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Wiki CRUK John/Pancreatic cancer (version g)
SpecialtyOncology

Pancreatic cancer arises when

ability to invade other parts of the body.[1] There are a number of types of pancreatic cancer. The most common, pancreatic adenocarcinoma, accounts for about 85% of cases, and the term "pancreatic cancer" is sometimes used to refer only to that type. These adenocarcinomas start within the part of the pancreas which 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 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.[2] By the time of diagnosis, pancreatic cancer has often spread to other parts of the body.[3][4]

Pancreatic cancer rarely occurs before the age of 40, and more than half of cases of pancreatic adenocarcinoma occur in those over 70.

computed tomography, blood tests, and examination of tissue samples (biopsy).[5][6] The disease is divided into stages, from early (stage I) to late (stage IV).[3] Screening the general population has not been found to be effective.[7]

The risk of developing pancreatic cancer is lower among non-smokers, and people who maintain a healthy weight and limit their consumption of red or processed meat.[8] A smoker's chance of developing the disease decreases if they stop smoking, and almost returns to that of the rest of the population after 20 years.[4] 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.[9] Pain management and medications to improve digestion are sometimes needed.[3] Early palliative care is recommended even for those receiving treatment that aims for a cure.[10][11]

In 2012, pancreatic cancers of all types were the seventh most common cause of cancer deaths, resulting in 330,000 deaths globally.[4] In the United States, pancreatic cancer is the fourth most common cause of deaths due to cancer.[12][13] The disease occurs most often in the developed world, where about 70% of the new cases in 2012 originated.[4] Pancreatic adenocarcinoma typically has a very poor prognosis: after diagnosis, 25% of people survive one year and 5% live for five years.[4][14] For cancers diagnosed early, the five-year survival rate rises to about 20%.[15] 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.[4]

Types

acinar cells
. Pancreatic cancer may arise from any of these and disrupt any of their functions.

The many types of pancreatic cancer can be divided into two general groups. The vast majority of cases (about 99%) occur in the part of the pancreas which produces

endocrine) tissue of the pancreas have different clinical characteristics. 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.[16][17]

Exocrine cancers

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.[2] This is despite the fact that the tissue from which it arises - the pancreatic ductal epithelium - represents less than 10% of the pancreas by cell volume.[18] This cancer originates in the ducts that carry certain hormones and enzymes away from the pancreas. About 60–70% of adenocarcinomas occur in the 'head' of the pancreas (see diagram, right).[2]

The next most common type, acinar cell carcinoma of the pancreas, arises in the clusters of cells that produce these enzymes, and represents 5% of exocrine pancreas cancers. Like the 'functioning' endocrine cancers described below, acinar cell carcinomas may cause over-production of certain molecules, in this case digestive enzymes, which may cause symptoms such as skin rashes and joint pain.

Cystadenocarcinomas account for 1% of pancreatic cancers, and they have a better prognosis than the other exocrine types.[19]

Solid pseudopapillary tumor is a rare low-grade neoplasm that mainly affects younger women, and generally has a very good prognosis.[2][20]

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, given that many are benign.[21]

Neuroendocrine

Main article: Pancreatic neuroendocrine tumor

The small minority of tumors that arise elsewhere in the pancreas are mainly pancreatic

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.[23]

As with other neuroendocrine tumors, the history of the terminology and classification of PanNETs is complex.

islet cells as previously thought.[23]

Signs and symptoms

Jaundice can be a symptom, due to biliary obstruction from a pancreatic tumor

Since pancreatic cancer usually does not cause recognizable symptoms in its early stages, the disease is typically not diagnosed until it has spread beyond the pancreas itself.[6] This is one of the main reasons for the generally poor survival rates. Exceptions to this are the functioning PanNETs, where over-production of various active hormones can give rise to symptoms (which depend on the type of hormone).[25]

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.[19] 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.[3]
  • Jaundice, a yellow tint to the whites of the eyes or skin, with or without pain, and possibly in combination with darkened urine. This results when a cancer in the head of the pancreas obstructs the common bile duct as it runs through the pancreas.[26]
  • poor digestion.[3]
  • 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.[3] Constipation is common.[27]
  • At least 50% of people with pancreatic adenocarcinoma have
    diabetes at the time of diagnosis.[2] 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.[28] 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.[3]

Other findings

  • 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.[5]
  • 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.[5]

Other common manifestations of the disease include: weakness and tiring easily; dry mouth; sleep problems; and a palpable abdominal mass."[27]

Symptoms of spread (metastasis)

Cross section of a human liver, at autopsy, showing multiple large pale tumor deposits, that are secondary tumors derived from pancreatic cancer

The spread of pancreatic cancer to other organs (

metastasis) may also cause symptoms. Typically, pancreatic adenocarcinoma first spreads to nearby lymph nodes, and later to the liver or to the peritoneal cavity, large intestine or lungs.[5] It is uncommon for it to spread to the bones or brain.[29]

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 then cancers of the skin, breast, and lung. Surgery may be performed on the pancreas in such cases, whether in hope of a cure or to alleviate symptoms.[30]

Risk factors

Risk factors for pancreatic adenocarcinoma include:[2][3][4][31]

  • Age, gender, and race; the risk of developing pancreatic cancer increases with age. Most cases occur after age 65,
    African Americans, though incidence in Africa is low.[4]
  • 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 almost that of non-smokers.[32]
  • Obesity; a BMI greater than 35 increases relative risk by about half.[3]
  • Family history; 5–10% of pancreatic cancer cases have an inherited component, where people have a family history of pancreatic cancer.
    lifetime risk of pancreatic cancer of 30–40% to the age of 70.[5] Screening for early pancreatic cancer may be offered to individuals with hereditary pancreatitis on a research basis.[34] Some people may choose to have their pancreas surgically removed to prevent cancer developing in the future.[5]
Pancreatic cancer has been associated with the following other rare hereditary syndromes:
von Hippel Lindau syndromes.[2][5][6]
  • Chronic pancreatitis appears to almost triple risk, and as with diabetes, new-onset pancreatitis may be a symptom of a tumor.[5] The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.[5][33]
  • Diabetes mellitus is a risk factor for pancreatic cancer and (as noted in the Signs and symptoms section) 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 50% increased risk, as compared with non-diabetics.[5]
  • Specific types of food (as distinct from obesity) have not been clearly shown to increase the risk of pancreatic cancer.[2] Dietary factors for which there is some evidence of slightly increased risk include processed meat, red meat, and meat cooked at very high temperatures (e.g. by frying, broiling or barbecuing).[35][36]

Alcohol

Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer. However, considerable research has failed to firmly establish alcohol consumption as a direct risk factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have found no association, with smoking a strong confounding factor. The evidence is stronger for a link with heavy drinking, of at least six drinks per day.[5][37]

Diagnosis

The head, body and tail of the pancreas. The stomach is faded out in this image to show the entire pancreas, of which the body and tail lie behind the stomach, and the neck partially behind.
Axial CT image with i.v. contrast and added color. Cross lines towards top left surround a macrocystic adenocarcinoma of the pancreatic head.

The symptoms of pancreatic adenocarcinoma do not usually appear in the disease's early stages, and are individually not distinctive to the disease.[3][5][26] The symptoms at diagnosis vary according to the location of the cancer in 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.

Regardless of a tumour's location, the most common symptom is unexplained weight loss, which may be considerable. A large minority (between 35% and 47%) of people diagnosed with the disease will have had nausea, vomiting or a feeling of weakness.

Tumors in the head of the pancreas typically also cause jaundice, pain, loss of appetite, dark urine, and light-colored stools. Tumors in the body and tail typically also cause pain.[26]

People sometimes have recent onset of atypical type 2 diabetes that is difficult to control, a history of recent but unexplained blood vessel inflammation caused by blood clots (thrombophlebitis) known as Trousseau sign, or a previous attack of pancreatitis.[26] A doctor may suspect pancreatic cancer when the onset of diabetes in someone over 50-years-old is accompanied by typical symptoms such as unexplained weight loss, persistent abdominal or back pain, indigestion, vomiting, or fatty feces.[3] Jaundice accompanied by a painlessly swollen gallbladder (known as Courvoisier's sign) may also raise suspicion, and can help differentiate pancreatic cancer from gallstones.[38]

Abdominal ultrasound is less sensitive and will miss small tumors, but can identify cancers that have spread to the liver and build-up of fluid in the peritoneal cavity (ascites).[3] It may be used for a quick and cheap first examination before other techniques.[39]

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.[3]

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.[2][3]

The most common form of pancreatic cancer (adenocarcinoma) is typically characterized by moderately to

stroma or structural tissue consisting of a range of cell types (including myofibroblasts, macrophages, lymphocytes and mast cells) and deposited material (such as type I collagen and hyaluronic acid). This creates a tumor microenvironment that is short of blood vessels (hypovascular) and so of oxygen (tumor hypoxia).[2] It is thought that this prevents many chemotherapy drugs from reaching the tumor, as one factor making the cancer especially hard to treat.[2][5]

Staging

Exocrine cancers

Pancreatic cancer is usually staged following a CT scan.[26] The most widely used cancer staging system for pancreatic cancer is the one formulated by the American Joint Committee on Cancer (AJCC) together with the Union for International Cancer Control (UICC). The AJCC-UICC staging system designates four main overall stages, ranging from early to advanced disease, based on TNM classification of Tumor size, spread to lymph Nodes, and Metastasis.[40]

To help decide treatment, the tumors are also divided into three broader categories based on whether surgical removal seems possible: in this way, tumors are judged to be "resectable", "borderline resectable", or "unresectable".

celiac axis and superior mesenteric artery are still free) and those that are "unresectable" (due to more locally advanced disease); in terms of the more detailed TNM classification, these two groups correspond to T3 and T4 respectively.[5]
Pancreatic cancer metastasized – stage M1

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 (stage IV disease) are the liver, peritoneal cavity and lungs, all of which occur in 50% or more of fully advanced cases.[42]

PanNETs

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").[17] The U.S. National Comprehensive Cancer Network recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma.[43]: 52  Using this scheme, the stage-by-stage outcomes for PanNETs are dissimilar to those of the exocrine cancers.[44] A different TNM system for PanNETs has been proposed by the European Neuroendocrine Tumor Society.[17]

Precursors

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

Exocrine cancers

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 lesions within the pancreas. But these lesions do not always 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.[5] Apart from pancreatic serous cystadenomas
(SCNs), which are almost always benign, three types of precancerous lesion are recognized.

The first is pancreatic

SMAD4 – are increasingly often found.[2]

Secondly, intraductal papillary mucinous neoplasms (IPMNs) are macroscopic lesions, which occur in about 2% of all adults, rising to about 10% by age 70, and have about a 25% risk of developing into invasive cancer. 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.[2] Even if removed surgically, there remains a considerably increased risk of pancreatic cancer developing subsequently.[5]

The last type, pancreatic mucinous cystic neoplasms (MCNs) mainly occur in women, and may remain benign or progress to cancer.[45] If they become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery.[5]

The genetic events found in ductal adenocarcinoma have been well characterized, and complete

TP53 (75%), and SMAD4 (55%). The last of these are especially associated with a poor prognosis.[5] SWI/SNF mutations/deletions occur in about 10−15% of the adenocarcinomas.[2] The genetic alterations in several other types of pancreatic cancer and precancerous lesions have also been researched.[5]

PanNETs

The genes often found mutated in PanNETs are different from those in pancreatic adenocarcinoma.

DAXX, mTOR and ATRX.[23]

Prevention and screening

Apart from not smoking, the

citrus fruits and curcumin reduced risk of pancreatic cancer, while whole grains, folate, selenium, and non-fried fish possibly also had a beneficial effect.[37]

In the general population, screening of large groups is not currently considered effective, although newer techniques, and the screening of tightly targeted groups, are being evaluated.[49][50] Nevertheless, regular screening with endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics.[6][39][50][51]

Management

Exocrine cancer

A key assessment that is made after diagnosis is whether surgical removal of the tumor is possible (see Staging), as this is the only cure for this cancer. Whether or not surgical resection can be offered depends on how much the cancer has spread. The exact location of the tumor is also a significant factor, and CT can show 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.[5]

Chemotherapy and, to a lesser extent, radiotherapy are likely to be offered to most people, whether or not surgery is possible. Specialists advise that the 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.[2][5]

Surgery

Parts of the body removed in Whipple's operation

Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases.[3] Although CT scans help, in practice 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. Whether or not surgical resection can be offered depends on various factors, including the precise extent of local anatomical adjacency to, or involvement of, the venous or arterial blood vessels,[2] as well as surgical expertise and a careful consideration of projected post-operative recovery.[52][53] The age of the person is not in itself a reason not to operate, but their general performance status needs to be adequate for a major operation.[3]

One particular feature that is looked is the encouraging presence, or discouraging absence, of a clear layer or plane of fat giving a barrier between the tumor and the vessels.[5] Traditionally, an assessment is made of the tumor's proximity to major venous or arterial vessels, in terms of "abutment" (defined as the tumor touching no more than half a blood vessel's circumference without any fat to separate it), "encasement" (when the tumor encloses most of the vessel's circumference), or full vessel involvement.[54]: 22  A resection that includes encased sections of blood vessels may be possible in some cases,[55][56] particularly if preliminary neoadjuvant therapy is feasible,[57][58][59] using chemotherapy[53][54]: 36 [60] and/or radiotherapy.[54]: 29–30 

Even when the operation appears to have been successful, cancerous cells are often found around the edges ("

cancer stem cells are usually not evident microscopically, and if they are present they may continue to develop and spread.[61][62] An exploratory laparoscopy (a small, camera-guided surgical procedure) may therefore be performed to gain a clearer idea of the outcome of a full operation.[63]

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

For cancers involving the head of the pancreas, the

minimally invasive surgery.[2][5]

Although curative surgery no longer entails the very high death rates that occurred until the 1980s, a high proportion of people (about 30–45%) still have to be treated for post-operative sickness that is not caused by the cancer itself. The most common complication of surgery is difficulty in emptying the stomach.[5] Certain more limited surgical procedures may also be used to ease symptoms (see Palliative care). For instance, 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.[3]

Chemotherapy

After surgery,

neoadjuvant chemotherapy or chemoradiotherapy may be used in cases that are considered to be "borderline resectable" (see Staging) in order to reduce the cancer to a level where surgery could be beneficial. In other cases neoadjuvant therapy remains controversial, because it delays surgery.[5][6][64]

Food and Drug Administration (FDA) 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.[65] This was the first chemotherapy drug approved by the FDA primarily for a nonsurvival clinical trial endpoint.[66] 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.[67]

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 (nab-paclitaxel), which was licensed by the FDA in 2013 for use with gemcitabine in pancreas cancer.[68] 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.[65] Clinical trials are often conducted for novel adjuvant therapies.[6]

Radiotherapy

The role of radiotherapy as an auxiliary (adjuvant) treatment after potentially curative surgery has been controversial since the 1980s.[5] The European Society for Medical Oncology recommends that adjuvant radiotherapy should only be used for people enrolled in clinical trials.[39] However, there is a continuing tendency for clinicians in the US to be more ready to use adjuvant radiotherapy than those in Europe. Many clinical trials have tested a variety of treatment combinations since the 1980s, but have failed to settle the matter conclusively.[5][6]

Radiotherapy may form part of treatment to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial as there are conflicting results from clinical trials. The preliminary results of one trial, presented in 2013, "markedly reduced enthusiasm" for its use on locally advanced tumors.[2]

PanNETs

Main articles: Neuroendocrine tumor and Pancreatic neuroendocrine tumor

Treatment of PanNETs, including the less common

malignant types, may include a number of approaches.[43][69][70][71] 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.[43] This depends on the assessed risk of surgery which is influenced by the site of the tumor and the presence of other medical problems.[43] 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.[17]

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, guidelines emphasize that treatment should be undertaken in a specialized center.[23][17]Use of liver transplantation may be considered in certain cases of liver metastasis.[72]

For functioning tumors, the

cytotoxic chemotherapy is generally not very effective for PanNETs, but may be used when other drug treatments fail to prevent the disease from progressing,[23][76] or in poorly differentiated PanNET cancers.[77]

Radiation therapy is occasionally used if there is pain due to anatomic extension, such as

radiolabeled peptides or hormones such as iobenguane (iodine-131-MIBG).[78][79][80][81] Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also be used.[82][83]

Palliative care

Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer, and improving quality of life.[84] 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.[85]

Palliative care focuses not on treating the underlying cancer, but on treating symptoms such as

hospice care will be beneficial.[86] 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.[5][87]

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.[26] Palliative care can also help treat depression that often comes with diagnosis of pancreatic cancer.[5]

Both surgery and advanced inoperable tumors often lead to

H2 antagonists, which both reduce production of gastric acid.[3]

Outcomes

Outcomes in pancreatic cancers according to clinical stage[41]
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.[2] 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%,[41] although the outlook varies considerably varies according to the type.[25]

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.[2][65] Overall five-year survival for pancreatic cancer in the US has improved from 2% in cases diagnosed in 1975–77, and 4% in 1987–89 diagnoses, to 6% in 2003–09.[88] In the less than 20% of cases of pancreatic adenocarcinoma with a diagnosis of a localized and small cancerous growth (less than 2 cm in Stage T1), approximately 20% of Americans survive to five years.[15]

Distribution

Age-standardized death from pancreatic cancer per 100,000 inhabitants in 2004[89]
  no data
  <1
  1
  2
  3
  4
  5
  6
  7
  8
  9
  10
  >10

As of 2012, pancreatic cancer resulted in 330,000 deaths globally,[4] up from 310,000 in 2010 and 200,000 in 1990.[90] 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.[2] Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.[91] It is the seventh highest cause of death from cancer worldwide.[4]

Globally pancreatic cancer is the 11th most common cancer in women and the 12th most common in men.

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.[4]

Pancreatic cancer is the 10th most common cancer in the UK (around 8,800 people were diagnosed with the disease in 2011), and it is the 5th most common cause of cancer death (around 8,700 people died in 2012).[94]

PanNETs

The annual

uncovered small PanNETs rather frequently, suggesting that the prevalence of tumors that remain inert and asymptomatic may be relatively high.[23] Overall PanNETs are thought to account for about 1 to 2% of all pancreatic tumors.[20] The definition and classification of PanNETs has changed over time, affecting what is known about their epidemiology and clinical relevance.[46]

History

The earliest recognition of pancreatic cancer has been attributed to the 18th-century Italian scientist

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.[95]

Regarding the recognition of PanNETs, the possibility of cancer of the islet cells was initially suggested in 1888. The first case of

peptic ulcers published in 1955.[95] In 2010, the WHO recommended that PanNETs be referred to as "neuroendocrine" rather than "endocrine" tumors.[22]

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 people would die if their duodenum was removed, and also, at first, if the flow of pancreatic juices stopped. 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.[96]

In 1912 the German surgeon

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.[96]

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,[96] but about 25% of people never left hospital alive as late as the 1970s.[97] 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%.[18] 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%.[96][97] Another series of 2,050 operations at the Massachusetts General Hospital between 1941 and 2011 showed a similar picture of improvement.[98]

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."[42]

Research directions

Worldwide efforts on many levels are underway to understand pancreatic cancer, but progress has been slow, particularly into understanding the disease's causes.[99] There are several fundamental unanswered questions.[100][101] The nature of the changes that lead to the disease are being intensely investigated, such as the roles played by genes such as KRAS and p53.[33][102][103] A key question is the timing of events as the disease develops and progresses – particularly the role of diabetes,[104] and how and when the disease spreads.[105]

Research on early detection is ongoing.

prevention if a workable screening strategy can be developed.[104][107][108]

Another area of interest is in assessing whether keyhole surgery (

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.[2]

Efforts are underway to develop new drugs.

molecular mechanisms.[113][114] Others aim to target the highly-resistant cancer stem cells.[62][115] Still others aim to affect the non-neoplastic stroma and microenvironment of the tumor, which is known to influence cell proliferation and metastasis.[114][115][116][117][118] A further approach involves the use of immunotherapy, such as oncolytic viruses.[119][120]

See also

References

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External links

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