This learning portal offers insight into Pancreatic Cancer and Cryotherapy.
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Pancreatic cancer is a malignant tumor that develops in the pancreatic tissues inside the small digestive organ, the pancreas. Cancers of the pancreas can occur in the exocrine pancreas (classic pancreatic adenocarcinoma) or the endocrine pancreas. It remains undetectable in the early stages, owing to widespread non-specific symptoms. Pancreatic cancer is most common in men and women between the ages of 60 and 75, making age the predominant risk factor. Apart from lifestyle-dependent factors such as smoking, alcohol consumption, and obesity, a personal or family history of pancreatitis, BRCA2 mutation, and old age predispose a person to pancreatic cancer.
What Is The Pancreas?
The pancreas is a 6-inch long organ located behind the stomach in the back of the abdomen. It is spongy and shaped somewhat like a fish, extended horizontally across the abdomen. The head of the pancreas is on the right side of the abdomen where the stomach is attached to the first part of the small intestine (the duodenum). The tail of the pancreas – its narrowest part – extends to the left side of the abdomen next to the spleen. The pancreas contains exocrine and endocrine glands that create pancreatic juices, hormones, and insulin. Pancreatic juices, or enzymes, made by the exocrine glands are released into the intestines by way of a series of ducts in order to help digest fat, proteins, and carbohydrates. Over 95% of the pancreas is made up of exocrine glands and ducts. The endocrine cells are arranged in small clusters called islets of Langerhans, which release insulin and glucagon into the bloodstream. These two hormones manage levels of sugar in the blood. When they are not working properly, the result is often diabetes.
What Is Pancreatic Cancer?
Cancer is a class of diseases characterized by out-of-control cell growth, and pancreatic cancer occurs when this uncontrolled cell growth begins in the pancreas. Rather than developing into healthy, normal pancreas tissue, these abnormal cells continue dividing and form lumps or masses of tissue called tumors. Tumors then interfere with the main functions of the pancreas. If a tumor stays in one spot and demonstrates limited growth, it is generally considered to be benign.
More dangerous, or malignant, tumors form when the cancer cells migrate to other parts of the body through the blood or lymph systems. When a tumor successfully spreads to other parts of the body and grows, invading and destroying other healthy tissues, it is said to have metastasized. This process itself is called metastasis, and the result is a more serious condition that is very difficult to treat.
In the United States each year, over 30,000 people are diagnosed with pancreatic cancer. Europe sees more than 60,000 diagnoses each year. Because pancreatic cancer is usually diagnosed late into its development, the five-year survival rate after diagnosis is less than 5%.
What is the Epidemiology of Pancreatic Cancer?
Pancreatic cancer is one of the most fatal cancers around the world, with the highest incidence and mortality rates found in developed countries (Michaud, 2004). Summarized in this overview are the risk factors and the global and historical epidemiological trends for pancreatic cancer in the seven major markets.
The risk of developing pancreatic cancer is associated with increasing age, as more than 75% of pancreatic cancer patients are over the age of 60 years (SEER Cancer Statistics Review, 2012). Tobacco smoking is one of the most common risk factors for pancreatic cancer, as smokers have a two-fold increased risk of developing the disease compared with nonsmokers (Lowenfels and Maisonneuve, 2006). Due to the short survival period and high mortality for pancreatic cancer, patients with the disease are less likely to suffer from comorbidities than patients with other types of cancer. North America and Western Europe have the highest incidence of pancreatic cancer compared with the rest of the world. The fatal nature of pancreatic cancer keeps the survival rates low and the duration of illness short. The low survival rate associated with pancreatic cancer is caused by the complexity of the disease, along with diagnosis usually occurring during the advanced stages, as the early symptoms typically go unnoticed. In the US, the five-year survival rate of pancreatic cancer is 4.8%, while the 10-year survival rate is only 3.6%; these survival rates showcase that the majority of pancreatic cancer mortality occurs within the first five years of diagnosis (Ries et al., 2007).
Current forecast indicate that the US and Germany will have the highest number of incident cases of pancreatic cancer in 2022, with 53,610 and 27,629 cases, respectively. Epidemiologists expect that the number of prevalent cases of pancreatic cancer in the eight major markets will increase during the forecast period to a total of >150,000 cases. The stage at diagnosis for pancreatic cancer is correlated with the availability of screening tests and the ability to identify early symptoms. Due to the inability to identify early indications of the illness, pancreatic cancer cases are most commonly diagnosed in Stage IV. Greater research in prevention and early diagnostic testing can help reduce the incidence of the disease. Through early detection, it may be possible to stop the spread of the cancer to other organs and decrease the overall mortality.
Currently there is no consensus about early detection of pancreatic cancer, and eligibility for screening tests is completely based on the physician’s decision. Commonly available imaging methods such as ultrasound, MRI, and CT scans are employed for diagnosis of the disease. Endoscopic retrograde cholangiopancreatography (ERCP), an advanced skill-based procedure, can be used as a confirmatory test. Biopsy samples may also be collected during ERCP for further histopathologic studies. The most common symptoms of the disease include abdominal pain, loss of appetite, significant weight loss, jaundice, and several digestive problems. If early diagnosis has been carried out, the front-line treatment strategy is a pancreatectomy if the tumor is on the body of the pancreas, and the Whipple procedure (pancreatoduodenectomy) for tumors in the pancreatic head. As with other cancers, radiation therapy is generally the follow-up step for surgery. Oncologists also use adjuvant chemotherapy across the world, though there is little evidence of its effectiveness in early stages.
The prevalence of pancreatic cancer is low across the world compared to other cancers, however the mortality rate is among the highest of all cancers, making pancreatic cancer a major focus area. The overall low prevalence is due to poor prognosis, late diagnosis, and low survival. The higher prevalence in Japan is due to the rising ratio of old people to young people and changing lifestyle features such as increased levels of smoking, alcohol intake, and reduced physical exercise and lower consumption of fibrous foods.
Pancreatic cancers in the seven major markets are expected to show the same growth trends through to 2020. According to Business Insights’ estimates, the prevalence of pancreatic cancer is projected to grow to 70,723 in 2020 from 66,400 in 2010, primarily driven by population dynamics. The rising elderly population is likely to fuel growth in this disease sector. Mortality rates are forecast to remain high across all markets and, as a result, prevalence is forecast to remain at low levels. Current forecast indicate that the US and Germany will have the highest incident of pancreatic cancer in 2020, with 53,610 and 27,629 cases, respectively. Epidemiologists expect that the number of prevalent cases of pancreatic cancer in the eight major markets will increase during the forecast period to a total of >150,000 cases. While the growth rate is relatively modest, the compelling numbers is that >95% of the individuals diagnosed with pancreatic cancer will die within 5 years as there are currently no truly effective treatment options. As such, the GastroCS System, once FDA clearance is obtained, will provide a treatment option in a medical space where a void currently exists.
What Are The Symptoms Of Pancreatic Cancer?
Cancer symptoms are quite varied and depend on where the cancer is located, where it has spread, and how big the tumor is. Pancreatic cancer is often called a “silent” disease because it rarely shows early symptoms and presents non-specific later symptoms. Tumors of the pancreas cancers are usually too small to cause symptoms. However, when the cancer grows, symptoms include:
- Pain in the upper abdomen from the tumor pushing against nerves
- A painless yellowing of the skin and eyes and darkening of the urine called jaundice, created when the cancer interferes with the bile duct and the liver.
- Loss of appetite, nausea, and vomiting
- Significant weight loss and weakness
- Acholic stool (pale or grey stool) and steatorrhea (excess fat in stool)
These symptoms of pancreatic cancer have numerous other causes, making it difficult to diagnose the disease before it is in an advanced stage. Cancers of the pancreas are also associated with Trousseau’s sign – spontaneous blood clots formed in the portal blood vessels, deep veins of the arms and legs, or other superficial veins. Clinical depression is another symptom that is sometimes reported before the cancer is diagnosed. If the cancer spreads, or metastasizes, additional symptoms can present themselves in the newly affected area. Symptoms of metastasis ultimately depend on the location to which the cancer has spread. Islet cell or neuroendocrine cancers of the pancreas may cause the organ to produce too much insulin or hormones. This may lead to weak or dizzy feelings, chills, muscle spasms, or diarrhea.
How Is Pancreatic Cancer Diagnosed?
In order to diagnose pancreatic cancer, physicians will request a complete physical exam as well as personal and family medical histories. The way in which the cancer presents itself will differ depending on whether the tumor is in the head or the tail of the pancreas. Tail tumors present with pain and weight loss while head tumors present with steatorrhea, weight loss, and jaundice. Doctors also look for recent onset of atypical diabetes mellitus, Trousseau’s sign, and recent pancreatitis.
In general, when making a pancreatic cancer diagnosis, physicians pay special attention to common symptoms such as abdominal or back pain, weight loss, poor appetite, tiredness, irritability, digestive problems, gallbladder enlargement, blood clots (deep venous thrombosis (DVT) or pulmonary embolism), fatty tissue abnormalities, diabetes, swelling of lymph nodes, diarrhea, steatorrhea, and jaundice. It is also common for doctors to administer blood, urine, and stool tests. Blood tests can detect a chemical called carcinoembryonic antigen (CEA) as well as CA 19-9 – a chemical released into the blood by pancreatic cancer cells. Liver function tests check for bile duct blockage. Several imaging techniques are employed in order to see if cancer exists and to find out how far it has spread. Common imaging tests include:
- Ultrasound – to visualize tumor
- Endoscopic ultrasound (EUS) – thin tube with a camera, ultrasound transducer and light on one end
- Abdominal computerized tomography (CT) scans – to visualize tumor
- Endoscopic retrograde cholangiopancreatography (ERCP) – to x-ray the common bile duct
- Angiogram – to x-ray blood vessels
- Barium swallows to x-ray the upper gastrointestinal tract
- Magnetic resonance imaging (MRI) – to visualize tumor
- Positron emission tomography (PET) scans – useful to detect if disease has spread
The only absolute way to make a cancer diagnosis is to remove a small sample of the tumor and look at it under the microscope in a procedure called a biopsy. A fine needle aspiration (FNA) biopsy is the most commonly used method. A thin needle is inserted into the pancreas through the skin, and the pathologist uses CT scan or ultrasound images as a guide. Another type is the brush biopsy performed during ERCP to gather cells. A laparotomy is sometimes ordered to determine the stage, or extent, of the disease because it provides access to a large part of the abdominal cavity.
Pancreatic Cancer Treatment
Pancreatic cancer treatment depends on the type of cancer, the stage of the cancer (how much it has spread), age, health status, and additional personal characteristics. There is no single treatment for cancer, and pancreatic cancer is usually only curable when found in its earliest stages. Surgery, radiation and chemotherapy are the most common treatment modalities. Cryoablation and RF ablation, although well-established treatment options for other cancers including prostate and renal cancer, represent new minimally invasive, in situ ablative strategies for treating pancreatic cancer. While all represent unique approaches, each treatment option seeks to remove the cancer and/or relieve painful symptoms that the cancer is causing.
Cryotherapy (cryoablation) is defined by the FDA as a “thermal therapy” along with the various heat-based therapies (RF, HIFU, microwave, etc.) Cryotherapy has several distinct advantages over heat-based therapies:
- Precise application and control during the clinical procedure
- Reduced associated co-morbidities
- Reduced pain
- Ease and speed of application
- Ability to visualize the ablative zone using ultrasound
One key to the successful application of a thermal-based treatment is control of the treatment margin (2-5 mm) as this rim or margin may account for a significant volume of damaged tissue. As such, the expansion of the zone of lethality with a heat-based therapy may well represent the “Achilles Heel” of this RF technology.
Heat-based therapies have a tendency to expand significantly beyond the “planned,” non-visualized tissue target, and the “cooked” tissue forms a rather rigid internal scar and painful adhesions are common. Cryotherapy, however, offers the control necessary to more precisely target the treatment zone, and post treatment leaves a fibrotic mass that is pliable and inert.
Biology of Cryotherapy
Cryotherapy is the use of cooling to extract heat from and freeze living tissue to affect cellular function and activity. During cryoablation, the removal of heat from the tissue creates a temperature gradient that extends from the catheter tip to the edge of the ice as explained in the following section. Multiple factors influence the effectiveness of cryotherapy. Chief among these are cryoprobe tip contact (to remove heat from the tissue, the catheter tip must be in contact with the tissue), tip temperature (the catheter tip temperature applied determines if the cells are subjected to hypothermia or lethal freezing) and freeze rate (faster freezing will cause more tissue damage and final temperature reached).
When cell temperatures are lowered below the freezing point of water, ice formation occurs inside and outside the cell, resulting in permanent tissue damage. At fast cooling rates, when cells at, or very close to the cryoprobe tip-tissue interface are affected, water cannot leave the cell fast enough, and therefore ice forms within the cell. Intracellular ice destroys internal cellular structure, resulting in cell death. At slower cooling rates cells further away from the tip tissue interface are also affected as ice crystals form in the extracellular space, creating an osmotic imbalance that causes the cell to dehydrate and shrink. As intracellular ice crystals form, they cause a rupture of the cell membrane, resulting in cell death.
Significant tissue destruction also occurs during thawing. As the temperature rises from approximately -100°C to body temperature of 37°C, small ice crystals reform into larger crystals. Throughout the thawing process, the overall volume of crystallization diminishes as the temperature rises. This reorganization of crystal size and shape causes further tissue disruption that results in cell death.
Cells continue to die after being exposed to the freeze/thaw cycle. This cell destruction occurs via two mechanisms, necrosis and apoptosis. The first of these, necrosis (or cell rupture), is delayed and peaks within six hours following thawing. Necrosis occurs in tissue that has been frozen or subjected to sub-zero temperatures. It does not cause new cell damage and does not increase the size of the lesion. The second post-thaw cell death mechanism is apoptosis (or cell suicide). The freeze affects genetic architecture, causing the cell to self-destruct.
Endoscopic surgeons are pioneering the development of novel strategies to treat and potentially cure pancreatic cancer; using a new visualization tool, EUS (endoscopic ultrasound). These new therapeutic options for unresectable pancreatic cancer include radiofrequency (RF) and cryotherapy. These have been successful in solid cancers, although few studies have examined ablation in pancreatic cancer because of the risk of thermal injury to important structures such as the bile duct, the duodenum, and the vessels close to the pancreas. Using the innovative SCN console and novel EUS compatible FrostBite Cryocatheter (the GastroCS System) will be the first truly endoscopic device for treating locally advanced pancreatic cancer, demonstrating the feasibility and safety of this technique. Combining our cryoablation products with EUS, which is currently the best procedure for real-time imaging of the pancreas, as it permits targeting lesions easily wherever they are located in the pancreas, this EUS-guided treatment will overcome several problems related to the surgical, laparoscopic or transcutaneous approaches used today.
Minimally Invasive Surgical Approach
Recently, surgeons have successfully performed the laparoscopic and transcutaneous procedures cryoablation. Even though these are minimally invasive surgeries, the patient still has substantial recovery time. These procedures allow patients to return to regular activities within 1 – 2 weeks, rather than 8-10 weeks after a more traditional incision. Due to power constraints of current cryoablation system’s limited success further drives the need for new alternative technologies such as SCN endoscopic catheter system.
Endoscopic Catheter Cryoablation
The treatment of tumors by radiofrequency (RF) to create lesions has been clinically accepted since the 1980’s. Recently, RF energy has been investigated and used extensively by endoscopists to create lesions. Today, RF is used as the energy source of choice for the catheter ablation treatment when treating unresectable pancreatic cancer. However, there are limitations to RF as an energy source which include charring and the risk of thermal injury to important structures such as the bile duct, the duodenum, and the vessels close to the pancreas. As a result, alternative energy sources for creation of ablation for treatment of unwanted pancreatic tissues have been sought. Cryogenic energy is one such source that has numerous advantages as well as an existing track record for safety and efficacy in the surgery forum. Potential advantages of endoscopic catheter ablation using cryogenic energy include precise ablation zones, reduced co-morbidities, safety within or near surrounding structures and significantly decreased levels of pain. A review of the current cryoablation systems available reveals that all suffer from the same potential limitation – the time required to create each lesion is several minutes. With GastroCS System using our novel endoscopic catheter, ice formation can be achieved in less than 20 seconds with a complete ablation achieved in approximately 3 minutes. The GI Cryo GastroCS System is currently the only endoscopic ultrasound compatible cryoablation systems known to be available.
Other Therapeutic Strategies
Surgery may be used to remove all or part of the pancreas. If a cancer has not metastasized, it is possible to completely cure a patient by surgically removing the cancer from the body. After the disease has spread, however, it is nearly impossible to remove all of the cancer cells. There are three main surgical procedures that are used when it seems possible to remove all of the cancer:
- Whipple procedure (most common in cancers of the head of the pancreas): the pancreas head, and sometimes the entire organ, is removed along with a portion of the stomach, duodenum, lymph nodes, and other tissue. The procedure is complex and risky with complications such as leaking, infections, bleeding, and stomach problems.
- Distal pancreatectomy: the pancreas tail is removed, and sometimes part of the body, along with the spleen. This procedure is usually used to treat islet cell or neuroendocrine tumors.
- Total pancreatectomy: The entire pancreas and spleen are removed. Although you can live without a pancreas, diabetes results because your body no longer produces insulin cells.
Palliative surgery is also an option when the cancer in the pancreas cannot be removed. Often, a surgeon will create a bypass around the common bile duct or the duodenum if either is blocked so that bile can still flow from the liver and pain or digestive problems can be kept at a minimum. Bile duct blockage can also be relieved by inserting a small stent in the duct to keep it open, a less invasive procedure using an endoscope.
Chemotherapy utilizes chemicals that interfere with the cell division process – damaging proteins or DNA – so that cancer cells will commit suicide. These treatments target any rapidly dividing cells (not necessarily just cancer cells), but normal cells can usually recover from any chemical-induced damage while cancer cells cannot. Chemotherapy is generally used to treat cancer that has spread or metastasized because the medicines travel throughout the entire body. Treatment occurs in cycles so the body has time to heal between doses. However, there are still common side effects such as hair loss, nausea, fatigue, and vomiting. Combination therapies often include multiple types of chemotherapy or chemotherapy combined with other treatment options.
Gemcitabine (Gemzar) is the chemotherapy drug used most often to treat pancreatic cancer, and it is usually administered intravenously on a weekly basis. Another commonly used drug is 5-fluorouracil (5-FU). Chemotherapy is not always administered with the intent to cure the cancer. Some patients receive treatments after surgery (adjuvant therapy) to kill any cancer cells that were missed, and others receive it as palliative chemotherapy to improve their quality of life if the cancer cannot be cured. Newer drugs that target specific parts of cancer cells are now being studied. These drugs work differently from standard chemotherapy drugs, and they often have fewer side effects. One such drug, erlotinib (Tarceva), has helped some patients with advanced pancreatic cancer and is taken orally in pill form. This drug has been used in combination with gemcitabine to show modest benefits.
Radiation treatment, also known as radiotherapy, destroys cancer by focusing high-energy rays on the cancer cells. This causes damage to the molecules that make up the cancer cells and leads them to commit suicide. Radiotherapy utilizes high-energy gamma-rays that are emitted from metals such as radium or high-energy x-rays that are created in a special machine. Radiotherapy can be used as a standalone treatment to shrink a tumor or destroy cancer cells, and it is also used in combination with other cancer treatments. Radiation treatments for pancreatic cancer are usually given 5 days a week for 5 to 6 weeks. Patients may receive radiation treatment in addition to surgery, chemotherapy, or other treatments. In addition, radiation therapy can be palliative, serving to relieve pain or digestive problems when the common bile duct or duodenum is blocked.
Side effects of radiation therapy may include mild skin changes resembling sunburn or suntan, nausea, vomiting, diarrhea, and fatigue. Patients also tend to lose their appetites and have trouble maintaining weight, many side effects subside a few weeks after completing treatment, however many patients will experience complications from collateral damage effects from radiation which appear after 6 to 12 months.