Pancreatic Cancer

Pancreatic Cancer



Definition of Pancreatic Cancer:

Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors, is adenocarcinoma (tumors exhibiting glandular architecture on light microscopy) arising within the exocrine component of the pancreas. A minority arise from islet cells, and are classified as neuroendocrine tumors. The signs and symptoms that eventually lead to the diagnosis depend on the location, the size, and the tissue type of the tumor, and may include abdominal pain, lower back pain, and jaundice (if the tumor compresses the bile duct).

Pancreatic cancer has an extremely poor prognosis: for all stages combined, the 1- and 5-year relative survival rates are 25% and 6%, respectively; for local disease the 5-year survival is approximately 15%  while the median survival for locally advanced and for metastatic disease, which collectively represent over 80% of individuals, is about 10 and 6 months respectively. Individuals vary, however – some are only diagnosed when they are terminally ill already and therefore only have a few days or weeks. Others have slower progression and may live a couple of years even if surgery is not possible. Men are 30% more likely to get pancreatic cancer than are women. Persons of African nationality or descent are more likely to develop pancreatic cancer than white persons.

Cause of Pancreatic Cancer:

Scientists still do not know exactly what causes most cases of pancreatic cancer, but they have found several risk factors that can make a person more likely to get this disease.Pancreatic cancer develops when a cell in the pancreas acquires damage to its DNA that causes it to behave and multiply abnormally. A single cancer cell grows and divides rapidly, becoming a tumor that does not respect normal boundaries in the body. Eventually, cells from the tumor travel elsewhere in the body (metastasize) through the blood or lymphatic system. 

Several cancer family syndromes have been found in which inherited DNA mutations cause a very high risk of developing certain cancers. In some of these, there is an increased risk of getting pancreatic cancer. Researchers have characterized many of these DNA changes in the past few years. Some of these mutations happen occur randomly. Others occur in response to things we do or experience in the environment. Some mutations may be inherited. When enough mutations accumulate, a cell becomes malignant and a tumor begins to grow. 

Other causes can be:

  • Cigarette smoking
  • Age
  • Race
  • Gender
  • Ethnicity
  • Chronic pancreatitis
  • Diabetes 
  • Obesity
  • Diet
  • Genetics

Signs and Symptoms of Pancreatic Cancer:

Early pancreatic cancer often does not cause symptoms, and the later symptoms are usually nonspecific and varied. Therefore, pancreatic cancer is often not diagnosed until it is advanced. Common symptoms include:

  • Pain in the upper abdomen that typically radiates to the back (seen in carcinoma of the body or tail of the pancreas)
  • Heartburn – acid stomach
  • Poor appetite or nausea and vomiting
  • Diarrhea, loose stools.
  • Significant weight loss (cachexia)
  • 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 sign, 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.
  • Pulmonary embolisms due to pancreatic cancers producing blood clotting chemicals.
  • 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, sometimes presenting before the cancer is diagnosed. However, the mechanism for this association is not known.
  • Symptoms of pancreatic cancer metastasis. Typically, pancreatic cancer first metastasizes to regional lymph nodes, and later to the liver or to the peritoneal cavity and, rarely, to the lungs; it rarely metastasizes to bone or brain.

Risk factors for Pancreatic Cancer:

Risk factors for pancreatic cancer may include:

  • 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 recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene, 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.
  • Age. The risk of developing pancreatic cancer increases with age. Most cases occur after age 60, while cases before age 40 are uncommon.
  • 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.
  • Diets low in vegetables and fruits.
  • Diets high in red meat. Processed meat consumption is positively associated with pancreatic cancer risk, and red meat consumption was associated with an increased risk of pancreatic cancer in men.
  • Diets high in sugar-sweetened drinks (soft drinks). In particular, the common soft drink sweetener fructose has been linked to growth of pancreatic cancer cells.
  • Obesity
  • Diabetes mellitus is both risk factor for pancreatic cancer, and, as noted earlier, new onset diabetes can be an early sign of the disease.
  • 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.
  • Helicobacter pylori infection
  • Gingivitis or periodontal disease
  • Partial gastrectomy

Alcohol

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.

Diagnosis of Pancreatic Cancer :

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 andalkaline 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.

Prevention from Pancreatic Cancer :

According to the American Cancer Society, there are no established guidelines for preventing pancreatic cancer, although cigarette smoking has been reported as responsible for 20–30% of pancreatic cancers.

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

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%. 

Screening 

People who may have a high risk of pancreatic cancer due to a family history can be followed, but there is no consensus on what constitutes optimal monitoring. Several small studies have shown promising preliminary results for new biomarkers, but further validation on a larger scale is needed. People with pancreatic cancer themselves, or family members, may wish to participate in the activities at a research facility, or identify a pancreas tumor registry.

A possible ‘dipstick screen’, developed by 15-year-old Jack Andraka with the collaboration of John Hopkins University, detects the level of a protein called mesothelin in the urine or blood, which is a biomarker for pancreatic cancer. Experts believe it stands a chance of becoming a cheap test for the disease but will take years to develop. 

Treatment of Pancreatic Cancer :

Exocrine pancreas cancer

Surgery

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 localised 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 has been shown in several large randomized studies to significantly increase the 5-year survival (from approximately 10 to 20%), and should be offered if the patient is fit after surgery (Oettle et al. JAMA 2007, Neoptolemos et al. NEJM 2004, Oettle et al. ASCO proc 2007).

Radiation 

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. 

Chemotherapy

In patients not suitable for resection with curative intent, palliative chemotherapy may be used to improve quality of life and gain a modest survival benefit. Gemcitabine was approved by the United States Food and Drug Administration in 1998, after a clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in patients with advanced pancreatic cancer. This marked the first FDA approval of a chemotherapy drug primarily for a nonsurvival clinical trial endpoint. Gemcitabine is administered intravenously on a weekly basis.

A Canadian-led Phase III randomised controlled trial, reported in 2005, involved 569 patients with advanced pancreatic cancer, led the US FDA in 2005 to license erlotinib (Tarceva) in combination with gemcitabine as a palliative regimen for pancreatic cancer. This trial compared the outcome of gemcitabine/erlotinib to gemcitabine/placebo, and demonstrated improved survival rates, improved tumor response and improved progression-free survival rates. Other trials are now investigating the effect of the above combination in the adjuvant (post surgery) and neoadjuvant(pre-surgery) settings.

Addition of oxaliplatin to Gemcitabine (Gem/Ox) was shown to confer benefit in small trials, but is not yet standard therapy.

Pancreatic neuroendocrine tumors

The majority of these tumors are histologically benign. 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.