management and unanswered questions.". Gastroenterology 144 (6): 1303–15. doi:10.1053/j.gastro.2013.01.073. PMID 23622140. 
  20. ^ a b The PanNET denomination is in line with current WHO guidelines. 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, Lloyd RV, Suster S (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. 
  21. ^ "Pancreatic neuroendocrine neoplasms (pNENs)". rarediseases.org - Rare Disease Database. National Organization for Rare Disorders. 28 January 2014. Retrieved 22 November 2014. 
  22. ^ a b c d e f g 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. 
  23. ^ 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
  24. ^ a b c d Vincent, A; Herman, J; Schulick, R; Hruban, RH; Goggins, M (13 Aug 2011). "Pancreatic cancer.". Lancet 378 (9791): 607–20. doi:10.1016/S0140-6736(10)62307-0. PMID 21620466. 
  25. ^ Tobias Jeffrey S., Hochhauser, Daniel, Cancer and its Management, 2010 (6th edn), pp. 276–277, ISBN 1118713257, 9781118713259
  26. ^ a b c d De La Cruz, MS; Young, AP; Ruffin, MT (15 April 2014). "Diagnosis and management of pancreatic cancer.". American family physician 89 (8): 626–32. PMID 24784121. 
  27. ^ 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. 
  28. ^ AJCC Cancer Staging Manual 2nd edition; Chapter 15; Pancreas – original pages 95–98; page 95 for citation regarding "...lesser degree of involvement of bones and brain and other anatomical sites." https://cancerstaging.org/references-tools/deskreferences/Documents/AJCC2ndEdCancerStagingManual.pdf
  29. ^ 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. 
  30. ^ "Causes of pancreatic cancer". NHS Choices. National Health Service, England. Retrieved 9 June 2014. 
  31. ^ Bosetti, C; Lucenteforte, E; Silverman, DT; et al. (Jul 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. 
  32. ^ a b c d Reznik, R; Hendifar, A. E.; Tuli, R (2014). "Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma". Frontiers in Physiology 5: 87.doi:10.3389/fphys.2014.00087. PMC 3939680. PMID 24624093
  33. ^ 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. 
  34. ^ a b 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. 
  35. ^ Cuomo, R; Andreozzi, P; Zito, FP (2014). "Alcoholic beverages and carbonated soft drinks: consumption and gastrointestinal cancer risks.". Cancer treatment and research 159: 97–120. doi:10.1007/978-3-642-38007-5_7. PMID 24114477. 
  36. ^ National Institute on Alcohol Abuse and Alcoholism Alcohol and Cancer – Alcohol Alert No. 21-1993
  37. ^ 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. 
  38. ^ Cancer Research UK Pancreatic cancer risks and causes
  39. ^ a b c "Pancreatic cancer survival by stage". American Cancer Society. Retrieved 29 September 2014. 
  40. ^ a b 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. p. Chapter 35. ISBN 978-0781765466. 
  41. ^ Delpu Y, Hanoun N, Lulka H, Sicard F, Selves J, Buscail L, Torrisani J, Cordelier P (2011). "Genetic and epigenetic alterations in pancreatic carcinogenesis". Curr Genomics 12 (1): 15–24. doi:10.2174/138920211794520132. PMC 3129039. PMID 21886451. 
  42. ^ Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M, Maitra A, Pollack JR (31 January 2012). "Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer". Proceedings of the National Academy of Sciences of the United States of America 109 (5): E252–9. doi:10.1073/pnas.1114817109. PMC 3277150. PMID 22233809. 
  43. ^ Jones S, Zhang X, Parsons DW, et al. (26 September 2008). "Core signaling pathways in human pancreatic cancers revealed by global genomic analyses". Science 321 (5897): 1801–6. doi:10.1126/science.1164368. PMC 2848990. PMID 18772397. 
  44. ^ "Diet and activity factors that affect risks for certain cancers: Pancreatic cancer section". American Cancer Society. Retrieved 4 November 2014. 
  45. ^ Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (Jan 2011). "Effect of daily aspirin on long term risk of death due to cancer: analysis of individual patient data from randomised trials". Lancet 337 (9759): 31–41. doi:10.1016/S0140-6736(10)62110-1. PMID 21144578. 
  46. ^ a b He, X. Y.; Yuan, Y. Z. (2014). "Advances in pancreatic cancer research: Moving towards early detection". World Journal of Gastroenterology 20 (32): 11241–8.doi:10.3748/wjg.v20.i32.11241. PMC 4145762. PMID 25170208
  47. ^ a b c Okano, K.; Suzuki, Y. Strategies for early detection of resectable pancreatic cancer. World J Gastroenterol. 2014 Aug 28;20(32):11230-40. doi: 10.3748/wjg.v20.i32.11230. PMID 25170207
  48. ^ Stoita, A; Penman, ID; Williams, DB (21 May 2011). "Review of screening for pancreatic cancer in high risk individuals.". World journal of gastroenterology : WJG 17 (19): 2365–71. doi:10.3748/wjg.v17.i19.2365. PMC 3103788. PMID 21633635. Retrieved 18 July 2014. 
  49. ^ Allen, VB; Gurusamy, KS; Takwoingi, Y; Kalia, A; Davidson, BR (25 November 2013). "Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer.". The Cochrane database of systematic reviews 11: CD009323. doi:10.1002/14651858.CD009323.pub2. PMID 24272022. 
  50. ^ a b c Thota, R; Pauff, JM; Berlin, JD (Jan 2014). "Treatment of metastatic pancreatic adenocarcinoma: a review.". Oncology (Williston Park, N.Y.) 28 (1): 70–4. PMID 24683721. 
  51. ^ Ryan, D.P. Chemotherapy for advanced exocrine pancreatic cancer. UpToDate. Review current through October 2014: Topic 2475, Version 46.0
  52. ^ National Cancer Institute. FDA Approval for Erlotinib Hydrochloride
  53. ^ Borazanci, E; von Hoff, D. D. (2014). "Nab-paclitaxel and gemcitabine for the treatment of patients with metastatic pancreatic cancer". Expert Review of Gastroenterology & Hepatology 8 (7): 739–47.doi:10.1586/17474124.2014.925799. PMID 24882381
  54. ^ "Palliative or Supportive Care". American Cancer Society. Retrieved 20 August 2014. 
  55. ^ Buanes, TA (14 August 2014). "Pancreatic cancer-improved care achievable.". World journal of gastroenterology : WJG 20 (30): 10405–10418. doi:10.3748/wjg.v20.i30.10405. PMID 25132756. 
  56. ^ "If treatment for pancreatic cancer stops working". American Cancer Society. Retrieved 20 August 2014. 
  57. ^ Arcidiacono PG, Calori G, Carrara S, McNicol ED, Testoni PA (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. 
  58. ^ "Pancreatic Cancer Treatment (PDQ®) Health Professional Version". NCI. 2014-02-21. 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. For patients 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 5-year survival rate of 18% to 24%"
  59. ^ "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved Nov 11, 2009. 
  60. ^ Lozano R, et al. (15 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. 
  61. ^ "Pancreatic Cancer — National Cancer Institute, U.S. National Institutes of Health (Accessed 28 April 2011)". Cancer.gov. Retrieved 2009-09-15. 
  62. ^ Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007). "Cancer statistics, 2007". CA 57 (1): 43–66. doi:10.3322/canjclin.57.1.43. PMID 17237035. 
  63. ^ "What are the key statistics about pancreatic cancer?". American Cancer Society. Retrieved 11 November 2014. 
  64. ^ "Pancreatic cancer statistics". Cancer Research UK. Retrieved 28 October 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 over the course of their lifetime is very low"
  65. ^ "Pancreatic cancer statistics". Cancer Research UK. Retrieved 28 October 2014. 
  66. ^ Benson AB, Myerson RJ, and Sasson AR. Pancreatic, Neuroendocrine GI, and Adrenal Cancers. Cancer Management 13th edition. http://www.cancernetwork.com/cancer-management/pancreatic/article/10165/1802606
  67. ^ "The prognosis of patients with PENs is difficult to predict, in part because the definition of malignancy in PENs has been ambiguous. By some, PENs have been defined as malignant only when lymph nodes are involved or liver metastases are documented. Other investigators have included vascular invasion or invasion of adjacent structures as evidence of malignancy. However, the concept that a PEN removed successfully without recurrence was therefore biologically benign could be challenged. In fact, strict separation of PENs into benign and malignant groups may be less clinically useful than the definition of prognostic factors."Hochwald SN, Zee S, Conlon KC, Colleoni R, Louie O, Brennan MF, Klimstra DS (2002). "Prognostic Factors in Pancreatic Endocrine Neoplasms: An Analysis of 136 Cases with a Proposal for Low-Grade and Intermediate-Grade Groups". Journal of Clinical Oncology 20 (11): 2633–2642. doi:10.1200/JCO.2002.10.030. PMID 12039924. 
  68. ^ "One of the most controversial aspects of PENs has been the prediction of prognosis."Klimstra DS (2007). "Nonductal neoplasms of the pancreas". Modern Pathology 20: S94–S112. doi:10.1038/modpathol.3800686. PMID 17486055. 
  69. ^ "The classification of these tumors remains controversial, and prognosis is difficult to predict" Wendy L. Frankel (2006) Update on Pancreatic Endocrine Tumors. Archives of Pathology & Laboratory Medicine: July 2006, Vol. 130, No. 7, pp. 963–966. http://www.archivesofpathology.org/doi/full/10.1043/1543-2165(2006)130[963:UOPET]2.0.CO;2
  70. ^ a b c Yao JC, Eisner MP, Leary C, Dagohoy C, Phan A, Rashid A, Hassan M, Evans DB (2007). "Population-Based Study of Islet Cell Carcinoma". Annals of Surgical Oncology 14 (12): 3492–3500. doi:10.1245/s10434-007-9566-6. PMC 2077912. PMID 17896148. 
  71. ^ a b c 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. 
  72. ^ a b 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. 
  73. ^ Fernández-del Castillo, C; Morales-Oyarvide, V; McGrath, D; Wargo, JA; Ferrone, CR; Thayer, SP; Lillemoe, KD; Warshaw, 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. PMID 22770961. 
  74. ^ Wolpin, B. M.; Stampfer, M. J. (26 June 2009). "Defining Determinants of Pancreatic Cancer Risk: Are We Making Progress?". JNCI Journal of the National Cancer Institute 101 (14): 972–973. doi:10.1093/jnci/djp182. 
  75. ^ "What’s new in pancreatic cancer research and treatment?". American Cancer Society. Retrieved 17 July 2014. 
  76. ^ "Pancreatic cancer research". Cancer Research UK. Retrieved 17 July 2014. 
  77. ^ "Australian Pancreatic Genome Initiative". Retrieved 17 July 2014. 
  78. ^ Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; et al. (24 October 2012). "Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes". Nature 491 (7424): 399–405. doi:10.1038/nature11547. 
  79. ^ a b 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. PMID 19111249. 
  80. ^ Graham, J. S.; Jamieson, N. B.; Rulach, R; Grimmond, S. M.; Chang, D. K.; Biankin, A. V. (2014). "Pancreatic cancer genomics: Where can the science take us?". Clinical Genetics: n/a. doi:10.1111/cge.12536.PMID 25388820
  81. ^ "European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) website". Retrieved 17 July 2014. 
  82. ^ Subar, D.; Gobardhan, P.D.; Gayet, B. "Laparoscopic pancreatic surgery". Best Practice & Research Clinical Gastroenterology 28 (1): 123–132. doi:10.1016/j.bpg.2013.11.011. 
  83. ^ a b Al Haddad, A. H.; Adrian, T. E. (2014). "Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma". Expert Opinion on Investigational Drugs 23(11): 1499–515. doi:10.1517/13543784.2014.933206. PMID 25078674
  84. ^ Kleger, A; Perkhofer, L; Seufferlein, T (2014). "Smarter drugs emerging in pancreatic cancer therapy". Annals of Oncology 25 (7): 1260–70. doi:10.1093/annonc/mdu013. PMID 24631947
  85. ^ Neesse, Albrecht; Gress, Thomas M.; Tuveson, David A.; Michl, Patrick; Krug, Sebastian. "Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma". OncoTargets and Therapy: 33. doi:10.2147/OTT.S38111. 
  86. ^ Heinemann, V; Reni, M; Ychou, M; et al. (2014). "Tumour-stroma interactions in pancreatic ductal adenocarcinoma: Rationale and current evidence for new therapeutic strategies". Cancer Treatment Reviews 40 (1): 118–28. doi:10.1016/j.ctrv.2013.04.004. PMID 23849556
  87. ^ Fong, Yuman; Ady, Justin; Heffner, Jacqueline; Klein, Elizabeth. "Oncolytic viral therapy for pancreatic cancer: current research and future directions". Oncolytic Virotherapy: 35. doi:10.2147/OV.S53858. 
  88. ^ Pavelic, J (2014). "Editorial: Combined cancer therapy". Current Pharmaceutical Design 20 (42): 6511–2. PMID 25341927

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