INTRODUCTION — Testicular cancer occurs when cancer cells develop in one or both of the testicles. Testicles are the male reproductive glands located within the scrotum (show figure 1). The scrotum is a sack of loose skin that contains the testicles and hangs directly below the penis.
Testicular cancer is the most common cancer arising in young men. Fortunately, it has become one of the most curable of all cancers, largely due to advances in medical treatment. More than 95 percent of all men diagnosed with testicular cancer survive their disease.
TYPES OF TESTICULAR CANCER — Approximately 95 percent of testicular cancers develop from a type of cell in the testicle called a germ cell. Thus, they are called testicular germ cell tumors.
Seminoma vs Nonseminomatous germ cell tumor (NSGCT) — There are two major types of testicular germ cell tumors: seminoma and nonseminomatous germ cell tumors (NSGCTs). Approximately one-third of all testicular germ cell tumors are seminomas; the remainder are NSGCGTs. Both seminoma and NSGCT primarily affect men between the ages of 15 and 35 years of age, although seminomas occur in a slightly older group of men (show table 1).
SYMPTOMS — For most men, the first symptom of testicular cancer is a painless lump or swelling in the scrotum. Some men may also experience a dull ache or heavy sensation in the lower abdomen, area around the anus, or scrotum. Pain is the first symptom in about 10 percent of men.
DIAGNOSIS — Men who detect a lump in their testicle should see a healthcare provider as soon as possible. The provider will perform a general examination, with special attention to the breasts (which can become enlarged in some men with testicular cancer), the abdomen (to evaluate the lymph nodes and abdominal organs) and the scrotum. Both testicles will be examined and compared. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors").
If testicular cancer is suspected, several tests may be ordered to support the diagnosis. However, the only way to be certain that the diagnosis is testicular cancer is to remove the testicle. Testicular ultrasound — Testicular ultrasound uses sound waves to measure the size and characteristics of the testicle and mass (lump), and can determine whether the mass is inside or outside of the testicle and whether it contains fluid or is a solid mass. Testicular cancers are solid and develop inside the testicle. Often, the ultrasound will strongly suggest the diagnosis of testicular cancer. Orchiectomy — The only way to confirm the diagnosis of testicular cancer is by surgically removing the testicle. This procedure is called a radical inguinal orchiectomy (see "Radical inguinal orchiectomy" below).
STAGING AND PROGNOSTIC CLASSIFICATION — Staging is used to determine if there is spread (metastasis) of the cancer beyond the testicle. Stage I testicular cancer is defined as cancer that is limited to the testis only. Stage II testicular cancer has spread (metastasized) to the retroperitoneal lymph nodes (located in the abdomen). Stage III testicular cancer has spread to other organs (show table 2 and show table 3).
Blood tests and imaging (eg, CT scan) are used in the process of staging.
Blood tests — Substances produced by a testicular cancer (called tumor markers) can be measured in the blood. The three most important markers are: Alpha fetoprotein (AFP) Beta human chorionic gonadotropin (beta-hCG) Lactate dehydrogenase (LDH)
High levels of these tumor markers are suggestive of testicular cancer, and can help determine the specific type of testicular cancer that is present. These markers are also used during and after treatment to monitor a patient's response.
CT scans — Most men with a suspected testicular cancer will undergo a CT scan (sometimes called a CAT scan) of the abdomen and pelvis. A chest x-ray or CT scan of the chest is also commonly done.
These tests are done to determine if the suspected cancer has spread beyond the testicle (metastasized). The most common site of metastasis in testicular cancer is the lymph nodes in the abdomen; metastasis to the lung, liver, bones, and brain is also possible.
Prognostic classification — Men with stage II or III testicular cancer (both seminomas and NSGCTs) can be classified as having a good, intermediate, or poor prognosis (chance of survival and recovery) based upon the stage of disease and particular type of testicular tumor. Men with stage I testicular cancer have an excellent prognosis, and are not included in this classification system.
Following radical inguinal orchiectomy, a physician treats testicular cancer according to the type of tumor (seminoma or nonseminomatous germ cell tumor), the stage of the disease, and the patient's prognosis.
All men with seminoma are classified as having a good or intermediate prognosis. Men with NSGCT may have a good, intermediate, or poor prognosis, depending upon the stage of their disease. Good prognosis — Men with seminoma have a good prognosis if the tumor has not metastasized to organs other than the lungs and if they have a normal AFP serum level.
Patients with NSGCTs have a good prognosis if the tumor is located only in the testicle or area outside or behind the abdominal wall, if the tumor has not metastasized to organs other than the lungs, and if their serum tumor markers are only slightly elevated. Intermediate prognosis — Patients with seminoma have an intermediate prognosis if the tumor has metastasized to organs other than the lungs and their AFP test is normal.
Patients with NSGCTs have an intermediate prognosis if the tumor is found in only one testicle or in the area outside or behind the abdominal wall, if the tumor has not spread to organs other than the lungs, and if serum tumor markers are not significantly elevated. Poor prognosis — Men with NSGCTs are classified as having a poor prognosis if the tumor develops in the center of the chest between the lungs (called the mediastinum), if it has spread to organs other than the lungs, or if any of the serum tumor markers are significantly elevated.
Even for patients with a poor prognosis, approximately one-half are cured with aggressive treatment.
TREATMENT — Treatment of both seminoma and NSGCT generally includes surgery to remove the affected testicle; this surgery is called radical inguinal orchiectomy (see "Radical inguinal orchiectomy" below). The need for further treatment is determined by the type of cancer, the stage of the cancer, and the prognosis. Advances in chemotherapy and radiation therapy, often used in combination with surgery, have improved the outcome for patients with testicular cancer, and approximately 95 percent of patients can be cured.
Radical inguinal orchiectomy — Radical inguinal orchiectomy is not only required for diagnosis, but is also the initial step in treatment for most patients.
Orchiectomy is usually done in an operating room after the patient receives general or epidural anesthesia. A small incision (cut) is made in the groin and the testicle is removed. The standard treatment is to remove the entire affected testicle to avoid the risk of spreading the tumor within the scrotum. Tissue from the testicle is then examined using a microscope.
Chemotherapy
What is chemotherapy? — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply. Because most of an adult's normal cells are not actively dividing or multiplying, they are not affected by chemotherapy. However, the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. The side effects of chemotherapy drugs are related to effects on these and other normal tissues (see "Chemotherapy side effects" below).
Most drugs are given intravenously (IV) rather than by mouth. They are not usually taken daily, but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. For example, a typical chemotherapy regimen could include a one hour IV infusion of two different chemotherapy medications given once every three weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three months, four cycles of chemotherapy would be administered.
Adjuvant chemotherapy — The term adjuvant therapy refers to additional anticancer treatment that is given after surgery to eliminate any remaining tumor cells in the body (often termed micrometastases). Adjuvant therapy significantly decreases the chance that the cancer will return (or recur), and also improves the likelihood of surviving cancer. As a result, adjuvant therapy has become an important component of treatment. Modern adjuvant chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens.
Chemotherapy for testicular cancer — Chemotherapy is sometimes used as an adjuvant treatment for men with early stage testicular cancer, as well as for men with more advanced disease. Patients with more advanced stages of cancer and those who have a disease relapse after radiation therapy usually undergo multiple cycles of combination chemotherapy. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. Combination chemotherapy involves giving more than one drug, which improves the chance of a cure and reduces the chance that the tumor will develop resistance to one chemotherapy drug.
Lymph node removal — The most common sites of spread for testicular cancer are the lymph nodes in the back of the abdomen, called the retroperitoneal lymph nodes. Surgical removal (called retroperitoneal lymph node dissection or RPLND) of these nodes may be needed in the following situations: If the CT scan of the abdomen shows enlarged nodes, raising suspicion that the cancer has spread to this area. For men who have no evidence of enlargement of the retroperitoneal lymph nodes, RPLND may still be performed because a CT cannot determine lymph node involvement in as many as one-third of cases.
There are alternatives to RPLND, including periodic physical examination and CT scans (called surveillance or watchful waiting), the administration of a short course of chemotherapy, or, in the case of seminomas, low-dose radiation therapy directed at the retroperitoneal lymph nodes.
Men with stage II or III testicular cancer may not undergo RPLND at all, or may only have it if there is still cancer present after chemotherapy.
RPLND requires specialized knowledge and training; patients who require this procedure should seek care in a facility where the surgeon is experienced with RPLND. Risks of the procedure depend upon the amount of surgery needed to remove the lymph nodes and whether the patient has undergone chemotherapy; patients are more likely to have complications if they have received chemotherapy.
Radiation therapy — Radiation therapy (RT) refers to the exposure of a tumor to high-energy x-rays in order to slow or stop its growth. Exposure to x-rays damages cells. Unlike normal cells, cancer cells cannot repair the damage caused by exposure to x-rays, particularly when it is administered over several days. This prevents the cancer cells from growing further and causes them to eventually die.
RT for testicular cancer is given as external beam radiation therapy, meaning that the radiation beam is generated by a machine that is outside the patient. The radiation is delivered to the patient, who is usually lying on a table underneath or in front of the machine. The high energy beams are directed at the paraaortic lymph nodes, not the scrotum (show figure 2).
Exposure to the beam typically takes only a few seconds (similar to having an x-ray). In general, treatment is repeated five days per week for approximately five to six weeks. Treatment cannot be given over a shorter period because the higher daily doses would cause too many side effects.
Radiation therapy (RT) is often recommended after orchiectomy for men with seminoma. RT effectively prevents relapse in over 95 percent of patients with clinical stage I seminoma. RT may also be used after orchiectomy for men with non-bulky stage II seminoma. However, there are potential risks of RT, including impaired fertility, second malignancy, or late cardiac disease (see "Radiation therapy side effects" below). For these reasons, RT is usually reserved for older men, men who could not tolerate chemotherapy, and men who are not good candidates for surveillance.
Surveillance — In some cases, men with small stage I testicular cancers do not require additional treatment after orchiectomy. However, these men do need to follow up regularly with a healthcare provider to monitor for signs or symptoms of relapse. This approach is called surveillance.
Surveillance is only appropriate for men who are motivated to participate in their care and willing to have follow up over a period of years. Men who are not able or willing to undergo this active surveillance may require additional treatment with either radiation therapy or chemotherapy (see "Seminoma" below). During surveillance, men are usually seen every few months for a physical examination, blood tests, and imaging studies (eg, CT scan of the abdomen and pelvis, chest x-ray). This schedule is recommended for the first three to four years, and then visits may become less frequent (eg, twice per year for several years, and then once per year until at least 10 years after diagnosis).
Recommendations
Seminoma — In general, seminomas grow slowly and do not spread rapidly to other areas of the body. About 80 percent of men have an early stage of cancer that is only in the testicle, and about 15 percent have cancer that metastasizes to the retroperitoneal lymph nodes.
Surgery (radical inguinal orchiectomy) is recommended for all men with early stage seminoma. Following surgery, three treatment options are possible, all of which have a cure rate of approximately 98 percent. Treatment options include surveillance (watchful waiting), radiation therapy, and chemotherapy. Retroperitoneal lymph node dissection is used in some situations after chemotherapy, but is not usually performed initially (see "Lymph node removal" above). A short course of chemotherapy or radiation therapy is sometimes used to treat patients with stage I seminoma who are not candidates for active surveillance.
Not all treatments are suitable for all patients; a physician will work with the patient to determine the most appropriate option based upon the individual's situation.
Nonseminomatous germ cell tumors — Surgery (radical inguinal orchiectomy) is recommended for all men with NSGCT. NSGCTs are not as sensitive to radiation therapy as seminomas. NSGCTs are also more likely to spread through the bloodstream to other areas of the body, such as the liver, lungs, and brain. Treatment with one or two cycles of adjuvant chemotherapy, usually with cisplatin and another chemotherapy agent, has a lower initial relapse rate than RPLND. Overall cure rates are similar to that seen with either careful surveillance or RPLND. Although enthusiasm for chemotherapy has been tempered by concerns about its long-term efficacy and adverse effects, one or two cycles of adjuvant chemotherapy is a reasonable option and is not as toxic as longer course of chemotherapy.
Men with stage II and III NSGCT are generally treated with combination chemotherapy following orchiectomy. Men who have a mass remaining after chemotherapy may require surgery to remove it. Patients who require this type of surgical treatment are best treated at a cancer center that treats a high volume of testicular cancer patients.
TREATMENT SIDE EFFECTS AND COMPLICATIONS — Side effects and complications related to treatment depend upon the type of treatment used and the severity of the disease.
Fertility issues — Testicular cancer frequently occurs in younger men who have not begun or completed having children. Treatment with surgery, radiation, or chemotherapy can reduce or eliminate sperm production, causing infertility. For reasons that are not well understood, up to 50 percent of men with testicular cancer have a low number of sperm, even before treatment.
For these reasons, men preparing to have treatment for testicular cancer should consider storing their sperm for future use. The storage process is called semen cryopreservation, and involves storing semen at very low temperatures. Cryopreservation requires that a man give several samples of semen. Ideally, a semen sample should be collected in a clinician's office after masturbation; if this is not possible, the man may be allowed to collect a sample at home in a sterile laboratory container or chemical-free condom. (See "Patient information: Evaluation of the infertile couple"). If possible, collection should be started before surgical removal of the testicle and before chemotherapy or radiation therapy; this allows the greatest number and healthiest sperm to be stored.
Even men with very low sperm counts (before cancer treatment) should be encouraged to store their sperm. Intracytoplasmic sperm injection (ICSI) is a type of in vitro fertilization (IVF) that requires a very small number of sperm. Approximately 30 percent of ICSI procedures result in a viable pregnancy and delivery of an infant.
Men who are unable to store sperm before treatment may still be able to father a child after treatment, depending upon the type and amount of treatment used. Advances in infertility treatment allow 30 and 60 percent of all men who undergo testicular cancer treatment to father a child. (See "Patient information: Treatment of infertility in men").
Chemotherapy side effects — There are a number of side effects and complications that can develop as a result of chemotherapy. These can be divided into acute side effects (that occur during and shortly after treatment) and long-term risks.
Short-term side effects — Men who undergo chemotherapy can have side effects such as fatigue, hair loss, and nausea or vomiting. Nausea can be prevented or treated with oral or intravenous medications, and hair regrows after treatment is completed. Low blood cell counts can occur in the first few weeks of chemotherapy, which can increase the risk of infection. This generally does not require that the dose or schedule of treatment be changed.
Long-term complications — Chemotherapy can cause serious problems in a number of organ systems within the body, especially when given in combination and if multiple cycles of chemotherapy are required. The type and severity of these problems depends upon the type and dose of chemotherapy. A few of the most common include: Impaired kidney function Damage to nerves, causing pain in the arms and feet or hearing loss Damage to blood vessels in the heart, potentially increasing the risk of cardiovascular disease. This typically occurs many years after treatment is completed. Lung inflammation and scarring
Another serious long-term risk of testicular cancer treatment is the development of a second cancer. This is not a metastasis of the testicular cancer, but is a new cancer that develops in the blood or blood forming organs (leukemia), lung, colon, pancreas, bladder, stomach, or other organ system.
Retroperitoneal lymph node dissection — The most common side effect of RPLND is decreased or absent semen with ejaculation. Advances in surgical techniques with nerve-sparing retroperitoneal lymph node dissection have reduced the incidence of this problem. For those men who do have decreased or absent ejaculatory volume, infertility treatments are available.
Radiation therapy side effects — During radiation therapy, fatigue is common but usually not debilitating. Gastrointestinal effects, including nausea, vomiting, increased stool frequency, and rapid gastric emptying, have been described, but are not typical. Anti-nausea medications may be used for control of nausea and vomiting. Suppression of the bone marrow can occur (potentially causing anemia), but is usually mild. Mild tanning of the treated skin occurs in the weeks after radiation.
POST-TREATMENT MONITORING — Relapses of testicular germ cell tumors usually occur within two years of the end of treatment, although they can occur later. As a result, all patients who have been successfully treated for testicular cancer should be monitored for cancer recurrence with blood tests, x-rays, computed tomography (CT) scans, and other imaging tests. Monitoring is generally more frequent in the first few years after treatment is completed.
Blood tests such as the beta-hCG and the AFP are used to monitor for early signs of a relapse. In 30 to 50 percent of patients who relapse, increases in serum tumor markers are the first sign of cancer relapse. A patient who relapses may have no changes in their tumor markers, and for this reason, the combination of blood testing, CT, and x-ray is recommended.
Stage I follow up — The optimal schedule for posttreatment surveillance is controversial. Most experts recommend frequent monitoring with blood tests and imaging studies (eg, x-ray, CT scan) every few months for the first few years, decreasing to twice per year for several years then once per year for the man's lifetime.
After RPLND — For men who undergo retroperitoneal lymph node dissection (RPLND) for limited stage disease, most experts recommend blood testing for tumor markers and a chest x-ray every few months initially, decreasing to once per year after several years. CT scan of the abdomen and pelvis may be done less frequently because of the decreased risk of retroperitoneal relapse.
Advanced disease follow up — Follow up of men with advanced disease is similar to that of men with stage 1 disease. Follow up does not begin until after the man has a complete response to chemotherapy. More intensive surveillance may be recommended for men who undergo chemotherapy for advanced disease followed by an RPLND.
PROGNOSIS — Patients with stage I, good prognosis disease have an excellent chance for cure when treated appropriately (see "Staging and prognostic classification" above). Patients who have an intermediate or poor prognosis also generally respond well to treatment, and require a more aggressive treatment regimen. Even for those with a poor prognosis, approximately one-half can be cured.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
SUMMARY Testicular cancer occurs when cancer cells develop in one or both of the testicles. Testicles are the male reproductive glands located within the scrotum (show figure 1). The scrotum is a sack of loose skin that hangs below the penis. There are two types of testicular cancer: seminoma and nonseminomatous germ cell tumors (NSGCTs). More than 95 percent of all men diagnosed with testicular cancer can be cured with treatment. Several tests are needed to diagnose testicular cancer. Testing is also needed to determine if cancer has spread to areas outside the testicle. The only way to know for sure if a man has testicular cancer is to remove the testicle. The tests used to diagnose cancer are also used to choose the best treatment. Treatment always requires surgery to remove the testicle that contains cancer. Some men also have lymph nodes (glands) removed at the same time. Some men require treatment with radiation (similar to an x-ray) or chemotherapy (medicine given into a vein) after surgery, depending upon the type of testicular cancer and whether the cancer has spread to other areas. Treatment for testicular cancer often has side effects, including difficulty with sex and infertility (being unable to father a child). Men should discuss these side effects with their doctor before treatment begins. After cancer treatment, men should see their doctor or nurse regularly. These visits are used to monitor for signs that the cancer has returned.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. American Cancer Society
(www.cancer.org)
Lance Armstrong Foundation
(www.laf.org)
National Cancer Institute
(www.cancer.gov)
National Institutes of Health: Clinical Trials
(www.clinicaltrials.gov)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
OncoLink
(www.oncolink.com/index.cfm)
Testicular Cancer Resource Center
(http://tcrc.acor.org)
Clinical Trials Links
(www.cancer.gov/clinicaltrials/ or http://clinicaltrials.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Arai, Y, Kawakita, M, Okada, Y, Yoshida, O. Sexuality and fertility in long-term survivors of testicular cancer. J Clin Oncol 1997; 15:1444.
2. National Cancer Institute. Testicular Cancer (PDQ®): Treatment: Patient Version. December 21, 2004. Available online at www.nci.nih.gov/cancertopics/pdq/treatment/testicular/patient. (Accessed 4/23/07).
3. Amato, RJ, Ro, JY, et al. Risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis. Urology 2004; 63:144.
4. Kondagunta, GV, Bacik, J, Bajorin, D, et al. Etoposide and Cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 2005; 23:9290.
5. American Cancer Society. Testicular cancer. Available online at http://www.cancer.org/docroot/CRI/content/CRI_2_4_7x_CRC_Testicular_Cancer_PDF.asp (Accessed 4/23/07).
Saturday, October 13, 2007
Treatment of localized melanoma
INTRODUCTION — Melanoma is a serious form of skin cancer that starts in the pigment-producing skin cells (melanocytes). Melanoma is the sixth most common cancer in the United States, and incidence rates (the number of melanoma cases diagnosed annually) are increasing faster than for any other cancer. Although the explanation for this is unknown, it may be related to increased recreational sun exposure and global changes such as ozone depletion.
In contrast to other types of skin cancers (eg, squamous cell or basal cell cancers) that usually develop on sun-exposed areas of the body, melanomas can develop anywhere on the skin surface (show figure 1), as well as on the mucous membranes lining the mouth, nose, and genital areas. If left untreated, melanoma can spread (metastasize) to other parts of the body much more frequently than is typical for other types of skin cancers. Fortunately, when detected at an early stage, treatment is often effective in limiting the spread of the disease.
This topic reviews the diagnosis and treatment of localized melanoma. A separate topic is available that discusses the treatment of advanced and metastatic melanoma (See "Patient information: Treatment of advanced or metastatic melanoma").
DIAGNOSIS
Appearance of lesion — Similar to other types of skin cancer, melanoma is diagnosed based upon the appearance of a skin lesion. Melanomas can occur anywhere on the skin surface, but it frequently develops on the back and other areas that may be easy to miss with self-inspection. Abnormal findings can be described with an acronym, ABCDE. A — Asymmetry (one side is different from opposite side) (show picture 1) B — Border irregularities (jagged, uneven edge) (show picture 2) C — Color variegation (ie, different colors within the same region, show picture 3) D — Diameter greater than 6 mm (if larger than a pencil eraser, evaluation recommended) E — Evolution (change) in color, shape, or symptoms over time (show picture 4)
Other abnormal features include inflammation (swelling) and bleeding or crusting. A person who notices any of these changes should make an appointment with a healthcare provider as soon as possible. Referral to a dermatologist (physician who specializes in skin conditions) may be recommended.
Biopsy — To determine if the abnormality is a melanoma, a small piece of the area (or if it is small, the entire area) is removed and examined under a microscope to determine if precancerous or cancerous cells are present.
CLINICAL STAGING — After melanoma is diagnosed, the next step is to determine the clinical stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment.
The American Joint Committee on Cancer has defined a staging system for melanoma that takes into consideration the following characteristics (show table 1): The thickness of the tumor The presence of ulceration (loss of skin) over the surface of the melanoma The presence and extent of tumor involvement of the draining lymphatics and/or "regional" lymph nodes The presence or absence of tumor spread beyond the lymph nodes (distant metastases)
A thorough physical examination, chest X-ray, and blood tests are typically performed to evaluate the possibility of lymph node or distant spread of the tumor.
Additional radiologic examinations (such as a CT scan) may also be recommended, particularly for patients with stage III disease, those with a previous melanoma, and those with signs or symptoms of metastasis. These scan are usually performed after the lymph nodes are evaluated and shown to be involved (see "Evaluating the lymph nodes" below).
Surgery — In most patients, surgery is required to remove (or excise) the entire tumor. Generally, one to two centimeters of normal skin surrounding the lesion must also be removed. This procedure is termed a wide local excision. This decreases the chance that the melanoma will recur at the same site. The amount of normal skin that is removed depends upon the thickness of the melanoma. However, it is rare to remove more than a 2 cm (around 1 inch) margin surrounding the melanoma.
The type of physician (eg, dermatologist or general surgeon) who will perform the surgery depends upon the location and size of the wide local excision. Most procedures are performed as a day surgery in a hospital or surgical center. Most patients are able to go home later the same day.
A dermatologist may be able to perform a wide local excision of small melanomas after the patient receives local anesthesia (numbing medication that is injected under the skin). For larger areas, a general surgeon or surgical oncologist may be needed and sedation may be necessary.
Occasionally, skin grafting may be necessary to promote healing and replace skin that has been removed. In some patients (such as those with a melanoma on the face or neck), it can be difficult to remove a sufficient amount of normal skin to ensure adequate margins. In this case, radiation therapy may be recommended after surgery.
If an enlarged lymph node (or gland) is present, it may be biopsied at the time of the wide local excision. Even if enlarged lymph nodes cannot be detected, the lymph nodes may be evaluated during or after the surgical removal of the melanoma.
Evaluating the lymph nodes — The most common site of melanoma spread is the surrounding lymph nodes (glands). Sometimes, lymph node involvement is obvious or strongly suspected because an enlarged lymph node can be felt. In this case, removal of all the lymph nodes in that lymph node basin (called a therapeutic node dissection) is considered the standard approach. Therapeutic node dissection provides an opportunity to cure the patient, particularly when used in conjunction with adjuvant systemic therapy (see "Adjuvant therapy" below).
In the majority of cases, enlarged lymph nodes are not visible, and the only way to determine if they are affected is to take a sample of the lymph node during surgery. The sample is then examined under a microscope to determine if abnormal cells are present. This is typically accomplished with a surgical technique known as sentinel lymph node (SLN) biopsy.
Sentinel lymph node biopsy — The sentinel lymph node (SLN) technique is based upon the theory that when tumor cells migrate, they spread to one or a few lymph nodes before involving other nodes. Further, these nodes can be identified by injecting a blue dye or radioactive material around the primary tumor before the wide local excision, and then searching for the node that has taken up the dye or the radioactive tracer at the time of surgery. This is known as lymphatic mapping.
Sentinel lymph node biopsy and lymphatic mapping are usually done at the time of the wide local excision. Most procedures are performed in a hospital after the patient is given general anesthesia to induce sleep and prevent pain. The patient may go home later the same day or the following day, after spending one night in the hospital.
The status of this first draining (sentinel) lymph node accurately predicts the status of the remaining regional lymph nodes. Because only one, or at most, a few lymph nodes, are removed at surgery and evaluated by the pathologist, the risk of this procedure is lower and the accuracy is greater than a full lymph node dissection.
The success of SLN biopsy is dependent upon the skill of the surgeon and the other physicians involved with the procedure. For optimal results, intraoperative lymphatic mapping and SLN biopsy requires coordination between a surgeon, nuclear medicine physician, and pathologist to achieve optimal results (see below). If later tests reveal that the cancer has spread to the SLN, a second procedure, termed a completion node dissection, is performed to remove the remaining lymph nodes. If the SLN is negative for tumor involvement, further lymph node dissection is usually not performed since the likelihood of finding tumor involvement is 5 percent or less.
SLN biopsy has become the standard technique for assessing the status of regional lymph nodes and is recommended for staging of most patients with newly diagnosed primary melanomas. However, patients whose melanomas are less than 1 mm in thickness (thin melanomas) may not require SLN, since the likelihood of tumor spread to the regional lymph nodes is less than 10 percent.
In contrast, SLN biopsy may be advised for thin melanomas with other high-risk features, such as ulceration, Clark's level IV or V (the tumor has invaded deeper levels of the skin, show table 1), or if there are significant areas of regression (spontaneous loss of tumor cells).
Clark's levels refer to how deeply the tumor has invaded the skin (show figure 2). Level II: the tumor invades the papillary dermis; level III: the tumor invades to the papillary-reticular dermal interface; level IV: the tumor invades the reticular dermis; level V: the tumor invades subcutaneous tissue.
PATHOLOGIC STAGING — Once the staging work-up is complete, a pathologic disease stage between I and IV is assigned (show table 2). A higher stage indicates more extensive disease. Stage I or IIA disease — The tumor is less than 4 millimeters thick without ulceration, or less than 2 millimeters thick if ulceration is present. This is considered to be localized disease. Surgery alone is curative in 70 to 90 percent of cases. Stage IIB or IIC disease — The tumor is 2.1 to 4 millimeters thick with ulceration, or 4 or more millimeters thick with or without ulceration. This is considered to be localized disease. Patients are at a higher risk of recurrence, even after the tumor has been completely surgically removed. For these patients, adjuvant (additional) therapy is often recommended (see "Adjuvant therapy" below). Stage III disease — There is evidence of melanoma spread in the lymphatic channels surrounding the tumor (called satellites) or nearby lymph nodes. The tumor may be any thickness. Adjuvant therapy is strongly recommended. Stage IV disease — The melanoma has metastasized to more distant locations in the body, which may or may not include the lymph nodes. The tumor may be any thickness. This is referred to as advanced disease. For a full discussion of treatment of advanced disease, see "Patient information: Treatment of advanced or metastatic melanoma").
Based upon the pathologic disease stage, the optimal treatment is chosen. For patients with localized disease who have no evidence of distant metastases, the goals of treatment are: Complete surgical removal of the primary melanoma Evaluation of regional lymph nodes for evidence of tumor involvement Preventing further spread or disease recurrence
ADJUVANT THERAPY — The term adjuvant therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. The objective of adjuvant treatment is to stop or slow the growth of any remaining cancer cells that were not removed during surgery.
Immunotherapy — Interferon alpha (IFN-a) is the agent most commonly used to treat patients with melanoma who are at high risk for recurrence. Research has shown that IFN-a, a form of immunotherapy, can help to decrease the chance of recurrence and increase the patient's chance of survival [3]. Immunotherapy may boost the patient's immune response so that it can more effectively fight the cancer.
Treatment with IFN-a begins after surgery, and may continue for up to twelve months. The best way of administering adjuvant IFN-a is not clear. The following IFN-a regimen is the standard for patients with high-risk melanoma. It includes two parts, which are given for up to 12 months. High dose intravenous therapy (at a dose of 20 MU/m2) five days per week for four weeks. A lower dose of IFN-a (10 MU/m2), is given under the skin (subcutaneously) three times weekly for up to 11 additional months. This injection can be given by the patient or a family member.
Although other regimens and doses have been studied, none has been shown to be as effective as this regimen. Because adjuvant IFN-a therapy helps only a minority of patients at risk for melanoma recurrence and is frequently associated with considerable side effects, patients should be encouraged, whenever possible, to enroll in clinical trials testing adjuvant strategies aimed at improving the outcomes of treatment with IFN-a (see "Clinical trials" below).
Benefits — In the first reported trial [3], benefit from IFN-a seemed to be limited to patients who had lymph node involvement (stage III disease). In this group of patients, there was an approximately two-fold increase in the number of patients who were free of disease recurrence at five years.
However, in subsequent trials, an improvement in recurrence-free survival (approximately 20 to 40 percent better than expected) was seen in patients with a lower risk of disease recurrence (stage IIB) as well [4].
We recommend adjuvant IFN-a therapy as the standard of care for patients with node-positive melanoma, and recommend that it be strongly considered for other patients whose risk of recurrence is estimated to be 30 to 40 percent or more (ie, those with stage IIB and IIC disease, show table 2).
Side effects — The problem with IFN-a is its risk of toxic side effects. Nearly all patients develop some side effects during treatment, although the type and severity are variable. Because patients have differing tolerances for side effects and differing ideas about the importance of quality versus quantity of life, the decision to pursue adjuvant IFN-a is an individual one, especially for patients who have node-negative but otherwise high-risk melanoma.
Side effects may include flu-like symptoms (low grade fever, muscle and joint aches, chills, fatigue), depression, mood changes, a drop in the number of white blood cells, and temporary liver enzyme abnormalities. The majority of these effects can be managed with appropriate supportive care and/or dose reduction. Most adverse reactions are completely reversible when treatment is stopped.
Future directions — Research is ongoing to identify other therapies that are effective in treating melanoma. It is hoped that combining interferon with a melanoma vaccine, radiation therapy, or other agents will yield a form of treatment that is more effective or equally effective and less toxic. As noted above, patients should be encouraged, when possible, to enroll in clinical trials testing different adjuvant strategies (see "Clinical trials" below).
MONITORING
Clinician monitoring — Because melanoma can recur in the same location or in new sites, routine follow-up and monitoring is very important. Seeing a healthcare provider regularly is the most important aspect of follow-up since most recurrences are discovered when the patient is seen and examined at regular intervals after treatment. Blood tests and a chest X-ray may be performed at periodic intervals to evaluate the possibility of distant spread of melanoma, while other imaging studies (eg, CT or PET scans) are usually recommended only if new symptoms or signs develop.
Self-examination — In addition to visits with a healthcare provider, monthly self-examination is recommended to identify any new or changing skin lesions. If a new or changing lesion is detected, contact a healthcare provider to determine if further evaluation is needed. To perform self-examination, stand in an area that is brightly lit. Use a hand-held mirror to examine the face, including the nose, lips, mouth, and ears. Face away from a full-length mirror and hold up the hand-held mirror to see the back of the head, ears, and neck. Examine both sides of the hands and arms, including between the findings and under the fingernails. Use the full-length mirror to examine the undersides and back of the arms and armpits. Examine the neck, chest, and abdomen. Women should lift the breasts to examine underneath. Using both mirrors, examine the shoulders, upper back, and upper arms. Scan the lower back, buttocks (including between the buttocks), and backs of both legs. Sit down, and rest one foot on a chair. Examine the legs, including the ankles, top and bottom of the feet, between the toes, and under the toenails. Switch legs and repeat. Use a hand-held mirror to examine the genitals.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Skin Cancer Foundation
(www.skincancer.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Rivers, JK. Melanoma. Lancet 1996; 347:803.
2. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA 1992; 268:1314.
3. Kirkwood, JM, Strawderman, MH, Ernstoff, MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:7.
4. Kirkwood, JM, Ibrahim, JG, Sosman, JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the gm2-klh/qs-21 vaccine in patients with resected stage iib-iii melanoma: Results of intergroup trial e1694/s9512/c509801. J Clin Oncol 2001; 19:2370.
5. Kirkwood, JM, Bender, C, Agarwala, S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20:3703.
In contrast to other types of skin cancers (eg, squamous cell or basal cell cancers) that usually develop on sun-exposed areas of the body, melanomas can develop anywhere on the skin surface (show figure 1), as well as on the mucous membranes lining the mouth, nose, and genital areas. If left untreated, melanoma can spread (metastasize) to other parts of the body much more frequently than is typical for other types of skin cancers. Fortunately, when detected at an early stage, treatment is often effective in limiting the spread of the disease.
This topic reviews the diagnosis and treatment of localized melanoma. A separate topic is available that discusses the treatment of advanced and metastatic melanoma (See "Patient information: Treatment of advanced or metastatic melanoma").
DIAGNOSIS
Appearance of lesion — Similar to other types of skin cancer, melanoma is diagnosed based upon the appearance of a skin lesion. Melanomas can occur anywhere on the skin surface, but it frequently develops on the back and other areas that may be easy to miss with self-inspection. Abnormal findings can be described with an acronym, ABCDE. A — Asymmetry (one side is different from opposite side) (show picture 1) B — Border irregularities (jagged, uneven edge) (show picture 2) C — Color variegation (ie, different colors within the same region, show picture 3) D — Diameter greater than 6 mm (if larger than a pencil eraser, evaluation recommended) E — Evolution (change) in color, shape, or symptoms over time (show picture 4)
Other abnormal features include inflammation (swelling) and bleeding or crusting. A person who notices any of these changes should make an appointment with a healthcare provider as soon as possible. Referral to a dermatologist (physician who specializes in skin conditions) may be recommended.
Biopsy — To determine if the abnormality is a melanoma, a small piece of the area (or if it is small, the entire area) is removed and examined under a microscope to determine if precancerous or cancerous cells are present.
CLINICAL STAGING — After melanoma is diagnosed, the next step is to determine the clinical stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment.
The American Joint Committee on Cancer has defined a staging system for melanoma that takes into consideration the following characteristics (show table 1): The thickness of the tumor The presence of ulceration (loss of skin) over the surface of the melanoma The presence and extent of tumor involvement of the draining lymphatics and/or "regional" lymph nodes The presence or absence of tumor spread beyond the lymph nodes (distant metastases)
A thorough physical examination, chest X-ray, and blood tests are typically performed to evaluate the possibility of lymph node or distant spread of the tumor.
Additional radiologic examinations (such as a CT scan) may also be recommended, particularly for patients with stage III disease, those with a previous melanoma, and those with signs or symptoms of metastasis. These scan are usually performed after the lymph nodes are evaluated and shown to be involved (see "Evaluating the lymph nodes" below).
Surgery — In most patients, surgery is required to remove (or excise) the entire tumor. Generally, one to two centimeters of normal skin surrounding the lesion must also be removed. This procedure is termed a wide local excision. This decreases the chance that the melanoma will recur at the same site. The amount of normal skin that is removed depends upon the thickness of the melanoma. However, it is rare to remove more than a 2 cm (around 1 inch) margin surrounding the melanoma.
The type of physician (eg, dermatologist or general surgeon) who will perform the surgery depends upon the location and size of the wide local excision. Most procedures are performed as a day surgery in a hospital or surgical center. Most patients are able to go home later the same day.
A dermatologist may be able to perform a wide local excision of small melanomas after the patient receives local anesthesia (numbing medication that is injected under the skin). For larger areas, a general surgeon or surgical oncologist may be needed and sedation may be necessary.
Occasionally, skin grafting may be necessary to promote healing and replace skin that has been removed. In some patients (such as those with a melanoma on the face or neck), it can be difficult to remove a sufficient amount of normal skin to ensure adequate margins. In this case, radiation therapy may be recommended after surgery.
If an enlarged lymph node (or gland) is present, it may be biopsied at the time of the wide local excision. Even if enlarged lymph nodes cannot be detected, the lymph nodes may be evaluated during or after the surgical removal of the melanoma.
Evaluating the lymph nodes — The most common site of melanoma spread is the surrounding lymph nodes (glands). Sometimes, lymph node involvement is obvious or strongly suspected because an enlarged lymph node can be felt. In this case, removal of all the lymph nodes in that lymph node basin (called a therapeutic node dissection) is considered the standard approach. Therapeutic node dissection provides an opportunity to cure the patient, particularly when used in conjunction with adjuvant systemic therapy (see "Adjuvant therapy" below).
In the majority of cases, enlarged lymph nodes are not visible, and the only way to determine if they are affected is to take a sample of the lymph node during surgery. The sample is then examined under a microscope to determine if abnormal cells are present. This is typically accomplished with a surgical technique known as sentinel lymph node (SLN) biopsy.
Sentinel lymph node biopsy — The sentinel lymph node (SLN) technique is based upon the theory that when tumor cells migrate, they spread to one or a few lymph nodes before involving other nodes. Further, these nodes can be identified by injecting a blue dye or radioactive material around the primary tumor before the wide local excision, and then searching for the node that has taken up the dye or the radioactive tracer at the time of surgery. This is known as lymphatic mapping.
Sentinel lymph node biopsy and lymphatic mapping are usually done at the time of the wide local excision. Most procedures are performed in a hospital after the patient is given general anesthesia to induce sleep and prevent pain. The patient may go home later the same day or the following day, after spending one night in the hospital.
The status of this first draining (sentinel) lymph node accurately predicts the status of the remaining regional lymph nodes. Because only one, or at most, a few lymph nodes, are removed at surgery and evaluated by the pathologist, the risk of this procedure is lower and the accuracy is greater than a full lymph node dissection.
The success of SLN biopsy is dependent upon the skill of the surgeon and the other physicians involved with the procedure. For optimal results, intraoperative lymphatic mapping and SLN biopsy requires coordination between a surgeon, nuclear medicine physician, and pathologist to achieve optimal results (see below). If later tests reveal that the cancer has spread to the SLN, a second procedure, termed a completion node dissection, is performed to remove the remaining lymph nodes. If the SLN is negative for tumor involvement, further lymph node dissection is usually not performed since the likelihood of finding tumor involvement is 5 percent or less.
SLN biopsy has become the standard technique for assessing the status of regional lymph nodes and is recommended for staging of most patients with newly diagnosed primary melanomas. However, patients whose melanomas are less than 1 mm in thickness (thin melanomas) may not require SLN, since the likelihood of tumor spread to the regional lymph nodes is less than 10 percent.
In contrast, SLN biopsy may be advised for thin melanomas with other high-risk features, such as ulceration, Clark's level IV or V (the tumor has invaded deeper levels of the skin, show table 1), or if there are significant areas of regression (spontaneous loss of tumor cells).
Clark's levels refer to how deeply the tumor has invaded the skin (show figure 2). Level II: the tumor invades the papillary dermis; level III: the tumor invades to the papillary-reticular dermal interface; level IV: the tumor invades the reticular dermis; level V: the tumor invades subcutaneous tissue.
PATHOLOGIC STAGING — Once the staging work-up is complete, a pathologic disease stage between I and IV is assigned (show table 2). A higher stage indicates more extensive disease. Stage I or IIA disease — The tumor is less than 4 millimeters thick without ulceration, or less than 2 millimeters thick if ulceration is present. This is considered to be localized disease. Surgery alone is curative in 70 to 90 percent of cases. Stage IIB or IIC disease — The tumor is 2.1 to 4 millimeters thick with ulceration, or 4 or more millimeters thick with or without ulceration. This is considered to be localized disease. Patients are at a higher risk of recurrence, even after the tumor has been completely surgically removed. For these patients, adjuvant (additional) therapy is often recommended (see "Adjuvant therapy" below). Stage III disease — There is evidence of melanoma spread in the lymphatic channels surrounding the tumor (called satellites) or nearby lymph nodes. The tumor may be any thickness. Adjuvant therapy is strongly recommended. Stage IV disease — The melanoma has metastasized to more distant locations in the body, which may or may not include the lymph nodes. The tumor may be any thickness. This is referred to as advanced disease. For a full discussion of treatment of advanced disease, see "Patient information: Treatment of advanced or metastatic melanoma").
Based upon the pathologic disease stage, the optimal treatment is chosen. For patients with localized disease who have no evidence of distant metastases, the goals of treatment are: Complete surgical removal of the primary melanoma Evaluation of regional lymph nodes for evidence of tumor involvement Preventing further spread or disease recurrence
ADJUVANT THERAPY — The term adjuvant therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. The objective of adjuvant treatment is to stop or slow the growth of any remaining cancer cells that were not removed during surgery.
Immunotherapy — Interferon alpha (IFN-a) is the agent most commonly used to treat patients with melanoma who are at high risk for recurrence. Research has shown that IFN-a, a form of immunotherapy, can help to decrease the chance of recurrence and increase the patient's chance of survival [3]. Immunotherapy may boost the patient's immune response so that it can more effectively fight the cancer.
Treatment with IFN-a begins after surgery, and may continue for up to twelve months. The best way of administering adjuvant IFN-a is not clear. The following IFN-a regimen is the standard for patients with high-risk melanoma. It includes two parts, which are given for up to 12 months. High dose intravenous therapy (at a dose of 20 MU/m2) five days per week for four weeks. A lower dose of IFN-a (10 MU/m2), is given under the skin (subcutaneously) three times weekly for up to 11 additional months. This injection can be given by the patient or a family member.
Although other regimens and doses have been studied, none has been shown to be as effective as this regimen. Because adjuvant IFN-a therapy helps only a minority of patients at risk for melanoma recurrence and is frequently associated with considerable side effects, patients should be encouraged, whenever possible, to enroll in clinical trials testing adjuvant strategies aimed at improving the outcomes of treatment with IFN-a (see "Clinical trials" below).
Benefits — In the first reported trial [3], benefit from IFN-a seemed to be limited to patients who had lymph node involvement (stage III disease). In this group of patients, there was an approximately two-fold increase in the number of patients who were free of disease recurrence at five years.
However, in subsequent trials, an improvement in recurrence-free survival (approximately 20 to 40 percent better than expected) was seen in patients with a lower risk of disease recurrence (stage IIB) as well [4].
We recommend adjuvant IFN-a therapy as the standard of care for patients with node-positive melanoma, and recommend that it be strongly considered for other patients whose risk of recurrence is estimated to be 30 to 40 percent or more (ie, those with stage IIB and IIC disease, show table 2).
Side effects — The problem with IFN-a is its risk of toxic side effects. Nearly all patients develop some side effects during treatment, although the type and severity are variable. Because patients have differing tolerances for side effects and differing ideas about the importance of quality versus quantity of life, the decision to pursue adjuvant IFN-a is an individual one, especially for patients who have node-negative but otherwise high-risk melanoma.
Side effects may include flu-like symptoms (low grade fever, muscle and joint aches, chills, fatigue), depression, mood changes, a drop in the number of white blood cells, and temporary liver enzyme abnormalities. The majority of these effects can be managed with appropriate supportive care and/or dose reduction. Most adverse reactions are completely reversible when treatment is stopped.
Future directions — Research is ongoing to identify other therapies that are effective in treating melanoma. It is hoped that combining interferon with a melanoma vaccine, radiation therapy, or other agents will yield a form of treatment that is more effective or equally effective and less toxic. As noted above, patients should be encouraged, when possible, to enroll in clinical trials testing different adjuvant strategies (see "Clinical trials" below).
MONITORING
Clinician monitoring — Because melanoma can recur in the same location or in new sites, routine follow-up and monitoring is very important. Seeing a healthcare provider regularly is the most important aspect of follow-up since most recurrences are discovered when the patient is seen and examined at regular intervals after treatment. Blood tests and a chest X-ray may be performed at periodic intervals to evaluate the possibility of distant spread of melanoma, while other imaging studies (eg, CT or PET scans) are usually recommended only if new symptoms or signs develop.
Self-examination — In addition to visits with a healthcare provider, monthly self-examination is recommended to identify any new or changing skin lesions. If a new or changing lesion is detected, contact a healthcare provider to determine if further evaluation is needed. To perform self-examination, stand in an area that is brightly lit. Use a hand-held mirror to examine the face, including the nose, lips, mouth, and ears. Face away from a full-length mirror and hold up the hand-held mirror to see the back of the head, ears, and neck. Examine both sides of the hands and arms, including between the findings and under the fingernails. Use the full-length mirror to examine the undersides and back of the arms and armpits. Examine the neck, chest, and abdomen. Women should lift the breasts to examine underneath. Using both mirrors, examine the shoulders, upper back, and upper arms. Scan the lower back, buttocks (including between the buttocks), and backs of both legs. Sit down, and rest one foot on a chair. Examine the legs, including the ankles, top and bottom of the feet, between the toes, and under the toenails. Switch legs and repeat. Use a hand-held mirror to examine the genitals.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Skin Cancer Foundation
(www.skincancer.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Rivers, JK. Melanoma. Lancet 1996; 347:803.
2. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA 1992; 268:1314.
3. Kirkwood, JM, Strawderman, MH, Ernstoff, MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:7.
4. Kirkwood, JM, Ibrahim, JG, Sosman, JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the gm2-klh/qs-21 vaccine in patients with resected stage iib-iii melanoma: Results of intergroup trial e1694/s9512/c509801. J Clin Oncol 2001; 19:2370.
5. Kirkwood, JM, Bender, C, Agarwala, S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20:3703.
Treatment of localized melanoma
INTRODUCTION — Melanoma is a serious form of skin cancer that starts in the pigment-producing skin cells (melanocytes). Melanoma is the sixth most common cancer in the United States, and incidence rates (the number of melanoma cases diagnosed annually) are increasing faster than for any other cancer. Although the explanation for this is unknown, it may be related to increased recreational sun exposure and global changes such as ozone depletion.
In contrast to other types of skin cancers (eg, squamous cell or basal cell cancers) that usually develop on sun-exposed areas of the body, melanomas can develop anywhere on the skin surface (show figure 1), as well as on the mucous membranes lining the mouth, nose, and genital areas. If left untreated, melanoma can spread (metastasize) to other parts of the body much more frequently than is typical for other types of skin cancers. Fortunately, when detected at an early stage, treatment is often effective in limiting the spread of the disease.
This topic reviews the diagnosis and treatment of localized melanoma. A separate topic is available that discusses the treatment of advanced and metastatic melanoma (See "Patient information: Treatment of advanced or metastatic melanoma").
DIAGNOSIS
Appearance of lesion — Similar to other types of skin cancer, melanoma is diagnosed based upon the appearance of a skin lesion. Melanomas can occur anywhere on the skin surface, but it frequently develops on the back and other areas that may be easy to miss with self-inspection. Abnormal findings can be described with an acronym, ABCDE. A — Asymmetry (one side is different from opposite side) (show picture 1) B — Border irregularities (jagged, uneven edge) (show picture 2) C — Color variegation (ie, different colors within the same region, show picture 3) D — Diameter greater than 6 mm (if larger than a pencil eraser, evaluation recommended) E — Evolution (change) in color, shape, or symptoms over time (show picture 4)
Other abnormal features include inflammation (swelling) and bleeding or crusting. A person who notices any of these changes should make an appointment with a healthcare provider as soon as possible. Referral to a dermatologist (physician who specializes in skin conditions) may be recommended.
Biopsy — To determine if the abnormality is a melanoma, a small piece of the area (or if it is small, the entire area) is removed and examined under a microscope to determine if precancerous or cancerous cells are present.
CLINICAL STAGING — After melanoma is diagnosed, the next step is to determine the clinical stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment.
The American Joint Committee on Cancer has defined a staging system for melanoma that takes into consideration the following characteristics (show table 1): The thickness of the tumor The presence of ulceration (loss of skin) over the surface of the melanoma The presence and extent of tumor involvement of the draining lymphatics and/or "regional" lymph nodes The presence or absence of tumor spread beyond the lymph nodes (distant metastases)
A thorough physical examination, chest X-ray, and blood tests are typically performed to evaluate the possibility of lymph node or distant spread of the tumor.
Additional radiologic examinations (such as a CT scan) may also be recommended, particularly for patients with stage III disease, those with a previous melanoma, and those with signs or symptoms of metastasis. These scan are usually performed after the lymph nodes are evaluated and shown to be involved (see "Evaluating the lymph nodes" below).
Surgery — In most patients, surgery is required to remove (or excise) the entire tumor. Generally, one to two centimeters of normal skin surrounding the lesion must also be removed. This procedure is termed a wide local excision. This decreases the chance that the melanoma will recur at the same site. The amount of normal skin that is removed depends upon the thickness of the melanoma. However, it is rare to remove more than a 2 cm (around 1 inch) margin surrounding the melanoma.
The type of physician (eg, dermatologist or general surgeon) who will perform the surgery depends upon the location and size of the wide local excision. Most procedures are performed as a day surgery in a hospital or surgical center. Most patients are able to go home later the same day.
A dermatologist may be able to perform a wide local excision of small melanomas after the patient receives local anesthesia (numbing medication that is injected under the skin). For larger areas, a general surgeon or surgical oncologist may be needed and sedation may be necessary.
Occasionally, skin grafting may be necessary to promote healing and replace skin that has been removed. In some patients (such as those with a melanoma on the face or neck), it can be difficult to remove a sufficient amount of normal skin to ensure adequate margins. In this case, radiation therapy may be recommended after surgery.
If an enlarged lymph node (or gland) is present, it may be biopsied at the time of the wide local excision. Even if enlarged lymph nodes cannot be detected, the lymph nodes may be evaluated during or after the surgical removal of the melanoma.
Evaluating the lymph nodes — The most common site of melanoma spread is the surrounding lymph nodes (glands). Sometimes, lymph node involvement is obvious or strongly suspected because an enlarged lymph node can be felt. In this case, removal of all the lymph nodes in that lymph node basin (called a therapeutic node dissection) is considered the standard approach. Therapeutic node dissection provides an opportunity to cure the patient, particularly when used in conjunction with adjuvant systemic therapy (see "Adjuvant therapy" below).
In the majority of cases, enlarged lymph nodes are not visible, and the only way to determine if they are affected is to take a sample of the lymph node during surgery. The sample is then examined under a microscope to determine if abnormal cells are present. This is typically accomplished with a surgical technique known as sentinel lymph node (SLN) biopsy.
Sentinel lymph node biopsy — The sentinel lymph node (SLN) technique is based upon the theory that when tumor cells migrate, they spread to one or a few lymph nodes before involving other nodes. Further, these nodes can be identified by injecting a blue dye or radioactive material around the primary tumor before the wide local excision, and then searching for the node that has taken up the dye or the radioactive tracer at the time of surgery. This is known as lymphatic mapping.
Sentinel lymph node biopsy and lymphatic mapping are usually done at the time of the wide local excision. Most procedures are performed in a hospital after the patient is given general anesthesia to induce sleep and prevent pain. The patient may go home later the same day or the following day, after spending one night in the hospital.
The status of this first draining (sentinel) lymph node accurately predicts the status of the remaining regional lymph nodes. Because only one, or at most, a few lymph nodes, are removed at surgery and evaluated by the pathologist, the risk of this procedure is lower and the accuracy is greater than a full lymph node dissection.
The success of SLN biopsy is dependent upon the skill of the surgeon and the other physicians involved with the procedure. For optimal results, intraoperative lymphatic mapping and SLN biopsy requires coordination between a surgeon, nuclear medicine physician, and pathologist to achieve optimal results (see below). If later tests reveal that the cancer has spread to the SLN, a second procedure, termed a completion node dissection, is performed to remove the remaining lymph nodes. If the SLN is negative for tumor involvement, further lymph node dissection is usually not performed since the likelihood of finding tumor involvement is 5 percent or less.
SLN biopsy has become the standard technique for assessing the status of regional lymph nodes and is recommended for staging of most patients with newly diagnosed primary melanomas. However, patients whose melanomas are less than 1 mm in thickness (thin melanomas) may not require SLN, since the likelihood of tumor spread to the regional lymph nodes is less than 10 percent.
In contrast, SLN biopsy may be advised for thin melanomas with other high-risk features, such as ulceration, Clark's level IV or V (the tumor has invaded deeper levels of the skin, show table 1), or if there are significant areas of regression (spontaneous loss of tumor cells).
Clark's levels refer to how deeply the tumor has invaded the skin (show figure 2). Level II: the tumor invades the papillary dermis; level III: the tumor invades to the papillary-reticular dermal interface; level IV: the tumor invades the reticular dermis; level V: the tumor invades subcutaneous tissue.
PATHOLOGIC STAGING — Once the staging work-up is complete, a pathologic disease stage between I and IV is assigned (show table 2). A higher stage indicates more extensive disease. Stage I or IIA disease — The tumor is less than 4 millimeters thick without ulceration, or less than 2 millimeters thick if ulceration is present. This is considered to be localized disease. Surgery alone is curative in 70 to 90 percent of cases. Stage IIB or IIC disease — The tumor is 2.1 to 4 millimeters thick with ulceration, or 4 or more millimeters thick with or without ulceration. This is considered to be localized disease. Patients are at a higher risk of recurrence, even after the tumor has been completely surgically removed. For these patients, adjuvant (additional) therapy is often recommended (see "Adjuvant therapy" below). Stage III disease — There is evidence of melanoma spread in the lymphatic channels surrounding the tumor (called satellites) or nearby lymph nodes. The tumor may be any thickness. Adjuvant therapy is strongly recommended. Stage IV disease — The melanoma has metastasized to more distant locations in the body, which may or may not include the lymph nodes. The tumor may be any thickness. This is referred to as advanced disease. For a full discussion of treatment of advanced disease, see "Patient information: Treatment of advanced or metastatic melanoma").
Based upon the pathologic disease stage, the optimal treatment is chosen. For patients with localized disease who have no evidence of distant metastases, the goals of treatment are: Complete surgical removal of the primary melanoma Evaluation of regional lymph nodes for evidence of tumor involvement Preventing further spread or disease recurrence
ADJUVANT THERAPY — The term adjuvant therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. The objective of adjuvant treatment is to stop or slow the growth of any remaining cancer cells that were not removed during surgery.
Immunotherapy — Interferon alpha (IFN-a) is the agent most commonly used to treat patients with melanoma who are at high risk for recurrence. Research has shown that IFN-a, a form of immunotherapy, can help to decrease the chance of recurrence and increase the patient's chance of survival [3]. Immunotherapy may boost the patient's immune response so that it can more effectively fight the cancer.
Treatment with IFN-a begins after surgery, and may continue for up to twelve months. The best way of administering adjuvant IFN-a is not clear. The following IFN-a regimen is the standard for patients with high-risk melanoma. It includes two parts, which are given for up to 12 months. High dose intravenous therapy (at a dose of 20 MU/m2) five days per week for four weeks. A lower dose of IFN-a (10 MU/m2), is given under the skin (subcutaneously) three times weekly for up to 11 additional months. This injection can be given by the patient or a family member.
Although other regimens and doses have been studied, none has been shown to be as effective as this regimen. Because adjuvant IFN-a therapy helps only a minority of patients at risk for melanoma recurrence and is frequently associated with considerable side effects, patients should be encouraged, whenever possible, to enroll in clinical trials testing adjuvant strategies aimed at improving the outcomes of treatment with IFN-a (see "Clinical trials" below).
Benefits — In the first reported trial [3], benefit from IFN-a seemed to be limited to patients who had lymph node involvement (stage III disease). In this group of patients, there was an approximately two-fold increase in the number of patients who were free of disease recurrence at five years.
However, in subsequent trials, an improvement in recurrence-free survival (approximately 20 to 40 percent better than expected) was seen in patients with a lower risk of disease recurrence (stage IIB) as well [4].
We recommend adjuvant IFN-a therapy as the standard of care for patients with node-positive melanoma, and recommend that it be strongly considered for other patients whose risk of recurrence is estimated to be 30 to 40 percent or more (ie, those with stage IIB and IIC disease, show table 2).
Side effects — The problem with IFN-a is its risk of toxic side effects. Nearly all patients develop some side effects during treatment, although the type and severity are variable. Because patients have differing tolerances for side effects and differing ideas about the importance of quality versus quantity of life, the decision to pursue adjuvant IFN-a is an individual one, especially for patients who have node-negative but otherwise high-risk melanoma.
Side effects may include flu-like symptoms (low grade fever, muscle and joint aches, chills, fatigue), depression, mood changes, a drop in the number of white blood cells, and temporary liver enzyme abnormalities. The majority of these effects can be managed with appropriate supportive care and/or dose reduction. Most adverse reactions are completely reversible when treatment is stopped.
Future directions — Research is ongoing to identify other therapies that are effective in treating melanoma. It is hoped that combining interferon with a melanoma vaccine, radiation therapy, or other agents will yield a form of treatment that is more effective or equally effective and less toxic. As noted above, patients should be encouraged, when possible, to enroll in clinical trials testing different adjuvant strategies (see "Clinical trials" below).
MONITORING
Clinician monitoring — Because melanoma can recur in the same location or in new sites, routine follow-up and monitoring is very important. Seeing a healthcare provider regularly is the most important aspect of follow-up since most recurrences are discovered when the patient is seen and examined at regular intervals after treatment. Blood tests and a chest X-ray may be performed at periodic intervals to evaluate the possibility of distant spread of melanoma, while other imaging studies (eg, CT or PET scans) are usually recommended only if new symptoms or signs develop.
Self-examination — In addition to visits with a healthcare provider, monthly self-examination is recommended to identify any new or changing skin lesions. If a new or changing lesion is detected, contact a healthcare provider to determine if further evaluation is needed. To perform self-examination, stand in an area that is brightly lit. Use a hand-held mirror to examine the face, including the nose, lips, mouth, and ears. Face away from a full-length mirror and hold up the hand-held mirror to see the back of the head, ears, and neck. Examine both sides of the hands and arms, including between the findings and under the fingernails. Use the full-length mirror to examine the undersides and back of the arms and armpits. Examine the neck, chest, and abdomen. Women should lift the breasts to examine underneath. Using both mirrors, examine the shoulders, upper back, and upper arms. Scan the lower back, buttocks (including between the buttocks), and backs of both legs. Sit down, and rest one foot on a chair. Examine the legs, including the ankles, top and bottom of the feet, between the toes, and under the toenails. Switch legs and repeat. Use a hand-held mirror to examine the genitals.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Skin Cancer Foundation
(www.skincancer.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Rivers, JK. Melanoma. Lancet 1996; 347:803.
2. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA 1992; 268:1314.
3. Kirkwood, JM, Strawderman, MH, Ernstoff, MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:7.
4. Kirkwood, JM, Ibrahim, JG, Sosman, JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the gm2-klh/qs-21 vaccine in patients with resected stage iib-iii melanoma: Results of intergroup trial e1694/s9512/c509801. J Clin Oncol 2001; 19:2370.
5. Kirkwood, JM, Bender, C, Agarwala, S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20:3703.
In contrast to other types of skin cancers (eg, squamous cell or basal cell cancers) that usually develop on sun-exposed areas of the body, melanomas can develop anywhere on the skin surface (show figure 1), as well as on the mucous membranes lining the mouth, nose, and genital areas. If left untreated, melanoma can spread (metastasize) to other parts of the body much more frequently than is typical for other types of skin cancers. Fortunately, when detected at an early stage, treatment is often effective in limiting the spread of the disease.
This topic reviews the diagnosis and treatment of localized melanoma. A separate topic is available that discusses the treatment of advanced and metastatic melanoma (See "Patient information: Treatment of advanced or metastatic melanoma").
DIAGNOSIS
Appearance of lesion — Similar to other types of skin cancer, melanoma is diagnosed based upon the appearance of a skin lesion. Melanomas can occur anywhere on the skin surface, but it frequently develops on the back and other areas that may be easy to miss with self-inspection. Abnormal findings can be described with an acronym, ABCDE. A — Asymmetry (one side is different from opposite side) (show picture 1) B — Border irregularities (jagged, uneven edge) (show picture 2) C — Color variegation (ie, different colors within the same region, show picture 3) D — Diameter greater than 6 mm (if larger than a pencil eraser, evaluation recommended) E — Evolution (change) in color, shape, or symptoms over time (show picture 4)
Other abnormal features include inflammation (swelling) and bleeding or crusting. A person who notices any of these changes should make an appointment with a healthcare provider as soon as possible. Referral to a dermatologist (physician who specializes in skin conditions) may be recommended.
Biopsy — To determine if the abnormality is a melanoma, a small piece of the area (or if it is small, the entire area) is removed and examined under a microscope to determine if precancerous or cancerous cells are present.
CLINICAL STAGING — After melanoma is diagnosed, the next step is to determine the clinical stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment.
The American Joint Committee on Cancer has defined a staging system for melanoma that takes into consideration the following characteristics (show table 1): The thickness of the tumor The presence of ulceration (loss of skin) over the surface of the melanoma The presence and extent of tumor involvement of the draining lymphatics and/or "regional" lymph nodes The presence or absence of tumor spread beyond the lymph nodes (distant metastases)
A thorough physical examination, chest X-ray, and blood tests are typically performed to evaluate the possibility of lymph node or distant spread of the tumor.
Additional radiologic examinations (such as a CT scan) may also be recommended, particularly for patients with stage III disease, those with a previous melanoma, and those with signs or symptoms of metastasis. These scan are usually performed after the lymph nodes are evaluated and shown to be involved (see "Evaluating the lymph nodes" below).
Surgery — In most patients, surgery is required to remove (or excise) the entire tumor. Generally, one to two centimeters of normal skin surrounding the lesion must also be removed. This procedure is termed a wide local excision. This decreases the chance that the melanoma will recur at the same site. The amount of normal skin that is removed depends upon the thickness of the melanoma. However, it is rare to remove more than a 2 cm (around 1 inch) margin surrounding the melanoma.
The type of physician (eg, dermatologist or general surgeon) who will perform the surgery depends upon the location and size of the wide local excision. Most procedures are performed as a day surgery in a hospital or surgical center. Most patients are able to go home later the same day.
A dermatologist may be able to perform a wide local excision of small melanomas after the patient receives local anesthesia (numbing medication that is injected under the skin). For larger areas, a general surgeon or surgical oncologist may be needed and sedation may be necessary.
Occasionally, skin grafting may be necessary to promote healing and replace skin that has been removed. In some patients (such as those with a melanoma on the face or neck), it can be difficult to remove a sufficient amount of normal skin to ensure adequate margins. In this case, radiation therapy may be recommended after surgery.
If an enlarged lymph node (or gland) is present, it may be biopsied at the time of the wide local excision. Even if enlarged lymph nodes cannot be detected, the lymph nodes may be evaluated during or after the surgical removal of the melanoma.
Evaluating the lymph nodes — The most common site of melanoma spread is the surrounding lymph nodes (glands). Sometimes, lymph node involvement is obvious or strongly suspected because an enlarged lymph node can be felt. In this case, removal of all the lymph nodes in that lymph node basin (called a therapeutic node dissection) is considered the standard approach. Therapeutic node dissection provides an opportunity to cure the patient, particularly when used in conjunction with adjuvant systemic therapy (see "Adjuvant therapy" below).
In the majority of cases, enlarged lymph nodes are not visible, and the only way to determine if they are affected is to take a sample of the lymph node during surgery. The sample is then examined under a microscope to determine if abnormal cells are present. This is typically accomplished with a surgical technique known as sentinel lymph node (SLN) biopsy.
Sentinel lymph node biopsy — The sentinel lymph node (SLN) technique is based upon the theory that when tumor cells migrate, they spread to one or a few lymph nodes before involving other nodes. Further, these nodes can be identified by injecting a blue dye or radioactive material around the primary tumor before the wide local excision, and then searching for the node that has taken up the dye or the radioactive tracer at the time of surgery. This is known as lymphatic mapping.
Sentinel lymph node biopsy and lymphatic mapping are usually done at the time of the wide local excision. Most procedures are performed in a hospital after the patient is given general anesthesia to induce sleep and prevent pain. The patient may go home later the same day or the following day, after spending one night in the hospital.
The status of this first draining (sentinel) lymph node accurately predicts the status of the remaining regional lymph nodes. Because only one, or at most, a few lymph nodes, are removed at surgery and evaluated by the pathologist, the risk of this procedure is lower and the accuracy is greater than a full lymph node dissection.
The success of SLN biopsy is dependent upon the skill of the surgeon and the other physicians involved with the procedure. For optimal results, intraoperative lymphatic mapping and SLN biopsy requires coordination between a surgeon, nuclear medicine physician, and pathologist to achieve optimal results (see below). If later tests reveal that the cancer has spread to the SLN, a second procedure, termed a completion node dissection, is performed to remove the remaining lymph nodes. If the SLN is negative for tumor involvement, further lymph node dissection is usually not performed since the likelihood of finding tumor involvement is 5 percent or less.
SLN biopsy has become the standard technique for assessing the status of regional lymph nodes and is recommended for staging of most patients with newly diagnosed primary melanomas. However, patients whose melanomas are less than 1 mm in thickness (thin melanomas) may not require SLN, since the likelihood of tumor spread to the regional lymph nodes is less than 10 percent.
In contrast, SLN biopsy may be advised for thin melanomas with other high-risk features, such as ulceration, Clark's level IV or V (the tumor has invaded deeper levels of the skin, show table 1), or if there are significant areas of regression (spontaneous loss of tumor cells).
Clark's levels refer to how deeply the tumor has invaded the skin (show figure 2). Level II: the tumor invades the papillary dermis; level III: the tumor invades to the papillary-reticular dermal interface; level IV: the tumor invades the reticular dermis; level V: the tumor invades subcutaneous tissue.
PATHOLOGIC STAGING — Once the staging work-up is complete, a pathologic disease stage between I and IV is assigned (show table 2). A higher stage indicates more extensive disease. Stage I or IIA disease — The tumor is less than 4 millimeters thick without ulceration, or less than 2 millimeters thick if ulceration is present. This is considered to be localized disease. Surgery alone is curative in 70 to 90 percent of cases. Stage IIB or IIC disease — The tumor is 2.1 to 4 millimeters thick with ulceration, or 4 or more millimeters thick with or without ulceration. This is considered to be localized disease. Patients are at a higher risk of recurrence, even after the tumor has been completely surgically removed. For these patients, adjuvant (additional) therapy is often recommended (see "Adjuvant therapy" below). Stage III disease — There is evidence of melanoma spread in the lymphatic channels surrounding the tumor (called satellites) or nearby lymph nodes. The tumor may be any thickness. Adjuvant therapy is strongly recommended. Stage IV disease — The melanoma has metastasized to more distant locations in the body, which may or may not include the lymph nodes. The tumor may be any thickness. This is referred to as advanced disease. For a full discussion of treatment of advanced disease, see "Patient information: Treatment of advanced or metastatic melanoma").
Based upon the pathologic disease stage, the optimal treatment is chosen. For patients with localized disease who have no evidence of distant metastases, the goals of treatment are: Complete surgical removal of the primary melanoma Evaluation of regional lymph nodes for evidence of tumor involvement Preventing further spread or disease recurrence
ADJUVANT THERAPY — The term adjuvant therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. The objective of adjuvant treatment is to stop or slow the growth of any remaining cancer cells that were not removed during surgery.
Immunotherapy — Interferon alpha (IFN-a) is the agent most commonly used to treat patients with melanoma who are at high risk for recurrence. Research has shown that IFN-a, a form of immunotherapy, can help to decrease the chance of recurrence and increase the patient's chance of survival [3]. Immunotherapy may boost the patient's immune response so that it can more effectively fight the cancer.
Treatment with IFN-a begins after surgery, and may continue for up to twelve months. The best way of administering adjuvant IFN-a is not clear. The following IFN-a regimen is the standard for patients with high-risk melanoma. It includes two parts, which are given for up to 12 months. High dose intravenous therapy (at a dose of 20 MU/m2) five days per week for four weeks. A lower dose of IFN-a (10 MU/m2), is given under the skin (subcutaneously) three times weekly for up to 11 additional months. This injection can be given by the patient or a family member.
Although other regimens and doses have been studied, none has been shown to be as effective as this regimen. Because adjuvant IFN-a therapy helps only a minority of patients at risk for melanoma recurrence and is frequently associated with considerable side effects, patients should be encouraged, whenever possible, to enroll in clinical trials testing adjuvant strategies aimed at improving the outcomes of treatment with IFN-a (see "Clinical trials" below).
Benefits — In the first reported trial [3], benefit from IFN-a seemed to be limited to patients who had lymph node involvement (stage III disease). In this group of patients, there was an approximately two-fold increase in the number of patients who were free of disease recurrence at five years.
However, in subsequent trials, an improvement in recurrence-free survival (approximately 20 to 40 percent better than expected) was seen in patients with a lower risk of disease recurrence (stage IIB) as well [4].
We recommend adjuvant IFN-a therapy as the standard of care for patients with node-positive melanoma, and recommend that it be strongly considered for other patients whose risk of recurrence is estimated to be 30 to 40 percent or more (ie, those with stage IIB and IIC disease, show table 2).
Side effects — The problem with IFN-a is its risk of toxic side effects. Nearly all patients develop some side effects during treatment, although the type and severity are variable. Because patients have differing tolerances for side effects and differing ideas about the importance of quality versus quantity of life, the decision to pursue adjuvant IFN-a is an individual one, especially for patients who have node-negative but otherwise high-risk melanoma.
Side effects may include flu-like symptoms (low grade fever, muscle and joint aches, chills, fatigue), depression, mood changes, a drop in the number of white blood cells, and temporary liver enzyme abnormalities. The majority of these effects can be managed with appropriate supportive care and/or dose reduction. Most adverse reactions are completely reversible when treatment is stopped.
Future directions — Research is ongoing to identify other therapies that are effective in treating melanoma. It is hoped that combining interferon with a melanoma vaccine, radiation therapy, or other agents will yield a form of treatment that is more effective or equally effective and less toxic. As noted above, patients should be encouraged, when possible, to enroll in clinical trials testing different adjuvant strategies (see "Clinical trials" below).
MONITORING
Clinician monitoring — Because melanoma can recur in the same location or in new sites, routine follow-up and monitoring is very important. Seeing a healthcare provider regularly is the most important aspect of follow-up since most recurrences are discovered when the patient is seen and examined at regular intervals after treatment. Blood tests and a chest X-ray may be performed at periodic intervals to evaluate the possibility of distant spread of melanoma, while other imaging studies (eg, CT or PET scans) are usually recommended only if new symptoms or signs develop.
Self-examination — In addition to visits with a healthcare provider, monthly self-examination is recommended to identify any new or changing skin lesions. If a new or changing lesion is detected, contact a healthcare provider to determine if further evaluation is needed. To perform self-examination, stand in an area that is brightly lit. Use a hand-held mirror to examine the face, including the nose, lips, mouth, and ears. Face away from a full-length mirror and hold up the hand-held mirror to see the back of the head, ears, and neck. Examine both sides of the hands and arms, including between the findings and under the fingernails. Use the full-length mirror to examine the undersides and back of the arms and armpits. Examine the neck, chest, and abdomen. Women should lift the breasts to examine underneath. Using both mirrors, examine the shoulders, upper back, and upper arms. Scan the lower back, buttocks (including between the buttocks), and backs of both legs. Sit down, and rest one foot on a chair. Examine the legs, including the ankles, top and bottom of the feet, between the toes, and under the toenails. Switch legs and repeat. Use a hand-held mirror to examine the genitals.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Skin Cancer Foundation
(www.skincancer.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Rivers, JK. Melanoma. Lancet 1996; 347:803.
2. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA 1992; 268:1314.
3. Kirkwood, JM, Strawderman, MH, Ernstoff, MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:7.
4. Kirkwood, JM, Ibrahim, JG, Sosman, JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the gm2-klh/qs-21 vaccine in patients with resected stage iib-iii melanoma: Results of intergroup trial e1694/s9512/c509801. J Clin Oncol 2001; 19:2370.
5. Kirkwood, JM, Bender, C, Agarwala, S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20:3703.
Treatment of advanced or metastatic melanoma
INTRODUCTION — Melanoma is a serious form of skin cancer that develops in the pigment-producing skin cells (melanocytes). Melanoma is the sixth most common cancer in the United States, and the number of melanoma cases diagnosed annually are increasing faster than for any other cancer. Although the explanation for this is unknown, it may be related, at least in part, to increased sun exposure and global changes such as ozone depletion.
After melanoma is diagnosed, the next step is to determine the stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment. Melanoma often starts as a single tumor or lesion (show figure 1). Cancer cells can spread to near-by lymph nodes and distant sites throughout the body. Once it spreads to distant locations, it is called advanced or metastatic melanoma.
This topic review discusses the treatment of stage IV (advanced or metastatic) melanoma. The diagnosis and treatment of localized melanoma is discussed separately. (See "Patient information: Treatment of localized melanoma").
STAGING — The American Joint Committee on Cancer (AJCC) has defined a staging system for melanoma (show table 1). Once the staging work-up is complete, a disease stage between I and IV is assigned, with stage IV meaning that there is more extensive disease (show table 2).
For patients with stage IV disease, the melanoma has spread beyond the local area into other areas or organs. The most common sites of metastases are the skin (subcutaneous tissue, show figure 2) and other soft tissues (including lymph nodes), the lungs, liver, brain, and bone. However, metastasis to organs such as the adrenal glands, spleen and gastrointestinal tract can also occur (show table 3).
TREATMENT — Treatment of advanced metastatic melanoma focuses on shrinking or eliminating the metastatic lesions, preventing further spread of the disease, and ensuring patient comfort. In most cases, it is not possible to completely eliminate the cancer. Depending on the location and extent of the metastases, treatment may involve the use of medical treatments (chemotherapy or immunotherapy), surgery, or radiation therapy.
Chemotherapy and immunotherapy treatments may be given alone or in combination. Most of these treatments must be given into a vein (intravenously) or injected under the skin, although a few can be given in pill form.
Each medication is given over a period of time, often several months or more, depending upon how the patient responds. Patients are monitored for signs of drug toxicity or side effects. Many side effects are temporary and can be managed so that patient discomfort is minimized.
Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal (GI) tract. Effects of chemotherapy on these and other normal tissues result in side effects during treatment.
Dacarbazine (DTIC) — DTIC is considered to be the most active chemotherapy drug for patients with metastatic melanoma. Although tumor shrinkage can be expected in about 20 percent of treated patients, the vast majority of these responses are only partial (that is, the tumor does not disappear entirely) and the average duration of benefit is only four to six months.
DTIC is given into a vein over one hour for five days every three weeks. It is generally well tolerated; nausea and vomiting are the most common side effects. Anti-nausea medications are administered with DTIC to reduce discomfort.
Temozolomide — Temozolomide is medication that is taken by mouth as a capsule. It is usually taken for five days every four weeks. It acts similar to DTIC. Unlike some other treatments, DTIC is able to penetrate into the brain and other structures in the nervous system. For this reason, it is often used to treat patients with metastases to the brain. However, clinical trials of temozolomide have produced mixed results; further study is needed to determine the optimal dose and schedule to temporarily slow or stop the growth of metastases.
Immunotherapy — In contrast to chemotherapy, immunotherapy works with the body's immune system to stop or slow the growth of cancer cells. Because immunotherapy works differently than chemotherapy, it has different side effects. Immunotherapy has less effect on the bone marrow, hair, and lining of the GI tract. However, many immunotherapy agents (eg, interferon alpha or IFNa) cause symptoms similar to the flu, such as low-grade fever, chills, muscle and/or joint aches, and headache.
Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that has been found to help some patients with metastatic melanoma when given in high doses. Although a significant benefit is seen only in a minority of patients, long-term follow-up of patients treated in early high-dose IL-2 trials confirms that the benefit can be long-lasting.
As an example, in an analysis of 270 patients treated in trials with high-dose IL-2 over eight years and followed for an additional 5 years,16 percent (about one in six) of all treated patients had shrinkage in the size of their tumors with treatment. The average duration of benefit was about nine months [2,3]. Sixty percent of those who achieved a complete response (no tumor was present after IL-2 treatment) remained progression-free at seven years. In addition, of the patients who responded to treatment for longer than 30 months, none had progression of their melanoma, suggesting that some patients may actually be "cured".
These encouraging results, although limited to a minority of patients, led to the approval of high dose IL-2 for patients with metastatic melanoma. However, high dose IL-2 can produce serious and toxic side effects and it is generally reserved for patients who are otherwise healthy (with good heart and lung function) who are treated in centers that specialize in this type of treatment.
Interferon alpha — IFNa is an immunotherapy agent that has limited effectiveness when used alone to treat metastatic melanoma; however, it does occasionally produce major tumor regressions, particularly in patients with a small amount of tissue affected by the melanoma. Thus, it is often used as an adjuvant treatment, following surgical removal of affected tissues.
Other treatments — Other medical treatment are being investigated for treatment of advanced and metastatic melanoma. These include monoclonal antibodies (specially formed proteins designed to attack cancer cells), melanoma vaccines, gene therapies, cellular therapies (adoptive immunotherapy) as well as various targeted (those that directly attack the growth of the melanoma) and anti-angiogenic agents (those that shrink the blood vessels of the cancer).
Surgery— Surgery may be recommended to remove the metastatic tumor in patients whose melanoma has spread to a limited or small number of sites. In some patients, surgery can prolong survival, particularly if the patient has a single site of metastasis. However, because metastatic melanoma usually spreads to many different locations, surgery is rarely curative. CT scans and/or PET scans are usually performed prior to surgery to evaluate the full extent of the disease and to help guide the plan for surgical treatment.
Surgery to remove brain metastases may be the best option for patients with a single brain metastasis. It may also be an option for patients with multiple brain metastases if a dominant lesion is present or if all the lesions are located within a single area of the brain.
Surgery can also be effective in relieving discomfort caused by a metastatic tumor, such as tumor in the lungs or brain. This type of surgery is often helpful in reducing symptoms and improving the patient's quality of life.
Whole brain radiation therapy — In some patients, surgery prolong survival, especially if the disease outside of the brain is controlled. A course of whole brain" radiation therapy or stereotactic radiation therapy (see below) to the tumor bed are generally administered after surgery to destroy any cancer cells that may remain in the brain.
Stereotactic radiosurgery — If the metastatic tumor or tumors are located in areas of the brain that cannot be reached by surgery, or if tumors are multiple and small, a procedure called stereotactic radiosurgery may be helpful in slowing or stopping the progression of brain metastases. Radiosurgery does not involve surgery, but instead uses precisely targeted radiation to destroy cancerous tissue. Stereotactic radiosurgery may be followed by a course of whole brain radiation therapy.
SURVIVAL — Modest progress has been made in the treatment of metastatic melanoma over the past decade. With the advent of high dose interleukin-2 (IL-2), it may be possible for a small number of patients to be cured of their disease (show figure 3).
Despite this, the average median survival in patients treated for metastatic disease may be as short as nine months (show figure 4). Because IL-2 treatment can have severe side effects, the risk of undergoing treatment with high dose IL-2 outweighs the small potential benefit for some patients (see "Interleukin-2 (IL-2)" above).
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Elwood, JM, Jopson, J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 1997; 73:198.
2. Atkins, MB, Lotze, MT, Dutcher, JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
3. Atkins, MB, Kunkel, L, Sznol, M, Rosenberg, SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 2000; 6 Suppl 1:S11.
4. Gothelf, A, Mir, LM, Gehl, J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29:371.
5. Crosby, T, Fish, R, Coles, B, Mason, MD. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; :CD001215.
After melanoma is diagnosed, the next step is to determine the stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment. Melanoma often starts as a single tumor or lesion (show figure 1). Cancer cells can spread to near-by lymph nodes and distant sites throughout the body. Once it spreads to distant locations, it is called advanced or metastatic melanoma.
This topic review discusses the treatment of stage IV (advanced or metastatic) melanoma. The diagnosis and treatment of localized melanoma is discussed separately. (See "Patient information: Treatment of localized melanoma").
STAGING — The American Joint Committee on Cancer (AJCC) has defined a staging system for melanoma (show table 1). Once the staging work-up is complete, a disease stage between I and IV is assigned, with stage IV meaning that there is more extensive disease (show table 2).
For patients with stage IV disease, the melanoma has spread beyond the local area into other areas or organs. The most common sites of metastases are the skin (subcutaneous tissue, show figure 2) and other soft tissues (including lymph nodes), the lungs, liver, brain, and bone. However, metastasis to organs such as the adrenal glands, spleen and gastrointestinal tract can also occur (show table 3).
TREATMENT — Treatment of advanced metastatic melanoma focuses on shrinking or eliminating the metastatic lesions, preventing further spread of the disease, and ensuring patient comfort. In most cases, it is not possible to completely eliminate the cancer. Depending on the location and extent of the metastases, treatment may involve the use of medical treatments (chemotherapy or immunotherapy), surgery, or radiation therapy.
Chemotherapy and immunotherapy treatments may be given alone or in combination. Most of these treatments must be given into a vein (intravenously) or injected under the skin, although a few can be given in pill form.
Each medication is given over a period of time, often several months or more, depending upon how the patient responds. Patients are monitored for signs of drug toxicity or side effects. Many side effects are temporary and can be managed so that patient discomfort is minimized.
Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal (GI) tract. Effects of chemotherapy on these and other normal tissues result in side effects during treatment.
Dacarbazine (DTIC) — DTIC is considered to be the most active chemotherapy drug for patients with metastatic melanoma. Although tumor shrinkage can be expected in about 20 percent of treated patients, the vast majority of these responses are only partial (that is, the tumor does not disappear entirely) and the average duration of benefit is only four to six months.
DTIC is given into a vein over one hour for five days every three weeks. It is generally well tolerated; nausea and vomiting are the most common side effects. Anti-nausea medications are administered with DTIC to reduce discomfort.
Temozolomide — Temozolomide is medication that is taken by mouth as a capsule. It is usually taken for five days every four weeks. It acts similar to DTIC. Unlike some other treatments, DTIC is able to penetrate into the brain and other structures in the nervous system. For this reason, it is often used to treat patients with metastases to the brain. However, clinical trials of temozolomide have produced mixed results; further study is needed to determine the optimal dose and schedule to temporarily slow or stop the growth of metastases.
Immunotherapy — In contrast to chemotherapy, immunotherapy works with the body's immune system to stop or slow the growth of cancer cells. Because immunotherapy works differently than chemotherapy, it has different side effects. Immunotherapy has less effect on the bone marrow, hair, and lining of the GI tract. However, many immunotherapy agents (eg, interferon alpha or IFNa) cause symptoms similar to the flu, such as low-grade fever, chills, muscle and/or joint aches, and headache.
Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that has been found to help some patients with metastatic melanoma when given in high doses. Although a significant benefit is seen only in a minority of patients, long-term follow-up of patients treated in early high-dose IL-2 trials confirms that the benefit can be long-lasting.
As an example, in an analysis of 270 patients treated in trials with high-dose IL-2 over eight years and followed for an additional 5 years,16 percent (about one in six) of all treated patients had shrinkage in the size of their tumors with treatment. The average duration of benefit was about nine months [2,3]. Sixty percent of those who achieved a complete response (no tumor was present after IL-2 treatment) remained progression-free at seven years. In addition, of the patients who responded to treatment for longer than 30 months, none had progression of their melanoma, suggesting that some patients may actually be "cured".
These encouraging results, although limited to a minority of patients, led to the approval of high dose IL-2 for patients with metastatic melanoma. However, high dose IL-2 can produce serious and toxic side effects and it is generally reserved for patients who are otherwise healthy (with good heart and lung function) who are treated in centers that specialize in this type of treatment.
Interferon alpha — IFNa is an immunotherapy agent that has limited effectiveness when used alone to treat metastatic melanoma; however, it does occasionally produce major tumor regressions, particularly in patients with a small amount of tissue affected by the melanoma. Thus, it is often used as an adjuvant treatment, following surgical removal of affected tissues.
Other treatments — Other medical treatment are being investigated for treatment of advanced and metastatic melanoma. These include monoclonal antibodies (specially formed proteins designed to attack cancer cells), melanoma vaccines, gene therapies, cellular therapies (adoptive immunotherapy) as well as various targeted (those that directly attack the growth of the melanoma) and anti-angiogenic agents (those that shrink the blood vessels of the cancer).
Surgery— Surgery may be recommended to remove the metastatic tumor in patients whose melanoma has spread to a limited or small number of sites. In some patients, surgery can prolong survival, particularly if the patient has a single site of metastasis. However, because metastatic melanoma usually spreads to many different locations, surgery is rarely curative. CT scans and/or PET scans are usually performed prior to surgery to evaluate the full extent of the disease and to help guide the plan for surgical treatment.
Surgery to remove brain metastases may be the best option for patients with a single brain metastasis. It may also be an option for patients with multiple brain metastases if a dominant lesion is present or if all the lesions are located within a single area of the brain.
Surgery can also be effective in relieving discomfort caused by a metastatic tumor, such as tumor in the lungs or brain. This type of surgery is often helpful in reducing symptoms and improving the patient's quality of life.
Whole brain radiation therapy — In some patients, surgery prolong survival, especially if the disease outside of the brain is controlled. A course of whole brain" radiation therapy or stereotactic radiation therapy (see below) to the tumor bed are generally administered after surgery to destroy any cancer cells that may remain in the brain.
Stereotactic radiosurgery — If the metastatic tumor or tumors are located in areas of the brain that cannot be reached by surgery, or if tumors are multiple and small, a procedure called stereotactic radiosurgery may be helpful in slowing or stopping the progression of brain metastases. Radiosurgery does not involve surgery, but instead uses precisely targeted radiation to destroy cancerous tissue. Stereotactic radiosurgery may be followed by a course of whole brain radiation therapy.
SURVIVAL — Modest progress has been made in the treatment of metastatic melanoma over the past decade. With the advent of high dose interleukin-2 (IL-2), it may be possible for a small number of patients to be cured of their disease (show figure 3).
Despite this, the average median survival in patients treated for metastatic disease may be as short as nine months (show figure 4). Because IL-2 treatment can have severe side effects, the risk of undergoing treatment with high dose IL-2 outweighs the small potential benefit for some patients (see "Interleukin-2 (IL-2)" above).
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Elwood, JM, Jopson, J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 1997; 73:198.
2. Atkins, MB, Lotze, MT, Dutcher, JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
3. Atkins, MB, Kunkel, L, Sznol, M, Rosenberg, SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 2000; 6 Suppl 1:S11.
4. Gothelf, A, Mir, LM, Gehl, J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29:371.
5. Crosby, T, Fish, R, Coles, B, Mason, MD. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; :CD001215.
Treatment of advanced or metastatic melanoma
INTRODUCTION — Melanoma is a serious form of skin cancer that develops in the pigment-producing skin cells (melanocytes). Melanoma is the sixth most common cancer in the United States, and the number of melanoma cases diagnosed annually are increasing faster than for any other cancer. Although the explanation for this is unknown, it may be related, at least in part, to increased sun exposure and global changes such as ozone depletion.
After melanoma is diagnosed, the next step is to determine the stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment. Melanoma often starts as a single tumor or lesion (show figure 1). Cancer cells can spread to near-by lymph nodes and distant sites throughout the body. Once it spreads to distant locations, it is called advanced or metastatic melanoma.
This topic review discusses the treatment of stage IV (advanced or metastatic) melanoma. The diagnosis and treatment of localized melanoma is discussed separately. (See "Patient information: Treatment of localized melanoma").
STAGING — The American Joint Committee on Cancer (AJCC) has defined a staging system for melanoma (show table 1). Once the staging work-up is complete, a disease stage between I and IV is assigned, with stage IV meaning that there is more extensive disease (show table 2).
For patients with stage IV disease, the melanoma has spread beyond the local area into other areas or organs. The most common sites of metastases are the skin (subcutaneous tissue, show figure 2) and other soft tissues (including lymph nodes), the lungs, liver, brain, and bone. However, metastasis to organs such as the adrenal glands, spleen and gastrointestinal tract can also occur (show table 3).
TREATMENT — Treatment of advanced metastatic melanoma focuses on shrinking or eliminating the metastatic lesions, preventing further spread of the disease, and ensuring patient comfort. In most cases, it is not possible to completely eliminate the cancer. Depending on the location and extent of the metastases, treatment may involve the use of medical treatments (chemotherapy or immunotherapy), surgery, or radiation therapy.
Chemotherapy and immunotherapy treatments may be given alone or in combination. Most of these treatments must be given into a vein (intravenously) or injected under the skin, although a few can be given in pill form.
Each medication is given over a period of time, often several months or more, depending upon how the patient responds. Patients are monitored for signs of drug toxicity or side effects. Many side effects are temporary and can be managed so that patient discomfort is minimized.
Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal (GI) tract. Effects of chemotherapy on these and other normal tissues result in side effects during treatment.
Dacarbazine (DTIC) — DTIC is considered to be the most active chemotherapy drug for patients with metastatic melanoma. Although tumor shrinkage can be expected in about 20 percent of treated patients, the vast majority of these responses are only partial (that is, the tumor does not disappear entirely) and the average duration of benefit is only four to six months.
DTIC is given into a vein over one hour for five days every three weeks. It is generally well tolerated; nausea and vomiting are the most common side effects. Anti-nausea medications are administered with DTIC to reduce discomfort.
Temozolomide — Temozolomide is medication that is taken by mouth as a capsule. It is usually taken for five days every four weeks. It acts similar to DTIC. Unlike some other treatments, DTIC is able to penetrate into the brain and other structures in the nervous system. For this reason, it is often used to treat patients with metastases to the brain. However, clinical trials of temozolomide have produced mixed results; further study is needed to determine the optimal dose and schedule to temporarily slow or stop the growth of metastases.
Immunotherapy — In contrast to chemotherapy, immunotherapy works with the body's immune system to stop or slow the growth of cancer cells. Because immunotherapy works differently than chemotherapy, it has different side effects. Immunotherapy has less effect on the bone marrow, hair, and lining of the GI tract. However, many immunotherapy agents (eg, interferon alpha or IFNa) cause symptoms similar to the flu, such as low-grade fever, chills, muscle and/or joint aches, and headache.
Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that has been found to help some patients with metastatic melanoma when given in high doses. Although a significant benefit is seen only in a minority of patients, long-term follow-up of patients treated in early high-dose IL-2 trials confirms that the benefit can be long-lasting.
As an example, in an analysis of 270 patients treated in trials with high-dose IL-2 over eight years and followed for an additional 5 years,16 percent (about one in six) of all treated patients had shrinkage in the size of their tumors with treatment. The average duration of benefit was about nine months [2,3]. Sixty percent of those who achieved a complete response (no tumor was present after IL-2 treatment) remained progression-free at seven years. In addition, of the patients who responded to treatment for longer than 30 months, none had progression of their melanoma, suggesting that some patients may actually be "cured".
These encouraging results, although limited to a minority of patients, led to the approval of high dose IL-2 for patients with metastatic melanoma. However, high dose IL-2 can produce serious and toxic side effects and it is generally reserved for patients who are otherwise healthy (with good heart and lung function) who are treated in centers that specialize in this type of treatment.
Interferon alpha — IFNa is an immunotherapy agent that has limited effectiveness when used alone to treat metastatic melanoma; however, it does occasionally produce major tumor regressions, particularly in patients with a small amount of tissue affected by the melanoma. Thus, it is often used as an adjuvant treatment, following surgical removal of affected tissues.
Other treatments — Other medical treatment are being investigated for treatment of advanced and metastatic melanoma. These include monoclonal antibodies (specially formed proteins designed to attack cancer cells), melanoma vaccines, gene therapies, cellular therapies (adoptive immunotherapy) as well as various targeted (those that directly attack the growth of the melanoma) and anti-angiogenic agents (those that shrink the blood vessels of the cancer).
Surgery— Surgery may be recommended to remove the metastatic tumor in patients whose melanoma has spread to a limited or small number of sites. In some patients, surgery can prolong survival, particularly if the patient has a single site of metastasis. However, because metastatic melanoma usually spreads to many different locations, surgery is rarely curative. CT scans and/or PET scans are usually performed prior to surgery to evaluate the full extent of the disease and to help guide the plan for surgical treatment.
Surgery to remove brain metastases may be the best option for patients with a single brain metastasis. It may also be an option for patients with multiple brain metastases if a dominant lesion is present or if all the lesions are located within a single area of the brain.
Surgery can also be effective in relieving discomfort caused by a metastatic tumor, such as tumor in the lungs or brain. This type of surgery is often helpful in reducing symptoms and improving the patient's quality of life.
Whole brain radiation therapy — In some patients, surgery prolong survival, especially if the disease outside of the brain is controlled. A course of whole brain" radiation therapy or stereotactic radiation therapy (see below) to the tumor bed are generally administered after surgery to destroy any cancer cells that may remain in the brain.
Stereotactic radiosurgery — If the metastatic tumor or tumors are located in areas of the brain that cannot be reached by surgery, or if tumors are multiple and small, a procedure called stereotactic radiosurgery may be helpful in slowing or stopping the progression of brain metastases. Radiosurgery does not involve surgery, but instead uses precisely targeted radiation to destroy cancerous tissue. Stereotactic radiosurgery may be followed by a course of whole brain radiation therapy.
SURVIVAL — Modest progress has been made in the treatment of metastatic melanoma over the past decade. With the advent of high dose interleukin-2 (IL-2), it may be possible for a small number of patients to be cured of their disease (show figure 3).
Despite this, the average median survival in patients treated for metastatic disease may be as short as nine months (show figure 4). Because IL-2 treatment can have severe side effects, the risk of undergoing treatment with high dose IL-2 outweighs the small potential benefit for some patients (see "Interleukin-2 (IL-2)" above).
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Elwood, JM, Jopson, J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 1997; 73:198.
2. Atkins, MB, Lotze, MT, Dutcher, JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
3. Atkins, MB, Kunkel, L, Sznol, M, Rosenberg, SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 2000; 6 Suppl 1:S11.
4. Gothelf, A, Mir, LM, Gehl, J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29:371.
5. Crosby, T, Fish, R, Coles, B, Mason, MD. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; :CD001215.
After melanoma is diagnosed, the next step is to determine the stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment. Melanoma often starts as a single tumor or lesion (show figure 1). Cancer cells can spread to near-by lymph nodes and distant sites throughout the body. Once it spreads to distant locations, it is called advanced or metastatic melanoma.
This topic review discusses the treatment of stage IV (advanced or metastatic) melanoma. The diagnosis and treatment of localized melanoma is discussed separately. (See "Patient information: Treatment of localized melanoma").
STAGING — The American Joint Committee on Cancer (AJCC) has defined a staging system for melanoma (show table 1). Once the staging work-up is complete, a disease stage between I and IV is assigned, with stage IV meaning that there is more extensive disease (show table 2).
For patients with stage IV disease, the melanoma has spread beyond the local area into other areas or organs. The most common sites of metastases are the skin (subcutaneous tissue, show figure 2) and other soft tissues (including lymph nodes), the lungs, liver, brain, and bone. However, metastasis to organs such as the adrenal glands, spleen and gastrointestinal tract can also occur (show table 3).
TREATMENT — Treatment of advanced metastatic melanoma focuses on shrinking or eliminating the metastatic lesions, preventing further spread of the disease, and ensuring patient comfort. In most cases, it is not possible to completely eliminate the cancer. Depending on the location and extent of the metastases, treatment may involve the use of medical treatments (chemotherapy or immunotherapy), surgery, or radiation therapy.
Chemotherapy and immunotherapy treatments may be given alone or in combination. Most of these treatments must be given into a vein (intravenously) or injected under the skin, although a few can be given in pill form.
Each medication is given over a period of time, often several months or more, depending upon how the patient responds. Patients are monitored for signs of drug toxicity or side effects. Many side effects are temporary and can be managed so that patient discomfort is minimized.
Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal (GI) tract. Effects of chemotherapy on these and other normal tissues result in side effects during treatment.
Dacarbazine (DTIC) — DTIC is considered to be the most active chemotherapy drug for patients with metastatic melanoma. Although tumor shrinkage can be expected in about 20 percent of treated patients, the vast majority of these responses are only partial (that is, the tumor does not disappear entirely) and the average duration of benefit is only four to six months.
DTIC is given into a vein over one hour for five days every three weeks. It is generally well tolerated; nausea and vomiting are the most common side effects. Anti-nausea medications are administered with DTIC to reduce discomfort.
Temozolomide — Temozolomide is medication that is taken by mouth as a capsule. It is usually taken for five days every four weeks. It acts similar to DTIC. Unlike some other treatments, DTIC is able to penetrate into the brain and other structures in the nervous system. For this reason, it is often used to treat patients with metastases to the brain. However, clinical trials of temozolomide have produced mixed results; further study is needed to determine the optimal dose and schedule to temporarily slow or stop the growth of metastases.
Immunotherapy — In contrast to chemotherapy, immunotherapy works with the body's immune system to stop or slow the growth of cancer cells. Because immunotherapy works differently than chemotherapy, it has different side effects. Immunotherapy has less effect on the bone marrow, hair, and lining of the GI tract. However, many immunotherapy agents (eg, interferon alpha or IFNa) cause symptoms similar to the flu, such as low-grade fever, chills, muscle and/or joint aches, and headache.
Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that has been found to help some patients with metastatic melanoma when given in high doses. Although a significant benefit is seen only in a minority of patients, long-term follow-up of patients treated in early high-dose IL-2 trials confirms that the benefit can be long-lasting.
As an example, in an analysis of 270 patients treated in trials with high-dose IL-2 over eight years and followed for an additional 5 years,16 percent (about one in six) of all treated patients had shrinkage in the size of their tumors with treatment. The average duration of benefit was about nine months [2,3]. Sixty percent of those who achieved a complete response (no tumor was present after IL-2 treatment) remained progression-free at seven years. In addition, of the patients who responded to treatment for longer than 30 months, none had progression of their melanoma, suggesting that some patients may actually be "cured".
These encouraging results, although limited to a minority of patients, led to the approval of high dose IL-2 for patients with metastatic melanoma. However, high dose IL-2 can produce serious and toxic side effects and it is generally reserved for patients who are otherwise healthy (with good heart and lung function) who are treated in centers that specialize in this type of treatment.
Interferon alpha — IFNa is an immunotherapy agent that has limited effectiveness when used alone to treat metastatic melanoma; however, it does occasionally produce major tumor regressions, particularly in patients with a small amount of tissue affected by the melanoma. Thus, it is often used as an adjuvant treatment, following surgical removal of affected tissues.
Other treatments — Other medical treatment are being investigated for treatment of advanced and metastatic melanoma. These include monoclonal antibodies (specially formed proteins designed to attack cancer cells), melanoma vaccines, gene therapies, cellular therapies (adoptive immunotherapy) as well as various targeted (those that directly attack the growth of the melanoma) and anti-angiogenic agents (those that shrink the blood vessels of the cancer).
Surgery— Surgery may be recommended to remove the metastatic tumor in patients whose melanoma has spread to a limited or small number of sites. In some patients, surgery can prolong survival, particularly if the patient has a single site of metastasis. However, because metastatic melanoma usually spreads to many different locations, surgery is rarely curative. CT scans and/or PET scans are usually performed prior to surgery to evaluate the full extent of the disease and to help guide the plan for surgical treatment.
Surgery to remove brain metastases may be the best option for patients with a single brain metastasis. It may also be an option for patients with multiple brain metastases if a dominant lesion is present or if all the lesions are located within a single area of the brain.
Surgery can also be effective in relieving discomfort caused by a metastatic tumor, such as tumor in the lungs or brain. This type of surgery is often helpful in reducing symptoms and improving the patient's quality of life.
Whole brain radiation therapy — In some patients, surgery prolong survival, especially if the disease outside of the brain is controlled. A course of whole brain" radiation therapy or stereotactic radiation therapy (see below) to the tumor bed are generally administered after surgery to destroy any cancer cells that may remain in the brain.
Stereotactic radiosurgery — If the metastatic tumor or tumors are located in areas of the brain that cannot be reached by surgery, or if tumors are multiple and small, a procedure called stereotactic radiosurgery may be helpful in slowing or stopping the progression of brain metastases. Radiosurgery does not involve surgery, but instead uses precisely targeted radiation to destroy cancerous tissue. Stereotactic radiosurgery may be followed by a course of whole brain radiation therapy.
SURVIVAL — Modest progress has been made in the treatment of metastatic melanoma over the past decade. With the advent of high dose interleukin-2 (IL-2), it may be possible for a small number of patients to be cured of their disease (show figure 3).
Despite this, the average median survival in patients treated for metastatic disease may be as short as nine months (show figure 4). Because IL-2 treatment can have severe side effects, the risk of undergoing treatment with high dose IL-2 outweighs the small potential benefit for some patients (see "Interleukin-2 (IL-2)" above).
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute
(www.melanomacenter.org)
Melanoma Research Foundation
(www.melanoma.org)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Elwood, JM, Jopson, J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 1997; 73:198.
2. Atkins, MB, Lotze, MT, Dutcher, JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
3. Atkins, MB, Kunkel, L, Sznol, M, Rosenberg, SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am 2000; 6 Suppl 1:S11.
4. Gothelf, A, Mir, LM, Gehl, J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29:371.
5. Crosby, T, Fish, R, Coles, B, Mason, MD. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; :CD001215.
Treatment of rectal cancer
INTRODUCTION — The rectum is the section of the gastrointestinal system that connects the colon (large intestine) to the anus, where waste (fecal) matter passes out of the body (show figure 1). Like the colon, the rectum is part of the large intestine, and rectal and colon cancers are often referred to together as colorectal cancers. While the two conditions are part of the same disease process, the treatment of rectal cancer is different from colon cancer because of its unique anatomic location.
Like colon cancer, rectal cancer develops slowly over a period of years. Most cancers begin within a polyp, also called an adenoma. These are small growths of non-cancerous tissue that protrude from the lining of the large intestine. Over time, as these polyps grow, they can become cancerous and begin to invade the layers of tissue that form the wall of the rectum. At this point, they can spread to lymph nodes and to other organs such as the lung and liver, a process called metastasis.
RECTAL CANCER STAGING — Treatment and prognosis (outcome) depend upon the stage of the cancer. Staging of rectal cancer is based upon how far the cancer has penetrated into the wall of the rectum, whether the cancer has spread to lymph nodes located around the rectum, and whether the cancer has spread via the bloodstream to other organs (a situation called distant metastatic spread).
The initial evaluation of a rectal cancer usually involves a colonoscopy (a test in which a flexible tube with a camera is guided through the rectum and the rest of the colon). Abdominal and pelvic CT scans (specialized x-rays), and a chest x-ray are often recommended to look for evidence of cancer spread within the abdominal cavity and/or lungs. Other possible tests include a specialized rectal ultrasound or magnetic resonance imaging (MRI) scan.
The final stage of a rectal cancer is confirmed by the findings during surgery, which is the most accurate way to determine how far the tumor has spread.
There are two staging systems for rectal cancers: The TNM system (tumor, nodes, metastases) is most comonly used (show table 1) Less frequently, a modification of the Dukes system is used (show table 2)
A blood test for carcinoembryonic antigen (CEA, a substance produced by most colorectal cancers that circulates in the blood) should be obtained before a patient has his or her initial surgery. An elevated CEA level that does not return to a normal after surgery may be a sign of persistent disease and requires further evaluation.
RECTAL CANCER TREATMENT — The majority of rectal cancers are treated with a combination of surgery, radiation, and chemotherapy. Surgery alone may be curative for patients with stage I disease. For patients with stage II or III disease (see below), chemotherapy and radiation therapy are typically recommended following surgery (in which case, they are referered to as adjuvant therapy), or in some cases, before surgery (termed neoadjuvant therapy). Patients with stage IV (metastatic) rectal cancer are predominantly treated with chemotherapy, with or without surgery and radiation therapy. (See "Patient information: Treatment of metastatic colorectal cancer").
SURGERY — Regardless of the extent of the disease, surgery has an important role in treating rectal cancer. For patients with tumors that have not spread beyond the rectum ("localized disease"), surgery permits the removal of the cancerous part of the rectum and the associated lymph nodes, and the surgeon can examine the abdominal area directly for signs of cancer spread. Sometimes an operation to remove the cancerous tumor from the rectum is performed even in patients who have metastases (stage IV rectal cancer, show table 1). This is done to prevent bleeding and obstruction of the intestine, two problems that can be caused by an untreated enlarging rectal cancer.
Types of surgery — Surgical treatment for rectal cancer varies according to the extent of tumor involvement and the location of the cancer. For example, some rectal cancers are very small and limited to the surface of the rectal lining while others have grown through the entire rectal wall and are adherent (stuck) to nearby structures and organs, such as the abdominal or pelvic wall, the sacrum, the bladder, or the prostate gland. The extent of surgery that will be needed to remove these two tumors is very different.
In general, there are four types of operations: Transanal excision Low anterior resection (LAR) Abdominoperineal resection (APR) Pelvic exenteration
Most rectal cancers require an open surgical procedure, meaning that an incision is made through the abdominal wall to gain access to the lower intestine so the tumor can be removed (resected). However, some early tumors can be removed without an abdominal incision in a procedure called transanal excision.
Transanal excision — The simplest type of surgery for rectal cancer is done without an abdominal incision by inserting instruments though the anal opening. This method can be used for removing large polyps and for removing tumors that are small and located relatively close to the anus (show figure 1). Most rectal tumors that can be succesfully treated in this way are stage I, and have a favorable appearance when they are examined under the microscope by the pathologist (ie, they are moderately-well or well differentiated rather than poorly differentiated). This means that the tissue forming the tumor is forming or beginning to form normal gland structures.
Superficial rectal cancers (T1, show table 1) are the most suitable for local excision, although selected patients with T2 tumors may be eligible for this approach as well.
When a rectal tumor is removed through a local excision, the tissue will be analyzed under the microscope to determine if further surgery is needed, and whether postoperative (adjuvant) therapy, which usually consists of a combination of radiation and chemotherapy, will or will not be recommended. These treatments are discussed below.
Low anterior resection — If an open approach is needed, the surgeon may be able to remove the tumor while leaving the anus intact if the tumor is located high enough in the rectum. This operation is called a low anterior resection (LAR) and requires an abdominal incision. LAR is used whenever possible in order to preserve rectal function. After removing cancerous tissue, the remaining colon is connected to the lower rectum, or in some cases, the upper anus, and the patient is able to have bowel movements in a normal fashion.
Sometimes, a temporary ileostomy or colostomy (in which the small intestine or colon is brought out to the skin of the abdominal wall allowing passage of the stool into an external bag) is necessary to allow the connected tissues to heal. After six to eight weeks, the ileostomy or colostomy is closed, an external bag is no longer needed to collect the stool, and the patient is able to have bowel movements in a normal fashion (from their anus).
During the LAR procedure, the surgeon will also remove all the lymph nodes (also called lymph glands) associated with the rectum. It is important to remove the lymph nodes when treating cancer because one way that cancer cells travel through the body is by using the lymphatic system. Lymph nodes contain special cells that trap cancer cells, and removing them helps to ensure that cancer cells from the primary tumor in the rectum are not able to spread beyond the lymph nodes. The tissue removed from the lymph nodes will also be examined to help determine whether further treatment is needed after surgery. A sufficient number of lymph nodes must be removed by the surgeon (typically at least 12) so that the pathologist can reliably determine whether nodal spread has occurred or not.
Abdominoperineal resection — Similar to the LAR, an abdominoperineal resection (APR) requires an abdominal incision and also requires an incision to remove the anus. This results in the need for a permanent colostomy (see "Life with a colostomy" below). The APR is used when tumors cannot be completely removed using LAR, most commonly because the tumor is too close to the anus. To remove enough surrounding tissue to ensure that the cancer is completely resected, the surgeon must remove the anus as well (show figure 2). During an APR, the lymph nodes in the vicinity of the rectum are removed, just as in the LAR.
Pelvic exenteration — If a cancer has invaded nearby organs, a more extensive operation may be needed. In this situation, it is often possible for the surgeon to remove a part of certain organs such as the bladder. If the function of these organs cannot be saved because of the extent of tumor involvement, the entire organ may need to be removed. Rarely, all of the tissues and organs within the pelvis (including the bladder, prostate [in men], and/or uterus [in women]), must be removed in order to successfully treat the cancer, a major operation called pelvic exenteration.
Most often, patients undergoing this procedure require a permanent colostomy. If the bladder is removed, the patient may also need a urostomy, an artificial opening on the front of the abdomen that allows urine to leave the body. Pelvic exenteration can cause a number of complications and may not result in a cure due to the widespread nature of the cancer.
For many patients with locally advanced rectal cancer, an alternative to pelvic exenteration is the administration of chemotherapy and radiation therapy before surgery. This can often shrink the tumor, allowing the surgeon to perform an LAR, an APR, or a more extensive operation, depending on how much cancer remains after chemotherapy and radiation therapy. This type of therapy is discussed in more detail below. (See "Preoperative (neoadjuvant) chemotherapy and radiation" below).
BOWEL FUNCTION AFTER SURGERY — Bowel function following rectal cancer surgery depends upon the specific operation that was performed and whether radiation therapy was also used (see below). Following a LAR, many patients experience initial difficulty with bowel control even if the anal sphincter (the valve that controls elimination of stool) has been preserved. You may feel a sense of bowel urgency and need to pass stool frequently. For most patients, bowel function improves over time, but it may not return to presurgery levels.
Patients in whom the connection between the colon and the anus was made very close to the anal opening have very little "rectal reservoir," or room, to store fecal matter before needing to move the bowels. These patients may have an increased frequency of bowel movements and some difficulty with evacuation (emptying the bowels). Sometimes a larger reservoir can be created out of the colon (colonic J Pouch) prior to connecting it to the lower rectum or anus. This provides more space to store fecal matter, and can result in better bowel function.
Life with a colostomy — Having a colostomy can alter a patient's body image, and this may be challenging, both physically and emotionally. However, with education and support about living with a colostomy, it is possible to lead an active life. A team effort that includes the colorectal surgeon, oncologist, and an enterostomal therapy (ET) nurse is vital to counsel and educate a patient and their family before surgery, and also in the care and rehabilitation following the procedure. The United Ostomy Associations of America is also a good source of information and support (www.uoaa.org).
CHEMOTHERAPY AND RADIATION — Chemotherapy and radiation therapy are recommended in addition to surgery for most patients with stage II or III rectal cancer. These treatments improve the likelihood of surviving the cancer. Even when all visible signs of cancer have been removed by the surgeon, between 20 and 50 percent of patients will have a recurrence of their cancer if it is treated with surgery alone.
One reason for this relatively high recurrence rate is that the area of the pelvis in which the rectum is located is a "tight space" and it is often difficult for the surgeon to remove a sufficient amount tissue around the tumor; this means that all of the cancer cells in the surrounding tissue may not be removed. In addition, tiny cancer cells may have "escaped" from the lymph nodes and spread to other organs. The combination of chemotherapy and radiation helps to reduce the chance of recurrence by targeting any remaining cancer cells.
There are two general ways to administer chemotherapy and radiation in patients who have rectal cancer:
Postoperative therapy — Postoperative (adjuvant) therapy is typically recommended for patients who have already undergone surgery. A commonly used treatment protocol (regimen) is as follows [1,2]: Two monthly courses of chemotherapy with the anticancer drug 5-fluorouracil (abbreviated 5-FU) given five days in a row, once per month. This is followed by: Radiation therapy over a five- or six-week period. During this time, a continuous intravenous infusion of 5-FU is administered. This approach requires that patients have a central venous access catheter (often termed a port) surgically inserted into one of the large blood vessels in the chest, and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is very small, battery-operated, and fits into a fanny pack that patients can wear around their waist to allow freedom of movement during therapy. Two further courses of chemotherapy with 5-FU given five days in a row, once per month.
For patients in whom ambulatory infusion pump therapy is not feasible, an alternative method of combining chemotherapy with radiation is to give one large dose (bolus) of 5-FU given into a vein in the arm for three days during the first and last weeks of radiation therapy. However, treatment-related toxic side effects may be greater with this approach [3]
Another increasingly popular alternative is to give a daily oral dose of the drug Xeloda (capecitabine). Although this regimen is more convenient for the patient, it has not yet been proven to be equivalent to therapy with infusional 5-FU.
Benefits — The use of combined chemotherapy and radiation after surgery reduces the risk of dying of rectal cancer by about 30 percent [4]. This benefit is relatively large, and as a result, adjuvant therapy with both chemotherapy and radiation is considered a standard approach in patients following rectal cancer surgery if the tumor involves the lymph nodes (stage III) or has grown through the entire bowel wall (stage II).
Preoperative (neoadjuvant) chemotherapy and radiation — Although often given after surgery, chemotherapy and radiation may be offered to a patient prior to the rectal operation, most commonly if the tumor is large or located low in the rectum. This is called neoadjuvant chemoradiotherapy. The purpose of such an approach is to try to shrink the tumor before the operation is performed.
Research indicates that, compared to the postoperative approach, neoadjuvant chemoradiotherapy provides better local control of the tumor, a twofold higher chance of avoiding a permanent colostomy, and fewer side effects of radiation, with no detrimental impact on survival [5].
The administration of chemotherapy in addition to radiation therapy is critical to the success of the approach. As in the postoperative setting (described above), the most common approach for preoperative chemotherapy and radiation is the administration of continuous intravenous 5-FU with an ambulatory infusion pump during the radiation.
An increasingly popular alternative to infusional 5-FU during radiation is to give a daily dose of oral Xeloda during radiation therapy, largely because it is more convenient for the patient. Although guidelines from the National Comprehensive Cancer Network (NCCN) endorse this approach as an acceptable alternative to infusional 5-FU, no study has shown that long-term outcomes are equivalent. Studies are underway to help answer this question.
Patients who undergo neoadjuvant chemotherapy and radiation therapy should receive an additional six months of chemotherapy alone after surgery. There are several reasonable options, including: Single agent 5-FU alone, given intravenously daily for five days every four weeks Oral therapy with the drug capecitabine (Xeloda®) A combination of 5-FU and leucovorin (with both drugs given once weekly for six of every eight weks) The addition of a third drug (oxaliplatin) to 5-FU and leucovorin (a regimen that is abbreviated FOLFOX)
Side effects — Both radiation and chemotherapy can cause side effects, particularly when used together.
Chemotherapy — The most common side effects with 5-FU are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. When 5-FU is given continuously, it can cause "hand-foot syndrome", which causes soreness, redness and peeling of the skin of the palms and soles of the feet. Supplemental vitamin B6 (also called pyridoxine) may provide benefit in this situation.
Orally active 5-FU derivatives like Xeloda® share the same side effects as intravenous 5-FU, although diarrhea and mucositis is less common with Xeloda® while hand-foot syndrome is somewhat more common.
Most patients tolerate chemotherapy reasonably well and many are able to continue working during treatment, often with a reduced schedule of hours due to fatigue. Hair loss is an uncommon side effect of the chemotherapy drugs used for rectal cancer.
Combined chemotherapy and radiation — Possible side effects of 5-FU and radiation include diarrhea, irritation or inflammation of intestinal tissue leading to a sense of bowel urgency, bleeding and discomfort in passing stool, and skin irritation around the anus.
PROGNOSIS — Each patient with cancer is different, and it is impossible to predict what to expect in the future. Both before and after cancer treatment, it is important to discuss ongoing management, lifestyle changes, and future treatment options.
Prognosis generally depends upon the stage of the cancer at the time that it is removed. Cancer that is identified and treated early has the best prognosis. The likelihood of dying is greater with increasingly advanced cancer. The average five year survival by stage is approximately [6]: Stage I — 66 to 78 percent Stage II — 55 to 62 percent Stage III — 31 to 42 percent
FOLLOW-UP AFTER TREATMENT — The term surveillance refers to the follow-up testing after surgery for colon cancer that is performed to detect a cancer recurrence or a new colorectal cancer. The following are recommendations for posttreatment surveillance (show table 3) [7]. Patients should see their clinician every three to six months for the first three years and then yearly thereafter. A medical history is done to determine if there have been signs or symptoms suggestive of a cancer recurrence. The physical examination should include a rectal examination for patients who have undergone low anterior resection. A blood test for carcinoembryonic antigen (CEA, a substance produced by most colon cancers that circulates in the blood) should be obtained every one to three months in patients with stage II and III disease for at least the first three years after primary resection. An increase in the CEA may be the first sign of a recurrence of the cancer. This is true even if preoperative CEA levels were normal.
The CEA level can help to detect recurrences that might be amenable to further curative surgery. Thus, periodic CEA levels may not be necessary in patients who would not be able to undergo resection for a recurrent cancer. All patients with rectal cancer should undergo a complete colonoscopy either before surgical resection or within a few months after resection. This will exclude polyps and other cancers that may be present in other areas of the colon. (See "Patient information: Colonoscopy").
An additional screening colonoscopy is recommended one year later to evaluate for polyps or new cancers [8]. If none are detected, the next colonoscopy is recommended in three years, and then every five years thereafter. Any symptoms or laboratory values that suggest recurrence require immediate colonoscopy. For patients who have had an abdominopelvic resection, colonoscopy is performed through the colostomy. For patients who have undergone low anterior resection for rectal cancer, flexible sigmoidoscopy (scope examination of just the lower part of the intestine) is recommended every six months for five years for patients who have not received pelvic radiation therapy. Flexible sigmoidoscopy is not needed for patients who have received pelvic radiation therapy. (See "Patient information: Flexible sigmoidoscopy"). The 2005 American Society of Clinical Oncology guidelines suggest that patients with stage II or III should have an annual CT scan of the chest and abdomen for three years. If radiation was not administered, an annual pelvic CT scan is also recommended for the first three years after treatment [7]. As with the CEA levels (see above), CT scans are used to detect recurrences that might be treatable with further surgery. Thus, periodic CT scanning may not be necessary in patients who would not be able to undergo surgery for a recurrent cancer.
If the CEA becomes elevated or the patient develops symptoms that are worrisome (eg, abdominal pain, bloating, inability to pass stools), an abdominal CT is recommended to determine if there are metastases.
The following tests are not necessary for routine surveillance: Testing for microscopic amounts of blood in the stool (guiac or stool cards) Liver function tests (a panel of blood tests) Complete blood count (a blood test) Yearly chest x-ray
OPTIONS FOR RECURRENT CANCER — If a rectal cancer recurs in the area of the rectum, the best therapy is determined by several factors, including what treatments were used previously and where the new cancer is located. Treatment options are similar to those for primary tumors, and include surgery, chemotherapy, radiation therapy.
The treatment of patients with advanced rectal cancer depends upon the extent and location of the tumor involvement. Although the majority of patients cannot be cured by any therapy, some patients with limited involvement may be cured by further surgery. In other cases, chemotherapy is the best option. (See "Patient information: Treatment of metastatic colorectal cancer").
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
IMPLICATIONS FOR THE FAMILY — A diagnosis of rectal cancer can be devastating for the patient and also for their family. The best way to cope with all of these issues varies from person to person and among families. Do not underestimate the importance of good support; it is something that each patient should discuss with their healthcare team.
An important issue for close relatives (siblings, parents, or children) of a person with colorectal cancer is the risk of developing colon cancer themselves. This also applies to family of persons with specific types of polyps, called adenomatous polyps.
Relatives should understand the following information: People who have one first-degree relative (parent, brother, sister, or child) with colorectal cancer or adenomatous polyps at a young age (before the age of 60 years), or two first-degree relatives diagnosed at any age should begin colon cancer screening earlier, typically at age 40, or 10 years younger than the earliest diagnosis in their family, whichever comes first, and screening should be repeated every 5 years. (See "Patient information: Screening for colon cancer"). People who have one first-degree relative (parent, brother, sister, or child) who has experienced colorectal cancer or an adenomatous polyps at age 60 or later should begin screening at age 40, and screening should be repeated as for average risk people. People with a second-degree relative (grandparent, aunt, or uncle) or third-degree relative (great-grandparent or cousin) with colorectal cancer are screened as average-risk people.
Some conditions (such as hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis) are associated with an even higher risk of colonic polyps or cancer in family members, and require more aggressive screening for family members. Patients and their family should discuss these issues with a healthcare provider who is experienced in these areas.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
[1-7,9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444.
2. O'Connell, MJ, Martenson, JA, Wieand, HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion 5-FU with radiation therapy after curative surgery. N Engl J Med 1994; 331:502.
3. Smalley, SR, Benedetti, JK, Williamson, SK, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006; 24:3542.
4. Krook, JE, Moertel, CG, Gunderson, LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324:709.
5. Sauer, R, Becker, H, Hohenberger, W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731.
6. Jessup, JM, Stewart, AK, Menck, HR. The National Cancer Data Base report on patterns of care for adenocarcinoma of the rectum, 1985-95. Cancer 1998; 83:2408.
7. Desch, CE, Benson AB, 3rd, Somerfield, MR, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2005; 23:8512.
8. Rex, DK, Kahi, CJ, Levin, B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2006; 130:1865.
9. Janjan, NA, Khoo, VS, Abbruzzese, J, et al. Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 1999; 44:1027.
Like colon cancer, rectal cancer develops slowly over a period of years. Most cancers begin within a polyp, also called an adenoma. These are small growths of non-cancerous tissue that protrude from the lining of the large intestine. Over time, as these polyps grow, they can become cancerous and begin to invade the layers of tissue that form the wall of the rectum. At this point, they can spread to lymph nodes and to other organs such as the lung and liver, a process called metastasis.
RECTAL CANCER STAGING — Treatment and prognosis (outcome) depend upon the stage of the cancer. Staging of rectal cancer is based upon how far the cancer has penetrated into the wall of the rectum, whether the cancer has spread to lymph nodes located around the rectum, and whether the cancer has spread via the bloodstream to other organs (a situation called distant metastatic spread).
The initial evaluation of a rectal cancer usually involves a colonoscopy (a test in which a flexible tube with a camera is guided through the rectum and the rest of the colon). Abdominal and pelvic CT scans (specialized x-rays), and a chest x-ray are often recommended to look for evidence of cancer spread within the abdominal cavity and/or lungs. Other possible tests include a specialized rectal ultrasound or magnetic resonance imaging (MRI) scan.
The final stage of a rectal cancer is confirmed by the findings during surgery, which is the most accurate way to determine how far the tumor has spread.
There are two staging systems for rectal cancers: The TNM system (tumor, nodes, metastases) is most comonly used (show table 1) Less frequently, a modification of the Dukes system is used (show table 2)
A blood test for carcinoembryonic antigen (CEA, a substance produced by most colorectal cancers that circulates in the blood) should be obtained before a patient has his or her initial surgery. An elevated CEA level that does not return to a normal after surgery may be a sign of persistent disease and requires further evaluation.
RECTAL CANCER TREATMENT — The majority of rectal cancers are treated with a combination of surgery, radiation, and chemotherapy. Surgery alone may be curative for patients with stage I disease. For patients with stage II or III disease (see below), chemotherapy and radiation therapy are typically recommended following surgery (in which case, they are referered to as adjuvant therapy), or in some cases, before surgery (termed neoadjuvant therapy). Patients with stage IV (metastatic) rectal cancer are predominantly treated with chemotherapy, with or without surgery and radiation therapy. (See "Patient information: Treatment of metastatic colorectal cancer").
SURGERY — Regardless of the extent of the disease, surgery has an important role in treating rectal cancer. For patients with tumors that have not spread beyond the rectum ("localized disease"), surgery permits the removal of the cancerous part of the rectum and the associated lymph nodes, and the surgeon can examine the abdominal area directly for signs of cancer spread. Sometimes an operation to remove the cancerous tumor from the rectum is performed even in patients who have metastases (stage IV rectal cancer, show table 1). This is done to prevent bleeding and obstruction of the intestine, two problems that can be caused by an untreated enlarging rectal cancer.
Types of surgery — Surgical treatment for rectal cancer varies according to the extent of tumor involvement and the location of the cancer. For example, some rectal cancers are very small and limited to the surface of the rectal lining while others have grown through the entire rectal wall and are adherent (stuck) to nearby structures and organs, such as the abdominal or pelvic wall, the sacrum, the bladder, or the prostate gland. The extent of surgery that will be needed to remove these two tumors is very different.
In general, there are four types of operations: Transanal excision Low anterior resection (LAR) Abdominoperineal resection (APR) Pelvic exenteration
Most rectal cancers require an open surgical procedure, meaning that an incision is made through the abdominal wall to gain access to the lower intestine so the tumor can be removed (resected). However, some early tumors can be removed without an abdominal incision in a procedure called transanal excision.
Transanal excision — The simplest type of surgery for rectal cancer is done without an abdominal incision by inserting instruments though the anal opening. This method can be used for removing large polyps and for removing tumors that are small and located relatively close to the anus (show figure 1). Most rectal tumors that can be succesfully treated in this way are stage I, and have a favorable appearance when they are examined under the microscope by the pathologist (ie, they are moderately-well or well differentiated rather than poorly differentiated). This means that the tissue forming the tumor is forming or beginning to form normal gland structures.
Superficial rectal cancers (T1, show table 1) are the most suitable for local excision, although selected patients with T2 tumors may be eligible for this approach as well.
When a rectal tumor is removed through a local excision, the tissue will be analyzed under the microscope to determine if further surgery is needed, and whether postoperative (adjuvant) therapy, which usually consists of a combination of radiation and chemotherapy, will or will not be recommended. These treatments are discussed below.
Low anterior resection — If an open approach is needed, the surgeon may be able to remove the tumor while leaving the anus intact if the tumor is located high enough in the rectum. This operation is called a low anterior resection (LAR) and requires an abdominal incision. LAR is used whenever possible in order to preserve rectal function. After removing cancerous tissue, the remaining colon is connected to the lower rectum, or in some cases, the upper anus, and the patient is able to have bowel movements in a normal fashion.
Sometimes, a temporary ileostomy or colostomy (in which the small intestine or colon is brought out to the skin of the abdominal wall allowing passage of the stool into an external bag) is necessary to allow the connected tissues to heal. After six to eight weeks, the ileostomy or colostomy is closed, an external bag is no longer needed to collect the stool, and the patient is able to have bowel movements in a normal fashion (from their anus).
During the LAR procedure, the surgeon will also remove all the lymph nodes (also called lymph glands) associated with the rectum. It is important to remove the lymph nodes when treating cancer because one way that cancer cells travel through the body is by using the lymphatic system. Lymph nodes contain special cells that trap cancer cells, and removing them helps to ensure that cancer cells from the primary tumor in the rectum are not able to spread beyond the lymph nodes. The tissue removed from the lymph nodes will also be examined to help determine whether further treatment is needed after surgery. A sufficient number of lymph nodes must be removed by the surgeon (typically at least 12) so that the pathologist can reliably determine whether nodal spread has occurred or not.
Abdominoperineal resection — Similar to the LAR, an abdominoperineal resection (APR) requires an abdominal incision and also requires an incision to remove the anus. This results in the need for a permanent colostomy (see "Life with a colostomy" below). The APR is used when tumors cannot be completely removed using LAR, most commonly because the tumor is too close to the anus. To remove enough surrounding tissue to ensure that the cancer is completely resected, the surgeon must remove the anus as well (show figure 2). During an APR, the lymph nodes in the vicinity of the rectum are removed, just as in the LAR.
Pelvic exenteration — If a cancer has invaded nearby organs, a more extensive operation may be needed. In this situation, it is often possible for the surgeon to remove a part of certain organs such as the bladder. If the function of these organs cannot be saved because of the extent of tumor involvement, the entire organ may need to be removed. Rarely, all of the tissues and organs within the pelvis (including the bladder, prostate [in men], and/or uterus [in women]), must be removed in order to successfully treat the cancer, a major operation called pelvic exenteration.
Most often, patients undergoing this procedure require a permanent colostomy. If the bladder is removed, the patient may also need a urostomy, an artificial opening on the front of the abdomen that allows urine to leave the body. Pelvic exenteration can cause a number of complications and may not result in a cure due to the widespread nature of the cancer.
For many patients with locally advanced rectal cancer, an alternative to pelvic exenteration is the administration of chemotherapy and radiation therapy before surgery. This can often shrink the tumor, allowing the surgeon to perform an LAR, an APR, or a more extensive operation, depending on how much cancer remains after chemotherapy and radiation therapy. This type of therapy is discussed in more detail below. (See "Preoperative (neoadjuvant) chemotherapy and radiation" below).
BOWEL FUNCTION AFTER SURGERY — Bowel function following rectal cancer surgery depends upon the specific operation that was performed and whether radiation therapy was also used (see below). Following a LAR, many patients experience initial difficulty with bowel control even if the anal sphincter (the valve that controls elimination of stool) has been preserved. You may feel a sense of bowel urgency and need to pass stool frequently. For most patients, bowel function improves over time, but it may not return to presurgery levels.
Patients in whom the connection between the colon and the anus was made very close to the anal opening have very little "rectal reservoir," or room, to store fecal matter before needing to move the bowels. These patients may have an increased frequency of bowel movements and some difficulty with evacuation (emptying the bowels). Sometimes a larger reservoir can be created out of the colon (colonic J Pouch) prior to connecting it to the lower rectum or anus. This provides more space to store fecal matter, and can result in better bowel function.
Life with a colostomy — Having a colostomy can alter a patient's body image, and this may be challenging, both physically and emotionally. However, with education and support about living with a colostomy, it is possible to lead an active life. A team effort that includes the colorectal surgeon, oncologist, and an enterostomal therapy (ET) nurse is vital to counsel and educate a patient and their family before surgery, and also in the care and rehabilitation following the procedure. The United Ostomy Associations of America is also a good source of information and support (www.uoaa.org).
CHEMOTHERAPY AND RADIATION — Chemotherapy and radiation therapy are recommended in addition to surgery for most patients with stage II or III rectal cancer. These treatments improve the likelihood of surviving the cancer. Even when all visible signs of cancer have been removed by the surgeon, between 20 and 50 percent of patients will have a recurrence of their cancer if it is treated with surgery alone.
One reason for this relatively high recurrence rate is that the area of the pelvis in which the rectum is located is a "tight space" and it is often difficult for the surgeon to remove a sufficient amount tissue around the tumor; this means that all of the cancer cells in the surrounding tissue may not be removed. In addition, tiny cancer cells may have "escaped" from the lymph nodes and spread to other organs. The combination of chemotherapy and radiation helps to reduce the chance of recurrence by targeting any remaining cancer cells.
There are two general ways to administer chemotherapy and radiation in patients who have rectal cancer:
Postoperative therapy — Postoperative (adjuvant) therapy is typically recommended for patients who have already undergone surgery. A commonly used treatment protocol (regimen) is as follows [1,2]: Two monthly courses of chemotherapy with the anticancer drug 5-fluorouracil (abbreviated 5-FU) given five days in a row, once per month. This is followed by: Radiation therapy over a five- or six-week period. During this time, a continuous intravenous infusion of 5-FU is administered. This approach requires that patients have a central venous access catheter (often termed a port) surgically inserted into one of the large blood vessels in the chest, and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is very small, battery-operated, and fits into a fanny pack that patients can wear around their waist to allow freedom of movement during therapy. Two further courses of chemotherapy with 5-FU given five days in a row, once per month.
For patients in whom ambulatory infusion pump therapy is not feasible, an alternative method of combining chemotherapy with radiation is to give one large dose (bolus) of 5-FU given into a vein in the arm for three days during the first and last weeks of radiation therapy. However, treatment-related toxic side effects may be greater with this approach [3]
Another increasingly popular alternative is to give a daily oral dose of the drug Xeloda (capecitabine). Although this regimen is more convenient for the patient, it has not yet been proven to be equivalent to therapy with infusional 5-FU.
Benefits — The use of combined chemotherapy and radiation after surgery reduces the risk of dying of rectal cancer by about 30 percent [4]. This benefit is relatively large, and as a result, adjuvant therapy with both chemotherapy and radiation is considered a standard approach in patients following rectal cancer surgery if the tumor involves the lymph nodes (stage III) or has grown through the entire bowel wall (stage II).
Preoperative (neoadjuvant) chemotherapy and radiation — Although often given after surgery, chemotherapy and radiation may be offered to a patient prior to the rectal operation, most commonly if the tumor is large or located low in the rectum. This is called neoadjuvant chemoradiotherapy. The purpose of such an approach is to try to shrink the tumor before the operation is performed.
Research indicates that, compared to the postoperative approach, neoadjuvant chemoradiotherapy provides better local control of the tumor, a twofold higher chance of avoiding a permanent colostomy, and fewer side effects of radiation, with no detrimental impact on survival [5].
The administration of chemotherapy in addition to radiation therapy is critical to the success of the approach. As in the postoperative setting (described above), the most common approach for preoperative chemotherapy and radiation is the administration of continuous intravenous 5-FU with an ambulatory infusion pump during the radiation.
An increasingly popular alternative to infusional 5-FU during radiation is to give a daily dose of oral Xeloda during radiation therapy, largely because it is more convenient for the patient. Although guidelines from the National Comprehensive Cancer Network (NCCN) endorse this approach as an acceptable alternative to infusional 5-FU, no study has shown that long-term outcomes are equivalent. Studies are underway to help answer this question.
Patients who undergo neoadjuvant chemotherapy and radiation therapy should receive an additional six months of chemotherapy alone after surgery. There are several reasonable options, including: Single agent 5-FU alone, given intravenously daily for five days every four weeks Oral therapy with the drug capecitabine (Xeloda®) A combination of 5-FU and leucovorin (with both drugs given once weekly for six of every eight weks) The addition of a third drug (oxaliplatin) to 5-FU and leucovorin (a regimen that is abbreviated FOLFOX)
Side effects — Both radiation and chemotherapy can cause side effects, particularly when used together.
Chemotherapy — The most common side effects with 5-FU are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. When 5-FU is given continuously, it can cause "hand-foot syndrome", which causes soreness, redness and peeling of the skin of the palms and soles of the feet. Supplemental vitamin B6 (also called pyridoxine) may provide benefit in this situation.
Orally active 5-FU derivatives like Xeloda® share the same side effects as intravenous 5-FU, although diarrhea and mucositis is less common with Xeloda® while hand-foot syndrome is somewhat more common.
Most patients tolerate chemotherapy reasonably well and many are able to continue working during treatment, often with a reduced schedule of hours due to fatigue. Hair loss is an uncommon side effect of the chemotherapy drugs used for rectal cancer.
Combined chemotherapy and radiation — Possible side effects of 5-FU and radiation include diarrhea, irritation or inflammation of intestinal tissue leading to a sense of bowel urgency, bleeding and discomfort in passing stool, and skin irritation around the anus.
PROGNOSIS — Each patient with cancer is different, and it is impossible to predict what to expect in the future. Both before and after cancer treatment, it is important to discuss ongoing management, lifestyle changes, and future treatment options.
Prognosis generally depends upon the stage of the cancer at the time that it is removed. Cancer that is identified and treated early has the best prognosis. The likelihood of dying is greater with increasingly advanced cancer. The average five year survival by stage is approximately [6]: Stage I — 66 to 78 percent Stage II — 55 to 62 percent Stage III — 31 to 42 percent
FOLLOW-UP AFTER TREATMENT — The term surveillance refers to the follow-up testing after surgery for colon cancer that is performed to detect a cancer recurrence or a new colorectal cancer. The following are recommendations for posttreatment surveillance (show table 3) [7]. Patients should see their clinician every three to six months for the first three years and then yearly thereafter. A medical history is done to determine if there have been signs or symptoms suggestive of a cancer recurrence. The physical examination should include a rectal examination for patients who have undergone low anterior resection. A blood test for carcinoembryonic antigen (CEA, a substance produced by most colon cancers that circulates in the blood) should be obtained every one to three months in patients with stage II and III disease for at least the first three years after primary resection. An increase in the CEA may be the first sign of a recurrence of the cancer. This is true even if preoperative CEA levels were normal.
The CEA level can help to detect recurrences that might be amenable to further curative surgery. Thus, periodic CEA levels may not be necessary in patients who would not be able to undergo resection for a recurrent cancer. All patients with rectal cancer should undergo a complete colonoscopy either before surgical resection or within a few months after resection. This will exclude polyps and other cancers that may be present in other areas of the colon. (See "Patient information: Colonoscopy").
An additional screening colonoscopy is recommended one year later to evaluate for polyps or new cancers [8]. If none are detected, the next colonoscopy is recommended in three years, and then every five years thereafter. Any symptoms or laboratory values that suggest recurrence require immediate colonoscopy. For patients who have had an abdominopelvic resection, colonoscopy is performed through the colostomy. For patients who have undergone low anterior resection for rectal cancer, flexible sigmoidoscopy (scope examination of just the lower part of the intestine) is recommended every six months for five years for patients who have not received pelvic radiation therapy. Flexible sigmoidoscopy is not needed for patients who have received pelvic radiation therapy. (See "Patient information: Flexible sigmoidoscopy"). The 2005 American Society of Clinical Oncology guidelines suggest that patients with stage II or III should have an annual CT scan of the chest and abdomen for three years. If radiation was not administered, an annual pelvic CT scan is also recommended for the first three years after treatment [7]. As with the CEA levels (see above), CT scans are used to detect recurrences that might be treatable with further surgery. Thus, periodic CT scanning may not be necessary in patients who would not be able to undergo surgery for a recurrent cancer.
If the CEA becomes elevated or the patient develops symptoms that are worrisome (eg, abdominal pain, bloating, inability to pass stools), an abdominal CT is recommended to determine if there are metastases.
The following tests are not necessary for routine surveillance: Testing for microscopic amounts of blood in the stool (guiac or stool cards) Liver function tests (a panel of blood tests) Complete blood count (a blood test) Yearly chest x-ray
OPTIONS FOR RECURRENT CANCER — If a rectal cancer recurs in the area of the rectum, the best therapy is determined by several factors, including what treatments were used previously and where the new cancer is located. Treatment options are similar to those for primary tumors, and include surgery, chemotherapy, radiation therapy.
The treatment of patients with advanced rectal cancer depends upon the extent and location of the tumor involvement. Although the majority of patients cannot be cured by any therapy, some patients with limited involvement may be cured by further surgery. In other cases, chemotherapy is the best option. (See "Patient information: Treatment of metastatic colorectal cancer").
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
IMPLICATIONS FOR THE FAMILY — A diagnosis of rectal cancer can be devastating for the patient and also for their family. The best way to cope with all of these issues varies from person to person and among families. Do not underestimate the importance of good support; it is something that each patient should discuss with their healthcare team.
An important issue for close relatives (siblings, parents, or children) of a person with colorectal cancer is the risk of developing colon cancer themselves. This also applies to family of persons with specific types of polyps, called adenomatous polyps.
Relatives should understand the following information: People who have one first-degree relative (parent, brother, sister, or child) with colorectal cancer or adenomatous polyps at a young age (before the age of 60 years), or two first-degree relatives diagnosed at any age should begin colon cancer screening earlier, typically at age 40, or 10 years younger than the earliest diagnosis in their family, whichever comes first, and screening should be repeated every 5 years. (See "Patient information: Screening for colon cancer"). People who have one first-degree relative (parent, brother, sister, or child) who has experienced colorectal cancer or an adenomatous polyps at age 60 or later should begin screening at age 40, and screening should be repeated as for average risk people. People with a second-degree relative (grandparent, aunt, or uncle) or third-degree relative (great-grandparent or cousin) with colorectal cancer are screened as average-risk people.
Some conditions (such as hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis) are associated with an even higher risk of colonic polyps or cancer in family members, and require more aggressive screening for family members. Patients and their family should discuss these issues with a healthcare provider who is experienced in these areas.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
[1-7,9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444.
2. O'Connell, MJ, Martenson, JA, Wieand, HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion 5-FU with radiation therapy after curative surgery. N Engl J Med 1994; 331:502.
3. Smalley, SR, Benedetti, JK, Williamson, SK, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006; 24:3542.
4. Krook, JE, Moertel, CG, Gunderson, LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324:709.
5. Sauer, R, Becker, H, Hohenberger, W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731.
6. Jessup, JM, Stewart, AK, Menck, HR. The National Cancer Data Base report on patterns of care for adenocarcinoma of the rectum, 1985-95. Cancer 1998; 83:2408.
7. Desch, CE, Benson AB, 3rd, Somerfield, MR, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2005; 23:8512.
8. Rex, DK, Kahi, CJ, Levin, B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2006; 130:1865.
9. Janjan, NA, Khoo, VS, Abbruzzese, J, et al. Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 1999; 44:1027.
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