Lung Cancer: The Basics

Christopher Dolinsky, MD and Christine Hill-Kayser, MD
Affiliation: The University of Pennsylvania Medical School
Last Modified: February 27, 2008

What are the lungs?

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

What is lung cancer?

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

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

Am I at risk for lung cancer?

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

Every smoker is at risk for lung cancer. It is estimated that 87% of all cases of lung cancer are caused by cigarette smoking. The major risk factor for lung cancer is cigarette smoking. Your risk of getting lung cancer from cigarette smoking increases the longer you smoke, the more you smoke, and the deeper you inhale. Smoking low tar cigarettes does not prevent you from getting lung cancer. Importantly, if you quit smoking, your risk of getting lung cancer declines. The longer you go without smoking, the greater your risk declines. It is never too late to quit because your risk declines somewhat no matter how long you have been smoking. Even patients who have been diagnosed with lung cancer have been demonstrated to respond to treatment better and live longer if they quit smoking at the time of their diagnosis.

Smoking also has an affect on people around you. Second-hand smoke, or smoke inhaled when you are near someone smoking, is another risk factor for lung cancer. It is estimated that 17% of cases of lung cancer in non-smokers are caused by second-hand smoke exposure in childhood and adolescence. Non-smoking spouses of smokers are 30% more likely than spouses of non-smokers to get lung cancer. Even though many people don't inhale them, smoking pipes and cigars is a risk factor for lung cancer as well. The more pipes or cigars you smoke, the more likely you are to get lung cancer. Although it is not as well established as cigarette smoking, smoking marijuana is also a risk factor for getting lung cancer. Both the magnitude and duration of marijuana use seems to be related to your overall risk.

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

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

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

How can I prevent lung cancer?

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

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

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

What screening tests are available?

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

What are the signs of lung cancer?

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

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

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

How is lung cancer diagnosed and staged?

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

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

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

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

Small Cell Lung Cancer - divided into two stages

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

Non Small Cell Lung Cancer - divided into four main stages

1. Stage IA- the tumor is less than 3 cm, isn't in a main bronchus, and hasn't spread to any lymph nodes
   Stage IB - the tumor doesn't invade any organs, isn't too close to the trachea if it is in the main bronchus, doesn't cause obstruction of the lung, and hasn't spread to any lymph nodes
2. Stage IIA- the tumor is less than 3 cm, isn't in a main bronchus and has spread to lymph nodes on the same side as the tumor
   Stage IIB - the tumor doesn't invade any organs, isn't too close to the trachea if it is in the main bronchus, doesn't cause obstruction of the entire lung but has spread to hilar lymph nodes on the same side as the tumor.
3. Stage IIIA - the tumor can have spread to different types of lymph nodes than Stage II (called mediastinal or subcarinal), but they are still on the same side as the tumor and it hasn't invaded any vital organs
   Stage IIIB - the tumor has either invaded vital adjacent organs and/or spread to lymph nodes on the other side of the mediastinum as the tumor, or specific lymph nodes called scalenes or supraclavicular. Also, the patient may have tumor spread to the fluid surrounding the lung
4. Stage IV- the tumor has spread (metastasized) to other organs in the body outside the lungs (like the bones, brain or liver)

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

What are the treatments for lung cancer?

Surgery

For patients with non small cell lung cancer, surgery is often employed in cancers up to and including stage IIIA. The purpose of the surgery is to remove all of the cancer if possible. If the tumor is small and in a favorable location, or the patient has limited lung function, the surgeon may choose to remove the tumor with a small section of lung; this is called a wedge resection. Most times the surgeon will choose to remove the entire lobe of the involved lung; this is known as a lobectomy. On occasion, the surgeon must remove the entire lung affected by the cancer; and this is known a pneumonectomy. Not every patient can tolerate these surgeries. Patients with diminished lung function due to other diseases may not be able to survive after such a surgery, or they may be severely limited in their activities. Preoperative pulmonary function tests (PFT's) are used to help predict who is a good candidate for surgery. Sometimes a quantified ventilation perfusion scan will be ordered which shows the amount that each area of lung is currently working. These tests may help the surgeon to predict how much lung function will be lost based on the amount of lung that will need to be removed, and how well the patient will feel after surgery. Surgery is not generally recommended for small cell lung cancer of any stage. Small cell lung cancer is usually treated with chemotherapy and radiation therapy. There have been some studies on the use of surgery in small cell lung cancer for very early stage lesions; however, this is not generally considered a standard option for patients with small cell lung cancer.

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

Chemotherapy

Despite the fact that the tumors are often removed by surgery, there is always a risk of recurrence because there may be microscopic cancer cells left that the surgeon cannot remove. Also, some patients are not candidates for surgery or choose not to have surgery. Chemotherapy is the use of anti-cancer drugs that go throughout the entire body. These drugs may be given through a vein or as pills by mouth. Chemotherapy is recommended after surgery for some stage I and stage II non-small cell lung cancer patients. Because current treatment of advanced stage non-small cell lung cancers (stage III) is often a combination of radiation and/or chemotherapy and/or surgery, the timing and use of chemotherapy may vary depending on the specifics of the case. It may be given at the same time as radiation, or before or after radiation. Chemotherapy is offered to many patients with stage IV disease.

Small cell lung cancer is very responsive to chemotherapy, and most patients with small cell lung cancer will be offered chemotherapy. Again, depending on the specifics of an individual case, it may be given during radiation, or before or after radiation is complete.

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

Targeted Therapies/Biologic Therapies

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

Radiotherapy

Lung cancer patients commonly are treated with radiation therapy. Radiation therapy uses high energy rays (similar to x-rays) to kill cancer cells. It comes from an external source, and it requires patients to come in 5 days a week for up to 6-8 weeks to a radiation therapy treatment center. The treatment takes just a few minutes, and it is painless. Radiation therapy is often combined with surgery and is important in the treatment of all types of lung cancer. It may be recommended before surgery to shrink a tumor to make it easier for the surgeon to remove. Radiation may be used after surgery if there are worrisome risk factors that make it likely for a tumor to come back in the chest. Sometimes radiation is used instead of surgery if a surgery is felt to be too dangerous for the patient, or if a tumor is too extensive to be removed with surgery.

Radiation is often used in the setting of metastatic disease (cancer cells that have spread to other regions of the body). Radiation can be used to reduce pain from metastatic disease, or reduce the risk of problems from cancer that may have spread to the brain.

In small cell lung cancer, brain radiation is sometimes used even if a patient does not have known cancer in the brain. This is called prophylactic cranial radiation. Clinical trials have shown that patients with small cell lung cancer may live longer if they have radiation to the brain; this is likely because cancer cells have spread to the brain, but tumor regions are too small to be seen with CT or MRI scans. Prophylactic cranial radiation can be used to kill these cells before they cause the patient problems.

Photodynamic Therapy

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

Follow-up testing

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

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

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

References

• Adjei, A.A., Marks, R.S., Bonner, J.A. (1999) Current Guidelines for the Management of Small Cell Lung Cancer. Mayo Clinic Proceedings, 74(8), 809-816
• The American Cancer Society All About Lung Cancer Overview www.cancer.org.
• Bunn, P.A. & Kelly, K. (2000) New Combinations in the Treatment of Lung Cancer: A Time for Optimism. Chest, 117(4) Supplement 1, 138S-143S
• Lippman, S.M. & Spitz, M.R. (2000) Lung Cancer Chemoprevention: An Integrated Approach. Journal of Clinical Oncology, 19(18S) Supplement, 74S-82S
• Marcus, P.M.(2000) Lung Cancer Screening: An Update. Journal of Clinical Oncology, 19(18S) Supplement, 83S-86S
• National Cancer Institute. What You Need To Know About Lung Cancer. www.cancer.gov.
• Rubin, P. and Williams, J.P., (Eds): Clinical Oncology: A Multidisciplinary Approach for Physicians and Students 8th ed. (2001). W.B. Saunders Company, Philadelphia, Pennsylvania.

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Breast Cancer: The Basics

Christopher Dolinsky, MD and Christine Hill-Kayser, MD
Affiliation: Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 18, 2011

What is the breast?

The breast is a collection of glands and fatty tissue that lies between the skin and the chest wall. The glands inside the breast produce milk after a woman has a baby. Each gland is also called a lobule, and many lobules make up a lobe. There are 15 to 20 lobes in each breast. The milk gets to the nipple from the glands by way of tubes called ducts. The glands and ducts get bigger when a breast is filled with milk, but the tissue that is most responsible for the size and shape the breast is the fatty tissue. There are also blood vessels and lymph vessels in the breast. Lymph is a clear liquid waste product that gets drained out of the breast into lymph nodes. Lymph nodes are small, pea-sized pieces of tissue that filter and clean the lymph. Most lymph nodes that drain the breast are under the arm in what is called the axilla.

What is breast cancer?

Collections of cells that are growing abnormally or without control are called tumors. Tumors that do not have the ability to spread throughout the body may be referred to as “benign” and are not thought of as cancerous. Tumors that have the ability to grow into other tissues or spread to distant parts of the body are referred to as “malignant.” Malignant tumors within the breast are called “breast cancer”. Theoretically, any of the types of tissue in the breast can form a cancer, cancer cells are most likely to develop from either the ducts or the glands. These tumors may be referred to as “invasive ductal carcinoma” (cancer cells developing from ducts), or “invasive lobular carcinoma” (cancer cells developing from lobes).

Sometimes, precancerous cells may be found within breast tissue, and are referred to as ductal carcinoma in-situ (DCIS) or lobular carcinoma in-situ (LCIS). DCIS and LCIS are diseases in which cancerous cells are present within breast tissue, but are not able to spread or invade other tissues. DCIS represents about 20% of all breast cancers. Because DCIS cells may become capable of invading breast tissue, treatment for DCIS is usually recommended. In contrast, treatment is usually not needed for LCIS.

Am I at risk for breast cancer?

Breast cancer is the most common malignancy affecting women in North America and Europe. Close to 200,000 cases of breast cancer were diagnosed in the United States in 2001. Breast cancer is the second leading cause of cancer death in American women behind lung cancer. The lifetime risk of any particular woman getting breast cancer is about 1 in 8 although the lifetime risk of dying from breast cancer is much lower at 1 in 28. Men are also at risk for development of breast cancer, although this risk is much lower than it is for women.

The most important risk factor for development of breast cancer is increasing age. As any woman ages, her risk of breast cancer increases. Risk is also affected by the age when a woman begins menstruating (younger age may increase risk), and her age at her first pregnancy(older age may increase risk). Use of exogenous estrogens, sometimes in the form of hormone replacement treatment (HRT) may increase breast cancer risk, but use of oral contraceptives most likely does not increase risk. Family history is very important in determining breast cancer risk. Any woman with a family history of breast cancer will be at increased risk for developing breast cancer herself. Furthermore, known genetic mutations that increase risk of breast cancer are present in some families; these include mutations in the genes BRCA1 and BRCA2. Between 3% to 10% of breast cancers may be related to changes in one of the BRCA genes. Women can inherit these mutations from their parents.. Genetic testing for mutations should be considered for any woman with a strong family history of breast cancer, especially breast cancers in family members less than 50 years, or strong family history of prostate or ovarian cancer. If a woman is found to carry either mutation, she has a 50% chance of getting breast cancer before she is 70. Family members may elect to get tested to see if they carry the mutation as well. If a woman does have the mutation, she may choose to undergo more rigorous screening or even undergo preventive (prophylactic) mastectomies to decrease her chances of contracting cancer. The decision to undergo genetic testing is a highly personal one that should be discussed with a doctor who is trained in counseling patients about genetic testing. For more information on genetic testing, see Let the Patient Beware: Implications of Genetic Breast-Cancer Testing, Psychological Issues in Genetic Testing for Breast Cancer, and To Test or Not to Test? Genetic Counseling Is the Key.

Some factors associated with breast cancer risk can be controlled by a woman herself. Use of hormone replacement therapy (HRT), drinking more than 5 alcoholic drinks/ week, being overweight, and being inactive may all contribute to breast cancer risk. These are called modifiable risk factors.It is important to remember that even someone without any risk factors can still get breast cancer. Proper screening and early detection are our best weapons in reducing the mortality associated with this disease. For further information about breast cancer risk factors, please see Risk Factors and Breast Cancer.

How can I prevent breast cancer?

The most important risk factors for the development of breast cancer, such as age and family history, cannot be controlled by the individual. Some risk factors may be in a woman’s control; however. These include things like avoiding long-term hormone replacement therapy, having children before age 30, breastfeeding, avoiding weight gain through exercise and proper diet, and limiting alcohol consumption to 1 drink a day or less. For women already at very high risk due to family history, risk of developing breast cancer can be reduced by about 50% by taking a drug called Tamoxifen for five years. Tamoxifen has some common side effects (like hot flashes and vaginal discharge), which are not serious and some uncommon side effects (like blood clots, pulmonary embolus, stroke, and uterine cancer) which are life threatening. Tamoxifen isn't widely used for prevention, but may be useful in some cases. Use of Tamoxifen for prophylactic reasons should be considered carefully by an individual and her doctor, as its use is very individualized. For more information on breast cancer prevention, see Risk and Prevention.

What screening tests are available?

The earlier that a breast cancer is detected, the more likely it is that treatment can be curable. For this reason, we screen for breast cancer using mammograms, clinical breast exams, and breast self-exams. Screening mammograms are simply x-rays of the breasts. Each breast is placed between two plates for a few seconds while the x-rays are taken. If something appears abnormal, or better views are needed, magnified views or specially angled films are taken during the mammogram. Mammograms often detect tumors before they can be felt and they can also identify tiny specks of calcium that could be an early sign of cancer. Regular screening mammograms can decrease the mortality of breast cancer by 30%. The majority of breast cancers are associated with abnormal mammographic findings. Woman should get a yearly mammogram starting at age 40 (although some groups recommend starting at 50), and women with a genetic mutation that increases their risk or a strong family history may want to begin even earlier. Many centers are now making use of digital mammograms, which may be more sensitive than conventional mammography.

Between the ages of 20 and 39, every woman should have a clinical breast exam every 3 years; and after age 40 every woman should have a clinical breast exam done each year. A clinical breast exam is an exam done by a health professional to feel for lumps and look for changes in the size or shape of the breasts. During the clinical breast exam, you can learn how to do a breast self-exam. Every woman should do a self breast exam once a month, about a week after her period ends. About 15% of tumors are felt but cannot be seen by regular mammographic screening.

In certain populations of women, MRI screening may be recommended. The American Cancer Society now recommends yearly breast MRI for breast cancer screening for women who carry a known BRCA 1 or 2 mutation, those with a very strong family history of breast or ovarian cancer, and those who have had prior radiation treatment to the chest (for example, radiation as part of treatment for Hodgkin’s Lymphoma). Other populations of women who may or may not benefit from MRI screening are those who have already had breast cancer, those with known lobular carcinoma in-situ (LCIS), and those with very dense breast which may be difficult to visualize on mammograms. Decisions regarding how to screen for breast cancer (with mammograms, MRI, or both) should be made between an individual and her physician, based on her individual breast cancer risk profile.

Other screening modalities that are currently being studied include, ductal lavage, ultrasound, optical tomography, and PET scan. For more information on these experimental techniques, see Advanced Breast Imaging, Penn Leads International Study on Breast Cancer Detection, and Komen Foundation Focuses Attention on the Need for Improved Breast Imaging and Early Detection Technologies: OncoLink Talks with President and CEO Susan Braun and Director of Grants Anice Thigpen, PhD

What are the signs of breast cancer?

Unfortunately, the early stages of breast cancer may not have any symptoms. This is why it is important to follow screening recommendations. As a tumor grows in size, it can produce a variety of symptoms including:

• lump or thickening in the breast or underarm
• change in size or shape of the breast
• nipple discharge or nipple turning inward
• redness or scaling of the skin or nipple
• ridges or pitting of the breast skin

These symptoms do not always signify the presence of breast cancer, but they should always be evaluated immediately by a healthcare professional.

How is breast cancer diagnosed and staged?

Once a patient has symptoms suggestive of a breast cancer or an abnormal screening mammogram, she will usually be referred for a diagnostic mammogram. A diagnostic mammogram is another set of x-rays with additional angles and close-up views. Often, and ultrasound will be performed during the same session. An ultrasound uses high-frequency sound waves to outline the suspicious areas of the breast. It is painless and can often distinguish between benign and malignant lesions.

Depending on the results of the mammograms and/or ultrasounds, your doctors may recommend that you get a biopsy. A biopsy is the only way to know for sure if you have cancer, because it allows your doctors to get cells that can be examined under a microscope. There are different types of biopsies; they differ on how much tissue is removed. Some biopsies use a very fine needle, while others use thicker needles or even require a small surgical procedure to remove more tissue. Your team of doctors will decide which type of biopsy you need depending on your particular breast mass.

Once the tissue is removed, a doctor known as a pathologist will review the specimen. The pathologist can tell if is the cells are cancerous or not, If the tumor does represent cancer, the pathologist will characterize it by what type of tissue it arose from, how abnormal it looks (known as the grade), whether or not it is invading surrounding tissues, and whether or not the entire lump was removed during surgery. The pathologist will also test the cancer cells for the presence of estrogen and progesterone receptors as well as a receptor known as HER-2/neu. The presence of estrogen and progesterone receptors is important because cancers that have those receptors can be treated with hormonal therapies. HER-2/neu expression may also help predict outcome. There are also some therapies directed specifically at tumors dependent on the presence of HER-2/nue. See Understanding Your Pathology Report for more information.

In order to guide treatment and offer some insight into prognosis, breast cancer is staged into five different groups. This staging is done in a limited fashion before surgery taking into account the size of the tumor on mammogram and any evidence of spread to other organs that is picked up with other imaging modalities; and it is done definitively after a surgical procedure that removes lymph nodes and allows a pathologist to examine them for signs of cancer. The staging system is somewhat complex, but here is a simplified version of it:

Stage 0 (called carcinoma in situ)

Lobular carcinoma in situ (LCIS) refers to abnormal cells lining a gland in the breast. This is a risk factor for the future development of cancer, but this is not felt to represent a cancer itself.

Ductal carcinoma in situ (DCIS) refers to abnormal cells lining a duct. Women with DCIS have an increased risk of getting invasive breast cancer in that breast. Treatment options are similar to patients with Stage I breast cancers.

Stage I : early stage breast cancer where the tumor is less that 2 cm, and hasn't spread beyond the breast

Stage II : early stage breast cancer in which the tumor is either less than 2 cm across and has spread to the lymph nodes under the arm; or the tumor is between 2 and 5 cm (with or without spread to the lymph nodes under the arm); or the tumor is greater than 5 cm and hasn't spread outside the breast

Stage III : locally advanced breast cancer in which the tumor is greater than 5 cm across and has spread to the lymph nodes under the arm; or the cancer is extensive in the underarm lymph nodes; or the cancer has spread to lymph nodes near the breastbone or to other tissues near the breast

Stage IV : metastatic breast cancer in which the cancer has spread outside the breast to other organs in the body

Depending on the stage of your cancer, your doctor may want additional tests to see if you have metastatic disease. If you have a stage III cancer, you will probably get a chest x-ray, CT scan and bone scan to look for metastases. Each patient is an individual and your doctors will decide what is necessary to adequately stage your cancer.

What are the treatments for breast cancer?

Surgery

Almost all women with breast cancer will have some type of surgery in the course of their treatment. The purpose of surgery is to remove as much of the cancer as possible, and there are many different ways that the surgery can be carried out. Some women will be candidates for what is called breast conservation therapy (BCT). In BCT, surgeons perform a lumpectomy which means they remove the tumor with a little bit of breast tissue around it, but do not remove the entire breast. BCT always needs to be combined with radiation therapy to make it an option for treating breast cancer. At the time of the surgery, the surgeon may also dissect the lymph nodes under the arm so the pathologist can review them for signs of cancer. Some patients will have a sentinel lymph node biopsy procedure first to determine if a formal lymph node dissection is required. Sometimes, the surgeon will remove a larger part (but not the whole breast), and this is called a segmental or partial mastectomy. This needs to be combined with radiation therapy as well. In early stage cancers (like stage I and II), BCT (limited surgery with radiation) is as effective as removal of the entire breast via mastectomy. The advantage of BCT is that the patient will not need a reconstruction or prosthesis, but will be able to keep her breast. Some patients with early-stage cancer prefer to have mastectomy, and this is an appropriate option as well..

More advanced breast cancers are usually treated with a modified radical mastectomy. Modified radical mastectomy refers to removal of the entire breast, as well as and dissection of the lymph nodes under the arm. Sometimes, patients who have modified radical mastectomy will require radiation treatment afterwards to decrease the risk of the cancer coming back.

Some patients with DCIS will be candidates for BCT, while others will require modified radical mastectomy because of the size or distribution of DCIS cells. Most patients with DCIS who have a lumpectomy are treated with radiation therapy to prevent the local recurrence of DCIS (although some of these DCIS patients may be candidates for close observation after surgery). Patients with DCIS that have a mastectomy do not need to have the lymph nodes removed from under the arm.

Your surgeon can discuss your options and the pros and cons of your needed surgical procedures. Many women who have modified radical mastectomies choose to undergo a reconstruction. A patient who desires reconstruction should try to meet with a plastic surgeon before her mastectomy to discuss reconstruction options. For more information on breast reconstruction, see Breast Reconstructive Surgery Options.

Chemotherapy

Even when tumors are removed by surgery, microscopic cancer cells can spread to distant sites in the body. In order to decrease a patient's risk of recurrence, many breast cancer patients are offered chemotherapy. Chemotherapy is the use of anti-cancer drugs that go throughout the entire body to eliminate cancer cells that have broken off from the breast tumor and spread. Many factors go into determining whether an individual patient should have chemotherapy. Generally, patients with higher stage disease need chemotherapy; however, chemotherapy can be beneficial even for patients with early-stage disease. Individual factors such as age, overall health, and biologic properties of a woman’s breast tumor may go into decisions regarding whether or not she should have chemotherapy. There are many different chemotherapy drugs, and they are usually given in combinations for 3 to 6 months after you receive your surgery. Depending on the type of chemotherapy regimen you receive, you may get medication every 2 to 4 weeks. Most chemotherapies used for breast cancer are given through a vein, so need to be given in an oncology clinic. Drugs that are commonly used in breast cancer treatment include adriamycin (doxorubicin), cyclophosphamide, and taxanes. There are advantages and disadvantages to each of the different regimens that your medical oncologist will discuss with you. Based on your own health, your personal values and wishes, and side effects you may wish to avoid, you can work with your doctors to come up with the best regimen for your lifestyle.

Generally, chemotherapy is given after surgery for early-stage breast cancer. Sometimes, chemotherapy may be given before surgery to shrink large tumors and allow surgery to be more effective. For patients with stage IV disease, chemotherapy may be given without surgery, and a variety of different agents may be tried until a response is achieved.

Radiotherapy

Breast cancer is often treated with radiation therapy. Radiation therapy refers to use of high energy x-rays to kill cancer cells. Patients having radiation usually need to come to a radiation therapy treatment center 5 days a week for up to 6 weeks to receive treatment. The treatment takes just a few minutes, and it is painless. Radiation therapy is used in all patients who receive breast conservation therapy (BCT). It is also recommended for patients after a mastectomy who have had large tumors, lymph node involvement, or close/positive margins after the surgery. Radiation is important in reducing the risk of local recurrence and is often offered in more advanced cases to kill tumor cells that may be living in lymph nodes. Your radiation oncologist can answer questions about the utility, process, and side effects of radiation therapy in your particular case.

Some newer techniques for radiation therapy are being used in certain centers. These are ways to reduce the treatment time needed for radiotherapy, and usually take 1 – 3 weeks instead of 6 weeks, and are called accelerated partial breast irradiation (APBI). These techniques may require a patient to have a radioactive implant placed inside the breast. These techniques are experimental, and are only indicated for early-stage breast cancer patients.

Hormonal Therapy

When the pathologist examines a tumor specimen, he or she may determine that the tumor is expressing estrogen and/ or progesterone receptors. Patients whose tumors express estrogen receptors are candidates for therapy with estrogen blocking drugs. Estrogen-blocking drugs include Tamoxifen and a family of drugs called aromatase inhibitors. These drugs are delivered in pill form for 5 - 10 years after breast cancer surgery. These drugs have been shown to drastically reduce your risk of recurrence if your tumor expresses estrogen receptors. They may be accompanied by side effects, however. When taking Tamoxifen, patients may experience weight gain, hot flashes and vaginal discharge.. Taking Tamoxifen may also increase risk of serious medical issues, such as blood clots, stroke, and uterine cancer. Patients taking aromatase inhibitors may experience bone or joint pain, and are at increased risk for thinning of the bones (osteopenia or osteoporosis). Patients taking aromatase inhibitors should have yearly bone density testing, and may require treatment for bone thinning.

Biologic Therapy

The pathologist also examines your tumor for the presence of HER-2/neu overexpression. HER-2/neu is a receptor that some breast cancers express. A compound called Herceptin (or Trastuzumab) is a substance that blocks this receptor and helps stop the breast cancer from growing. Patients with tumors that express HER-2/neu may benefit from Herceptin, and this should be discussed with a medical oncologist when the treatment plan is decided upon.

Follow-up testing

Once a patient has been treated for breast cancer, she needs to be closely followed for a recurrence. At first, you will have follow-up visits every 3-4 months. The longer you are free of disease, the less often you will have to go for checkups. After 5 years, you could see your doctor once a year. You should have a mammogram of the treated and untreated breasts every year. Because having had breast cancer is a risk factor for getting it again, having your mammograms done every year is extremely important. If you are taking Tamoxifen, it is important that you get a pelvic exam each year and report any abnormal vaginal bleeding to your doctor.

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

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

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Anal Cancer: The Basics

Christine Hill-Kayser, MD
Updated by Lara Bonner Millar, MD
Affiliation: The Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 23, 2012

What is the anus?

The anus is an organ that lies at the end of the digestive tract below the rectum. It consists of two sections: the anal canal and the anus (or anal verge). The anal canal is a 3-4 cm long structure that lies between the anal sphincter (one of the muscles controlling bowel movements) just below the rectum and the anal verge which represents the transition point between the digestive tract and the skin on the outside of the body. Muscles within the anal canal and anus control the passage of stool from the rectum to outside the body.

What is anal cancer?

Normally, cells in the body will grow and divide to replace old or damaged cells in the body. This growth is highly regulated, and once enough cells are produced to replace the old ones, normal cells stop dividing. Tumors occur when there is an error in this regulation and cells continue to grow in an uncontrolled way. Tumors can either be benign or malignant. Although benign tumors may grow in an uncontrolled fashion sometimes, they do not spread beyond the part of the body where they started (metastasize) and do not invade into surrounding tissues. Malignant tumors, however, will grow in such a way that they invade and damage other tissues around them. They also may spread to other parts of the body, usually through the blood stream or through the lymphatic system where the lymph nodes are located. Over time, the cells within a malignant tumor become more abnormal and appear less like normal cells. This change in the appearance of cancer cells is called the tumor grade, and cancer cells are described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are quite normal appearing and resemble the normal cells from which they originated. Undifferentiated cells are cells that have become so abnormal that often we cannot tell what types of cells they started from.

Anal cancer is a malignant tumor of either the anal canal or anal verge. In the United States, 80% of anal cancers are squamous cell cancers, resembling the cells found in the anal canal, This is not true in other parts of the world, however. In Japan, 80% of anal cancers are adenocarcinomas, resembling the glandular cells seen in the rectum. Cancers of the anal verge may be referred to as "perianal skin cancers," because they usually behave more like skin cancers than like anal cancers. They may respond more poorly to treatment than other forms of anal cancers. Perianal skin cancers represent about 25% of all anal cancers. Occasionally, other types of cancer, such as melanoma, Kaposi's sarcoma, and lymphoma may develop in the anus. These other types of cancer will be discussed separately, and will not be addressed further in this review.

Anal cancers frequently begin as anal dysplasia. Anal dysplasia is made up of cells of the anus that have abnormal changes, but do not show evidence of invasion into the surrounding tissue. The most severe form of anal dysplasia is called carcinoma in situ. In the case of carcinoma in situ, cells have become cancerous, but have not begun to invade normal tissue yet. Over time, anal dysplasia changes to the point where cells become invasive and gain the ability to metastasize, or break way to other parts of the body. Anal dysplasia is sometimes referred to as anal intraepithelial neoplasia (AIN), or a "pre-cancer." When anal cancer does spread, it most commonly spreads through direct invasion into the surrounding tissue or through the lymphatic system. Spread of anal cancer through the blood is less common, although it can occur.

What causes anal cancer and am I at risk?

Each year, there are approximately 4,000 cases of anal cancer in the United States. In general, the incidence of anal cancers has been increasing over the past 30-40 years. The vast majority (85%) of cases are in Caucasians. The incidence of anal cancer increases with age: patients with anal cancer have an average (median) age of 62 years. Cancers of the anal canal are more common in women, while the incidence of cancers of the anal verge is roughly equal in both men and women.

Several factors have been associated with anal cancer. Most importantly, infection with the human papilloma virus (HPV) has been shown to be related to anal cancers and has been associated with several other cancers, including cervical cancer and cancers of the head and neck. HPV can be transmitted from person to person through sexual contact, so individuals with a history of multiple sexual partners, anal receptive intercourse, and genital warts are at an increased risk for infection. Probably due to the association between HPV and anal cancer, women with history of cervical cancer are at increased risk of developing anal cancer. Another sexually transmitted virus, the human immunodeficiency virus (HIV), has been linked to anal cancers, and individuals infected with HIV are at increased risk for infection with HPV. The relationship between HIV and anal cancer will be discussed in more detail in the next section (entitled "How are anal cancer and HIV/AIDS related?")

Several other factors have been linked to anal cancer. Anal cancer has been associated with smoking. Patients who smoke are three times more likely to develop anal cancer as those that don't smoke. The risk of anal cancer increases with the number of cigarettes smoked per day and the number of years that a person has been smoking.

There may be an association between anal cancer and suppression of the immune system. The rate of anal cancer is higher in patients who are immunosuppressed after organ transplants, although this relationship is not clear.

Although there appears to be an increased rate of anal cancer in patients who have benign anal conditions such as anal fistulae, anal fissures, perianal abscesses, or hemorrhoids, it does not appear that these benign conditions are a cause of anal cancer. Alternatively, an undiagnosed anal cancer may actually be causing these conditions, and then is subsequently diagnosed when the benign condition is being treated.

How are anal cancer and HIV/AIDS related?

HIV is the virus responsible for Acquired Immune Deficiency Syndrome (AIDS), a severe disease that results in loss of the ability of the body to fight off certain types of infections. The incidence of anal cancer is increased in patients with HIV. This is likely related to the fact that patients with HIV are at an increased risk for infection with HPV as well. This relationship between HIV and HPV is not related to the immune status or the sexual practices of the patient infected with HIV. The rate of infection of HPV is increased in patients with HIV even if they do not engage in anal receptive intercourse and do not have evidence of suppression of their immune system. A patient is considered to have progressed from being HIV positive to having AIDS if they develop certain infections or diseases that are uncommon except in AIDS patients. Currently, anal cancer is not considered an AIDS-defining illness. However, frequently, patients who have been newly diagnosed with anal cancer are tested for HIV if they have other risk factors for infection with HIV.

How can I prevent anal cancer?

Anal cancer is an uncommon cancer, and the risk of developing anal cancer is quite low. Avoidance of risk factors for anal cancer, however, will reduce the risk of development of anal cancer even further. By far, the most important factor in developing anal cancer is infection with HPV. Recently, Gardasil, a vaccine directed against HPV, has been developed. This vaccination is currently recommended only for girls and young women for prevention of cervical cancer. Vaccination against HPV would certainly be expected to reduce the incidence of anal cancer in both men and women, but, to date, no studies have been published confirming this. The vaccine has not been studied in boys and men, but data on this topic will likely be available in the future. A number of studies examining the role of HPV vaccines and anal cancer are currently under development.

Avoiding smoking and unsafe sexual practices can reduce the risk of anal cancer. This is because the immune system in people who smoke is less able to clear the HPV virus than those who do not smoke. In patients who are known to have anal dysplasia, careful surveillance can result in early detection of anal cancer, and a higher rate of cure with treatment.  Removal of areas of anal dysplasia is usually unsuccessful and the rate of recurrence of anal dysplasia after surgical or laser removal is very high. This is likely due to the fact that even if areas of dysplasia are removed, the patient remains infected with HPV, which can cause the development of additional areas of anal dysplasia.

What are the signs of anal cancer?

The most common initial symptom of anal cancer is rectal bleeding, which occurs in about half of patients with new anal cancers. Pain is somewhat less common, seen in about 30% of patients with new anal cancers; however, it can be quite severe. Occasionally, patients have the sensation of having a mass in the anus and may experience itching or anal discharge. In certain patients, these symptoms may be associated with the presence of warts in the anal region. Rarely, in advanced cases, anal cancers can disrupt the function of the anal muscles, resulting in loss of control of bowel movements. In general, these symptoms are vague and non-specific. As a result, in one-half to two-thirds of patients with anal cancer, a delay of up to 6 months occurs between the time when symptoms start and when a diagnosis is made.

How is anal cancer diagnosed?

When anal cancer is suspected, the physician should perform a thorough history and physical examination. The physical exam should consist of a digital rectal examination (DRE) as well as visualization of the anal canal using an anoscope or bronchoscope (a long, thin instrument that is inserted into the anus to allow the physician to see the inside of the anus and rectum). Ultimately, anal cancer can only be diagnosed with a biopsy. To perform a biopsy, the physician uses a needle or a small pair of scissors or clamps to remove a piece of the tumor. It is common for there to be some mild bleeding after a biopsy is taken, and this bleeding can last for a few days after the procedure. The tissue is then sent to a pathologist who looks at the tissue underneath a microscope to determine whether the tumor is cancerous or not. Because a number of benign tumors and lesions can resemble anal cancer on physical examination, a biopsy should always be performed before initiating treatment for anal cancer.

How is anal cancer staged?

Once a diagnosis of anal cancer is made, additional test should be ordered to determine the extent of the disease. A CT (CAT) scan or MRI of the abdomen and pelvis should be performed to look for abnormally enlarged lymph nodes, which can result from spread of the cancer, and to examine the liver for metastatic disease. A PET/CT is useful to assess the extent of disease including the lymph nodes, and to detect distant metastases.  In some cases, an ultrasound of the tumor using a probe that is inserted into the anus can be used to determine the amount of invasion of the tumor into the surrounding tissues.  Women with advanced tumors should also have a pelvic exam to assess if the tumor has invaded into the vagina.

Anal cancer is most commonly staged using the TNM staging system which is determined by the American Joint Committee on Cancer. The "T stage" represents the extent of the primary tumor itself. The "N stage" represents the degree of involvement of the lymph nodes. The "M stage" represents whether or not there is spread of the cancer to distant parts of the body. These are scored as follows:

T Stage

• TX: Primary Tumor cannot be assessed
• Tis: Carcinoma in situ
• T0: No evidence of primary tumor
• T1: Tumor < 2 cm in greatest dimension
• T2: Tumor is > 2 cm but < 5 cm in greatest dimension
• T3: Tumor is > 5 cm in greatest dimension
• T4: Tumor of any size that invades adjacent organs including the vagina, urethra, or bladder. Tumors that invade the rectal wall, perirectal skin or anal sphincter only do not qualify as T4 tumors

N Stage

• NX: Lymph nodes cannot be assessed

• N0: No evidence of spread to the lymph node
• N1: Spread of cancer to the lymph nodes directly adjacent to the rectum (perirectal lymph nodes)
• N2: Spread of the cancer to lymph nodes of the inguinal or internal iliac lymph node chains on one side only.
• N3: Spread of the cancer to lymph nodes of the inguinal or internal iliac lymph node chains on both sides OR cancer involvement of both the perirectal lymph nodes and the inguinal lymph nodes

M Stage

• M0: No evidence of distant spread of the cancer
• M1: Evidence of distant spread of the cancer to other organs, or to lymph node chains other than the ones lists under "N stage"

The stage of the cancer is reported by stating the stage of the T, the N, and the M. For example, a patient with a 4 cm tumor that had spread to perirectal lymph nodes, but did not invade into adjacent organs or spread to any other lymph nodes would be classified as T2N1M0.

The staging can be further condensed into a stage group, which takes the various combinations of TNM and places them into groups designated stage 0-IV (See below). While there is a system for stage grouping of anal cancers, these tumors are more commonly referred to by their direct TNM stage.

Stage	T	N	M
O	Tis	N0	M0
I	T1	N0	M0
II	T2	N0	M0
	T3	N0	M0
IIIA	T1	N1	M0
	T2	N1	M0
	T3	N1	M0
	T4	N0	M0
IIIB	T4	N1	M0
	Any T	N2	M0
	Any T	N3	M0
IV	Any T	Any N	M1

Although this system of cancer staging is quite complicated, it is designed to help physicians describe the extent of the cancer, and therefore, helps to direct what type of treatment is given.

How is anal cancer treated?

Radiation Therapy

Radiation therapy has become the mainstay of treatment of anal squamous cell cancer. The radiation comes in the form of high energy x-rays that are delivered to the patient only in the areas at highest risk for cancer. These x-rays are similar to those used for diagnostic x-rays, but they are of a much high energy. The high energy of x-rays in radiation therapy results in damage to the DNA of cells. Cancer cells divide faster than healthy cells, and so their DNA is more likely to be damaged than that of normal cells. Additionally, cancer cells are generally less able to repair damaged DNA than normal cells are, so cancer cells are killed more easily by radiation than normal cells are. Radiation therapy exploits this difference to treat cancers by killing cancer cells, while killing fewer cells in normal, healthy tissue.

Typically, radiation for anal cancer is given daily, Monday through Friday, for 5 to 6 weeks. The radiation treatments themselves are short, lasting only a few minutes. Like diagnostic x-rays, radiation treatments cannot be felt and do not hurt. Radiation is delivered like a beam of light, only affecting areas where it is aimed. In treatment of anal cancer, the radiation is usually aimed at the entire pelvis for the first 2-3 weeks so that any cells in the lymph nodes surrounding the anus are treated with radiation. After this, the radiation is aimed more specifically at the anus in the lower part of the pelvis.

Most commonly, radiation treatment for anal cancer can result in irritation to the skin. This reaction can be quite severe with redness, dryness, and breakdown of the skin. Often, patients will require a break during radiation treatment to allow the skin to heal prior to resuming treatment. Other side effects of radiation can include fatigue, diarrhea, and lowering of blood counts. Increasingly, a technique of radiation delivery called IMRT is being used in an attempt to decrease skin and gastrointestinal toxicities, as well as decrease treatment breaks.

Chemotherapy

Chemotherapy refers to medications that are usually given intravenously or in pill form. Chemotherapy travels throughout the bloodstream and throughout the body to kill cancer cells. This is one of the big advantages of chemotherapy. If cancer cells have broken off from the tumor and are somewhere else inside the body, chemotherapy has the chance killing them, while radiation does not. In the setting of anal cancer, chemotherapy is most commonly given at the same time as radiation. This will be discussed further below under the section entitled "Combined Modality (Chemoradiotherapy)."

A number of different chemotherapeutic agents exist, each with their own side effects. The preferred chemotherapies used in anal cancer are 5 flourouracil (5FU) and mitomycin C. Sometimes, mitomycin C may be replaced with cisplatin in order to reduce toxicities from chemotherapy. Exactly which chemotherapeutic agents are given for anal cancer varies according to the physician's preference. It is important to discuss the risk of each of these medications with your medical oncologist. Based on your own health status and the risks of side effects that you are willing to accept, the choice of chemotherapy can vary.

Chemotherapy is used in different situations to treat anal cancer. If the cancer is localized to the anus and pelvic lymph nodes, it may be used in combination with radiation therapy to achieve the best chance of killing all of the cancer cells (see "Combined Modality (Chemoradiotherapy)." If the cancer has spread to distant parts of the body, chemotherapy drugs such as cisplatin, carboplatin, and 5FU may be used without radiation to reduce the number of tumor cells and prevent or minimize symptoms all over the body. This is the case because chemotherapy is able to travel throughout the bloodstream, while radiation is not. In this setting, radiation may be used separately to relieve certain symptoms, such as pain, from cancer in other parts of the body. Unfortunately, if cancer is present in organs distant from the anus, chemotherapy is generally not very successful at controlling it.

Combined Modality (Chemoradiotherapy)

Chemotherapy has been shown to be radiosensitizing when given at the same time as radiation therapy. This means that the effect of the radiation is increased when given together with chemotherapy. Several large trials have shown that local control of the tumor is significantly improved when 5FU and mitomycin with chemotherapy are used, as compared to radiation alone. Using chemotherapy and radiation together has not been shown to change the rate of survival of patients when compared to radiation alone; however, using chemotherapy and radiation together has been shown to reduce the risk of cancer recurring (coming back) in the anus. For this reason, combined modality treatment is recommended for most patients with anal cancer, unless a certain patient is unable to tolerate chemotherapy and radiation together. If this is the case, the patient may have radiation with or without chemotherapy given at a separate time.

Surgery

Although surgery was the primary treatment for anal cancer 20 years ago, its role has greatly diminished since then. When performed, surgical resection usually is an abdominal perineal resection (APR), which consists of a wide excision of the anus, including the anal muscles, with placement of a permanent colostomy. A colostomy is performed by connecting the bowel to a hole in the abdominal wall (called a stoma). The stool that passes through the stoma is collected in a bag that is attached to the outside of the abdominal wall with adhesive. This bag can then be emptied by the patient as needed. Because the combination of chemotherapy and radiation for squamous cell carcinoma results in similar rates of local control and survival when compared to surgery, chemoradiation has been favored over surgery because it offers patients a good chance at preserving anal sphincter function, avoiding the need for permanent colostomy. In contrast, for adenocarcinomas of the anus, surgery is still recommended after chemoradiation.

There are several situations in which surgery should be considered up front for anal cancer. Patients with carcinoma in situor small, well-differentiated anal cancers that have not invaded into the anal sphincter can sometimes undergo a surgical excision without removing the anal muscles. In these early cases, the results of surgical excision can be quite good, and the patient can avoid the potential side effects of chemoradiotherapy. Alternatively, extensive anal cancers that have destroyed the anal sphincter, such that the patient cannot control bowel movements, are often treated with surgery (an APR). In these cases, patients have already lost their sphincter function, and require a colostomy to handle bowel movements. Because patients in this situation usually have very large tumors, they may require surgical removal of the tumor, which will usually be followed by radiation, with or without chemotherapy, after the operation. Surgery can also be performed in patients who cannot otherwise tolerate radiation therapy, or who do not want radiation therapy. Finally, surgery is often performed if cancer recurs in the anus following previous treatment with radiation therapy if additional chemotherapy and radiation cannot be given.

After I am treated for anal cancer, how will I be followed?

After treatment for anal cancer, patients are usually followed every 3-6 months for several years with or without CT scans. The most important aspect of follow-up after completion of treatment is a thorough physical examination including a digital rectal exam. Anal cancers can take some time to respond to treatment and often continue to shrink months after chemotherapy and radiation have ended. Therefore, it is not unusual to have a residual mass immediately after treatment. The presence of a residual mass does not mean that the treatment did not work. Overall, the chance of long-term cure of anal cancer depends on the extent of the disease at the time it was first diagnosed. Patients with smaller disease without lymph node involvement or distant metastases have a better chance at long-term tumor control than those with larger disease or with lymph node involvement or distant metastases. If anal cancers do recur, they usually do so within the first 2 years after treatment, although recurrences after 2 years can occur. In general, the further out from treatment a patient is without evidence of a recurrence, the better the chances that the cancer will never come back.

The treatment of anal cancer should be a cooperative effort among the patient, the radiation oncology, the medical oncologist, and the surgeon. It is important that all patients with anal cancer know about their disease so that they can make an informed decision about their treatment. This article was intended to help answer some of the common questions patients face when they have anal cancer. If you have any additional questions, please contact your doctor.

References

Cotter SE, Grigsby PW, Siegel BA, et al. FDG-PET in the evaluation of anal carcinoma Int J Rad Oncol Biol Phys 2006; 65: 720-725.

Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 165-73.

Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of U.S GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: comparison of concurrent chemoradiation with 5FU-mitomycin vs 5FU-cisplatin for disease-free and overall survival. Abstract # 367. ASCO 2011 Gastrointestinal Cancers Symposium. San Francisco, CA

Kachnic LA, Winter KA, Myerson J, et al. Two-year outcomes of RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouroacil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Abstract #368. ASCO 2011 Gastrointestinal Cancers Symposium. San Francisco, CA

Zeller JL, Lymn C, Glass RM. Anal Cancer. J Am Med Assoc. 2008:299(16). http://jama.ama-assn.org/content/299/16/1980.full.pdf

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