Pancreatic cancer

Pancreatic cancer is a group of primary malignant tumours that are localized in the ducts and acinuses of the pancreas.

These tumours include: ductal adenocarcinomas, giant cell adenocarcinomas, mucinous adenocarcinomas, mucinous cystadenocarcinomas, ferruginous-squamous cell carcinomas, acinar carcinomas, pancreatoblastomas, intracellular papillary-mucoid tumours.

The main clinical manifestations of pancreatic cancer are: weight loss, intense abdominal pain, jaundice , fatigue, nausea, vomiting, anorexia.

The diagnosis is based on the evaluation of the history and physical examination, as well as on the results of detecting the pancreatic cancer markers; endoscopic ultrasonography, CT Scan, MRI of the abdominal cavity, retrograde endoscopic cholangiopancreatography, laparoscopy, aspiration biopsy.

If the tumor is operable (resectable), which is observed in 15-20% of cases by the time of the first diagnosis, the treatment consists of performing pancreaticoduodenal resection (Whipple's operation) followed by postoperative chemoradiotherapy. The remaining patients undergo neoadjuvant treatment, as well as palliative measures.

• Classification of pancreatic cancer
• Histological classification
• Protocol adenocarcinomas.

Adenocarcinomas with greater frequency are found in the pancreatic ducts than in the acini. In 80% of cases, they are localized in the head of the organ. The average age of patients is 55 years. A 1.5-2 tumor is more common in men than in women. The main risk factors for adenocarcinomas are: smoking, history of chronic pancreatitis, long-term diabetes (mainly in women). The average size of the tumor at the time of the first diagnosis is 5 cm.

Median survival is 16 weeks. One-year survival is observed in 17% of patients, 5-year-old - in 1% of patients.

• Giant cell adenocarcinomas.

Registered in 6% cases. In appearance, they resemble hemorrhagic cysts. It is 1.5 times more common in men than in women. In 50% of patients, giant cell adenocarcinomas are localized in the head of the pancreas. In the initial diagnosis, tumors reach a size of 11 cm.

The outlook is unfavorable. Median survival is 8 weeks.

• Mucinous adenocarcinomas.  The occurrence of mucinous adenocarcinomas is 2% of all pancreatic tumors. In 78% of patients, the tumor is localized in the head of the pancreas. The size of tumor with primary diagnosis is approximately 6 cm.

The outlook is unfavorable. Median survival is 44 weeks. One-year survival is observed in 33% of patients.

• Mucinous cystadenocarcinomas.  Are (in 1% of cases) adenomatous  malignant tumors  often found in women. The type of Tumor Occurs as a result of a malignant mucoid (mucosal) cystadenoma. In 60% of patients, the tumor is located in the body of the gland. In primary diagnosis, the size of the tumor can be 16 cm. Patients normally complain of abdominal pain. During examination, a tumor-like formations can be palpated in the abdominal cavity. The diagnosis is established based on the results of CT or MRI of the abdominal cavity.

In 20% of patients, metastases are detected during surgery. Complete pancreas resection can achieve 5-year survival in 65% of cases.

• Iron-squamous cell carcinoma.It is observed with a frequency of 4% (in the structure of all tumors of the pancreas). In men, it is diagnosed 3 times more often than in women. The tumor is localized in the head of the pancreas in 60% of cases. Median survival is 24 weeks. The parameters of one-year survival rate - 5%.

• Acinar cancerAcinar carcinoma (grapesiform) is noted in 1.5% of patients. Men are diagnosed 2.5 times more often than women. There are many young people among the patients. Tumors are localized approximately at the same frequency in the head and body of the pancreas. The average size of tumors with primary diagnosis can reach 5 cm or more.
  The outlook is unfavorable. Median survival is 28 weeks. The indicators of annual survival are only 14% of patients.

• PancreatoblastomaObserved in children. The outlook is unfavorable.

• Intra-flow papillary-mucinous tumorsObserved very rarely. Occur as a result of hypersecretion of mucus and duct obstruction. The results of a histological examination of the tumor can be indicative of both the benign nature of the pathological process and its malignancy. In 80% of cases, patients are women. In 66% of patients, the tumor is located in the tail of the pancreas.

• Staging of pancreatic cancerStages (TNM) of pancreatic cancer, in the modification of the American Joint Cancer Committee (American Joint Committee on Cancer, 2002).
• T - tumor.
• T - there is no primary tumor.
• Tis - carcinoma in situ.
• T ₁ - the tumor is located within the gland; sizes - up to 2 cm.
• T ₂ - the tumor is located within the gland; sizes - more than 2 cm.
• T ₃ - the tumor extends beyond the gland (invasion of the duodenum, bile duct, portal or superior mesenteric veins), but without involvement of the celiac trunk or superior mesenteric artery.
• T4 - invasion of the tumor of the celiac trunk and the superior mesenteric artery.
• N - regional lymph nodes.
• N - in regional lymph nodes there are no metastases.
• N ₁ - metastases in regional lymph nodes.

M - distant metastases.

• M - no distant metastases.
• M ₁ - distant metastases.

Determination of the stage of pancreatic cancer

• Step 0: Tis, N0, M0.
• Stage IA: T1, N0, M0.
• Stage IB: T2, N0, M0.
• Stage IIA: T3, N0, M0.
• Stage IIB: T1-3, N1, M0.
• Stage III: T4, any N, M0.
• Stage IV: any T, any N, M1.

By the time of primary diagnosis, 20% of patients have stage I pancreatic cancer; 40% have locally advanced cancer; 40% have cancer with metastases to regional lymph nodes or distant metastases.

Epidemiology of pancreatic cancer
In the world, the annual incidence of this type of cancer is (8-10): 100,000 people. Annually, about 30 thousand new cases of pancreatic cancer are diagnosed in the USA.

In 63% of cases, the disease is diagnosed in patients older than 70 years. In men, it is observed in 1,2-1,5 times more often than in women. So, in the US, the annual incidence of pancreatic cancer in men is 8.2: 100,000; women - 6: 100,000 population.

• ICD-10 codeK86 - Other pancreatic diseases.

Etiology and pathogenesis

In 40% of cases, pancreatic cancer is sporadic, that is, the etiology of the disease is not determined.
    Risk factors for pancreatic cancer

• Smoking.May be the cause of the disease in 30% of cases. The risk of developing pancreatic cancer in people who smoke one cigarette a day is four times higher than that of non-smokers. If a person smokes more than 40 cigarettes a day, then the likelihood of cancer increases 10 times.

• Errors in nutrition.
  May be the cause of the disease in 20% of cases. Alcohol is an independent risk factor. In addition, pancreatic cancer is more common in people who consume foods high in carbohydrates.

• Diabetes.
  It was found that in patients with type I or II diabetes for 5 years or more, the risk of pancreatic cancer is doubled.

• Hereditary diseases.
  Approximately 5-10% of patients with pancreatic cancer are the result of hereditary pathology. Thus, this disease is diagnosed in patients with hereditary non-lipopic colorectal cancer, ataxia-telangiectasia, hereditary pancreatitis, familial adenomatous polyposis, Gardner's syndromes and Gippel-Landau syndromes, and mutations of the BRCA2 gene.

Pancreatic cancer in patients with hereditary pancreatitis develops, as a rule, at the age of 57 years. By the age of 70, 40% of patients with hereditary pancreatitis have pancreatic cancer.

• Chronic pancreatitis .Chronic pancreatitis is a risk factor for pancreatic cancer in 5% of patients. 4% of patients with chronic pancreatitis within 20 years develop pancreatic cancer.

• Gastrectomy and gastric resection.These operations, performed in patients with peptic ulcers, benign gastric tumors, increase the risk of developing pancreatic cancer 3-5 times. This is due to the fact that the stomach is involved in the degradation of carcinogenic agents.

In the absence of the stomach in the mucous membrane of the small intestine and pylorus, cholecystokinin and gastrin are more actively synthesized, which stimulate hypersecretion of pancreatic juice and disrupt the regulation of the functioning of this organ.

                   Pathogenesis of pancreatic cancer

Approximately 75% of cases of carcinomas are found in the head; in 15-20% of patients - in the body; in 5-10% of patients - in the tail of the pancreas.

Tumors of the pancreas metastasize to regional lymph nodes, liver, lungs. They can invade the duodenum, stomach, and large intestine.

In 80-95% of patients with adenocarcinomas, mutations in the KRAS2 gene are detected; in 85-98% - in the gene CDKN2; in 50% - in the gene TP53; in 55% - in the Smad4 gene. Approximately 30% of patients with chronic pancreatitis have mutations in the TP16 gene.

Clinic and complications

The initial symptoms of pancreatic cancer (weight loss, weakness, fatigue, abdominal pain, nausea, vomiting, anorexia) are nonspecific. As the disease progresses, the symptoms become more pronounced.

• The main manifestations of pancreatic cancer
• Stomach acheAs the tumor grows, the pain in the abdomen becomes intense, acute, irradiated to the back and intensified when the torso is tilted forward. Irradiation of pain in the back indicates a lesion with a tumor of the retroperitoneal region.

When the tumor is localized in the tail of the pancreas, pain is recorded in 87% of patients, with head cancer in 72% of patients.

• JaundiceAdenocarcinomas localized in the head of the pancreas, in 80-90% of cases lead to the appearance of jaundice (as a result of compression of the common bile duct by the tumor). There are also skin itching, darkening of urine and clarification of feces.
• Decreased body weight.This symptom is observed in 92% of patients with tumor localization in the head and in 100% of patients with pancreatic body or tail disease. Decrease in body weight may be associated with steatorrhea (as a result of a violation of the exocrine function of the pancreas).
• Anorexia.Anorexia is noted in 64% of patients with head cancer and approximately in 30% of patients with tumor localization in other parts of the pancreas.
• Nausea and vomiting.Nausea and vomiting are noted in 43-45% of cases with head cancer and in 37% of cases - with cancer of the tail and body of the gland. These symptoms can be the result of squeezing the duodenum and the stomach with a tumor.
• Development of secondary diabetes mellitus.Diabetes mellitus as a consequence of cancer is diagnosed in 25-50% of patients, leading to the appearance of such symptoms as polyuria and polydipsia.

• If the tumor is located in the body or the tail of the pancreas, then it contributes to the occurrence of splenomegaly, bleeding from varicose veins of the esophagus and stomach.
• In some cases, a clinical picture of acute cholecystitis or acute pancreatitis develops .
• Metastases on the peritoneum can cause compression of the intestine with the symptoms of constipation or obstruction.

• Relationship between clinical manifestations of pancreatic cancer and patient cohabitation

All patients with pancreatic cancer in terms of severity of symptoms can be divided into 3 groups, on the basis of which a decision is made about the expediency of performing resection of the organ.

• Patients who can undergo a pancreas resection.

In this group, approximately 90% of patients show pancreatic head cancer. Jaundice is noted in 70-90%, abdominal pain - in 25% of cases. Jaundice without pain is observed in 50% of patients. The median survival rate of such patients is 70 weeks.

• Patients who can not perform a pancreas resection.

This group includes 46% of patients. In 80% of them, the tumor is located in the head of the pancreas. Jaundice is noted in 65-75%, abdominal pain - in 50-80% of cases. Jaundice without pain is observed in 15% of patients. The median survival of such patients is 30 weeks.

• Patients who can not perform a pancreas resection because of distant metastases.

This group includes 49% of patients. Jaundice is noted in 15-30%, abdominal pain - in 85% of cases. Jaundice without pain is observed in 5% of patients. The median survival of these patients is 10 weeks.

• Complications of pancreatic cancerIn 90% of patients, pancreatic tumors metastasize to the lymph nodes, lungs and liver.

Diagnostics

It is difficult to suspect the presence of pancreatic cancer in the early stages of development, since the clinical manifestations of the disease are not specific. Pancreatic cancer is difficult to diagnose at an early stage. Only in 30% of patients the diagnosis is established within 2 months. after the manifestation of the disease. This is due to the fact that the initial symptoms of pancreatic cancer (weight loss, weakness, fatigue, abdominal pain, nausea, vomiting, anorexia) are nonspecific. Therefore, the most important is the timely treatment of patients to doctors and conducting a full survey.

It is possible to suspect pancreatic cancer if there is jaundice and the intensity of pain in the abdomen.

• Objectives of diagnosis
• Identify pancreatic cancer.
• Set its localization.
• To reveal metastases.
• Set the stage of cancer.
• Set resectability or non-resectability of the tumor.

• Diagnostic Methods
• Anamnesis historyAs the disease progresses, the initial symptoms (weight loss, weakness, fatigue, abdominal pain, nausea, vomiting, anorexia) become more pronounced.

When collecting anamnesis, it is important to assess the place and effect on the life of patients of various risk factors.

• Smoking can be the cause of pancreatic cancer in 30% of cases.
• The disease is more common in people who consume foods high in carbohydrates.
• In patients with type I or II diabetes for 5 years or more, the risk of pancreatic cancer is doubled.
• Approximately 5-10% of patients with pancreatic cancer are the result of hereditary pathology. Thus, this disease is diagnosed in patients with hereditary non-lipopic colorectal cancer, ataxia-telangiectasia, hereditary pancreatitis, familial adenomatous polyposis, Gardner's syndromes and Gippel-Landau syndromes, and mutations of the BRCA2 gene.
• Chronic pancreatitis is a risk factor for pancreatic cancer in 5% of patients.
• Gastrectomy and gastrectomy performed in patients with peptic ulcers, benign gastric tumors, increase the risk of developing pancreatic cancer 3-5 times.

• Physical examination
• Pain in the abdomen is the main symptom of pancreatic cancer. When the tumor is localized in the tail of the pancreas, they are recorded in 87% of patients, with head cancer in 72% of patients. As the disease progresses, the pain in the abdomen becomes intense, acute, irradiated to the back and intensified when the torso is tilted forward. Irradiation of pain in the back indicates a lesion with a tumor of the retroperitoneal region.
• Adenocarcinomas localized in the head of the pancreas, in 80-90% of cases lead to the appearance of jaundice (as a result of compression of the common bile duct by the tumor). Therefore, patients complain of skin itching, darkening of urine and clarification of feces. On the skin of patients, it is possible to detect traces of scratching (because of severe itching).
• Weight loss is observed in 92% of patients with tumor localization in the head and in 100% of patients with pancreatic body or tail disease.
• Anorexia is noted in 64% of patients with head cancer and approximately in 30% of patients with tumor localization in other parts of the pancreas.
• Nausea and vomiting are observed in 43-45% of cases with head cancer and in 37% - with cancer of the tail and body of the gland.
• Diabetes mellitus as a consequence of cancer is diagnosed in 25-50% of patients, leading to the appearance of such symptoms as polyuria and polydipsia. However, only 1% of patients with newly diagnosed diabetes mellitus can establish the connection of this disease with pancreatic cancer.
• In some cases, a clinical picture of acute cholecystitis or acute pancreatitis develops (in 5% of patients).
• When physically examining patients with pancreatic cancer, tension in the nearepigastric region can be detected by palpation.
• In 50% of patients with jaundice (with cancer of the head of the pancreas) it is possible to identify the symptom of Courvosier (palpable stretched gallbladder).
• If the tumor is located in the body or the tail of the pancreas, then it contributes to the development of splenomegaly, bleeding from the varicose veins of the esophagus and stomach.
• At the late stage of the disease, ascites, hepatomegaly develops.
• In a number of cases, thromboses of deep veins, thrombophlebitis are noted.
• Metastases on the peritoneum can lead to compression of the intestine with the symptoms of constipation or obstruction.
• Almost 67% of patients are in severe depression.

• Laboratory diagnostic methods
• 
  
• General blood analysis Blood chemistry
• Determination of markers of pancreatic cancer

• Instrumental diagnostic methods
• Transabdominal ultrasonography - ultrasound of the abdominal cavity
• Endoscopic ultrasonography
• Computed Tomography (CT)
• Magnetic resonance imaging (MRI)
• Positron Emission Tomography
• Transhepatic cholangiography
• Retrograde endoscopic cholangiopancreatography
• Laparoscopy
• Aspiration biopsy

• The tactics of diagnosis in pancreas cancerThe diagnosis of pancreatic cancer is based on the assessment of the symptoms of the disease (abdominal pain, jaundice, anorexia, weight loss, nausea, vomiting), blood biochemical data, tumor markers; results of ultrasound, CT, MRI, endoscopy, biopsy.

• In most cases, the examination begins with transabdominal ultrasonography, CT or MRI of the abdominal cavity.
• CT allows to determine the staging of the disease, the invasion of neighboring organs, metastasis to the liver and other organs, to conclude that the tumor is resectable.
• If a patient in the course of CT has found pathological changes in the pancreas, which do not allow to say with a high degree of probability that this is a cancer, then it is necessary to perform endoscopic ultrasonography.
• Patients with jaundice diagnosis is preferable to begin with the implementation of retrograde endoscopic cholangiopancreatography.
• Confirm the diagnosis with an aspiration biopsy.
• If patients have metastases to the liver, they should perform a biopsy of one of the metastases.
• The greatest diagnostic difficulties arise when pancreatic cancer is detected in patients with chronic pancreatitis.
• After confirming the diagnosis, it is important to determine the stage of the disease and assess the resectability of the tumor.
• With the help of CT, tumor resectability can be estimated at 72%; non-recurrence in 100% of cases. If the tumor has a size on CT not more than 2-3 cm, and there is no vascular involvement, then it is resectable.
• Radiological criteria for resectability:
• Absence of extrapancreatic metastases.
• The absence of direct spread of the tumor to the superior mesenteric artery and the celiac plexus (the presence of a fat layer between the tumor and arterial structures).
• To assess the resectability of the tumor, you can determine the levels of the marker CA19-9 .
• Less than 4% of patients with a CA-19-9 level of more than 300 U / ml have resectable tumors.
• The marker exceeds the reference values ​​for tumors that are more than 3 cm in size.
• If the level of CA-19-9 is more than 1000 U / ml, then the tumor has a size of more than 5 cm.

• Differential diagnosis for pancreas cancerDifferential diagnosis for pancreas cancer should be carried out with the following diseases:
• Aneurysm of the abdominal aorta.
• Strictures of bile ducts.
• Tumors of the bile ducts.
• Cholangitis .
• Cholecystitis.
• Choledocholithiasis.
• Stomach ulcer and duodenal ulcer .
• Endocrine tumors of the pancreas.
• Acute pancreatitis .
• Chronic pancreatitis .
• Lymphoma of the stomach.
• Hepatocellular carcinoma .

Treatment

• Objectives of treatment
• Removal of the tumor in the case of resectability (pancreatoduodenal resection-Whipple's operation is performed).
• Increase the percentage of resectable tumors by restad.
• Reducing the severity of clinical manifestations of cancer (relief of pain syndrome, reduction of jaundice, correction of impairments of exocrine pancreatic gland function).
• Increased survival rates.

• Methods of treatment
• Dietotherapy Anorexia is observed in most patients with pancreatic cancer. They also develop malabsorption syndrome due to impairment of the exocrine function of the pancreas. Therefore, from the diet of these patients should be excluded from foods high in fat and protein.

• Medication methods of treatment
• Chemotherapy for disseminated pancreatic cancer in monotherapy
• Fluorouracil .Fluorouracil (FU) - a synthetic analogue of naturally occurring pyrimidine - uracil. The main target is the thymidylate synthetase enzyme, which controls the synthesis of normal thymidine nucleotides. In infusions, the fluorouracil solution should be protected from light. Patients are advised not to use together with fluorouracil aspirin and other non-steroidal anti-inflammatory drugs.

The drug is used in different modes:

• 500 mg / m ² IV for 5 consecutive days, every 4 weeks or
• 500-600 mg / m ² in / in, spraying once a week, 6 weeks or
• 1000 mg / m ² IV, infusion 5 days (120 hours) every 4 weeks or
• 200-300 mg / m ² IV, infuzionno for a month or
• 2.6 g / m ² IV, infusion for 24 hours, once a week, 4-5 weeks.
• Mitomycin C (MMC).
  MMC is an antibiotic by origin, the mechanism of action refers to alkylating agents that require in vivo activation. Among the side effects of MMC - leukopenia and especially thrombocytopenia. Rarely the drug causes the development of interstitial pneumonia, when applied together with anthracyclines increases the cardiotoxicity of the latter.

The drug is administered iv. It is prescribed for 10-20 mg / m ² every 6-8 weeks, or 5-6 mg / m ² every 4 weeks.

• Streptozocin (Szt). The chemical structure of the drug refers to nitrosoureas with a D-glucopyranose bond. By the mechanism of action, Szt is a typical DNA alkylator. It enters the cells of the islet apparatus and this explains its antitumor activity in neoplasms of the endocrine part of the pancreas.
  
  The drug is administered strictly IV in 500 mg / m ² for 5 days every 6 weeks.

Complications include renal toxicity, vomiting, moderate myelosuppression, hypoglycemia, fever, depression, lethargy.

• Semustin or methylnitrosourea (Methyl CCNU). Refers to the class of nitrosoureas. It is an alkylating agent. In pancreatic cancer, the drug is effective in 13% of cases.

• Doxorubicin (ADM). Antibiotic from the group of anthracyclines, consisting of a multi-ring chromophore and aminosugar. The main thing in the mechanism of action of ADM is intercalation of the chromophore between DNA spirals. In addition, the topoisomerase II enzyme, responsible for DNA topology, is suppressed and free radicals are generated that are cytotoxic for tumor and normal tissues.
  
  ADM is administered intravenously or intra-arterially. It is prescribed in doses of 25-30 mg / m2 ² days every 3-4 weeks, or 20 mg / m ² weekly, or 60-75 mg / m ² once in 3 weeks.

The most serious complication is cardiotoxicity.

• Epirubicin (EPI). It is a stereoisomer of doxorubicin, differs from it by the orientation of the hydroxyl group at the 4 position in the amino sugars. The antitumor effect is recorded in the range of 13-37%. The annual survival rate is 12%.
  
  It is used in doses of 75-90 mg / m ² every 21 days. The drug is administered strictly in / in. The total dose should not exceed 700 mg / m ² .

Among the frequent complications, myelosuppression, mucositis, nausea and vomiting. Among the rare side effects of increased uric acid, thrombocytopenia, phlebosclerosis, diarrhea, dark spots on the skin, nail changes, allergic reactions.

• Ifosfamide (IFO). Refers to chloroethylamines, is a synthetic analogue of cyclophosphamide. It is activated in the liver by microsomal enzymes. Its active metabolite - 4-hydroxyphosphamide alkylates DNA causing its ruptures, as well as RNA and inhibits the synthesis of proteins.

Of complications are observed: myelosuppression, nausea, vomiting, diarrhea and sometimes constipation, alopecia, hepatotoxicity, rarely lethargy, hallucinations; there may be symptoms of cystitis - dysuria, frequent urination.

The most common modes (in / in):

• 1000 mg / m ² 5 days in a row every 3 weeks or
• 1,2-2,4 g / m ² 3 days in a row every 3 weeks or
• 5000 mg / m ² once in 3 weeks.
• Thomedex (Ralthirexed). Hinazoline antifolate, is a direct and specific inhibitor of thymidylate synthetase. After entering the tumor cell, the drug undergoes polyglutamine treatment under the action of folylyglutamate synthetase. Tomudex shows activity in monotherapy in 12-14% of cases. In 29% of patients, tumor growth is stabilized.  Entered 3 mg / m ² IV once every 3 weeks.  Among the complications: leukopenia (18%), diarrhea (10%), mucositis (3%), asthenia (18%), vomiting (13%), increased transaminases (7%).

• UFT.

UFT is a drug consisting of fluoroufur and uracil. The molar ratio of these components is 1: 4. The effectiveness of the drug is registered in 22.7% of cases.

• UDR (floxouridine). This synthetic analogue of deoxyuridine is a metabolite of fluorouracil. The drug is administered intravenously or intraarterially. With IV introduction, the dose of FUDR is 0.1-0.15 mg / kg per day - 14 days; cycles are repeated every 4 weeks. When administered intraarterially, the dose of FUDR is 0.2-0.3 mg / kg per day, 14 days; cycles are repeated every 4 weeks. Of the complications of FUDR are: nausea, vomiting, mucositis, diarrhea (29%), gastritis, headache, itching, dermatitis, increased transaminases.
• Irinotecan or Campto (Cpt-11). Refers to topoisomerase I inhibitors. It is analogous to camptothecin.  It is administered intravenously, in a dose of 350 mg / m ² once in 3 weeks (5-6 doses).  Among the complications are diarrhea, neutropenia, sometimes with fever, vomiting, allergic reactions, stomatitis. In pancreatic cancer, 12% of patients are effective.
• Paclitaxel (Tach). It is a complex diterpen with a taxane ring and a carbohydrate chain (necessary for antitumor activity). Paclitaxel is of vegetable origin, isolated from the bark of the Californian yew. Tah - (the first active drug from the taxane group) stimulates chaotic and incorrect formation of microtubules from tubulin and then prevents their disintegration. These disorders of the skeleton of tumor cells lead them to death. In 20% of Tach, the stabilization of the tumor process was noted. Tach is administered in doses of 175-200 mg / m ² IV, infusion, for 3 hours (sometimes 24) 1 every 3 weeks with premedication. Of the side effects observed myelosuppression, anemia and thrombocytopenia, a drop in pressure (12%), neurotoxicity (60%), anorexia, alopecia, vomiting and mucositis are not frequent.
• Docetaxel or Taxotere (Thx). The mechanism of action of the drug consists in the destruction of the cell skeleton due to the stimulation of the formation of microtubules and the suppression of their depolymerization. Txt IV is used in doses of 100 mg / m ² once in 3 weeks (5-6 cycles). To reduce hypersensitivity, premedication with diphenhydramine and steroids is also required.Of the side effects observed: neutropenia (70%), dermatological toxicity (60%), fluid retention (30-68%), diarrhea (31%), stomatitis (20%), neurotoxicity (12%), other complications are rare.
• Gemcitabine or Gemzar (Gem).Gem is a fluorine-substituted deoxycytidine analogue, close in structure to the cytosar. However, unlike the latter, it is more lipophilic, and as a result, it quickly passes through the membranes of tumor cells. He has more affinity for the target - deoxycidinase, his active metabolite gemcitabine triphosphate for longer than the cytosar is in the tumor cell.Gemzar is applied iv in 1000 mg / m ² in 1,8,15 days, every 4 weeks. Among complications from the use of Gem: leukopenia (19%), thrombocytopenia (22%), asthenia (12%), peripheral edema (10%).
• Erlotinib (Tarceva).Erlotinib (Tarceva) is a reversible and highly specific inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR). The tyrosine kinase is responsible for the process of intracellular phosphorylation of HER1 / EGFR. Expression of HER1 / EGFR is observed on the surface of both normal and tumor cells. Inhibition of phosphotyrosine EGFR inhibits the growth of tumor cell lines and / or leads to their death.In pancreatic cancer, 100 mg daily is used, long-term, in combination with gemcitabine.

• Combined chemotherapy of unresectable pancreatic cancer

In recent decades, various combinations of chemotherapy have been used to treat pancreatic cancer.

• Combinations based on fluorouracil.
• Combination FAM.The combination consists of fluorouracil, used at 600 mg / m ² IV once a week for 1,2,5,6 and 9 weeks; doxorubicin, applied at 30 mg / m ² once a week for 1.5 and 9 weeks; mitomycin C, applied at 10 mg / m ² once a week for 1 and 9 weeks.

• Combination of SMF.From FAM, the combination is distinguished by the replacement of doxorubicin with streptozotocin.
  There were 2 varieties of SMF:

• SMF1 (streptozotocin 1 g / m2 IV, once a week, at 1,2,5,6 and 9 weeks, mitomycin C 10 mg / m ² IV once a week at 1, 6 and 9 weeks, fluorouracil 600 mg / m ² once a week at 1,2,5,6 and 9 weeks).
• SMF2 (streptozotocin 350 mg / m ² once a week, at 1-5 and 9th weeks, mitomycin C 10 mg / m ² once a week at 1 and 9 weeks, fluorouracil 600 mg / m ² once in week 1-5 and 9th week).
• MFL mode. Mitomycin C 12 mg / m ² day 1, fluorouracil 400 mg / m ² 1-5 days and leucovorin 200 mg / m ² 1-5 days. The regimen is applied every 4 weeks.

• Combination of EVFL. It consists of epirubicin (60 mg / m ² day 1), etoposide (80 mg / m ² intravenously 1-3 days), fluorouracil (340 mg / m ² 1-3 days) and leucovorin (100 mg / m ² intravenously 1 - 3 days). Antitumor effect was registered in 15% of patients.

• Combinations based on cisplatin.
• Combination of FAP. It consists of fluorouracil, doxorubicin and cisplatin.
• The combination of FP includes fluorouracil (1 g / m ² IV / 1-5 days) and cisplatin (100 mg / m ² day 2). The cycles are repeated every 4 weeks. The effect was registered in 26% of patients.
• The combination of CAS consists of cisplatin, cytosar and caffeine. Achieved The effect is achieved in 39% of cases.
• Combinations using gemcitabine (gemzar).
• Gemzar (1000 mg / m ^2, 1.8.15 days) is combined with infusion of fluorouracil (200 mg / m ² 1-5 days).
• The combination of gemzar + fluorouracil + leucovorin. The recommended Gem regimen is 1000 mg / m ² IV IV, 1.8.15 days; FU 500 mg / m ² 1-5 days; FA 20 mg / m ² 1-5 days.

• Radiation therapy

The treatment is performed preoperatively, intraoperatively, postoperatively, in combination with chemotherapy.

Radiation therapy of patients with pancreatic cancer uses different doses of radiation.

For palliative purposes (control of pain syndrome, jaundice, prevention of bleeding), the dose of irradiation is 50 Gy. Higher doses greater than 60 Gy are given to patients with a view to improving survival rates.

Preoperative irradiation is rarely used.

Intraoperative irradiation can be combined with the external one in order to increase the dose to the pancreas and provide better local disease control. The dose of intraoperative radiation varies from 10 to 20 Gy; outdoor - from 45 to 50 Gy. Remission during the year is observed in 82% of patients.

• Chemoradiation treatment of pancreatic cancer One of the ways to improve the results for inoperable pancreatic cancer is the combination of radiation therapy and promising antitumor drugs.

• Radiation therapy and gemzar.
• 20 external irradiation fractions (dose 35 Gy) with a 2-week break after 10 fractions. Gemzar in a dose of 400 mg / m ²is prescribed 2 times a week for 1-3 and 5-7 weeks.
• Gemzar in a dose of 1000 mg / m ² for 1.8.15 days of external radiation therapy (dose of 27 Gy, 15 fractions).
• Radiation therapy and fluorouracil.
• The combination of radiotherapy (60Gy) + (FAP) fluorouracil + doxorubicin + cisplatin.
• The combination of FEP (fluorouracil 200 mg / m ² - long infusion + epirubicin 50 mg / m2 and cisplatin 60 mg / m ²once every 3 weeks, together with conformal irradiation (63 Gy for 6 weeks).
• Other combinations. Radiation therapy (45 Gy) is combined with UFT (150-300 mg per day) and leucovorin (90 mg per day).

• Neoadjuvant and adjuvant therapy of pancreatic cancer Adjuvant therapy (surgery and postoperative chemoradiotherapy) is one of the options for treating pancreatic cancer. However, less than 20% of patients are operable by the time of primary diagnosis, so the maximum result from adjuvant treatment can be obtained only in 4% of patients from the total number of cases.
  
  The neoadjuvant approach to the treatment of locally advanced pancreatic cancer allows to increase the percentage of resectable tumors to 40% (20% due to potentially resectable patients and 20% due to unresectable patients at the time of primary diagnosis by restaging) and to extend the life of patients.
  In the context of the neoadjuvant approach, chemoradiation can be used prior to surgery. In some cases, preoperative radiotherapy is carried out followed by intraoperative irradiation. This type of therapy increases the survival rate of patients under 2 years in 27% of cases; up to 5 years - in 7% of cases.Use as a neoadjuvant treatment only chemotherapy does not lead to a significant increase in survival rates.

• Palliative Therapy
• Management of pain syndrome.
• For this purpose, narcotic analgesics are used in combination with tricyclic antidepressants or antimetics (which can also potentiate the action of analgesics).
• Neurolysis of the celiac ganglia can lead to a decrease in the intensity of pain. The procedure is performed transthoracally, transabdominally, transgastrically or during surgery.
• Radiotherapy also contributes to partial relief of pain syndrome.
• Elimination of jaundice.
• When obstructive jaundice appears, patients begin to worry about itching, pain in the upper right quadrant of the abdomen (they increase after eating), or they develop cholangitis.
• If patients have pancreatic duct obstruction (in 5% of cases) or biliary tract, then endoscopic decompression with stenting is performed.
• Endoscopic decompression with stenting is performed during choledochojunostomy, cholecystectomy, gastroejunostomy or when performing a pancreatic tumor resection. For these purposes, metal and plastic stents are used (they must be changed every 3-4 months).
• If the results are unsatisfactory procedures, the patients assigned: cholestyramine (Questran) inside, 4 g 4.1 p / d .; phenobarbital (Luminal) inside, 30-60 mg 2-4 r / day.
• Treatment of violations of the exocrine function of the pancreas. Enzyme preparations are prescribed (for example, Creon ).

• Surgery

Surgical treatment is performed in the absence of distant metastases and radiographic or clinical signs of tumor non-resectability.

Preoperative notions of tumor resectability are preliminary. The final decision is made after intraoperative examination of the abdominal cavity organs (liver, peritoneum, periaortal and celiac lymph nodes) to exclude distant metastases. Then the possibilities of local resectability of the tumor are elucidated.

Pancreatoduodenal resection (Whipple's operation) is the main type of radical surgery. It is not performed when the tumor is invaded by the inferior vena cava, the aorta, the superior mesenteric artery, the superior mesenteric vein, the portal vein. To make a decision about the operation, it is necessary to mobilize the duodenum and the pancreas head from the underlying inferior vena cava and the aorta. This technique also allows you to judge the involvement of the superior mesenteric artery. It is important to assess the possibility of dissection of the portal vein and the superior mesenteric vein.

Anatomical drug removed from pancreatoduodenal resection consists of the common bile duct, gallbladder, head, neck and secretory part of the pancreas, duodenum, proximal part of the colon, small and part of the large epiploon, distal half of the stomach. In addition, paracaval tissue is excised, suprapiloric, infraroporic, anterior pancreatoduodenal, posterior pancreatoduodenal lymph nodes are removed. Lymph nodes of the hepatoduodenal ligament and in the course of the common hepatic artery are also excised. The upper scarlet vein is excised with isolated tumor lesions, or the place of its fusion with the portal vein.

The surgeon needs to perform a series of restorative manipulations (pancreatojunostomy, biliodigestive anastomosis, gastroejunostomy and intercusive anastomosis).

Extended pancreatoduodenal resection involves the removal of the portal vein segment and the arteries involved in the tumor process with vascular reconstruction. In addition, retroperitoneal lymph nodes are removed (from the celiac artery to the ileal bifurcation).

The risk of a fatal outcome in the postoperative period is 5%. The parameters of 5-year survival after pancreaticoduodenal resections reach 20-25%, with an average survival of 8-11 months.

Tactics of management of patients with pancreatic cancer

Patients with pancreatic cancer should be observed by a gastroenterologist, oncologist, surgeon and radiologist.

• Only 15-20% of patients with pancreatic cancer are resectable. He underwent pancreatoduodenal resection (Whipple's operation) followed by postoperative chemoradiotherapy.
• Approximately 30% of patients are diagnosed with unresectable, locally advanced tumors without distant metastases. In these cases, chemotherapy and ionizing radiation are prescribed.
• The neoadjuvant approach to the treatment of locally advanced pancreatic cancer can increase the percentage of resectable tumors and extend the life of patients.
• Prior to surgery, chemoradiotherapy may be used. In some cases, preoperative radiotherapy is carried out followed by intraoperative irradiation. This type of therapy increases the survival rate of patients under 2 years in 27% of cases; up to 5 years - in 7% of cases.
• If the tumor is not resectable, and there is jaundice, then chemotherapy and palliative surgical procedures are performed (endoscopic decompression with stenting).
• In the presence of distant metastases, chemotherapy and palliative treatment are carried out, aimed at stopping the symptoms of the disease (pain).

Prognosis

The prognosis for pancreatic cancer is generally unfavorable.

The average life expectancy of patients is 4-6 months. The indicators of 5-year survival are less than 3% of patients.

Annually, about 30 thousand patients with pancreatic cancer die in the United States. Among patients aged 70 years, the death rates from pancreatic cancer are 60: 100,000 annually.

Pancreatic cancer in the United States ranks fourth in the structure of the causes of death after lung cancer, lactic and prostate gland, colorectal cancer.

Factors affecting the prognosis include: timeliness of diagnosis, stage of the disease, type of tumor. In most cases, pancreatic cancer is diagnosed in later stages. Approximately in 80-90% of patients at the time of diagnosis, the tumor is inoperable, due to metastases or invasion of nearby organs.

• Median survival in patients with unexplained cancer is 12 months.
• Median survival in patients with metastatic cancer is 3-6 months.
• Only 15-20% of patients have surgery in a timely manner. In these cases, the median survival is 12-19 months.
• After surgical treatment (Whipple's operation - complete pancreatoduodenectomy) the prognosis remains unfavorable, since the relapse rate is 80-90%. Five-year survival rates after Whipple's operation reach only 25-30% of patients without metastases and 10% of patients with metastases.
• The type of tumor affects the life expectancy of patients.
• In patients with protocol adenocarcinomas, the median survival is 16 weeks. One-year survival is observed in 17% of patients, 5-year survival in 1% of patients.
• With giant cell adenocarcinomas, the median survival is 8 weeks; with mucinous adenocarcinomas - 44 weeks (and one-year survival is observed in 33% of cases).
• In ferruginous-squamous cell carcinoma - 24 weeks (indicators of one-year survival rate - 5%); with acinar cancer - 28 weeks (the indicators of one-year survival reach only 14% of patients).
• In mucinous cystadenocarcinomas, complete pancreas resection allows patients to achieve 5-year survival in 65% of cases.