Ryan+Chavkin+1

Pancreatic Cancer

The patient in focus is a seventy five year old, white, gentleman who has been diagnosed with Stage III pancreatic cancer. Staging of the cancer ranks from I-IV with IV being the most lethal; the greater the stage, the more severe the cancer is. Two types of tumors can form in the pancreas: exocrine and endocrine. An endocrine tumor is benign and not very harmful, whereas an exocrine tumor is extremely harmful. The exocrine tumor starts in the exocrine glands of the pancreas, where enzymatic “juices” produced to breakdown food. The tumor in our patient is exocrine, meaning that even if the patient were to have a Stage I tumor, at best his chance for survival over a five-year period is 14%. Seeing that his disease is at Stage III, unfortunately his chance of survival (over a five-year period) is 3%.

Early in the patient's life, he worked in a metal refinery where he was exposed to a multitude of chemicals. Studies have shown that workers from certain manufacturing fields are more susceptible to developing cancer later in their lives. Theses workers were more likely to be exposed to solvents and other chemical exposures in manufacturing operations. The specific cause of the cancer development has not been pinpointed, rather there is a connection between the occupation and the disease. This particular disease isn’t necessarily an inherited one, however it should be noted that he is the first member of his family to have pancreatic cancer. Keeping this in mind, his cancer was likely cause by the chemicals he was exposed to. These chemicals pose as a risk factor as they are the cause of the mutations in the genes that promote the cancer development. Two other risk factors tied to the disease are obesity and tobacco usage, and this gentleman has avoided both of these criteria.

In most cases, the disease is from an acquired mutation, meaning that it is a mutation that isn’t passed on from his parents. Rather it is a mutation that has occurred in his DNA after his birth. This is specific to his case, as the chemicals he was exposed to in the workplace are likely to blame for the cancer. The mutation occurs in the TP53 gene, which ultimately leads to the proliferation of the cancerous cells. When this gene is affected, the cell cycle’s checkpoints don’t operate as they are intended to. This means that damaged DNA is allowed to replicate, where the damaged DNA would be destroyed via “programmed cell death” if TP53 was working as it properly should. There are other genes that are affected, like KRAS, BRAF, and DPC4, though the affects are best explained in terms of the mutation of the TP53 gene.

A frightening fact about this patient's case, specifically regarding the exocrine tumor, is that there aren’t symptoms in the early stages. Often by the time any symptoms arise, the tumor has already formed. After the tumor has formed, jaundice is often seen in patients. Such was the case for him, as he was diagnosed after his jaundice had become overwhelmingly noticeable. The jaundice stems from the exocrine tumor’s effects on the bile duct. The liver sends bilirubin to the duct to eventually be sent to the intestines to leave the body. If the tumor is blocking the passage of the bilirubin, then yellowing of the eyes and skin (jaundice) will be seen. This patient’s tumor is progressive, which means that the liver can eventually be affected by pancreatic cancer as well, as the organs are linked via the bile duct. Because this is a Stage III disease, it is likely that tumor will spread this far if it hasn’t already. (University of Chicago Medicine 2014)

Pain in the mid-abdomen and back will also occur as the tumor spreads and stresses nerves around the pancreas. Along with this, digestive troubles will occur as the exocrine cells will have trouble excreting the necessary enzymes for the breakdown of food.

Moving forward, it is important for his family to understand that their risks for pancreatic cancer do not increase because this gentleman has the disease. They are not anymore susceptible to the cancer than a person whose family has no history of the cancer. This man was exposed to chemicals that are to blame for the cancer. That being said, the patient should decide whether treatment of the disease is necessary for him. His future is bleak in the next five years given the customary treatment plan, including surgical removal of the tumor and chemotherapy. However, if this cancer is left untreated, the pain associated with the cancer will likely worsen.

With regard to pancreatic cancer, it’s important to consider the molecular pathways involved to understand what exactly is going on. Having knowledge regarding the development of the disease is pertinent to understanding how to defeat it.

Our patients particular cancer is in a late stage of development, meaning that it is conceivable for metastasis has occurred. Two hallmarks of cancer are relevant in this instance: Inducing Angiogenesis and Sustaining Proliferative Cell Growth. Focusing on the proliferation of cell growth, the KRAS oncoprotein is compromised, resulting in cell proliferation. Once the oncoprotein is affected, the “off switch” in the pathway is never enacted, causing micrometastasis to form and invade the surrounding areas of the pancreas. The induction of angiogenesis is where unhealthy blood vessels form, in our case around the pancreas, and support tumorgenesis by provided nutrients to the cancerous tumor. This generally occurs around wounded areas, or where a lesion has happened due to the tumor, and is a response to hypoxia. VEGF induces the blossoming of these blood vessels. Figure 1. The diagram on the left outlines a healthy KRAS oncoprotein where the diagram on the right shows a mutated oncoprotein.

Sunitinib is a targeted therapy drug used to combat angiogenesis. Specifically targeting the VEGF molecule, the drug binds to the molecule, and disallows connection between it, and its receptor. In doing so, the blood vessels are inhibited from growing towards the tumor. This inhibits further tumor genesis, however it does not kill off the tumor like chemotherapy drugs usually do. This is used as a palliative measure, rather than a cure. Given our patient’s situation, palliative care is not a bad option.

Noting that our patient’s cancer was likely onset by his exposure to chemicals, the mutations involved in pancreatic cancer are worth exploring. The majority of the mutations found are point mutations, all involved in a core set of cellular signaling pathways. These pathways include notable tumor suppressor TP53, as well as the KRAS oncogene.

Specifically in the TP53, these mutations are allowed to pass through the cell cycle unhindered, which leads to damaged DNA being transcribed. As mentioned previously, the TP53 serves as a growth suppressor of damaged DNA, and often times induces apoptosis of the affected cells. When the TP53 gene is functioning at an uninhibited level, the p53 gene is transcribed and promotes the transcription of healthy DNA, where it is allowed to enter the S phase of the cell cycle and have its information transcribed. If the p53 gene, or its pathway are impaired, then the damaged DNA is allowed to proliferate. The KRAS functions by promoting cell growth via GTPase activating the protein. When necessary, GTPase is dephosphorylated and the promotion in turned off. The mutated KRAS pathway is never turned off. As mentioned above, this leads to metastasis and promotes angiogenesis.

Various mutations occur that lead to the growth of the tumor. Missense mutations occur in the first or second nucleotide in a codon, which almost always causes a change in the prescribed amino acid from the RNA. Sometimes this can cause a unplanned exon to form, which can prove to be problematic. It can be hypothesized that in a tumor, a missense mutation occurred, causing a tumor suppressor gene to not be transcribed. These deletions can be sourced as the cause of the tumor. This cause for the disease is less likely to be accepted in the cancer world, as it is rationalized via hypothesis of what is within a spliced exon. However, it is still plausible that something of this nature can in fact occur. 3

FOLFIRINOX is a chemotherapy drug, using a combination of 5-flourouracil, leucovorin, oxaliplatin and irinotecan to combat proliferative cancer cells. The study using the combined chemotherapy found that the drug caused an inhibition of adaptor protein Grb2 binding to EGFR protein after being activated by EGF. The binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. When unregulated, the resulting over-expression of EGFR is responsible for angiogenesis and apoptosis inhibition. It’s safe to say that it must be involved in the cell pathways involving KRAS as well as p53. Because of this relation, we now understand these pathways better, as the tumorgenesis involving angiogenesis (KRAS) and apoptosis inhibition (p53). By inhibiting Grb2 to bind to the EGFR receptor, the cancer cannot be supported by the necessary blood vessels, nor can it continue to grow.

Understanding how pancreatic cancer works is vital to the patient’s treatment. The targeted therapies for combating angiogenesis show how the cancerous tumor is cut off from its necessary nutrients. The chemotherapy using FOLFIRINOX demonstrates an understanding of the pathway that the tumor has effected in order to prosper, and how this can be reversed. The treatment plan that follows will likely involve these therapies.

Understanding the available treatment options is crucial to developing a treatment trajectory. Pancreatic Cancer comes with a certain connotation that tends to entail a bleak, helpless feeling. It’s important to understand the potential paths one can take after the diagnosis. There are a multitude of options to understand, but helplessness is a feeling that should be avoided. Our patient must understand and decide on a treatment plan.

Surgery is often the primary method of treatment, especially if the disease entails an exocrine tumor. In this patient, the tumor is exocrine. The two types of surgeries are either potentially curative, or palliative. The difference between the two lies in the overall goal of the procedure. Palliative means that the surgery is performed in an effort to relieve the symptoms, including relieving a blocked bile duct or intestine. It’s done when the cancer is too widespread, which would require an understanding that the cancer will still be present post-surgery.

The surgery that is most often done is called the Whipple procedure. This is almost always done on exocrine tumors, and is sometimes the curative method for an endocrine tumor. The head of the pancreas is removed, along with infected areas of the internal organs surrounding the area. After the pancreatic parts are removed, the bile duct and the remaining pancreas are then attached to the small intestine. It should be noted that often times during the operation, the doctor finds that the procedure’s outcome shifts from a curative to a palliative one, as the cancer can be worse than what was initially diagnosed.

Starting the treatment process with surgery is the standard of care with regards pancreatic cancer. The reason being that it is the most effective at removing the tumor itself. Following this, it is most likely to stop the proliferation of cancer as well. The Whipple procedure, though varying in what exactly is removed from the pancreas, is the the best surgery, as it generally allows for the necessary enzymes to continue to enter the small intestine. It is also the only surgery that gives the patient the best chance at survival. Following the Whipple procedure, the five year life expectancy is 21%.

Radiation, along with chemotherapy, is often done in preparation for a surgery and as a post-surgery measure. Radiation is the use of high energy x-rays that target the exocrine tumor (radiation is not used on endocrine tumor treatment). Chemotherapy targets cells that show rapid reproduction and proliferation. Although this can target cancerous and noncancerous cells, it is still a demonstratively beneficial treatment option. Chemo enters the bloodstreams via pills and injections. It can be used in all stages of cancer, and also can be used during, pre and post surgery.

The standard of care for chemotherapy has been utilizing the drug gemcitabine. This treatment is used after a palliative surgery has been performed, and can be used prior to surgery. However, using this drug in tandem with nab-paclitaxel has been clinically tested to improve the life expectancy of those with the disease. The nab-paclitaxel treatment involves the binding of the paclitaxel to albumin cells in the body which deliver nutrients to other cells, including cancer cells. When the paclitaxel interacts with the cancer cells, it damages the microtubule structures within the cell, and halts the proliferative cell division. This combination treatment plan has proven to increase the one year life expectancy by 13%, moving from 22-35%. This has proven to be the most effective clinical trial that has been published.

Ablation treatment can be done to lessen the severity of the tumor. In short, the use of extreme temperatures, hot or cold, is used to kill the tumor. Radiofrequency ablation is done on smaller tumors, where a thin needle is used as a probe inside the tumor, and then a high frequency current passes inside, heating and killing cancer cells. Microwave thermotherapy and Cryoablation are performed on larger tumors. The difference in microwave thermotherapy is that it targets abnormal tissue rather than cancer cells specifically (although cancer cells are considered abnormal). Cryoablation is the same as radiofrequency ablation, except that cold gasses are used rather than a heated current.

Ablation has become a sort of last chance effort to remove the tumor. It is usually done when the patient’s tumor is unresectable, and other methods of treatment have either failed. There are open clinical trials being done, however it has not been proven to be a better substitute to surgery.

Side effects are to be expected when treating cancer. Because the target area for all treatment plans is the mid-abdomen, it is extremely likely that abdominal pain will occur. Chemo has been known to leave patients feeling nauseous, and it also can target non-cancerous cells. In doing so, healthy cells can be damaged as a byproduct of the treatment. Radiation also damages healthy cells, and will likely lead to a fatigued patient.

The best, and recommended, treatment plan starts with the Whipple procedure. It is the best surgery for a reduction of cancer symptoms, along with a prolonged five year life expectancy. Following this, the chemo plan involving the combo of nab-paclitaxel with the reputable gemcitabine. The grouping of these, along with radiation if the patient if fit enough, gives the best opportunity for a better quality of life for the patient.

Understanding the treatment options and how they work to combat the disease is pertinent to any decision made regarding pancreatic cancer. Initially, comprehending the basic principles behind how their cancer developed, and the Whipple procedure they will likely undergo, followed by how the chemotherapy drugs will combat it, is important so they can thoroughly understand what lies in the future for them. If the patient were to decide on following the customary treatment plan, it’s important that they comprehend that the road ahead of them is not an easy one, though the ultimate goal is to improve their quality of life.

Apreçu: It is important to keep in mind that whichever path is decided, a positive conclusion can still come from this situation. Pancreatic cancer, in its late stages, is not a damning situation because of the dire diagnosis. From a research prospective, future patients with similar predicaments can benefit from what can be learned through whatever treatment plan our patients chooses. From a personal perspective, keeping an open mind and remaining optimistic are two things that can contribute to maintaining a good quality of life.