The most important form of prevention is to cease smoking, after which the risk of the disease returns to normal within 20 years. Other recommendations include limiting alcohol intake and eating a healthy diet.Screening the general population has not been found to be effective. For people affected by the disease treatments may include: surgery, radiation therapy, chemotherapy, or a combination of treatments. Recommendations are partly based on the cancer stage. Surgery may be done in an effort to cure the disease or to try to improve quality of life without trying to cure. Pain management and medications to improve digestion are sometimes needed. Early palliative care is recommended even in those who are receiving active treatment.
In 2012 pancreatic cancer caused 330,000 deaths globally, the seventh most common cause of deaths due to cancer. In the United States it is the fourth most common cause of deaths due to cancer. The disease occurs more often in the developed world, where 68% of new cases occur in 2012. It often has poor outcomes with the average percentage alive for at least one and five years being 25% and 5% respectively. In localized disease where the cancer is small (< 2 cm) the number alive at five years is approximately 20%. For those with neuroendocrine cancer the number alive at five years is better at 65%. In the United States, as of 2006, the economic costs of pancreatic cancer are estimated at $8.6 billion.
Early pancreatic cancer usually does not cause symptoms, so that the disease is typically not diagnosed until it has spread beyond the pancreas itself. This is one of the key factors in the poor survival rate.
Common symptoms 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 worst at night and may increase over time to become "severe and unremitting". It may be slightly relieved by bending forwards. 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 2/3 of patients have abdominal pain, 46% accompanied by jaundice, with 13% having jaundice without pain.
Painless jaundice (yellow tint to whites of eyes (sclera) or yellowish skin, possibly in combination with darkened urine) when a cancer of the head of the pancreas (75% of cases) obstructs the common bile duct as it runs through the pancreas. This may also cause pale-colored stool and steatorrhea. The jaundice may be associated with itching as the salt from excess bile can cause skin irritation.
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.
Diabetes mellitus, or elevated blood sugar levels. Many patients with pancreatic cancer develop diabetes months to even years before they are diagnosed with pancreatic cancer, suggesting new onset diabetes in an elderly individual may be an early warning sign of pancreatic cancer.
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.
Age, gender and race. The risk of developing pancreatic cancer increases with age. Most cases occur after age 65, while cases before age 40 are uncommon. The disease is somewhat 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.
Smoking. Cigarette smoking has a risk ratio of 1.74 with regard to pancreatic cancer; a decade of nonsmoking after heavy smoking is associated with a risk ratio of 1.2.
Obesity; a BMI greater than 35 is associated with a risk ratio of 1.55.
Family history: 5–10% of pancreatic cancer patients have a family history of pancreatic cancer. The genes have not been identified. Pancreatic cancer has been associated with the following syndromes: autosomal recessiveataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2gene and PALB2gene, Peutz-Jeghers syndrome due to mutations in the STK11 tumor suppressor gene, hereditary non-polyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, and the familial atypical multiple mole melanoma-pancreatic cancer syndrome (FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene. There may also be a history of familial pancreatitis.
Chronic pancreatitis has been linked, but is not known to be causal. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.
Diabetes mellitus is both a risk factor for pancreatic cancer, and, as noted earlier, new onset diabetes can be an early sign of the disease.
It is controversial whether alcohol consumption is a risk factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have found no association. Although drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, chronic pancreatitis associated with alcohol consumption is less frequently a precursor for pancreatic cancer than other types of chronic pancreatitis.
Some studies suggest a relationship, the risk increasing with increasing amount of alcohol intake. The risk is greatest in heavy drinkers, mostly on the order of four or more drinks per day. There appears to be no increased risk for people consuming up to 30g of alcohol a day, which is approximately 2 alcoholic beverages/day, so most people who take alcohol do so at a level that "is probably not a risk factor for pancreatic cancer". A pooled analysis concluded, "Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day".
Several studies caution that their findings could be due to confounding factors. Even if a link exists, it "could be due to the contents of some alcoholic beverages" other than the alcohol itself. One Dutch study even found that drinkers of white wine had lower risk.
Axial CT image with i.v. contrast. Macrocystic adenocarcinoma of the pancreatic head.
Most patients with pancreatic cancer experience pain, weight loss, or jaundice.
Pain is present in 80% to 85% of patients with locally advanced or advanced metastatic disease. The pain 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. Weight loss can be profound; it can be associated with anorexia, early satiety, diarrhoea, or steatorrhea. Jaundice is often accompanied by pruritus and dark urine. Painful jaundice is present in approximately one-half of patients with locally unresectable disease, while painless jaundice is present in approximately one-half of patients with a potentially resectable and curable lesion.
The initial presentation varies according to location of the cancer. Malignancies in the pancreatic body or tail usually present with pain and weight loss, while those in the head of the gland typically present with steatorrhea, weight loss, and jaundice. The recent onset of atypical diabetes mellitus, a history of recent but unexplained thrombophlebitis (Trousseau sign), or a previous attack of pancreatitis are sometimes noted. Courvoisier sign defines the presence of jaundice and a painlessly distended gallbladder as strongly indicative of pancreatic cancer, and may be used to distinguish pancreatic cancer from gallstones. Tiredness, irritability and difficulty eating because of pain also exist. Pancreatic cancer is often discovered during the course of the evaluation of aforementioned symptoms.
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. When a cutoff above 37 U/mL is used, this marker has a sensitivity of 77% and specificity of 87% in discerning benign from malignant disease. CA 19-9 might be normal early in the course, and could be elevated because of benign causes of biliary obstruction. Imaging studies, such as computed tomography (CT scan) and endoscopic ultrasound (EUS) can be used to identify the location and form of the cancer. The definitive diagnosis is made by an endoscopic needle biopsy or surgical excision of the radiologically suspicious tissue. Endoscopic ultrasound is often used to visually guide the needle biopsy procedure. Nonetheless, pancreatic cancer is usually staged using a CT scan. In fact, a histologic diagnosis is not usually required for resection of the tumor, rather histologic analysis helps determine which chemotherapeutic regimen to start.
Micrograph of pancreatic ductal adenocarcinoma (the most common type of pancreatic cancer). H&E stain.
The development of pancreatic cancer may involve the over-expression of oncogenes, inactivation of tumor suppressor genes or the deregulation of various signaling proteins. Mutations leading to carcinoma may be accelerated by genetic or environmental factors and other risk factors already described. Specific mutations vary among and even within the cyto-histologic categories discussed below.
Exocrine pancreas cancers
Micrographs of normal pancreas, pancreatic intraepithelial neoplasia (precursors to pancreatic carcinoma) and pancreatic carcinoma. H&E stain.
The most common form of pancreatic cancer (ductal adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. 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 tumour found in the pancreas arose from it.
The genetic events that cause ductal adenocarcinoma have been well characterized. The most common are KRAS mutations (96%), CDKN2A mutations/deletions (75%), TP53 mutations (55%), SMAD4 deletions/mutations (50%), and SWI/SNF mutations/deletions (35%).
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 carcinoma is thought to arise from progressive tissue changes. Three types of precancerous lesion are recognized: pancreatic intraepithelial neoplasia – a microscopic lesions of the pancreas, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms both of which are macroscopic lesions. The cellular origin of these lesions is debated.
Pancreatoblastoma is a rare form, mostly occurring in childhood, and with a relatively good prognosis.
Pancreatic mucinous cystic neoplasms are a broad group of pancreas tumors that have varying malignant potential. They are being detected at a greatly increased rate as CT scans become more powerful and common, and discussion continues as how best to assess and treat them, as many are benign.
Endocrine pancreatic tumors have been variously called islet cell tumors, pancreas endocrine tumors (PETs), and pancreatic neuroendocrine tumors (PNETs). The annual clinically recognized incidence is low, about five per one million person-years. However, autopsy studies incidentally identify PETs in up to 1.5% most of which would remain inert and asymptomatic.
The majority of PNETs are usually categorized as benign but the definition of malignancy in pancreas endocrine tumors has been ambiguous. A small subset of endocrine pancreatic tumors are incontrovertible pancreatic endocrine cancers, that make up about 1% of pancreas cancers. Low- to intermediate-grade neuroendocrine carcinomas of the pancreas may be called islet cell tumors. Some sources have also termed these pancreatic carcinoid, a practice that has sometimes been strongly condemned. Definitional migration has caused some complexity of PNET classification, which has adversely affected what is known about the epidemiology and natural history of these tumors. It is probable that some of these tumors have been included in ICD-O-3 histology classifications 8240–8245, in that they were labeled pancreatic carcinoid tumours but most islet cell carcinomas have been coded as ICD-O-3 system 8150–8155.
The ACS recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains, while decreasing red meat intake, although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically. In 2006, a large prospective cohort study of over 80,000 subjects failed to prove a definite association. The evidence in support of this lies mostly in small case-control studies.
A long-term study found that people who consumed in the range of 300 to 449 international units (IU) of vitamin D daily had a 43% lower risk of pancreatic cancer than those who took less than 150 IU per day; 150 IU is appreciably less than what was then, or is now, recommended. The World Health Organization (WHO) International Agency for Research on Cancer (IARC) concluded that there were insufficient studies in pancreatic cancer. Furthermore, while the IARC found evidence for an inverse association between vitamin D and colorectal cancer to be persuasive, it found evidence for a causal link to be limited, and also found that randomized controlled trials (RCTs) were inconclusive. Taking too much vitamin D may be harmful. Poor general diet, obesity, and relative physical inactivity can be risk factors in some cancers, so the role of vitamin D itself is not certain.
A Harvard study from 2007 showed a modest inverse trend between blood circulation of B vitamins, such as B12, B6, and folate and pancreatic cancer incidence, but not when the vitamins were ingested in tablet form. However, the results of a meta-analysis of randomized trials by Rothwell and colleagues indicate that taking a daily low-dose aspirin regimen for more than five years decreases the risk of developing pancreatic adenocarcinoma (ductal pancreatic cancer) by 75%.
It is generally agreed that general screening of large groups is not at present likely to be effective, and outside clinical trials there are no programmes for this. The European Society for Medical Oncology recommends regular screening with endoscopic ultrasound and MRI/CT imaging for those at high risk from inherited genetics, in line with other recommendations, which may also include CT.
The first and most crucial clinical decision to be made after diagnosis is whether surgical removal of the tumor is possible, as only this offers hope of a cure. This will require a tumor that has not metastasized, and will then depend on the location and spread 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, defined as the tumor touching up to 180° of a blood vessel's circumference, may be operable, but encasement, defined as more 180° engaged, is not. The general health of the patient must also be assessed, though age in itself is not an obstacle to surgery.
Chemotherapy and, to a lesser extent, radiotherapy, are likely to be offered to most patients, 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.
Treatment of pancreatic cancer depends on the stage of the cancer. Although only localized cancer is considered suitable for surgery with curative intent at present, only 20% of cases present with localized disease at diagnosis. Surgery can also be performed for palliation, if the malignancy 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.
The Whipple procedure is the most common attempted curative surgical treatment for cancers involving the head of the pancreas. This procedure 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 patient is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed in only the minority of cases.
Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy. Recently, localized cancers of the pancreas have been resected using minimally invasive (laparoscopic) approaches.
After surgery, adjuvant chemotherapy with gemcitabine or 5-FU should be offered if the patient is fit after surgery. There has been controversy as to whether it is beneficial to add radiotherapy since the 1980s, and ESMO recommend that this should only be used for patients in clinical trials. However it is more likely to be used in the USA.
Those with inoperable pancreatic cancer may have significant abdominal pain. A celiac plexusblock (CPB), which destroys the nerves that transmit pain from the abdomen, is a safe and effective way to reduce the pain. CPB generally reduces the need to use pain killers like opioids, which have significant negative side effects.
Principles of radiation therapy in pancreas adenocarcinoma are reviewed extensively in guidelines by the National Comprehensive Cancer Network. Radiation can be considered in several situations. One situation is the addition of radiation therapy after potentially curative surgery. Groups in the US have been more apt to use adjuvant radiation therapy than groups in Europe.
Chemotherapy using gemcitabine alone was the standard for the years following, as a number of trials testing it in varying dosage regimes and in combination with other drugs failed to demonstrate significantly better outcomes. However the combination of gemcitabine with Erlotinib was found to increase survival, and Erlotinib was licensed by the FDA for use in pancreatic cancer. The FOLFIRINOXchemotherapy regimen using four drugs was found more effective than gemcitabine, but with serious side effects, and thus only suitable for patients 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. By the end of 2013, both FOLFIRINOX and nab-paclitaxel were regarded as good choices for those patients who were able to withstand the side-effects, with gemcitabine remaining an 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.
The majority of these tumors are histologicallybenign. Treatment of pancreatic endocrine tumors, including the less common malignant tumors, may include:
Watchful waiting: incidentally identified small tumors, for example on a computed tomography (CT) scan performed for other purposes, may conceptually not always need intervention, but criteria for watchful waiting are unclear.
Surgery: tumors within the pancreas only (localized tumors), or with limited metastases, may be removed. For localized tumors, the surgical procedure is much less extensive than the types of surgery used to treat pancreatic adenocarcinoma.
Hormone therapy: if the tumor is not amenable to surgical removal and is causing symptoms by secreting functional hormones, a synthetic hormone analog medication, octreotide, may lessen the symptoms, and sometimes also slows tumor growth.
Radiation therapy: occasionally used if there is pain due to anatomic extension, such as metastasis to bone.
Chemotherapy and targeted medication for PNETs receive Wikipedia discussion in the relevant section of that article.
Palliative care is medical care which focuses on treatment of symptoms from serious illness, like cancer, and improving quality of life. Because pancreatic cancer is one of the most aggressive cancers, the cancer is usually diagnosed after it has progressed to an advanced stage, and there are fewer treatment options compared to other cancers, life expectancy of less than one year is expected in 80-90% of patients, in which case many of these patients would benefit from palliative care as a treatment of symptoms.
Palliative care will focus 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. Pain can be managed with medications such as opioids or through procedural intervention such as celiac plexus blocks, which alters the nerves that may be causing pain. Other symptoms/complications that can be treated with palliative surgery are biliary or intestinal obstruction. Palliative care can also help treat depression that often comes with diagnosis of pancreatic cancer, as well as fatigue and cachexia.
Exocrine pancreatic cancer (adenocarcinoma and less common variants) typically has a poor prognosis, partly because the cancer usually causes no symptoms early on, leading to locally advanced or metastatic disease at time of diagnosis.
Pancreatic cancer may occasionally result in diabetes. Insulin production is hampered, and it has been suggested the cancer can also prompt the onset of diabetes and vice versa. It can be associated with pain, fatigue, weight loss, jaundice, and weakness. Additional symptoms are discussed above.
For pancreatic cancer:
For all stages combined, the 1-year relative survival rate is 25%, and the 5-year survival is estimated as less than 5% to 6%.
For local disease, the 5-year survival is approximately 20%.
For locally advanced and for metastatic disease, which collectively represent over 80% to 85-90% of individuals, the median survival is about 10 and 6 months, respectively. Without active treatment, metastatic pancreatic cancer has a median survival of 3–5 months; complete remission is very rare.
Outcomes with pancreatic endocrine tumors, many of which are benign and completely without clinical symptoms, are much better, as are outcomes with symptomatic benign tumors; even with actual pancreatic endocrine cancers, outcomes are rather better, but variable.
Globally, as of 2012, pancreatic cancer resulted in 330,000 deaths, up from 310,000 in 2010 and 200,000 in 1990. In 2010, an estimated 43,000 people in the US were diagnosed with pancreas cancer and almost 37,000 died from the disease. 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. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.
Worldwide efforts are under way to understand pancreatic cancer on many levels, and there are several fundamental unanswered questions. Research on pancreatic cancer has been recognized as an area in need of prioritization due to limited progress over recent decades.
The nature of the genetic changes that lead to the disease are being intensely scrutinized, for example by the Australian Pancreatic Genome Initiative as part of the International Cancer Genome Consortium. These and others have uncovered the key role played by genes such as KRAS and p53 in the disease’s development. A key question is the timing of key events in the disease’s progression – particularly how and when it spreads (metastasizes), and how these are affected by lifestyle risk factors such as obesity and smoking.
Research on early detection is ongoing, 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.
Parallel to this, efforts are underway to develop new drugs to target the disease, or to test existing drugs that are currently not used to treat it. Some of these involve treatments to target cancer cells themselves using targeted therapies. Others aim to target the tissue surrounding the pancreatic tumour (the Stroma (animal tissue) or microenvironment). The availability of new genetically engineered mouse models has substantially advanced this research in recent years. A third key strand of research on treating the disease is immunotherapy – particularly using oncolytic viruses.
Another key 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.
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^ abc"In summary, a weak positive association between alcohol intake during adulthood and pancreatic cancer risk was observed in the highest category of intake (≥30g/day or approximately 2 alcoholic beverages/day). Associations with alcohol intake were stronger among individuals who were normal weight. Thus, our findings are consistent with a modest increase in risk of pancreatic cancer for alcohol intakes of at least 30 grams/day."Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, van den Brandt PA, English DR, Freudenheim JL, Fuchs CS, Giles GG, Giovannucci E, Hankinson SE, Horn-Ross PL, Leitzmann M, Männistö S, Marshall JR, McCullough ML, Miller AB, Reding DJ, Robien K, Rohan TE, Schatzkin A, Stevens VL, Stolzenberg-Solomon RZ, Verhage BA, Wolk A, Ziegler RG, Smith-Warner SA (March 2009). "ALCOHOL INTAKE AND PANCREATIC CANCER RISK: A POOLED ANALYSIS OF FOURTEEN COHORT STUDIES". Cancer Epidemiology, Biomarkers & Prevention18 (3): 765–76. doi:10.1158/1055-9965.EPI-08-0880. PMC2715951. PMID19258474.
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^"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 Oncology20 (11): 2633–2642. doi:10.1200/JCO.2002.10.030. PMID12039924.
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^"Health | Vitamin D 'slashes cancer risk'". BBC News. 2006-09-15. Retrieved 2009-09-15.The BBC quoted the lead researcher: "I would make no specific recommendation for vitamin D supplementation to prevent pancreatic cancer until we can carry out a trial to determine definitively who might benefit from such an intervention." The BBC quoted Henry Scowcroft, science information officer at the charity Cancer Research UK: "The results of this study don't mean that people should take vitamin D supplements to ward off pancreatic cancer, especially as vitamin D can be harmful in large quantities...As the authors themselves point out, this is the very first study to find any association between the disease and vitamin D intake...So this result needs to be repeated in other large studies, and scientists need to show exactly how vitamin D might prevent pancreatic cancer before we could issue any specific lifestyle advice."
^ abInstitute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx Dietary Reference Intakes for Calcium and Vitamin D IOM, 30 November 2010: "The IOM finds that the evidence supports a role for vitamin D and calcium in bone health but not in other health conditions. Further, emerging evidence indicates that too much of these nutrients may be harmful, challenging the concept that "more is better."
^World Health Organization; International Agency for Research on Cancer (IARC). Vitamin D and Cancer. IARC Working Group Reports Vol.5, International Agency for research on Cancer, Lyon, 25 November 2008
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^Cite error: The named reference ESMOPA was invoked but never defined (see the help page).
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