Cancers of the pancreas are divided into two categories:
- tumors of the exocrine pancreas (with main function the production of enzymes)
- tumors of the endocrine pancreas (main function of which is the production of insulin) which are called "islet cell tumors" or "pancreatic neuroendocrine tumors".
The Islet cell tumors are relatively rare and slow growing in comparison to exocrine pancreatic tumors. Islet cell cancers sometimes release biologically active substances into the bloodstream and produce distinctive biological syndroms depending on the hormone they produce (insulin, glucagon, gastrin, and other hormones).
On the contrary, tumors of the exocrine pancreas developed from cells from the lumen of the ducts that deliver enzymes to the gastrointestinal system are called pancreatic carcinomas. Carcinomas of the pancreas are adenocarcinomas in their vast majority comprising the 95% of all pancreatic tumors while the pancreatic neuroendocrine tumors are the remaining 5% with or without biological syndrome.
The mechanism by which the cancer is developed is unknown. The postulated hypothesis is as follows: The cells that cover the interior of the ducts in the exocrine part of the pancreas for several reasons undergo some changes that are called dysplasia. These dysplastic cells can undergo additional genetic alterations and become malignant. That means that they have the ability to proliferate without any control, to invade nearby organs and to move(metastasis) to other sites of the body.
Annually 40,000 new cases of pancreatic cancer occur in the United States. Proven risk factors are not well known, probably apart from the increased age. Senior citizens above the age of 60 have increased risk to develop pancreatic cancer.
However individuals in families with known mutated BRCA-2 gene and, to a lesser extent, BRCA-1 gene are prone to suffer from pancreatic cancer. Familial syndromes are not so unusual and it is very important for everybody to inform his doctor about the cancer history of the family. A history of diabetes, the presence of obesity, chronic inflammation of the organ like pancreatitis, and a fatty diet are factors that may increase the risk of the individual for pancreatic cancer.
Despite the above mentioned associated risks there are a few others associated with pancreatic adenocarcinoma like prior stomach surgery, chronic infections from hepatitis B, infection with H. pylori, and the presence of certain types of pancreatic cysts.
Pancreatic cancer is a silent killer at least at the early stages of the disease due to the fact that the pancreas lies deep in the abdomen and grows silently for months before it is manifested by symptoms and signs.
Most patients with pancreatic cancer initially are complaining of nonspecific symptoms. Early symptoms may be quite subtle.
Identifiable symptoms and signs develop once the tumor becomes large enough to press or infiltrate nearby organs such as nerves, the intestines, the bile ducts or the portal vein. The pressure or the infiltration of these organs may produce devastating pain, nausea vomiting and/or loss of appetite, reduction of body weight, jaundice with yellow eyes or yellowish skin with itching and the appearance of leg edema. There are no gender differences.
Once the tumor metastasizes, the subsequent symptoms and signs depend on the location of metastasis and the organ involved. Frequent sites of distant metastasis for pancreatic adenocarcinoma include mainly the liver, the regional lymph nodes and the peritoneum.
These include physical examination, blood tests, chest X-rays, and other imaging studies. The ultrasound is positive approximately at the 75% of the cases. The Computed Tomograph (CT) scan and the Magnetic Resonance Imaging (MRI) are useful tools to disclose the tumor and its extent. Nevertheless when a pancreatic tumor is suspected it is absolutely necessary to obtain adequate tumor tissue (biopsy) to establish a definite diagnosis.
There are different approaches to confirm the diagnosis. The most common is the needle biopsy of a liver lesion providing that this lesion is accessible technically. But if the tumor is localized to the pancreas, a biopsy of the pancreas directly is feasible either using a CT guidance or via an endoscopic approaches throughout a gastroscopy. In order to locate the exact position of the tumor an ultrasound probe guides the biopsy needle of the endoscope. The correct diagnosis based on adequate tumor sample is the base for any therapeutic decision.
The tumor markers are useful tools but they are unable to substitute for a biopsy. The problem is that the antigen CA19-9 is tumor associated and not tumor specific that means that there are many false positive and false negative results. In other words, patients with pancreatic cancer have low or even normal CA19-9 (10%) while people with abnormal level of CA19-9 do not have pancreatic cancer. Despite the fact that CA 19-9 is not suitable to confirm a pancreatic cancer diagnosis remains a useful tool for the evaluation of the tumor response to the implemented treatment and for the follow-up.
The entity of pancreatic cancer is divided into four stages according to the tumor size, the extend of the lymph nodes involvement and the presence or absence of distant metastases (the so-called TNM system). This division give a better idea of the exact anatomic spread of the disease and has prognostic significance while directs the most useful and suitable therapeutic intervention.
Traditionally patients with pancreatic cancer are grouped into those with local disease, those with cancer in and around the pancreas (locally advanced), and those with metastatic disease. The meaning of this grouping is the different initial treatment respectively.
- Stage 1 and Stage 2 cancers (local disease) are "resectable"
- Stage 3 disease corresponds locally advanced tumors which are considered unresectable.
- Stage 4 or metastatic disease are not candidates for local interventions and need systematic approach.
Treatment for early stages
Surgery is the only treatment with curative intent for pancreatic cancer. However it is feasible only in the case where the pancreatic cancer is found at early stage (stage 1 and 2) and is localized within the pancreas. Patients with locally advanced disease may be operable under special circumstances. Approximately 20% of the patients diagnosed with pancreatic cancer have disease for which surgical intervention is applicable.
The name of the surgical procedure which performed is “pancreatoduodenectomy” or Whipple. The surgeon usually removes a part of the stomach, the duodenum, the pancreas, the bile ducts, the regional lymph nodes, and the gallbladder. It is well known that the volume of the hospital and that of the surgical team is a very significant factor for the favorable outcome for the patient.
The mortality from the surgical procedure in good hands is approximately 4%, and the 5-year survival 20%.
Treatment for locally advanced or unresectable tumors
Locally advanced or unresectable pancreatic cancer (stage 3) is by definition the pancreatic cancer which is spread into nearby local structures but without distant metastases.
In this situation the optimal treatment is the parallel administration of radiosensitizing chemotherapy with external beam radiotherapy to the pancreas and the involved areas. The goal of this treatment is to stop the growth of the cancer itself and to reduce the severity of symptoms due to the local extension of the disease. The addition of chemotherapy offers enhancement of the radiotherapy effectiveness and an effort to minimizing the risk of distant spread of the cancer cells.
Recently newer forms of radiation techniques are being applied, like Intensity Modulated Radiation Therapy (IMRT) or Stereotactic Body Radiation Therapy (SBRT), gamma knife radiation and cyber knife radiation, in order to minimize the toxicity to surroundings tissues and increase the effectiveness of the method. Of course, when the chemoradiation treatment is completed, the patient continues with chemotherapy, either on its own (monotherapy) or combined. In certain cases chemotherapy may decrease the size of the tumor and subsequently operation is possible and effective (this kind of chemotherapy is called neoadjuvant chemotherapy).
Following a "pancreatoduodenectomy" or "Whipple" operation for pancreatic cancer, the patient usually has no evidence of residual disease. In that case the patient receives a form of chemotherapy named adjuvant treatment (i.e. treatment after surgery) in order to kill any surviving cancer cell and to reduce the risk of cancer recurrence.
The duration of this prophylactic adjuvant treatment is usually six months.
Treatment for metastatic pancreatic cancer
A cancer of the pancreas has given "distant metastases" when it has spread away and has involved other tissues and organs beyond the surrounding tissues of the pancreas.
In that case, there is only one treatment option: the administration of systematic chemotherapy. This treatment is given if the patient is fit and able to receive such a therapy or to receive only palliative care. The administration of chemotherapy offers the possibility of life prolongation or better quality of life.
However, the overall benefit from chemotherapy administration in pancreatic cancer patients is limited. The life gain for a responsive patient to chemotherapy is only a few months. The benefit from the improvement of quality of life is not negligible.
During the last decade there are quite a few drugs against the pancreatic cancer. All of them have been successful in the clinical trials and have been granted approval by the Food and Drug Administration.
Capecitabine is an orally given drug, gemcitabine is another given intravenously but the most successful combination is that of irrinotecan and oxaliplatin in combination with follinic acid and 5-fluorouracil.
All the forms of pancreatic cancer treatment have serious side effects. Of course they vary greatly depending on the type of treatment and their appearance depends on the kind of treatment given. They are different for the radiation treatment and absolutely different for the chemotherapy. It is even different among monotherapy (when a single agent is used) or polychemotherapy (when more than two agents are used).
Radiation treatment side effects are divided into early and late side effects depending on the time elapsed from the initiation of the treatment. Usually they include fatigue, nausea vomiting and diarrhea.
On the other hand chemotherapy’s side effects depend on the agents given and include fatigue, diarrhea nausea vomiting, loss of appetite, altering of taste, skin reactions, mucositis and disturbances of the white blood cells and platelets leading to infections, anemia and bleeding disorders.
One must keep in mind that there is always a balance between the uncontrolled pancreatic cancer development with subsequent devastating quality of life, and the side effects of treatments that are necessary for life prolongation and symptoms amelioration. Despite this, there are many supportive agents that make the administration of chemotherapy and/or radiation treatment much easier and smooth, as well as new sophisticated techniques of radiation delivery.
In general the pancreatic adenocarcinoma is a difficult disease. The risk of cancer recurrence even for surgically resectable tumors remains high. It is a treatable but not curable disease even in the early stages.
It is noticeable that only 20% of patients undergoing a total pancreatectomy for early pancreatic cancer live five years, while the rest 80% survive approximately less than 24 months. For patients with locally advanced or metastatic disease, survival is less than 12 months. For patients with metastatic disease the life expectancy is even worse, with an average survival time only six months.
However, during the last decade substantial improvement took place with the addition of new drugs in our arsenal, and new therapeutic programs and steady progress has been a reality.
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