Testicular Cancer

Testicular cancers are relatively rare but highly curable, and occur predominantly in young and middle aged males. Testicular cancers were among the first types of cancers to be cured by radiation and/or chemotherapy, and treatment has been refined over the last two decades. Currently, over 70% of all patients are curable regardless of the extent of cancer. Thus, all treatment of testicular cancer is delivered with the intent to cure. However, it is important to know the extent of cancer and the specific type of testicular cancer in order to administer the best therapy.

The testicles are located inside the scrotum (a sac of loose skin that lies directly under the penis). The testicles are similar to the ovaries in women. Sperm and male hormones are made in the testicles. Testicular cancer—also called germ cell cancer—occurs in the tissues of one or both testicles. Similar cancers called "non-gonadal germ cell cancers" can also occur outside the testicle; non-gonadal germ cell cancers are not discussed in this section.

Testicular cancer is the most common cancer in men 15 to 35 years old. Men who have an undescended testicle (a testicle that has never moved down into the scrotum) are at higher risk of developing testicular cancer than men whose testicles have moved normally down into the scrotum. This is true even if surgery has been performed early in life to place the testicle in the appropriate place in the scrotum.

A swelling in the scrotum is usually the first sign of testicular cancer. A doctor will examine the testicles to feel for any lumps. If any lumps are found, the doctor will perform an ultrasound examination, which uses sound waves to make a picture of the inside of the testes. In addition, the physician may perform a computed tomography (CT) or positron emission tomography (PET) scan to determine whether cancer is present. A PET scan is similar to a CT scan; however, PET scans can detect live cancer tissue. Prior to a PET scan, the patient receives an injection of a substance that contains a type of sugar attached to a radioactive isotope. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons). The positrons react with electrons in the cancer cells, which creates the production of gamma rays. The gamma rays are then detected by the PET machine, which transforms the information into a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.

When cancer is suspected, the entire testicle is surgically removed (orchiectomy) through an incision in the groin. The surgically removed tissue is then examined under a microscope to determine whether cancer cells are present. Removal of a small piece of tissue (biopsy) is usually not done because this is thought to cause spread of the cancer. When the cancer is small and localized to the testicle, removal of the testicle may be all of the treatment that is necessary to cure the cancer. The surgically removed testicle is examined under the microscope to determine the type of cancer. In some patients the cancer consists of only one cell type. But for many patients, the cancer under the microscope consists of a mixture of cell types.

Testicular cancer is broadly divided into two different types, seminoma and nonseminoma, based on the appearance of cells under the microscope. Nonseminomas are, in general, more difficult to cure than seminomas. Nonseminoma cell types include: embryonal carcinoma, teratoma, yolk sac carcinoma, choriocarcinoma, and various combinations that are referred to as “mixed cell types”. For nonseminoma cancer teratoma presents the lowest risk of spread and choriocarcinoma presents the highest risk of spread; the other cell types are of intermediate risk.

Treatment planning depends upon whether the testicular cancer is classified as seminoma or nonseminoma. Seminomas are more sensitive to radiation therapy and are easier to cure than nonseminomas. Patients with all stages of seminoma have a cure rate that exceeds 90%, and patients with seminoma confined to the testicle have a cure rate approaching 100%. If there is a mixture of seminoma and nonseminoma components upon examination under the microscope, the cancer is diagnosed as nonseminoma because the cancer will be more aggressive due to the nonseminoma part of the cancer.

The extent of disease, or “stage” is determined after surgical removal of the testicle. All patients will require CT or magnetic resonance imaging (MRI) scans of the abdomen, chest, and sometimes the brain or bones to look for spread of disease beyond the testicle.

Lymph nodes are small, bean-shaped structures that are an essential component of the immune system. They are found throughout the body and are interconnected with lymph channels. Testicular cancer tends to spread through lymph channels that drain into lymph nodes in the groin area, into channels near the large blood vessel (the aorta) carrying blood from the heart, and into lymph nodes between the abdomen and back called retroperitoneal lymph nodes.

Retroperitoneal Lymph Node Dissection (RPLND)
Direct surgical evaluation of the retroperitoneal lymph nodes is an important aspect of treatment planning in many adults with testicular cancer, especially those with clinically localized nonseminoma Stage I and II disease. This is because some patients will appear to have no evidence of cancer in the retroperitoneal lymph nodes on CT scan and will appear to have a Stage I cancer. They may actually have lymph nodes involved with cancer that were not detectable by the CT scan and may actually have Stage II cancer. Some patients who appear to have cancer on CT scan will not have lymph nodes involved and actually have a Stage I cancer.

RPLND for diagnosis and prevention of relapse is a relatively major operation requiring skill to sample and remove all the nodes. The major complication is damage or removal of the connections of the sympathetic nervous system, which are located next to the lymph nodes. This can lead to disruption of ejaculation of sperm, thereby leading to infertility. Surgeons have devised techniques to spare the sympathetic nervous system connections while still removing most lymph nodes; this preserves normal ejaculation in approximately 90% of patients.[1] Newer treatment strategies involving the adjuvant (post-surgery) administration of chemotherapy have decreased the number of patients requiring lymph node dissection.

Tumor or Cancer Markers
An important aspect of the evaluation of testicular cancer is the use of blood or serum tests to detect cancer markers. Cancer markers are abnormal substances in the blood associated with the presence of cancer somewhere in the body. Common cancer markers that are present in the blood of patients with testicular cancer include:

•Alpha-fetoprotein (AFP)
•Beta human chorionic gonadotropin (BHCG)
•Lactate dehydrogenase (LDH)..
These cancer markers may detect cancers that are too small to be detected with a CT scan. In males under age 15, about 90% of testicular germ cell cancers are yolk sac tumors that make AFP, which is an excellent indicator of response to therapy and disease status.

It is important to realize that the absence of cancer markers in the blood following treatment does not always mean the absence of cancer, even when cancer markers were present at diagnosis. Patients who appear to have seminoma when the cancer is examined under the microscope and have elevated serum levels of AFP are treated as if they have nonseminoma because seminoma cells do not secrete this cancer marker and other cell types must be present, even though they may not be visible under the microscope. Elevation of the BHCG is found in approximately 10% of patients with pure seminoma and is an indication of metastatic spread of disease, but does not change the cellular diagnosis.

Type of treatment and outcomes depend on the stage and spread of the cancer. In order to learn more about the most recent information available concerning the treatment of testicular cancer, click on the appropriate stage.

Stage I Seminoma: Stage I testicular cancer is limited to the testes. Pathologic Stage I cancer refers to patients who have a lymph node dissection that is free of cancer. Clinical Stage I cancer is used to classify patients who do not undergo a lymph node dissection.

Stage II Seminoma: Stage II testicular cancer involves the testes and the retroperitoneal lymph nodes. Retroperitoneal lymph node involvement is further characterized by the number and size of involved lymph nodes.

Stage III Seminoma: Stage III testicular cancer has spread beyond the retroperitoneal lymph nodes. Stage III seminoma is subdivided into "non-bulky" Stage III and "bulky" Stage III based on the amount of cancer present at diagnosis.

Recurrent and/or Refractory Seminoma: Cancer has returned or progressed after primary treatment and may be resistant to chemotherapy.

Stage I Nonseminoma: Stage I testicular cancer is limited to the testes. Pathologic Stage I cancer refers to patients who have a lymph node dissection that is free of cancer. Clinical Stage I cancer is used to classify patients who do not undergo a lymph node dissection. A retroperitoneal lymph node dissection detects cancer spread in 15–30% of patients whose diagnostic tests indicated no spread prior to surgery.

Stage II Nonseminoma: Stage II testicular cancer involves the testes and the retroperitoneal lymph nodes. Retroperitoneal lymph node involvement is further characterized by the number and size of involved lymph nodes.

Stage III Nonseminoma: Stage III testicular cancer has spread beyond the retroperitoneal lymph nodes. Stage III testicular cancer is subdivided into "non-bulky" Stage III and "bulky" Stage III based on the amount of tumor present at diagnosis.

Recurrent and/or Refractory Nonseminoma: Cancer has returned after primary treatment and may be resistant to chemotherapy.

READ MORE - Testicular Cancer

Thyroid Cancer

The thyroid gland is located in the front of the neck and is attached to the lower part of the voice box (larynx) and to the upper part of the windpipe (trachea). It has two sides, or lobes, that are connected by a narrow neck. The thyroid gland produces thyroid hormones, which regulate metabolism, growth, and development and are essential for life.

Diagnosing Thyroid Cancer
Thyroid cancer may be suspected if a small abnormal growth—called a nodule—is found to protrude from the thyroid gland. Since the vast majority of thyroid nodules are benign, diagnostic tests must be conducted to determine if the nodule is malignant or cancerous.

Diagnosing thyroid cancer may involve tests that generate an image of the thyroid, such as ultrasound or PET imaging. A sample of the cells is also typically evaluated under a microscope. The sample may be removed using a needle and syringe or may be removed during surgery to treat the nodule. If initial tests indicate that the nodule is cancerous, a surgery will be scheduled to remove as much of the cancer as possible and to determine the extent of the disease—also called the stage of disease—and whether it has spread outside the thyroid gland.

Tests used to diagnose thyroid cancer include the following:

Ultrasound: Ultrasound uses high frequency sound waves and their echoes to create a two-dimensional image that is projected on a screen. Ultrasound is a simple procedure that may allow doctors to determine if a thyroid nodule is cancerous or benign based on the appearance of the image that is produced. A limitation of ultrasound is that it does not produce a sample of the cells that can be evaluated under a microscope.

Fine needle aspiration: Fine needle aspiration is a technique that uses a needle and syringe to withdraw a sample of the cells from a thyroid nodule. The cells can then be evaluated under a microscope to determine if they are cancerous or benign. Since many thyroid nodules are benign, this technique provides a minimally invasive way to determine if surgery is necessary.

Positron emission tomography (PET): Unlike techniques that provide anatomical images, such as X-ray or ultrasound, PET scans show chemical and physiological changes related to metabolism.

Before a PET scan, a patient will receive an injection of a drug that has a biological element—called an isotope—attached to it. The isotope becomes visible when a small amount of radiation is passed through the body. The most active cells take up more of the drug, allowing the doctor to see which areas are more active—a possible sign of cancer.

The radiation from a PET scan is roughly equivalent to what is administered in two chest X-rays. After the scan is complete, the radiation does not stay in the body for very long.

PET scans are covered by Medicare for the diagnosis of thyroid cancer.

Types of Thyroid Cancer
Cancer may arise from different cells of the thyroid gland. By evaluating a sample of the cancer under a microscope, doctors can determine the type of thyroid cancer. There are four main types of thyroid cancer:

Papillary: Papillary tumors are the most common form of thyroid cancer, accounting for more than 70% of all cases. Papillary cancers are typically irregular or solid masses that arise from otherwise normal thyroid tissue. More than half of papillary cancers have spread to lymph nodes in the neck. However, papillary cancers rarely spread to distant locations in the body. Papillary cancers typically occur in younger patients (30-50 years) and are commonly associated with a prior exposure to radiation. Patients with papillary cancer are highly curable with currently available treatment techniques.

Follicular: Follicular cancers account for a smaller percentage of all thyroid cancers (approximately 15%) and rarely occur after radiation exposure. Follicular cancers are more aggressive; they tend to invade blood vessels rather than lymph nodes, and distant spread is therefore more common. Potential sites of distant spread include the lung, bone, brain, liver, bladder, and skin. Patients over 40 have more aggressive disease that is more difficult to treat. Nonetheless, most follicular cancers are very curable.

Medullary: There are two subtypes of medullary thyroid cancer: sporadic and familial. Sporadic almost always occurs on both sides of the thyroid gland. Familial tumors may be malignant or benign and may be associated with a variety of symptoms.

Approximately half of medullary thyroid cancers have spread to lymph nodes. Prognosis depends on the extent of disease at diagnosis—especially spread to lymph nodes—and the ability to completely remove the cancer with surgery.

Anaplastic: Anaplastic thyroid cancer is a rare disease that may also be called undifferentiated cancer. This type of thyroid cancer is very aggressive, grows rapidly, and commonly extends beyond the thyroid gland. It typically occurs in older patients and is characterized by extensive spread in the neck area and rapid progression. Patients typically die of their disease within months of diagnosis.

Stages of Thyroid Cancer
Following a diagnosis of cancer, the most important step is to accurately determine the stage of cancer. Stage describes how far the cancer has spread. Identifying the stage of cancer is important because each stage of cancer may be treated differently.

Stage I-II: Stage I-II thyroid cancers are generally confined to the thyroid, but many include multiple sites of cancer within the thyroid. Thyroid cancer that has spread to nearby lymph nodes is still considered to be in stage I-II when the patient is younger than 45 years of age as the presence of cancer in the lymph nodes does not worsen the prognosis for these younger patients.

Early stage thyroid cancer is very treatable and many patients are cured with surgery alone.

Stage III: Stage III thyroid cancer is greater than 4 cm in diameter and is limited to the thyroid or may have minimal spread outside the thyroid. Lymph nodes near the trachea may be affected. Stage III thyroid cancer that has spread to adjacent cervical (neck) tissue or nearby blood vessels has a worse prognosis than cancer confined to the thyroid. However, lymph node metastases do not worsen the prognosis for patients younger than 45 years.

Stage III thyroid cancer is also referred to as locally advanced disease.

Stage IV: Stage IV thyroid cancer has spread beyond the thyroid to the soft tissues of the neck, lymph nodes in the neck, or distant locations in the body. The lungs and bone are the most frequent sites of distant spread. Papillary carcinoma more frequently spreads to regional lymph nodes than to distant sites. Follicular carcinoma is more likely to invade blood vessels and spread to distant locations.

Recurrent: Thyroid cancer that has recurred after treatment or progressed with treatment is called recurrent disease.

READ MORE - Thyroid Cancer

Skin Cancer

More than 1 million people are diagnosed with skin cancer every year in the United States - and many of these cases could have been prevented. Most damage that leads to skin cancer is caused by over-exposure to Ultraviolet (UV) rays from the sun or from tanning beds. This is damage that is easily preventable.

Limiting sun exposure, using sunscreen and avoiding tanning beds are all highly recommended actions that can lower the risk of skin cancer. Yet, despite efforts to inform the public of these preventative measures, the number of new skin cancer cases has been increasing over the past few decades - a strong indication that our current efforts are far from sufficient.

In addition to more public education about recommended risk-lowering actions, much more research is needed to find new ways to protect our skin.

Although most skin cancers are curable, a serious type known as melanoma was estimated to claim 8,420 American people's lives last year alone, accounting for more than 70% of all skin cancer deaths. Melanoma is more difficult to prevent because, unlike in other types of skin cancer, heredity plays a major role in melanoma development. It is also more aggressive in spreading (metastasizing) to distant body parts, and treatment is often ineffective once metastasis occurs. Studies show that only 15% of patients with metastatic melanoma could survive for 5 years or longer. Better treatment strategies are in high demand for this lethal skin cancer.

Research

NFCR funds leading cancer researchers who are dedicated to finding new and better strategies for skin cancer prevention and treatment. Below are two examples of outstanding NFCR research programs, each holding great promise in the effort to fight skin cancer and save more lives:

Searching for "A Second Layer of Sunscreen"
NFCR Fellow Helmut Sies, M.D., from Heinrich Heine Universitat, Germany

Back in the 1980s, Dr. Helmut Sies discovered the powerful anti-oxidation activity of lycopene, the famous red pigment in tomatoes and other fruits and vegetables. His recent research with volunteers showed that lycopene and other carotenoids (natural pigments) effectively ameliorated UV-induced skin damage (erythma) in humans, which consequently helped reduce the risk of skin cancer. Dr. Sies' discovery increases the possibilities of using dietary intervention for skin cancer protection, and helps the development of functional foods that may enable humans to create a second layer of powerful sunscreen from inside out.

Stopping the Lethal Spread of Melanoma
NFCR Center of Metastasis Research, University of Alabama (Birmingham) directed by Danny Welch, Ph.D

Melanoma can take a patient's life within 4-6 months once it has spread. Very little is known how cancer cells spread to distant sites in the body and many researchers have shied away from the complex biology of metastatic cancer.

Dr. Welch and his collaborators are opening the research doors toward an understanding of the metastatic process and finding ways to stop its killing. They have discovered six "metastasis suppressor genes" including BRMS1 and KISS1 genes that stop the spread of melanoma. The impact of this research is enormously significant, as it could lead to novel anti-cancer therapies that prevent metastasis from happening or keep it dormant, putting the cancer under control and giving patients new hope for a cure and extended life.


More than one million new cases of skin cancer are diagnosed each year in the United States, making it the most commonly diagnosed type of cancer.[1]

Overview of the Skin
The skin is the largest organ in the body. It protects against germs, covers internal organs, and helps regulate the body’s temperature. The two main layers of the skin are the epidermis and the dermis. The epidermis forms the top, outer layer of the skin. The dermis is a thicker layer beneath the epidermis.

Skin cancer generally develops in the epidermis. The three main types of cells in the epidermis are squamous cells, basal cells, and melanocytes. Squamous cells form a flat layer of cells at the top of the epidermis. Basal cells are round cells found beneath the squamous cells. Melanocytes are pigment-producing cells that are generally found in the lower part of the epidermis.

Types of Skin Cancer
Skin cancer is often categorized as melanoma or non-melanoma. Melanoma is a cancer that begins in melanocytes. It is less common than non-melanoma skin cancer, but tends to be more aggressive. In 2006 an estimated 62,000 individuals in the U.S. will be diagnosed with melanoma, and close to 8,000 will die of the disease.[1]

The most common type of non-melanoma skin cancer is basal cell carcinoma. This type of cancer rarely spreads to distant sites in the body, but it can be disfiguring and may invade nearby tissues.

The second most common type of non-melanoma skin cancer is squamous cell carcinoma. Although this type of cancer is more likely to metastasize (spread to lymph nodes or other sites in the body) than basal cell carcinoma, metastasis is still rare. Both basal cell carcinoma and squamous cell carcinoma most commonly develop on sun-exposed parts of the skin, but can develop on other parts of the skin as well.

An alarming trend in both melanoma and non-melanoma skin cancers is that the frequency of these cancers in children and young adults appears to be increasing.[2] This highlights the importance of prevention at all ages.

Because of their very different characteristics and treatment, melanoma and non-melanoma skin cancer are discussed further in separate sections.

Go to the Melanoma Information Center

Go to the Non-Melanoma Information Center

READ MORE - Skin Cancer

Uterine Cancer

The uterus is the female reproductive organ where the unborn baby grows and develops until birth. This muscular organ is connected to the vagina by the cervix and contains entrances for the two fallopian tubes, which transfer eggs from the ovaries. The uterus is a highly hormone sensitive organ with monthly bleeding and shedding cycles (menstruation) in the absence of pregnancy. The growth of the most common uterine cancer, adenocarcinoma, is also sensitive to female hormones. Uterine cancer usually arises from the surface of the uterus or endometrium and less frequently from glands in the uterus. For most women, uterine cancer is brought to medical attention because of unanticipated or problematic bleeding from the uterus, usually occurring after menopause. Fortunately, 80% of women diagnosed after developing abnormal bleeding will have cancer limited to the uterus (stage I and II) and a high proportion are cured.

Uterine (endometrial) cancer is one of the most common gynecologic cancers in women, with 36,100 new cases each year. The incidence of uterine cancer would be even higher if it weren’t for the relatively large number of hysterectomies performed for non-cancerous reasons. It is estimated that approximately 6,500 women will die of uterine cancer in the U.S. in 2001. There has been an increase in the incidence of uterine cancer since the mid 1970s, which has been attributed to the use of hormone replacement therapy. Surgery is the primary treatment for uterine cancer and approximately 82% of women survive 5 years after diagnosis. For more information about the cause of uterine cancer and programs for early detection, go to Prevention and Screening.

Currently, a dilation and curettage (D&C) is the most reliable method for diagnosing uterine cancer. During a D&C, a sample of the cells lining the uterus is removed for examination under a microscope to determine if cancer is present. Following a diagnosis of uterine cancer, additional tests are performed on the cancer cells to determine the stage of the cancer in order to provide optimal treatment.

There are several types of uterine cancer, which vary based on their appearance under the microscope. The most common type of uterine cancer is adenocarcinoma. Other variants of uterine cancer that behave more aggressively include serous carcinoma, uterine clear cell carcinoma and mixed type. These cancers, stage for stage, have a worse outcome than adenocarcinoma. Outcomes following treatment of adenocarcinoma can also be affected by the appearance of cancer when examined under the microscope. Doctors grade adenocarcinomas, as poorly, moderately or well differentiated. These terms describe how closely the cancer resembles normal cells of the uterus. In general, the less differentiated the cells, the more aggressive the cancer. More poorly differentiated cancers have a higher rate of recurrence. The reason doctors are interested in this is that more or better treatments may be indicated for patients with more aggressive cancers.

In addition to the type and grade of the cancer, the stage or extent of spread of cancer is the most useful predictor of survival and is relevant for treatment planning. Currently, surgery to remove the uterus, ovaries and lymph nodes is relied upon to determine the stage of the cancer.

Other tests that may be utilized to help stage the cancer include magnetic resonance imaging (MRI) scans and ultrasound. The most common method for examining the uterus is with transvaginal sonography. During transvaginal sonography, an ultrasound apparatus is passed through the vagina in order to examine the uterus. Another test, sonohysterography, improves the accuracy of sonography by first infusing a salt solution into the uterus through the cervix. MRI scans can also be useful in determining whether the lymph nodes are involved with cancer and may prevent the need for lymph node dissection.

In order to learn more about the most recent information available concerning the treatment of uterine cancer, click on the appropriate stage.

Stage I: Cancer does not spread outside the body of the uterus.

Stage II: Cancer involves the body of the uterus and the cervix.

Stage III: Cancer extends outside the uterus, but is confined to the pelvis.

Stage IV: Cancer involves the bladder or bowel or distant sites.

Recurrent: Cancer has returned after initial treatment.

READ MORE - Uterine Cancer

Uterine Cancer

The uterus is the female reproductive organ where the unborn baby grows and develops until birth. This muscular organ is connected to the vagina by the cervix and contains entrances for the two fallopian tubes, which transfer eggs from the ovaries. The uterus is a highly hormone sensitive organ with monthly bleeding and shedding cycles (menstruation) in the absence of pregnancy. The growth of the most common uterine cancer, adenocarcinoma, is also sensitive to female hormones. Uterine cancer usually arises from the surface of the uterus or endometrium and less frequently from glands in the uterus. For most women, uterine cancer is brought to medical attention because of unanticipated or problematic bleeding from the uterus, usually occurring after menopause. Fortunately, 80% of women diagnosed after developing abnormal bleeding will have cancer limited to the uterus (stage I and II) and a high proportion are cured.

Uterine (endometrial) cancer is one of the most common gynecologic cancers in women, with 36,100 new cases each year. The incidence of uterine cancer would be even higher if it weren’t for the relatively large number of hysterectomies performed for non-cancerous reasons. It is estimated that approximately 6,500 women will die of uterine cancer in the U.S. in 2001. There has been an increase in the incidence of uterine cancer since the mid 1970s, which has been attributed to the use of hormone replacement therapy. Surgery is the primary treatment for uterine cancer and approximately 82% of women survive 5 years after diagnosis. For more information about the cause of uterine cancer and programs for early detection, go to Prevention and Screening.

Currently, a dilation and curettage (D&C) is the most reliable method for diagnosing uterine cancer. During a D&C, a sample of the cells lining the uterus is removed for examination under a microscope to determine if cancer is present. Following a diagnosis of uterine cancer, additional tests are performed on the cancer cells to determine the stage of the cancer in order to provide optimal treatment.

There are several types of uterine cancer, which vary based on their appearance under the microscope. The most common type of uterine cancer is adenocarcinoma. Other variants of uterine cancer that behave more aggressively include serous carcinoma, uterine clear cell carcinoma and mixed type. These cancers, stage for stage, have a worse outcome than adenocarcinoma. Outcomes following treatment of adenocarcinoma can also be affected by the appearance of cancer when examined under the microscope. Doctors grade adenocarcinomas, as poorly, moderately or well differentiated. These terms describe how closely the cancer resembles normal cells of the uterus. In general, the less differentiated the cells, the more aggressive the cancer. More poorly differentiated cancers have a higher rate of recurrence. The reason doctors are interested in this is that more or better treatments may be indicated for patients with more aggressive cancers.

In addition to the type and grade of the cancer, the stage or extent of spread of cancer is the most useful predictor of survival and is relevant for treatment planning. Currently, surgery to remove the uterus, ovaries and lymph nodes is relied upon to determine the stage of the cancer.

Other tests that may be utilized to help stage the cancer include magnetic resonance imaging (MRI) scans and ultrasound. The most common method for examining the uterus is with transvaginal sonography. During transvaginal sonography, an ultrasound apparatus is passed through the vagina in order to examine the uterus. Another test, sonohysterography, improves the accuracy of sonography by first infusing a salt solution into the uterus through the cervix. MRI scans can also be useful in determining whether the lymph nodes are involved with cancer and may prevent the need for lymph node dissection.

In order to learn more about the most recent information available concerning the treatment of uterine cancer, click on the appropriate stage.

Stage I: Cancer does not spread outside the body of the uterus.

Stage II: Cancer involves the body of the uterus and the cervix.

Stage III: Cancer extends outside the uterus, but is confined to the pelvis.

Stage IV: Cancer involves the bladder or bowel or distant sites.

Recurrent: Cancer has returned after initial treatment.

READ MORE - Uterine Cancer

Rectal Cancer

The colon and rectum are parts of the body's digestive system and together form a long, muscular tube called the large intestine. The colon is the first 6 feet of the large intestine and the rectum is the last 8-10 inches. The last part of the rectum contains the rectal sphincter or anus. The rectal sphincter is the muscle that controls defecation. Preservation of the rectal sphincter during surgery for rectal cancer is necessary in order to maintain control of bowel function. Treatment approaches differ between cancers of the colon or rectum, and are therefore discussed separately. A separate section has been created for Colon Cancer.

Adenocarcinoma is the most common type of cancer that originates in the cells that line the rectum or large intestine. It accounts for over 90-95% of cancers originating in the rectum. Other types of cancer including carcinoid and leiomyosarcoma also originate in the rectum, but are not referred to as rectal cancer. This treatment overview deals only with adenocarcinoma of the rectum, which will be referred to as rectal cancer.

The treatment of rectal cancer may involve several physicians, including a gastroenterologist, a surgeon, a medical oncologist, a radiation oncologist, and/or other specialists. Care must be carefully coordinated between the various treating physicians involved in management of your cancer.

Staging
In order to understand the best treatment options available for treatment of rectal cancer, it is important to first determine where the cancer has spread in the body. The initial spread of rectal cancer occurs circumferentially around the rectum and laterally into the adjacent fat and muscles. Rectal cancer can then invade nearby organs and spread through the lymph and blood systems. Rectal cancer cells may spread via the blood throughout the body to the liver, lungs and other organs.

Determining the stage of the cancer or the extent of the spread requires a number of tests and is ultimately confirmed by surgical removal of the cancer and exploration of the abdominal cavity.

Computerized Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body. This method is more sensitive and precise than the chest x-ray.

Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays, and can often distinguish more accurately between healthy and diseased tissue. MRI gives better pictures of tumors located near bone than CT, does not use radiation as CT does, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the tumor.

Colonoscopy: A colonoscopy may be used to identify whether a second cancer is present in the colon or rectum prior to surgery. During a colonoscopy, a long flexible tube that is attached to a camera is inserted through the rectum, allowing physicians to examine the internal lining of the colon for polyps or other abnormalities. The physician may perform a biopsy during a colonoscopy in order to collect samples of suspicious tissues or cells for closer examination.

Endorectal Ultrasound (EUS): Endorectal ultrasound (EUS) involves the use of a special probe that is inserted into the rectum to help determine the thickness of the cancer. By determining the thickness of the cancer, EUS can help determine the stage.

Doppler Ultrasound: One technique that may help predict an increased risk of cancer recurrence is Doppler ultrasound. Doppler ultrasound has been used to measure blood flow in the artery to the liver (hepatic artery) and total liver flow in patients with rectal cancer. This measurement may be helpful because abnormalities occurring in hepatic artery blood flow can be used to detect early cancer metastasis to the liver.

Surgery
Upon completion of the clinical "staging evaluation", surgery is performed to remove the cancer, along with part of the normal adjacent tissues of the rectum. Surgery also helps to further determine the level of spread within the rectal wall and abdomen. The type of surgery performed depends on the size and the location of the cancer. Surgery is commonly performed through an abdominal incision. In some cases, the rectal cancer is located close to the anus and the anus is removed with the cancer. Large rectal cancers close to the anus that cannot be removed without damaging anal function are sometimes treated with chemotherapy to help shrink the cancer before surgery. This is referred to as neoadjuvant chemotherapy. If there is enough shrinkage of the cancer, surgery may be performed that preserves anal function. However, in some cases, the cancer is too close to the anus and the anus is removed with the cancer. In other instances, the cancer may be localized, but too large to remove surgically. In these cases, administration of chemotherapy and/or radiation before surgery may shrink the cancer and allow complete surgical removal. For more information, go to Surgical Management of Rectal Cancer.

Following surgical removal of rectal cancer, a final "pathologic" stage will be given. This is based on extent of spread of cancer after looking at the removed tissue under a microscope. The stage may be a letter or a number, as several different staging systems are used to describe rectal cancer. All new treatment information concerning rectal cancer is categorized and discussed by the stage. In order to learn more about the most recent information available concerning the treatment of rectal cancer, click on the appropriate stage.

Stage I (A-B1): Cancer is confined to the lining of the rectum.

Stage II (B2-3): Cancer may penetrate the wall of the rectum into the surrounding fat or muscles or other adjacent organs, but does not invade any local lymph nodes.

Stage III (C1-3): Cancer invades one or more of the local lymph nodes, but has not spread to other distant organs.

Stage IV (D): Cancer has spread to distant locations in the body, which may include the liver, lungs, bones or other sites.

Recurrent/Relapsed: The rectal cancer has progressed or returned (recurred/relapsed) following an initial treatment.

READ MORE - Rectal Cancer

Renal Cancer

The kidneys are organs that are responsible for eliminating waste material from the blood by making urine. The kidneys also produce hormones, which regulate blood pressure and control red blood cell production. Located just above the kidneys are the adrenal glands, which produce several essential hormones. Adrenal hormones help to regulate metabolism, blood pressure, inflammation, and response to stress. The adrenal glands also produce small amounts of sex hormones (androgens and estrogens).The body can function perfectly well with one kidney and one adrenal gland if they are normal. This allows for the removal of one entire kidney and adrenal gland when necessary to remove a cancer localized to the kidney area. If patients have poor kidney function before developing cancer of the kidney, it may not be possible to remove one kidney and still have normal function.

Normal Anatomy: Most people have two kidneys. The kidneys produce urine, which drains through narrow tubes (called ureters) into the urinary bladder (Figure 1). The kidneys are located toward the back of the flank, with one kidney on either side (Figure 2). The kidney is contained within a fibrous sheath called Gerota’s fascia (Figure 3). Within this fascia is a layer of fat that surrounds the kidney. The capsule is a thin layer that covers the outer surface of the kidney (analogous to the red external layer of an apple). The primary vein that drains the kidney (renal vein) merges with the vein that takes blood to the heart (vena cava). The term “renal” means pertaining to the kidney. An adrenal gland is located above each kidney within Gerota's fascia.







Several types of tumors both benign and malignant may occur in the kidney. A kidney tumor is an abnormal area within the kidney. The terms mass, lesion, and tumor are often used interchangeably. Tumors may be benign (not cancerous) or malignant (cancerous). The most common type of kidney tumor is a fluid-filled area called a cyst. Simple cysts are benign and have a typical appearance on imaging studies. Simple cysts do not progress to cancer and usually require no follow-up treatment. Complex cysts do not have the typical benign appearance and may contain cancer. When complex cysts are present, the need for treatment is determined on an individual basis. Another type of kidney tumor is a solid kidney tumor (i.e. not fluid-filled). Solid kidney tumors may be benign, but are usually malignant. In fact, more than 90% of solid kidney tumors are cancerous.

In the United States, kidney cancer accounts for about 3% of all cancers, with approximately 12,000 kidney cancer deaths each year. Kidney cancer occurs slightly more often in males and is usually diagnosed between the ages of 50 and 70, but can occur at any age. In adults, the most common type of kidney cancer is renal cell cancer, also called renal adenocarcinoma or hypernephroma.

Symptoms: Many kidney tumors go undetected due to the lack of symptoms and are incidentally detected during the medical evaluation of an unrelated problem. Kidney tumors can cause symptoms by compressing, stretching or invading structures near or within the kidney. Symptoms caused by these processes include pain (in the flank, abdomen or back) and blood in the urine (small amounts may not be visible). If cancer spreads beyond the kidney, symptoms depend upon which organ is involved. Shortness of breath or coughing up blood may occur when cancer is in the lungs; bone pain or fracture may occur when cancer in the bone; and neurologic symptoms may occur when cancer is in the brain. In some cases, the cancer causes associated clinical or laboratory abnormalities called paraneoplastic syndromes. These syndromes are observed in approximately 30% of patients with kidney cancer and can occur in any stage. Clinical symptoms include weight loss, loss of appetite, fever, sweats and high blood pressure. Laboratory findings include elevated erythrocyte sedimentation rate, low red blood cell count (anemia), high calcium level in the blood, abnormal liver function tests, elevated alkaline phosphatase in the blood, and high white blood cell count. In many cases, the paraneoplastic syndrome resolves after the cancer is removed.

Detecting Kidney Cancer: When a kidney tumor is suspected, a kidney imaging study is obtained. The initial imaging study is usually an ultrasound or CT scan. In some cases, a combination of imaging studies may be required to completely evaluate the tumor. If cancer is suspected, the patient should be evaluated to see if the cancer has spread beyond the kidney.

Staging: Determining the extent of the spread or the stage of the cancer requires a number of tests. Staging tests include X-rays, computerized tomography (CT) scans, ultrasonography or magnetic resonance imaging (MRI). Other tests include an intravenous pyelogram (IVP) and arteriography. Intravenous pyelogram involves the injection of dye into a vein to help visualize the kidneys, ureters and bladder. If the patient has bone pain, recent bone fractures, or certain abnormalities on the blood tests, a bone scan is also recommended. Additional tests may be obtained as needed. Kidney cancer has the propensity to grow into the renal vein and vena cava. The portion of the cancer that extends into these veins is called “tumor thrombus.” Imaging studies help determine if tumor thrombus is present. There are no blood or urine tests that directly detect the presence of kidney tumors. Arteriography involves the injection of dye into the blood vessels supplying the kidney. Staging is ultimately confirmed by surgical removal of the cancer and exploration of the area adjacent to the kidney. The surgeon will often remove regional lymph nodes for examination under the microscope. Examination of both kidneys is essential to assure that one is working normally. Sometimes, more progressed stages of the disease can be determined by such tests without the need for surgery.

In 40% of patients, renal cell cancer will be limited to the kidney and is treated exclusively by surgery, which is curative 90% of the time. In the 60% of patients with renal cell cancer that has spread outside the kidney, the disease is generally not curable with surgery and other specialists, such as medical oncologists and possibly even radiation therapists, are involved with treatment.

Following completion of all diagnostic tests and surgery, a final "pathologic" stage and grade will be given. All new treatment information concerning renal cell cancer is categorized and discussed by the stage. Tumor grade is a subjective measure of how aggressive the tumor looks under the microscope; therefore, it is determined from a surgical specimen. Grade cannot be determined from radiographic imaging (CT scans, MRI, etc..), blood tests or urine tests. Grade usually ranges from 1 to 4 with higher numbers indicating a more aggressive tumor. Thus, higher grade implies a worse prognosis.

The following are simplified definitions of the various stages of kidney cancer. Click on each for a stage by stage overview of the most recent information available concerning the comprehensive treatment of renal cancer.

Stage I: The primary cancer is 7 centimeters (about 3 inches) or less and is limited to the kidney, with no spread to lymph nodes or distant sites.

Stage II: The primary cancer is greater than 7 centimeters (about 3 inches) and is limited to the kidney, with no spread to lymph nodes or distant sites.

Stage III: The primary cancer is less or greater than 7 centimeters (about 3 inches), but has spread to only a single regional lymph node. The primary tumor may have spread to the renal veins or vena cava (large vein returning blood to the heart located in the middle of the abdomen near the back), but has only spread directly and not out of the local area of the kidney.

Stage IV: The cancer has spread to distant sites, invades directly beyond the local area or has more than one lymph node involved.

Recurrent Renal Cell Cancer: Renal cell cancer has returned after primary treatment with surgery, chemotherapy, radiation or biological modifiers.

Clinical stage is based on radiographic imaging before surgery, whereas pathologic stage is based on the analysis of surgically removed tissue. Staging the cancer helps predict prognosis and survival.

Physicians further denote the stage of a cancer according to a system developed by the American Joint Committee on Cancer (AJCC). This staging system includes the following criteria:

1.) the size or extent of the primary kidney tumor growth into the kidney or T stage

Primary Tumor Stage (T stage) Graphic Representation Description
T1 Tumor is confined to the kidney (i.e. no penetration through the capsule) and is7 centimeters or less in greatest dimension
T2 Tumor is confined to the kidney (i.e. no penetration through the capsule) and is greater than 7 centimeters in greatest dimension
T3a Tumor penetrates through the kidney capsule into the surrounding fat or the adrenal gland, but not through Gerota’s fascia.
T3b or T3c

Tumor extends into the renal vein or into the vena cava.

-T3b indicates that the tumor thrombus does not extend above the level of the chest diaphragm.

-T3c indicates that the tumor thrombus extends above the level of the chest diaphragm.

T4 Tumor penetrates through Gerota’s fascia.

2.) the status of lymph nodes near the kidney or N stage (in renal cell cancer the lymph nodes near the kidney are referred to as regional lymph nodes); and

Regional Lymph Nodes (N stage) Description
N0 No cancer in the lymph nodes
N1 Cancer in a single lymph node
N2 Cancer in more than one lymph node

3.) the presence or absence of cancer spread to distant sites (metastases) or M stage

Distant Metastasis (M Stage) Description
M0 No metastasis
M1 Distant metastasis present

In general, cancers with higher T stage, lymph node metastasis (N stage) or distant metastasis (M stage) are associated with a worse prognosis and typically shorter survival periods.

READ MORE - Renal Cancer

Prostate Cancer

Prostate cancer is the most common male malignancy in the United States: it is estimated that 192,280 new cases of prostate cancer will be diagnosed in 2009 alone. Over the past 25 years, dramatic improvements have been made in patient survival of this disease; in fact, the 5-year survival rate has increased from 69% to nearly 99%. However, once the cancer has spread, or "metastasized," the disease is fatal. Currently, no eff ective treatment is currently available. That is why prostate cancer remains the second leading cause of cancer death in American males, and an estimated 27,360 patients will lose their battle to the disease this year, dying predominantly from metastatic prostate cancer.

Patients with late stage prostate cancer may benefit from hormone therapy (androgen ablation), which removes the main source of fuel to tumor growth by suppressing male hormones (androgens). Unfortunately, patients ultimately become non-responsive to this treatment after a few years, resulting in uncontrolled disease status and patient death. New and more effective treatments must be developed quickly to address this critical issue.

Research

NFCR is currently supporting scientists whose research is focused on unraveling the root causes of prostate cancer metastasis and developing new and effective treatment for patients with metastatic prostate cancer. Here are some highlights:

NFCR Project Director Paul B. Fisher, M.Ph., Ph.D.
Virginia Commonwealth University School of Medicine, Richmond, VA

NFCR Project Director Paul B. Fisher, M.Ph., Ph.D., has developed an innovative gene therapy to treat prostate cancer - especially metastatic prostate cancer, which aff ects 60% of patients. This new therapeutic is a genetically reprogrammed virus, called "Cancer Terminator Virus" (CTV). CTV is designed to specifi cally infect tumor cells and destroy them by replicating itself within the cells. Th e secret of restricted tumor targeting lies in a special control system employed in CTV. Dr. Fisher's therapeutic virus employs a special gene element he discovered earlier which can only turn on virus replication in tumor cells, but not in normal cells. Once turned on, the virus copies itself inside a tumor cell and eventually causes cell death. On the other hand, the normal cells are prevented from being harmed because CTV can not replicate in them. This smart control system ensures that this small biological killing machine only fi res on tumor cells.

To further improve its killing eff ects, Dr. Fisher's team made the virus capable of producing another tumor-killing molecule, interferon gamma (IFNγ), when replicating in the tumor cells. IFNγ, a natural product of our immune system, can directly kill tumor cells as well as indirectly by eliciting immune responses. Intriguingly, both the viruses and IFNγ generated by them go and seek out tumor cells, whether localized or metastatic, and destroy them, without harming normal healthy cells in the body. This unique feature could make it especially useful for patients whose prostate cancer has already metastasized.

Currently, with NFCR support, Dr. Fisher is further testing CTV in prostate cancer cell lines and tumor models to confi rm its eff ects and observe potential side eff ects. In fact, this novel gene therapy has been tested in pancreatic cancer cells and tumor models and the results are very encouraging. If tests in the laboratory run well, CTV may soon be used in clinical studies and provide a more effective treatment to late stage prostate cancer patients. This new "lethal weapon" could be especially encouraging to patients whose prostate cancer has stopped responding to other treatments.

NFCR Project Director David Lyden, M.D., Ph.D.
Cornell University, New York, NY

NFCR Project Director, David Lyden, M.D., Ph.D., at Cornell University, has reasoned that the failure of current therapies to treat prostate cancer is due to the lack of deep down understanding of how cancer progresses and spreads in the body. Dr. Lyden has been looking into this issue from an important perspective - cancer microenvironments.

More and more scientific evidence suggests that cancer does not spread randomly in the body. Instead, it is a "seed and soil" matching process -- once the cancer cells (the "seed") get into the bloodstream, they must interact with a proper receptive environment (the "soil") at distant tissue or organs to prepare for the start of metastasis. Intriguingly, Dr. Lyden and his research team have found that prostate cancer cells produce growth factors which stimulate certain adult bone marrow immature (stem) cells to grow and enter the blood stream. These cells then travel to the tumor to support the growth of new blood vessels, which are a critical nutrient provider for rapid tumor growth.

Interestingly, Dr. Lyden discovered that these bone marrow stem cells also travel to distant organs and "prepare" them for the arrival of the metastatic tumor cells. Upon arrival at the distant organs, these bone marrow cells appear to interact with the surrounding tissues (cancer microenvironments) and change them to a more fertile nest for the tumor cells to attach and grow.

These intriguing findings suggest that these bone marrow stem cells may be an important factor for prostate cancer growth and metastasis. Dr. Lyden hypothesizes that the metastasis of prostate cancer is mediated by a well-defined sequence of events dependent upon the proliferation and mobilization of bone marrow stem cells.

With NFCR's support, Dr. Lyden will further explore how these bone marrow stem cells promote prostate cancer to grow and spread. This critical research may lead to breakthroughs in prediction and treatment of prostate cancer metastasis in patients. By measuring the stem cells identified in Dr. Lyden's lab, it is possible to predict which patients will be more prone to developing metastasis of their prostate cancer. Moreover, Dr. Lyden's team has identified key molecules on the surface of these stem cells and has developed drugs that specifically target those proteins and kill the stem cells, hence removing essential factors that support tumor metastasis. Without the necessary support and nourishment from these bone marrow cells, the tumor cells and especially those at metastatic locations will die. These drugs will be used in clinical trials for patients whose prostate cancer does not respond to any other therapies. If the clinical trials prove to be successful, these new drugs developed in Dr. Lyden's lab will be further tested and may soon be available to more prostate cancer patients. Dr. Lyden's work may change the entire scope of treating prostate cancer and lead to increased survival in late stage prostate cancer patients.

READ MORE - Prostate Cancer

Ovarian Cancer

Ovarian cancer is the most deadly cancer of the female reproductive system. In 2009, it is estimated that this cancer alone will claim 14,600 American women's lives. Often known as "the silent killer," ovarian cancer is difficult to detect early because the ovaries are deep within the pelvis and initial symptoms are often ambiguous. Too often the cancer goes undiagnosed until after the disease is far advanced and has spread throughout the abdomen or to distant organs. After the cancer has metastasized, survival rates plummet because the current treatments are largely ineffective in fighting late stage ovarian cancer. More effective treatments and better early detection tools must be developed to meet the unmet needs of ovarian cancer patients and save their lives.

Research

The National Foundation for Cancer Research funds an array of research projects conducted by leading scientists in the field of ovarian cancer research. Listed below are some notable ovarian cancer research programs that NFCR currently supports:

Developing a New Model for Ovarian Cancer Treatment
Robert C. Bast, Jr., M.D., University of Texas M.D. Anderson Cancer Center

Ovarian cancer continues to claim the lives of three out of four women with the disease, due mainly to the persistence of drug-resistant cancer cells that survive despite standard chemotherapy. These resistant cancer cells can remain dormant or "asleep" for years, only to awaken later and grow progressively until they cause the death of the patient.

A key to understanding and perhaps killing off dormant ovarian cancer cells may lie in a recent discovery by NFCR Project Director Robert C. Bast, Jr., M.D. Dr. Bast and his research team at the M.D. Anderson Cancer Center found a gene called ARHI, which plays a critical role in the survival of dormant cancer cells. The team further developed a new experimental model in which ARHI can be switched on and off to closely mimic the actual tumor dormancy and regrowth that occurs in humans. This model will help cancer researchers understand the molecular mechanism of cell dormancy and open the door to the development of new treatments that eliminate these cells before they can become reactivated in the body. In addition, because of the similarities between this new model and the actual disease in humans, new therapeutics can be rapidly moved into clinical trials to treat ovarian cancer patients and give them renewed hope.

Making Taxol Work More Effectively
Susan Band Horwitz, Ph.D., Albert Einstein College of Medicine

Paclitaxel, better known by its brand name, Taxol®, is one of the most widely used chemotherapy drugs in the world. It has been used to treat over a million cancer patients with ovarian, breast, and lung cancer. But Taxol is not a magic bullet - it gradually loses its effectiveness as tumors develop resistance to it during treatment. Internationally renowned for her discovery of the molecular mechanism of Taxol, NFCR Fellow Susan Band Horwitz, Ph.D., at the Albert Einstein College of Medicine, is now exploring why tumor resistance to Taxol occurs and how to make the drug work better. Dr. Horwitz reasoned that during chemotherapy treatment, tumor cells may activate a protective molecular pathway which renders tumors resistant to Taxol. Once she had confirmed that alternate pathway, she proposed a combinatory drug approach in which a second drug is used to inhibit the activated molecular pathway and make the tumor cells regain sensitivity to Taxol. This rational combination strategy turned out to be very effective in experiments with tumor models, and may soon enter clinical trials with cancer patients to confirm its value as a treatment option.

Stopping Cancer's Lethal Spread
NFCR Center of Metastasis Research, University of Alabama (Birmingham)
Center Director: Danny Welch, Ph.D.

Two-thirds of ovarian cancer cases are diagnosed when the disease has already spread throughout the abdomen and to distant organs, and only 30% of women with late stage ovarian cancer now survive five years or longer. Very little is known about how cancer cells spread to distant sites in the body and many researchers have shied away from the complex biology of metastatic cancer.

At the NFCR Center for Metastasis Research, the Center Director Danny Welch, Ph.D., and his collaborators from five universities across the United States are opening the research doors to an understanding of the metastatic process. They have discovered six "metastasis suppressor genes" including the BRMS1 gene found in metastatic breast and ovarian cancer. Using cancer cell lines and DNA chip technology (microarray), they are identifying molecular factors (microRNAs) which may mediate the suppression of cancer metastasis by BRMS1. The impact of this research is enormously significant as it could lead to novel anti-cancer therapies that prevent breast and ovarian cancer from spreading to distant organs, bringing the cancer under control and giving patients increased likelihood of long term survival.

Fighting Ovarian Cancer on a Global Scale
NFCR-Tianjin Cancer Institute Joint Tissue Banking Facility in Tianjin, China

High quality cancer tissues and blood samples obtained directly from actual cancer patients are a most valuable resource for cancer researchers. From these specimens, scientists can extract DNA, RNA, and protein data to discover and analyze the underpinning molecular abnormalities of cancer. NFCR and our partner in China established a cancer tissue bank that systematically collects human cancer tissues, blood, and other biospecimens, and preserves these precious samples for cancer research. To date, the tissue bank has collected and systematically annotated over 19,000 cancer tissues and nearly 8,000 blood samples, including about 400 ovarian tumor specimens and more than 200 blood samples from ovarian cancer patients. These samples are well preserved to keep them suitable for research with all the cutting-edge molecular techniques (such as DNA chip technology) for identifying new cancer biomarkers for early detection and molecular targets for drug development. This international research facility is currently partnering with two major pharmaceutical companies, Amgen and Pfizer, to develop early diagnostic tests and more effective targeted cancer therapies.

Further growth of the tissue bank will continue to promote collaborative efforts on molecular cancer research for producing new life-saving treatments and diagnostic tools for patients around the world.

How You Can Help

These research projects hold great promise for yielding more effective therapies for patients with ovarian cancer. With more funding, however, they could ramp up their efforts and accelerate progress to save more lives! When you donate to NFCR, your dollars help our scientists accomplish many important research goals aimed at developing better cancer treatment and prevention strategies. Click here to learn more.

All About Ovarian Cancer

READ MORE - Ovarian Cancer

Pancreatic Cancer

In 2008, an estimated 37,680 individuals will be diagnosed with pancreatic cancer, and approximately 34,290 people will die of this disease in the same year. Pancreatic cancer has the lowest survival rate of all types of malignancies, with the one-year relative survival rate less than 24% and the fi ve-year survival rate of only about 5%.

There are two main reasons that account for the extremely low survival rate of this disease. First, pancreatic cancer patients seldom exhibit disease-specific symptoms until later stages, and in 80-90% of patients the tumor is already at an advanced stage upon diagnosis. Second, the treatment options currently available for pancreatic cancer are limited and ineffective. Thus, NFCR has been focusing on projects that improve early detection and treatment of pancreatic cancer.

Research

NFCR scientists are exploring new approaches for early diagnosis and improved treatment of
pancreatic cancer. Their innovative research could lead to enormous clinical benefits for pancreatic cancer patients:

NFCR Center for Targeted Cancer Therapies
Daniel Von Hoff, M.D. and Laurence Hurley, Ph.D.
Translational Genomics Research Institute (TGen), Phoenix, AZ

NFCR Center for Targeted Cancer Th erapies (NCTCT) at TGen, Arizona, is dedicated to discovering novel and effective therapeutics to treat pancreatic cancer. Led by Center Directors Dr. Von Hoff and Dr. Hurley, researchers at NCTCT have been developing new therapies which block the growth of pancreatic cancer cells by interfering with pancreatic cancer-promoting molecules-an approach called targeted cancer therapy.

While traditional chemotherapeutic drugs function through impairing cell division in a general way, targeted therapies specifically kill cancer cells and leave normal cells unharmed, resulting in enhanced cancer-killing power with less side effects. As pancreatic cancer cells often become resistant to chemotherapy and radiation, targeted therapies may offer new treatment options to kill resistant cancer cells.

In the past few years, NCTCT has made enormous progress in developing new targeted therapies for pancreatic cancer. Researchers at the Center first demonstrated that pancreatic cancer cells produce an abnormally large amount of uPA, a protein that promotes tumor progression and invasion. Using uPA as the drug target, they further identified UK122, a compound that very potently inhibits uPA. When cultured pancreatic cancer cells were treated with UK122, their migration and invasion behaviors - characteristics of cancer cells - were significantly suppressed, suggesting that UK122 is an exciting potential drug candidate for targeted therapy.

Moreover, a computer-based chemical compound screening for more uPA inhibitors has been conducted jointly between NCTCT and the NFCR Center for Computational Drug Discovery at Oxford University. The successful collaboration between the two NFCR centers yielded a pool of over 900 compounds which are potential uPA inhibitors. Together with UK122, these new compounds will be further screened and optimized to generate potent drugs to combat pancreatic cancer.

NFCR Fellow Waun Ki Hong, M.D.
M.D. Anderson Medical Center, Houston, TX

Dr. Hong and his team of research are developing new drugs targeting another pancreatic cancer-promoting molecule, the hepatoma-derived growth factor (HDGF). The HDGF protein is overly expressed in a number of human cancers, including pancreatic and lung cancers. In fact, its overexpression in tumors is directly attributable to tumor progression, recurrence, and metastasis. Dr. Hong's team has successfully developed monoclonal antibodies (mAbs) against HDGF. mAbs are a group of immune proteins that can accurately bind to their targets. When used as anti-cancer drugs, mAbs specifi cally block the function of the targeted cancer-related proteins, generating powerful anti-cancer effects.

Further research conducted by Dr. Hong's team showed that the anti-HDGF mAbs were very effective in treating lung and pancreatic cancers in tumor models. Their work will soon be extended to clinical trials and may save more patients' lives in the near future.

NFCR Project Director Jiayuh Lin, Ph.D.
Children's Research Institute, Columbus, OH

Pancreatic cancer is often resistant to conventional treatments such as chemotherapy and radiation therapy. NFCR Project Director Dr. Jianyuh Lin is now developing new drugs that target pancreatic cancer-specific proteins, which may lead to more eff ective therapies to overcome drug resistance.

Dr. Lin has developed novel compounds that inhibit Stat3 activity in pancreatic cancer cells. Stat3 is frequently observed to be constantly activated in many types of cancer, including pancreatic cancer. Th e persistent "on" mode of Stat3 is critical for cancer cells to survive and also for them to become resistant to chemotherapy. The new compounds developed by Dr. Lin's team, named LLL-3, LLL-7, and LLL-8, work by preventing two Stat3 molecules from pairing up with each other, a decisive step during Stat3 activation, making them very potent Stat3 inhibitors. Compared to other Stat3 inhibitors, these compounds have many distinct advantages: because they are not proteins, these compounds are not easily metabolized, which keeps them stable and produces long-lasting anti-cancer eff ects. In addition, they are very small, thus can easily enter the cells to find their targets. Preliminary work using these novel compounds on pancreatic cancer cell lines and tumor models has generated very encouraging results - they eff ectively inhibit Stat3 activity, and cause cancer cells to die quickly in the experimental models.

Because inhibition of Stat3 activity will make cancer cells sensitive to chemotherapy, Dr. Lin will combine these novel inhibitors with conventional chemotherapy agents, gemcitabine and oxaliplatin, to treat pancreaticcancer cells. This approach should maximize the therapeutic effects of chemotherapy, lower dosage of those cytotoxic agents, and reduce their harmful eff ects on normal cells. Dr. Lin's NFCR-supported research will provide ample laboratory evidence that their newly developed Stat3 inhibitors may provide a promising treatment for pancreatic cancer patients, especially those whose cancer has become resistant to chemotherapy.

How You Can Help

These research projects hold great promise for yielding more effective therapies for pancreatic cancer. With more funding, however, they could ramp up their efforts and accelerate progress to save more lives! When you donate to NFCR, your dollars help our scientists accomplish many important research goals aimed at developing better cancer treatment and prevention strategies. Click here to learn more.

READ MORE - Pancreatic Cancer

Non-Hodgkin's Lymphoma

Cancers that begin in cells of the lymph system are referred to as malignant lymphomas. The lymph system includes the spleen, thymus, tonsils, bone marrow, lymph nodes and circulating white blood cells called lymphocytes. Lymphocytes and the lymph system are part of the immune system that protects the body from disease and infection. Cancers of the lymph system are referred to as Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.

Understanding treatment of lymphoma is fairly complicated because patients must know the correct histologic diagnosis and the stage of their lymphoma. Histologic classification of non-Hodgkin's lymphomas has undergone considerable changes that can lead to confusion for patients and doctors. In order to learn about treatment options, patients need to know the answers to the following questions:

•Is the lymphoma classified as Hodgkin's or non-Hodgkin's lymphoma?
•If it is non-Hodgkin's lymphoma, what kind (histologic type) of non-Hodgkin's lymphoma is it?
•What is the stage or extent of spread of the lymphoma?
In order to understand the best treatment options available for lymphoma, it is important to determine the stage or where the cancer has spread in the body. All new treatment information is categorized and discussed by the stage, or extent, of the disease. Determining the extent of spread or the stage of the cancer requires a number of procedures including computerized tomography (CT) and/or Magnetic resonance imaging (MRI) scans and blood tests. The goal of staging lymphoma is to determine which patients have early and which have advanced stage cancer.

Stage I: Cancer is found only in a single lymph node, in the area immediately surrounding that node, or in a single organ.

Stage II: Cancer involves more than one lymph node area on one side of the diaphragm (the breathing muscle separating the abdomen from the chest).

Stage III: The cancer involves lymph node regions above and below the diaphragm. For example, there may be swollen lymph nodes under the arm and in the abdomen.

Stage IV: Cancer involves one or more organs outside the lymph system or a single organ and a distant lymph node site.

In some patients, the lymphoma may grow out of the lymph system into adjacent organs. This is referred to as extranodal extension and designated by an "E" following the stage. For example, a stage II lymphoma that extended into the lungs would be referred to as stage IIE.

Patients with malignant lymphoma may also experience general symptoms from their disease. Patients with fever, night sweats or significant weight loss are said to have "B" symptoms. If these specific symptoms are not present, patients are further classified as "A".

READ MORE - Non-Hodgkin's Lymphoma

Multiple Myeloma

Multiple myeloma is a cancer of plasma cells. Plasma cells are a special type of white blood cell that are part of the body’s immune system. Plasma cells normally live in the bone marrow and make proteins, called antibodies, that circulate in the blood and help fight certain types of infections. Plasma cells also play a role in the maintenance of bone, by secretion of a hormone, called osteoclast activating factor, which causes the breakdown of bone. Patients with multiple myeloma have increased numbers of abnormal plasma cells that may produce increased quantities of dysfunctional antibodies detectable in the blood and/or urine. These abnormal antibodies are referred to as paraproteins or monoclonal proteins in the blood (M proteins) or urine (Bence Jones protein).

In multiple myeloma, plasma cells infiltrate the bone marrow, spreading into the cavities of all the large bones of the body. In a majority of patients with multiple myeloma the bones develop multiple holes, referred to as osteolytic lesions, that cause the bones to be fragile and subject to fracture. [1] Osteolytic lesions are caused by the rapid growth of myeloma cells, which push aside normal bone-forming cells, preventing them from repairing general wear and tear of the bones. Multiple myeloma also causes the secretion of osteoclast-activating factor, a substance that contributes to bone destruction.

Other complications of multiple myeloma include kidney problems and decreased bone marrow blood cell production. Kidney problems develop when abnormal proteins produced by the myeloma cells are deposited in the kidneys, clogging the tubules. Decreased bone marrow blood cell production results from the replacement of normal bone marrow cells with abnormal plasma cells, and can lead to problems such as anemia. Patients with multiple myeloma may also have decreased quantities of normal antibodies necessary to fight certain types of infection.

Multiple myeloma may be preceded by two precancerous conditions: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma. These conditions do not cause symptoms and are generally not treated, but can eventually progress to multiple myeloma. The rate of progression of MGUS to multiple myeloma is roughly 1% per year. Smoldering multiple myeloma carries a higher risk of progression.[2]

In 2008, an estimated 19,920 individuals will be diagnosed with multiple myeloma;[3] half of these new diagnoses will occur among individuals over the age of 70 years.[4] When multiple myeloma is diagnosed, approximately 70% of patients will have bone involvement with their cancer and one-third will have impaired kidney function. In order to understand the best treatment options available for the treatment of multiple myeloma, it is important to first determine the amount of cancer in the body. Determining the amount, or the stage, of the cancer requires a number of tests. These tests may include the following:[5]

•Measurement of beta-2 microglobulin in the blood. This provides information about tumor mass.
•Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE) to measure the amount and type of abnormal myeloma protein in the blood.
•Urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE) to measure the amount and type of abnormal myeloma protein in the urine.
•A skeletal survey (a series of x-rays) to detect bone damage.
•Bone marrow aspiration and biopsy. A sample of cells is removed from the bone marrow in order to determine the percentage of myeloma cells in the marrow. The sample also allows doctors to assess specific characteristics of the myeloma cells (such as chromosomal abnormalities) that may influence prognosis.
•A complete blood count (CBC) to identify problems such as anemia.
•Blood tests to measure kidney function.
•Measurement of blood calcium levels. An estimated 15 to 20% of patients with multiple myeloma have hypercalcemia (high levels of calcium in the blood) at the time of diagnosis, due at least in part to myeloma-related bone destruction.1 If left untreated, hypercalcemia can cause excessive thirst, frequent urination, dehydration, constipation, and even coma.
The results of these tests will determine the stage of the disease. In order to learn more about the treatment of myeloma, select the appropriate stage.

Stage I: Tests indicate a low tumor amount. Lab values will fall in the following range: M protein IgG less than 5.0 gm/100 ml serum; IgA less than 3.0 gm/100 ml serum or urine Bence Jones protein less than 4 gm in 24 hours; normal serum calcium, normal bones and hemoglobin over 10.0 gm/100 ml serum.

Stage II: An intermediate tumor mass. Lab values are between Stage I and Stage III

Stage III: Tests indicate a high tumor amount. Lab values fall in the following range: M protein IgG greater than 7.0 gm/100 ml serum; IgA greater than 5.0 gm/100 ml serum; urine Bence Jones protein over 12.0 gm in 24 hours; advanced bone lesions; hemoglobin less than 8.5 gm/100 ml serum or calcium over 12 gm/100 ml serum.

Recurrent/Relapsed: The multiple myeloma has persisted or returned (recurred/relapsed) following treatment.

Within each stage, patients may be furthered classified according to the presence or absence of kidney problems.[6] The subclassification “A” refers to patients with normal kidney function; “B” refers to patients with abnormal kidney function. Kidney function is assessed by blood tests.

References:





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[1] Blade J, Rosinol L. Complications of multiple myeloma. Hematology/Oncology Clinics of North America. 2007;21(6):1231-1246.

[2] Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Hematology/Oncology Clinics of North America. 2007;21(6):1093-113.

[3] American Cancer Society. Cancer Facts & Figures 2008. Available at: http://www.cancer.org/docroot/stt/stt_0.asp (Accessed March 12, 2008).

[4] Ries LAG, Harkins D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Eisner MP, Horner MJ, Howlader N, Hayat M, Hankey BF, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2004/, based on November 2006 SEER data submission, posted to the SEER web site 2007.

[5] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. V.1.2008. © National Comprehensive Cancer Network, Inc. 2005/2006. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National Comprehensive Cancer Network, Inc.

[6] Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller, DG et al. AJCC CancerStaging Manual. 6th ed. New York (NY): Springer-Verlag; 2002.

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Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) are a group of diseases marked by abnormal production of blood cells by the bone marrow. Healthy bone marrow produces immature blood cells—called blasts—that then develop into red blood cells, white blood cells, and platelets. MDS disrupts this normal process so that the bone marrow is overactive, producing many immature cells. These blasts, however, do not fully develop into mature blood cells. As a result, patients with MDS have fewer mature blood cells, and those they do have may be abnormal and not function properly.

Any or all blood cell types may be affected by MDS, which is different from leukemia in which only white blood cells are overproduced. The direct effects of MDS may include:

•Anemia and fatigue if red blood cells counts are low
•Increased risk of infection if white blood cell counts are low
•Compromised ability to control bleeding if platelets counts are low
Failure of the bone marrow to produce normal cells is a gradual process. As such, MDS is primarily a disease of the aging and most patients are over 65 years of age. Some patients may survive with MDS while approximately one-third will have their disease progress to acute myeloid leukemia (AML). AML that develops from MDS is a difficult disease to treat.

The possible treatments for MDS, which may be used alone or in combination, include the following:

•Supportive care through administration of growth factors to stimulate immature cells to development into mature blood cells
•Destruction of abnormal cells through administration of chemotherapy, at either low, conventional, or high doses, depending on the condition of the patient and the aggressiveness of their disease
•Replacement of damaged bone marrow with healthy cells that develop into blood cells, a procedure called stem cell transplantation
Targeted therapy that may include the new drug Revlimid® (lenalidomide), which is thought to work by regulating the immune system

About this MDS Treatment Information
The information contained on this site is a general overview of treatment for MDS. Treatment may consist of growth factors, chemotherapy with or without stem cell transplantation, targeted therapy, or a combination of these treatment techniques. Multi-modality treatment, which utilizes two or more treatment techniques, is increasingly recognized as an important approach for improving a patient's chance of cure or prolonging survival.

In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Information about treatments for MDS that are being evaluated in clinical trials is discussed under Strategies to Improve Treatment.

Circumstances unique to each patient's situation may influence how these general treatment principles are applied. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

•Background: Normal Blood Cell Production
•Diagnosing MDS
•Types of MDS
•Planning Treatment for MDS
•Overview of Treatment for MDS
MDS Treatment Sections:

•Supportive Care for MDS: Blood Cell Growth Factors
•High-Dose Therapy with Stem Cell Transplant for MDS
•Chemotherapy without Stem Cell Transplant for MDS
•Targeted Therapy for MDS
•Strategies to Improve Treatment of MDS
Background: Normal Blood Cell Production
In order to better understand MDS and its treatment, a basic understanding of normal blood cell production is useful. Normal blood is made up of fluid called plasma and three main types of blood cells--white blood cells, red blood cells, and platelets. Each type of blood cell has a specific function:

•White blood cells, also called leukocytes, help the body fight infections and other diseases.
•Red blood cells, also called erythrocytes, make up half of the blood's total volume and are filled with hemoglobin, which picks up oxygen from the lungs and carries it to the body's organs.
•Platelets, or thrombocytes, help form blood clots to control bleeding.
Blood cells are produced inside the bones in a spongy space called the bone marrow. The process of blood cell formation is called hematopoiesis. All blood cells develop from one common cell type, called a stem cell. Stem cells become mature blood cells by a process called differentiation. Immature blood cells are called blasts. Blasts grow or differentiate into mature red blood cells, white blood cells, and platelets. Once they are fully developed, these cells are released into the blood where they circulate throughout the body and perform their respective functions. In healthy individuals, there are adequate stem cells to continuously produce new blood cells and mature blood cells are produced in a continuous and orderly fashion.

MDS disrupts this normal process resulting in many blasts and few mature, healthy blood cells.

Diagnosing MDS
In order to diagnose MDS and plan treatment, a physician must evaluate the patient's bone marrow cells to determine the specific type of MDS. The cells are removed through a technique called a bone marrow biopsy, which uses a large needle to withdraw cells directly from the bone marrow.

A special laboratory test is conducted on the sample cells, called a cytogenetic analysis. The purpose of this test is to determine whether there are abnormalities in the DNA of the blood cells. DNA contains the genetic code for the cell, which can be thought of as the instructions for what the cell looks like, what it does, and how it grows. Most forms of MDS and leukemias are characterized by specific abnormalities. Identifying these provides useful information about the patient's prognosis, or duration of survival.

Types of MDS
There are several different types of MDS, which are classified by how the abnormal cells that were removed from the bone marrow appear under the microscope and how many blasts can be identified. At the time of bone marrow evaluation, cells are also removed for cytogenetic analysis. MDS is classified into five different diseases characterized by ineffective blood cell production in the bone marrow and varying rates of progression to acute leukemia. Following is a description of the five classifications:

Refractory Anemia (RA): Patients have low blood counts, bone marrow blasts are less than 5%, and sideroblasts (iron containing cells) are less than 15%. The average survival is approximately 43 months, but can be influenced by specific chromosomal abnormalities.

Refractory Anemia with Ringed Sideroblasts (RARS): Patients have low blood counts, bone marrow blasts are less than 5%, and sideroblasts are greater than 15%. The average survival is 55 months, but can be influenced by specific chromosomal abnormalities.

Refractory Anemia with Excess Blasts (RAEB): Patients have low blood counts, 1-5% blasts in the blood, and bone marrow blasts between 5 and 20%. The average survival is 12 months, but can be influenced by specific chromosomal abnormalities.

Refractory Anemia with Excess Blasts in Transition (RAEBt): Patients have low blood counts, over 5% blasts in the blood or cells in the blood containing an abnormality referred to as Auer rods, and bone marrow blasts between 20 and 30%. The average survival is 5 months, but can be influenced by specific chromosomal abnormalities.

Chronic Myelomonocytic Leukemia (CMML): Blood cells called monocytes make up more than 1,000 ml in the blood and patients have less than 5% blasts. Bone marrow blasts are less than 20% and the average survival is 30 months, but can be influenced by specific chromosomal abnormalities.

Planning Treatment for MDS
Since a stem cell transplant utilizing cells from a donor—called an allogeneic stem cell transplant—holds the most hope for cure, a major decision faced by patients with MDS is not whether to undergo transplantation, but when. Patients with MDS that is likely to progress to leukemia early—which results in shorter survival—may be willing to accept higher risks of treatment and proceed quickly to a stem cell transplant. Patients with MDS that progresses more slowly are likely to live longer and may wish to pursue a more conservative treatment approach, opting to use supportive care and wait a longer period before undergoing a stem cell transplant.

However, patients who choose conservative treatment approaches should always be prepared to receive more aggressive treatment in case their disease progresses more rapidly than anticipated. To prepare for a possible stem cell transplant, patients should consider arranging for a stem cell donor and/or having their own stem cells collected and stored shortly after diagnosis. This is important because as MDS progresses and treatment is initiated, it becomes increasingly difficult to collect stem cells.

In order to better plan treatment, doctors try to identify how quickly patients are likely to progress to acute myeloid leukemia (AML). A score is assigned that reflects this tendency to progress, and is based on a system called the International Prognostic Scoring System (IPSS). A higher score is associated with a type of MDS that is likely to progress to leukemia more quickly. The IPSS score takes into account three important factors in MDS:

•The percent of bone marrow blasts—more blasts contributes to a higher score
•Genetic abnormalities—more abnormalities contribute to a higher score
•Severity of low white blood cell counts—lower counts of white blood cells, platelets, and red blood cells contribute to a higher score
Relationship between a patient's risk of progressing to leukemia and timing of stem cell transplant: Research shows that knowing a patient's risk of progressing to leukemia is important for determining optimal timing of stem cell transplantation. Based on information about 1,000 patients who had been diagnosed with MDS, researchers from several U.S. cancer centers have determined that patients with a low or low-intermediate risk of progression to leukemia have better outcomes if their transplant was not performed at the time of diagnosis, but was delayed. Patients with a high or high-intermediate risk experienced optimal survival if they underwent an allogeneic transplant at the time of diagnosis, without delay. Furthermore, the patients with lower risk achieved optimal outcomes if their transplant was administered prior to progression of their disease to acute myeloid leukemia compared to after progression. [1]

Overview of Treatment of MDS
The objective of treatment is to control the growth of the abnormal cells so that more normal cells can grow and improve blood cell production. Some treatments are designed to manage the complications associated with ineffective blood cell production, while others extend survival or even cure the disease.

Treatment of MDS is individualized and depends on two main factors:

1.The severity of low blood counts
2.The risk of progression to acute myeloid leukemia
Other factors that influence treatment decisions include patient's age, other medical conditions, and the severity of the myelodysplastic syndrome.

The potential treatment options for MDS include the following:

•Supportive Care for MDS: Blood Cell Growth Factors
•High-Dose Therapy with Stem Cell Transplant for MDS
•Chemotherapy without Stem Cell Transplant for MDS
◦Vidaza® (azacitadine)
•Targeted Therapy for MDS
◦Revlimid (lenalidomide)
•Strategies to Improve Treatment of MDS
Currently, only stem cell transplant utilizing cells from a donor—called an allogeneic transplant—can consistently cure patients with MDS. Other therapies are directed at prolonging survival and decreasing the symptoms from these diseases.

References
[1] Cutler C, Lee S, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104:579-585.

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Melanoma

Malignant melanoma is predominantly a disease of the skin, but may in rare instances occur at other sites, including the mucous membranes (vulva, vagina, lip, throat, esophagus and perianal region), as well as in the eye (uvea and retina). Melanoma arises from melanocytes, which are cells located in the upper layer of the skin that are responsible for producing pigment (skin color). Most melanomas are dark in color (black/brown) because they contain pigment; however, some melanomas do not contain pigment (amelanotic malignant melanoma) and are difficult to diagnose.

Since the majority of patients enrolled in clinical trials have skin (cutaneous) melanoma, this treatment overview will focus on that type of melanoma. It is important to realize that the treatment principles derived from clinical trials involving patients with skin melanoma are applicable to melanomas of the vulva, vagina, male genitalia or anorectal areas but, in general, melanomas in these sites have a worse prognosis than skin melanomas.

Melanoma occurs predominantly in adults, who comprise most of the 54,000 new cases per year in the U.S. The incidence of melanoma of the skin appears to be on a steady rise throughout the world due to increased ultraviolet exposure from the sun and possibly tanning beds. In the United States, researchers have estimated that there is a 2-3% increase per year in the incidence of cutaneous melanoma. Approximately 7,000 individuals in the U.S. die of malignant melanoma every year.

In order to diagnose malignant melanoma, a physician will remove the primary cancer and a pathologist will examine the tumor under the microscope. Once melanoma is diagnosed, there are two critical factors that need to be determined: the thickness of the tumor and whether or not the cancer has spread (metastasized) to other parts of the body. These factors are part of the staging procedures for melanoma. It is important to determine the stage of disease in order to determine treatment options and outcomes.

Thickness: The most important feature of the tumor is the thickness, which is measured in millimeters. Melanoma is divided into 3 groups based on thickness: (a) thin melanomas (< 1 mm thickness), (b) intermediate melanomas (1 to 4 mm in thickness), and (c) thick melanomas (> 4 mm). The thickness of the tumor is important because it will have an impact on whether the tumor has spread, which is the other critical factor used to determine the stage of disease. The thicker a melanoma is, the more likely it is to have spread to lymph nodes at the time of diagnosis.

Spread: In general, when melanoma spreads, it spreads to lymph nodes in the region of the tumor first. Lymph nodes are small, bean-shaped structures that are part of the immune system. They are found throughout the body and are interconnected by lymph channels. Melanoma tends to spread through lymph channels that drain into lymph nodes in the local area of the primary skin melanoma. Once a pathologist has determined the thickness of the tumor, the next step in pathological staging may involve surgical removal and examination of the local lymph nodes to determine if apparently normal lymph nodes contain melanoma cells.

Over the past decade, sentinel lymph node (SLN) biopsy techniques have improved the ability to detect small amounts of tumor in lymph nodes. SLN biopsy is a technique that relies on intra-operative lymphatic mapping. During a SLN biopsy, a physician injects a tracer (radioactive isotope and/or blue dye) into the area of the primary tumor. The tracer, which is taken up by the lymph system, identifies the so-called "sentinel lymph node” (SLN), which is the first lymph node that could be potentially involved with melanoma. Lymphatic mapping can be performed prior to surgery to aid the physician in determining which lymph node group is the primary drainage basin for any particular area of skin and it can also be used on the day of surgery to identify which lymph node is the first node (sentinel lymph node).

During a SLN biopsy, the physician removes the SLN through a small incision and then a pathologist examines the SLN under the microscope to detect whether or not there is any evidence of melanoma cells. Patients who have a positive sentinel node (tumor identified) are counseled to undergo removal of all the lymph nodes in the region, while patients who have a negative sentinel node do not undergo further surgery. Although there is an intense effort to develop blood tests for detecting metastatic disease, none have proven completely reliable.

There is evidence that surgical removal of involved lymph nodes may improve survival. This may especially be true when only one lymph node is involved with melanoma. Ideally, if there is no melanoma involvement in the lymph nodes, the removal of lymph nodes should be avoided. It is important to know about the presence of local lymph nodes involved with spread of melanoma, as this is one of the criteria frequently used to identify patients at high risk for development of recurrent disease and is also an entry criteria for clinical trials evaluating the role of additional therapy.

Melanoma can spread by local extension (through the lymph system, as described above) and/or by the blood to distant sites. Satellite lesions can also occur in the skin adjacent but separate from the primary melanoma. These are sometimes called in-transit metastases, implying that secondary melanomas have grown in the skin on their way to spreading to local lymph nodes. Any organ can be involved by metastases from malignant melanoma, but the lungs and liver are the most common sites.

In 3-5% of patients, melanoma is present in lymph nodes or other organs without an identifiable primary site and these patients are said to have "melanoma of unknown origin." In such cases, it is believed that the primary melanoma underwent spontaneous regression, while the metastasis remained. Patients with unknown primary in the lymph nodes or in distant sites have stage III or IV disease and are treated as outlined for malignant melanomas of these stages.

Treatment Outcomes: Most patients with disease localized to the skin can be cured with surgery. The majority of patients with spread of melanoma to local lymph nodes cannot be cured with current therapies. The average survival of patients with melanoma that has spread outside the local area is only 7.5 months, with only 5-10% of patients surviving beyond 5 years. Thus, there is a great interest in improving early diagnosis, which is the most effective way of improving the cure rate for patients with melanoma. There is generally a survival advantage for females over males for all stages of disease. In Scotland, the melanoma-free survival for men is reported to be 69% at 5 years, compared to 82% for women.

Melanoma is one of the few cancers that has shown regression without treatment. Spontaneous partial regression can be common, but complete and permanent regression is rare, with only 33 cases being documented in the world's literature. It has been suggested that spontaneous regressions occur because the patient’s immune system rejects the cancer. This observation has caused physicians to try treatments with interferons, interleukins, vaccines and other treatments that stimulate the immune system to react against the malignant melanoma.

Prognosis: For disease confined to the site of origin, the greater the thickness or depth of local invasion of the melanoma, the higher the chance of lymph node metastases and the worse the prognosis. Following surgery, the highest risk of recurrence is within the first two years, but late relapses are not uncommon.

Staging System: The staging system for melanoma has recently been revised, but continues to be based on primary tumor thickness, ulceration of the primary tumor, lymph node involvement, and distant metastasis. Historically, the staging system for primary melanoma was based on the Clark’s level and Breslow thickness. A common mistake with a new diagnosis has been to confuse Clark’s level with stage. Unlike stage, the Clark’s level describes a primary melanoma tumor microscopically, dividing the skin into 5 levels and assigning the melanoma to a different level based on how deep the melanoma penetrated.

•Clark’s Level I: Melanomas confined to the outermost layer of the skin, the epidermis. Also called "melanoma in-situ."
•Clark’s Level II: Penetration by melanomas into the second layer of the skin, the dermis.
•Clark’s Levels III-IV: Melanomas invade deeper through the dermis, but are still contained completely within the skin.
•Clark’s Level V: Penetration of melanoma into the fat of the skin beneath the dermis, penetration into the third layer of the skin, the subcutis.
Since the division of skin layers and skin thickness is variable, the Clark’s level is somewhat subjective according to the pathologist making the reading. Due to its subjectivity and variability, the Clark’s Level is a less significant prognostic factor in the new staging system. However, the Breslow thickness continues to be an important measurement since it is more exact, more reproducible, and less subjective. The Breslow thickness is measured in millimeters and defines the vertical thickness (how far tumor extends into the skin) of a primary melanoma.

The Tumor-Node-Metastasis (TNM) classification system may also be encountered in melanoma staging. The TNM classification is used by pathologists to stage melanoma by describing tumor thickness, nodal involvement and presence of metastasis.

Recent studies indicate that ulceration (microscopic absence of continuous epidermis in tissue overlying the melanoma) of the primary tumor, the number of lymph nodes involved, sites of distant metastases and elevation in levels of blood enzyme called lactate dehydrogenase (LDH) are the most valuable prognostic factors for melanoma. A revised staging system by the American Joint Committee on Cancer (AJCC) took effect nationwide in January 2003.

The following is a simplified staging system useful for determining treatment and estimating outcomes. This staging system implies that the status of local lymph nodes is known from examination under the microscope. If direct surgical examination is not done, some patients staged as clinical stage II will in fact have stage III disease with lymph node involvement. In order to learn more about the most recent information available concerning the treatment of melanoma cancer, click on the appropriate stage.

Melanoma in Situ : Malignant melanoma cells are found only in the outer layer of skin cells (epidermis) and have not invaded to deeper layers.

Stage I: Malignant melanoma is found in the outer layer of the skin (epidermis) and/or the upper part of the inner layer of skin (dermis), but has not spread to lymph nodes. The melanoma is < 1 mm with or without ulceration or 1-2 mm without ulceration. Stage I melanoma is further divided into stage IA and IB.

•Stage IA: The malignant melanoma is not more than 1 millimeter (less than 1/16 of an inch) thick, with no ulceration. The tumor is in the epidermis and upper layer of the dermis.
•Stage IB: The malignant melanoma is either not more than 1 millimeter thick, with ulceration, and may have spread into the dermis or the tissues below the skin; or 1 to 2 millimeters (more than 1/16 inch) thick, with no ulceration.
Stage II: The malignant melanoma is 1 to 2 millimeters with ulceration or > 2 mm with or without ulceration. Malignant melanoma has spread to the lower part of the inner layer of skin (dermis), but has not spread into the tissue below the dermis or into nearby lymph nodes. Stage II melanoma is further divided into stage IIA, IIB and IIC.

•Stage IIA: The malignant melanoma is either 1 to 2 millimeters thick, with ulceration; or 2 to 4 millimeters (a little more than 1/8 of an inch) thick, with no ulceration.
•Stage IIB: The malignant melanoma is either 2 to 4 millimeters thick, with ulceration; or more than 4 millimeters thick, with no ulceration.
•Stage IIC: The malignant melanoma is more than 4 millimeters thick, with ulceration.
Stage III: The malignant melanoma can be any thickness with spread to regional lymph nodes. Stage III melanoma is further divided into stage IIIA, IIIB and IIIC.

•Stage IIIA: The malignant melanoma may have spread to as many as 3 nearby lymph nodes, but can only be seen with a microscope.
•Stage IIIB: The malignant melanoma has either spread to as many as 3 lymph nodes and may not be visible without a microscope; or has satellite tumors (additional tumor growths within 1 inch of the original tumor) and has not spread to lymph nodes.
•Stage IIIC: The malignant melanoma has either spread to as many as 4 or more lymph nodes and can be seen without a microscope; or has lymph nodes that may not be moveable; or has satellite tumors and may have spread to lymph nodes.
Stage IV : The primary malignant melanoma is any size, but has spread to distant lymph nodes and/or distant sites.

Locally Recurrent Melanoma : Malignant melanoma has recurred, but is limited to skin and/or regional lymph nodes.

Recurrent and Refractory Stage IV Melanoma : Patients who have not responded to or progressed after initial systemic therapy (chemotherapy and/or biologic therapy) or have malignant melanoma that has recurred.

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