Research of Pancreatic Cancer

Pancreatic cancer or adenocarcinoma is a type of cancer that occurs when mutations in your DNA can cause cells in pancreas to grow uncontrollably and have a greater mortality than the normal cells. Pancreas is a gland that is located behind the stomach and in front of the spine. Pancreatic cancer is usually detected at a very later stage and cannot be removed surgically. Giovanni Battista Morgagni is the first to provide description of pancreatic cancer in 1761. (ref2). Survival of pancreatic cancer patients even today is very low as it has very less effect on conventional treatment such as gemcitabine chemotherapy. Pancreatic cancer is one of the major disease that is unresolved and around 56,770 adults are diagnosed and 30,000 die in USA per year (ref1). There is a 3% of acquiring this disease when compared to other kinds of cancer. (ref3) Many ongoing researchers are conducting many clinical trials to study several types of immunotherapy to find treatment for the disease, genetically modified T-cells are also been researched to cure the disease. (ref4) however, the aggressive nature of the disease remain poorly understood.

Giovanni was not fortunate enough to have the access to microscope which makes his diagnosis questionable, his publication “de Sedibus Et Causis Morborum Per Anatomen Indagatis Libri Quinque” gave the first description of pancreatic cancer. However, when microscope was more accesable during the 1858 Jacob Mendez Da Costa described the first microscopic observation of adednocarcinoma. First surgery in attempt to remove pancreatic tumour was attempted by William stewart Halsted which was not succesfull. However, Walther Carl Eduard Kausch was the first to perform a successful pancreaticoduodenectomy. Pancreatic cancer is now a safe procedure performed in many hospitals that have a low mortality of less than 3%.

Pancreatic cancers usually shows signs and symptoms in advance stages and not in the intial stages which make them even more fatal. Some of the symptoms of pancreatic cancer are jaundice when the pancreatic head is small, steatorrhea, abdomen and upper back pain, loss of appetite, gas, indigestion and many more. The disease is usually diagnosed when brought into medical attention cause of the symptoms.The doctor usually conducts a health exam, that includes problems like obesity, smoking tobacco,diabetes. Many studies were conducted to see the environmental influence on the presence on pancreatic cancer, A large scale case study showed an interaction between chain smokers and Arg399Gln polymorphism of DNA repair gene called XRCC1. The same study showed the relationship between GSTT1 null genotype and smoking in pancreatic cancer. (ref1-17). This shows us that increased risk of pancreatic cancer depends on detoxification of carcinogen and DNA repair capacity of indivduals.

K-ras mutation is aldo 3% higher among alcoholics compared to non-drinkers. The k-ras mutation is the highest among all the human cancers, research shows that K-ras mutation can be influenced by environmental factors, In contrary, more research and knowledge is required to assure this statement. (ref1-24) The family history is also examined by the doctor which include history of pancreatic cancer, breast or ovarian cancer, Peutz-jeghers syndrome, lynch syndrome in family. Several other tests such as Complete blood count, blood chemistry test, Turmour marker tests, CT scans, ultra scan, MRI, ERCP, PET scan can be conducted to detect the presence of cancerous cells. CT scans are the most recommended diagnostic procedure as compared to ERCP due to the appearance of biliary tree. A plastic stent implanted by an experienced gastroenterology is recommended when the patient has a localized tumour. In advance cases an expandable stent is preferred. CT-guided fine-needle aspiration is then conducted to diagnose the tissue. Resuctability of the tumour is identified using a thin-cut dynamic multiphase helical CT scan of the abdomen and pelvis.

Presence of an activating point at the K-ras gene is seen in more than 85% of pancreatic cancer patients. Early detection of K-ras mutation can be detected by examining the stool or pancreatic juice of the diseased. (ref1-29) Also, p16 tumour-suppressor gene and TP53 is seen inactivated in almost 95% of the cases.(ref1-31). Growth factors and receptors like epidermal growth factor, interleukin6, interleukin1, transforming growth factor are overexpressed by the pancreatic cancer causes the cancer to reach metastasis easily.(ref1-49). The article also shows that endothelial growth factors are present around the tumours and these result from several alterations in transcriptional activities. Transcription can be disturbed through two mechanism one that is due to mutations of oncogenes which is usually genetic. This can be the cause in the early stages but in more advance stages is related to stress factors such as hypoxia, acidosis and free radicals. These factors lead to metastasis and results in death of the diseased.

There are several ways through which the disease can be handled, pancreatic cancer can be decided into two types one is localized tumour which can be surgically removed, advanced tumour (when mesenteric-portal venous is involved) which is unresuctable which is also called metastatic. Resuctable pancreatic cancer are completely curable and have a 20% survival rate that is the patients can live upto 5 years, around 15-16% of the patients have resuctable pancreatic cancer(ref1-69). The tumour size and condition can be predicted by examining nodal status and surgical margin status. Different treatments such as chemoradiation with flurouracil, chemotherapy, ESPAC-1 trial and a combination of these are also recommended and are researched. ESPAC-1 trial was not completely accepted as physicians had the flexibility to use additional treatments aswell. ESPAC-3 trial is being conducted in which patients were given flurouracil-based chemoradiation and were given postoperative gemcitabine and hopefully this will help understand the pancreatic oncology practice.

Locally advanced or unresuctable cancer have tumours that are have moved to vascular structures such as coelic axis, mesenteric artery or mesenteric vein portal.Tumours that are involved with bulky peripancreatic lymphadenopathy are also unresuctable. But this does not include metastatic tumours that occur in places further away like liver,chest or peritoneum. Gastrointestinal Tumour Study Group conducted three trials which showed that patients who received both fluorouracil and radiation had doubled in survival rate.(ref1-79). However, this is not a long-term solution as within a few months the patients developed other metastatic diseases. Further research might shed light into finding cure but for now survival rate of the patients are generally poor. Metastatic pancreatic cancer are almost uncurable they are treated with gemcitabine. Adults suffering from metastatic pancreatic cancer experience a lot of pain, gastric outlet obstruction, thromboembolic events. Tumour burden and performance status at presentation of gemcitabine affect the survival rate. Survival rate of diseased treated with gemcitabine is higher than when treated with flurouracil. When gemcitabine is incorporated into the DNA chain it leads to premature termination of the chain, this property of the chemical is used to treat the disease. However, gemcitabine as a second-line treatment has a lower mortality rate but stands as the current standard care for metastatic pancreatic cancer.

The pancreatic cancerous cells are differentiated two ways that are graded based on the cancerous cell growth, low and high grade. The low grade includes well differentiated cells that resemble normal cells and grow at a lower rate and are less likely to be malignant. However, the high grade are undifferentiated and is more likely to spread. The grade of the cells are important to plan the treatment and predict future prognosis. The TNM staging system stages pancreatic cancer in five stages. Stage 0 can also be called in situ as the cells are usually only found on the lining of pancreas. The next stage, Stage 1 is divided into 1a and 1b, 1a is a stage that has tumour is 2 cm or smaller and 1b is a stage with tumour larger than 2 cm but less than 4 cm. Stage 2 includes tumours larger than 2 cm in 2a and 2b includes tumours of any size and has spread to lymph nodes nearby (usually just 1-3 places). (ref5). Stage 3 is when the tumour has spread to more than 4 places nearby lymph nodes. It also includes the tumours that have grown outside pancreas close to blood vessels. Stage 4 is when the cancer has spread to other parts of the body and is called metastasis cancer.

Adults who sufferered from pancreatic cancer between October 1999 and august 2006 were evaluated and the data was maintained by the department of surgical oncology. Patients that also suffered from neoplasms, nonpancreatic cancer of periampullary region, cystadenocarcinomas were excluded from the study. Eastern cooperative oncology group scale was used to record performance state of patients whose detail record of blood chemistry, medical history, CT scans of abdomen were evaluated for planned pancreatectomy. Patients age was recorded at the beginning of first evaluation and presence of serum CA 19-9 was recorded for referral but this serum was not obtained in young patients. After initial assessment of the patients, only patients with borderline resuctable pancreatic cancer were included in the assessment and were categorized into three groups, Group A included patients with short – segmented occlusion of the superior mesenteric vein. They has one or more tumour abutment of SMA (with less than 180˚ of the vessel circumference). Group B included has suggestive spread of tumour but not metastasis. This group includes disease that might concern for possible extrapancreatic metastasis disease.

They exclude patients who are known with N1 disease from endoscopic ultrasonograohy-guided fine needle aspiration or laporatomy and lastly Group C included patients that were initially treated with chemoradiation, chemotherapy or both. Patients that completed both these preoperative treatments without progression of the disease were included for surgery. Group C patients were managed by a special multidisciplinary group which included physicians, pancreatic dietician, therapists and internal medical faculty members dedicated in preoperative assessment clinic. Group C was the most prioritized followed by Group B and Group A. Subjects that suffered from MD Anderson Group B and Group C were also classified as Group C. The three groups were initialy treated with chemoradiation, chemotherapy or both. Most of the patients were treated off protocol and were administered under patients reffered oncologist.

The treatment was about 2 to 4 months of systematic therapy which mainly inclused gemcitabine followed by chemoradiation addictional to this restaging was conducted ever 2 months. After the treatment patients that showed no signs of progression disease were administered and CT scans and complete physiologic assessment were checked and ideal candidates were then safe to undergo major abdominal surgery. Surgery was planned and a planned resuction of the primary tumour was conducted. Usually pancreaticodenectomy is performed as a standard procedure but in the presence of tangential or segmental resection of PV, SMV the surgeon could not operate the pancreatic head ricking incontrolled venectomy. So primary anastomosis or interposition grafting was performed when lower involvement of common hepatic artery was seen. Surgical bypass was practiced on patients that were found to have unresectable disease at operation.

After the surgery, the SMA margin was identified and inked by the pathologist immediately. After dissection of the tumour the margins were carefully examined using frozen-section analysis and if positive assition pancreatic parenchyma or bile duct was resucted. If all the final margins were negative then the operation was designated R0 and R1 if any of the final margins were positive microscopically. The tumour size was then calculated by the pathologist, the size was hard to determine in some patients after preoperative therapy as it gets hard to distinguish the tumour size with adjacent pancreatic parenchyma. The treatment was then scored by a gastrointestinal pathologist. The grading system included grade I that is more than 90% of the viable cells remained after the therapy, grade IIa where 50-89% of viable tumour cells remain after therapy, IIb where 10-49% of the viable cells remain and a score of IV indicates no remaining viable tumour cells are present. (ref1). The operated patients were then followed up every three to four months by physical examination, abdominal CT and radiography. Evaluations were reduced to 6-month intervals when no evidence of disease were seen after 2-years of follow up.

Reference

1. https://www.sciencedirect.com/science/article/pii/S0140673604158418
2. https://www.futuremedicine.com/doi/10.2217/fon-2016-0010#F0001
3. https://www.cancer.net/cancer-types/pancreatic-cancer/statistics
4. https://www.cancer.net/cancer-types/pancreatic-cancer/latest-research