Researchers Discover New Biomarker for Predicting Liver Cancer Spread and Survival

New research has shown that a unique pattern of microRNAs, small RNA molecules that regulate gene activity, can accurately predict whether liver cancer will spread and whether liver cancer patients will have shorter or longer survival, even patients with early stage disease. The study, which appeared online January 7, 2008 in Hepatology, was conducted by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues at Ohio State University, Columbus, and the Liver Cancer Institute in Shanghai, China.

"The aggressive nature of hepatocellular carcinoma, a prevalent type of liver cancer, is largely due to its tendency to spread or recur after surgery," said the study's lead author, Anuradha Budhu, Ph.D., a staff scientist in the laboratory of Xin Wei Wang, Ph.D., head of the Liver Carcinogenesis Section of NCI's Center for Cancer Research (CCR). "Identifying new diagnostic and prognostic biomarkers for liver cancer is a first step in alleviating the dismal outcome of this disease."

MicroRNAs, or miRNAs, have been implicated in various aspects of human disease, including cancer. Their abundance in different tissues and cancer types indicate that miRNAs are functionally significant and have the potential to be used as cancer biomarkers. Since miRNAs can effectively regulate the activity of multiple cancer-related genes and pathways, they are prime candidates for coordinating the intricate events that lead to the spread of cancer, which is known as metastasis.

In this study, Budhu and her colleagues used miRNA microarray techniques, which allow researchers to examine the expression of thousands of genes simultaneously. They analyzed the miRNA expression profiles (showing the extent to which individual miRNAs are turned on or off) in cancerous and noncancerous liver samples from 131 patients with or without metastasis who underwent surgery at the Liver Cancer Institute and Zhongshan Hospital in Shanghai. The analysis revealed a set of 20 miRNAs with different patterns of expression in tumors with metastasis compared to tumors without metastasis. MiRNAs are capable of regulating the expression of one or more genes, including cancer-related genes, potentially affecting multiple cell functions that could lead to malignancy.

"This is an important and unique finding because it is the first study to show that miRNAs play a significant role in liver metastasis," explained Budhu. "In fact, miRNAs have not previously been related to cancer spread in any other organ."

Using the new gene expression profile, the researchers found that patients with the metastasis-miRNA profile had a two-fold higher risk of shorter survival compared to those without the profile. This latest finding in hepatocellular carcinoma, or HCC, in combination with earlier research by this team on early stage HCC and the tumor microenvironment, suggests a real potential for increasing the accuracy of liver cancer diagnosis and prognosis, as well as in monitoring recurrence.

"MiRNAs are also very stable molecules, which is an ideal property that could allow for more dependable measurements in clinical diagnostic or prognostic methods. Since miRNAs can affect multiple genes, including those related to cancer, they are also promising new targets for therapeutic approaches to liver cancer treatment," said Budhu.

HCC is the most common liver cancer diagnosed in adults and has a high prevalence in Asian and African populations. The rate of new HCC cases has been rising over the past 10 years in the United States and occurs twice as often in men as in women. HCC is a very aggressive disease; patients usually survive less than one year after diagnosis. In 2007, an estimated 19,160 Americans were newly diagnosed with liver cancer and an estimated 16,780 people died of the disease.

Thyroid Cancer

What is the Thyroid?

The thyroid gland is located on the anterior aspect (front) of the neck. It can be felt just below the thyroid cartilage, or "Adam's apple". It is a butterfly shaped organ that stretches across the midline of the neck just below the Adam's apple, with its "wings" spreading superiorly (towards the head) on either side of the Adam's apple. These "wings" are called the lobes of the thyroid, with the portion extending across midline called the isthmus. As an endocrine gland, the thyroid gland produces and secretes thyroid hormones into the bloodstream. The thyroid does this as a response to a hormone produced by the pituitary gland called thyroid stimulating hormone, or TSH. When the thyroid gland is "turned on" by TSH, it increases its uptake of iodine, which is required to make thyroid hormone, and manufactures and secretes thyroid hormones. These thyroid hormones are very important for many functions ranging from the regulation of our metabolic rate to helping to maintain the function of our heart to regulation of body temperature. An increase in the production (hyperthyroid) or a decrease in the production (hypothyroid) of thyroid hormone can be easily managed, though can cause serious problems if not properly treated. The principal cells of the thyroid are called follicular cells, and are mainly responsible for the production of thyroid hormone.

What is Thyroid cancer?

The definition of a tumor is a mass of abnormally growing cells. Tumors can be either benign or malignant. Benign tumors have uncontrolled cell growth, but without any invasion into normal tissues and without any spread. A malignant tumor is called cancer when these tumor cells gain the propensity to invade tissues and spread locally as well as to distant parts of the body. In this sense, thyroid cancer occurs when cells of the thyroid gland grow uncontrollably to form tumors that can invade the tissues of the neck, spread to the surrounding lymph nodes, or to the bloodstream and then to other parts of the body. The most common types of cancers of the thyroid gland are derived from the cells responsible for thyroid hormone production. The general term for cancers that come from glandular tissue is adenocarcinoma. In the thyroid, the most common types of cancer are papillary adenocarcinoma of the thyroid (75-80%) and follicular adenocarcinoma of the thyroid (~15%). Papillary thyroid cancer takes on a folded appearance under the microscope, which eases its diagnosis. Follicular thyroid cancer may closely resemble normal thyroid tissue, but as a malignancy, has a propensity to divide uncontrollably and invade and spread. The next most common type of cancer of the thyroid is called medullary thyroid cancer (5%), which is derived from the parafollicular cells of the thyroid. This is often associated with a familial genetic predisposition to develop certain types of cancers (see below). The other major type of thyroid cancer often described is called anaplastic thyroid cancer (2%). This cancer usually affects older people and is very aggressive. Other types of cancers, such as lymphomas (cancer of the lymph gland cells), sarcomas (cancer of soft tissues such as muscle or cartilage cells), or metastases (cancers from other sites that have spread to the thyroid gland) are also seen in the thyroid gland.

Am I at risk for thyroid cancer?

Thyroid cancer is fairly common, as it is found at autopsy in approximately 5% of people with no known thyroid disease. However, death due to thyroid cancer is uncommon, explained by the fact that thyroid cancer is usually an indolent disease, tending to remain localized to the thyroid gland for many years. Most cases of thyroid cancer are sporadic; meaning there is no obvious predisposition or risk factor for development. However, it is more common in women, occurring in a 3:1 ratio. This has prompted studies into the investigation of estrogen as a possible risk factor for thyroid cancer, though this has never been proven. Studies have also shown a preponderance of certain types of thyroid cancer in regions with a high incidence of goiters (enlarged thyroid glands), which occur as a result of a lack of dietary iodine. This is further supported by the decrease of thyroid cancers in population given supplemental iodine.

The most firmly established risk factor for the development of thyroid cancer is exposure to ionizing radiation to the neck region. This is supported by the high incidence of thyroid cancer seen in many populations exposed to radiation. Notably, this includes patients with Graves' disease (a hyperthyroid condition) treated with radiation, Hodgkin's disease patients treated with radiation, survivors of atomic blasts at Nagasaki and Hiroshima, and survivors of the Chernobyl explosion. In fact, thyroid cancer is one of the most common cancers noted in populations exposed to large doses of radiation through accident or war.

A notable genetic predisposition is associated with medullary thyroid cancer, which is associated with a syndrome called multiple endocrine neoplasia (MEN) type 2 syndrome. Patients with MEN type 2 (Sippler's syndrome) have a strong familial history of medullary thyroid cancers and a type of adrenal cancer, called pheochromocytoma.

How can I prevent thyroid cancer?

As most cases of thyroid cancers are sporadic and not associated with any risk factors, there is usually no method to prevent the development of thyroid cancer. Careful examination of the thyroid and consideration of screening for patients at high risk could be considered, though the general prevention of thyroid cancers is impossible.

What screening tests are available?

Ultrasound testing has been proven to detect thyroid nodules-benign or malignant-of sizes of less than 1 cm. However, using ultrasound for mass screening is not likely to be efficacious because of the incidences and natural history of thyroid cancer. Notably, the majority of thyroid cancers are papillary thyroid cancer, which are historically very indolent cancers. Therefore, the small tumors that ultrasound has the ability to detect are likely to be very small papillary thyroid cancers, which are unlikely to affect the survival of most patients-akin to very early stage indolent prostate cancers and non-melanoma skin cancers. Hence, the early detection of thyroid cancers is generally through careful physical examination of the neck. Palpation of the neck will detect most clinically significant thyroid cancers.

Obviously, the story can be quite different in patients diagnosed with MEN type 2 and the subsequent high risk of medullary thyroid cancer. The present recommendation for patients with the genetic mutation associated with MEN type 2 is to undergo a prophylactic total thyroidectomy (complete removal of the thyroid) to prevent the development of a possibly aggressive medullary thyroid cancer.

What are the signs of thyroid cancer?

By far, the most common presentation of thyroid cancer is a solitary nodule on the thyroid, which can be felt on physical exam. As the thyroid gland is a fairly superficial organ in the neck, a thyroid nodule could be noticed early, at which time medical attention should be sought. By no means is every thyroid nodule a thyroid cancer. In fact, most represent hyperplasia (benign growth of the thyroid) of the thyroid gland.

Less commonly, thyroid cancer can present as multiple nodules in the thyroid or a large mass in the neck. The large mass can be located either in the region of the thyroid, representing the primary thyroid cancer, or in a separate region of the neck, representing a spread of cancer to the lymph nodes. Thyroid tumors can also at times present as hoarseness or with symptoms of tracheal or esophageal compression, such as shortness of breath, air hunger, problems or pain with swallowing, or neck pain.

How is thyroid cancer diagnosed and staged?

Any thyroid nodule deserves attention. Once a thyroid nodule is noted, the next steps are all designed to determine if the nodule represents a benign growth or malignant tumor. The most common etiology behind a thyroid nodule is a small portion of benign functioning thyroid tissue, which must be differentiated from a thyroid cancer. Obviously a careful physical exam should be done by a physician, with attention to the examination of the neck to attempt to detect enlarge lymph nodes. Other laboratory tests are also usually done to determine the function of the thyroid gland. Tests that indicate an over-functioning gland point more toward the nodule being composed of benign functional tissue. A test to determine the etiology of a thyroid nodule is a nuclear medicine study with radioactive iodine. This test is efficacious because functioning thyroid tissue takes up iodine to produce normal thyroid hormones. Therefore, radioactive iodine will be preferentially taken up by normally functioning thyroid tissue and will show up on tests that are designed to detect radioactivity. Hence, a nodule composed of functioning thyroid tissue will appear "hot" in these nuclear medicine scans (i.e., expelling a large amount of radioactivity because of the concentration of active thyroid tissue). These "hot nodules" are almost always benign and often require no further work-up. Nodules that are "cold" (i.e., do not take up much iodine) are also often benign, though can be malignant in 15-20% of cases. Therefore, these especially deserve more attention and further work-up.

The first step in investigating a suspicious or cold nodule, and often the definitive step in diagnosis, is a fine needle aspiration (FNA), which involves placing a needle into the nodule and drawing up cells from it so that they can be analyzed. FNAs have a diagnostic accuracy of over 98%, though it is highly dependent on the physician's expertise in performing the test. After a diagnosis is made, further work-up is done to determine if there was spread of disease to the local lymph nodes and distant areas of the body including the lungs and bones. Hence, this includes a CT scan of the neck to evaluate lymph nodes and an MRI of the neck to evaluate muscle or tracheal involvement. Some also recommend a bone scan and chest x-ray, as thyroid cancer can (rarely) metastasize to the bones and lungs.

Staging

The staging of a cancer basically describes how much it is grown before the diagnosis has been made, documenting the extent of disease. Before the staging systems are introduced, first some background on how cancers grow and spread, and therefore advance in stage. Cancers cause problems because they spread and can disrupt the functioning of normal organs. One way thyroid cancers can spread is by local extension to invade through the normal structures in the throat and into adjacent structures in the neck. Although this uncommonly happens in this fairly indolent disease, this invasion can include the tracheal and esophageal extension, causing possible airway compromise and disruption of swallowing function. Thyroid cancer spreads most commonly by accessing the lymphatic system. The lymphatic circulation is a complete circulation system in the body (somewhat like the blood circulatory system) that drains into various lymph nodes. When cancer cells access this lymphatic circulation, they can travel to lymph nodes and start new sites of cancer. This is called lymphatic spread, and usually denotes a poorer prognosis. Thyroid cancer can commonly spread to the lymph nodes of the neck, though (especially with papillary thyroid cancer) this may not carry a worse outcome. The lymph nodes commonly involved in thyroid cancer are those found in the anterior portion of the neck, called the cervical or jugular lymph node chains. They can be found in front of the large muscles on either side of the neck that contract when the head is turned from side to side. Tumor cells that spread to the jugular lymph nodes can then spread to the "supraclavicular" lymph nodes (found behind the collarbone) and to other lymph nodes in the neck. Eventually, they can spread to lymph nodes in the chest, called the mediastinal lymph nodes.

Thyroid cancers can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream and the tumors that arise from cells' travel to other organs are called metastases. Cancers of the thyroid generally spread locally or to lymph nodes before spreading distantly through the bloodstream. Hence, the incidence of distant metastases is low, with less than 5% of papillary thyroid cancers showing distant spread and between 5 and 20% of follicular thyroid cancers exhibiting metastases. If spread through the bloodstream does occur, the lungs and bones are the most common organs involved.

The staging system used in thyroid cancer is designed to describe the extent of disease in both the thyroid itself and the neck (with spread to the lymph nodes). The staging system used to describe thyroid tumors is the "TNM system", as described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three components: T-describing the extent of the "primary" tumor (the tumor in the thyroid itself); N-describing the spread to the lymph nodes; M-describing the spread to other organs (i.e.-metastases).

The "T" stage is as follows:

• T1-tumor 1 cm or less within the thyroid gland
• T2-tumor sized 1-4 cm within the thyroid gland
• T3-tumor size greater than 4 cm within the thyroid gland
• T4-tumor of any size extending outside of the thyroid gland itself

The "N" stage is as follows:

• N0-no spread to lymph nodes
• N1-tumor spread to lymph nodes
• N1a-spread to lymph nodes on the same side of the neck as the primary tumor
• N1b-spread to lymph nodes bilaterally or to the opposite side of the primary tumor

The "M" stage is as follows:

• M0-no tumor spread to other organs
• M1-tumor spread to other organs

The overall stage is based on a combination of these T, N, and M parameters as well as age (to emphasize the fact that younger patients have a better prognosis) and type of thyroid cancer (to emphasize that papillary and follicular thyroid cancers have excellent prognoses while anaplastic thyroid cancers have poor prognoses).

• Papillary or Follicular Thyroid Cancer, age > 45 years
• Stage I-T1, N0, M0
• Stage II-T2-3, N0, M0
• Stage III-T4, N0, M0 or any N1, M0
• Stage IV-any M1

• Papillary or Follicular Thyroid Cancer, age <45>
• Stage I-any M0
• Stage II-any M1

• Medullary Thyroid Cancer, any age
• Stage I-T1, N0, M0
• Stage II-T2, N0, M0
• Stage III-any N1, M0
• Stage IV-any M1

• Anaplastic Thyroid Cancer, any age
• ALL designated as Stage IV to denote the aggressiveness of anaplastic thyroid cancer

Though complicated, these staging systems help physicians determine the extent of the cancer, and therefore make treatment decisions regarding a patient's cancer. The stage of cancer, or extent of disease, is based on the information gathered through the various tests done (described above) as the diagnosis and work-up of the cancer is being performed.

What are the treatments for thyroid cancer?

The treatment of thyroid cancer can involve an approach combining surgery, radioactive iodine and radiation therapy, depending on the stage and type of thyroid cancer. Surgery always plays the central role, with the removal of the cancer being key. Usually the surgical procedure is a total thyroidectomy (the removal of the entire thyroid gland) or a near total thryroidectomy (leaving only a small remnant of thyroid tissue with parathyroid glands, which are attached to the thyroid). These more extensive surgical procedures have been shown to be more efficacious than more conservative surgeries, such as the removal of a single lobe of the thyroid gland (lobectomy). An exception to this philosophy can be in patients with small, Stage I papillary thyroid cancers, where a lobectomy may be appropriate. However, if the thyroid gland is not completely removed at the first surgical procedure, the patient is always at risk for recurrence in the portion of the thyroid left behind. Secondary operations to remove the remaining portion of the thyroid gland can be performed to attempt to salvage a cure in these patients, though the complication rates in these "completion thyroidectomies" may be high.

A controversy in the surgical treatment of thyroid cancer is how to address the lymph nodes of the neck. When lymph nodes are felt on physical exam or found by ultrasound, they are obviously removed. However, the role of a prophylactic removal of the lymph nodes of the neck when they are not obviously involved is unclear. The lymph nodes very close to the thyroid gland are usually dissected without much difficulty and therefore should be removed. However, most would agree that radical neck dissections to remove a majority of the lymph nodes of the neck are not indicated unless lymph nodes are known to be involved.

In more advanced cases of thyroid cancers, surgical treatment is not enough, and patients require various adjuvant therapies. The first and simplest is the use of supplemental thyroid hormone following surgery. Patients with near total or total thyroidectomies are likely to be hypothyroid anyway, hence requiring supplemental thyroid hormone regardless of the state of the cancer. The standard of care is therefore to use this supplemental thyroid hormone in order to keep the remaining thyroid gland (or remaining thyroid cancer) "asleep" or inactive through a feedback system. In other words, if the body detects that there is a sufficient amount of thyroid hormone already present (through supplementation), it will not produce signals to "turn on" the thyroid to create hormone itself. This can be quite successful in keeping residual thyroid cancers dormant.

As thyroid tissue (and often thyroid cancers) preferentially take up iodine into their cells as part of normal functioning, the use of radioactive iodine (RAI) can be used to kill any remaining cancer cells. The iodine is simply taken up into the cell and the radiation within the radioactive iodine itself is released locally, delivering a lethal dose of radiation to the cancer cells. Indications for RAI include tumors with high risk features such as sizes of >1.5 cm, invasion of the cancer through the thyroid capsule or into the soft tissues of the neck, spread to the lymph nodes or more distantly, or recurrent disease (thyroid cancer that has come back). RAI can be a very effective therapy in many cases, though there are thyroid tumors that do not take up iodine, rendering RAI useless.

Radiation therapy can also be used in the adjuvant setting, if it is felt that the patient has a high risk of recurrence following surgery alone. It is often used in patients with papillary, follicular, or medullary thyroid cancer with high risk features, such as incomplete resection or spread outside the thyroid gland to soft tissues of the neck or to regional lymph nodes that do not take up RAI. It is also used in all cases of anaplastic thyroid cancer to attempt to halt this aggressive disease. In practice, the most common indications for radiation therapy are when the thyroid cancer is adherent to the trachea, has mediastinal lymph node involvement, or does not take up RAI. In these cases, radiation therapy has been proven to decrease the risk of local recurrences. Also, a rare type of papillary thyroid cancer called "Tall Cell Variant" has a very high risk of recurrence after surgery. Radiation therapy is also indicated for this type of thyroid cancer.

Chemotherapy has not classically been used in the treatment of thyroid cancer. However, chemotherapy drugs such as adriamycin, cisplatin, and etoposide have been used in anaplastic thyroid cancers or disease that has progressed through RAI or radiation therapy.

Overall, surgery is the mainstay of treatment. RAI has been shown to improve the outcome of patients with higher risk disease (basically anyone with greater than Stage I disease). Radiation therapy has been shown to be efficacious in certain subsets of patients; namely, those with aggressive types of thyroid cancer, those with more advanced disease who do not respond to RAI, or those with residual disease still present after surgery. The vast majority of patients with thyroid cancer are curable using these modalities. However, further research is needed in patients who do not respond to conventional therapy and in patients with poor prognosis anaplastic disease.

Pancreatic Cancer

What is the Pancreas?

The pancreas is a pear-shaped gland, about six inches in length, located deep within the abdomen, between the stomach and the spine. It is referred to in three parts: the widest part is called the head, the middle section is the body, and the thin end is called the tail. The pancreas is responsible for making hormones, including insulin, which help regulate blood sugar levels, and enzymes, which are used by the bowel for the digestion of food. These enzymes are transported through ducts within the pancreas, emptied into the common bile duct, which carries the enzymes into the bowel.

What is Pancreatic Cancer?

Pancreatic cancer happens when cells in the pancreas begin to grow out of control. These cancer cells then have the ability to spread to nearby lymph nodes and organs (such as the liver and lungs). When cancer spreads, it is called metastatic. About seventy percent of pancreatic cancers occur in the head of the pancreas, and most of these begin in the ducts that carry the enzymes.

Am I at Risk For Pancreatic Cancer?

The incidence of pancreatic cancer is highest between 60 and 80 years of age, and is only rarely seen in people under 40. It is seen about equally in men and women, although the rates in women have risen in recent years, which may be due to higher rates of smoking in women. Cigarette smokers are two to three times more likely to develop pancreatic cancer. It is slightly more common in blacks and members of the Jewish community. It is seen more commonly in people who have diabetes, but this link is not yet well understood. Certain occupational exposures are thought to put a person at higher risk. These include chemists, coal, gas, and metal industry workers, and industries where pesticides are used more frequently. A person's risk triples if their mother, father, or siblings have had the disease. A family history of breast or colon cancer also increases risk. This increased risk is due to inherited mutations in cancer causing genes (changes that allow cancer to develop). The actual cause of this disease is not known, but is thought to be a result of a combination of inherited genetic changes and changes caused by environmental exposures.

How Can I Prevent Pancreatic Cancer?

Unfortunately, no one really knows what causes the disease, so it is difficult to prevent. One important point is that the risk for smokers who quit does decrease; so giving up cigarettes is helpful. Be aware of your family's health history. This can make you and your healthcare providers aware of any increased risk.

What Screening Tests are Available?

There are no screening tests currently available for pancreatic cancer. Researchers have been able to discover the genetic changes present in cancer of the pancreas. These genes are detectable in stool, bowel and enzyme fluid, bile, and blood. Researchers are looking at this as a way to screen people for pancreatic cancer in the future.

What are the Signs of Pancreatic Cancer?

Unfortunately, the signs of early stage pancreatic cancer are vague, and often attributed to other problems by both patients and physicians. More specific symptoms tend to develop after the tumor has grown to invade other organs or blocked the bile ducts. Symptoms include weight loss, loss of appetite, jaundice (a condition that causes yellowing of the eyes and skin and darkening of urine), pain in the upper abdomen or back, weakness, or nausea and vomiting. These symptoms can vary depending on where the tumor is located in the pancreas (head, body or tail). Newly developed diabetes is the presenting sign in ten to twenty percent of patients. This is caused by the cancerous pancreas' inability to produce insulin.

How is Pancreatic Cancer Diagnosed and Staged?

When a physician suspects that a patient may have pancreatic cancer there are several tests that can be done to make a diagnosis. A high quality CT Scan (called a spiral or helical CT) can detect a tumor in the pancreas, enlarged lymph nodes (which may indicate tumor involvement), tumors in the liver, or obstructions of the bile duct. It is the test most commonly used to diagnose this cancer in the United States. Ultrasound can also be used and is the more commonly used test in other areas of the world. Ultrasound uses a device that emits sound waves, which bounce off the organs, producing echoes that are used to create an image of the organ. This can be done on the outside of the abdomen (called transabdominal ultrasound) or from inside the bowel (a catheter is passed through the mouth down to the bowel), this is called endoscopic ultrasound.

If a patient has jaundice, the doctor may want to do a test to find out where the bile duct is blocked and if this blockage is caused by a tumor or another condition. Tests that can determine this are endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC). In ERCP, a tube is passed through the mouth down the throat to the bowel, where a small catheter is inserted into the bile and pancreatic ducts. Dye is injected and x-rays are taken. The x-rays will show where the blockage is and what it is caused by. In PTC, dye is injected through a needle that is inserted through the skin, into the liver. The dye moves into the bile ducts, again allowing the blockage and its cause to be seen with an x-ray. In some cases, a small sample of tissue (biopsy) may be removed during these procedures to be examined by a pathologist.

Some patients with pancreatic cancer may have an elevated level of carbohydrate antigen 19-9 (CA 19-9), but this is not present in all cases and may be caused by other things. In patients who have an elevated level, it is useful in confirming a diagnosis in conjunction with other tests and for monitoring the disease during treatment. The level can be periodically checked during treatment to see if the cancer is stable or worsening.

When the physicians talk about staging, they are referring to determining the size of the tumor and if it has spread or not. This information is then used to determine the best treatment. In the case of pancreatic cancer, the size of the tumor and if it involves important blood vessels determines if it can be surgically removed. Pancreatic cancer is staged on the TNM system (also called tumor - node - metastasis system). This describes the size of the tumor (T), if the lymph nodes are involved (N), and if it has spread to other areas of the body (M).

What are the Treatments For Pancreatic Cancer?

A small percentage of patients have localized tumors and are offered surgery to remove the cancerous area of the pancreas. This surgery, called a Whipple procedure, is an extensive and complicated one, and recovery can be difficult for the patient. For this reason, it is important to only perform the procedure on patients who are likely to benefit.

Unfortunately, medical treatment (chemotherapy and radiation) for pancreatic cancer does not result in many cures, but new therapies and combinations of therapies are allowing patients to live longer and have a better quality of life. In the majority of patients with locally advanced cancer (cancer that has not spread to other organs), treatment consists of chemotherapy (either fluorouracil (5-FU) or gemcitabine (Gemzar^®)), in conjunction with radiation therapy. Sadly, the average survival for these patients is still only six to twelve months.

Patients with disease that has spread to other organs are usually treated with either chemotherapy (fluorouracil or gemcitabine) alone or palliative care, which aims to improve quality of life by controlling pain and other symptoms. Palliative care can consist of pain medications, radiation therapy or nerve blocks to control pain, and biliary stents to relieve symptoms of a bile duct obstruction. Unfortunately, even with treatment these patients have an average survival of three to six months.

Due to the poor results with standard therapies, patients may choose to participate in clinical trials, which test newly developed medications. Patients can discuss available clinical trials with their physician.

Follow-up Testing

After completion of therapy, patients are followed closely with CT scans and tumor marker levels (CA 19-9) for any sign of recurrence.

Mesothelioma

What is mesothelial tissue?

The mesothelium is a protective sac that covers and protects most internal organs in the body. It is composed of two layers, one layer covers the organ and the second layer forms a sac around it. The mesothelium produces a lubricating fluid that is released between these layers, allowing moving organs (such as the lungs) to move easily. The area between the two layers is often called the pleural space. Mesothelial tissue is found lining the abdominal cavity organs, the lungs and the heart. What is mesothelioma?

Mesothelioma occurs when the mesothelial cells grow out of control. These cells also lose the ability to stop producing the lubricating fluid when there is enough. This results in organs being encased with a thick rind of tumor tissue and excess fluid build up, causing symptoms. These cells can grow and invade other organs, or spread to other areas of the body. When the cells spread to other areas of the body, it is called metastasis.

The majority of mesotheliomas are found in the lining of the lung. About ten percent of cases are found in the abdominal cavity lining, and even more rarely, mesothelioma is found in the lining of the heart.

Am I at risk for mesothelioma?

Mesothelioma is a rare cancer, with only 2,300 cases diagnosed in 2000, in the United States. It is eight times more common in men, which is due in most part to work-related exposure to asbestos. Risk also increases with age. The biggest risk factor for developing the disease is exposure to asbestos, accounting for 70 to 80 percent of all cases. Asbestos has been used in many products, including cement, brake linings, roof shingles, flooring products, textiles, and insulation. Particles can be released from these products, particularly during the manufacturing process, and inhaled. Prior to knowing the dangers, asbestos miners and other workers exposed to asbestos worked without wearing any protection. Since the 1970's, the U.S. Occupational Safety and Health Administration (OSHA) sets limits for acceptable levels of asbestos exposure and requires protective equipment in the workplace. Family members of people who worked with asbestos were also exposed to the toxin when it was carried home on clothing and hair, putting them at increased risk for mesothelioma. It takes 20 to 40 years from the time of asbestos exposure until mesothelioma is detected. This exposure was usually over a period of time, but has been reported to be as little as one or two months of exposure. Smoking does not seem to increase the risk of developing the disease.

The incidence of mesothelioma in Western Europe is much higher, with 5,000 new cases in 2000. This is because maximal exposure to asbestos in Europe occurred around 1970, whereas the maximum exposure in the U.S. was from the 1930s to 60s. It is expected that rates in the U.S. should begin to decline, whereas rates in Europe are expected to plateau in 2018 before declining.

How can I prevent mesothelioma?

By decreasing exposure to asbestos, the risk of mesothelioma is decreased. Workers who are exposed to asbestos on the job should wear protective clothing and masks. These workers should change their clothing before leaving the work site to avoid carrying any particles home. OSHA has set standards regulating these procedures. What screening tests are available?

There is no good screening test for mesothelioma. Radiologic studies (x-ray, CT scan) are not sensitive enough to detect tumors before symptoms occur.

What are the signs of mesothelioma?

The symptoms of mesothelioma are caused by a build-up of tumor tissue surrounding the lung and fluid in the pleural space that prevents the lung from expanding fully. This causes pressure on the lung, leading to pain and shortness of breath. As the disease progresses, patients may lose weight and have a dry, hacking cough. In the abdomen, this fluid and tumor tissue causes abdominal swelling, pain and weight loss.

How is mesothelioma diagnosed and staged?

Patients who present with symptoms worrisome for mesothelioma may have a chest x-ray done, indicating a build-up of fluid in the lining of the lung. These patients would then undergo CT scan to further evaluate the cancer. In the case of abdominal mesothelioma, a CT scan obtained to visualize the anatomy in the abdomen.

Patients would then undergo a biopsy to have the diagnosis confirmed. In the lung, a thoracoscope is used to go through the chest wall, between the ribs to obtain a sample of the tissue. A peritoneoscope is used to enter the abdomen to obtain a tissue sample in abdominal mesothelioma.

Staging refers to determining the extent of the disease and this dictates the treatment. Physicians use the TNM system (also called tumor - node - metastasis system). This describes the size of the tumor (T), if the lymph nodes are involved (N), and if it has spread to other areas of the body (M). This is then interpreted to a stage between one and four. Patients with earlier stage tumors tend to live longer and respond better to available treatments.

What are the treatments for mesothelioma?

Treatment is dependent on the stage of the disease, the location of the tumor, the patient's age and state of health at the time. Younger, healthy patients, with early stage disease may be candidates for surgery that removes the mesothelial tissue around the tumor. This surgery is extensive and it is not well understood how much benefit it provides the patient.

Traditional radiation therapy has not shown a benefit, and can cause damage to the healthy lung tissue in the process of treating the cancer. Research is investigating ways of giving radiation directly to the tumor, using implants or UV light therapy. Chemotherapy has often been used to treat patients with mesothelioma, but until recently trials did not find any one medication to be superior to others. These medications have had responses in 10 to 20 percent of patients, but combining more than one medication has not increased these rates. Recently, a new medication called pemetrexed (Alimta) was given in combination with cisplatin with positive results. Patients received either cisplatin alone or cisplatin in combination with pemetrexed. Patients who received the combination of drugs had increased response rates, survived longer, and had fewer side effects. This regimen is now considered standard of care for mesothelioma not treatable with surgery. Researchers are conducting studies that administer the chemotherapy directly into the pleural space. So far, the results of these studies have been disappointing.

Because the current therapies have limited effectiveness, researchers are studying new ways to treat mesothelioma. Some of the treatments being investigated include interleukin 2 (a biologic therapy), lovastatin (a cholesterol-lowering drug), immunotherapy, gene therapy (a method that attempts to correct the abnormal gene that causes the cancer to grow out of control), and Photodynamic Therapy (PDT-a treatment that uses a laser to activate a photosensitizing drug during the surgical removal of the cancer). Patients should talk with their physicians about current clinical trials for mesothelioma.

One problem that patients may encounter is the recurring build-up of fluid in the pleural space. This fluid can be removed with a chest tube (a tube that is put into the chest wall and left in for a period of time to allow drainage) or a procedure called thoracentesis (a small needle is put through the chest wall, into the pleural space, the fluid is drained, and the needle removed). In the abdomen, the procedure to remove fluid is called paracentesis. In this procedure, a needle is inserted through the abdomen into the fluid filled space, and the fluid is drained.

If this is a chronic problem, patients may have a catheter placed in the chest semi-permanently, allowing them to drain the fluid themselves at home as they need to. Removal of the fluid alleviates the difficulty breathing and chest pain caused by the build-up.

Follow-up testing?

The physician will follow the patient with physical examinations, chest x-rays, and CT scans.

Lung Cancer

What is the lung?

The lungs are two spongy organs found in the chest. They are responsible for delivering oxygen to the bloodstream. When you take a breath in, air moves into the lungs causing them to expand. The air can then come very close to blood that is traveling in small vessels called capillaries. When you breathe out, you exhale stuff that you don't need like carbon dioxide. The lungs are specially designed to place blood in close contact with as much air as possible, so their tissues are very delicate. The right lung has three sections called lobes. The left lung has only two lobes. Air comes in through your mouth and nose and then travels down a tube to the lungs called the trachea. The trachea divides into smaller branches called bronchi, and the bronchi keep dividing and dividing like branches on a tree. As the branches get smaller, they are called bronchioles. At the end of the branches, there are little sacs of air called alveoli. The air comes into contact with blood in the alveoli. The lungs are exposed to whatever you breathe in, so any toxic chemicals or pollutants in the air you breathe can get into your body through your lungs.

What is lung cancer?

Lung cancer happens when cells in the lung begin to grow out of control and can then invade nearby tissues or spread throughout the body. Large collections of this out of control tissue are called tumors. Any of the tissues in the lung can become cancer; but most commonly, lung cancer comes from the lining of the bronchi. Lung cancer is not really thought of as a single disease, but rather a collection of several diseases that are characterized by the cell type that makes them up, how they behave, and how they are treated. Lung cancer is divided into two main categories:

• Small cell lung cancer (SCLC) - the rarer of the two types (about 20% of all lung cancers), small cell lung cancer is more aggressive than non small cell lung cancer because is grows quicker and is more likely to spread to other organs
• Non small cell lung cancer (NSCLC) - the more common of the two types (80% of all lung cancers), non small cell lung cancer is generally slower growing than small cell lung cancer and is divided into three different types based on how the cells look that make it up- adenocarcinoma, large cell carcinoma, and squamous cell carcinoma

Am I at risk for lung cancer?

Lung cancer is the most common cause of cancer death in the world for both men and women. In the United States alone, it is estimated that 163,510 people will die from lung cancer in 2005. In comparison, 127,500 people are expected to die from colon, breast and prostate cancer combined in 2005 (the 2nd, 3rd, and 4th most common cancers in the U.S.). In the U.S., there has been a striking increase in the number of women getting lung cancer; in the 1990s, lung cancer overtook breast cancer as the most common cause of cancer death amongst women.

Every smoker is at risk for lung cancer. It is estimated that 87% of all cases of lung cancer are caused by cigarette smoking. The major risk factor for lung cancer is cigarette smoking. Your risk of getting lung cancer from cigarette smoking increases the longer you smoke, the more you smoke, and the deeper you inhale. Smoking low tar cigarettes does not prevent you from getting lung cancer. Importantly, if you quit smoking, your risk of getting lung cancer declines. The longer you go without smoking, the greater your risk declines; but it is never too late to quit because your risk declines somewhat no matter how long you have been smoking. Smoking also has an affect on people around you. Second-hand smoke, or smoke inhaled when you are near someone smoking, is another risk factor for lung cancer. It is estimated that 17% of cases of lung cancer in non-smokers are caused by second-hand smoke exposure in childhood and adolescence. Non-smoking spouses of smokers are 30% more likely than spouses of non-smokers to get lung cancer. Even though many people don't inhale them, smoking pipes and cigars is a risk factor for lung cancer as well. The more pipes or cigars you smoke, the more likely you are to get lung cancer. Although it is not as well established as cigarette smoking, smoking marijuana is also a risk factor for getting lung cancer. Both the magnitude and duration of marijuana use seems to be related to your overall risk.

Although smoking cigarettes is by far the most common and important risk factor for getting lung cancer, there are some environmental exposures that increase your risk for lung cancer as well. People who work with asbestos are more likely to get lung cancer; and if they smoke cigarettes too, their risk rises even higher. Asbestos is found in industries like shipbuilding, brake manufacture, insulation/fireproofing, and asbestos mining and production. Other substances that have been associated with lung cancer in workers who are exposed to them on a regular basis include arsenic, chromium, nickel, vinyl chloride, hard metal dusts, talc, uranium, and gasoline and diesel exhaust fumes.

Radon is an invisible, odorless gas that exists naturally in areas where there is a lot of uranium in the ground. Radon can collect in both uranium mines and peoples' houses. Exposure to radon has been associated with a slightly increased risk of lung cancer. You can check for radon with detectors available at your hardware store, and getting rid of it is usually as easy as opening a basement window.

People who have already had lung cancer are at risk for getting it again. A history of interstitial lung disease or tuberculosis (TB) also increases your risk of getting lung cancer. However, it should be stressed that cigarette smoking is far and away the most important and dangerous risk factor for developing lung cancer.

How can I prevent lung cancer?

The best way to prevent lung cancer is to quit smoking, or to never have started in the first place. You should try and avoid being around people who are smoking; and also avoid pipes, cigars, and marijuana. If you live in an area with radon, you should make sure there is adequate ventilation in your basement to get rid of it. Use a detector to make sure the radon levels are low. If you work in an industry where you are exposed to substances known to cause lung cancer, make sure and use all the proper protective equipment and attire made available by your employer.

There has been some suggestion that a diet high in fruits and vegetables may decrease your risk of lung cancer. This has yet to be definitively proven. Many substances, including antioxidants like vitamin A, vitamin E, and beta-carotene, have been suggested to decrease your risk of getting lung cancer. None of these has been shown to be beneficial in randomized controlled trials and cannot be recommended for this purpose. In fact, large clinical trials have shown and increased risk of lung cancer in patients that take increased quantities of vitamin E, vitamin A, and beta-carotene.

The future of lung cancer prevention will rely on sophisticated analysis of patients' genes and molecular markers for lung cancer risk; this coupled with "smart drug" design and novel imaging techniques may one day help decrease the risk of developing lung cancer.

What screening tests are available?

It is generally held that there are no good screening tests available for lung cancer. In all of the studies conducted to date, comparing people who are screened with chest x- rays and/or sputum samples, there has never been a documented decrease in deaths from lung cancer due to screening. However, this is an issue that is hotly debated because some studies have shown that cancers can be picked up in earlier stages if patients are screened with chest x-rays. The only problem is that picking up the cancers earlier hasn't translated to a decrease in deaths because of the screening. Some doctors may choose to screen high risk patients (usually those patients over 50 years old with a significant smoking history) with annual chest x-rays in an effort to find cancers earlier, however, no professional society has endorsed this practice. Currently, there is debate about the utility of screening people with CT scans (3-D x-rays that are more sensitive than standard chest x-rays). The debate is the same as with chest x-rays; no one has demonstrated a decreased mortality in patients screened with CT scans thus far. As more data is collected and more sophisticated imaging techniques are developed, perhaps one day there will be a good screening test for lung cancer. In the absence of a good screening tool, the best way we can decrease the number of lung cancer deaths is to get people to quit smoking.

What are the signs of lung cancer?

Unfortunately, the early stages of lung cancer may not have any symptoms. As the tumor grows in size, it can produce a variety of symptoms including:

• cough (especially one that doesn't go away or gets worse in character)
• chest pain
• shortness of breath
• coughing up blood or bloody phlegm
• new onset hoarseness or wheezing
• recurrent problems with pneumonia or bronchitis
• weight loss
• loss of appetite
• fatigue
• bone pain
• dizziness or double vision
• numbness or tingling in your arms or legs
• turning yellow (jaundice)

Many of these symptoms are non-specific, and could represent a variety of different conditions; however, your doctor needs to see you if you have any of these problems. Most patients (85%-90%) who are diagnosed with lung cancer have symptoms that prompt a doctor to order tests to look for a problem. A cough is the most common presenting symptom of lung cancer; however, many long term smokers have a chronic cough, so it is especially important for someone with a chronic cough to see their doctor if their cough changes in character or severity.

How is lung cancer diagnosed and staged?

When a patient at risk for lung cancer has symptoms suggestive of a lung tumor, they will usually first be referred for a chest x-ray. If the chest x-ray looks abnormal, then they will be referred for a CT scan (a 3-D x-ray) to better characterize the lesion. The other thing that your doctor may do is called sputum cytology, which means examining your phlegm for cancer cells.

Depending on the results of the sputum cytology, chest x-rays, and/or CT scans, your doctors may recommend that you get a biopsy. A biopsy is the only way to know for sure if you have cancer, because it allows your doctors to get cells that can be examined under a microscope. There are different ways that a biopsy can be done. Your doctors may want to do fiberoptic bronchoscopy, which means putting a thin, lighted tube down your nose or mouth and into your lung to look at the tumor and take samples of it. Another way to get a biopsy sample is to do a needle biopsy, which means placing a needle through the skin into the tumor to get cells. Sometimes, tumors cells can get into the fluid around your lungs, and your doctor may want to drain off some fluid (called a thoracentesis) and examine it under a microscope.

Once the tissue is removed, a doctor known as a pathologist will review the specimen. The pathologist can tell if it is cancer or not; and if it is cancerous, then the pathologist will characterize it by what type of tissue it arose from and what subtype of lung cancer it is, how abnormal it looks (known as the grade), whether or not it is invading surrounding tissues.

In order to guide treatment and offer some insight into prognosis, lung cancer is staged into different groups. The staging system is different for the two main types of lung cancer: small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC). This staging is done in a limited fashion before surgery taking into account the size of the tumor on CT scan, where it is, and any evidence of spread to other organs that is picked up with imaging modalities; and it is done definitively after a surgical procedure that removes lymph nodes and allows a pathologist to examine them for signs of cancer. Sometimes, surgeons will do procedures just for staging. One such procedure is called a mediastinoscopy. A mediastinoscopy is a procedure where a surgeon uses a scope to sample the lymph nodes near the trachea (the windpipe) so that the pathologist can examine them for signs of cancer. Often, your doctors will want to know the exact stage of your cancer before treatment is planned, because the stage of the cancer drastically affects how it is treated. The staging system is somewhat complex, but here is a simplified version of it:

Small Cell Lung Cancer - divided into two stages

1. Limited Stage - means the cancer is on only one side of the chest (lung and/or lymph nodes), so it could be reasonably treated with a radiation field
2. Extended Stage - means the cancer is on both sides of the chest (spread to both lungs and/or lymph nodes on both sides of the body) or spread outside of the chest to other areas of the body, so it could not be reasonably treated with a radiation field

Non Small Cell Lung Cancer - divided into four main stages

1. Stage IA- the tumor is less than 3 cm, isn't in a main bronchus and hasn't spread to any lymph nodes
   Stage IB - the tumor doesn't invade any organs, isn't too close to the trachea if it is in the main bronchus, doesn't cause obstruction of the lung and hasn't spread to any lymph nodes



2. Stage IIA- the tumor is less than 3 cm, isn't in a main bronchus and has spread to lymph nodes on the same side as the tumor
   Stage IIB - the tumor doesn't invade any organs, isn't too close to the trachea if it is in the main bronchus, doesn't cause obstruction of the entire lung but has spread to hilar lymph nodes on the same side as the tumor OR the tumor hasn't spread to any lymph nodes but doesn't invade any vital organs



3. Stage IIIA - the tumor can have spread to different types of lymph nodes than Stage II (called mediastinal or subcarinal), but they are still on the same side as the tumor and it hasn't invaded any vital organs
   Stage IIIB - the tumor has either invaded vital adjacent organs and/or spread to lymph nodes on the other side of the mediastinum as the tumor or specific lymph nodes called scalenes or supraclavicular. Also, the patient may have tumor spread to the fluid surrounding the lung



4. Stage IV- the tumor has spread (metastasized) to other organs in the body outside the lungs (like the bones, brain or liver)

Stage IIIB and stage IV non small cell lung cancers are generally considered inoperable, so it is very important to know if the cancer has spread to lymph nodes on the opposite side of the body as the tumor. Part of your workup to look for spread of the tumor (metastasis) will probably also entail CT scans of the liver and adrenals, a CT scan or MRI (a different sort of scan which uses magnets) of your brain, and a PET scan. If you are having particular symptoms, then your doctor may want different or more specific exams. Often times, if there is a plan for surgery, your doctor will order tests called PFT's (pulmonary function tests) to assess your lung capacity. Overall, your doctors want to know as much about your particular tumor as possible so that they can plan the best available treatments.

What are the treatments for lung cancer?

Surgery
For patients with non small cell lung cancer, surgery is often employed in cancers up to and including stage IIIA. The purpose of the surgery is to remove all of the cancer if possible. If the tumor is small and in a favorable location or the patient has limited lung function, the surgeon may choose to remove the tumor with a small section of lung; this is called a wedge resection. Most times the surgeon will choose to remove the entire lobe of the involved lung; this is known as a lobectomy. On occasion, the surgeon must remove the entire lung affected by the cancer; and this is known a pneumonectomy. Not every patient can tolerate these surgeries. Patients with diminished lung function due to other diseases may not be able to survive after such a surgery, or they may be severely limited in their activities. Preoperative pulmonary function tests (PFT's) are used to help predict who is a good candidate for surgery. Sometimes a quantified ventilation perfusion scan will be ordered which shows the amount that each area of lung is currently working. This way the surgeon can predict how much lung function will be lost based on the amount of lung that will need to be removed. Also, if you have other health problems, particularly heart problems, surgery may be too dangerous. Talk with your doctors about your options and the different procedures that you may be a candidate for.

Because it tends to behave differently, surgery is not generally recommended for small cell lung cancer of any stage. Small cell lung cancer is usually treated with chemotherapy and radiation therapy. There have been some studies on the use of surgery in small cell lung cancer for very early stage lesions; however, this is not generally considered a standard option for patients with small cell lung cancer.

Another potential use for surgery with lung cancer lies in treating solitary brain metastases. If a patient has a solitary lesion in the brains, surgeons will sometimes elect to remove them surgically. Talk with your doctor about the different ways to approach treatment of your particular disease.

Chemotherapy
Despite the fact that the tumors are often removed by surgery, there is always a risk of recurrence because there may be microscopic cancer cells left that the surgeon cannot remove. Also, some patients are not candidates for surgery or choose not to have surgery. Chemotherapy is the use of anti-cancer drugs that go throughout the entire body. These drugs may be given through a vein or with pills by mouth. Chemotherapy is recommended after surgery for some stage I patients and most stage II patients. Because current treatment of advanced stage lung cancers (stage III) is often a combination of radiation and/or chemotherapy and/or surgery, the timing and use of chemotherapy is debated and may vary depending on the specifics of the case. Chemotherapy is offered to many patients with stage IV disease and in patients with small cell lung cancer who have minimal weight loss and good performance status (how well they are living life without symptoms).

There are many different chemotherapy drugs, and they are often given in combinations. Patients will usually have to go to a clinic to get the chemotherapy because many of the drugs have to be given through a vein. Different chemotherapy regimens are used for different purposes. Some of the drugs used in lung cancer chemotherapy include: Etoposide (and Teniposide), Cisplatin (and Carboplatin), Ifosfamide, Cyclophosphamide, Vincristine, Doxorubicin, Paclitaxel, Docetaxel, Gemcitabine (Gemzar^®) and Vinorelbine (Navelbine). There are advantages and disadvantages to each of the different regimens that your medical oncologist will discuss with you. Based on your own health, your personal values and wishes, and side effects you may wish to avoid, you can work with your doctors to come up with the best regimen for your cancer and your lifestyle.

Targeted Therapies/Biologic Therapies
Targeted (also called "biologic") therapies are a new class of medications that have been specifically designed to combat precise pathways in various cancers. Cancers have abnormal genetic pathways and receptors, and recent research has helped characterize the particular molecular pathways that make cells cancerous and resistant to treatment with chemotherapy and radiation. Sophisticated laboratory research and pharmaceutical design have created a new class of medications, known as targeted therapies. These medications often produce less significant side effects than standard chemotherapy drugs. They can be given both though a vein or with pills by mouth. They can also be given in combination with standard chemotherapy. Benefits in stage IV lung cancer patients have been recently reported using two different targeted therapies: "Bevacizumab (Avastin)" and "Erlotinib (Tarceva)". Clinical trials are ongoing to determine the benefit of other targeted therapies in this disease. For more information on targeted therapies see the Targeted Therapy Basics and Types of Targeted Thearpies sections of Oncolink and talk to your doctor.

Radiotherapy
Lung cancer patients commonly are treated with radiation therapy. Radiation therapy uses high energy rays (similar to x-rays) to kill cancer cells. It comes from an external source, and it requires patients to come in 5 days a week for up to 6-8 weeks to a radiation therapy treatment center. The treatment takes just a few minutes, and it is painless. Radiation therapy is often combined with surgery and is important in the treatment of all types of lung cancer. It may be recommended before surgery to shrink a tumor to make it easier for the surgeon to remove. Radiation may be used after surgery if there are worrisome risk factors that make it likely for a tumor to come back in the chest. Sometimes radiation is used instead of surgery in patients who are not surgical candidates. Radiation can also be used in the palliative setting to ease the pain of metastases, stop tumors from bleeding, and prevent airway obstruction. Radiation is important in reducing the risk of local recurrence of tumors and is often offered in more advanced cases to kill tumor cells that may be living in lymph nodes. Generally, doctors try to limit the amount of radiation that your vital organs get, and don't like to treat large portions of the lungs. Your radiation oncologist can answer questions about the utility, process, and side effects of radiation therapy in your particular case.

Photodynamic Therapy
Photodymanic therapy (PDT) involves injecting a patient with a drug that preferentially gets taken up in cancer cells and then makes them sensitive to a particular kind of light. When you shine the right kind of light on the tumor, the drug is activated and cancer cells are killed. Photodyamic therapy is occasionally used in the treatment of lung cancer for lesions in the airway. There are also clinical trials ongoing at the Hospital of the University of Pennsylvania to treat cancers with PDT that have spread to the fluid surrounding the lung cavity. Please visit the OncoLink/Emergingmed Clinical Trials Resource Center to see if you qualify for any of these studies.

Follow-up testing

Once a patient has been treated for lung cancer, they need to be closely followed for a recurrence. At first, you will have follow-up visits fairly often. The longer you are free of disease, the less often you will have to go for checkups. Your doctor will tell you when he or she wants follow-up chest x-rays, CT scans, or other tests. Lung cancer is generally considered an aggressive tumor that often comes back after treatment; thus it is very important that you let your doctor know about any symptoms you are experiencing and that you keep all of your follow-up appointments. Finally, if you haven't yet done it, you need to quit smoking. Remember, it is never too late to get the health benefits of smoking cessation.

Clinical trials are extremely important in furthering our knowledge of this disease. It is though clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your doctor about participating in clinical trials in your area.

This article is meant to give you a better understanding of lung cancer. Use this knowledge when meeting with your physician, making treatment decisions, and continuing your search for information. You can learn more about lung cancer on OncoLink through the related links to the left.

Prostate Cancer

What is the prostate?

The prostate is a small gland that only men have. It is normally about the size of a walnut. The prostate is located underneath the bladder and in front of the rectum. Because the prostate is close to the rectum, it can be felt by a doctor during a digital rectal exam (the part of a physical where the doctor inserts a gloved, lubricated finger into a man's anus). The prostate makes and stores fluid that is part of semen, and this fluid is released from a man's penis during ejaculation. The prostate is signaled to do its job by the male hormone testosterone, which can influence the behavior of the prostate gland and prostate cancer. Nerves to the penis that are important in producing and maintaining an erection run very close to the prostate. The prostate completely encircles the tube that carriers urine from the bladder to the penis, called the urethra. If the prostate enlarges, it can block the flow of urine from the bladder making it difficult for a man to urinate.

What is prostate cancer?

Prostate cancer happens when cells in the prostate begin to grow out of control and can then invade nearby tissues or spread throughout the body. Large collections of this out of control tissue are called tumors. However, some tumors are not really cancer because they cannot spread or threaten someone's life. These are called benign tumors. The tumors that can spread throughout the body or invade nearby tissues are considered cancer and are called malignant tumors. Usually, prostate cancer is very slow growing. However, sometimes it will grow quickly and spread to nearby lymph nodes. Lymph nodes are small, pea-sized pieces of tissue that filter and clean lymph, a clear liquid waste product. If prostate cancer has spread to your lymph nodes when it is diagnosed, it means that there is higher chance that it has spread to other areas of the body.

Am I at risk for prostate cancer?

Every man over the age of 45 is at risk for prostate cancer. Although prostate cancer can occasionally strike younger men, the risk of getting prostate cancer increases with age and more than 70% of men diagnosed with prostate cancer are over the age of 65. Prostate cancer is the most common cancer that men get in the United States behind skin cancer. It is estimated that there will be 189,000 new cases of prostate cancer and 30,200 deaths from prostate cancer in the year 2002 in the United States.

Although there are several known risk factors for getting prostate cancer, no one knows exactly why one man gets it and another doesn't. Some of the most important risk factors for prostate cancer include age, ethnicity, genetics and diet. Age is generally considered the most important risk factor for prostate cancer. The incidence of prostate cancer rises quickly after the age of 60, and the majority of men will have some form of prostate cancer after the age of 80. One of the sayings about prostate cancer is that older men (over the age of 80) die with prostate cancer not from prostate cancer. This saying means that many older men have microscopic disease that doesn't shorten their life expectancy because the cancer takes a long time to grow and become clinically important. However, this saying is only a generalization; sometimes prostate cancer can grow quickly even in older patients.

Another important risk factor for prostate cancer is ethnicity. No one knows exactly why, but prostate cancer is more common in African-American and Latino men than Caucasian men. African-American men have a 1.6 fold higher chance of getting and dying from prostate cancer than Caucasian men. Asian and Native American men have the lowest chances of getting prostate cancer. Some doctors believe that genetic differences are important in explaining the different rates of prostate cancer between different ethnic groups; however, there is some evidence that differences in diets may be the cause. When Asian men move to Western countries like the United States, their chances of getting prostate cancer rise. Men who live in the United States and Northern Europe have the highest rates of prostate cancer, while men who live in South America, Central America, Africa, and Asia all have much lower chances of developing prostate cancer.

There is some evidence that a man's diet may affect his risk of developing prostate cancer. The most common dietary culprit implicated in raising prostate cancer risk is a high fat diet, particularly a diet high in animal fats. Also, a few studies have suggested that a diet low in vegetables causes an increased risk of prostate cancer. There are a few foods that have been implicated in decreasing prostate cancer risk: a diet high in tomatoes (lycopene) has been suggested as well as diet high in omega-3-fatty acids (oils found in fish like salmon and mackerel). Doctors and scientists aren't in full agreement as to the usefulness of eating these foods when in comes to decreasing prostate cancer risk. Diets high in selenium, vitamin D, and soy have all been suggested to decrease prostate cancer risk; but a these are currently under study and data from large trials is needed before firm recommendations can be given about their use for this purpose.

A family history of prostate cancer increases a man's chances of developing the disease. This increase shows itself when a man has either a father or brothers (or both) with prostate cancer, and is even greater when his relatives develop prostate cancer at a young age. A variety of different genetic factors are currently being researched. Variations and mutations in certain genes may be responsible for some increases in prostate cancer rates in families. Men who carry mutations in genes known as BRCA1 or BRCA2 (these are genes implicated in breast and ovarian cancer in women) may have a 2 to 5 fold increase in prostate cancer risk. Men with high levels of testosterone or a hormone known as IGF-1 (insulin-like growth factor 1) seem to be at a higher risk for developing prostate cancer as well.

How can I prevent prostate cancer?

Because prostate cancer is a common disease and often has a very slow growing course, there is a lot of interest in trying to prevent prostate cancer with drugs, foods, or nutrients. Even a compound that could slow the progression of the disease could potentially decrease mortality. Right now, the best way to try and prevent prostate cancer is to modify the risk factors for prostate cancer that you have control over. You may want to try to eat a low fat diet that is rich in fruits and vegetables. Although certain foods, vitamins and minerals have been suggested to decrease your chances for getting prostate cancer, doctors still need more data before any particular food or supplement can be endorsed for preventing prostate cancer. Currently, there are studies looking at selenium, lycopene, vitamin A and other retinoids, vitamin D, vitamin E, and soy for prostate cancer prevention.

There is also interest in preventing prostate cancer by using drugs. We know that hormones like testosterone can cause prostate cancers to grow and develop, so there are experiments looking at drugs that can decrease the levels of testosterone in the prostate to attempt to stop prostate cancer from forming and growing. Drugs like Flutamide and Finasteride work in this manner, and they are currently under investigation for prostate cancer prevention. Another way to decrease testosterone in the prostate is to decrease the total amount of testosterone in the body. Drugs that decrease total body testosterone have a whole host of undesirable side effects (drugs that do this are currently used to treat men who have already developed prostate cancer and will be discussed later in the treatment section), so they aren't nearly as good choices for prostate cancer prevention

What screening tests are available?

Whether or not men should be screened for prostate cancer is an intensely debated issue. We know that prostate cancer usually grows very slowly, so intuitively it would make sense that we could reduce mortality from prostate cancer by picking it up early so it could be treated before it spreads. However, in order for a screening test to be fully embraced, we need to prove that picking up a disease early actually does help reduce the number of deaths. Right now, there is no good data showing that screening for prostate cancer reduces deaths from prostate cancer. There are currently very large trials on-going to see which populations of men will benefit most.

Currently, there are two methods that physicians use to screen for prostate cancer. One of them is called a digital rectal exam (DRE). A digital rectal exam is done in your primary care physician's office. Because your prostate is so close to your rectum, your doctor can feel it by inserting a gloved, lubricated finger into your anus. Your doctor can feel if there are lumps, asymmetries, or if your prostate is enlarged. A digital rectal exam is uncomfortable, but not painful. It is a useful test, but it is not perfect because some small cancers can be missed and only the bottom and sides of the prostate can be examined in this manner. Although it isn't a perfect test, it becomes more useful when it is combined with another test called a PSA.

A PSA (prostate specific antigen) test is a blood test that looks for a protein that the prostate makes. Normal prostate tissue makes a little bit of PSA, but prostate cancer usually makes much more. By checking to see if your PSA is elevated, your doctor can screen you for prostate cancer. The PSA test isn't perfect either, because some tumors won't elevate the PSA and some other processes (like benign prostatic hyperplasia and prostatitis) can cause it to be falsely elevated. However, the higher your PSA is, the more likely the elevation is caused by a prostate cancer. The cut-off that your doctor usually uses is 4.0 ng/ml, meaning that anything below 4.0 ng/ml is normal and anything above it is abnormal. If your PSA is elevated, or you have an abnormal digital rectal exam, then you need to get further evaluation; however, this doesn't necessarily mean that you have prostate cancer. The only way to know for sure whether or not you have cancer is to get a sample of your prostate from a biopsy.

Both a digital rectal exam and a PSA are simple, non-invasive tests. Most physicians recommend screening for prostate cancer with these tests in men with a life expectance of 10 years or more. However, some doctors don't think screening for prostate cancer is worth doing. One of the downsides is that you may go through an extensive workup and treatment for a disease that never would have shortened your life. We know that some prostate cancers are very slow growing (often taking more than 10 years to become significant), so if your life expectancy is less than 10 years it may not be worthwhile to go through the process of screening, biopsy and treatment. The treatment options for prostate cancer are not completely benign, and all of them have the potential for side effects. However, it is difficult for physicians to determine which prostate cancers will progress versus those that will remain indolent in any individual patient. Another argument against prostate cancer screening is that it has never been proven to save lives in studies of large populations. However, many doctors think that newer treatments for early stage prostate cancers may make this argument obsolete. Data from large trials currently being carried out should help to settle this argument in the near future.

The American Cancer Society and the American Urological Society recommend regular prostate cancer screening. The American Cancer Society recommends that men start getting annual PSAs and digital rectal exams starting at age 50, unless they are high risk (meaning they have a family history of prostate cancer or are African-American), who should begin screening at age 45. However, they mention that screening should only be carried out if your life expectancy is greater than 10 years, so men in their 80s and 90s (especially if they have other serious medical problems) should probably not be screened. The most important thing is to discuss the issue with your doctor. Decisions about screening should be individualized and reached after hearing about the potential benefits and harms of screening, biopsy and treatment.

What are the signs of prostate cancer?

Most early prostate cancers are detected with PSA tests or digital rectal exams before they cause any symptoms. However, more advanced prostate cancers can cause a variety of symptoms including:

• trouble starting urination
• urinating much more frequently than usual
• the feeling that you can't release all of your urine
• pain on urination or ejaculation
• blood in your urine or semen
• impotence
• bone pain

All of these symptoms can be caused by a variety of things besides prostate cancer, so experiencing them doesn't necessarily mean you have prostate cancer. When older men have problems urinating, it is usually caused by process called benign prostatic hyperplasia (BPH) which is not prostate cancer. If you experience any of these symptoms, you need to see your doctor for evaluation.

How is prostate cancer diagnosed and staged?

If you have symptoms suspicious for prostate cancer, your doctor will do a digital rectal exam and a PSA blood test. If either of those two test are abnormal, then most likely your doctor will recommend that you receive a biopsy. Also, your doctor may want to get a biopsy if there is an abnormal result on a screening PSA or digital rectal exam. A biopsy is the only way to know for sure if you have cancer, because it allows your doctors to get cells that can be examined under a microscope. The most common way that a biopsy is done is with a transrectal ultrasound (TRUS). A transrectal ultrasound is a thin cylinder that emits sound waves and monitors them when they bounce off of tissue. It is inserted into your rectum, and allows your doctor to view your prostate and choose where to remove tissue from. Any suspicious areas are biopsied, plus some tissue will be removed from all of the different parts of the prostate (to make sure they don't miss any cancers that may be small and growing in one particular area). The procedure is done while you are awake, with the help of some numbing medicine. Unfortunately, a transrectal ultrasound isn't a perfect tool because even though many samples are taken, it can occasionally miss the area of the cancer. If this happens, and your PSA remains elevated, you will probably need to have the procedure repeated in a few months.

Once the tissue is removed, a doctor known as a pathologist will review the specimen. The pathologist can tell if it is cancer or not; and if it is cancerous, then the pathologist will characterize it by what type of prostate cancer it is and how abnormal it looks (known as the grade). The vast majority of all prostate cancers (at least 95%) are a subtype known as adenocarcinoma, but occasionally they can be small cell carcinomas or lymphomas (two rare types of prostate cancer that are treated differently than the more standard adenocarcinomas). The pathologist then characterizes how much the cancer looks like normal prostate tissue, and this is known as the grade of the tumor. Pathologists often use a scale when they grade prostate tumors known as the Gleason score. The Gleason score runs from 2 to 10, with 2 being a very normal looking tumor and 10 being a very abnormal looking tumor. Generally, the more abnormal the tumor looks, the more aggressive it is. We characterize grades on a scale because, together with staging, it gives us a way to offer a prognosis and it often guides our choice of therapy.

Prostate cancer is divided into four different stages to help guide our treatments and offer information about the chances for a cure. This staging is done in a limited fashion before surgery taking into account whether or not the tumor can be felt on digital rectal exam and the results of any imaging modalities; it is done definitively after a surgical procedure that removes lymph nodes and allows a pathologist to examine them for signs of cancer. The staging system is somewhat complex, but here is a simplified version of it:

• Stage I - tumor cannot be felt during a digital rectal exam; it was detected by an elevated PSA blood test or incidentally found during another prostate procedure for a benign condition.
• Stage II - tumor can be felt during a digital rectal exam, but it has not spread beyond the prostate and it hasn't spread to lymph nodes or other organs
• Stage III - tumor extends outside the prostate and can be in the seminal vesicles, but not in any other organs or lymph nodes
• Stage IV - tumor has spread to other organs or lymph nodes

Although the clinical stage is important, the pathological stage is a more accurate predictor of the course of your cancer because it actually examines the prostate and the lymph nodes in the area. If your stage, grade, or PSA are high enough, you may be referred for other tests before treatment to look for spread to other parts of your body. Tests like CT scans (a 3-D x-ray) or MRIs (like a CT scan but done with magnets) can examine the prostate and localized lymph nodes. Some patients are referred for a bone scan, which is a test using a radioactive tracer to look for metastasis to any of your bones. Another test that you may be referred for is called a ProstaScint scan, which uses a radioactive tracer that can localize prostate cancer to either bones or lymph nodes. Finally, if your doctors are very worried about spread to lymph nodes, they may choose to perform a surgical lymph node sampling before proceeding with any definitive treatment.

What are the treatments for prostate cancer?

There are many different ways to treat prostate cancer, and you will most likely be consulting multiple types of doctors before making a final decision. Physicians are not always in agreement as to the way to proceed because there haven't been enough large trials that compare the different treatment modalities. For prostate cancer, it is important that you get a second opinion and you should talk to both urologists and radiation oncologists to hear about the benefits and risks of surgery, hormonal therapy and radiation in your particular case. If your prostate cancer has already spread at the time of diagnosis, you will also need a medical oncologist to talk about chemotherapy. The most important thing is to discuss your options and make a decision that suits your lifestyle, beliefs and values.

Surgery
Surgery is a common form of treatment for men with prostate cancer. Surgery attempts to cure prostate cancer by removing the entire prostate and getting all of the cancer out of the body. An attempt at a surgical cure for prostate cancer is usually done with early stage prostate cancers, but sometimes surgery will be used to relieve symptoms in advanced stage prostate cancers. Surgery for prostate cancer is generally felt to be equivalent to radiation for prostate cancer in terms of survival, especially in early stage, low to intermediate grade cancers. The decision to have surgery versus radiation is often made on the basis of the patient's age and health status; the two different approaches have different side effect profiles depending on the patient's age.

The most common surgical procedure for prostate cancer is known as a radical prostatectomy. Radical prostatectomy means that the entire prostate gland is removed from around the tube that connects the bladder to the penis (the urethra). This surgery can be done in two different ways, the retropubic approach and the perineal approach. The retropubic approach means that incision in made in the lower abdomen, while the perineal approach means that the incision is made between the scrotum and the anus. Often times during a retropubic approach, the surgeon will remove some lymph nodes in the area and have them quickly examined by a pathologist for signs of cancer. If the nodes have cancer, then the surgeon will not to proceed with the operation. This is the major reason a retropubic approach is used in most surgeries today.

Radical prostatectomies are very safe surgeries with few life threatening complications; however, there is a significant risk for other side effects. Both urinary incontinence (not being able to hold in your urine) and impotence (inability to achieve and maintain an erection) are commonly associated with this procedure. The risk for having either of these side effects increases with age; this is why younger men are often recommended to have surgery while older men are recommended to have radiation. The skill of your particular surgeon influences your chances of having these side effects during a radical prostatectomy. Talk to your surgeon about their complication rates before your operation. Sometimes, particularly with lower grade and smaller cancers, a nerve sparing prostatectomy can be performed. This type of prostatectomy can decrease the chances that you will be impotent after the procedure. However, there is always a risk and not every patient is a candidate for a nerve sparing prostatectomy. With surgery, urinary incontinence and impotence are often most severe right after the operation and get better with time. There are things that your doctors can recommend to help you with either of these problems. Talk to your urologist about your options.

Radiotherapy
Prostate cancer commonly is treated with radiation therapy. Radiation therapy uses high energy rays (similar to x-rays) to kill cancer cells. Radiation therapy is another option besides surgery for early stage prostate cancer; and when advanced stage prostate cancer needs to be treated, it is usually done with radiation therapy. Radiation helps avoid surgery in patients who are too ill to risk having anaesthesia. Radiation is usually offered to older patients in the case of early stage prostate cancer because of its side effect profile is less than surgery in the elderly. Radiation can have impotence rates similar to surgery, but the risk of urinary incontinence is very low. Impotence develops months to years after the radiation treatment, unlike with surgery, which tends to have the side effects occur immediately. Other side effects from radiation include bladder irritation, which can cause urinary frequency and urgency as well as bladder pain, and diarrhea or rectal bleeding. Your radiation oncologist tries to limit the amount of radiation to other organs, but often the bladder and rectum can get some dosage because they are in such close proximity to the prostate.

Radiation therapy for prostate cancer either comes from an external source (external beam radiation) or an internal source where small radioactive seeds are implanted into the patient's prostate (brachytherapy). External beam radiation therapy requires patients to come in 5 days a week for up 6-8 weeks to a radiation therapy treatment center. The treatment takes just a few minutes, and it is painless. Brachytherapy is done as a one-time insertion, in the operating room. Brachytherapy cannot be done in all patients and is usually reserved for early stage prostate cancers. Your radiation oncologist can answer questions about the utility, process, and side effects of both of these types of radiation therapy in your particular case.

Hormonal Therapy
Both normal prostate tissue and prostate cancers depend on male sex hormones, called androgens, to grow and replicate. Testosterone is an androgen very important to the prostate gland. Men make androgens in their testicles. One of the ways to treat prostate cancer is to remove androgens from the body, thus making the cancer shrink and then grow more slowly. There are a few different ways to remove androgens: you can remove a man's testicles (called an orchiectomy), you can give a man drugs that block the production of androgens (called LHRH agonists), you can give a man drugs that block androgen receptors (called anti-androgens) or you can give a man estrogens. Different methods of deceasing androgens are often used in the same patient: using LHRH agonists with anti-androgens can achieve what is known as a total androgen blockade. Hormone therapy can also be used in conjunction with other treatments, especially in the case of advanced stage prostate cancer being treated with radiation therapy. In that case, hormonal therapy is often given before the radiation and this is known as neoadjuvant hormonal therapy. Another use for hormones is in patients who present with metastatic disease. After a while, all prostate cancers will become resistant to hormonal therapy. However, this often takes many years and hormonal therapy can buy a lot of time in patients with extensive disease or patients who choose not to undergo surgery or radiation.

There are a number of side effects associated with hormonal therapy. Hormonal therapy will almost universally cause impotence and the loss of your sex drive. It can also cause breast enlargement, hot flashes, and muscle and bone loss (osteoporosis). There are some things your doctors can prescribe to help with bone loss and hot flashes, but little can be done about loss of libido and impotence.

Chemotherapy
Chemotherapy is the use of anti-cancer drugs that go throughout the entire body. Chemotherapy is prescribed by medical oncologists, who are experts at choosing appropriate regimens for particular patients. Chemotherapy for prostate cancer is generally only reserved for very advanced cancers that are no longer responsive to hormonal therapy. There are a number of chemotherapy drugs that can be used for prostate cancer, and they are often used in combinations. A common chemotherapy regimen is Mitoxantrone with Coritcosteroids; and other regimens that are becoming increasingly popular use a drug called Estramustane with drugs called Taxanes. The use of chemotherapy in prostate cancer is currently being studied and men who get chemotherapy are encouraged to talk to their doctors about experimental trials. There are advantages and disadvantages to each of the different regimens that your medical oncologist will discuss with you. Based on your own health, your personal values and wishes, and side effects you may wish to avoid, you can work with your doctors to come up with the best regimen for your lifestyle

Cryosurgery
Cryosurgery is a somewhat experimental approach to treating prostate cancer whereby probes with liquid nitrogen are implanted into the prostate and then the tissue is frozen. This freezing kills the cancer cells, and it can be repeated multiple times if needed. However, data to date has shown that cryosurgery is not as effective as radiation and surgery for treating prostate cancer. Cryosurgery also has a variety of side effects including urinary incontinence and impotence.

Watchful Waiting
Some patients choose to receive no therapy for their prostate cancer in the hopes that it will grow very slowly. By avoiding any therapy, they avoid the side effects that come along with surgery, radiation, or hormones. Watchful waiting is appropriate for older men with small, low-grade tumors, and slowly rising PSAs, and multiple other medical problems. Watchful waiting can be considered in patients who have a life expectancy less than 10 years as long as the cancer isn't large or of a high grade. Men who choose to undergo watchful waiting should have PSAs and digital rectal exams done every 3-6 months, and need to be re-biopsied at some point to make sure the grade hasn't become less favorable. However, it is never really clear what change in clinical status should institute treatment. Also, if the tumor has progressed, they may no longer be eligible for curative therapy.

Follow-up testing
Once a patient has been treated for prostate cancer, they need to be closely followed for a recurrence. At first, you will have follow-up visits fairly often. The longer you are free of disease, the less often you will have to go for checkups. Your doctor will tell you when he or she wants follow-up visits, PSAs and x-rays or scans depending on your case. Your doctor will also probably do digital rectal exams regularly during your office visits. It is very important that you let your doctor know about any symptoms you are experiencing and that you keep all of your follow-up appointments.

Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your doctor about participating in clinical trials in your area.

This article is meant to give you a better understanding of prostate cancer. Use this knowledge when meeting with your physician, making treatment decisions, and continuing your search for information. You can learn more about prostate cancer on OncoLink through the related links to the left.

Bladder Cancer

What is the Bladder?

The bladder serves as a reservoir for urine in our bodies. It permits the storage of urine for a period of time before releasing it as we urinate. It can be thought of as a muscular balloon; a flattened structure when there is no urine (immediately after a person urinates) but able to be filled to up to a liter (though this would be very uncomfortable) with urine. Normally, as the bladder nears 500 cc (1/2 of a liter), we feel the urge to urinate. The muscular structure of the bladder also helps other pelvic muscles push the urine out when it is released. The bladder is located deep in the pelvis, just above the pubic symphysis, which is a bone that can be felt in the midline on the front of our pelvis. In fact, when the bladder is over distended, it can be felt by a physician. Ureters empty urine into the bladder from the kidneys, and the urethra leads out from the bladder, emptying urine out of our bodies.

What is bladder cancer?

The definition of a tumor is a mass of quickly and abnormally growing cells. Tumors can be either benign or malignant. Benign tumors have uncontrolled cell growth, but without any invasion into normal tissues and without any spread. A malignant tumor is called cancer when these tumor cells gain the propensity to invade tissues and spread locally as well as to distant parts of the body. In this sense, bladder cancer occurs when cells in the lining of the bladder grow uncontrollably and form tumors that can invade normal tissues and spread to other parts of the body.

Cancers are described by the types of cells from which they arise. Bladder cancers arise almost exclusively from the lining of the bladder. In the United States, 98% of bladder cancers are called transitional cell carcinomas. This simply means that the cancer started in the lining of the bladder, which is made up of transitional cells that appear elliptical under the microscope. Less commonly are other types of cancers that arise from the lining of the bladder, called adenocarcinomas, squamous cell carcinomas and small cell carcinomas. A common way for bladder cancers to grow is called a papillary growth pattern. When a bladder cancer grows this way, it can be noninvasive, i.e., not invading into tissues at all, and hence not having a risk for distant spread (as long as it is treated). In addition to other invasive cancers, patients are sometimes diagnosed with precancerous lesions, called carcinoma-in-situ. Carcinoma-in-situ occurs when the lining of the bladder undergoes changes similar to cancerous changes without any invasion into the deeper tissues. Hence, while the cells themselves have cancer-like qualities, there is no risk of spread, as no invasion has occurred. However, both papillary bladder cancers and cancer-in-situ may become invasive and cause problems if not treated.

Am I at risk for bladder cancer?

Bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. Over 50,000 cases are diagnosed every year in the United States, with over 12,000 deaths. Internationally, the incidence of bladder cancer varies substantially, with highest rates in Europe and North America and in areas (Northern Africa) endemic with a type of fluke called Schistosoma haematobium, which induces a predominance of squamous cell carcinomas. Classically, bladder cancer is thought of as a disease that affects older men, with men affected more than women by a 3:1 ratio and 2/3 of the cases diagnosed in people over the age of 65.

Cigarette smoking is the largest risk factor for bladder cancer (yet another reason to stop smoking). Smokers have 2-4 times the risk of having bladder cancer, and it contributes to up to 50% of all bladder cancers that are diagnosed. Other than the previously mentioned Schistosoma haematobium infections, the only other risk factors known are from occupational exposures, such as polychromatic hydrocarbons (benzene, benzidine). More recently, an association has been made between chlorinated drinking water and bladder cancer. Though there have been suggestions of saccharin and high intake of dietary fat and cholesterol being causative for bladder cancer, these have yet to be substantiated.

How can I prevent bladder cancer?

Smoking is the strongest risk factor associated with the development of bladder cancer. Therefore, smoking cessation is the best way to prevent bladder cancer. Also, obviously reducing the exposure to carcinogenic compounds should decrease the risk of developing bladder cancer. Other than these preventative measures, decreasing the risk of bladder cancer relies on early detection of symptoms and possibly screening high-risk individuals.

What screening tests are available?

The goal of screening tests are to detect cancers early and initiate treatment when the cancer is in an early stage, or even before it becomes invasive. Cytologic examination of urine (looking for abnormal cells in urine) has been the most commonly tested screening tool. It involves testing urine for the presence of abnormal cells, which would indicate the possibility of a cancer. This method is fairly inexpensive and without risk to the patient. If abnormal cells are seen, over 95% of the time it accurately predicts the presence of bladder cancer. However, a fair amount of cancers can be missed using this method. Also, the incidence of preclinical (too small to cause any symptoms) bladder cancer in the general population is likely too low for cytologic examination of urine to be useful as a mass screening tool. Routine examination of the urine for the detection of blood (by far the most common presentation of bladder cancer) has also been tested and also appears to be inadequate for mass screening. Therefore, there is no tried screening method for bladder cancer, so the best method for detecting bladder cancer and preventing an aggressive bladder cancer is to not smoke or stop smoking and to not ignore the symptoms of bladder cancer, which usually involves blood noted in the urine (see below).

What are the signs of bladder cancer?

By far the most common sign of bladder cancer is the presence of blood in the urine, called hematuria. The blood in the urine can either be noticeable by the naked eye, called gross hematuria, or noted only when the urine is analyzed in a laboratory, called microscopic hematuria. Either gross hematuria or microscopic hematuria is present in over 80% of cases of bladder cancer. Therefore, when someone is noted to have blood in the urine, it must be proven to be something other than bladder cancer.

Other signs of bladder cancer could include symptoms of a urinary tract infection. These include increased frequency of urination, a feeling of urgency to urinate, pain (burning) with urination, and the feeling of incomplete bladder emptying. These are all caused by irritation of the bladder wall by the tumor.

In advanced cases of bladder cancer, the tumor can actually obstruct either the entrance of urine into the bladder or the exit of urine from the bladder. This causes severe flank pain, infection, and damage to the kidneys. Obviously, bladder cancers that cause these symptoms need to be dealt with immediately.

How is bladder cancer diagnosed and staged?

Diagnosis

Anyone with either gross or microscopic hematuria should undergo a work-up to insure the symptoms are not from bladder cancer. Often, the first thing that is done is a urine cytology, which as mentioned above, is looking at the urine under a microscope to detect cancerous appearing cells. Again, if these cells are seen, it is diagnostic. However, the test does not detect all cases of bladder cancer. If bladder cancer is highly suspected, or after diagnosis, X-ray imaging of the upper urinary tract (including the ureters and kidneys) is done, to rule out any involvement of these structures with cancer. Ultrasound can be used to study the kidneys and a CT scan is often very good at studying the entire length of the urinary tract. A simpler method of studying the (upper) urinary tract is with an intravenous pyelogram (IVP). This involves administering a dye through a patient's vein and taking a regular x-ray a short time later. The dye can be seen in the x-ray, showing the full extent of the kidney collecting system, ureters, and often the bladder.

Though the above tests are useful or even required, the mainstay of diagnosis and staging is endoscopic evaluation. In this case, this type of evaluation is called a cystoscopy. It involves placing a fiberoptic camera into the bladder via the urethra. Cystoscopy allows for direct visualization of the entire bladder and also allows for biopsy for any suspicious lesions. If the biopsy reveals cancer, a repeat cystoscopy and resection (called a transurethral resection (TUR)) is done to completely evaluate the tumor and the extent and depth of disease.

With a diagnosis of bladder cancer obtained, a complete physical examination is done as well as the previously mentioned radiologic studies to fully evaluate the urinary tract, the local extent of disease, and any metastatic disease.

Staging

The staging of a cancer basically describes how much it is grown before the diagnosis has been made, documenting the extent of disease. Bladder cancer often presents at an early stage, as it produces hematuria early on in the course of the disease. Unfortunately, sometimes bladder cancer can advance to invasive disease prior to causing symptoms. As will be discussed in the treatment section, a big distinction is whether the bladder cancer is superficial or invading into the muscle, because the treatments are much different. Before the staging systems are introduced, first some background on how cancers grow and spread, and therefore advance in stage.

Cancers cause problems because they spread and can disrupt the functioning of normal organs. Bladder cancers often start very superficial, involving only the lining of the bladder. Eventually, however, bladder cancers can invade into the bladder, involving the muscular layers of the wall. If the bladder cancer is allowed to grow long enough or is aggressive enough, it may eventually invade the entire way through the wall and into the fat surrounding the bladder or even into other organs (prostate, uterus, vagina). This local extension is the most common way bladder cancer spreads.

Cancer can also spread by accessing the lymphatic system. The lymphatic circulation is a complete circulation system in the body (somewhat like the blood circulatory system) that drains into various lymph nodes. When cancer cells access this lymphatic circulation, they can travel to lymph nodes and start new sites of cancer. This is called lymphatic spread. Bladder cancer can spread this way. If it does, it usually first spreads to the lymph nodes surrounding the bladder (perivesicular lymph nodes). From there, it can spread to lymph nodes that are in close proximity to the external iliac and internal iliac arteries and veins, which are the very large blood vessels that run into the leg and into pelvis, respectively. The presence of lymph node spread is best evaluated by CT scan or at surgical exploration.

Bladder cancer can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream and the tumors that arise from cells' travel to other organs are called metastases. Cancers of the bladder generally spread locally or to lymph nodes before spreading distantly through the bloodstream, though this is not always the case. If spread through the bloodstream does occur, the lungs and bones are the most common sites to be involved.

The staging system used to describe bladder tumors is the "TNM system", as described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three components: T-describing the extent of the "primary" tumor (the tumor in the throat itself); N-describing the spread to the lymph nodes; M-describing the spread to other organs (i.e.-metastases).

There are two "T" stages that are often reported: the clinical stage, which is based on the physical exam of the physician, and the pathologic stage, which is noted after the tumor is resected, or taken out surgically.

Clinical Staging

• T1-Physician feels nothing on exam prior to transurethral resection (TUR)
• T2-Physician feels nothing on exam after TUR
• T3a-Any visually incomplete TUR or persistent tumor felt after TUR
• T3b-Any tumor that extends beyond bladder on exam
• T4-Tumor that involves other organs

Pathologic Staging

• Ta-noninvasive papillary tumor
• Tis-carcinoma-in-situ (explained above)
• T1-tumor invading the mucosa (lining of bladder)
  Above are considered "superficial"
• T2-tumor invades superficially into muscle of wall
• T3a-tumor invades deeply into muscle of the bladder wall
• T3b-tumor invades the entire way through the wall
• T4-tumor invades other organs

The "N" stage is as follows:

• N0-no spread to lymph nodes
• N1-tumor spread to a single lymph node, but this tumor spread must be less than 2 cm
• N2-tumor spread to lymph nodes sized 2-5 cm
• N3-tumor spread to lymph nodes greater than 5 cm

The "M" stage is as follows:

• M0-no tumor spread to other organs
• M1-tumor spread to other organs

The overall stage is based on a combination of these T, N, and M parameters. Though complicated, these staging systems help physicians determine the extent of the cancer, and therefore make treatment decisions regarding a patient's cancer. The stage of cancer, or extent of disease, is based on information gathered through the various tests done as the diagnosis and work-up of the cancer is being performed. An important distinction in bladder cancer is between superficial disease (Ta, Tis, T1) or muscular invasive disease. It has large implications for treatment, as will be discussed below.

What are the treatments for bladder cancer?

Superficial Bladder Cancer

Superficial bladder cancer is that which has not invaded at all into the muscle. As noted above, the extent of disease is based mainly on the transurethral resection (TUR). Likewise, the primary treatment for superficial disease is the TUR. Given the fact that the cancer is superficial, all of the tumor should be able to be removed by the TUR. However, superficial bladder cancer has a high incidence of recurrence, and hence the goal of treatment switches to the prevention of these recurrences and to prevent progression to an invasive stage. The treatment of a superficial bladder cancer always involves TUR. In high grade tumors, large tumors, multiply recurrent superficial tumors, or any tumor that invades into the lining of the bladder (T1 tumors), additional agents are infused directly into the bladder to help to decrease recurrences. The most commonly used is a compound that causes an inflammatory reaction, called BCG. BCG is instilled directly into the bladder for several treatments over several months. Though other agents have also been used, BCG has the best results, decreasing recurrence rates and progression rates in patients with superficial cancers. Though BCG is successful, it is not without side effects-causing bladder spasm and irritation, often with every instillation.