Pancreatic cancer

from Wikipedia, the free encyclopedia
Pancreas and adjacent organs
Classification according to ICD-10
C25.- Malignant neoplasm of the pancreas
C25.0 Pancreatic head
C25.1 Pancreatic body
C25.2 Pancreatic tail
C25.3 Pancreatic duct
C25.4 Endocrine glandular portion of the pancreas, including: islets of Langerhans
C25.7 Other parts of the pancreas, including the neck of the pancreas
C25.8 Pancreas, overlapping several areas
C25.9 Pancreas, unspecified
ICD-10 online (WHO version 2019)

Pancreatic cancer , technically pancreatic carcinoma , are malignant (malignant) tumors of the pancreas ( ancient Greek πάγκρεας pánkreas ). The majority of tumors affect the part of the pancreas that forms the digestive enzymes and mainly the ducts within the organ. These "ductal adenocarcinomas " are among the most common cancers . The most important risk factors are inflammation of the pancreas , alcohol abuse , tobacco smoking and some hereditary diseases . The most common symptoms are a steadily increasing jaundice , abdominal pain radiating into the back and increasing in strength at night, as well as indigestion and weight loss .

Pancreatic carcinomas grow aggressively and form daughter tumors ( metastases ) early on . So far, they can only be treated by surgical removal , but four out of five malignant pancreatic tumors are only recognized at such an advanced stage that a cure is no longer possible. Chemotherapy and radiation therapy play a supportive role in the treatment of pancreatic cancer. During the operation, the pancreas is partially or completely removed ( pancreatectomy ) and the interrupted bile and pancreas outlets are reconnected to the intestinal tract. The cure rate has gotten better over the past few decades; Nevertheless, palliation (relief) and the best possible supportive treatment measures ( best supportive care ) still play a large role in the pancreatic centers.

In addition to the malignant tumors of the pancreas, there are also benign tumors , such as the serous cystadenoma.

history

The Greek doctor Rufus of Ephesus is said to have described the pancreas as an organ for the first time. Galenus noticed that it secreted a secretion , but thought the organ was a cushion for the stomach - an idea that lasted until the mid-17th century. The digestive function of the secretion was finally proven by Claude Bernard in the middle of the 19th century .

Operations on the pancreas, especially with the removal (resection) of larger parts of the gland, have long been considered impossible. It was not until the end of the 19th century that individual such interventions were made, and by 1898 only nine distances had been published. A successful left resection (see below) by Friedrich Trendelenburg in 1882 is known. In 1890, Oskar Minkowski and Josef von Mering discovered that the removal of the pancreas causes diabetes , and thus indirectly discovered insulin , which Frederick Banting and Charles Best isolated for the first time in 1921 has been. In 1940 Allen Oldfather Whipple standardized the surgical technique developed by Walther Kausch and presumably also at about the same time by Alessandro Codivilla , in which the pancreas and duodenum are removed together. This procedure is still one of the standard procedures in use today. The most difficult problem with resections was always ensuring that pancreatic secretions could flow into the intestines. From around 1950 surgeons developed improved methods and instruments for this, starting with Charles Frey's idea of sewing up the rest of the pancreas with an opened loop of intestine.

Deaths of celebrities like that of the actor Patrick Swayze in the fall of 2009 or the tenor singer Luciano Pavarotti in February 2007 as well as the years of struggle of the Apple founder Steve Jobs with this disease - he suffered from a rare but easily treatable sub-form ( neuroendocrine pancreatic tumor ) and died in October 2011 - helped make pancreatic cancer more widely known.

anatomy

Location of the pancreas

The pancreas is a 40 to 120 g gland in the retroperitoneum , behind the stomach , to the left of the duodenum and is divided into a head, a body and a tail. The tail touches the spleen and kidney on the left . The main bile duct crosses the head of the pancreas on the right. The aorta and several large intestinal arteries ( celiac trunk , upper mesenteric artery , splenic artery ) are in close contact with the pancreas, as are the inferior vena cava and the portal vein . All of these structures can be affected by pancreatic cancer. The ducts for the pancreatic secretion ( Wirsung duct and the Santorini duct, which rarely occurs in humans ) run through the entire organ and can be blocked by the tumor. The pancreas receives its blood supply from the celiac trunk and the upper mesenteric artery, sometimes also from a deviating hepatic artery , which can make operations much more difficult. The used blood drains into the superior mesenteric vein and the splenic vein. The lymph flows in all directions to the nearest lymph node groups ( pancreas , upper and lower pancreas-duodenum , liver , celiac , upper mesenteric , spleen and upper para- aortic lymph nodes), all of which can be affected by metastasis.

The pancreas is predominantly exocrine ("excreting to the outside"): its digestive secretions are released into the duodenum through the two ducts. It also contains endocrine ("inwardly excreting") cell groups in the so -called islets of Langerhans , which produce hormones (including insulin and glucagon ) and release them into the blood. Both tissues can in principle develop tumors. Over 95% of pancreatic tumors arise from the exocrine organ, more precisely from the duct epithelium and the acinar cells . In addition to benign cystadenomas and mucinous cystomas, they are mainly carcinomas . In contrast, tumors of the endocrine pancreatic tissue occur almost exclusively in hereditary syndromes . They are counted among the neuroendocrine tumors .

Three quarters of the tumors arise in the head of the pancreas, the rightmost part of the duodenum. 20% of the tumors occur in the middle part (corpus) and five percent in the left-sided tail of the pancreas.

Frequency and causes

New cancer cases in Germany in 2012

Pancreatic carcinoma, by far the most common pancreatic tumor, causes around 14,000 new cases in Germany every year - the rate of new cases is around 18 per 100,000 inhabitants per year. In the German cancer statistics it is tenth for men and ninth for women (as of 2006). It ranks fourth in cancer deaths. The sick are mostly older than 60 years. Men are more often affected than women (1.6: 1). In Switzerland, between 2010 and 2014, an average of 1,292 people fell ill each year (51.5% women; 48.5% men) and 1,177 people died each year.

In addition to age, the most important risk factor is chronic pancreatitis (inflammation of the pancreas): around one in 50 people affected will develop carcinoma within ten years. Diabetes doubles the risk of carcinoma for an unknown reason. Lifestyle- related dangers are cigarette smoking (smoking cessation reduces the risk by half after two years), vitamin D deficiency , extremely overweight ( BMI > 30) and a high-fat diet. Congenital risks are syndromes with a generally increased incidence of cancer such as Peutz-Jeghers syndrome , hereditary pancreatitis and cystic fibrosis . Two or more pancreatic cancer cases in close relatives increase the risk many times over. Screening is currently only recommended for families with hereditary pancreatitis or multiple cases of pancreatic cancer; An annual endoscopic ultrasound from the age of 50 is then common . Approximately 5% of patients have an inherited mutation in one of the two genes BRCA1 or BRCA2 . This mutation brings with it an increased risk of developing certain types of cancer ( breast cancer is most common in women , but also pancreatic cancer). If these types of cancer have occurred conspicuously frequently in the family, the patient suffering from pancreatic cancer should also be genetically tested for it, as this may offer the possibility of more targeted treatment (see below).

Chemical carcinogens ( naphthylamine , benzidine or nitrosamines ) can increase the risk of the disease. Also chlorinated organic compounds and polyaromatic hydrocarbons are suspected.

The cancers are characterized by aggressive growth, rapid metastasis, and poor response to available treatments. This is also due to the particularly high degree of degeneration: growth-regulating or tumor-suppressing genes such as those for HER2 / neu , KRAS , p16 , p53 and DPC4 are very often inactivated by mutations in the tumor cells .

pathology

Surgically removed tumor with attached duodenum
Histology of ductal adenocarcinoma of the pancreas

Pancreatic tumor cells can be similar to cells of the ducts, the acini and islets of Langerhans , but they can also have a mixed character. As a rule, the pathologists use the WHO classification of malignant tumors, currently in the 2010 edition. Most malignant tumors ( malignancies ) are then referred to as variants of ductal adenocarcinoma , classified from highly differentiated to undifferentiated. There are also acinar cell carcinomas, mucinous cystadenocarcinomas and intraductal neoplasms (see below) . Endocrine Langerhans cell carcinomas, nonepithelial malignancies ( lymphomas and sarcomas ) are rare, as are pancreatic metastases from other organ tumors. The most common benign tumor is the serous cystadenoma.

Adenocarcinoma

Adenocarcinomas of the duct system can form directly or develop from so-called precancerous lesions . These are superficial growths of the epithelium , whereby especially papillary hyperplasia - according to the new nomenclature pancreatic epithelial neoplasia 3 (PanIN 3) - are considered dangerous. Benign tumors such as the cystadenoma and intraductal papillary neoplasms also show an increasing risk of degeneration with increasing size.

In the case of adenocarcinomas, depending on their degree of degeneration, glandular tubes filled with mucus with a cylindrical epithelium can still be seen under the microscope (“ductal type”). The nerve sheaths are almost always tumor-infiltrated. Another characteristic is a compression of the surrounding connective tissue (“desmoplastic reaction”), which is difficult to distinguish from the actual tumor in the imaging process . The most important histological variants of ductal adenocarcinoma are adenosquamous carcinoma , mucinous non-cystic carcinoma, and anaplastic (undifferentiated) carcinoma . After the degree of de-differentiation, the pathologist assigns the grading G1 to G4.

Carcinomas are usually 2 to 5 cm in size at the time of diagnosis (can be detected by imaging from about 1 cm in size). They are indistinctly delimited, of a firm consistency and gray-yellowish color, often centrally necrotic . There is often a narrowing ( stenosis ) of the stretch of the bile duct running through the pancreas, and often also a stenosis of the pancreatic duct . The tumor can grow into the wall of the duodenum , and it can also infiltrate important vascular structures such as the upper mesenteric artery , the splenic vein , the portal vein and / or the inferior vena cava . The determination of these investments for the staging (staging) and thus for the further therapeutic approach of great importance.

Most ductal adenocarcinomas express mucins 1 (Ca 15-3), 3, 5/6, and 16 (Ca 125) as well as the glycoprotein CA 19-9 on cell membranes .

The first metastases are found in the neighboring lymph nodes and - via the bloodstream of the portal vein - in the liver . Tumors in the pancreatic body and tail are usually larger than pancreatic head tumors at the time of diagnosis and have mostly already led to liver metastases or infiltration of the peritoneum ( peritoneal carcinosis ).

Papilla tumors of the Vateri

The tumors in the area of ​​the joint mouth of the bile duct and pancreatic duct ( Papilla Vateri ) are mostly adenocarcinomas; they are sometimes said to arise from tubulovillous adenomas . The prognosis for optic disc carcinoma is relatively good, since jaundice , which occurs quickly, leads to early detection. Spread and metastasis are the same as in pancreatic cancer.

Intraductal papillary-mucinous tumor (IPMT)

Magnetic resonance imaging of an IPMT

The IPMT is also known as intraductal papillary-mucinous carcinoma . This tumor spreads within the duct system, usually starting in the head part of the pancreas. A distinction is made between a main duct type (poorer prognosis), a side branch type and a combined type. The normal duct epithelium is replaced by highly cylindrical neoplastic cells in small-nodular wart-shaped (papillary) growths that form viscous mucus that is difficult to drain off and the duct section irregularly expands to three or four centimeters. The tumor cells can cover the entire pancreas. About 30% of the patients already have vascular invasions and thus an invasive carcinoma; because of the mucous pools in the microscopic image, it is often referred to as mucinous non-cystic carcinoma or colloid carcinoma . Nevertheless, the prognosis for this type of tumor is comparatively very good with more than 90% long-term survival.

Mucinous cystic tumor

The mucinous cystic tumor is also called mucinous cystadenoma or cystadenocarcinoma . This tumor can be benign or malignant. Computed tomography or magnetic resonance tomography images cannot differentiate between these, which is why benign and malignant variants are summarized under this term and always operated on, regardless of the symptoms. 40 to 60 year old women are particularly affected. The tumors, 2 to 12 cm in size, have a wide capsule of connective tissue . They usually consist of fewer than six large cysts that are lined with mucin-producing columnar epithelium. If the surgical removal is successful, the prognosis for this tumor is good; even the malignant variant achieves five-year survival rates around 75%.

Acinar cell carcinoma

This rare acinar cell tumor is twice as common in men as in women (peak age: 55–65 years). Although the tumors are usually relatively large (4–6 cm), they are often not discovered until they have metastasized to the liver. Occasionally, due to a massive secretion of lipases , fatty tissue necrosis under the skin and joint pain occur.

Serous cystadenoma

Histology of a serous cystadenoma of the pancreas

Serous cystadenoma, also known as microcystic (cyst) adenoma , is a benign tumor that is predominantly observed in older women. It is more often in the head of the pancreas, but any region can be affected. Cystadenomas can grow 6 to 10 cm in size. In contrast to the mucinous-cystic tumor (see above), they consist of small cysts with serous content that are separated by delicate septa. In the center there is a scar-like compression and often also calcifications. These cysts are lined with cubic epithelium , histologically no atypia or mitotic figures can be found . An association with the von Hippel-Lindau syndrome has been described, the tumor can occupy large sections of the pancreas. Serous cystadenoma has no tendency to degenerate and should only be removed if its size causes symptoms.

Endocrine tumors

Endocrine pancreatic tumors (synonym pancreatic neuroendocrine neoplasia, PaNEN, obsolete: carcinoids ) arise from the endocrine gland cells of the pancreas and form only about 1–2% of pancreatic tumors. At most 50% are functional, i.e. H. they produce more hormones and thereby cause symptoms of illness. These include:

An increased occurrence is found in the syndrome of multiple endocrine neoplasia (MEN1 syndrome). Apart from that, there are practically no neuroendocrine pancreatic tumors in childhood; later they appear about equally seldom in all age groups and in men and women. The prevalence is below 1 / 100,000.

Endocrine tumors are limited, single, round tumors 1 to 4 cm in diameter and can occur in any part of the pancreas. Histologically, these are tumor cells with a uniform appearance and a fine-grained cytoplasm . The cells are solid, trabecular and pseudoglandular. Endocrine tumors are immunohistologically positive for the markers NSE , Synaptophysin and Chromogranin A (CgA), the latter is also elevated in the blood serum of many patients. Under the electron microscope , neurosecretory hormone granules can be seen in the tumor cells .

According to the WHO classification from 2010, all PaNEN are potentially malignant. The histologically well differentiated tumors (neuroendocrine tumors NET) are divided into highly and moderately differentiated (<2% = G1, 2-20% = G2) according to the Ki67 / MIB1 index . The highly proliferating (Ki67 index> 20%) so-called neuroendocrine carcinomas NEC are classified as G3 and again divided into small and large cell subtypes.

Criteria for the prognostic assessment of neuroendocrine pancreatic tumors (WHO 2010) are, in addition to this degree of differentiation and the TNM classification, the presence of microscopic vascular incursions and the hormonal activity:

Risk of metastasis from PanNEN
Risk of metastasis histology differentiation TNM
minimal (benign behavior) NET, no angio invasion G1 T1 N0 M0
low NET G2 T1-2 N0 M0
considerable NET G1-2 T2> 4 cm or T3, N0-1, M0-1
highly malignant behavior NEC G3, functionally inactive every T, N, M

Insulin-producing tumors are benign in more than 90% of cases, whereas gastrinomas, glucagonomas, VIPomas and ACTH-producing and non-functional panNENs are mostly malignant. They grow and metastasize comparatively slowly, so that patients with metastases can still achieve a mean survival time of over four years.

Symptoms and Diagnosis

Cystic adenocarcinoma on CT (tumor marked red, pancreas marked in green)

Unspecific symptoms such as abnormal sensations / pressure in the upper abdomen, loss of appetite , nausea , digestive problems and depressive moods can be the first signs of pancreatic head cancer. Later, the main symptom of pancreatic head carcinoma often shows up , increasing jaundice (jaundice) that is not accompanied by colic and is caused by the narrowing of the bile duct. This jaundice is an early symptom only in papillary tumors, otherwise it is a sign of advanced findings. Abdominal pain radiating to the back (including a belt-shaped radiating pain in the middle back area) are also common, but uncharacteristic. However, the excruciating, dull pain, worsening at night, which gradually increases over the course of months and which is caused by the infiltration of the solar plexus, is often the first reason to consult a doctor. A Courvoisier sign (bulging gallbladder) is possible. Narrowing of the pancreatic duct interferes with the function of the glands , causing indigestion , weight loss of more than 10% and diabetes (including sudden onset). Other signs can be diarrhea and fatty stools (clay-like, light). Thromboses (including leg vein thrombosis) and new pigmentation of the skin are warning signs of a tumor in the abdomen. In the late stages of the disease, metastases can lead to liver enlargement , liver dysfunction, ascites and severe emaciation .

In the serum one finds unspecific inflammatory parameters such as increased CRP , as well as the pancreatic enzymes trypsin , lipase and amylase . CA 19-9 and, with reservations, also CEA are mentioned as tumor markers , but they are not specific (CA 19-9: sensitivity and specificity approx. 70%) and are therefore unsuitable as screening parameters. Better diagnostic parameters are still being sought; Research is currently focused on proteomics (protein profiles), microRNAs and on KRAS mutations in serum and bile, the latter parameter reaching over 90% sensitivity and specificity in preliminary studies.

In the case of adenocarcinoma of the pancreas (PDAC), the examination of DNA-based biomarkers in exosomal salivary DNA (exoDNA) using liquid biopsy can be used to carry out early detection, tumor stratification , therapy stratification and monitoring in patients with PDAC.

Sonography , computed tomography and magnetic resonance imaging are the diagnostic methods of choice. The task of these methods is to distinguish cancer from benign tumors. It can also be seen whether a tumor is operable. This depends on whether there are metastases and whether the arteries adjacent to the pancreas (arteria mesenterica superior, truncus celiacus, arteria hepatica) are affected by the tumor. The display of the blood vessels is usually improved by administering contrast media. The ERCP (a combination of endoscopy and X-ray contrast display) can prove the closure of the biliary or pancreatic duct and, if the location is favorable, enable a biopsy of the tumor. The endoscopic ultrasound works similarly, with a high accuracy in the assessment of the tumor and possible metastases in the environment. The puncture of the tumor is easier to perform endosonographically than with the ERCP. Special clinics occasionally also offer the newly developed pancreaticoscopy , an endoscopy that extends into the pancreatic duct system, which is still being tested and which can possibly best depict neoplasms restricted to the duct system.

If the diagnostic methods mentioned are not sufficient to reliably distinguish a severe chronic pancreatitis from a tumor, or a peritoneal prove last remains the laparoscopy (laparoscopy). Today, this procedure is usually combined with a laparoscopic ultrasound probe and an abdominal irrigation, which is known as "extended diagnostic laparoscopy" (EDL).

The clinical and technical examinations provide the tumor diagnosis and the tumor stage (degree of spread). The TNM classification is used for the internationally standardized classification of the spread of malignant tumors. In pancreatic cancer, it is done as follows:

TNM nomenclature for pancreatic cancer
T Primary tumor
TX Primary tumor cannot be assessed.
T0 no primary tumor detectable
Tis Carcinoma in situ (= earliest, not yet invasive tumor stage)
T1 largest diameter of the primary tumor ≤ 2 cm
T1a largest diameter of the primary tumor ≤ 0.5 cm
T1b largest diameter of the primary tumor> 0.5 cm and ≤ 1 cm
T1c largest diameter of the primary tumor> 1 cm and ≤ 2 cm
T2 largest diameter of the primary tumor> 2 cm and ≤ 4 cm
T3 largest diameter of the primary tumor> 4 cm
T4 Adjacent large arteries are infiltrated ( celiac trunk , superior mesenteric artery and / or common hepatic artery ).
N regional lymph nodes
NX The regional lymph nodes cannot be assessed.
N0 no regional lymph node metastases
N1 Metastases in 1 to 3 regional lymph nodes
N2 Metastases in> 3 regional lymph nodes
M. Distant metastases
MX Distant metastases cannot be assessed.
M0 no distant metastases
M1 Distant metastases

The spread of the tumor determines the stage of the tumor, according to which the treatment will be based.

UICC stages for pancreatic cancer
stage
IA T1 N0 M0 (tumor up to 2 cm, no metastases)
IB T2 N0 M0 (tumor within the pancreas, no metastases)
IIA T3 N0 M0 (tumor still operable, no metastases)
IIB T1-3 N1 M0 (tumor still operable, with regional lymph node metastases)
III T1-4 N2 M0 (locally advanced, without distant metastases)
IV T1-4 N0-2 M1 (distant metastases)

Notes: This classification only applies to carcinomas of the exocrine pancreas. A separate classification applies to tumors of the ampulla of Vater and to well-differentiated neuroendocrine tumors of the pancreas

Stages T1 to T3 also apply if there is an invasion of the peripancreatic soft tissue.

Regional lymph nodes of pancreatic head carcinoma are located

Regional lymph nodes of pancreatic carcinoma of the body and tail are located

  • on the common hepatic artery
  • on the splenic artery and on the splenic hilum
  • celiac lymph nodes
  • lateral aortic lymph nodes

Any involvement of non-regional lymph nodes requires the classification M1.

treatment

Scheme of partial removal of the middle pancreas

Blocked biliary tracts can first be cleared with an endoscopically placed stent (tube) to improve the general condition of the patient. There are also procedures in which the bile is drained out of the liver through a catheter. If both are impossible, limited surgery can provide relief. In the case of operable tumors, due to the risk of ascending infections and wound healing disorders, prior discharge is usually dispensed with, with the exception of the most severe congestion (e.g. bilirubin level> 10 mg / dl). Further initial measures are directed against the often (25%) existing malnutrition , which significantly increases the risk of surgery, against protein and vitamin deficiencies (especially fat-soluble vitamins) and against diabetic metabolic disorders.

In December 2013, the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) published an updated S3 guideline "Exocrine pancreatic carcinoma" in order to improve care and meet current findings.

Operative treatment

Are about four of five pancreatic cancer, if detected, too advanced and can no longer (with the aim of healing curative ) surgery are. Even if there are only individual liver metastases, in contrast to colon cancer , removing them does not cure. Tumors that have neither infiltrated large arteries nor caused distant metastases (UICC stages I and II) can in principle be removed completely. Infiltrated veins do not make the procedure impossible; Affected lymph nodes are also removed. It is controversial whether unaffected lymph nodes should be removed as a precaution.

It makes sense to preserve part of the organ and reconnect it with the intestine. Depending on the location of the tumor, a right-sided partial resection ( duodenopancreatectomy , several variants), a middle partial resection, a left-sided partial resection (pancreatic tail resection, usually with removal of the spleen ) or a total resection (complete removal) of the pancreas is performed, mostly including all regional lymph nodes. The stomach and bile duct need to be reconnected to the intestines. Either one or more pulled up small intestine loops are used for this, which are connected without tension. If several loops of the small intestine are used, these are reconstructed using the classic method devised by César Roux . After a partial resection, the duct of the remaining pancreas can be connected to both the small intestine and the stomach.

All of the interventions mentioned are serious and time-consuming. Early complications such as pancreatitis , sepsis , anastomotic leakage (leaks in the intestinal sutures), wound healing disorders and fistulas (abnormal duct systems) are very common. If the lymph ducts are severely injured, chylascos (lymph leakage into the abdominal cavity) can result. The most threatening complication is rebleeding from large blood vessels, which is a threat especially in the event of multiple perioperative manipulations (ERCP) or inflammation in the surgical area. About ten percent of patients get diabetes after partial resections and, without exception, all of them after total resection of the pancreas. The missing digestive enzymes usually have to be replaced in capsule or tablet form for life.

  • Operation variants

  • Pylorus- conserving partial resection

  • Final state after Whipple operation

  • Total pancreatic resection

  • Final condition after total resection

The enucleation (enucleation) is a highly tissue-saving technique in which only the tumor is removed. It is suitable for benign findings and superficial neuroendocrine tumors. The tumor must be at a distance from the duct system.

With a segment resection , defined parts of the pancreas are removed: either the head including the duodenum, the middle (central) section or the left-sided part. The spleen can be removed with it or, in appropriate cases, left in place. Tissue cut from the duct must either be drained into a Roux Y-shaped (i.e. end-to-side) loop of the small intestine or drained into the stomach.

The pylorus-preserving duodenopancreatectomy by the Californian surgeons Longmire and Traverso, in contrast to the Kausch-Whipple operation, preserves the entire stomach up to the porter muscle ( pylorus ).

The subtotal or total removal of the pancreas brings the highest mortality with it as a maximum intervention. It is used in around 6% of operations. Brittle diabetes , which is difficult to control, is a dreaded complication .

The extent to which the neighboring lymph nodes should also be removed as a preventive measure has not yet been conclusively clarified. Every second patient has developed lymph node metastases on admission to the hospital. The standard lymphadenectomy includes the lymph nodes around the pancreas and the duodenum, as well as those to the right of the upper mesenteric artery and partially those from the hepatic-duodenal ligament . The radical concept completely skeletonizes the celiac trunk, the liver-duodenal ligament and the aorta at the level of the pancreas. A Japanese approach that goes even further includes all lymph nodes in the abdominal aorta from the diaphragm to the terminal branch. An increase in the healing rate of these variants has not yet been proven.

Palliative operations serve to relieve symptoms. For example, a choledochojejunostomy creates a connection between the congested bile duct and the intestine to drain the bile from the liver. If there is a threat of occlusion of the duodenum, establishing a connection between the stomach and intestines (gastrojejunostomy) can be useful.

Chemotherapy and radiation therapy

According to the current phase II studies, chemotherapy performed before the operation (“ neoadjuvant ”) can shrink some advanced tumors so much that they become operable, but the data are still too weak for a general recommendation. The same applies to the neoadjuvant combination of chemotherapy and radiation therapy ( radiochemotherapy ), which is being tested in smaller studies. Only when the standard chemotherapy no longer works is a combination of oxaliplatin , 5-fluorouracil (5-FU) and folinic acid (OFF scheme) used as a second line . As a first-line therapy against neuroendocrine tumors, the ENETS recommends the administration of somatostatin receptor analogues or everolimus, depending on the growth tendency. Furthermore, a combination chemotherapy of streptozocin with doxorubicin or 5-FU is used, for highly malignant neuroendocrine tumors cisplatin and etoposide . Alternatively, temozolomide and capecitabine are being tried. Another treatment specific to neuroendocrine tumors is peptide-mediated radioreceptor therapy.

On the other hand, post-operative ( adjuvant ) chemotherapy is the recognized standard because the recurrence rate (see below) is extremely high. 1 × 1000 mg / (m² KOF ) gemcitabine every week for three weeks, then a one-week break, then the next cycle, is the most common scheme in Europe. In the USA, 5-fluorouracil is more commonly used. Combinations of several cytostatics have not yet improved the effect on carcinomas, but are the standard for NETs. Radiochemotherapy has been shown to increase local tumor control, but it does not reduce metastasis or mortality, so it is usually avoided.

Chemotherapy options for metastatic or inoperable pancreatic cancer
chemotherapy Therapy benefit / median survival
Gemcitabine
monotherapy
3 weeks		 Overall survival at 5.9 months
Gemcitabine
+ Erlotinib		 Erlotinib was only beneficial in those patients who developed a rash; Overall survival in these patients 10.5 months
FOLFIRINOX only in patients with ECOG 0 to 1, age <75 years, normal bilirubin, many side effects!
Overall survival 11.1 months
Gemcitabine
+ nab-paclitaxel		 Overall survival increased from 6.6 to 8.7 months compared to gemcitabine monotherapy
nal-irinotecan
+ 5FU / FA		 Approved for patients after therapy containing gemcitabine; Overall survival was significantly better compared to 5FU / FA monotherapy with 6.1 versus 4.2 months
Olaparib maintenance therapy In metastatic patients with a BRCA1 / 2 mutation who had previously received platinum-containing therapy under which they were not progressive (progression-free, but not overall survival improved).
So far (08/2019) not approved!

Incurable (i.e., primarily inoperable or metastatic) tumors can be treated palliatively with chemotherapy , e.g. B. with gemcitabine . Carefully dosed chemoradiotherapy can also help relieve pain. Another approach is to inject the cytostatic agent into an artery supplying the tumor via a catheter inserted from the inguinal artery, e.g. B. in the arteria pancreatica magna (locoregional chemotherapy) . This allows the dose to the tumor to be increased without additional side effects. So far, however, there have only been phase I studies (small case series) on this expensive and technically very complex method.

As with many other cancers, the medicine is also in pancreatic cancer increasingly on targeted cancer therapy (targeted therapy) , d. H. on monoclonal antibodies , other biologics and small molecules . Outside of studies, the tyrosine kinase inhibitor Erlotinib is approved against pancreatic cancer; also the tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus against endocrine tumors.

Erlotinib is usually given in combination with gemcitabine (3 weeks). A therapeutic study showed that adding Erlotinib to Gemcitabine resulted in a small but statistically significant increase in median overall survival (6.24 versus 5.91 months). However, this benefit was only limited to the subgroup of patients who developed a significant rash during therapy. This group of patients had a median overall survival of 10.5 months. It is therefore recommended to only continue treatment with erlotinib if a rash has appeared after eight weeks at the latest.

More intensive therapies can also be carried out in metastatic or primarily inoperable patients who are in very good general condition ( ECOG score 0-1). One such therapy regimen is FOLFIRINOX (5-fluorouracil, leukovorin, oxaliplatin, irinotecan). With FOLFIRINOX, these patients had significantly better overall survival than with gemcitabine monotherapy (11.1 versus 6.8 months). However, this advantage has to be paid for with significantly higher side effects. The situation is similar with the combination of gemcitabine / nab paclitaxel (albunmin nanoparticle-bound paclitaxel), which in a phase III study improved the median overall survival of metastatic patients to 8.7 months. Paclitaxel is approved in Germany in combination with gemcitabine for the treatment of adenocarcinoma of the pancreas.

In February 2016, the results of a three-arm international phase III study were published in the journal The Lancet . In this so-called NAPOLI-1 study , patients with metastatic pancreatic cancer who had previously received a therapy containing gemcitabine were treated. One study arm consisted of treatment with 5-fluorouracil and folinic acid (5FU / FA), a second of treatment with nanoliposomal irinotecan (“nal-irinotecan”, “nalIRI”), and a third, later added study arm contained a combination of all three drugs . The median survival of the patients in the third study arm was, at 6.1 months, significantly better than that of the patients in the first study arm (5FU / FA, 4.2 months). In contrast, nalIRI monotherapy was not significantly better than 5FU / FA therapy. As a consequence of this study, the combination treatment nalIRI + 5FU / FA for patients with metastatic pancreatic cancer and prior gemcitabine-containing therapy was approved in October 2016.

Somastostatin analogues such as octreotide and interferon- alpha can be used against the symptoms caused by hormone-producing (functionally active) tumors, but this does not stop the disease. If first-line chemotherapy fails, peptide receptor radionuclide therapy (PRRT) can be tried, in which an effective radionuclide is chemically coupled to a suitable ligand and injected into the bloodstream.

A study published in July 2019 found that disease-free survival (but not overall survival) in patients with metastatic pancreatic cancer who had a BRCA1 or BRCA2 mutation and had previously received platinum-containing therapy (e.g. FOLFIRINOX) , significantly improved when they subsequently received maintenance therapy consisting of olaparib (2 × 300 mg daily). Only patients were included in the study who had shown no disease progression on previous platinum-containing therapy.

forecast

Liver metastasis

With the improved surgical techniques and chemotherapy, the cure rates have improved somewhat. However, the prognosis for pancreatic carcinomas is still one of the worst of all cancers: according to recent studies, the five-year survival rate after a curative procedure followed by chemotherapy is 20%, at most 30%. Only 10 to 20% of the tumors are still operable at the time of diagnosis. In four out of five operated patients, the tumor returns within two years and only in isolated cases can it be removed a second time. Inoperable tumors respond only to a limited extent to chemotherapy ; these patients only have a mean survival time of four to seven months, which cannot be significantly extended even with palliative chemotherapy.

In this situation, it is the responsibility of oncologists to prioritize the patient's subjective quality of life when making therapeutic decisions . This hermeneutic endpoint must be considered at least equally as well as the mechanistic endpoints such as survival rate, survival time, progression-free survival, etc. Medical practice should be based on standardized treatment paths (clinical pathways) and should take into account both scientific evidence and economic efficiency.

Important factors for the quality of life are an adequate, sufficiently high-dose pain therapy according to the WHO level scheme and expert help in coping with psychological illnesses. Best Supportive Care means not to withdraw from incurable patients, but on the contrary to offer them permanent medical help at all times. For example, it is important for cancer patients to be able to eat normally for as long as possible; Suitable diet products are to be prescribed for this and mechanical obstacles are to be eliminated as far as possible, including with palliative interventions. In the final phase, passable stents can be inserted into the intestinal tract, at least for porridge and liquid food, or it can be switched to tube feeding via a PEG . In addition to the cancer pain is itching another very stressful symptom of advanced pancreatic cancer that can be treated quite targeted and effective in a careful palliative concept.

In addition, healed patients also need care. The main goals of her rehabilitation are diet and nutritional advice, enzyme substitution with digestive enzymes ( pancreatins , fungal enzymes ), diabetes control and psychotherapeutic support measures such as group and individual discussions. Social medical assistance by appropriate specialist staff is advice according to the law on severely disabled persons , occupational rehabilitation services , home nursing , domestic help , food supply, etc. They still have to be initiated in the hospital as part of a planned discharge management.

literature

Web links

Commons : Pancreatic Cancer  - Collection of Pictures, Videos and Audio Files
Wiktionary: pancreatic tumor  - explanations of meanings, word origins, synonyms, translations

Individual evidence

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