INTRODUCTION — Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications.
In the United States, about 4 out of 100,000 individuals are diagnosed with MM each year. This condition is slightly more common among men than women, and almost twice as common among blacks as among whites. The average age at diagnosis is 65 to 70 years.
The current treatment options for MM include watchful waiting (for early or smoldering multiple myeloma), chemotherapy, immune-modulating drugs, and stem cell transplantation. Multiple myeloma is seldom cured, but treatment can relieve symptoms, induce remission, and prolong life.
The cause of MM is unknown. Exposure to radiation, organic chemicals (such as benzene), herbicides, and insecticides may play a role. Genetic factors and viral infection may also influence the risk of developing multiple myeloma.
FEATURES — Multiple myeloma can produce a wide variety of symptoms.
Bone symptoms — Most individuals develop bone pain in the back or chest or, less commonly, the arms and legs, at the time of diagnosis. The pain is usually triggered by movement and is absent at night, except when changing positions.
MM causes both generalized bone loss throughout the body as well as bone erosions (lytic lesions on x-ray) in specific areas. The bone loss and erosions can lead to osteoporosis and fractures. Many individuals with multiple myeloma experience fractures of the vertebrae (the bones of the spine), which can lead to a loss of height; about 30 percent of individuals experience fractures in other bones, often with little or no preceding trauma. For this reason they are called "pathologic fractures."
High blood calcium levels — Because bones contain large amounts of calcium, the breakdown of bone in MM can lead to high blood calcium levels (called hypercalcemia). High blood calcium levels occur in 10 to 15 percent of individuals, and the symptoms may include loss of appetite, nausea, vomiting, frequent urination, increased thirst, constipation, weakness, confusion, stupor, or coma.
Anemia — About two thirds of individuals have anemia (low red cell count) at the time of diagnosis, and anemia eventually occurs in almost all individuals. The signs and symptoms of anemia include paleness, weakness, and fatigue.
Impaired kidney function — The excess proteins and high blood calcium levels associated with MM can damage the kidneys. Kidney function is abnormal at diagnosis in about half of individuals with multiple myeloma. Occasionally, kidney failure is the first symptom of MM.
Thickened blood — The excessive production of proteins by the malignant plasma cells in MM can cause a thickening of the blood (called hyperviscosity syndrome). The symptoms may include bleeding from the nose and mouth, blurred vision, neurologic symptoms, and congestive heart failure.
Neurologic symptoms — Fractures of the vertebrae can lead to increased pressure on the nerve roots where they exit the spine, causing neurologic symptoms (called radiculopathy). This complication of multiple myeloma most commonly affects the chest, lower back, or legs, and the symptoms may include odd sensations (numbness or tingling), pain, or muscle weakness.
Occasionally, neurologic symptoms occur because plasma cells grow within the spinal canal and press on the spinal cord. The symptoms may include severe back pain, muscle weakness, especially of the legs, numbness or tingling, and loss of control of bowel or bladder function (incontinence). Spinal cord compression is a medical emergency and requires immediate treatment to relieve the pressure and prevent permanent damage.
Generalized symptoms — The generalized symptoms of MM include an increased susceptibility to infections (especially during chemotherapy) and weight loss. Occasionally, it causes increased bleeding or tumors of the ribs. In individuals with advanced MM, tumor cells may accumulate beneath the skin, causing large purple-colored bumps.
DIAGNOSTIC TESTING — The diagnosis of MM is based upon the presence of characteristic signs and symptoms of the disease and on the results of tests of the blood and bone marrow. Several different tests are used to determine the presence and severity of MM. In some individuals with early MM or related conditions, it may be necessary to repeat these tests periodically until the diagnosis is certain.
After MM is confirmed, additional tests are used to check for the presence of impaired kidney function, anemia, thickening of the blood, and other complications of multiple myeloma.
Blood and urine tests for monoclonal protein — An abnormal protein produced by the plasma cells, called a monoclonal (M) protein (sometimes called a "paraprotein"), can be found in the blood or urine of almost all patients with MM, which helps establish the diagnosis. These proteins serve no useful function, and may be responsible for increases in the thickness of the blood, kidney damage, or bleeding problems.
However, it is important to remember that not everyone with a monoclonal protein has MM. The diagnosis requires, in addition to the monoclonal protein, one or more abnormalities such as anemia, bone lesions (see "X-rays" below), kidney failure, or high calcium levels in the blood (see "Criteria for diagnosis" below).
Bone marrow examination — In most individuals with MM, a bone marrow aspiration and biopsy (a collection of a small sample of bone marrow for laboratory analysis, usually taken from the hip) shows that plasma cells comprise an abnormally high percentage of bone marrow cells (more than 10 percent). It may be necessary to collect samples from different areas because MM may affect the marrow of some bones but not others.
X-rays — In about 80 percent of individuals, routine x-rays show distinct, round (lytic) areas of bone erosion; generalized thinning of the bones; and/or fractures at the time of diagnosis. The bones most commonly involved are the vertebrae, the ribs, the pelvic bones, and the bones of the thigh and upper arm.
Genetic and chromosomal tests — Specialized tests may reveal genetic or chromosomal abnormalities of the plasma cells in individuals with MM. In general, such abnormalities are associated with a poorer prognosis. The results of these tests are helpful for predicting the response to treatment and survival.
Plasma cell labeling index — The plasma cell labeling index determines how rapidly the abnormal plasma cells are growing and dividing. Patients in whom the labeling index is low tend to have slower disease progression than those with high values. This test is also useful for distinguishing MM from related conditions that generally have a better prognosis. A normal plasma cell labeling index suggests that MM is less likely, while an elevated index suggests that multiple myeloma is more likely. However, this test is not generally available.
Criteria for diagnosis — The diagnosis of multiple myeloma requires the following: A bone marrow aspirate or biopsy showing that at least 10 percent of the cells are plasma cells or the presence of a plasma cell tumor (called a plasmacytoma), plus: M protein in the blood or urine, or Evidence of damage to the body as a result of the plasma cell growth, such as destructive bone lesions, kidney failure, anemia, or high calcium in the blood.
STAGING AND PROGNOSIS — The simplest measure of prognosis in MM is based on blood levels of two markers: beta-2-microglobulin and albumin. In general, higher levels of beta-2-microglobulin and lower levels of albumin are associated with a poorer prognosis. This staging system is referred to as the International Staging System, or ISS.
The older Durie-Salmon staging system divided patients into three stages: Stages I, II, and III, corresponding to low, intermediate, and high cell mass, depending on such factors as the degree of anemia, calcium level, kidney function, presence or absence of bone lesions, and the amount of the abnormal protein. It is best used as a measure of the overall amounts of malignant plasma cells present in the patient, and is less useful as a measure of prognosis.
TREATMENT OVERVIEW — The treatment of MM is complex because of rapid advances in stem cell transplantation, medications, and better supportive care. The main options for therapy include: Chemotherapy Stem cell (bone marrow) transplantation
Each option needs to be weighed carefully. Because current therapy is rarely curative, patients will likely go through many treatment options during the course of their illness. Stem cell transplantation may not be an option for many patients because of advanced age, presence of other serious illness, or other physical limitations (see "Stem cell transplantation" below).
CHEMOTHERAPY — Chemotherapy is usually the first treatment recommended. In most individuals, chemotherapy partially controls MM; rarely, chemotherapy leads to complete remission. The response to initial chemotherapy also helps to estimate how long an individual will survive.
A person who "responds" to chemotherapy must have a 50 percent reduction in blood and urine levels of the abnormal M protein and an improvement of symptoms. Individuals who have any response to chemotherapy (even if it does not meet the above definition) survive approximately three years, while individuals who do not have a response survive approximately one to two years.
The treatment of MM is tailored to a variety of individual factors, including the stage of MM, age, overall health, and personal preferences.
Timing of chemotherapy — Multiple myeloma can remain stable for prolonged periods of time. Individuals with early myeloma (stage I: low cell mass by the Durie-Salmon staging system) who have no symptoms (often called smoldering or indolent myeloma) may be advised to wait months to years before considering chemotherapy.
Individuals with a related condition, called monoclonal gammopathy of undetermined significance (MGUS), do not require treatment, although long-term follow-up is needed; a percentage of patients with MGUS will eventually develop full-blown myeloma.
Chemotherapy is recommended for individuals who have symptoms of multiple myeloma at the time of diagnosis.
Initial chemotherapy options — The type of chemotherapy initially recommended for treatment of MM depends upon the patient's age, underlying medical illnesses, and the likelihood of undergoing stem cell transplantation in the future. Melphalan prednisone (MP) chemotherapy is usually recommended first for individuals over the age of 75 and younger individuals who will not be undergoing stem cell (bone marrow) transplantation at a later time because of associated illnesses or poor health. If later transplantation is a possibility, stem cells should be collected before the start of melphalan chemotherapy because this drug can cause long-lasting damage to stem cells. For individuals between 65 and 75 years who do not plan to undergo stem cell transplantation, melphalan, prednisone, and thalidomide (MPT) is recommended. This is also recommended if a rapid response is needed.
For either of the above groups, chemotherapy is usually continued until the patient reaches a plateau phase (see "Plateau phase" below). For individuals who hope to undergo stem cell transplantation, treatment with dexamethasone plus thalidomide is recommended (thal/dex) or another similar regimen is recommended. These treatments do not interfere with later collection of stem cells. For individuals who have renal failure at the time initial chemotherapy is needed, treatment with dexamethasone alone or dexamethasone plus thalidomide is often preferred.
Melphalan prednisone (MP) chemotherapy — Melphalan (Alkeran, a drug in the alkylating agent class of chemotherapy drugs) and prednisone (a steroid) are taken by mouth three times daily for seven days; this is repeated every four to six weeks. A one week dose is called a cycle. It may take 6 to 12 months or even longer for blood tests to reflect the full effects of this chemotherapy on multiple myeloma.
Between 50 and 60 percent of individuals with MM have a response to melphalan-prednisone chemotherapy. The average survival among individuals treated with this chemotherapy is three years.
During melphalan-prednisone chemotherapy, periodic blood tests are needed to ensure that an individual has adequate levels of white blood cells (cells that fight infection) and platelets (blood components that are important for clotting). The dose of melphalan must be adjusted based on these findings.
Thalidomide — Thalidomide (Thalomid®) is an immune-modulating drug that is effective in the treatment of relapsed MM, either alone or in combination with steroids such as dexamethasone or chemotherapy. Thalidomide is not yet approved for the initial treatment of myeloma, but is commonly used "off label" for this purpose.
Among individuals treated with thalidomide alone for relapsed myeloma, 58 percent survive at least one year, and, on average, 48 percent survive at least two years. The possible side effects of thalidomide, when used for prolonged periods of time, include nerve damage, usually involving the sensory and motor functions of nerves serving the arms and legs, which may not be reversible.
Thalidomide is taken orally. The main side effects are sleepiness, constipation, skin rash, and nerve damage. The use of this medicine in combination with dexamethasone or chemotherapy increases the chance of developing blood clots, and may require the use of anticoagulants ("blood thinners") to prevent this from happening. Thalidomide causes severe birth defects and it is absolutely unsafe (contraindicated) for pregnant women.
Lenalidomide (Revlimid®) is a closely related drug (analogue) of thalidomide. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It has shown clinical activity in MM with fewer side effects than thalidomide (see "Clinical trials" below).
Bortezomib — Bortezomib (Velcade™) is a proteasome inhibitor that is effective in treating patients with refractory MM and other tumors. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It is given intravenously, and its main side effects are low blood counts and nerve damage.
Chemotherapy-related infections — There is an increased risk of infection during the first two months of chemotherapy. Infections often require stopping chemotherapy. Therefore, daily antibiotics may be recommended for individuals starting chemotherapy to reduce the risk of infection and the severity of infections that do occur.
Plateau phase — Chemotherapy is usually continued until MM enters a stable (plateau) phase. The plateau phase is reached when the myeloma becomes stable and shows no signs of progressing. Although this phase is usually temporary, it typically lasts six months or longer. The plateau phase occurs in about one half of individuals after chemotherapy.
Achieving this phase usually requires at least six cycles of chemotherapy, but it may require additional cycles. Additional chemotherapy is not needed or recommended during the plateau phase.
STEM CELL TRANSPLANTATION — Stem cell or bone marrow transplantation is a treatment option for some individuals with MM. There are three types of transplantation, based on the source of the stem cells: Autologous transplantation: the stem cells are obtained from the individual with MM. This is the type of transplantation that is most commonly recommended. Allogeneic transplantation: the stem cells or bone marrow are obtained from a donor with a tissue type matching that of the patient. This type of transplantation carries very high risks and is not recommended for most individuals with MM. Syngeneic transplantation: the stem cells or bone marrow are obtained from an identical twin of the individual. This is the optimal form of transplant at this time, but only rare individuals with MM have an available identical twin who can serve as a donor.
Transplantation, when successful, prolongs survival, leads to a remission, and, infrequently, cures MM. However, transplantation has several limitations. The high-dose chemotherapy (even with radiation) given before transplantation usually fails to kill all of plasma cells, allowing the condition to relapse. Such treatment also puts the patient at risk for serious infections and bleeding, which might be fatal. (See "Patient information: Overview of bone marrow transplantation").
Autologous stem cell transplantation — Autologous stem cell transplantation refers to transplantation with an individual's own stem cells. During this procedure, stem cells are collected and frozen for later use. High-dose chemotherapy is then given to kill as many plasma cells as possible, and the stem cells are thawed and returned to the patient. Stem cells obtained from the peripheral blood of the patient are preferred over bone marrow, because peripheral blood stem cells take up residence in tissues more quickly and are less likely to be contaminated with residual malignant plasma cells.
At present, autologous stem cell (or bone marrow) transplantation is appropriate for up to 50 percent of individuals with multiple myeloma.
Procedure — After initial therapy with a regimen such as thalidomide/dexamethasone for about four months, an individual is given granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to stimulate the production of stem cells. Stem cells are then collected from the blood, frozen, and stored for later use.
After an individual recovers from the stem cell collection, he or she is given high-dose chemotherapy with melphalan (or similar drugs) to kill as many of the malignant plasma cells as possible; then the previously collected stem cells are thawed and returned to the patient. In about one-half of patients, this procedure can be done on an outpatient basis.
Alternatively, after stem cell collection, an individual may be given standard chemotherapy with melphalan (or similar drugs) to achieve a plateau phase. At the time of relapse, high doses of melphalan (or similar drugs) are given, and the previously collected stem cells are returned to the patient ("delayed transplantation").
Role of age and stage of myeloma — Because autologous transplantation has serious side effects, it is generally not recommended for individuals over the age of 70. However, this procedure may be an option for some individuals over the age of 70 who are otherwise healthy. The likelihood of a good response to transplantation is somewhat lower for older adults than for younger adults, but the effects of age on survival after transplantation are still uncertain.
Autologous stem cell transplantation is not recommended for individuals with early stage (Durie-Salmon stage I) or smoldering myeloma.
Importance of prior treatment — Autologous transplantation is not recommended for individuals who have received prolonged chemotherapy with alkylating drugs (such as melphalan). In such instances, it is very difficult to collect a sufficient number of healthy stem cells for transplantation.
If transplantation is a possibility, initial therapy with dexamethasone alone or thalidomide plus dexamethasone is usually recommended. In contrast to alkylating drugs such as melphalan, these agents do not cause damage to the stem cells.
Effectiveness — About one to two percent of individuals die from complications related to transplantation. However, compared with chemotherapy, autologous stem cell transplantation is more likely to produce a response, and is associated with survival approximately 12 months longer than that produced by chemotherapy alone.
Single versus double autologous transplantation — Double autologous transplantation (two consecutive autologous transplantations) may be more effective than single autologous transplantation if the first transplant has not produced a complete or near complete response. The second transplantation is usually performed within six months of the first.
Among individuals undergoing double transplantation, 51 percent have a complete response, lasting, on average, 50 months. One study has shown that double transplantation improves long-term survival relative to single transplantation with the greatest benefit seen in patients who have not achieved an excellent response with the first transplant.
Allogeneic bone marrow transplantation — An allogeneic stem cell or bone marrow transplantation is a treatment option for only 5 to 10 percent of individuals with multiple myeloma. This type of transplantation has two advantages over autologous transplantation: the donated stem cells do not contain any malignant plasma cells, and the transplanted cells may target and help control any remaining myeloma cells. This latter beneficial effect is called the "graft versus tumor" effect. However, allogeneic transplantation is also associated with a "graft versus host" effect, in which cells from the donor attack tissues of the host, resulting in damage to various organs, such as the skin, liver, and intestines.
Allogeneic transplantation requires bone marrow or stem cells from a donor with a matching tissue type. Under the best conditions, a sibling may qualify as a donor; otherwise national bone marrow donor banks may be employed to find a donor with a matching tissue type. The donated bone marrow or stem cells are given to the patient after he/she receives appropriate doses of high-dose chemotherapy and radiation to reduce the number of malignant plasma cells.
About one half of individuals have a complete response after allogeneic transplantation. Thirty percent of individuals live for at least four years, and 20 percent of individuals live for at least 10 years. The likelihood of a complete response to allogeneic bone marrow transplantation is highest in individuals with a lower number of myeloma cells and in individuals who have had a complete response to the initial chemotherapy.
Although multiple myeloma usually relapses after allogeneic transplantation, some individuals are cured of multiple myeloma after this type of transplantation.
Unfortunately, approximately 25 percent of individuals who undergo allogeneic transplantation die from transplant-related complications, such as infection, lung inflammation, and graft-versus-host disease. Thus, the potential benefit of allogeneic transplantation (long-term disease control or cure) must be weighed against the potential for immediate morbidity and mortality. Primarily because of this toxicity, allogeneic transplantation is seldom used for the treatment of myeloma.
Nonmyeloablative allogeneic transplantation — Because autologous transplantation is not often curative and allogeneic transplantation carries a high mortality, other solutions have been sought. These include nonmyeloablative allogeneic transplants (often called "mini transplants") in which the patient receives a lower dose of chemotherapy prior to an allogeneic transplant.
The best results have been seen when a nonmyeloablative allogeneic transplantation is conducted following an initial autologous transplantation. However, the best preparative regimen and the control of graft versus host disease are evolving. We believe that this procedure should be done only in a research setting.
Donor lymphocyte infusion — Donor lymphocyte infusion is an experimental procedure that is a good option for individuals who have a relapse of multiple myeloma after allogeneic stem cell transplantation. During this procedure, lymphocytes collected from the original donor are given to the individual; these lymphocytes target the myeloma cells and may produce a beneficial "graft versus tumor" effect. Fifty-two percent of individuals have a response to this procedure, and 22 percent of individuals have a complete response.
Syngeneic transplantation — A syngeneic transplantation refers to a transplantation between identical twins. For individuals who have an identical twin, this treatment option is more effective than either autologous or allogeneic transplantation.
Remission after transplantation — The strict definition of remission requires that there are no signs or symptoms of multiple myeloma and that highly sensitive tests do not detect any abnormal plasma cells. This type of remission occurs in about 4 percent of individuals after autologous transplantation and about 19 percent of individuals after allogeneic transplantation.
TREATMENT OF COMPLICATIONS — Multiple myeloma can cause a variety of complications, some of which are life-threatening. It is important to treat these complications in addition to treating MM itself.
High blood calcium levels — High blood calcium levels develop as bone is lost. Individuals with MM should remain as active as possible because physical activity helps counter bone loss.
The treatment of high blood calcium levels usually includes use of intravenous fluids and prednisone. If this treatment is not effective, treatment with drugs that counter bone loss, such as zoledronic acid (Zometa™) or pamidronate (Aredia™), a class of drugs called bisphosphonates, may be recommended.
Impaired kidney function — Kidney function becomes impaired in about one half of individuals with multiple myeloma. The treatment of impaired kidney function is aimed at the specific underlying cause.
Treatment usually includes intravenous fluids; it may also include dialysis (a type of blood filtration used for kidney failure), prednisone (a steroid that can indirectly lower blood calcium levels), and allopurinol, a drug that can lower blood levels of uric acid, a waste product from the increased turnover of the malignant plasma cells, which can damage the kidneys.
Patients are advised to stay well-hydrated and should drink enough fluid to produce three liters of urine daily if they have Bence Jones proteinuria (increased light chains in the urine). They should also avoid using any nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil®, Motrin®, Aleve®) because these drugs might worsen kidney function.
If impaired kidney function has progressed to kidney failure, the treatment options include hemodialysis or peritoneal dialysis. Advanced degrees of kidney failure are usually not reversible even if the multiple myeloma later responds to treatment. (See "Patient information: Renal replacement therapy").
Infection — Bacterial infections, often indicated by the presence of fever, require prompt treatment with antibiotics. Daily use of the antibiotic trimethoprim-sulfamethoxazole (Bactrim) can help prevent infections. Individuals who get frequent infections may be advised to take penicillin daily or rarely to have periodic intravenous infusions of gamma globulin.
All individuals with MM should receive the pneumococcal vaccine (which reduces the likelihood of pneumonia) and the influenza vaccine (which reduces the likelihood of flu). (See "Patient information: Influenza").
Bone pain and fractures — Physical activity, with careful avoidance of injury, can promote bone strength in individuals with MM. The bone pain associated with MM can be controlled with chemotherapy, analgesics (pain relieving drugs), radiation, and bone strengthening drugs such as zoledronic acid (Zometa™) or pamidronate (Aredia™) (commonly referred to as bisphosphonates) that can also reduce the likelihood of fractures.
In individuals who have early signs of bone erosion, bisphosphonates reduce the risk of fractures and reduce bone pain. Therefore, bisphosphonates are recommended for all individuals who have early signs of bone erosions on x-rays. Bisphosphonates are usually given by intravenous infusion every four weeks; this treatment is continued for approximately two years. Zoledronic acid requires infusion times as short as 15 to 30 minutes. These medications may affect kidney function, which should be monitored on a regular basis to avoid this complication.
Dental procedures, such as root canal or extraction of teeth, may be associated with infection or osteonecrosis of the jaw in patients treated with intravenous bisphosphonates. Accordingly, patients should avoid such procedures while taking these agents; any needed dental procedures should be performed before these agents are started.
Spinal cord compression — Spinal cord compression is a medical emergency that requires prompt treatment to prevent irreversible damage, such as paralysis. Initial treatment may consist of radiation and dexamethasone (a steroid) to reduce swelling around the spinal cord; if these measures are not effective, surgery is needed to relieve pressure on the spinal cord.
Anemia — Anemia that is causing symptoms can be treated with erythropoietin (EPO), a substance that stimulates the production of red blood cells. Erythropoietin is usually given by injection one to three times per week. This treatment effectively increases levels of hemoglobin (the protein in red blood cells that helps carry oxygen to the tissues), improves symptoms, and reduces the need for blood transfusion.
Thickening of the blood — Thickening of the blood (called hyperviscosity syndrome) rarely occurs in individuals with MM. This complication is treated with plasmapheresis, a type of blood filtration that removes the excess monoclonal proteins responsible for the increased viscosity.
TREATMENT OF RELAPSED OR REFRACTORY DISEASE — Almost all patients with MM who survive their first cycle of treatment eventually relapse, and a modest percentage are resistant to initial treatment.
MM that responds poorly or not at all to melphalan-prednisone or other chemotherapy is called refractory MM. This condition can occur during initial chemotherapy or during chemotherapy given after a relapse. Refractory MM is more difficult to treat.
Thalidomide, bortezomib, and lenalidomide have all shown significant single-agent activity in relapsed or refractory MM; together with alkylators and corticosteroids, they form the major treatment options for relapsed or resistant disease. Relapses occurring more than six months after completing chemotherapy are usually treated by resuming the initial chemotherapy. Most individuals will again have a response to chemotherapy when it is given a second time, but the response is usually shorter and less marked than the original response. Selected patients can consider autologous or allogeneic stem cell transplantation. The lack of response to initial induction chemotherapy does not always mean that the person will not have good response to autologous hematopoietic cell transplantation. Said another way, if a person does not respond to induction chemotherapy, he or she may still respond to autologous stem cell transplantation.
CLINICAL TRIALS — Progress in treating multiple myeloma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies; clinical trials are conducted all over the world. 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. The International Myeloma Foundation
(www.myeloma.org)
Multiple Myeloma Research Foundation
(www.multiplemyeloma.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Diagnosis and management of multiple myeloma. Br J Haematol 2001; 115:522.
2. Kyle, RA. Multiple myeloma: an odyssey of discovery. Br J Haematol 2000; 111:1035.
3. Riedel, DA, Pottern, LM. The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 1992; 6:225.
4. Kyle, RA, Rajkumar, SV. Multiple Myeloma. N Engl J Med 2004; 351:1860.
5. Rajkumar, SV, Kyle, RA. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc 2005; 80:1371.
Saturday, October 13, 2007
Multiple myeloma
INTRODUCTION — Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications.
In the United States, about 4 out of 100,000 individuals are diagnosed with MM each year. This condition is slightly more common among men than women, and almost twice as common among blacks as among whites. The average age at diagnosis is 65 to 70 years.
The current treatment options for MM include watchful waiting (for early or smoldering multiple myeloma), chemotherapy, immune-modulating drugs, and stem cell transplantation. Multiple myeloma is seldom cured, but treatment can relieve symptoms, induce remission, and prolong life.
The cause of MM is unknown. Exposure to radiation, organic chemicals (such as benzene), herbicides, and insecticides may play a role. Genetic factors and viral infection may also influence the risk of developing multiple myeloma.
FEATURES — Multiple myeloma can produce a wide variety of symptoms.
Bone symptoms — Most individuals develop bone pain in the back or chest or, less commonly, the arms and legs, at the time of diagnosis. The pain is usually triggered by movement and is absent at night, except when changing positions.
MM causes both generalized bone loss throughout the body as well as bone erosions (lytic lesions on x-ray) in specific areas. The bone loss and erosions can lead to osteoporosis and fractures. Many individuals with multiple myeloma experience fractures of the vertebrae (the bones of the spine), which can lead to a loss of height; about 30 percent of individuals experience fractures in other bones, often with little or no preceding trauma. For this reason they are called "pathologic fractures."
High blood calcium levels — Because bones contain large amounts of calcium, the breakdown of bone in MM can lead to high blood calcium levels (called hypercalcemia). High blood calcium levels occur in 10 to 15 percent of individuals, and the symptoms may include loss of appetite, nausea, vomiting, frequent urination, increased thirst, constipation, weakness, confusion, stupor, or coma.
Anemia — About two thirds of individuals have anemia (low red cell count) at the time of diagnosis, and anemia eventually occurs in almost all individuals. The signs and symptoms of anemia include paleness, weakness, and fatigue.
Impaired kidney function — The excess proteins and high blood calcium levels associated with MM can damage the kidneys. Kidney function is abnormal at diagnosis in about half of individuals with multiple myeloma. Occasionally, kidney failure is the first symptom of MM.
Thickened blood — The excessive production of proteins by the malignant plasma cells in MM can cause a thickening of the blood (called hyperviscosity syndrome). The symptoms may include bleeding from the nose and mouth, blurred vision, neurologic symptoms, and congestive heart failure.
Neurologic symptoms — Fractures of the vertebrae can lead to increased pressure on the nerve roots where they exit the spine, causing neurologic symptoms (called radiculopathy). This complication of multiple myeloma most commonly affects the chest, lower back, or legs, and the symptoms may include odd sensations (numbness or tingling), pain, or muscle weakness.
Occasionally, neurologic symptoms occur because plasma cells grow within the spinal canal and press on the spinal cord. The symptoms may include severe back pain, muscle weakness, especially of the legs, numbness or tingling, and loss of control of bowel or bladder function (incontinence). Spinal cord compression is a medical emergency and requires immediate treatment to relieve the pressure and prevent permanent damage.
Generalized symptoms — The generalized symptoms of MM include an increased susceptibility to infections (especially during chemotherapy) and weight loss. Occasionally, it causes increased bleeding or tumors of the ribs. In individuals with advanced MM, tumor cells may accumulate beneath the skin, causing large purple-colored bumps.
DIAGNOSTIC TESTING — The diagnosis of MM is based upon the presence of characteristic signs and symptoms of the disease and on the results of tests of the blood and bone marrow. Several different tests are used to determine the presence and severity of MM. In some individuals with early MM or related conditions, it may be necessary to repeat these tests periodically until the diagnosis is certain.
After MM is confirmed, additional tests are used to check for the presence of impaired kidney function, anemia, thickening of the blood, and other complications of multiple myeloma.
Blood and urine tests for monoclonal protein — An abnormal protein produced by the plasma cells, called a monoclonal (M) protein (sometimes called a "paraprotein"), can be found in the blood or urine of almost all patients with MM, which helps establish the diagnosis. These proteins serve no useful function, and may be responsible for increases in the thickness of the blood, kidney damage, or bleeding problems.
However, it is important to remember that not everyone with a monoclonal protein has MM. The diagnosis requires, in addition to the monoclonal protein, one or more abnormalities such as anemia, bone lesions (see "X-rays" below), kidney failure, or high calcium levels in the blood (see "Criteria for diagnosis" below).
Bone marrow examination — In most individuals with MM, a bone marrow aspiration and biopsy (a collection of a small sample of bone marrow for laboratory analysis, usually taken from the hip) shows that plasma cells comprise an abnormally high percentage of bone marrow cells (more than 10 percent). It may be necessary to collect samples from different areas because MM may affect the marrow of some bones but not others.
X-rays — In about 80 percent of individuals, routine x-rays show distinct, round (lytic) areas of bone erosion; generalized thinning of the bones; and/or fractures at the time of diagnosis. The bones most commonly involved are the vertebrae, the ribs, the pelvic bones, and the bones of the thigh and upper arm.
Genetic and chromosomal tests — Specialized tests may reveal genetic or chromosomal abnormalities of the plasma cells in individuals with MM. In general, such abnormalities are associated with a poorer prognosis. The results of these tests are helpful for predicting the response to treatment and survival.
Plasma cell labeling index — The plasma cell labeling index determines how rapidly the abnormal plasma cells are growing and dividing. Patients in whom the labeling index is low tend to have slower disease progression than those with high values. This test is also useful for distinguishing MM from related conditions that generally have a better prognosis. A normal plasma cell labeling index suggests that MM is less likely, while an elevated index suggests that multiple myeloma is more likely. However, this test is not generally available.
Criteria for diagnosis — The diagnosis of multiple myeloma requires the following: A bone marrow aspirate or biopsy showing that at least 10 percent of the cells are plasma cells or the presence of a plasma cell tumor (called a plasmacytoma), plus: M protein in the blood or urine, or Evidence of damage to the body as a result of the plasma cell growth, such as destructive bone lesions, kidney failure, anemia, or high calcium in the blood.
STAGING AND PROGNOSIS — The simplest measure of prognosis in MM is based on blood levels of two markers: beta-2-microglobulin and albumin. In general, higher levels of beta-2-microglobulin and lower levels of albumin are associated with a poorer prognosis. This staging system is referred to as the International Staging System, or ISS.
The older Durie-Salmon staging system divided patients into three stages: Stages I, II, and III, corresponding to low, intermediate, and high cell mass, depending on such factors as the degree of anemia, calcium level, kidney function, presence or absence of bone lesions, and the amount of the abnormal protein. It is best used as a measure of the overall amounts of malignant plasma cells present in the patient, and is less useful as a measure of prognosis.
TREATMENT OVERVIEW — The treatment of MM is complex because of rapid advances in stem cell transplantation, medications, and better supportive care. The main options for therapy include: Chemotherapy Stem cell (bone marrow) transplantation
Each option needs to be weighed carefully. Because current therapy is rarely curative, patients will likely go through many treatment options during the course of their illness. Stem cell transplantation may not be an option for many patients because of advanced age, presence of other serious illness, or other physical limitations (see "Stem cell transplantation" below).
CHEMOTHERAPY — Chemotherapy is usually the first treatment recommended. In most individuals, chemotherapy partially controls MM; rarely, chemotherapy leads to complete remission. The response to initial chemotherapy also helps to estimate how long an individual will survive.
A person who "responds" to chemotherapy must have a 50 percent reduction in blood and urine levels of the abnormal M protein and an improvement of symptoms. Individuals who have any response to chemotherapy (even if it does not meet the above definition) survive approximately three years, while individuals who do not have a response survive approximately one to two years.
The treatment of MM is tailored to a variety of individual factors, including the stage of MM, age, overall health, and personal preferences.
Timing of chemotherapy — Multiple myeloma can remain stable for prolonged periods of time. Individuals with early myeloma (stage I: low cell mass by the Durie-Salmon staging system) who have no symptoms (often called smoldering or indolent myeloma) may be advised to wait months to years before considering chemotherapy.
Individuals with a related condition, called monoclonal gammopathy of undetermined significance (MGUS), do not require treatment, although long-term follow-up is needed; a percentage of patients with MGUS will eventually develop full-blown myeloma.
Chemotherapy is recommended for individuals who have symptoms of multiple myeloma at the time of diagnosis.
Initial chemotherapy options — The type of chemotherapy initially recommended for treatment of MM depends upon the patient's age, underlying medical illnesses, and the likelihood of undergoing stem cell transplantation in the future. Melphalan prednisone (MP) chemotherapy is usually recommended first for individuals over the age of 75 and younger individuals who will not be undergoing stem cell (bone marrow) transplantation at a later time because of associated illnesses or poor health. If later transplantation is a possibility, stem cells should be collected before the start of melphalan chemotherapy because this drug can cause long-lasting damage to stem cells. For individuals between 65 and 75 years who do not plan to undergo stem cell transplantation, melphalan, prednisone, and thalidomide (MPT) is recommended. This is also recommended if a rapid response is needed.
For either of the above groups, chemotherapy is usually continued until the patient reaches a plateau phase (see "Plateau phase" below). For individuals who hope to undergo stem cell transplantation, treatment with dexamethasone plus thalidomide is recommended (thal/dex) or another similar regimen is recommended. These treatments do not interfere with later collection of stem cells. For individuals who have renal failure at the time initial chemotherapy is needed, treatment with dexamethasone alone or dexamethasone plus thalidomide is often preferred.
Melphalan prednisone (MP) chemotherapy — Melphalan (Alkeran, a drug in the alkylating agent class of chemotherapy drugs) and prednisone (a steroid) are taken by mouth three times daily for seven days; this is repeated every four to six weeks. A one week dose is called a cycle. It may take 6 to 12 months or even longer for blood tests to reflect the full effects of this chemotherapy on multiple myeloma.
Between 50 and 60 percent of individuals with MM have a response to melphalan-prednisone chemotherapy. The average survival among individuals treated with this chemotherapy is three years.
During melphalan-prednisone chemotherapy, periodic blood tests are needed to ensure that an individual has adequate levels of white blood cells (cells that fight infection) and platelets (blood components that are important for clotting). The dose of melphalan must be adjusted based on these findings.
Thalidomide — Thalidomide (Thalomid®) is an immune-modulating drug that is effective in the treatment of relapsed MM, either alone or in combination with steroids such as dexamethasone or chemotherapy. Thalidomide is not yet approved for the initial treatment of myeloma, but is commonly used "off label" for this purpose.
Among individuals treated with thalidomide alone for relapsed myeloma, 58 percent survive at least one year, and, on average, 48 percent survive at least two years. The possible side effects of thalidomide, when used for prolonged periods of time, include nerve damage, usually involving the sensory and motor functions of nerves serving the arms and legs, which may not be reversible.
Thalidomide is taken orally. The main side effects are sleepiness, constipation, skin rash, and nerve damage. The use of this medicine in combination with dexamethasone or chemotherapy increases the chance of developing blood clots, and may require the use of anticoagulants ("blood thinners") to prevent this from happening. Thalidomide causes severe birth defects and it is absolutely unsafe (contraindicated) for pregnant women.
Lenalidomide (Revlimid®) is a closely related drug (analogue) of thalidomide. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It has shown clinical activity in MM with fewer side effects than thalidomide (see "Clinical trials" below).
Bortezomib — Bortezomib (Velcade™) is a proteasome inhibitor that is effective in treating patients with refractory MM and other tumors. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It is given intravenously, and its main side effects are low blood counts and nerve damage.
Chemotherapy-related infections — There is an increased risk of infection during the first two months of chemotherapy. Infections often require stopping chemotherapy. Therefore, daily antibiotics may be recommended for individuals starting chemotherapy to reduce the risk of infection and the severity of infections that do occur.
Plateau phase — Chemotherapy is usually continued until MM enters a stable (plateau) phase. The plateau phase is reached when the myeloma becomes stable and shows no signs of progressing. Although this phase is usually temporary, it typically lasts six months or longer. The plateau phase occurs in about one half of individuals after chemotherapy.
Achieving this phase usually requires at least six cycles of chemotherapy, but it may require additional cycles. Additional chemotherapy is not needed or recommended during the plateau phase.
STEM CELL TRANSPLANTATION — Stem cell or bone marrow transplantation is a treatment option for some individuals with MM. There are three types of transplantation, based on the source of the stem cells: Autologous transplantation: the stem cells are obtained from the individual with MM. This is the type of transplantation that is most commonly recommended. Allogeneic transplantation: the stem cells or bone marrow are obtained from a donor with a tissue type matching that of the patient. This type of transplantation carries very high risks and is not recommended for most individuals with MM. Syngeneic transplantation: the stem cells or bone marrow are obtained from an identical twin of the individual. This is the optimal form of transplant at this time, but only rare individuals with MM have an available identical twin who can serve as a donor.
Transplantation, when successful, prolongs survival, leads to a remission, and, infrequently, cures MM. However, transplantation has several limitations. The high-dose chemotherapy (even with radiation) given before transplantation usually fails to kill all of plasma cells, allowing the condition to relapse. Such treatment also puts the patient at risk for serious infections and bleeding, which might be fatal. (See "Patient information: Overview of bone marrow transplantation").
Autologous stem cell transplantation — Autologous stem cell transplantation refers to transplantation with an individual's own stem cells. During this procedure, stem cells are collected and frozen for later use. High-dose chemotherapy is then given to kill as many plasma cells as possible, and the stem cells are thawed and returned to the patient. Stem cells obtained from the peripheral blood of the patient are preferred over bone marrow, because peripheral blood stem cells take up residence in tissues more quickly and are less likely to be contaminated with residual malignant plasma cells.
At present, autologous stem cell (or bone marrow) transplantation is appropriate for up to 50 percent of individuals with multiple myeloma.
Procedure — After initial therapy with a regimen such as thalidomide/dexamethasone for about four months, an individual is given granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to stimulate the production of stem cells. Stem cells are then collected from the blood, frozen, and stored for later use.
After an individual recovers from the stem cell collection, he or she is given high-dose chemotherapy with melphalan (or similar drugs) to kill as many of the malignant plasma cells as possible; then the previously collected stem cells are thawed and returned to the patient. In about one-half of patients, this procedure can be done on an outpatient basis.
Alternatively, after stem cell collection, an individual may be given standard chemotherapy with melphalan (or similar drugs) to achieve a plateau phase. At the time of relapse, high doses of melphalan (or similar drugs) are given, and the previously collected stem cells are returned to the patient ("delayed transplantation").
Role of age and stage of myeloma — Because autologous transplantation has serious side effects, it is generally not recommended for individuals over the age of 70. However, this procedure may be an option for some individuals over the age of 70 who are otherwise healthy. The likelihood of a good response to transplantation is somewhat lower for older adults than for younger adults, but the effects of age on survival after transplantation are still uncertain.
Autologous stem cell transplantation is not recommended for individuals with early stage (Durie-Salmon stage I) or smoldering myeloma.
Importance of prior treatment — Autologous transplantation is not recommended for individuals who have received prolonged chemotherapy with alkylating drugs (such as melphalan). In such instances, it is very difficult to collect a sufficient number of healthy stem cells for transplantation.
If transplantation is a possibility, initial therapy with dexamethasone alone or thalidomide plus dexamethasone is usually recommended. In contrast to alkylating drugs such as melphalan, these agents do not cause damage to the stem cells.
Effectiveness — About one to two percent of individuals die from complications related to transplantation. However, compared with chemotherapy, autologous stem cell transplantation is more likely to produce a response, and is associated with survival approximately 12 months longer than that produced by chemotherapy alone.
Single versus double autologous transplantation — Double autologous transplantation (two consecutive autologous transplantations) may be more effective than single autologous transplantation if the first transplant has not produced a complete or near complete response. The second transplantation is usually performed within six months of the first.
Among individuals undergoing double transplantation, 51 percent have a complete response, lasting, on average, 50 months. One study has shown that double transplantation improves long-term survival relative to single transplantation with the greatest benefit seen in patients who have not achieved an excellent response with the first transplant.
Allogeneic bone marrow transplantation — An allogeneic stem cell or bone marrow transplantation is a treatment option for only 5 to 10 percent of individuals with multiple myeloma. This type of transplantation has two advantages over autologous transplantation: the donated stem cells do not contain any malignant plasma cells, and the transplanted cells may target and help control any remaining myeloma cells. This latter beneficial effect is called the "graft versus tumor" effect. However, allogeneic transplantation is also associated with a "graft versus host" effect, in which cells from the donor attack tissues of the host, resulting in damage to various organs, such as the skin, liver, and intestines.
Allogeneic transplantation requires bone marrow or stem cells from a donor with a matching tissue type. Under the best conditions, a sibling may qualify as a donor; otherwise national bone marrow donor banks may be employed to find a donor with a matching tissue type. The donated bone marrow or stem cells are given to the patient after he/she receives appropriate doses of high-dose chemotherapy and radiation to reduce the number of malignant plasma cells.
About one half of individuals have a complete response after allogeneic transplantation. Thirty percent of individuals live for at least four years, and 20 percent of individuals live for at least 10 years. The likelihood of a complete response to allogeneic bone marrow transplantation is highest in individuals with a lower number of myeloma cells and in individuals who have had a complete response to the initial chemotherapy.
Although multiple myeloma usually relapses after allogeneic transplantation, some individuals are cured of multiple myeloma after this type of transplantation.
Unfortunately, approximately 25 percent of individuals who undergo allogeneic transplantation die from transplant-related complications, such as infection, lung inflammation, and graft-versus-host disease. Thus, the potential benefit of allogeneic transplantation (long-term disease control or cure) must be weighed against the potential for immediate morbidity and mortality. Primarily because of this toxicity, allogeneic transplantation is seldom used for the treatment of myeloma.
Nonmyeloablative allogeneic transplantation — Because autologous transplantation is not often curative and allogeneic transplantation carries a high mortality, other solutions have been sought. These include nonmyeloablative allogeneic transplants (often called "mini transplants") in which the patient receives a lower dose of chemotherapy prior to an allogeneic transplant.
The best results have been seen when a nonmyeloablative allogeneic transplantation is conducted following an initial autologous transplantation. However, the best preparative regimen and the control of graft versus host disease are evolving. We believe that this procedure should be done only in a research setting.
Donor lymphocyte infusion — Donor lymphocyte infusion is an experimental procedure that is a good option for individuals who have a relapse of multiple myeloma after allogeneic stem cell transplantation. During this procedure, lymphocytes collected from the original donor are given to the individual; these lymphocytes target the myeloma cells and may produce a beneficial "graft versus tumor" effect. Fifty-two percent of individuals have a response to this procedure, and 22 percent of individuals have a complete response.
Syngeneic transplantation — A syngeneic transplantation refers to a transplantation between identical twins. For individuals who have an identical twin, this treatment option is more effective than either autologous or allogeneic transplantation.
Remission after transplantation — The strict definition of remission requires that there are no signs or symptoms of multiple myeloma and that highly sensitive tests do not detect any abnormal plasma cells. This type of remission occurs in about 4 percent of individuals after autologous transplantation and about 19 percent of individuals after allogeneic transplantation.
TREATMENT OF COMPLICATIONS — Multiple myeloma can cause a variety of complications, some of which are life-threatening. It is important to treat these complications in addition to treating MM itself.
High blood calcium levels — High blood calcium levels develop as bone is lost. Individuals with MM should remain as active as possible because physical activity helps counter bone loss.
The treatment of high blood calcium levels usually includes use of intravenous fluids and prednisone. If this treatment is not effective, treatment with drugs that counter bone loss, such as zoledronic acid (Zometa™) or pamidronate (Aredia™), a class of drugs called bisphosphonates, may be recommended.
Impaired kidney function — Kidney function becomes impaired in about one half of individuals with multiple myeloma. The treatment of impaired kidney function is aimed at the specific underlying cause.
Treatment usually includes intravenous fluids; it may also include dialysis (a type of blood filtration used for kidney failure), prednisone (a steroid that can indirectly lower blood calcium levels), and allopurinol, a drug that can lower blood levels of uric acid, a waste product from the increased turnover of the malignant plasma cells, which can damage the kidneys.
Patients are advised to stay well-hydrated and should drink enough fluid to produce three liters of urine daily if they have Bence Jones proteinuria (increased light chains in the urine). They should also avoid using any nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil®, Motrin®, Aleve®) because these drugs might worsen kidney function.
If impaired kidney function has progressed to kidney failure, the treatment options include hemodialysis or peritoneal dialysis. Advanced degrees of kidney failure are usually not reversible even if the multiple myeloma later responds to treatment. (See "Patient information: Renal replacement therapy").
Infection — Bacterial infections, often indicated by the presence of fever, require prompt treatment with antibiotics. Daily use of the antibiotic trimethoprim-sulfamethoxazole (Bactrim) can help prevent infections. Individuals who get frequent infections may be advised to take penicillin daily or rarely to have periodic intravenous infusions of gamma globulin.
All individuals with MM should receive the pneumococcal vaccine (which reduces the likelihood of pneumonia) and the influenza vaccine (which reduces the likelihood of flu). (See "Patient information: Influenza").
Bone pain and fractures — Physical activity, with careful avoidance of injury, can promote bone strength in individuals with MM. The bone pain associated with MM can be controlled with chemotherapy, analgesics (pain relieving drugs), radiation, and bone strengthening drugs such as zoledronic acid (Zometa™) or pamidronate (Aredia™) (commonly referred to as bisphosphonates) that can also reduce the likelihood of fractures.
In individuals who have early signs of bone erosion, bisphosphonates reduce the risk of fractures and reduce bone pain. Therefore, bisphosphonates are recommended for all individuals who have early signs of bone erosions on x-rays. Bisphosphonates are usually given by intravenous infusion every four weeks; this treatment is continued for approximately two years. Zoledronic acid requires infusion times as short as 15 to 30 minutes. These medications may affect kidney function, which should be monitored on a regular basis to avoid this complication.
Dental procedures, such as root canal or extraction of teeth, may be associated with infection or osteonecrosis of the jaw in patients treated with intravenous bisphosphonates. Accordingly, patients should avoid such procedures while taking these agents; any needed dental procedures should be performed before these agents are started.
Spinal cord compression — Spinal cord compression is a medical emergency that requires prompt treatment to prevent irreversible damage, such as paralysis. Initial treatment may consist of radiation and dexamethasone (a steroid) to reduce swelling around the spinal cord; if these measures are not effective, surgery is needed to relieve pressure on the spinal cord.
Anemia — Anemia that is causing symptoms can be treated with erythropoietin (EPO), a substance that stimulates the production of red blood cells. Erythropoietin is usually given by injection one to three times per week. This treatment effectively increases levels of hemoglobin (the protein in red blood cells that helps carry oxygen to the tissues), improves symptoms, and reduces the need for blood transfusion.
Thickening of the blood — Thickening of the blood (called hyperviscosity syndrome) rarely occurs in individuals with MM. This complication is treated with plasmapheresis, a type of blood filtration that removes the excess monoclonal proteins responsible for the increased viscosity.
TREATMENT OF RELAPSED OR REFRACTORY DISEASE — Almost all patients with MM who survive their first cycle of treatment eventually relapse, and a modest percentage are resistant to initial treatment.
MM that responds poorly or not at all to melphalan-prednisone or other chemotherapy is called refractory MM. This condition can occur during initial chemotherapy or during chemotherapy given after a relapse. Refractory MM is more difficult to treat.
Thalidomide, bortezomib, and lenalidomide have all shown significant single-agent activity in relapsed or refractory MM; together with alkylators and corticosteroids, they form the major treatment options for relapsed or resistant disease. Relapses occurring more than six months after completing chemotherapy are usually treated by resuming the initial chemotherapy. Most individuals will again have a response to chemotherapy when it is given a second time, but the response is usually shorter and less marked than the original response. Selected patients can consider autologous or allogeneic stem cell transplantation. The lack of response to initial induction chemotherapy does not always mean that the person will not have good response to autologous hematopoietic cell transplantation. Said another way, if a person does not respond to induction chemotherapy, he or she may still respond to autologous stem cell transplantation.
CLINICAL TRIALS — Progress in treating multiple myeloma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies; clinical trials are conducted all over the world. 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. The International Myeloma Foundation
(www.myeloma.org)
Multiple Myeloma Research Foundation
(www.multiplemyeloma.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Diagnosis and management of multiple myeloma. Br J Haematol 2001; 115:522.
2. Kyle, RA. Multiple myeloma: an odyssey of discovery. Br J Haematol 2000; 111:1035.
3. Riedel, DA, Pottern, LM. The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 1992; 6:225.
4. Kyle, RA, Rajkumar, SV. Multiple Myeloma. N Engl J Med 2004; 351:1860.
5. Rajkumar, SV, Kyle, RA. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc 2005; 80:1371.
In the United States, about 4 out of 100,000 individuals are diagnosed with MM each year. This condition is slightly more common among men than women, and almost twice as common among blacks as among whites. The average age at diagnosis is 65 to 70 years.
The current treatment options for MM include watchful waiting (for early or smoldering multiple myeloma), chemotherapy, immune-modulating drugs, and stem cell transplantation. Multiple myeloma is seldom cured, but treatment can relieve symptoms, induce remission, and prolong life.
The cause of MM is unknown. Exposure to radiation, organic chemicals (such as benzene), herbicides, and insecticides may play a role. Genetic factors and viral infection may also influence the risk of developing multiple myeloma.
FEATURES — Multiple myeloma can produce a wide variety of symptoms.
Bone symptoms — Most individuals develop bone pain in the back or chest or, less commonly, the arms and legs, at the time of diagnosis. The pain is usually triggered by movement and is absent at night, except when changing positions.
MM causes both generalized bone loss throughout the body as well as bone erosions (lytic lesions on x-ray) in specific areas. The bone loss and erosions can lead to osteoporosis and fractures. Many individuals with multiple myeloma experience fractures of the vertebrae (the bones of the spine), which can lead to a loss of height; about 30 percent of individuals experience fractures in other bones, often with little or no preceding trauma. For this reason they are called "pathologic fractures."
High blood calcium levels — Because bones contain large amounts of calcium, the breakdown of bone in MM can lead to high blood calcium levels (called hypercalcemia). High blood calcium levels occur in 10 to 15 percent of individuals, and the symptoms may include loss of appetite, nausea, vomiting, frequent urination, increased thirst, constipation, weakness, confusion, stupor, or coma.
Anemia — About two thirds of individuals have anemia (low red cell count) at the time of diagnosis, and anemia eventually occurs in almost all individuals. The signs and symptoms of anemia include paleness, weakness, and fatigue.
Impaired kidney function — The excess proteins and high blood calcium levels associated with MM can damage the kidneys. Kidney function is abnormal at diagnosis in about half of individuals with multiple myeloma. Occasionally, kidney failure is the first symptom of MM.
Thickened blood — The excessive production of proteins by the malignant plasma cells in MM can cause a thickening of the blood (called hyperviscosity syndrome). The symptoms may include bleeding from the nose and mouth, blurred vision, neurologic symptoms, and congestive heart failure.
Neurologic symptoms — Fractures of the vertebrae can lead to increased pressure on the nerve roots where they exit the spine, causing neurologic symptoms (called radiculopathy). This complication of multiple myeloma most commonly affects the chest, lower back, or legs, and the symptoms may include odd sensations (numbness or tingling), pain, or muscle weakness.
Occasionally, neurologic symptoms occur because plasma cells grow within the spinal canal and press on the spinal cord. The symptoms may include severe back pain, muscle weakness, especially of the legs, numbness or tingling, and loss of control of bowel or bladder function (incontinence). Spinal cord compression is a medical emergency and requires immediate treatment to relieve the pressure and prevent permanent damage.
Generalized symptoms — The generalized symptoms of MM include an increased susceptibility to infections (especially during chemotherapy) and weight loss. Occasionally, it causes increased bleeding or tumors of the ribs. In individuals with advanced MM, tumor cells may accumulate beneath the skin, causing large purple-colored bumps.
DIAGNOSTIC TESTING — The diagnosis of MM is based upon the presence of characteristic signs and symptoms of the disease and on the results of tests of the blood and bone marrow. Several different tests are used to determine the presence and severity of MM. In some individuals with early MM or related conditions, it may be necessary to repeat these tests periodically until the diagnosis is certain.
After MM is confirmed, additional tests are used to check for the presence of impaired kidney function, anemia, thickening of the blood, and other complications of multiple myeloma.
Blood and urine tests for monoclonal protein — An abnormal protein produced by the plasma cells, called a monoclonal (M) protein (sometimes called a "paraprotein"), can be found in the blood or urine of almost all patients with MM, which helps establish the diagnosis. These proteins serve no useful function, and may be responsible for increases in the thickness of the blood, kidney damage, or bleeding problems.
However, it is important to remember that not everyone with a monoclonal protein has MM. The diagnosis requires, in addition to the monoclonal protein, one or more abnormalities such as anemia, bone lesions (see "X-rays" below), kidney failure, or high calcium levels in the blood (see "Criteria for diagnosis" below).
Bone marrow examination — In most individuals with MM, a bone marrow aspiration and biopsy (a collection of a small sample of bone marrow for laboratory analysis, usually taken from the hip) shows that plasma cells comprise an abnormally high percentage of bone marrow cells (more than 10 percent). It may be necessary to collect samples from different areas because MM may affect the marrow of some bones but not others.
X-rays — In about 80 percent of individuals, routine x-rays show distinct, round (lytic) areas of bone erosion; generalized thinning of the bones; and/or fractures at the time of diagnosis. The bones most commonly involved are the vertebrae, the ribs, the pelvic bones, and the bones of the thigh and upper arm.
Genetic and chromosomal tests — Specialized tests may reveal genetic or chromosomal abnormalities of the plasma cells in individuals with MM. In general, such abnormalities are associated with a poorer prognosis. The results of these tests are helpful for predicting the response to treatment and survival.
Plasma cell labeling index — The plasma cell labeling index determines how rapidly the abnormal plasma cells are growing and dividing. Patients in whom the labeling index is low tend to have slower disease progression than those with high values. This test is also useful for distinguishing MM from related conditions that generally have a better prognosis. A normal plasma cell labeling index suggests that MM is less likely, while an elevated index suggests that multiple myeloma is more likely. However, this test is not generally available.
Criteria for diagnosis — The diagnosis of multiple myeloma requires the following: A bone marrow aspirate or biopsy showing that at least 10 percent of the cells are plasma cells or the presence of a plasma cell tumor (called a plasmacytoma), plus: M protein in the blood or urine, or Evidence of damage to the body as a result of the plasma cell growth, such as destructive bone lesions, kidney failure, anemia, or high calcium in the blood.
STAGING AND PROGNOSIS — The simplest measure of prognosis in MM is based on blood levels of two markers: beta-2-microglobulin and albumin. In general, higher levels of beta-2-microglobulin and lower levels of albumin are associated with a poorer prognosis. This staging system is referred to as the International Staging System, or ISS.
The older Durie-Salmon staging system divided patients into three stages: Stages I, II, and III, corresponding to low, intermediate, and high cell mass, depending on such factors as the degree of anemia, calcium level, kidney function, presence or absence of bone lesions, and the amount of the abnormal protein. It is best used as a measure of the overall amounts of malignant plasma cells present in the patient, and is less useful as a measure of prognosis.
TREATMENT OVERVIEW — The treatment of MM is complex because of rapid advances in stem cell transplantation, medications, and better supportive care. The main options for therapy include: Chemotherapy Stem cell (bone marrow) transplantation
Each option needs to be weighed carefully. Because current therapy is rarely curative, patients will likely go through many treatment options during the course of their illness. Stem cell transplantation may not be an option for many patients because of advanced age, presence of other serious illness, or other physical limitations (see "Stem cell transplantation" below).
CHEMOTHERAPY — Chemotherapy is usually the first treatment recommended. In most individuals, chemotherapy partially controls MM; rarely, chemotherapy leads to complete remission. The response to initial chemotherapy also helps to estimate how long an individual will survive.
A person who "responds" to chemotherapy must have a 50 percent reduction in blood and urine levels of the abnormal M protein and an improvement of symptoms. Individuals who have any response to chemotherapy (even if it does not meet the above definition) survive approximately three years, while individuals who do not have a response survive approximately one to two years.
The treatment of MM is tailored to a variety of individual factors, including the stage of MM, age, overall health, and personal preferences.
Timing of chemotherapy — Multiple myeloma can remain stable for prolonged periods of time. Individuals with early myeloma (stage I: low cell mass by the Durie-Salmon staging system) who have no symptoms (often called smoldering or indolent myeloma) may be advised to wait months to years before considering chemotherapy.
Individuals with a related condition, called monoclonal gammopathy of undetermined significance (MGUS), do not require treatment, although long-term follow-up is needed; a percentage of patients with MGUS will eventually develop full-blown myeloma.
Chemotherapy is recommended for individuals who have symptoms of multiple myeloma at the time of diagnosis.
Initial chemotherapy options — The type of chemotherapy initially recommended for treatment of MM depends upon the patient's age, underlying medical illnesses, and the likelihood of undergoing stem cell transplantation in the future. Melphalan prednisone (MP) chemotherapy is usually recommended first for individuals over the age of 75 and younger individuals who will not be undergoing stem cell (bone marrow) transplantation at a later time because of associated illnesses or poor health. If later transplantation is a possibility, stem cells should be collected before the start of melphalan chemotherapy because this drug can cause long-lasting damage to stem cells. For individuals between 65 and 75 years who do not plan to undergo stem cell transplantation, melphalan, prednisone, and thalidomide (MPT) is recommended. This is also recommended if a rapid response is needed.
For either of the above groups, chemotherapy is usually continued until the patient reaches a plateau phase (see "Plateau phase" below). For individuals who hope to undergo stem cell transplantation, treatment with dexamethasone plus thalidomide is recommended (thal/dex) or another similar regimen is recommended. These treatments do not interfere with later collection of stem cells. For individuals who have renal failure at the time initial chemotherapy is needed, treatment with dexamethasone alone or dexamethasone plus thalidomide is often preferred.
Melphalan prednisone (MP) chemotherapy — Melphalan (Alkeran, a drug in the alkylating agent class of chemotherapy drugs) and prednisone (a steroid) are taken by mouth three times daily for seven days; this is repeated every four to six weeks. A one week dose is called a cycle. It may take 6 to 12 months or even longer for blood tests to reflect the full effects of this chemotherapy on multiple myeloma.
Between 50 and 60 percent of individuals with MM have a response to melphalan-prednisone chemotherapy. The average survival among individuals treated with this chemotherapy is three years.
During melphalan-prednisone chemotherapy, periodic blood tests are needed to ensure that an individual has adequate levels of white blood cells (cells that fight infection) and platelets (blood components that are important for clotting). The dose of melphalan must be adjusted based on these findings.
Thalidomide — Thalidomide (Thalomid®) is an immune-modulating drug that is effective in the treatment of relapsed MM, either alone or in combination with steroids such as dexamethasone or chemotherapy. Thalidomide is not yet approved for the initial treatment of myeloma, but is commonly used "off label" for this purpose.
Among individuals treated with thalidomide alone for relapsed myeloma, 58 percent survive at least one year, and, on average, 48 percent survive at least two years. The possible side effects of thalidomide, when used for prolonged periods of time, include nerve damage, usually involving the sensory and motor functions of nerves serving the arms and legs, which may not be reversible.
Thalidomide is taken orally. The main side effects are sleepiness, constipation, skin rash, and nerve damage. The use of this medicine in combination with dexamethasone or chemotherapy increases the chance of developing blood clots, and may require the use of anticoagulants ("blood thinners") to prevent this from happening. Thalidomide causes severe birth defects and it is absolutely unsafe (contraindicated) for pregnant women.
Lenalidomide (Revlimid®) is a closely related drug (analogue) of thalidomide. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It has shown clinical activity in MM with fewer side effects than thalidomide (see "Clinical trials" below).
Bortezomib — Bortezomib (Velcade™) is a proteasome inhibitor that is effective in treating patients with refractory MM and other tumors. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It is given intravenously, and its main side effects are low blood counts and nerve damage.
Chemotherapy-related infections — There is an increased risk of infection during the first two months of chemotherapy. Infections often require stopping chemotherapy. Therefore, daily antibiotics may be recommended for individuals starting chemotherapy to reduce the risk of infection and the severity of infections that do occur.
Plateau phase — Chemotherapy is usually continued until MM enters a stable (plateau) phase. The plateau phase is reached when the myeloma becomes stable and shows no signs of progressing. Although this phase is usually temporary, it typically lasts six months or longer. The plateau phase occurs in about one half of individuals after chemotherapy.
Achieving this phase usually requires at least six cycles of chemotherapy, but it may require additional cycles. Additional chemotherapy is not needed or recommended during the plateau phase.
STEM CELL TRANSPLANTATION — Stem cell or bone marrow transplantation is a treatment option for some individuals with MM. There are three types of transplantation, based on the source of the stem cells: Autologous transplantation: the stem cells are obtained from the individual with MM. This is the type of transplantation that is most commonly recommended. Allogeneic transplantation: the stem cells or bone marrow are obtained from a donor with a tissue type matching that of the patient. This type of transplantation carries very high risks and is not recommended for most individuals with MM. Syngeneic transplantation: the stem cells or bone marrow are obtained from an identical twin of the individual. This is the optimal form of transplant at this time, but only rare individuals with MM have an available identical twin who can serve as a donor.
Transplantation, when successful, prolongs survival, leads to a remission, and, infrequently, cures MM. However, transplantation has several limitations. The high-dose chemotherapy (even with radiation) given before transplantation usually fails to kill all of plasma cells, allowing the condition to relapse. Such treatment also puts the patient at risk for serious infections and bleeding, which might be fatal. (See "Patient information: Overview of bone marrow transplantation").
Autologous stem cell transplantation — Autologous stem cell transplantation refers to transplantation with an individual's own stem cells. During this procedure, stem cells are collected and frozen for later use. High-dose chemotherapy is then given to kill as many plasma cells as possible, and the stem cells are thawed and returned to the patient. Stem cells obtained from the peripheral blood of the patient are preferred over bone marrow, because peripheral blood stem cells take up residence in tissues more quickly and are less likely to be contaminated with residual malignant plasma cells.
At present, autologous stem cell (or bone marrow) transplantation is appropriate for up to 50 percent of individuals with multiple myeloma.
Procedure — After initial therapy with a regimen such as thalidomide/dexamethasone for about four months, an individual is given granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to stimulate the production of stem cells. Stem cells are then collected from the blood, frozen, and stored for later use.
After an individual recovers from the stem cell collection, he or she is given high-dose chemotherapy with melphalan (or similar drugs) to kill as many of the malignant plasma cells as possible; then the previously collected stem cells are thawed and returned to the patient. In about one-half of patients, this procedure can be done on an outpatient basis.
Alternatively, after stem cell collection, an individual may be given standard chemotherapy with melphalan (or similar drugs) to achieve a plateau phase. At the time of relapse, high doses of melphalan (or similar drugs) are given, and the previously collected stem cells are returned to the patient ("delayed transplantation").
Role of age and stage of myeloma — Because autologous transplantation has serious side effects, it is generally not recommended for individuals over the age of 70. However, this procedure may be an option for some individuals over the age of 70 who are otherwise healthy. The likelihood of a good response to transplantation is somewhat lower for older adults than for younger adults, but the effects of age on survival after transplantation are still uncertain.
Autologous stem cell transplantation is not recommended for individuals with early stage (Durie-Salmon stage I) or smoldering myeloma.
Importance of prior treatment — Autologous transplantation is not recommended for individuals who have received prolonged chemotherapy with alkylating drugs (such as melphalan). In such instances, it is very difficult to collect a sufficient number of healthy stem cells for transplantation.
If transplantation is a possibility, initial therapy with dexamethasone alone or thalidomide plus dexamethasone is usually recommended. In contrast to alkylating drugs such as melphalan, these agents do not cause damage to the stem cells.
Effectiveness — About one to two percent of individuals die from complications related to transplantation. However, compared with chemotherapy, autologous stem cell transplantation is more likely to produce a response, and is associated with survival approximately 12 months longer than that produced by chemotherapy alone.
Single versus double autologous transplantation — Double autologous transplantation (two consecutive autologous transplantations) may be more effective than single autologous transplantation if the first transplant has not produced a complete or near complete response. The second transplantation is usually performed within six months of the first.
Among individuals undergoing double transplantation, 51 percent have a complete response, lasting, on average, 50 months. One study has shown that double transplantation improves long-term survival relative to single transplantation with the greatest benefit seen in patients who have not achieved an excellent response with the first transplant.
Allogeneic bone marrow transplantation — An allogeneic stem cell or bone marrow transplantation is a treatment option for only 5 to 10 percent of individuals with multiple myeloma. This type of transplantation has two advantages over autologous transplantation: the donated stem cells do not contain any malignant plasma cells, and the transplanted cells may target and help control any remaining myeloma cells. This latter beneficial effect is called the "graft versus tumor" effect. However, allogeneic transplantation is also associated with a "graft versus host" effect, in which cells from the donor attack tissues of the host, resulting in damage to various organs, such as the skin, liver, and intestines.
Allogeneic transplantation requires bone marrow or stem cells from a donor with a matching tissue type. Under the best conditions, a sibling may qualify as a donor; otherwise national bone marrow donor banks may be employed to find a donor with a matching tissue type. The donated bone marrow or stem cells are given to the patient after he/she receives appropriate doses of high-dose chemotherapy and radiation to reduce the number of malignant plasma cells.
About one half of individuals have a complete response after allogeneic transplantation. Thirty percent of individuals live for at least four years, and 20 percent of individuals live for at least 10 years. The likelihood of a complete response to allogeneic bone marrow transplantation is highest in individuals with a lower number of myeloma cells and in individuals who have had a complete response to the initial chemotherapy.
Although multiple myeloma usually relapses after allogeneic transplantation, some individuals are cured of multiple myeloma after this type of transplantation.
Unfortunately, approximately 25 percent of individuals who undergo allogeneic transplantation die from transplant-related complications, such as infection, lung inflammation, and graft-versus-host disease. Thus, the potential benefit of allogeneic transplantation (long-term disease control or cure) must be weighed against the potential for immediate morbidity and mortality. Primarily because of this toxicity, allogeneic transplantation is seldom used for the treatment of myeloma.
Nonmyeloablative allogeneic transplantation — Because autologous transplantation is not often curative and allogeneic transplantation carries a high mortality, other solutions have been sought. These include nonmyeloablative allogeneic transplants (often called "mini transplants") in which the patient receives a lower dose of chemotherapy prior to an allogeneic transplant.
The best results have been seen when a nonmyeloablative allogeneic transplantation is conducted following an initial autologous transplantation. However, the best preparative regimen and the control of graft versus host disease are evolving. We believe that this procedure should be done only in a research setting.
Donor lymphocyte infusion — Donor lymphocyte infusion is an experimental procedure that is a good option for individuals who have a relapse of multiple myeloma after allogeneic stem cell transplantation. During this procedure, lymphocytes collected from the original donor are given to the individual; these lymphocytes target the myeloma cells and may produce a beneficial "graft versus tumor" effect. Fifty-two percent of individuals have a response to this procedure, and 22 percent of individuals have a complete response.
Syngeneic transplantation — A syngeneic transplantation refers to a transplantation between identical twins. For individuals who have an identical twin, this treatment option is more effective than either autologous or allogeneic transplantation.
Remission after transplantation — The strict definition of remission requires that there are no signs or symptoms of multiple myeloma and that highly sensitive tests do not detect any abnormal plasma cells. This type of remission occurs in about 4 percent of individuals after autologous transplantation and about 19 percent of individuals after allogeneic transplantation.
TREATMENT OF COMPLICATIONS — Multiple myeloma can cause a variety of complications, some of which are life-threatening. It is important to treat these complications in addition to treating MM itself.
High blood calcium levels — High blood calcium levels develop as bone is lost. Individuals with MM should remain as active as possible because physical activity helps counter bone loss.
The treatment of high blood calcium levels usually includes use of intravenous fluids and prednisone. If this treatment is not effective, treatment with drugs that counter bone loss, such as zoledronic acid (Zometa™) or pamidronate (Aredia™), a class of drugs called bisphosphonates, may be recommended.
Impaired kidney function — Kidney function becomes impaired in about one half of individuals with multiple myeloma. The treatment of impaired kidney function is aimed at the specific underlying cause.
Treatment usually includes intravenous fluids; it may also include dialysis (a type of blood filtration used for kidney failure), prednisone (a steroid that can indirectly lower blood calcium levels), and allopurinol, a drug that can lower blood levels of uric acid, a waste product from the increased turnover of the malignant plasma cells, which can damage the kidneys.
Patients are advised to stay well-hydrated and should drink enough fluid to produce three liters of urine daily if they have Bence Jones proteinuria (increased light chains in the urine). They should also avoid using any nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil®, Motrin®, Aleve®) because these drugs might worsen kidney function.
If impaired kidney function has progressed to kidney failure, the treatment options include hemodialysis or peritoneal dialysis. Advanced degrees of kidney failure are usually not reversible even if the multiple myeloma later responds to treatment. (See "Patient information: Renal replacement therapy").
Infection — Bacterial infections, often indicated by the presence of fever, require prompt treatment with antibiotics. Daily use of the antibiotic trimethoprim-sulfamethoxazole (Bactrim) can help prevent infections. Individuals who get frequent infections may be advised to take penicillin daily or rarely to have periodic intravenous infusions of gamma globulin.
All individuals with MM should receive the pneumococcal vaccine (which reduces the likelihood of pneumonia) and the influenza vaccine (which reduces the likelihood of flu). (See "Patient information: Influenza").
Bone pain and fractures — Physical activity, with careful avoidance of injury, can promote bone strength in individuals with MM. The bone pain associated with MM can be controlled with chemotherapy, analgesics (pain relieving drugs), radiation, and bone strengthening drugs such as zoledronic acid (Zometa™) or pamidronate (Aredia™) (commonly referred to as bisphosphonates) that can also reduce the likelihood of fractures.
In individuals who have early signs of bone erosion, bisphosphonates reduce the risk of fractures and reduce bone pain. Therefore, bisphosphonates are recommended for all individuals who have early signs of bone erosions on x-rays. Bisphosphonates are usually given by intravenous infusion every four weeks; this treatment is continued for approximately two years. Zoledronic acid requires infusion times as short as 15 to 30 minutes. These medications may affect kidney function, which should be monitored on a regular basis to avoid this complication.
Dental procedures, such as root canal or extraction of teeth, may be associated with infection or osteonecrosis of the jaw in patients treated with intravenous bisphosphonates. Accordingly, patients should avoid such procedures while taking these agents; any needed dental procedures should be performed before these agents are started.
Spinal cord compression — Spinal cord compression is a medical emergency that requires prompt treatment to prevent irreversible damage, such as paralysis. Initial treatment may consist of radiation and dexamethasone (a steroid) to reduce swelling around the spinal cord; if these measures are not effective, surgery is needed to relieve pressure on the spinal cord.
Anemia — Anemia that is causing symptoms can be treated with erythropoietin (EPO), a substance that stimulates the production of red blood cells. Erythropoietin is usually given by injection one to three times per week. This treatment effectively increases levels of hemoglobin (the protein in red blood cells that helps carry oxygen to the tissues), improves symptoms, and reduces the need for blood transfusion.
Thickening of the blood — Thickening of the blood (called hyperviscosity syndrome) rarely occurs in individuals with MM. This complication is treated with plasmapheresis, a type of blood filtration that removes the excess monoclonal proteins responsible for the increased viscosity.
TREATMENT OF RELAPSED OR REFRACTORY DISEASE — Almost all patients with MM who survive their first cycle of treatment eventually relapse, and a modest percentage are resistant to initial treatment.
MM that responds poorly or not at all to melphalan-prednisone or other chemotherapy is called refractory MM. This condition can occur during initial chemotherapy or during chemotherapy given after a relapse. Refractory MM is more difficult to treat.
Thalidomide, bortezomib, and lenalidomide have all shown significant single-agent activity in relapsed or refractory MM; together with alkylators and corticosteroids, they form the major treatment options for relapsed or resistant disease. Relapses occurring more than six months after completing chemotherapy are usually treated by resuming the initial chemotherapy. Most individuals will again have a response to chemotherapy when it is given a second time, but the response is usually shorter and less marked than the original response. Selected patients can consider autologous or allogeneic stem cell transplantation. The lack of response to initial induction chemotherapy does not always mean that the person will not have good response to autologous hematopoietic cell transplantation. Said another way, if a person does not respond to induction chemotherapy, he or she may still respond to autologous stem cell transplantation.
CLINICAL TRIALS — Progress in treating multiple myeloma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies; clinical trials are conducted all over the world. 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. The International Myeloma Foundation
(www.myeloma.org)
Multiple Myeloma Research Foundation
(www.multiplemyeloma.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Diagnosis and management of multiple myeloma. Br J Haematol 2001; 115:522.
2. Kyle, RA. Multiple myeloma: an odyssey of discovery. Br J Haematol 2000; 111:1035.
3. Riedel, DA, Pottern, LM. The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 1992; 6:225.
4. Kyle, RA, Rajkumar, SV. Multiple Myeloma. N Engl J Med 2004; 351:1860.
5. Rajkumar, SV, Kyle, RA. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc 2005; 80:1371.
Staging and treatment for Hodgkin's disease
DEFINITION — Hodgkin's disease, also known as Hodgkin's lymphoma, is one of two common types of cancer of the body's lymphatic system. The lymphatic system is a network of lymph nodes and interconnecting lymph vessels (show figure 1). Lymph nodes are small, pea-shaped organs that make and store lymphocytes, a type of white blood cell that fights infection. Lymph vessels are similar to blood vessels, and carry a watery fluid (lymphatic fluid) that contains lymphocytes. The thymus, spleen, and bone marrow are other organs in the lymphatic system.
In Hodgkin's lympoma, a cancerous tumor develops in a lymph node, usually in the neck or chest. If Hodgkin's lympoma spreads, its pattern is to first spread to adjacent lymph nodes, and then to the spleen, liver, or bone marrow. As it progresses, Hodgkin's lympoma may affects the body's ability to fight infection.
Fortunately, Hodgkin's disease is one of the most treatable forms of cancer. About 75 percent of patients diagnosed with Hodgkin's disease can be cured with treatment. Over 90 percent are expected to live at least 10 years following diagnosis and treatment.
The following discussion will review the staging and treatment for Hodgkin's lympoma. Issues regarding the risk factors and diagnosis of the disease are discussed in a separate topic review. (See "Patient information: Features and diagnosis of Hodgkin's disease").
STAGING — One of the reasons that Hodgkin's lympoma treatment is successful is the ability to carefully plan treatment based upon a patient's stage of illness. Staging involves dividing patients with Hodgkin's lympoma into groups (stages) based upon criteria at the time of diagnosis. Treatment decisions are based in large part on the stage of disease that is found.
The following are terms used in the staging criteria: Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show figure 3). Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland. Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.
Stage I — Only one lymph node region is involved, or only one lymph structure is involved.
Stage II — Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.
Stage III — Lymph node regions or structures on both sides of the diaphragm are involved.
Stage IV — There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.
Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". E — The presence of local spread of the disease from one nodal area or structure to surrounding or extranodal tissue in the same area of the body is indicated by the letter "e," as in stage IIe. S — Involvement of the spleen is designated by the letter "s", as in stage IIIs. X — The presence of "bulky disease," referring to larger masses of cancerous tissue, is indicated by the letter x.
For example, a patient with Hodgkin's disease involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.
DETERMINING STAGE — A number of tests are used in the process of disease staging. However, not all patients will require every test.
History and physical exam — A careful history and physical examination will help determine whether symptoms related to Hodgkin's disease have been present (eg, fever, night sweats, weight loss). The physical exam may reveal swollen lymph nodes in various locations (show figure 1).
Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected by Hodgkin's disease. Tests that may be done include: Chest X-ray CT scan of the chest, abdomen, and pelvic area Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. This is done for persons with stage IIB and higher. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.
Staging laparotomy — In the past, surgery was done in order to directly visualize and take samples from areas in the abdomen in order to determine the stage of the Hodgkin's disease. The operation, called a staging laparotomy, is now rarely done because there are other procedures that do not require a surgical procedure.
However, staging laparotomy may still be offered to patients who have early stage Hodgkin's disease with a good prognosis. Staging laparotomy provides reassurance that the disease is not widespread and allows patients the option of avoiding some of the risks and side effects associated with more extensive treatment.
TREATMENT — The mainstays of treatment for Hodgkin's lympoma are chemotherapy and radiation. Chemotherapy uses strong medicines to kill cancer cells while radiation therapy uses high-energy particles (gamma rays) to slow or stop the growth of cancer cells. Decisions about whether to use chemotherapy, radiation, or both depend upon several factors, including the stage of the disease and the presence or absence of large tumor masses.
Radiation therapy — Radiation therapy is administered to the region of affected lymph nodes with a carefully focused beam of radiation; this is called involved field radiation. Radiation therapy must be given in small daily doses over a period of weeks in order to minimize the side effects; the number of weeks depends upon the amount of radiation to be administered.
Side effects — During radiation treatment, some patients develop skin changes in the area that was treated, similar to a sunburn. These changes fade over time. Other side effects can include fatigue, and nausea.
Some forms of radiation therapy increase the risk of developing cancer in areas that have received incidental radiation (such as to the lungs and breast tissue) years after therapy is completed. Women under 30 are at increased risk of breast cancer, and smokers have an increased risk of lung cancer (beyond the already increased risk of lung cancer from smoking). A patient and his or her healthcare provider should discuss these issues when deciding upon a treatment plan.
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.
Modern chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. 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 is a one hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.
Chemotherapy regimens are identified by their initials and include: ABVD — ABVD includes Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine, and is the most commonly used chemotherapy regimen. Stanford V — Stanford V includes Adriamycin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone. BEACOPP — BEACOPP includes bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin®, procarbazine, and prednisone. This regimen is more commonly used in Europe. MOPP — MOPP includes mechlorethamine, Oncovin® (vincristine), procarbazine, and prednisone, and was one of the first chemotherapy regimens to be used for Hodgkin's lymphoma. It is no longer recommended for most patients due to its serious toxic side effects.
These regimens have been created to maximize effectiveness and minimize short-term and long-term side effects; as new medications and combinations are developed, it is hoped that survival will continue to improve as life-threatening and long-term complications diminish.
Side effects — The type and severity of side effects depends upon the type, combination, and dose of chemotherapy medication used. The most common treatment-related side effects include hair loss, nausea, vomiting, fatigue, loss of appetite, increased risk of infections, and becoming bruised or bleeding easily. Many of these side effects can be prevented or treated with other medications, such as those used for nausea and vomiting.
Long-term side effects of chemotherapy include infertility; in one study, 36 percent of men and 20 percent of women were infertile after undergoing ABVD [4]. This is an improvement over MOPP therapy, which caused 97 percent of men to become infertile. However, men and women who would like to have children after treatment should consider sperm or egg banking before chemotherapy begins.
A long-term side effect of bleomycin is damage to the lungs; this risk is highest in children and those who have radiation therapy to the mediastinum (mid-chest).
Stage I or II — For patients with Stage I or II disease, additional criteria are used to define the extent of disease. Criteria include: the presence of a large mass in the chest, the number of lymph node regions are affected by Hodgkin's lympoma, the age of the patient, the presence of B symptoms, and a specific abnormality in the erythrocyte sedimentation rate (a blood test).
Persons without these criteria are referred to as having favorable disease, while those with these characteristics are referred to as having unfavorable disease.
Favorable disease — A number of choices are available for patients with stage I or II disease with a favorable designation. As noted above, some of these patients may undergo staging laparotomy in order to be sure that the disease has not spread. If spread is not found, a patient may be treated with only radiation to the affected area.
Treatment choices include chemotherapy and radiation or radiation alone. The use of chemotherapy along with radiation is associated with a lower relapse rate, but potentially higher toxicity. Radiation or chemotherapy alone carry a higher risk of relapse, but patients who do relapse may be easier to treat than those who relapse following chemotherapy plus radiation.
A patient should discuss these options with their clinician because the patient's preferences (risk of recurrence of disease versus possible toxic effects of treatment) are an important part of the decision-making process. The treatment of early stage Hodgkin's disease has become so successful that at 15 to 20 years posttreatment, the overall mortality rate from causes other than Hodgkin's disease may be higher than that seen from Hodgkin's disease (show figure 4).
Unfavorable disease — Patients at Stage I or II with an unfavorable designation are generally treated with chemotherapy and radiation. Combination therapy allows approximately 80 to 85 percent of patients with unfavorable Hodgkin's lympoma to be alive and without disease relapse 10 years after treatment.
Stage III and IV — The primary treatment for patients with stage III and IV Hodgkin's lympoma is chemotherapy. Radiation therapy may be added if there are large masses that remain after chemotherapy or areas that do not show a complete response to chemotherapy.
Most patients will receive the ABVD regimen. With this, 60 to 70 percent of patients will be alive and free of disease at five years. ABVD is much less likely to cause severe bone marrow suppression (called myelosuppression, which can lead to very low white and red blood cell and platelet counts), acute leukemia, or sterility compared to treatment regimens, such as MOPP. ABVD alone is the treatment of choice for most patients with advanced disease, although Stanford V and BEACOPP combined with involved field radiotherapy are reasonable alternatives for some patients.
Bone marrow transplantation — Bone marrow transplantation (also called hematopoietic cell transplantation) may be offered to some patients who have recurrent Hodgkin's lympoma, or Hodgkin's lympoma that is resistant to other forms of treatment. This includes patients whose disease relapses following initial treatment. A separate topic review is available about bone marrow transplantation. (See "Patient information: Overview of bone marrow transplantation").
CLINICAL TRIALS — Many patients with Hodgkin's disease will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your healthcare provider for more information, or read about clinical trials at: National Cancer Institute
(www.cancer.gov/clinicaltrials/)
National Library of Medicine
(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 Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
CancerNet, from the National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
Cure for Lymphoma Foundation
(www.cfl.org)
Lymphoma Research Foundation of America
(www.lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
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. Lister, TA, Crowther, D, Sutcliffe, SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989; 7:1630.
2. Henry-Amar, M, Somers, R. Survival outcome after Hodgkin's disease: A report from the international data base on Hodgkin's disease. Semin Oncol 1990; 17:758.
3. Advani, RH, Horning, SJ. Treatment of early-stage Hodgkin's disease. Semin Hematol 1999; 36:270.
4. Viviani, S, Santoro, A, Ragni, G, et al. Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 1985; 21:601.
In Hodgkin's lympoma, a cancerous tumor develops in a lymph node, usually in the neck or chest. If Hodgkin's lympoma spreads, its pattern is to first spread to adjacent lymph nodes, and then to the spleen, liver, or bone marrow. As it progresses, Hodgkin's lympoma may affects the body's ability to fight infection.
Fortunately, Hodgkin's disease is one of the most treatable forms of cancer. About 75 percent of patients diagnosed with Hodgkin's disease can be cured with treatment. Over 90 percent are expected to live at least 10 years following diagnosis and treatment.
The following discussion will review the staging and treatment for Hodgkin's lympoma. Issues regarding the risk factors and diagnosis of the disease are discussed in a separate topic review. (See "Patient information: Features and diagnosis of Hodgkin's disease").
STAGING — One of the reasons that Hodgkin's lympoma treatment is successful is the ability to carefully plan treatment based upon a patient's stage of illness. Staging involves dividing patients with Hodgkin's lympoma into groups (stages) based upon criteria at the time of diagnosis. Treatment decisions are based in large part on the stage of disease that is found.
The following are terms used in the staging criteria: Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show figure 3). Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland. Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.
Stage I — Only one lymph node region is involved, or only one lymph structure is involved.
Stage II — Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.
Stage III — Lymph node regions or structures on both sides of the diaphragm are involved.
Stage IV — There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.
Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". E — The presence of local spread of the disease from one nodal area or structure to surrounding or extranodal tissue in the same area of the body is indicated by the letter "e," as in stage IIe. S — Involvement of the spleen is designated by the letter "s", as in stage IIIs. X — The presence of "bulky disease," referring to larger masses of cancerous tissue, is indicated by the letter x.
For example, a patient with Hodgkin's disease involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.
DETERMINING STAGE — A number of tests are used in the process of disease staging. However, not all patients will require every test.
History and physical exam — A careful history and physical examination will help determine whether symptoms related to Hodgkin's disease have been present (eg, fever, night sweats, weight loss). The physical exam may reveal swollen lymph nodes in various locations (show figure 1).
Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected by Hodgkin's disease. Tests that may be done include: Chest X-ray CT scan of the chest, abdomen, and pelvic area Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. This is done for persons with stage IIB and higher. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.
Staging laparotomy — In the past, surgery was done in order to directly visualize and take samples from areas in the abdomen in order to determine the stage of the Hodgkin's disease. The operation, called a staging laparotomy, is now rarely done because there are other procedures that do not require a surgical procedure.
However, staging laparotomy may still be offered to patients who have early stage Hodgkin's disease with a good prognosis. Staging laparotomy provides reassurance that the disease is not widespread and allows patients the option of avoiding some of the risks and side effects associated with more extensive treatment.
TREATMENT — The mainstays of treatment for Hodgkin's lympoma are chemotherapy and radiation. Chemotherapy uses strong medicines to kill cancer cells while radiation therapy uses high-energy particles (gamma rays) to slow or stop the growth of cancer cells. Decisions about whether to use chemotherapy, radiation, or both depend upon several factors, including the stage of the disease and the presence or absence of large tumor masses.
Radiation therapy — Radiation therapy is administered to the region of affected lymph nodes with a carefully focused beam of radiation; this is called involved field radiation. Radiation therapy must be given in small daily doses over a period of weeks in order to minimize the side effects; the number of weeks depends upon the amount of radiation to be administered.
Side effects — During radiation treatment, some patients develop skin changes in the area that was treated, similar to a sunburn. These changes fade over time. Other side effects can include fatigue, and nausea.
Some forms of radiation therapy increase the risk of developing cancer in areas that have received incidental radiation (such as to the lungs and breast tissue) years after therapy is completed. Women under 30 are at increased risk of breast cancer, and smokers have an increased risk of lung cancer (beyond the already increased risk of lung cancer from smoking). A patient and his or her healthcare provider should discuss these issues when deciding upon a treatment plan.
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.
Modern chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. 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 is a one hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.
Chemotherapy regimens are identified by their initials and include: ABVD — ABVD includes Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine, and is the most commonly used chemotherapy regimen. Stanford V — Stanford V includes Adriamycin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone. BEACOPP — BEACOPP includes bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin®, procarbazine, and prednisone. This regimen is more commonly used in Europe. MOPP — MOPP includes mechlorethamine, Oncovin® (vincristine), procarbazine, and prednisone, and was one of the first chemotherapy regimens to be used for Hodgkin's lymphoma. It is no longer recommended for most patients due to its serious toxic side effects.
These regimens have been created to maximize effectiveness and minimize short-term and long-term side effects; as new medications and combinations are developed, it is hoped that survival will continue to improve as life-threatening and long-term complications diminish.
Side effects — The type and severity of side effects depends upon the type, combination, and dose of chemotherapy medication used. The most common treatment-related side effects include hair loss, nausea, vomiting, fatigue, loss of appetite, increased risk of infections, and becoming bruised or bleeding easily. Many of these side effects can be prevented or treated with other medications, such as those used for nausea and vomiting.
Long-term side effects of chemotherapy include infertility; in one study, 36 percent of men and 20 percent of women were infertile after undergoing ABVD [4]. This is an improvement over MOPP therapy, which caused 97 percent of men to become infertile. However, men and women who would like to have children after treatment should consider sperm or egg banking before chemotherapy begins.
A long-term side effect of bleomycin is damage to the lungs; this risk is highest in children and those who have radiation therapy to the mediastinum (mid-chest).
Stage I or II — For patients with Stage I or II disease, additional criteria are used to define the extent of disease. Criteria include: the presence of a large mass in the chest, the number of lymph node regions are affected by Hodgkin's lympoma, the age of the patient, the presence of B symptoms, and a specific abnormality in the erythrocyte sedimentation rate (a blood test).
Persons without these criteria are referred to as having favorable disease, while those with these characteristics are referred to as having unfavorable disease.
Favorable disease — A number of choices are available for patients with stage I or II disease with a favorable designation. As noted above, some of these patients may undergo staging laparotomy in order to be sure that the disease has not spread. If spread is not found, a patient may be treated with only radiation to the affected area.
Treatment choices include chemotherapy and radiation or radiation alone. The use of chemotherapy along with radiation is associated with a lower relapse rate, but potentially higher toxicity. Radiation or chemotherapy alone carry a higher risk of relapse, but patients who do relapse may be easier to treat than those who relapse following chemotherapy plus radiation.
A patient should discuss these options with their clinician because the patient's preferences (risk of recurrence of disease versus possible toxic effects of treatment) are an important part of the decision-making process. The treatment of early stage Hodgkin's disease has become so successful that at 15 to 20 years posttreatment, the overall mortality rate from causes other than Hodgkin's disease may be higher than that seen from Hodgkin's disease (show figure 4).
Unfavorable disease — Patients at Stage I or II with an unfavorable designation are generally treated with chemotherapy and radiation. Combination therapy allows approximately 80 to 85 percent of patients with unfavorable Hodgkin's lympoma to be alive and without disease relapse 10 years after treatment.
Stage III and IV — The primary treatment for patients with stage III and IV Hodgkin's lympoma is chemotherapy. Radiation therapy may be added if there are large masses that remain after chemotherapy or areas that do not show a complete response to chemotherapy.
Most patients will receive the ABVD regimen. With this, 60 to 70 percent of patients will be alive and free of disease at five years. ABVD is much less likely to cause severe bone marrow suppression (called myelosuppression, which can lead to very low white and red blood cell and platelet counts), acute leukemia, or sterility compared to treatment regimens, such as MOPP. ABVD alone is the treatment of choice for most patients with advanced disease, although Stanford V and BEACOPP combined with involved field radiotherapy are reasonable alternatives for some patients.
Bone marrow transplantation — Bone marrow transplantation (also called hematopoietic cell transplantation) may be offered to some patients who have recurrent Hodgkin's lympoma, or Hodgkin's lympoma that is resistant to other forms of treatment. This includes patients whose disease relapses following initial treatment. A separate topic review is available about bone marrow transplantation. (See "Patient information: Overview of bone marrow transplantation").
CLINICAL TRIALS — Many patients with Hodgkin's disease will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your healthcare provider for more information, or read about clinical trials at: National Cancer Institute
(www.cancer.gov/clinicaltrials/)
National Library of Medicine
(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 Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
CancerNet, from the National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
Cure for Lymphoma Foundation
(www.cfl.org)
Lymphoma Research Foundation of America
(www.lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
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. Lister, TA, Crowther, D, Sutcliffe, SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989; 7:1630.
2. Henry-Amar, M, Somers, R. Survival outcome after Hodgkin's disease: A report from the international data base on Hodgkin's disease. Semin Oncol 1990; 17:758.
3. Advani, RH, Horning, SJ. Treatment of early-stage Hodgkin's disease. Semin Hematol 1999; 36:270.
4. Viviani, S, Santoro, A, Ragni, G, et al. Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 1985; 21:601.
Staging and treatment for Hodgkin's disease
DEFINITION — Hodgkin's disease, also known as Hodgkin's lymphoma, is one of two common types of cancer of the body's lymphatic system. The lymphatic system is a network of lymph nodes and interconnecting lymph vessels (show figure 1). Lymph nodes are small, pea-shaped organs that make and store lymphocytes, a type of white blood cell that fights infection. Lymph vessels are similar to blood vessels, and carry a watery fluid (lymphatic fluid) that contains lymphocytes. The thymus, spleen, and bone marrow are other organs in the lymphatic system.
In Hodgkin's lympoma, a cancerous tumor develops in a lymph node, usually in the neck or chest. If Hodgkin's lympoma spreads, its pattern is to first spread to adjacent lymph nodes, and then to the spleen, liver, or bone marrow. As it progresses, Hodgkin's lympoma may affects the body's ability to fight infection.
Fortunately, Hodgkin's disease is one of the most treatable forms of cancer. About 75 percent of patients diagnosed with Hodgkin's disease can be cured with treatment. Over 90 percent are expected to live at least 10 years following diagnosis and treatment.
The following discussion will review the staging and treatment for Hodgkin's lympoma. Issues regarding the risk factors and diagnosis of the disease are discussed in a separate topic review. (See "Patient information: Features and diagnosis of Hodgkin's disease").
STAGING — One of the reasons that Hodgkin's lympoma treatment is successful is the ability to carefully plan treatment based upon a patient's stage of illness. Staging involves dividing patients with Hodgkin's lympoma into groups (stages) based upon criteria at the time of diagnosis. Treatment decisions are based in large part on the stage of disease that is found.
The following are terms used in the staging criteria: Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show figure 3). Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland. Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.
Stage I — Only one lymph node region is involved, or only one lymph structure is involved.
Stage II — Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.
Stage III — Lymph node regions or structures on both sides of the diaphragm are involved.
Stage IV — There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.
Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". E — The presence of local spread of the disease from one nodal area or structure to surrounding or extranodal tissue in the same area of the body is indicated by the letter "e," as in stage IIe. S — Involvement of the spleen is designated by the letter "s", as in stage IIIs. X — The presence of "bulky disease," referring to larger masses of cancerous tissue, is indicated by the letter x.
For example, a patient with Hodgkin's disease involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.
DETERMINING STAGE — A number of tests are used in the process of disease staging. However, not all patients will require every test.
History and physical exam — A careful history and physical examination will help determine whether symptoms related to Hodgkin's disease have been present (eg, fever, night sweats, weight loss). The physical exam may reveal swollen lymph nodes in various locations (show figure 1).
Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected by Hodgkin's disease. Tests that may be done include: Chest X-ray CT scan of the chest, abdomen, and pelvic area Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. This is done for persons with stage IIB and higher. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.
Staging laparotomy — In the past, surgery was done in order to directly visualize and take samples from areas in the abdomen in order to determine the stage of the Hodgkin's disease. The operation, called a staging laparotomy, is now rarely done because there are other procedures that do not require a surgical procedure.
However, staging laparotomy may still be offered to patients who have early stage Hodgkin's disease with a good prognosis. Staging laparotomy provides reassurance that the disease is not widespread and allows patients the option of avoiding some of the risks and side effects associated with more extensive treatment.
TREATMENT — The mainstays of treatment for Hodgkin's lympoma are chemotherapy and radiation. Chemotherapy uses strong medicines to kill cancer cells while radiation therapy uses high-energy particles (gamma rays) to slow or stop the growth of cancer cells. Decisions about whether to use chemotherapy, radiation, or both depend upon several factors, including the stage of the disease and the presence or absence of large tumor masses.
Radiation therapy — Radiation therapy is administered to the region of affected lymph nodes with a carefully focused beam of radiation; this is called involved field radiation. Radiation therapy must be given in small daily doses over a period of weeks in order to minimize the side effects; the number of weeks depends upon the amount of radiation to be administered.
Side effects — During radiation treatment, some patients develop skin changes in the area that was treated, similar to a sunburn. These changes fade over time. Other side effects can include fatigue, and nausea.
Some forms of radiation therapy increase the risk of developing cancer in areas that have received incidental radiation (such as to the lungs and breast tissue) years after therapy is completed. Women under 30 are at increased risk of breast cancer, and smokers have an increased risk of lung cancer (beyond the already increased risk of lung cancer from smoking). A patient and his or her healthcare provider should discuss these issues when deciding upon a treatment plan.
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.
Modern chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. 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 is a one hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.
Chemotherapy regimens are identified by their initials and include: ABVD — ABVD includes Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine, and is the most commonly used chemotherapy regimen. Stanford V — Stanford V includes Adriamycin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone. BEACOPP — BEACOPP includes bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin®, procarbazine, and prednisone. This regimen is more commonly used in Europe. MOPP — MOPP includes mechlorethamine, Oncovin® (vincristine), procarbazine, and prednisone, and was one of the first chemotherapy regimens to be used for Hodgkin's lymphoma. It is no longer recommended for most patients due to its serious toxic side effects.
These regimens have been created to maximize effectiveness and minimize short-term and long-term side effects; as new medications and combinations are developed, it is hoped that survival will continue to improve as life-threatening and long-term complications diminish.
Side effects — The type and severity of side effects depends upon the type, combination, and dose of chemotherapy medication used. The most common treatment-related side effects include hair loss, nausea, vomiting, fatigue, loss of appetite, increased risk of infections, and becoming bruised or bleeding easily. Many of these side effects can be prevented or treated with other medications, such as those used for nausea and vomiting.
Long-term side effects of chemotherapy include infertility; in one study, 36 percent of men and 20 percent of women were infertile after undergoing ABVD [4]. This is an improvement over MOPP therapy, which caused 97 percent of men to become infertile. However, men and women who would like to have children after treatment should consider sperm or egg banking before chemotherapy begins.
A long-term side effect of bleomycin is damage to the lungs; this risk is highest in children and those who have radiation therapy to the mediastinum (mid-chest).
Stage I or II — For patients with Stage I or II disease, additional criteria are used to define the extent of disease. Criteria include: the presence of a large mass in the chest, the number of lymph node regions are affected by Hodgkin's lympoma, the age of the patient, the presence of B symptoms, and a specific abnormality in the erythrocyte sedimentation rate (a blood test).
Persons without these criteria are referred to as having favorable disease, while those with these characteristics are referred to as having unfavorable disease.
Favorable disease — A number of choices are available for patients with stage I or II disease with a favorable designation. As noted above, some of these patients may undergo staging laparotomy in order to be sure that the disease has not spread. If spread is not found, a patient may be treated with only radiation to the affected area.
Treatment choices include chemotherapy and radiation or radiation alone. The use of chemotherapy along with radiation is associated with a lower relapse rate, but potentially higher toxicity. Radiation or chemotherapy alone carry a higher risk of relapse, but patients who do relapse may be easier to treat than those who relapse following chemotherapy plus radiation.
A patient should discuss these options with their clinician because the patient's preferences (risk of recurrence of disease versus possible toxic effects of treatment) are an important part of the decision-making process. The treatment of early stage Hodgkin's disease has become so successful that at 15 to 20 years posttreatment, the overall mortality rate from causes other than Hodgkin's disease may be higher than that seen from Hodgkin's disease (show figure 4).
Unfavorable disease — Patients at Stage I or II with an unfavorable designation are generally treated with chemotherapy and radiation. Combination therapy allows approximately 80 to 85 percent of patients with unfavorable Hodgkin's lympoma to be alive and without disease relapse 10 years after treatment.
Stage III and IV — The primary treatment for patients with stage III and IV Hodgkin's lympoma is chemotherapy. Radiation therapy may be added if there are large masses that remain after chemotherapy or areas that do not show a complete response to chemotherapy.
Most patients will receive the ABVD regimen. With this, 60 to 70 percent of patients will be alive and free of disease at five years. ABVD is much less likely to cause severe bone marrow suppression (called myelosuppression, which can lead to very low white and red blood cell and platelet counts), acute leukemia, or sterility compared to treatment regimens, such as MOPP. ABVD alone is the treatment of choice for most patients with advanced disease, although Stanford V and BEACOPP combined with involved field radiotherapy are reasonable alternatives for some patients.
Bone marrow transplantation — Bone marrow transplantation (also called hematopoietic cell transplantation) may be offered to some patients who have recurrent Hodgkin's lympoma, or Hodgkin's lympoma that is resistant to other forms of treatment. This includes patients whose disease relapses following initial treatment. A separate topic review is available about bone marrow transplantation. (See "Patient information: Overview of bone marrow transplantation").
CLINICAL TRIALS — Many patients with Hodgkin's disease will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your healthcare provider for more information, or read about clinical trials at: National Cancer Institute
(www.cancer.gov/clinicaltrials/)
National Library of Medicine
(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 Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
CancerNet, from the National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
Cure for Lymphoma Foundation
(www.cfl.org)
Lymphoma Research Foundation of America
(www.lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
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. Lister, TA, Crowther, D, Sutcliffe, SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989; 7:1630.
2. Henry-Amar, M, Somers, R. Survival outcome after Hodgkin's disease: A report from the international data base on Hodgkin's disease. Semin Oncol 1990; 17:758.
3. Advani, RH, Horning, SJ. Treatment of early-stage Hodgkin's disease. Semin Hematol 1999; 36:270.
4. Viviani, S, Santoro, A, Ragni, G, et al. Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 1985; 21:601.
In Hodgkin's lympoma, a cancerous tumor develops in a lymph node, usually in the neck or chest. If Hodgkin's lympoma spreads, its pattern is to first spread to adjacent lymph nodes, and then to the spleen, liver, or bone marrow. As it progresses, Hodgkin's lympoma may affects the body's ability to fight infection.
Fortunately, Hodgkin's disease is one of the most treatable forms of cancer. About 75 percent of patients diagnosed with Hodgkin's disease can be cured with treatment. Over 90 percent are expected to live at least 10 years following diagnosis and treatment.
The following discussion will review the staging and treatment for Hodgkin's lympoma. Issues regarding the risk factors and diagnosis of the disease are discussed in a separate topic review. (See "Patient information: Features and diagnosis of Hodgkin's disease").
STAGING — One of the reasons that Hodgkin's lympoma treatment is successful is the ability to carefully plan treatment based upon a patient's stage of illness. Staging involves dividing patients with Hodgkin's lympoma into groups (stages) based upon criteria at the time of diagnosis. Treatment decisions are based in large part on the stage of disease that is found.
The following are terms used in the staging criteria: Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show figure 3). Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland. Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.
Stage I — Only one lymph node region is involved, or only one lymph structure is involved.
Stage II — Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.
Stage III — Lymph node regions or structures on both sides of the diaphragm are involved.
Stage IV — There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.
Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". E — The presence of local spread of the disease from one nodal area or structure to surrounding or extranodal tissue in the same area of the body is indicated by the letter "e," as in stage IIe. S — Involvement of the spleen is designated by the letter "s", as in stage IIIs. X — The presence of "bulky disease," referring to larger masses of cancerous tissue, is indicated by the letter x.
For example, a patient with Hodgkin's disease involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.
DETERMINING STAGE — A number of tests are used in the process of disease staging. However, not all patients will require every test.
History and physical exam — A careful history and physical examination will help determine whether symptoms related to Hodgkin's disease have been present (eg, fever, night sweats, weight loss). The physical exam may reveal swollen lymph nodes in various locations (show figure 1).
Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected by Hodgkin's disease. Tests that may be done include: Chest X-ray CT scan of the chest, abdomen, and pelvic area Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. This is done for persons with stage IIB and higher. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.
Staging laparotomy — In the past, surgery was done in order to directly visualize and take samples from areas in the abdomen in order to determine the stage of the Hodgkin's disease. The operation, called a staging laparotomy, is now rarely done because there are other procedures that do not require a surgical procedure.
However, staging laparotomy may still be offered to patients who have early stage Hodgkin's disease with a good prognosis. Staging laparotomy provides reassurance that the disease is not widespread and allows patients the option of avoiding some of the risks and side effects associated with more extensive treatment.
TREATMENT — The mainstays of treatment for Hodgkin's lympoma are chemotherapy and radiation. Chemotherapy uses strong medicines to kill cancer cells while radiation therapy uses high-energy particles (gamma rays) to slow or stop the growth of cancer cells. Decisions about whether to use chemotherapy, radiation, or both depend upon several factors, including the stage of the disease and the presence or absence of large tumor masses.
Radiation therapy — Radiation therapy is administered to the region of affected lymph nodes with a carefully focused beam of radiation; this is called involved field radiation. Radiation therapy must be given in small daily doses over a period of weeks in order to minimize the side effects; the number of weeks depends upon the amount of radiation to be administered.
Side effects — During radiation treatment, some patients develop skin changes in the area that was treated, similar to a sunburn. These changes fade over time. Other side effects can include fatigue, and nausea.
Some forms of radiation therapy increase the risk of developing cancer in areas that have received incidental radiation (such as to the lungs and breast tissue) years after therapy is completed. Women under 30 are at increased risk of breast cancer, and smokers have an increased risk of lung cancer (beyond the already increased risk of lung cancer from smoking). A patient and his or her healthcare provider should discuss these issues when deciding upon a treatment plan.
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.
Modern chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. 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 is a one hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.
Chemotherapy regimens are identified by their initials and include: ABVD — ABVD includes Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine, and is the most commonly used chemotherapy regimen. Stanford V — Stanford V includes Adriamycin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone. BEACOPP — BEACOPP includes bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin®, procarbazine, and prednisone. This regimen is more commonly used in Europe. MOPP — MOPP includes mechlorethamine, Oncovin® (vincristine), procarbazine, and prednisone, and was one of the first chemotherapy regimens to be used for Hodgkin's lymphoma. It is no longer recommended for most patients due to its serious toxic side effects.
These regimens have been created to maximize effectiveness and minimize short-term and long-term side effects; as new medications and combinations are developed, it is hoped that survival will continue to improve as life-threatening and long-term complications diminish.
Side effects — The type and severity of side effects depends upon the type, combination, and dose of chemotherapy medication used. The most common treatment-related side effects include hair loss, nausea, vomiting, fatigue, loss of appetite, increased risk of infections, and becoming bruised or bleeding easily. Many of these side effects can be prevented or treated with other medications, such as those used for nausea and vomiting.
Long-term side effects of chemotherapy include infertility; in one study, 36 percent of men and 20 percent of women were infertile after undergoing ABVD [4]. This is an improvement over MOPP therapy, which caused 97 percent of men to become infertile. However, men and women who would like to have children after treatment should consider sperm or egg banking before chemotherapy begins.
A long-term side effect of bleomycin is damage to the lungs; this risk is highest in children and those who have radiation therapy to the mediastinum (mid-chest).
Stage I or II — For patients with Stage I or II disease, additional criteria are used to define the extent of disease. Criteria include: the presence of a large mass in the chest, the number of lymph node regions are affected by Hodgkin's lympoma, the age of the patient, the presence of B symptoms, and a specific abnormality in the erythrocyte sedimentation rate (a blood test).
Persons without these criteria are referred to as having favorable disease, while those with these characteristics are referred to as having unfavorable disease.
Favorable disease — A number of choices are available for patients with stage I or II disease with a favorable designation. As noted above, some of these patients may undergo staging laparotomy in order to be sure that the disease has not spread. If spread is not found, a patient may be treated with only radiation to the affected area.
Treatment choices include chemotherapy and radiation or radiation alone. The use of chemotherapy along with radiation is associated with a lower relapse rate, but potentially higher toxicity. Radiation or chemotherapy alone carry a higher risk of relapse, but patients who do relapse may be easier to treat than those who relapse following chemotherapy plus radiation.
A patient should discuss these options with their clinician because the patient's preferences (risk of recurrence of disease versus possible toxic effects of treatment) are an important part of the decision-making process. The treatment of early stage Hodgkin's disease has become so successful that at 15 to 20 years posttreatment, the overall mortality rate from causes other than Hodgkin's disease may be higher than that seen from Hodgkin's disease (show figure 4).
Unfavorable disease — Patients at Stage I or II with an unfavorable designation are generally treated with chemotherapy and radiation. Combination therapy allows approximately 80 to 85 percent of patients with unfavorable Hodgkin's lympoma to be alive and without disease relapse 10 years after treatment.
Stage III and IV — The primary treatment for patients with stage III and IV Hodgkin's lympoma is chemotherapy. Radiation therapy may be added if there are large masses that remain after chemotherapy or areas that do not show a complete response to chemotherapy.
Most patients will receive the ABVD regimen. With this, 60 to 70 percent of patients will be alive and free of disease at five years. ABVD is much less likely to cause severe bone marrow suppression (called myelosuppression, which can lead to very low white and red blood cell and platelet counts), acute leukemia, or sterility compared to treatment regimens, such as MOPP. ABVD alone is the treatment of choice for most patients with advanced disease, although Stanford V and BEACOPP combined with involved field radiotherapy are reasonable alternatives for some patients.
Bone marrow transplantation — Bone marrow transplantation (also called hematopoietic cell transplantation) may be offered to some patients who have recurrent Hodgkin's lympoma, or Hodgkin's lympoma that is resistant to other forms of treatment. This includes patients whose disease relapses following initial treatment. A separate topic review is available about bone marrow transplantation. (See "Patient information: Overview of bone marrow transplantation").
CLINICAL TRIALS — Many patients with Hodgkin's disease will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your healthcare provider for more information, or read about clinical trials at: National Cancer Institute
(www.cancer.gov/clinicaltrials/)
National Library of Medicine
(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 Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
CancerNet, from the National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
Cure for Lymphoma Foundation
(www.cfl.org)
Lymphoma Research Foundation of America
(www.lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
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. Lister, TA, Crowther, D, Sutcliffe, SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989; 7:1630.
2. Henry-Amar, M, Somers, R. Survival outcome after Hodgkin's disease: A report from the international data base on Hodgkin's disease. Semin Oncol 1990; 17:758.
3. Advani, RH, Horning, SJ. Treatment of early-stage Hodgkin's disease. Semin Hematol 1999; 36:270.
4. Viviani, S, Santoro, A, Ragni, G, et al. Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 1985; 21:601.
Follicular lymphoma
INTRODUCTION — Lymphoma is a cancer of lymphocytes, a type of white blood cell. Lymphocytes circulate in the body through a network referred to as the lymphatic system, which includes the bone marrow, spleen, thymus, and lymph nodes. The organs and vessels of the lymphatic system work together to produce and store cells that fight infection (show figure 1).
There are two main types of lymphoma: Hodgkin's lymphoma (also called Hodgkin's disease) Non-Hodgkin's lymphoma (NHL).
NHL is the most common type of lymphoma. Follicular lymphoma is one form of NHL. In contrast to some of the other forms of NHL, follicular lymphoma usually grows slowly and thus may not require treatment for many years. Because of its slow growth characteristics, follicular lymphoma is referred to as being an indolent (rather than aggressive or highly aggressive) lymphoma.
The following discussion will review the risk factors, classification, and clinical symptoms of follicular lymphoma.
RISK FACTORS — Age, gender, and race/ethnicity affect a person's likelihood of developing follicular lymphoma, although most persons have no known risk factors. Follicular lymphoma is slightly more likely to be diagnosed in women than men, and is less commonly found in persons of Asian and black ethnicity. Nearly all persons diagnosed with follicular lymphoma are adults, with the average age at diagnosis being 60 years.
SYMPTOMS — The initial symptoms of follicular lymphoma include painless swelling in one or more of the body's lymph nodes, particularly in the neck, armpit, or groin areas; this is called adenopathy. Often, patients with follicular lymphoma complain that their lymph nodes have been swollen for a long time; the size may increase and decrease several times before the patient seeks medical attention.
Some persons with follicular lymphoma develop large tumors in the abdomen. These may cause no symptoms, but can cause obstruction of the gastrointestinal, vascular, or urinary tract.
In the early stages, only one or two lymph nodes may be involved with the lymphoma. However, staging studies typically show that follicular lymphoma affects lymph node sites throughout the body:
DIAGNOSIS — The diagnosis of follicular lymphoma is confirmed by removing all or part of an enlarged lymph node to examine its cells under a microscope, a procedure known as a biopsy. Additional diagnostic tests are used to obtain more information about the type of lymphoma and the extent to which the disease has spread in the body. This process is called staging. The results of these tests will help determine the most effective course of treatment.
History and physical exam — A careful history and physical examination will help determine the extent of the disease. The physical exam may reveal swollen lymph nodes in various locations (show figure 1).
Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected. Tests that may be done include: CT scan of the chest, abdomen, and pelvis Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.
STAGING — Staging involves dividing patients into groups (stages) based upon how much of the lymphatic system is involved at the time of diagnosis. Staging helps determine a person's prognosis and whether treatment is required (show table 1).
The following are terms used in the staging criteria: Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show figure 3). Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland. Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.
Stage I — Only one lymph node region is involved, or only one lymph structure is involved.
Stage II — Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.
Stage III — Lymph node regions or structures on both sides of the diaphragm are involved.
Stage IV — There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.
Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". About one in five patients with follicular lymphoma experiences systemic "B" symptoms E — The presence of local spread of the disease from one nodal area or structure to surrounding tissue in the same area of the body is indicated by the letter "e," as in stage IIe.
For example, a patient with follicular lymphoma involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.
CLASSIFICATION — The World Health Organization (WHO) classifies follicular lymphoma into three different grades, according to the number of large cells they contain. This is determined by a pathologist, who looks at tumor sections under a microscope. A high-power field refers to what the pathologist sees in one area of the tissue using high-power magnification. Grade I: Fewer than five large cells are seen per high power field. Grade I is the most common type of follicular lymphoma. Generally, physicians consider grades I and II to be indolent or slow growing. Grade II: Between 6 and 15 large cells are seen per high power field. Grade III: More than 15 large cells are seen per high power field. This is also referred to as follicular large cell lymphoma. Unlike other grades of follicular lymphoma, this variant is less likely to invade the bone marrow and more likely to occur as large masses in the lymph tissues. Although this is similar to the lower grades of lymphoma, the symptoms and growth pattern of follicular large cell lymphoma is similar to that seen in patients with diffuse large B-cell lymphoma. (See "Patient information: Diffuse large B-cell lymphoma").
DISEASE PROGRESSION — The disease progression of follicular lymphoma varies from one person to another, depending upon the speed of the tumor's growth and the involvement of other organs. Sometimes patients with the disease have no symptoms for many years and do not need treatment. In other patients, treatment may be required for symptoms such as fever, night sweats, weight loss, pain, obstruction of organs, or the development of anemia and other changes in blood counts.
Treatment for follicular lymphoma depends on the patient's symptoms, tumor grade, age and general health. Early treatment does not always improve overall survival if a patient has no symptoms and the disease is not affecting their organs. Thus, close observation (a "watch and wait" approach) is often recommended.
Because of follicular lymphoma's ability to change into a more aggressive, widespread form of lymphoma (an aggressive B-cell lymphoma that occurs in 10 to 70 percent of patients), continued follow-up is required. (See "Patient information: Diffuse large B-cell lymphoma").
TREATMENT — The majority of patients with follicular lymphoma have widespread, advanced-stage disease when first diagnosed. However, because follicular lymphoma is slow-growing, it may take many years for the disease to progress, during which time patients may not need any form of treatment. Furthermore, the slow-growth characteristics make the tumors relatively less responsive to standard forms of cancer treatment (compared to the more aggressive lymphomas). As a result, a cure is not usually possible; the main reason to treat is to improve symptoms.
Features that may warrant treatment include one or more of the following: Progressively enlarging lymph nodes Fever, weight loss, or night sweats Low blood counts
Patients without these features are usually monitored with frequent physical examination and blood testing. For older patients who have symptoms but have no evidence of organ obstruction, monoclonal antibody therapy with rituximab (Rituxan®) may be recommended (see "Monoclonal antibody treatment" below).
Early stage disease — Patients with early stage disease (stage I or II) who develop symptoms may be treated with radiation therapy alone.
Radiation therapy — Radiation therapy uses high-energy beams (gamma rays) to slow or stop the growth of cancer cells, and is administered to the region of affected lymph nodes (called involved field radiation) or to the affected and surrounding lymph nodes (called extended field radiation). Radiation therapy must be given in small daily doses over a period of weeks to minimize the side effects; the number of weeks depends upon the amount of radiation to be administered.
Advanced stage disease — Advanced stage disease includes persons with stage II, III and IV disease. There are many treatment options for patients with advanced stage disease. The choice of treatment depends upon the patient's preference and the need for the treatment to act quickly (if organ function is threatened by the follicular lymphoma). Most advanced stage disease is treated with either a single chemotherapy drug or combination of chemotherapy drugs.
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.
A chemotherapy drug or combination of drugs is referred to as a regimen. Regimens used for the treatment of follicular lymphoma may include a single agent taken by mouth on a daily basis, while other regimens are given intravenously in treatment 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 is a one-hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three- or four-week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.
Monoclonal antibody treatment — A monoclonal antibody is a purified protein that targets a specific group of cells (usually cancer cells). This has advantages over other cancer treatments such as chemotherapy, which targets all rapidly growing cells. There are usually fewer side effects and long-term risks of monoclonal antibody therapies as compared to traditional chemotherapy.
Rituximab (Rituxan®) is a monoclonal antibody treatment that may be used for patients with follicular lymphoma who have relapsed or not responded to other treatments. Rituximab is frequently combined with chemotherapy treatments, and is being tested as a long-term maintenance treatment after chemotherapy. It has also been tested as an initial treatment for follicular lymphoma; follow-up trials are needed to determine if this treatment can prolong overall survival.
Radioimmunotherapy — Radioimmunotherapy (RIT) uses radioactive isotopes that are linked to monoclonal antibodies. As a result, radiation therapy can be delivered directly to proteins on cancer cells, which reduces the exposure of healthy tissues to radiation. The radioimmunotherapy treatments used for follicular lymphoma includes 90 Y-ibritumomab tiuxetan (Zevalin®) or 131I-tositumomab (Bexxar®), both of which are administered through a vein. The patient is usually given treatment in a hospital-based setting, but may go home after treatment is completed.
RIT is currently reserved for patients who have relapsed or failed to respond to other treatments. Administering RIT requires specialized equipment and additional training of physicians, nurses, and other involved personnel. The cost of RIT is quite high, and there are potentially serious short and long-term side effects of the treatment.
Bone marrow transplantation — Hematopoietic cell (bone marrow) transplantation is generally reserved for patients whose lymphoma has recurred after treatment. (See "Patient information: Overview of bone marrow transplantation").
Summary — For patients with advanced stage follicular lymphoma that has never been treated, the following table summarizes treatment recommendations (show table 2). For patients who have received treatment and relapsed, the following table summarizes treatment recommendations (show table 3).
Clinical trials — A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Clinical trials are especially important for persons with follicular lymphoma since there is no treatment currently available to cure this disease. Ask a healthcare provider for more information, or read about clinical trials at: National Cancer Institute
(www.cancer.gov/clinicaltrials/)
National Library of Medicine
(http: clinicaltrials.gov/)
PROGNOSIS — For patients with advanced forms of follicular lymphoma (ie, stages III and IV disease, show table 1), the average survival is approximately 10 years. Despite its slow-growing nature, most cases of follicular lymphoma are not curable with currently available therapies.
The Follicular Lymphoma International Prognostic Index (FLIPI) has identified five factors that are useful for predicting survival (prognosis). In addition, physicians can use these data to predict which patients benefit from specific chemotherapy treatments. Age >60 years Advanced clinical stages (ie, stages III or IV, show table 1) Low hemoglobin level More than 4 involved lymph node areas (show figure 1) Serum lactate dehydrogenase level greater than the upper limit of normal
Persons with zero to one of these factors are considered to have a low risk of dying; on average, 91 percent of this group is alive at 5 years after diagnosis, and 71 percent are alive 10 years after diagnosis.
Persons with 2 of these factors are considered to have an intermediate risk of dying; on average, 78 percent of this group is alive at 5 years after diagnosis, and 51 percent are alive 10 years after diagnosis.
Persons with 3 or more of these factors are considered to have a higher risk of dying; on average, 52 percent of this group is alive at 5 years after diagnosis, and 36 percent are alive 10 years after diagnosis.
It is important to remember that these numbers represent averages, and do not necessarily predict which persons with follicular lymphoma will live or die.
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)
National Cancer Institute
(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 Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
OncoLink
(www.oncolink.com/index.cfm)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
[1-3]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. The Non-Hodgkin's Classification Project. Blood 1997; 89:3909.
2. Glass, A, Karnell, L, Menck, H. The National Cancer Data Base report on non-Hodgkin's lymphoma. Cancer 1997; 80:2311.
3. American Cancer Society. What is non-Hodgkin's lymphoma? www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_Is_Non_Hodgkins_Lymphoma_32.asp. (Accessed 3/7/05).
There are two main types of lymphoma: Hodgkin's lymphoma (also called Hodgkin's disease) Non-Hodgkin's lymphoma (NHL).
NHL is the most common type of lymphoma. Follicular lymphoma is one form of NHL. In contrast to some of the other forms of NHL, follicular lymphoma usually grows slowly and thus may not require treatment for many years. Because of its slow growth characteristics, follicular lymphoma is referred to as being an indolent (rather than aggressive or highly aggressive) lymphoma.
The following discussion will review the risk factors, classification, and clinical symptoms of follicular lymphoma.
RISK FACTORS — Age, gender, and race/ethnicity affect a person's likelihood of developing follicular lymphoma, although most persons have no known risk factors. Follicular lymphoma is slightly more likely to be diagnosed in women than men, and is less commonly found in persons of Asian and black ethnicity. Nearly all persons diagnosed with follicular lymphoma are adults, with the average age at diagnosis being 60 years.
SYMPTOMS — The initial symptoms of follicular lymphoma include painless swelling in one or more of the body's lymph nodes, particularly in the neck, armpit, or groin areas; this is called adenopathy. Often, patients with follicular lymphoma complain that their lymph nodes have been swollen for a long time; the size may increase and decrease several times before the patient seeks medical attention.
Some persons with follicular lymphoma develop large tumors in the abdomen. These may cause no symptoms, but can cause obstruction of the gastrointestinal, vascular, or urinary tract.
In the early stages, only one or two lymph nodes may be involved with the lymphoma. However, staging studies typically show that follicular lymphoma affects lymph node sites throughout the body:
DIAGNOSIS — The diagnosis of follicular lymphoma is confirmed by removing all or part of an enlarged lymph node to examine its cells under a microscope, a procedure known as a biopsy. Additional diagnostic tests are used to obtain more information about the type of lymphoma and the extent to which the disease has spread in the body. This process is called staging. The results of these tests will help determine the most effective course of treatment.
History and physical exam — A careful history and physical examination will help determine the extent of the disease. The physical exam may reveal swollen lymph nodes in various locations (show figure 1).
Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected. Tests that may be done include: CT scan of the chest, abdomen, and pelvis Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.
STAGING — Staging involves dividing patients into groups (stages) based upon how much of the lymphatic system is involved at the time of diagnosis. Staging helps determine a person's prognosis and whether treatment is required (show table 1).
The following are terms used in the staging criteria: Lymph node regions: An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show figure 3). Lymph structures: Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland. Diaphragm: A large muscle that separates the chest cavity from the abdominal cavity.
Stage I — Only one lymph node region is involved, or only one lymph structure is involved.
Stage II — Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.
Stage III — Lymph node regions or structures on both sides of the diaphragm are involved.
Stage IV — There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow.
Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". About one in five patients with follicular lymphoma experiences systemic "B" symptoms E — The presence of local spread of the disease from one nodal area or structure to surrounding tissue in the same area of the body is indicated by the letter "e," as in stage IIe.
For example, a patient with follicular lymphoma involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.
CLASSIFICATION — The World Health Organization (WHO) classifies follicular lymphoma into three different grades, according to the number of large cells they contain. This is determined by a pathologist, who looks at tumor sections under a microscope. A high-power field refers to what the pathologist sees in one area of the tissue using high-power magnification. Grade I: Fewer than five large cells are seen per high power field. Grade I is the most common type of follicular lymphoma. Generally, physicians consider grades I and II to be indolent or slow growing. Grade II: Between 6 and 15 large cells are seen per high power field. Grade III: More than 15 large cells are seen per high power field. This is also referred to as follicular large cell lymphoma. Unlike other grades of follicular lymphoma, this variant is less likely to invade the bone marrow and more likely to occur as large masses in the lymph tissues. Although this is similar to the lower grades of lymphoma, the symptoms and growth pattern of follicular large cell lymphoma is similar to that seen in patients with diffuse large B-cell lymphoma. (See "Patient information: Diffuse large B-cell lymphoma").
DISEASE PROGRESSION — The disease progression of follicular lymphoma varies from one person to another, depending upon the speed of the tumor's growth and the involvement of other organs. Sometimes patients with the disease have no symptoms for many years and do not need treatment. In other patients, treatment may be required for symptoms such as fever, night sweats, weight loss, pain, obstruction of organs, or the development of anemia and other changes in blood counts.
Treatment for follicular lymphoma depends on the patient's symptoms, tumor grade, age and general health. Early treatment does not always improve overall survival if a patient has no symptoms and the disease is not affecting their organs. Thus, close observation (a "watch and wait" approach) is often recommended.
Because of follicular lymphoma's ability to change into a more aggressive, widespread form of lymphoma (an aggressive B-cell lymphoma that occurs in 10 to 70 percent of patients), continued follow-up is required. (See "Patient information: Diffuse large B-cell lymphoma").
TREATMENT — The majority of patients with follicular lymphoma have widespread, advanced-stage disease when first diagnosed. However, because follicular lymphoma is slow-growing, it may take many years for the disease to progress, during which time patients may not need any form of treatment. Furthermore, the slow-growth characteristics make the tumors relatively less responsive to standard forms of cancer treatment (compared to the more aggressive lymphomas). As a result, a cure is not usually possible; the main reason to treat is to improve symptoms.
Features that may warrant treatment include one or more of the following: Progressively enlarging lymph nodes Fever, weight loss, or night sweats Low blood counts
Patients without these features are usually monitored with frequent physical examination and blood testing. For older patients who have symptoms but have no evidence of organ obstruction, monoclonal antibody therapy with rituximab (Rituxan®) may be recommended (see "Monoclonal antibody treatment" below).
Early stage disease — Patients with early stage disease (stage I or II) who develop symptoms may be treated with radiation therapy alone.
Radiation therapy — Radiation therapy uses high-energy beams (gamma rays) to slow or stop the growth of cancer cells, and is administered to the region of affected lymph nodes (called involved field radiation) or to the affected and surrounding lymph nodes (called extended field radiation). Radiation therapy must be given in small daily doses over a period of weeks to minimize the side effects; the number of weeks depends upon the amount of radiation to be administered.
Advanced stage disease — Advanced stage disease includes persons with stage II, III and IV disease. There are many treatment options for patients with advanced stage disease. The choice of treatment depends upon the patient's preference and the need for the treatment to act quickly (if organ function is threatened by the follicular lymphoma). Most advanced stage disease is treated with either a single chemotherapy drug or combination of chemotherapy drugs.
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.
A chemotherapy drug or combination of drugs is referred to as a regimen. Regimens used for the treatment of follicular lymphoma may include a single agent taken by mouth on a daily basis, while other regimens are given intravenously in treatment 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 is a one-hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three- or four-week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.
Monoclonal antibody treatment — A monoclonal antibody is a purified protein that targets a specific group of cells (usually cancer cells). This has advantages over other cancer treatments such as chemotherapy, which targets all rapidly growing cells. There are usually fewer side effects and long-term risks of monoclonal antibody therapies as compared to traditional chemotherapy.
Rituximab (Rituxan®) is a monoclonal antibody treatment that may be used for patients with follicular lymphoma who have relapsed or not responded to other treatments. Rituximab is frequently combined with chemotherapy treatments, and is being tested as a long-term maintenance treatment after chemotherapy. It has also been tested as an initial treatment for follicular lymphoma; follow-up trials are needed to determine if this treatment can prolong overall survival.
Radioimmunotherapy — Radioimmunotherapy (RIT) uses radioactive isotopes that are linked to monoclonal antibodies. As a result, radiation therapy can be delivered directly to proteins on cancer cells, which reduces the exposure of healthy tissues to radiation. The radioimmunotherapy treatments used for follicular lymphoma includes 90 Y-ibritumomab tiuxetan (Zevalin®) or 131I-tositumomab (Bexxar®), both of which are administered through a vein. The patient is usually given treatment in a hospital-based setting, but may go home after treatment is completed.
RIT is currently reserved for patients who have relapsed or failed to respond to other treatments. Administering RIT requires specialized equipment and additional training of physicians, nurses, and other involved personnel. The cost of RIT is quite high, and there are potentially serious short and long-term side effects of the treatment.
Bone marrow transplantation — Hematopoietic cell (bone marrow) transplantation is generally reserved for patients whose lymphoma has recurred after treatment. (See "Patient information: Overview of bone marrow transplantation").
Summary — For patients with advanced stage follicular lymphoma that has never been treated, the following table summarizes treatment recommendations (show table 2). For patients who have received treatment and relapsed, the following table summarizes treatment recommendations (show table 3).
Clinical trials — A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Clinical trials are especially important for persons with follicular lymphoma since there is no treatment currently available to cure this disease. Ask a healthcare provider for more information, or read about clinical trials at: National Cancer Institute
(www.cancer.gov/clinicaltrials/)
National Library of Medicine
(http: clinicaltrials.gov/)
PROGNOSIS — For patients with advanced forms of follicular lymphoma (ie, stages III and IV disease, show table 1), the average survival is approximately 10 years. Despite its slow-growing nature, most cases of follicular lymphoma are not curable with currently available therapies.
The Follicular Lymphoma International Prognostic Index (FLIPI) has identified five factors that are useful for predicting survival (prognosis). In addition, physicians can use these data to predict which patients benefit from specific chemotherapy treatments. Age >60 years Advanced clinical stages (ie, stages III or IV, show table 1) Low hemoglobin level More than 4 involved lymph node areas (show figure 1) Serum lactate dehydrogenase level greater than the upper limit of normal
Persons with zero to one of these factors are considered to have a low risk of dying; on average, 91 percent of this group is alive at 5 years after diagnosis, and 71 percent are alive 10 years after diagnosis.
Persons with 2 of these factors are considered to have an intermediate risk of dying; on average, 78 percent of this group is alive at 5 years after diagnosis, and 51 percent are alive 10 years after diagnosis.
Persons with 3 or more of these factors are considered to have a higher risk of dying; on average, 52 percent of this group is alive at 5 years after diagnosis, and 36 percent are alive 10 years after diagnosis.
It is important to remember that these numbers represent averages, and do not necessarily predict which persons with follicular lymphoma will live or die.
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)
National Cancer Institute
(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 Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
OncoLink
(www.oncolink.com/index.cfm)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
[1-3]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. The Non-Hodgkin's Classification Project. Blood 1997; 89:3909.
2. Glass, A, Karnell, L, Menck, H. The National Cancer Data Base report on non-Hodgkin's lymphoma. Cancer 1997; 80:2311.
3. American Cancer Society. What is non-Hodgkin's lymphoma? www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_Is_Non_Hodgkins_Lymphoma_32.asp. (Accessed 3/7/05).
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