INTRODUCTION — Many women feel anxious about their chance of developing breast or ovarian cancer, particularly if they have one or several close relatives with either condition. Women who have a family history of breast or ovarian cancer often wish to know if they have inherited a tendency to develop these tumors, and if so, what their lifetime risk is of developing breast or ovarian cancer.
Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.
Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).
However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.
This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.
Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.
GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.
How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.
Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.
An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.
Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.
Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.
WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.
BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.
Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.
However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.
Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.
Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.
When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).
TESTING PROCEDURE
Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].
An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.
Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.
While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.
Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.
The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.
Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460
A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.
The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.
Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).
Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.
During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.
INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.
The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.
If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.
OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.
Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.
However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.
Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.
Ovarian cancer screening
High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).
Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.
Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.
Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.
Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.
Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].
Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.
Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.
Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.
Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.
Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.
There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)
Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.
Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)
Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society
Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation
(www.komen.org)
National Ovarian Cancer Coalition
(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)
(www.facingourrisk.com)
[1-4,6-14]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. BRCAPRO is a component of the CancerGene program, available online at www3.utsouthwestern.edu/cancergene/ (Accessed April 24, 2007).
2. www.cancer.gov/search/genetics_services/ (accessed April 24, 2007).
3. www.genome.gov/PolicyEthics/ (acceessed April 24, 2007).
4. www.facingourrisk.org (accessed April 24, 2007).
5. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
6. Rebbeck, TR, Friebel, T, Lynch, HT, et al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2004; 22:1055.
7. Hartmann, LC, Schaid, DJ, Woods, JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340:77.
8. Rebbeck, TR, Lynch, HT, Neuhausen, SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346:1616.
9. Kauff, ND, Satagopan, JM, Robson, ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346:1609.
10. Metcalfe, K, Lynch, HT, Ghadirian, P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328.
11. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; 339:424.
12. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005; 143:355.
13. Hampel, H, Sweet, K, Westman, JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004; 41:81.
14. Segal, J, Esplen, MJ, Toner, B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet 2004; 125A:267.
15. Geiger, AM, Nekhlyudov, L, Herrinton, LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007; 14:686.
Friday, October 12, 2007
Genetic testing for breast and ovarian cancer
INTRODUCTION — Many women feel anxious about their chance of developing breast or ovarian cancer, particularly if they have one or several close relatives with either condition. Women who have a family history of breast or ovarian cancer often wish to know if they have inherited a tendency to develop these tumors, and if so, what their lifetime risk is of developing breast or ovarian cancer.
Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.
Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).
However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.
This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.
Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.
GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.
How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.
Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.
An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.
Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.
Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.
WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.
BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.
Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.
However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.
Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.
Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.
When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).
TESTING PROCEDURE
Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].
An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.
Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.
While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.
Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.
The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.
Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460
A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.
The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.
Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).
Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.
During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.
INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.
The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.
If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.
OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.
Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.
However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.
Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.
Ovarian cancer screening
High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).
Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.
Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.
Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.
Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.
Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].
Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.
Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.
Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.
Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.
Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.
There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)
Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.
Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)
Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society
Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation
(www.komen.org)
National Ovarian Cancer Coalition
(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)
(www.facingourrisk.com)
[1-4,6-14]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. BRCAPRO is a component of the CancerGene program, available online at www3.utsouthwestern.edu/cancergene/ (Accessed April 24, 2007).
2. www.cancer.gov/search/genetics_services/ (accessed April 24, 2007).
3. www.genome.gov/PolicyEthics/ (acceessed April 24, 2007).
4. www.facingourrisk.org (accessed April 24, 2007).
5. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
6. Rebbeck, TR, Friebel, T, Lynch, HT, et al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2004; 22:1055.
7. Hartmann, LC, Schaid, DJ, Woods, JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340:77.
8. Rebbeck, TR, Lynch, HT, Neuhausen, SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346:1616.
9. Kauff, ND, Satagopan, JM, Robson, ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346:1609.
10. Metcalfe, K, Lynch, HT, Ghadirian, P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328.
11. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; 339:424.
12. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005; 143:355.
13. Hampel, H, Sweet, K, Westman, JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004; 41:81.
14. Segal, J, Esplen, MJ, Toner, B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet 2004; 125A:267.
15. Geiger, AM, Nekhlyudov, L, Herrinton, LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007; 14:686.
Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.
Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).
However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.
This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.
Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.
GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.
How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.
Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.
An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.
Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.
Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.
WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.
BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.
Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.
However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.
Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.
Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.
When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).
TESTING PROCEDURE
Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].
An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.
Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.
While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.
Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.
The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.
Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460
A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.
The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.
Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).
Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.
During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.
INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.
The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.
If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.
OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.
Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.
However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.
Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.
Ovarian cancer screening
High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).
Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.
Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.
Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.
Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.
Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].
Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.
Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.
Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.
Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.
Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.
There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)
Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.
Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
(www.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)
Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society
Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation
(www.komen.org)
National Ovarian Cancer Coalition
(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)
(www.facingourrisk.com)
[1-4,6-14]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. BRCAPRO is a component of the CancerGene program, available online at www3.utsouthwestern.edu/cancergene/ (Accessed April 24, 2007).
2. www.cancer.gov/search/genetics_services/ (accessed April 24, 2007).
3. www.genome.gov/PolicyEthics/ (acceessed April 24, 2007).
4. www.facingourrisk.org (accessed April 24, 2007).
5. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
6. Rebbeck, TR, Friebel, T, Lynch, HT, et al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2004; 22:1055.
7. Hartmann, LC, Schaid, DJ, Woods, JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340:77.
8. Rebbeck, TR, Lynch, HT, Neuhausen, SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346:1616.
9. Kauff, ND, Satagopan, JM, Robson, ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346:1609.
10. Metcalfe, K, Lynch, HT, Ghadirian, P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328.
11. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; 339:424.
12. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005; 143:355.
13. Hampel, H, Sweet, K, Westman, JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004; 41:81.
14. Segal, J, Esplen, MJ, Toner, B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet 2004; 125A:267.
15. Geiger, AM, Nekhlyudov, L, Herrinton, LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007; 14:686.
Complementary and alternative medicine treatments (CAM) for cancer
INTRODUCTION — Complementary and alternative medicine (CAM) has been defined by the National Center for Complementary and Alternative Medicine as "a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine" [1]. For some CAM practices, there is scientific evidence that a treatment is both beneficial and safe. For many other practices, evidence is lacking or inconclusive.
Between 48 and 88 percent of patients with cancer use some form of CAM. Most patients who use CAM are not dissatisfied with traditional medicine, but find that complementary and alternative treatments appeal to their values and beliefs about health and life. Being diagnosed with cancer and undergoing treatment can be a frightening, exhausting, and demanding experience. CAM appeals to many patients with cancer because these treatments often offer a chance to feel better and decrease uncomfortable symptoms such as pain, fatigue, and nausea.
The focus of this topic is to highlight a few of the available treatments that may be beneficial, as well as to review those that are ineffective and could potentially be dangerous. The list of complementary and alternative medicine treatments is ever changing; the best resource for advice about complementary as well as traditional therapies is the healthcare team.
Placebo effect — A placebo is an inactive medication or treatment. Well-designed studies include a placebo treatment as well as a real treatment so that the two may be compared. The placebo effect is the positive or negative result that occurs when a patient believes they have been given a treatment, when in fact they have been given none (or a look-alike substitute). For example, a CAM treatment that claims to improve symptoms of nausea in 50 percent of patients is of little benefit if a placebo treatment also improves symptoms in 50 percent of patients.
The placebo effect is not well understood, but has a strong influence on the results of any research study, whether in traditional or complementary medicine.
COMPLEMENTARY MEDICINE — Complementary medicine is a treatment, practice, or product that is used alongside traditional medical treatment. It is not meant to replace traditional cancer treatment, but is available to alleviate side effects or improve a patient's sense of well-being.
Alternative medical systems — Alternative medical systems are healing techniques and beliefs that have developed over time, and include homeopathy, naturopathy, and traditional Chinese medicine (which includes acupuncture).
Acupuncture — Acupuncture involves inserting hair-thin, metal needles into the skin at specific points on the body. It causes little to no pain. Electrical stimulation is sometimes applied to the acupuncture needle. There have been numerous studies of acupuncture's efficacy in reducing nausea, pain, and hot flashes, and results have been mixed. Acupuncture with electrical stimulation has been found to be useful in treating nausea and vomiting from chemotherapy; women using acupuncture required less medication for nausea and vomiting than women who used no acupuncture [2]. Some trials suggest that acupuncture can reduce cancer pain, although a review of multiple trials showed it to be of no benefit. Acupuncture with electrical stimulation may be of benefit in reducing hot flashes in men undergoing hormonal treatments for prostate cancer. Further study is needed to confirm this result.
Other forms of traditional Chinese medicine, which use standard combinations of herbs or botanicals for various illnesses, are difficult to study. Little information is available from controlled studies regarding the safety and efficacy of this form of treatment.
Homeopathy and naturopathy — Naturopathy has not been studied in controlled, well-designed studies, and the risks, benefits, and efficacy have not been established. There have been several clinical studies of homeopathy, but the results were contradictory and systematic reviews (which combine the results of multiple clinical trials) have not shown homeopathy to be of proven benefit for any medical condition. In addition, patients and their families are not advised to spend large amounts of money on treatments that are not proven to be of benefit.
Mind-body techniques — Mind-body techniques include practices such as hypnosis, guided imagery, meditation, yoga, biofeedback, and prayer. They may be useful before or during painful or stress-inducing medical procedures, chemotherapy, or radiation treatment to control anxiety, pain, or nausea and vomiting. Patients of any age can learn mind-body techniques.
Hypnotherapy — Hypnosis is a state of altered consciousness that allows a patient to focus away from their pain, anxiety, or nausea. Patients who are hypnotized are not sleeping, but are actually in a state of heightened imagination, similar to daydreaming. An expert can hypnotize an individual, or a patient can learn self-hypnosis techniques. Hypnosis is safe and has few side effects.
It is not clear how or if hypnosis is helpful, though studies have suggested that it may be useful for controlling pain and nausea/vomiting in various settings, and may reduce vomiting that can develop before starting chemotherapy (called anticipatory emesis). Hypnosis may also be useful in children for preventing anxiety and pain from difficult procedures such as lumbar puncture (spinal tap) or bone marrow biopsy.
Visual or guided imagery — Visual or guided imagery is a technique that encourages the patient to relax by focusing on calming thoughts or experiences. The patient sits or lies in a comfortable position while imagining a pleasant experience such as relaxing on the beach. In one study, women receiving chemotherapy for newly diagnosed breast cancer had a better quality of life if they used relaxation training and guided imagery, as compared to a group that had chemotherapy alone [3].
Spirituality — A majority of individuals have religious beliefs, and many of these persons rely on their religion or spirituality in difficult times, such as during treatments for cancer [4]. Researchers found that spirituality, when combined with conventional medicine, was an important component in the healing process and was of benefit not only to the patient but also to caregivers and healthcare professionals [5]. Some, but not all, studies have shown that religious involvement and spirituality are associated with better health outcomes, including longer life, improved coping skills, better health in general, and lower rates of anxiety, depression, and suicide [6].
Body-based therapies — Body-based therapies use movement or manipulation of one or more parts of the body.
Massage therapy — Massage is a body-based therapy that uses therapeutic touch, which involves stroking and kneading the skin, muscle, and connective tissues. There are several types of massage therapy. Classic or Swedish massage is massage aimed primarily at muscles. It reduces tension and increases blood flow. Reflexology is massage of the hands and feet based on a system of points that correlate to other areas of the body. Chair massage is done while the patient sits fully clothed in a special chair that slopes forward, allowing the therapist access to the back, neck, and shoulders. Deep tissue massage is a form of intense tissue manipulation.
A study was done in 1,290 cancer patients who received massage therapy at Memorial Sloan-Kettering Cancer Center. It found that pain, anxiety, fatigue, and nausea decreased by 50 percent in patients who received massage. Some patients reported benefits lasting up to 48 hours [7]. A small number of insurance companies cover massage therapy as a complementary cancer treatment.
Energy therapies — Energy therapies involve using the body's energy fields to heal and maintain wellness. Believers in energy medicine describe disruptions in the energy field as a cause for illness, and teach that balancing energy can aid in healing. It is difficult to study the effectiveness of energy medicine due to the intangible nature of the body's "energy."
Reiki is a form of energy medicine, and has been evaluated in several clinical trials for treatment of anxiety and improvement of well-being in cancer patients. Some, but not all, trials showed positive results, although the studies showing benefit were not well designed and it is difficult to distinguish the true benefit from placebo effect.
ALTERNATIVE CANCER TREATMENTS — Alternative cancer treatments (ACTs) are usually promoted as replacements to traditional cancer treatments. Cancer patients may seek them out in the hope of a cure. Some ACTs require the patient to receive treatment at their clinics, often located outside the United States. In many cases, reliable clinical trials have found these treatments ineffective or unsafe, and the FDA has not given approval for these treatments inside the United States.
Dietary ACTs — Good nutrition is important for cancer patients. None of the ACTs are proven to prolong life or cure cancer. In addition, some alternative cancer diet treatments are costly and potentially harmful.
Gerson regimen — The Gerson regimen requires an organic, vegetarian diet, and includes a strict schedule for ingesting juice made from fruit and vegetables. In addition, patients are given a number of vitamin supplements. No clinical study has proven this regimen's efficacy. It is not recommended and may be expensive and harmful.
Macrobiotic diets — Macrobiotic diets are low-fat, vegetarian diets that include large amounts of complex carbohydrates. One report found that one-third of cancer patients who followed a macrobiotic diet lost weight, which resulted in other problems [8]. This was likely due to several factors, including the expense or inaccessibility of some of the required foods, time spent preparing the meals, and the restrictive, sometimes unpleasant, nature of the diet. Macrobiotic diets are not recommended for persons with cancer.
Selected vegetables — Selected vegetables (SV), also called Sun's soup, is a blended, boiled, and freeze-dried product that claims to have immune-stimulatory and anticancer properties. Two small studies have been conducted in patients with late stage non-small cell lung cancer, both of which found that patients who received the supplement had an improved survival. Patients in both studies received traditional medical treatments as well as the SV mix. However, the studies were small and had weaknesses in study design; further studies are needed before the treatment can be considered safe and effective.
Herbal medicine — Combinations of herbs (also called botanicals) are often promoted as ACTs. Herbal medicines may come in the form of a powder, liquid, or pill. Examples of herbal treatments include essiac, green tea, mistletoe, PC-SPES (a mixture of herbs marketed for prostate cancer, now recalled due to an increased risk of blood clots), sho-saik-to, and St. John's wort [9].
None of these herbals have proven to cure or improve cancer in reliable clinical studies; some can cause dangerous side effects (show table 1). In addition, some herbal products can interact with traditional cancer treatments, making traditional treatments less effective (show table 2) [9].
Other supplements — A number of dietary supplements have been advertised as being useful ACTs. These include coenzyme Q10, hydrazine, melatonin, shark cartilage, shiitake mushroom extract, and thymus extract. No supplement has proven reliable as either an alternative or complement to traditional cancer treatment [9].
PATIENTS CONSIDERING CAM
General recommendations — Any person who is considering use of a complementary, alternative, or traditional medical treatment should gather information about the safety, risks, and benefits of the treatment. Reliable information sources include the healthcare team (physician, nurse, dietitian) and government-sponsored web sites.
It is important to choose the person providing CAM with care; patients should inquire about education and licensing requirements since these vary by state. The safety of CAM treatments should be considered. Being "natural" does not mean that a product or treatment is safe.
The cost of a CAM treatment must also be considered, as these are generally not covered by commercial or government-funded health insurance. A patient or family who uses their life's savings for an unproven "cure" is likely to be disappointed.
Questions to consider — When evaluating an alternative or complementary treatment, consider the following questions: Does the treatment require patients to stop traditional medical care? Does it claim to cure cancer? Is it offered by only one individual or by an established, recognized cancer treatment facility? Is it a secret that only certain people can share? Does it require travel to another country? Is it approved in the United States? Is it based on well-controlled, scientific research? Is it expensive? Is the group or person promoting the CAM treatment an expert in cancer treatment? Do the promoters attack the scientific and medical research community?
Combining CAM and traditional treatments — Patients who are considering a CAM treatment must consider the safety and potential benefit of the treatment itself, and must also consider how the CAM treatment could interact with traditional treatments, such as chemotherapy. It is possible for a CAM treatment, especially a dietary ACT, herbal medicine, or other supplement, to alter the body's metabolism and clearance of chemotherapy in unexpected ways. Because CAM treatments are not generally tested for use in combination with standard chemotherapy, they could interfere with the beneficial effect of the chemotherapy, or potentially increase the risk of toxic side effects.
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
1-800-ACS-2345
(www.cancer.org/)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
National Center for Complementary and Alternative Medicine
(nccam.nih.gov/)
Memorial Sloan-Kettering Cancer Center
(www.mskcc.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-12]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. NIH Consensus Conference: Acupuncture. JAMA 1998; 280:1518.
2. Ezzo, J, Vickers, A, Richardson, MA, et al. Acupuncture-point stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol 2005; 23:7188.
3. Walker, LG, Walker, MB, Ogston, K, et al. Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. Br J Cancer 1999; 80:262.
4. www.cancer.gov (Accessed January 20, 2006).
5. Rummans, TA, Clark, MM, Sloan, JA, et al. Impacting quality of life for patients with advanced cancer with a structured multidisciplinary intervention: a randomized controlled trial. J Clin Oncol 2006; 24:635.
6. Mueller, PS, Plevak, DJ, Rummans, TA. Religious involvement, spirituality, and medicine: implications for clinical practice. Mayo Clin Proc 2001; 76:1225.
7. Cassileth, BR, Vickers, AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage 2004; 28:244.
8. Downer, SM, Cody, MM, McCluskey, P, et al. Pursuit and practice of complementary therapies by cancer patients receiving conventional treatment. BMJ 1994; 309:86.
9. Ernst E, Pittler MH, Wider B, Boddy K. The desktop guide to complementary and alternative medicine, Edinburgh 2006.
10. Lee, H, Schmidt, K, Ernst, E. Acupuncture for the relief of cancer-related pain--a systematic review. Eur J Pain 2005; 9:437.
11. The National Center for Complementary and Alternative Medicine, publications available online at www.nccam.nih.gov (Accessed January 20, 2006).
12. Ernst, E. Intangible risks of complementary and alternative medicine. J Clin Oncol 2001; 19:2365.
Between 48 and 88 percent of patients with cancer use some form of CAM. Most patients who use CAM are not dissatisfied with traditional medicine, but find that complementary and alternative treatments appeal to their values and beliefs about health and life. Being diagnosed with cancer and undergoing treatment can be a frightening, exhausting, and demanding experience. CAM appeals to many patients with cancer because these treatments often offer a chance to feel better and decrease uncomfortable symptoms such as pain, fatigue, and nausea.
The focus of this topic is to highlight a few of the available treatments that may be beneficial, as well as to review those that are ineffective and could potentially be dangerous. The list of complementary and alternative medicine treatments is ever changing; the best resource for advice about complementary as well as traditional therapies is the healthcare team.
Placebo effect — A placebo is an inactive medication or treatment. Well-designed studies include a placebo treatment as well as a real treatment so that the two may be compared. The placebo effect is the positive or negative result that occurs when a patient believes they have been given a treatment, when in fact they have been given none (or a look-alike substitute). For example, a CAM treatment that claims to improve symptoms of nausea in 50 percent of patients is of little benefit if a placebo treatment also improves symptoms in 50 percent of patients.
The placebo effect is not well understood, but has a strong influence on the results of any research study, whether in traditional or complementary medicine.
COMPLEMENTARY MEDICINE — Complementary medicine is a treatment, practice, or product that is used alongside traditional medical treatment. It is not meant to replace traditional cancer treatment, but is available to alleviate side effects or improve a patient's sense of well-being.
Alternative medical systems — Alternative medical systems are healing techniques and beliefs that have developed over time, and include homeopathy, naturopathy, and traditional Chinese medicine (which includes acupuncture).
Acupuncture — Acupuncture involves inserting hair-thin, metal needles into the skin at specific points on the body. It causes little to no pain. Electrical stimulation is sometimes applied to the acupuncture needle. There have been numerous studies of acupuncture's efficacy in reducing nausea, pain, and hot flashes, and results have been mixed. Acupuncture with electrical stimulation has been found to be useful in treating nausea and vomiting from chemotherapy; women using acupuncture required less medication for nausea and vomiting than women who used no acupuncture [2]. Some trials suggest that acupuncture can reduce cancer pain, although a review of multiple trials showed it to be of no benefit. Acupuncture with electrical stimulation may be of benefit in reducing hot flashes in men undergoing hormonal treatments for prostate cancer. Further study is needed to confirm this result.
Other forms of traditional Chinese medicine, which use standard combinations of herbs or botanicals for various illnesses, are difficult to study. Little information is available from controlled studies regarding the safety and efficacy of this form of treatment.
Homeopathy and naturopathy — Naturopathy has not been studied in controlled, well-designed studies, and the risks, benefits, and efficacy have not been established. There have been several clinical studies of homeopathy, but the results were contradictory and systematic reviews (which combine the results of multiple clinical trials) have not shown homeopathy to be of proven benefit for any medical condition. In addition, patients and their families are not advised to spend large amounts of money on treatments that are not proven to be of benefit.
Mind-body techniques — Mind-body techniques include practices such as hypnosis, guided imagery, meditation, yoga, biofeedback, and prayer. They may be useful before or during painful or stress-inducing medical procedures, chemotherapy, or radiation treatment to control anxiety, pain, or nausea and vomiting. Patients of any age can learn mind-body techniques.
Hypnotherapy — Hypnosis is a state of altered consciousness that allows a patient to focus away from their pain, anxiety, or nausea. Patients who are hypnotized are not sleeping, but are actually in a state of heightened imagination, similar to daydreaming. An expert can hypnotize an individual, or a patient can learn self-hypnosis techniques. Hypnosis is safe and has few side effects.
It is not clear how or if hypnosis is helpful, though studies have suggested that it may be useful for controlling pain and nausea/vomiting in various settings, and may reduce vomiting that can develop before starting chemotherapy (called anticipatory emesis). Hypnosis may also be useful in children for preventing anxiety and pain from difficult procedures such as lumbar puncture (spinal tap) or bone marrow biopsy.
Visual or guided imagery — Visual or guided imagery is a technique that encourages the patient to relax by focusing on calming thoughts or experiences. The patient sits or lies in a comfortable position while imagining a pleasant experience such as relaxing on the beach. In one study, women receiving chemotherapy for newly diagnosed breast cancer had a better quality of life if they used relaxation training and guided imagery, as compared to a group that had chemotherapy alone [3].
Spirituality — A majority of individuals have religious beliefs, and many of these persons rely on their religion or spirituality in difficult times, such as during treatments for cancer [4]. Researchers found that spirituality, when combined with conventional medicine, was an important component in the healing process and was of benefit not only to the patient but also to caregivers and healthcare professionals [5]. Some, but not all, studies have shown that religious involvement and spirituality are associated with better health outcomes, including longer life, improved coping skills, better health in general, and lower rates of anxiety, depression, and suicide [6].
Body-based therapies — Body-based therapies use movement or manipulation of one or more parts of the body.
Massage therapy — Massage is a body-based therapy that uses therapeutic touch, which involves stroking and kneading the skin, muscle, and connective tissues. There are several types of massage therapy. Classic or Swedish massage is massage aimed primarily at muscles. It reduces tension and increases blood flow. Reflexology is massage of the hands and feet based on a system of points that correlate to other areas of the body. Chair massage is done while the patient sits fully clothed in a special chair that slopes forward, allowing the therapist access to the back, neck, and shoulders. Deep tissue massage is a form of intense tissue manipulation.
A study was done in 1,290 cancer patients who received massage therapy at Memorial Sloan-Kettering Cancer Center. It found that pain, anxiety, fatigue, and nausea decreased by 50 percent in patients who received massage. Some patients reported benefits lasting up to 48 hours [7]. A small number of insurance companies cover massage therapy as a complementary cancer treatment.
Energy therapies — Energy therapies involve using the body's energy fields to heal and maintain wellness. Believers in energy medicine describe disruptions in the energy field as a cause for illness, and teach that balancing energy can aid in healing. It is difficult to study the effectiveness of energy medicine due to the intangible nature of the body's "energy."
Reiki is a form of energy medicine, and has been evaluated in several clinical trials for treatment of anxiety and improvement of well-being in cancer patients. Some, but not all, trials showed positive results, although the studies showing benefit were not well designed and it is difficult to distinguish the true benefit from placebo effect.
ALTERNATIVE CANCER TREATMENTS — Alternative cancer treatments (ACTs) are usually promoted as replacements to traditional cancer treatments. Cancer patients may seek them out in the hope of a cure. Some ACTs require the patient to receive treatment at their clinics, often located outside the United States. In many cases, reliable clinical trials have found these treatments ineffective or unsafe, and the FDA has not given approval for these treatments inside the United States.
Dietary ACTs — Good nutrition is important for cancer patients. None of the ACTs are proven to prolong life or cure cancer. In addition, some alternative cancer diet treatments are costly and potentially harmful.
Gerson regimen — The Gerson regimen requires an organic, vegetarian diet, and includes a strict schedule for ingesting juice made from fruit and vegetables. In addition, patients are given a number of vitamin supplements. No clinical study has proven this regimen's efficacy. It is not recommended and may be expensive and harmful.
Macrobiotic diets — Macrobiotic diets are low-fat, vegetarian diets that include large amounts of complex carbohydrates. One report found that one-third of cancer patients who followed a macrobiotic diet lost weight, which resulted in other problems [8]. This was likely due to several factors, including the expense or inaccessibility of some of the required foods, time spent preparing the meals, and the restrictive, sometimes unpleasant, nature of the diet. Macrobiotic diets are not recommended for persons with cancer.
Selected vegetables — Selected vegetables (SV), also called Sun's soup, is a blended, boiled, and freeze-dried product that claims to have immune-stimulatory and anticancer properties. Two small studies have been conducted in patients with late stage non-small cell lung cancer, both of which found that patients who received the supplement had an improved survival. Patients in both studies received traditional medical treatments as well as the SV mix. However, the studies were small and had weaknesses in study design; further studies are needed before the treatment can be considered safe and effective.
Herbal medicine — Combinations of herbs (also called botanicals) are often promoted as ACTs. Herbal medicines may come in the form of a powder, liquid, or pill. Examples of herbal treatments include essiac, green tea, mistletoe, PC-SPES (a mixture of herbs marketed for prostate cancer, now recalled due to an increased risk of blood clots), sho-saik-to, and St. John's wort [9].
None of these herbals have proven to cure or improve cancer in reliable clinical studies; some can cause dangerous side effects (show table 1). In addition, some herbal products can interact with traditional cancer treatments, making traditional treatments less effective (show table 2) [9].
Other supplements — A number of dietary supplements have been advertised as being useful ACTs. These include coenzyme Q10, hydrazine, melatonin, shark cartilage, shiitake mushroom extract, and thymus extract. No supplement has proven reliable as either an alternative or complement to traditional cancer treatment [9].
PATIENTS CONSIDERING CAM
General recommendations — Any person who is considering use of a complementary, alternative, or traditional medical treatment should gather information about the safety, risks, and benefits of the treatment. Reliable information sources include the healthcare team (physician, nurse, dietitian) and government-sponsored web sites.
It is important to choose the person providing CAM with care; patients should inquire about education and licensing requirements since these vary by state. The safety of CAM treatments should be considered. Being "natural" does not mean that a product or treatment is safe.
The cost of a CAM treatment must also be considered, as these are generally not covered by commercial or government-funded health insurance. A patient or family who uses their life's savings for an unproven "cure" is likely to be disappointed.
Questions to consider — When evaluating an alternative or complementary treatment, consider the following questions: Does the treatment require patients to stop traditional medical care? Does it claim to cure cancer? Is it offered by only one individual or by an established, recognized cancer treatment facility? Is it a secret that only certain people can share? Does it require travel to another country? Is it approved in the United States? Is it based on well-controlled, scientific research? Is it expensive? Is the group or person promoting the CAM treatment an expert in cancer treatment? Do the promoters attack the scientific and medical research community?
Combining CAM and traditional treatments — Patients who are considering a CAM treatment must consider the safety and potential benefit of the treatment itself, and must also consider how the CAM treatment could interact with traditional treatments, such as chemotherapy. It is possible for a CAM treatment, especially a dietary ACT, herbal medicine, or other supplement, to alter the body's metabolism and clearance of chemotherapy in unexpected ways. Because CAM treatments are not generally tested for use in combination with standard chemotherapy, they could interfere with the beneficial effect of the chemotherapy, or potentially increase the risk of toxic side effects.
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
1-800-ACS-2345
(www.cancer.org/)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
National Center for Complementary and Alternative Medicine
(nccam.nih.gov/)
Memorial Sloan-Kettering Cancer Center
(www.mskcc.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-12]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. NIH Consensus Conference: Acupuncture. JAMA 1998; 280:1518.
2. Ezzo, J, Vickers, A, Richardson, MA, et al. Acupuncture-point stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol 2005; 23:7188.
3. Walker, LG, Walker, MB, Ogston, K, et al. Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. Br J Cancer 1999; 80:262.
4. www.cancer.gov (Accessed January 20, 2006).
5. Rummans, TA, Clark, MM, Sloan, JA, et al. Impacting quality of life for patients with advanced cancer with a structured multidisciplinary intervention: a randomized controlled trial. J Clin Oncol 2006; 24:635.
6. Mueller, PS, Plevak, DJ, Rummans, TA. Religious involvement, spirituality, and medicine: implications for clinical practice. Mayo Clin Proc 2001; 76:1225.
7. Cassileth, BR, Vickers, AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage 2004; 28:244.
8. Downer, SM, Cody, MM, McCluskey, P, et al. Pursuit and practice of complementary therapies by cancer patients receiving conventional treatment. BMJ 1994; 309:86.
9. Ernst E, Pittler MH, Wider B, Boddy K. The desktop guide to complementary and alternative medicine, Edinburgh 2006.
10. Lee, H, Schmidt, K, Ernst, E. Acupuncture for the relief of cancer-related pain--a systematic review. Eur J Pain 2005; 9:437.
11. The National Center for Complementary and Alternative Medicine, publications available online at www.nccam.nih.gov (Accessed January 20, 2006).
12. Ernst, E. Intangible risks of complementary and alternative medicine. J Clin Oncol 2001; 19:2365.
Complementary and alternative medicine treatments (CAM) for cancer
INTRODUCTION — Complementary and alternative medicine (CAM) has been defined by the National Center for Complementary and Alternative Medicine as "a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine" [1]. For some CAM practices, there is scientific evidence that a treatment is both beneficial and safe. For many other practices, evidence is lacking or inconclusive.
Between 48 and 88 percent of patients with cancer use some form of CAM. Most patients who use CAM are not dissatisfied with traditional medicine, but find that complementary and alternative treatments appeal to their values and beliefs about health and life. Being diagnosed with cancer and undergoing treatment can be a frightening, exhausting, and demanding experience. CAM appeals to many patients with cancer because these treatments often offer a chance to feel better and decrease uncomfortable symptoms such as pain, fatigue, and nausea.
The focus of this topic is to highlight a few of the available treatments that may be beneficial, as well as to review those that are ineffective and could potentially be dangerous. The list of complementary and alternative medicine treatments is ever changing; the best resource for advice about complementary as well as traditional therapies is the healthcare team.
Placebo effect — A placebo is an inactive medication or treatment. Well-designed studies include a placebo treatment as well as a real treatment so that the two may be compared. The placebo effect is the positive or negative result that occurs when a patient believes they have been given a treatment, when in fact they have been given none (or a look-alike substitute). For example, a CAM treatment that claims to improve symptoms of nausea in 50 percent of patients is of little benefit if a placebo treatment also improves symptoms in 50 percent of patients.
The placebo effect is not well understood, but has a strong influence on the results of any research study, whether in traditional or complementary medicine.
COMPLEMENTARY MEDICINE — Complementary medicine is a treatment, practice, or product that is used alongside traditional medical treatment. It is not meant to replace traditional cancer treatment, but is available to alleviate side effects or improve a patient's sense of well-being.
Alternative medical systems — Alternative medical systems are healing techniques and beliefs that have developed over time, and include homeopathy, naturopathy, and traditional Chinese medicine (which includes acupuncture).
Acupuncture — Acupuncture involves inserting hair-thin, metal needles into the skin at specific points on the body. It causes little to no pain. Electrical stimulation is sometimes applied to the acupuncture needle. There have been numerous studies of acupuncture's efficacy in reducing nausea, pain, and hot flashes, and results have been mixed. Acupuncture with electrical stimulation has been found to be useful in treating nausea and vomiting from chemotherapy; women using acupuncture required less medication for nausea and vomiting than women who used no acupuncture [2]. Some trials suggest that acupuncture can reduce cancer pain, although a review of multiple trials showed it to be of no benefit. Acupuncture with electrical stimulation may be of benefit in reducing hot flashes in men undergoing hormonal treatments for prostate cancer. Further study is needed to confirm this result.
Other forms of traditional Chinese medicine, which use standard combinations of herbs or botanicals for various illnesses, are difficult to study. Little information is available from controlled studies regarding the safety and efficacy of this form of treatment.
Homeopathy and naturopathy — Naturopathy has not been studied in controlled, well-designed studies, and the risks, benefits, and efficacy have not been established. There have been several clinical studies of homeopathy, but the results were contradictory and systematic reviews (which combine the results of multiple clinical trials) have not shown homeopathy to be of proven benefit for any medical condition. In addition, patients and their families are not advised to spend large amounts of money on treatments that are not proven to be of benefit.
Mind-body techniques — Mind-body techniques include practices such as hypnosis, guided imagery, meditation, yoga, biofeedback, and prayer. They may be useful before or during painful or stress-inducing medical procedures, chemotherapy, or radiation treatment to control anxiety, pain, or nausea and vomiting. Patients of any age can learn mind-body techniques.
Hypnotherapy — Hypnosis is a state of altered consciousness that allows a patient to focus away from their pain, anxiety, or nausea. Patients who are hypnotized are not sleeping, but are actually in a state of heightened imagination, similar to daydreaming. An expert can hypnotize an individual, or a patient can learn self-hypnosis techniques. Hypnosis is safe and has few side effects.
It is not clear how or if hypnosis is helpful, though studies have suggested that it may be useful for controlling pain and nausea/vomiting in various settings, and may reduce vomiting that can develop before starting chemotherapy (called anticipatory emesis). Hypnosis may also be useful in children for preventing anxiety and pain from difficult procedures such as lumbar puncture (spinal tap) or bone marrow biopsy.
Visual or guided imagery — Visual or guided imagery is a technique that encourages the patient to relax by focusing on calming thoughts or experiences. The patient sits or lies in a comfortable position while imagining a pleasant experience such as relaxing on the beach. In one study, women receiving chemotherapy for newly diagnosed breast cancer had a better quality of life if they used relaxation training and guided imagery, as compared to a group that had chemotherapy alone [3].
Spirituality — A majority of individuals have religious beliefs, and many of these persons rely on their religion or spirituality in difficult times, such as during treatments for cancer [4]. Researchers found that spirituality, when combined with conventional medicine, was an important component in the healing process and was of benefit not only to the patient but also to caregivers and healthcare professionals [5]. Some, but not all, studies have shown that religious involvement and spirituality are associated with better health outcomes, including longer life, improved coping skills, better health in general, and lower rates of anxiety, depression, and suicide [6].
Body-based therapies — Body-based therapies use movement or manipulation of one or more parts of the body.
Massage therapy — Massage is a body-based therapy that uses therapeutic touch, which involves stroking and kneading the skin, muscle, and connective tissues. There are several types of massage therapy. Classic or Swedish massage is massage aimed primarily at muscles. It reduces tension and increases blood flow. Reflexology is massage of the hands and feet based on a system of points that correlate to other areas of the body. Chair massage is done while the patient sits fully clothed in a special chair that slopes forward, allowing the therapist access to the back, neck, and shoulders. Deep tissue massage is a form of intense tissue manipulation.
A study was done in 1,290 cancer patients who received massage therapy at Memorial Sloan-Kettering Cancer Center. It found that pain, anxiety, fatigue, and nausea decreased by 50 percent in patients who received massage. Some patients reported benefits lasting up to 48 hours [7]. A small number of insurance companies cover massage therapy as a complementary cancer treatment.
Energy therapies — Energy therapies involve using the body's energy fields to heal and maintain wellness. Believers in energy medicine describe disruptions in the energy field as a cause for illness, and teach that balancing energy can aid in healing. It is difficult to study the effectiveness of energy medicine due to the intangible nature of the body's "energy."
Reiki is a form of energy medicine, and has been evaluated in several clinical trials for treatment of anxiety and improvement of well-being in cancer patients. Some, but not all, trials showed positive results, although the studies showing benefit were not well designed and it is difficult to distinguish the true benefit from placebo effect.
ALTERNATIVE CANCER TREATMENTS — Alternative cancer treatments (ACTs) are usually promoted as replacements to traditional cancer treatments. Cancer patients may seek them out in the hope of a cure. Some ACTs require the patient to receive treatment at their clinics, often located outside the United States. In many cases, reliable clinical trials have found these treatments ineffective or unsafe, and the FDA has not given approval for these treatments inside the United States.
Dietary ACTs — Good nutrition is important for cancer patients. None of the ACTs are proven to prolong life or cure cancer. In addition, some alternative cancer diet treatments are costly and potentially harmful.
Gerson regimen — The Gerson regimen requires an organic, vegetarian diet, and includes a strict schedule for ingesting juice made from fruit and vegetables. In addition, patients are given a number of vitamin supplements. No clinical study has proven this regimen's efficacy. It is not recommended and may be expensive and harmful.
Macrobiotic diets — Macrobiotic diets are low-fat, vegetarian diets that include large amounts of complex carbohydrates. One report found that one-third of cancer patients who followed a macrobiotic diet lost weight, which resulted in other problems [8]. This was likely due to several factors, including the expense or inaccessibility of some of the required foods, time spent preparing the meals, and the restrictive, sometimes unpleasant, nature of the diet. Macrobiotic diets are not recommended for persons with cancer.
Selected vegetables — Selected vegetables (SV), also called Sun's soup, is a blended, boiled, and freeze-dried product that claims to have immune-stimulatory and anticancer properties. Two small studies have been conducted in patients with late stage non-small cell lung cancer, both of which found that patients who received the supplement had an improved survival. Patients in both studies received traditional medical treatments as well as the SV mix. However, the studies were small and had weaknesses in study design; further studies are needed before the treatment can be considered safe and effective.
Herbal medicine — Combinations of herbs (also called botanicals) are often promoted as ACTs. Herbal medicines may come in the form of a powder, liquid, or pill. Examples of herbal treatments include essiac, green tea, mistletoe, PC-SPES (a mixture of herbs marketed for prostate cancer, now recalled due to an increased risk of blood clots), sho-saik-to, and St. John's wort [9].
None of these herbals have proven to cure or improve cancer in reliable clinical studies; some can cause dangerous side effects (show table 1). In addition, some herbal products can interact with traditional cancer treatments, making traditional treatments less effective (show table 2) [9].
Other supplements — A number of dietary supplements have been advertised as being useful ACTs. These include coenzyme Q10, hydrazine, melatonin, shark cartilage, shiitake mushroom extract, and thymus extract. No supplement has proven reliable as either an alternative or complement to traditional cancer treatment [9].
PATIENTS CONSIDERING CAM
General recommendations — Any person who is considering use of a complementary, alternative, or traditional medical treatment should gather information about the safety, risks, and benefits of the treatment. Reliable information sources include the healthcare team (physician, nurse, dietitian) and government-sponsored web sites.
It is important to choose the person providing CAM with care; patients should inquire about education and licensing requirements since these vary by state. The safety of CAM treatments should be considered. Being "natural" does not mean that a product or treatment is safe.
The cost of a CAM treatment must also be considered, as these are generally not covered by commercial or government-funded health insurance. A patient or family who uses their life's savings for an unproven "cure" is likely to be disappointed.
Questions to consider — When evaluating an alternative or complementary treatment, consider the following questions: Does the treatment require patients to stop traditional medical care? Does it claim to cure cancer? Is it offered by only one individual or by an established, recognized cancer treatment facility? Is it a secret that only certain people can share? Does it require travel to another country? Is it approved in the United States? Is it based on well-controlled, scientific research? Is it expensive? Is the group or person promoting the CAM treatment an expert in cancer treatment? Do the promoters attack the scientific and medical research community?
Combining CAM and traditional treatments — Patients who are considering a CAM treatment must consider the safety and potential benefit of the treatment itself, and must also consider how the CAM treatment could interact with traditional treatments, such as chemotherapy. It is possible for a CAM treatment, especially a dietary ACT, herbal medicine, or other supplement, to alter the body's metabolism and clearance of chemotherapy in unexpected ways. Because CAM treatments are not generally tested for use in combination with standard chemotherapy, they could interfere with the beneficial effect of the chemotherapy, or potentially increase the risk of toxic side effects.
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
1-800-ACS-2345
(www.cancer.org/)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
National Center for Complementary and Alternative Medicine
(nccam.nih.gov/)
Memorial Sloan-Kettering Cancer Center
(www.mskcc.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-12]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. NIH Consensus Conference: Acupuncture. JAMA 1998; 280:1518.
2. Ezzo, J, Vickers, A, Richardson, MA, et al. Acupuncture-point stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol 2005; 23:7188.
3. Walker, LG, Walker, MB, Ogston, K, et al. Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. Br J Cancer 1999; 80:262.
4. www.cancer.gov (Accessed January 20, 2006).
5. Rummans, TA, Clark, MM, Sloan, JA, et al. Impacting quality of life for patients with advanced cancer with a structured multidisciplinary intervention: a randomized controlled trial. J Clin Oncol 2006; 24:635.
6. Mueller, PS, Plevak, DJ, Rummans, TA. Religious involvement, spirituality, and medicine: implications for clinical practice. Mayo Clin Proc 2001; 76:1225.
7. Cassileth, BR, Vickers, AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage 2004; 28:244.
8. Downer, SM, Cody, MM, McCluskey, P, et al. Pursuit and practice of complementary therapies by cancer patients receiving conventional treatment. BMJ 1994; 309:86.
9. Ernst E, Pittler MH, Wider B, Boddy K. The desktop guide to complementary and alternative medicine, Edinburgh 2006.
10. Lee, H, Schmidt, K, Ernst, E. Acupuncture for the relief of cancer-related pain--a systematic review. Eur J Pain 2005; 9:437.
11. The National Center for Complementary and Alternative Medicine, publications available online at www.nccam.nih.gov (Accessed January 20, 2006).
12. Ernst, E. Intangible risks of complementary and alternative medicine. J Clin Oncol 2001; 19:2365.
Between 48 and 88 percent of patients with cancer use some form of CAM. Most patients who use CAM are not dissatisfied with traditional medicine, but find that complementary and alternative treatments appeal to their values and beliefs about health and life. Being diagnosed with cancer and undergoing treatment can be a frightening, exhausting, and demanding experience. CAM appeals to many patients with cancer because these treatments often offer a chance to feel better and decrease uncomfortable symptoms such as pain, fatigue, and nausea.
The focus of this topic is to highlight a few of the available treatments that may be beneficial, as well as to review those that are ineffective and could potentially be dangerous. The list of complementary and alternative medicine treatments is ever changing; the best resource for advice about complementary as well as traditional therapies is the healthcare team.
Placebo effect — A placebo is an inactive medication or treatment. Well-designed studies include a placebo treatment as well as a real treatment so that the two may be compared. The placebo effect is the positive or negative result that occurs when a patient believes they have been given a treatment, when in fact they have been given none (or a look-alike substitute). For example, a CAM treatment that claims to improve symptoms of nausea in 50 percent of patients is of little benefit if a placebo treatment also improves symptoms in 50 percent of patients.
The placebo effect is not well understood, but has a strong influence on the results of any research study, whether in traditional or complementary medicine.
COMPLEMENTARY MEDICINE — Complementary medicine is a treatment, practice, or product that is used alongside traditional medical treatment. It is not meant to replace traditional cancer treatment, but is available to alleviate side effects or improve a patient's sense of well-being.
Alternative medical systems — Alternative medical systems are healing techniques and beliefs that have developed over time, and include homeopathy, naturopathy, and traditional Chinese medicine (which includes acupuncture).
Acupuncture — Acupuncture involves inserting hair-thin, metal needles into the skin at specific points on the body. It causes little to no pain. Electrical stimulation is sometimes applied to the acupuncture needle. There have been numerous studies of acupuncture's efficacy in reducing nausea, pain, and hot flashes, and results have been mixed. Acupuncture with electrical stimulation has been found to be useful in treating nausea and vomiting from chemotherapy; women using acupuncture required less medication for nausea and vomiting than women who used no acupuncture [2]. Some trials suggest that acupuncture can reduce cancer pain, although a review of multiple trials showed it to be of no benefit. Acupuncture with electrical stimulation may be of benefit in reducing hot flashes in men undergoing hormonal treatments for prostate cancer. Further study is needed to confirm this result.
Other forms of traditional Chinese medicine, which use standard combinations of herbs or botanicals for various illnesses, are difficult to study. Little information is available from controlled studies regarding the safety and efficacy of this form of treatment.
Homeopathy and naturopathy — Naturopathy has not been studied in controlled, well-designed studies, and the risks, benefits, and efficacy have not been established. There have been several clinical studies of homeopathy, but the results were contradictory and systematic reviews (which combine the results of multiple clinical trials) have not shown homeopathy to be of proven benefit for any medical condition. In addition, patients and their families are not advised to spend large amounts of money on treatments that are not proven to be of benefit.
Mind-body techniques — Mind-body techniques include practices such as hypnosis, guided imagery, meditation, yoga, biofeedback, and prayer. They may be useful before or during painful or stress-inducing medical procedures, chemotherapy, or radiation treatment to control anxiety, pain, or nausea and vomiting. Patients of any age can learn mind-body techniques.
Hypnotherapy — Hypnosis is a state of altered consciousness that allows a patient to focus away from their pain, anxiety, or nausea. Patients who are hypnotized are not sleeping, but are actually in a state of heightened imagination, similar to daydreaming. An expert can hypnotize an individual, or a patient can learn self-hypnosis techniques. Hypnosis is safe and has few side effects.
It is not clear how or if hypnosis is helpful, though studies have suggested that it may be useful for controlling pain and nausea/vomiting in various settings, and may reduce vomiting that can develop before starting chemotherapy (called anticipatory emesis). Hypnosis may also be useful in children for preventing anxiety and pain from difficult procedures such as lumbar puncture (spinal tap) or bone marrow biopsy.
Visual or guided imagery — Visual or guided imagery is a technique that encourages the patient to relax by focusing on calming thoughts or experiences. The patient sits or lies in a comfortable position while imagining a pleasant experience such as relaxing on the beach. In one study, women receiving chemotherapy for newly diagnosed breast cancer had a better quality of life if they used relaxation training and guided imagery, as compared to a group that had chemotherapy alone [3].
Spirituality — A majority of individuals have religious beliefs, and many of these persons rely on their religion or spirituality in difficult times, such as during treatments for cancer [4]. Researchers found that spirituality, when combined with conventional medicine, was an important component in the healing process and was of benefit not only to the patient but also to caregivers and healthcare professionals [5]. Some, but not all, studies have shown that religious involvement and spirituality are associated with better health outcomes, including longer life, improved coping skills, better health in general, and lower rates of anxiety, depression, and suicide [6].
Body-based therapies — Body-based therapies use movement or manipulation of one or more parts of the body.
Massage therapy — Massage is a body-based therapy that uses therapeutic touch, which involves stroking and kneading the skin, muscle, and connective tissues. There are several types of massage therapy. Classic or Swedish massage is massage aimed primarily at muscles. It reduces tension and increases blood flow. Reflexology is massage of the hands and feet based on a system of points that correlate to other areas of the body. Chair massage is done while the patient sits fully clothed in a special chair that slopes forward, allowing the therapist access to the back, neck, and shoulders. Deep tissue massage is a form of intense tissue manipulation.
A study was done in 1,290 cancer patients who received massage therapy at Memorial Sloan-Kettering Cancer Center. It found that pain, anxiety, fatigue, and nausea decreased by 50 percent in patients who received massage. Some patients reported benefits lasting up to 48 hours [7]. A small number of insurance companies cover massage therapy as a complementary cancer treatment.
Energy therapies — Energy therapies involve using the body's energy fields to heal and maintain wellness. Believers in energy medicine describe disruptions in the energy field as a cause for illness, and teach that balancing energy can aid in healing. It is difficult to study the effectiveness of energy medicine due to the intangible nature of the body's "energy."
Reiki is a form of energy medicine, and has been evaluated in several clinical trials for treatment of anxiety and improvement of well-being in cancer patients. Some, but not all, trials showed positive results, although the studies showing benefit were not well designed and it is difficult to distinguish the true benefit from placebo effect.
ALTERNATIVE CANCER TREATMENTS — Alternative cancer treatments (ACTs) are usually promoted as replacements to traditional cancer treatments. Cancer patients may seek them out in the hope of a cure. Some ACTs require the patient to receive treatment at their clinics, often located outside the United States. In many cases, reliable clinical trials have found these treatments ineffective or unsafe, and the FDA has not given approval for these treatments inside the United States.
Dietary ACTs — Good nutrition is important for cancer patients. None of the ACTs are proven to prolong life or cure cancer. In addition, some alternative cancer diet treatments are costly and potentially harmful.
Gerson regimen — The Gerson regimen requires an organic, vegetarian diet, and includes a strict schedule for ingesting juice made from fruit and vegetables. In addition, patients are given a number of vitamin supplements. No clinical study has proven this regimen's efficacy. It is not recommended and may be expensive and harmful.
Macrobiotic diets — Macrobiotic diets are low-fat, vegetarian diets that include large amounts of complex carbohydrates. One report found that one-third of cancer patients who followed a macrobiotic diet lost weight, which resulted in other problems [8]. This was likely due to several factors, including the expense or inaccessibility of some of the required foods, time spent preparing the meals, and the restrictive, sometimes unpleasant, nature of the diet. Macrobiotic diets are not recommended for persons with cancer.
Selected vegetables — Selected vegetables (SV), also called Sun's soup, is a blended, boiled, and freeze-dried product that claims to have immune-stimulatory and anticancer properties. Two small studies have been conducted in patients with late stage non-small cell lung cancer, both of which found that patients who received the supplement had an improved survival. Patients in both studies received traditional medical treatments as well as the SV mix. However, the studies were small and had weaknesses in study design; further studies are needed before the treatment can be considered safe and effective.
Herbal medicine — Combinations of herbs (also called botanicals) are often promoted as ACTs. Herbal medicines may come in the form of a powder, liquid, or pill. Examples of herbal treatments include essiac, green tea, mistletoe, PC-SPES (a mixture of herbs marketed for prostate cancer, now recalled due to an increased risk of blood clots), sho-saik-to, and St. John's wort [9].
None of these herbals have proven to cure or improve cancer in reliable clinical studies; some can cause dangerous side effects (show table 1). In addition, some herbal products can interact with traditional cancer treatments, making traditional treatments less effective (show table 2) [9].
Other supplements — A number of dietary supplements have been advertised as being useful ACTs. These include coenzyme Q10, hydrazine, melatonin, shark cartilage, shiitake mushroom extract, and thymus extract. No supplement has proven reliable as either an alternative or complement to traditional cancer treatment [9].
PATIENTS CONSIDERING CAM
General recommendations — Any person who is considering use of a complementary, alternative, or traditional medical treatment should gather information about the safety, risks, and benefits of the treatment. Reliable information sources include the healthcare team (physician, nurse, dietitian) and government-sponsored web sites.
It is important to choose the person providing CAM with care; patients should inquire about education and licensing requirements since these vary by state. The safety of CAM treatments should be considered. Being "natural" does not mean that a product or treatment is safe.
The cost of a CAM treatment must also be considered, as these are generally not covered by commercial or government-funded health insurance. A patient or family who uses their life's savings for an unproven "cure" is likely to be disappointed.
Questions to consider — When evaluating an alternative or complementary treatment, consider the following questions: Does the treatment require patients to stop traditional medical care? Does it claim to cure cancer? Is it offered by only one individual or by an established, recognized cancer treatment facility? Is it a secret that only certain people can share? Does it require travel to another country? Is it approved in the United States? Is it based on well-controlled, scientific research? Is it expensive? Is the group or person promoting the CAM treatment an expert in cancer treatment? Do the promoters attack the scientific and medical research community?
Combining CAM and traditional treatments — Patients who are considering a CAM treatment must consider the safety and potential benefit of the treatment itself, and must also consider how the CAM treatment could interact with traditional treatments, such as chemotherapy. It is possible for a CAM treatment, especially a dietary ACT, herbal medicine, or other supplement, to alter the body's metabolism and clearance of chemotherapy in unexpected ways. Because CAM treatments are not generally tested for use in combination with standard chemotherapy, they could interfere with the beneficial effect of the chemotherapy, or potentially increase the risk of toxic side effects.
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
1-800-ACS-2345
(www.cancer.org/)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
National Center for Complementary and Alternative Medicine
(nccam.nih.gov/)
Memorial Sloan-Kettering Cancer Center
(www.mskcc.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-12]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. NIH Consensus Conference: Acupuncture. JAMA 1998; 280:1518.
2. Ezzo, J, Vickers, A, Richardson, MA, et al. Acupuncture-point stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol 2005; 23:7188.
3. Walker, LG, Walker, MB, Ogston, K, et al. Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. Br J Cancer 1999; 80:262.
4. www.cancer.gov (Accessed January 20, 2006).
5. Rummans, TA, Clark, MM, Sloan, JA, et al. Impacting quality of life for patients with advanced cancer with a structured multidisciplinary intervention: a randomized controlled trial. J Clin Oncol 2006; 24:635.
6. Mueller, PS, Plevak, DJ, Rummans, TA. Religious involvement, spirituality, and medicine: implications for clinical practice. Mayo Clin Proc 2001; 76:1225.
7. Cassileth, BR, Vickers, AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage 2004; 28:244.
8. Downer, SM, Cody, MM, McCluskey, P, et al. Pursuit and practice of complementary therapies by cancer patients receiving conventional treatment. BMJ 1994; 309:86.
9. Ernst E, Pittler MH, Wider B, Boddy K. The desktop guide to complementary and alternative medicine, Edinburgh 2006.
10. Lee, H, Schmidt, K, Ernst, E. Acupuncture for the relief of cancer-related pain--a systematic review. Eur J Pain 2005; 9:437.
11. The National Center for Complementary and Alternative Medicine, publications available online at www.nccam.nih.gov (Accessed January 20, 2006).
12. Ernst, E. Intangible risks of complementary and alternative medicine. J Clin Oncol 2001; 19:2365.
Treatment of metastatic colorectal cancer
INTRODUCTION — Despite early diagnosis and treatment, cancers involving the colon or rectum (together referred to as colorectal cancer) can reappear at a later time, even if the cancer was entirely removed during the initial treatment. This reappearance of the cancer is referred to as a recurrence or a relapse.
A colorectal cancer recurrence can be either local (confined to the large intestine or nearby tissues) or at a more distant site. Areas of distant tumor involvement are called metastases. Although most patients with metastatic colorectal cancer develop the tumor recurrence months to years after initial treatment, a small percentage already have metastatic cancer when their cancer is first discovered.
The treatment of patients with colorectal cancer that has spread or metastasized depends upon the extent and location of the tumor involvement. Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement (particularly involving the liver) may be cured by further surgery. For others, chemotherapy is the most appropriate option. Chemotherapy does not cure metastatic colorectal cancer, but it can improve symptoms and prolong life.
This topic review will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere (See "Patient information: Treatment of colon cancer" and see "Patient information: Treatment of rectal cancer").
SURGERY FOR RESECTABLE ADVANCED DISEASE — Sometimes surgery can be considered for patients whose colorectal cancer has spread in a limited way outside of the intestine, to an area such as the liver. Up to 30 percent of patients may be cured if the tumor(s) in the liver can be completely removed or resected [1]. In order for this approach to succeed, there must be no cancer outside of the liver.
In some cases, intravenous chemotherapy may be recommended prior to attempted surgical removal of the liver metastases. This approach might permit some patients who have liver metastases that are initially unresectable or borderline resectable (because of size or location) to have successful surgery [2].
It is not clear if additional chemotherapy is beneficial after successful surgical removal of liver metastases. Although several clinical trials have studied this issue, none have shown that survival is better in patients who get chemotherapy after liver surgery compared to those who do not. However, none of the studies used what would be considered to be "modern" chemotherapy regimens. Treatment guidelines suggest that six months of treatment with chemotherapy or observation alone are both reasonable options [3]. Contemporary chemotherapy regimens for metastatic colorectal cancer are described in detail below (See "First-line chemotherapy" below).
At some institutions, the chemotherapy is given directly into the liver (an approach called hepatic intraarterial chemotherapy) with or without additional chemotherapy given into the veins (intravenous chemotherapy) [4]. However, whether this approach is better than intravenous chemotherapy alone is unclear, and the most commonly used approach is intravenous chemotherapy.
CHEMOTHERAPY FOR UNRESECTABLE DISEASE — As noted above, surgery is the only way to cure a patient who has metastatic colorectal cancer. If surgery is not possible, then chemotherapy is generally recommended. Chemotherapy clearly benefits patients by improving symptoms and prolonging survival; it is not intended to cure the cancer.
Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include: 5-fluorouracil (abbreviated 5-FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity Orally active 5-FU-like drugs such as capecitabine (Xeloda®) Oxaliplatin (Eloxatin®), which is given intravenously Irinotecan (Camptosar®), also given intravenously
These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment. (See "Chemotherapy side effects" below).
Targeted therapies — Three other drugs that are active in metastatic colorectal cancer, called bevacizumab (Avastin®), cetuximab (Erbitux®), and panitumumab (Vectibix®) work by a different mechanism. All three are referred to as "targeted chemotherapy agents" since they are antibodies (a type of protein) that work to inhibit a protein that is important for the growth and/or survival of colon cancer cells: Avastin binds a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Avastin also enhance the antitumor effect of other chemotherapy drugs. Erbitux targets a different protein, the epidermal growth factor receptor (EGFR), which is found in approximately 80 percent of colorectal cancers. Erbitux is effective even if EGFR is not detected within a person's tumor, possibly because the test is not sensitive in detecting a small number of receptors. Vectibix also targets the EGFR, but in a different way than Erbitux.
Because these drugs do not directly inhibit rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy drugs such as irinotecan, oxaliplatin, and 5-FU. However, they have other unique side effects, which are described in detail below. (See "Chemotherapy side effects" below).
Avastin is not effective when given by itself, without other anticancer drugs. It is used only in combination with 5-FU and irinotecan or oxaliplatin. On the other hand, Erbitux can be used alone or in combination with irinotecan. Ongoing trials are currently evaluating Erbitux and Avastin (both alone and together) with other chemotherapeutic agents in an attempt to find more active combinations.
In the United States, Vectibix is only approved as a "last resort" treatment of metastatic colorectal cancer, after other drugs have failed. Its role in combination with chemotherapy and Avastin is under study.
Assessment during therapy — Regardless of the particular drugs that are chosen, the response to chemotherapy is typically assessed using periodic x-ray studies (such as CT scans), often recommended after every two to three cycles of therapy, and by measuring blood levels of a tumor marker called carcinoembryonic antigen (CEA). CEA levels are typically high in patients who have advanced colorectal cancer, and levels are checked every one to three months during therapy. Persistently rising CEA levels suggest that disease is progressing and that a change in therapy is warranted. However, disease progression should be confirmed with radiographic testing (eg, CT scan) or biopsy before a change in treatment is recommended.
FIRST-LINE CHEMOTHERAPY — Conventional chemotherapy drugs and targeted agents are generally used in combination for patients with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed, and studies are ongoing to determine which combinations and schedules are best. Several different combinations are currently recommended for initial (first-line) treatment.
FOLFOX and FOLFIRI — Two different combination regimens are considered standard approaches for the initial treatment for patients with metastatic colorectal cancer [5,6]. Each of these regimens consists of three drugs, used together in a specific way: Oxaliplatin plus 5-FU and leucovorin (referred to as FOLFOX) Irinotecan plus 5-FU and leucovorin (referred to as FOLFIRI)
In both regimens, the oxaliplatin or irinotecan are typically administered intravenously all at once on the first day of treatment (day 1). The leucovorin and 5-FU are administered on two consecutive days (day 1 and 2) with an initial intravenous bolus (rapidly infused) dose of leucovorin and 5-FU, followed by a continuous infusion of 5-FU administered into the vein over 22 hours. The same doses and schedule of all three drugs are repeated every two weeks. Frequently, the delivery of 5-FU is modified so that the infusion runs for 46 instead of 22 hours, thus eliminating the need for patients to come in for the bolus infusion of 5-FU and leucovorin on day 2.
Both the FOLFOX and FOLFIRI regimens require that patients have a central venous access catheter (often termed a "port") surgically inserted into one of the large blood vessels in the chest and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is actually very small, and it fits into a fanny pack that can be worn around the patient's waist.
Both FOLFIRI and FOLFOX have similar outcomes when used as first-line therapy [5,6] and the choice between them is sometimes based upon expected side effects with each regimen (see "Chemotherapy side effects" below). At least in the United States, most patients are offered first-line FOLFOX, and FOLFIRI is reserved for second-line therapy unless there are coexisting medical conditions (such as neuropathy) that might favor the initial use of FOLFIRI.
For patients in whom ambulatory infusion pump therapy is not feasible, the combination of the oral drug Xeloda plus oxaliplatin is an acceptable alternative to the infusional regimens FOLFOX. This regimen is more convenient for the patient, and probably similarly effective for first-line therapy as FOLFOX. However, some side effects (including diarrhea and redness, tenderness, and peeling of the skin of the palms and soles of the feet) may be more pronounced than with FOLFOX.
Combinations of Xeloda with irinotecan may not be as effective and are more toxic than FOLFIRI. As a result, they are usually not recommended.
Benefit of adding Avastin — Encouraging results have been reported when bevacizumab (Avastin®) is combined with 5-FU plus leucovorin and either oxaliplatin or irinotecan (FOLFOX or FOLFIRI). Adding Avastin results in a significantly higher likelihood of a tumor response, and it prolongs survival compared to treatment without Avastin. As long as there are not reasons Avastin should not be used, it is recommended for first-line treatment in persons who receive either FOLFIRI or FOLFOX. Avastin is administered intravenously once every two weeks.
Patients who can't tolerate irinotecan or oxaliplatin — For patients who are not appropriate candidates for an aggressive chemotherapy regimen like FOLFOX or FOLFIRI (for example, because of their age, physical condition or coexisting medical problems), intravenous 5-FU plus leucovorin with or without Avastin may be a reasonable, less toxic alternative. In this regimen, both agents are administered as a short injection weekly for six of every eight weeks.
Another alternative is Xeloda alone, which is taken in pill form twice daily for 14 of every 21 days. Xeloda has about the same level of effectiveness as intravenous 5-FU plus leucovorin. These regimens are slightly less effective than oxaliplatin or irinotecan-containing chemotherapy regimens (FOLFOX or FOLFIRI), but in general, they have fewer side effects and do not require a central venous access catheter or ambulatory infusion pump.
SECOND-LINE THERAPY — If the cancer continues to grow despite chemotherapy, or it begins to enlarge again after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried (if the patient is well enough to tolerate additional therapy). Because survival can be prolonged by second-line (as well as third-line) therapy, exposure to all of the most active medications at some point in the treatment (ie, 5-FU, oxaliplatin, irinotecan, Avastin, Erbitux, Vectibix) is thought to be more important than the specific sequence or order of drug administration.
The choice of second-line treatment typically depends on what was given originally. Two different approaches may be considered, but it is unknown whether either approach is superior to the other: If FOLFOX (or Xeloda plus oxaliplatin) plus Avastin was the first-line regimen, patients are typically switched to FOLFIRI with or without Avastin. If FOLFIRI plus Avastin was given as the first-line therapy, the patient is usually switched to FOLFOX or Xeloda plus oxaliplatin with or without Avastin.
Whether or not Avastin should be continued with the second-line regimen is a very controversial area, and should be discussed with a physician.
Erbitux — Adding Erbitux to irinotecan can shrink tumors in patients who stop responding to irinotecan-containing chemotherapy combinations (such as FOLFIRI or even irinotecan alone). Most often, the combination of Erbitux plus irinotecan is used for third-line therapy after failure of both FOLFOX and FOLFIRI. However, it is also sometimes used as second line therapy if there is progression on FOLFIRI plus Avastin.
Erbitux is also approved for use as a single agent to treat metastatic colorectal cancer in patients who cannot tolerate irinotecan-based chemotherapy.
Vectibix — In the United States, panitumamab (Vectibix®) is approved as a "last resort" treatment of metastatic CRC, after other drugs have failed. In one trial, patients receiving panitumumab after failing irinotecan and oxaliplatin-containing chemotherapy were significantly more likely to be alive and disease-free 8 weeks after treatment, than were those who had supportive care only without further chemotherapy (49 versus 30 percent). Combinations of panitumumab with conventional chemotherapy and bevacizumab are currently being studied.
CHEMOTHERAPY SIDE EFFECTS — The side effects of chemotherapy depend upon the type, combination, and schedule of drugs that are administered. The most common side effects of each agent are listed below, but is important to review all of the potential side effects of any therapy with the healthcare team.
5-FU and leucovorin — The most common side effects are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. In general, diarrhea and mucositis are more likely when 5-FU and leucovorin are given five days in a row (rather than weekly), especially in older patients. For this reason, most oncologists prefer the weekly regimen. Hair loss is less common with 5-FU plus leucovorin than with combinations of irinotecan or oxaliplatin plus 5-FU/leucovorin.
Xeloda — The most common side effect of Xeloda is hand-foot syndrome, a condition that causes soreness, redness and peeling of the skin of the palms and soles of the feet. Otherwise, oral 5-FU-like drugs such as Xeloda have the same side effects as intravenous 5-FU, although diarrhea and mucositis are somewhat less common.
Irinotecan — Irinotecan usually causes more diarrhea, lower blood counts, more fatigue, and more hair loss compared to 5-FU. When irinotecan is combined with 5-FU and leucovorin (FOLFIRI), the most common side effect is diarrhea. Patients should call their healthcare provider immediately if severe diarrhea develops.
Oxaliplatin — Oxaliplatin can cause numbness and tingling of the hands and feet, and this is more likely with longer durations of therapy. This drug can also cause an unusual sensitivity to cold temperatures. This can result in painful spasms of the throat while inhaling cold air or ingesting cold liquids. Patients should not drink cold fluids in the several days surrounding their oxaliplatin infusions, avoid inhaling cold air, and avoid exposing the hands and feet to cold when possible.
Avastin — Avastin can rarely cause an allergic reaction. If the reaction is severe, the drug may need to be stopped. Because there is a small risk that Avastin can impair wound healing, surgery should be avoided for at least four weeks before and after Avastin (if possible) to avoid this potential side effect.
Avastin may also cause bleeding or, uncommonly, perforation of the bowel during treatment. It can also increase blood pressure or cause protein in the urine. Close monitoring is necessary to detect these problems early so that they can be effectively treated.
There is an increased risk of blood clots for patients using Avastin in combination with 5-FU. Approximately 5 percent of patients have serious events such as strokes and heart attacks during therapy. The risk appears to be highest in patients with prior heart problems, and in those over the age of 65.
Erbitux — Erbitux can cause allergic reactions slightly more frequently than Avastin. If severe, treatment with Erbitux may be stopped. Patients will be closely monitored for allergic reactions during and after their infusion.
Other side effects include a skin rash that resembles acne, and low blood levels of magnesium. Low magnesium levels can cause weakness, heart rhythm abnormalities, and lead to low levels of other components of the blood, such as potassium and calcium.
Vectibix — Vectibix can also cause allergic reactions which, if severe, may require that drug treatment be stopped. Other side effects are similar to those with Erbitux, including skin rash, which may be severe and accompanied by infection, and low blood levels of magnesium.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Goldberg, RM, Fleming, TR, Tangen, CM, et al. Surgery for recurrent colon cancer: Strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 1998; 129:27.
2. Adam, R, Delvart, V, Pascal, G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644.
3. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls.asp.
4. Kemeny, N, Huang, Y, Cohen, AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039.
5. Goldberg, RM, Sargent, DJ, Morton, RF, et al. A randomized controlled trial of Fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23.
6. Tournigand, C, Andre, T, Achille, E, et al. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. J Clin Oncol 2004; 22:229.
A colorectal cancer recurrence can be either local (confined to the large intestine or nearby tissues) or at a more distant site. Areas of distant tumor involvement are called metastases. Although most patients with metastatic colorectal cancer develop the tumor recurrence months to years after initial treatment, a small percentage already have metastatic cancer when their cancer is first discovered.
The treatment of patients with colorectal cancer that has spread or metastasized depends upon the extent and location of the tumor involvement. Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement (particularly involving the liver) may be cured by further surgery. For others, chemotherapy is the most appropriate option. Chemotherapy does not cure metastatic colorectal cancer, but it can improve symptoms and prolong life.
This topic review will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere (See "Patient information: Treatment of colon cancer" and see "Patient information: Treatment of rectal cancer").
SURGERY FOR RESECTABLE ADVANCED DISEASE — Sometimes surgery can be considered for patients whose colorectal cancer has spread in a limited way outside of the intestine, to an area such as the liver. Up to 30 percent of patients may be cured if the tumor(s) in the liver can be completely removed or resected [1]. In order for this approach to succeed, there must be no cancer outside of the liver.
In some cases, intravenous chemotherapy may be recommended prior to attempted surgical removal of the liver metastases. This approach might permit some patients who have liver metastases that are initially unresectable or borderline resectable (because of size or location) to have successful surgery [2].
It is not clear if additional chemotherapy is beneficial after successful surgical removal of liver metastases. Although several clinical trials have studied this issue, none have shown that survival is better in patients who get chemotherapy after liver surgery compared to those who do not. However, none of the studies used what would be considered to be "modern" chemotherapy regimens. Treatment guidelines suggest that six months of treatment with chemotherapy or observation alone are both reasonable options [3]. Contemporary chemotherapy regimens for metastatic colorectal cancer are described in detail below (See "First-line chemotherapy" below).
At some institutions, the chemotherapy is given directly into the liver (an approach called hepatic intraarterial chemotherapy) with or without additional chemotherapy given into the veins (intravenous chemotherapy) [4]. However, whether this approach is better than intravenous chemotherapy alone is unclear, and the most commonly used approach is intravenous chemotherapy.
CHEMOTHERAPY FOR UNRESECTABLE DISEASE — As noted above, surgery is the only way to cure a patient who has metastatic colorectal cancer. If surgery is not possible, then chemotherapy is generally recommended. Chemotherapy clearly benefits patients by improving symptoms and prolonging survival; it is not intended to cure the cancer.
Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include: 5-fluorouracil (abbreviated 5-FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity Orally active 5-FU-like drugs such as capecitabine (Xeloda®) Oxaliplatin (Eloxatin®), which is given intravenously Irinotecan (Camptosar®), also given intravenously
These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment. (See "Chemotherapy side effects" below).
Targeted therapies — Three other drugs that are active in metastatic colorectal cancer, called bevacizumab (Avastin®), cetuximab (Erbitux®), and panitumumab (Vectibix®) work by a different mechanism. All three are referred to as "targeted chemotherapy agents" since they are antibodies (a type of protein) that work to inhibit a protein that is important for the growth and/or survival of colon cancer cells: Avastin binds a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Avastin also enhance the antitumor effect of other chemotherapy drugs. Erbitux targets a different protein, the epidermal growth factor receptor (EGFR), which is found in approximately 80 percent of colorectal cancers. Erbitux is effective even if EGFR is not detected within a person's tumor, possibly because the test is not sensitive in detecting a small number of receptors. Vectibix also targets the EGFR, but in a different way than Erbitux.
Because these drugs do not directly inhibit rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy drugs such as irinotecan, oxaliplatin, and 5-FU. However, they have other unique side effects, which are described in detail below. (See "Chemotherapy side effects" below).
Avastin is not effective when given by itself, without other anticancer drugs. It is used only in combination with 5-FU and irinotecan or oxaliplatin. On the other hand, Erbitux can be used alone or in combination with irinotecan. Ongoing trials are currently evaluating Erbitux and Avastin (both alone and together) with other chemotherapeutic agents in an attempt to find more active combinations.
In the United States, Vectibix is only approved as a "last resort" treatment of metastatic colorectal cancer, after other drugs have failed. Its role in combination with chemotherapy and Avastin is under study.
Assessment during therapy — Regardless of the particular drugs that are chosen, the response to chemotherapy is typically assessed using periodic x-ray studies (such as CT scans), often recommended after every two to three cycles of therapy, and by measuring blood levels of a tumor marker called carcinoembryonic antigen (CEA). CEA levels are typically high in patients who have advanced colorectal cancer, and levels are checked every one to three months during therapy. Persistently rising CEA levels suggest that disease is progressing and that a change in therapy is warranted. However, disease progression should be confirmed with radiographic testing (eg, CT scan) or biopsy before a change in treatment is recommended.
FIRST-LINE CHEMOTHERAPY — Conventional chemotherapy drugs and targeted agents are generally used in combination for patients with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed, and studies are ongoing to determine which combinations and schedules are best. Several different combinations are currently recommended for initial (first-line) treatment.
FOLFOX and FOLFIRI — Two different combination regimens are considered standard approaches for the initial treatment for patients with metastatic colorectal cancer [5,6]. Each of these regimens consists of three drugs, used together in a specific way: Oxaliplatin plus 5-FU and leucovorin (referred to as FOLFOX) Irinotecan plus 5-FU and leucovorin (referred to as FOLFIRI)
In both regimens, the oxaliplatin or irinotecan are typically administered intravenously all at once on the first day of treatment (day 1). The leucovorin and 5-FU are administered on two consecutive days (day 1 and 2) with an initial intravenous bolus (rapidly infused) dose of leucovorin and 5-FU, followed by a continuous infusion of 5-FU administered into the vein over 22 hours. The same doses and schedule of all three drugs are repeated every two weeks. Frequently, the delivery of 5-FU is modified so that the infusion runs for 46 instead of 22 hours, thus eliminating the need for patients to come in for the bolus infusion of 5-FU and leucovorin on day 2.
Both the FOLFOX and FOLFIRI regimens require that patients have a central venous access catheter (often termed a "port") surgically inserted into one of the large blood vessels in the chest and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is actually very small, and it fits into a fanny pack that can be worn around the patient's waist.
Both FOLFIRI and FOLFOX have similar outcomes when used as first-line therapy [5,6] and the choice between them is sometimes based upon expected side effects with each regimen (see "Chemotherapy side effects" below). At least in the United States, most patients are offered first-line FOLFOX, and FOLFIRI is reserved for second-line therapy unless there are coexisting medical conditions (such as neuropathy) that might favor the initial use of FOLFIRI.
For patients in whom ambulatory infusion pump therapy is not feasible, the combination of the oral drug Xeloda plus oxaliplatin is an acceptable alternative to the infusional regimens FOLFOX. This regimen is more convenient for the patient, and probably similarly effective for first-line therapy as FOLFOX. However, some side effects (including diarrhea and redness, tenderness, and peeling of the skin of the palms and soles of the feet) may be more pronounced than with FOLFOX.
Combinations of Xeloda with irinotecan may not be as effective and are more toxic than FOLFIRI. As a result, they are usually not recommended.
Benefit of adding Avastin — Encouraging results have been reported when bevacizumab (Avastin®) is combined with 5-FU plus leucovorin and either oxaliplatin or irinotecan (FOLFOX or FOLFIRI). Adding Avastin results in a significantly higher likelihood of a tumor response, and it prolongs survival compared to treatment without Avastin. As long as there are not reasons Avastin should not be used, it is recommended for first-line treatment in persons who receive either FOLFIRI or FOLFOX. Avastin is administered intravenously once every two weeks.
Patients who can't tolerate irinotecan or oxaliplatin — For patients who are not appropriate candidates for an aggressive chemotherapy regimen like FOLFOX or FOLFIRI (for example, because of their age, physical condition or coexisting medical problems), intravenous 5-FU plus leucovorin with or without Avastin may be a reasonable, less toxic alternative. In this regimen, both agents are administered as a short injection weekly for six of every eight weeks.
Another alternative is Xeloda alone, which is taken in pill form twice daily for 14 of every 21 days. Xeloda has about the same level of effectiveness as intravenous 5-FU plus leucovorin. These regimens are slightly less effective than oxaliplatin or irinotecan-containing chemotherapy regimens (FOLFOX or FOLFIRI), but in general, they have fewer side effects and do not require a central venous access catheter or ambulatory infusion pump.
SECOND-LINE THERAPY — If the cancer continues to grow despite chemotherapy, or it begins to enlarge again after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried (if the patient is well enough to tolerate additional therapy). Because survival can be prolonged by second-line (as well as third-line) therapy, exposure to all of the most active medications at some point in the treatment (ie, 5-FU, oxaliplatin, irinotecan, Avastin, Erbitux, Vectibix) is thought to be more important than the specific sequence or order of drug administration.
The choice of second-line treatment typically depends on what was given originally. Two different approaches may be considered, but it is unknown whether either approach is superior to the other: If FOLFOX (or Xeloda plus oxaliplatin) plus Avastin was the first-line regimen, patients are typically switched to FOLFIRI with or without Avastin. If FOLFIRI plus Avastin was given as the first-line therapy, the patient is usually switched to FOLFOX or Xeloda plus oxaliplatin with or without Avastin.
Whether or not Avastin should be continued with the second-line regimen is a very controversial area, and should be discussed with a physician.
Erbitux — Adding Erbitux to irinotecan can shrink tumors in patients who stop responding to irinotecan-containing chemotherapy combinations (such as FOLFIRI or even irinotecan alone). Most often, the combination of Erbitux plus irinotecan is used for third-line therapy after failure of both FOLFOX and FOLFIRI. However, it is also sometimes used as second line therapy if there is progression on FOLFIRI plus Avastin.
Erbitux is also approved for use as a single agent to treat metastatic colorectal cancer in patients who cannot tolerate irinotecan-based chemotherapy.
Vectibix — In the United States, panitumamab (Vectibix®) is approved as a "last resort" treatment of metastatic CRC, after other drugs have failed. In one trial, patients receiving panitumumab after failing irinotecan and oxaliplatin-containing chemotherapy were significantly more likely to be alive and disease-free 8 weeks after treatment, than were those who had supportive care only without further chemotherapy (49 versus 30 percent). Combinations of panitumumab with conventional chemotherapy and bevacizumab are currently being studied.
CHEMOTHERAPY SIDE EFFECTS — The side effects of chemotherapy depend upon the type, combination, and schedule of drugs that are administered. The most common side effects of each agent are listed below, but is important to review all of the potential side effects of any therapy with the healthcare team.
5-FU and leucovorin — The most common side effects are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. In general, diarrhea and mucositis are more likely when 5-FU and leucovorin are given five days in a row (rather than weekly), especially in older patients. For this reason, most oncologists prefer the weekly regimen. Hair loss is less common with 5-FU plus leucovorin than with combinations of irinotecan or oxaliplatin plus 5-FU/leucovorin.
Xeloda — The most common side effect of Xeloda is hand-foot syndrome, a condition that causes soreness, redness and peeling of the skin of the palms and soles of the feet. Otherwise, oral 5-FU-like drugs such as Xeloda have the same side effects as intravenous 5-FU, although diarrhea and mucositis are somewhat less common.
Irinotecan — Irinotecan usually causes more diarrhea, lower blood counts, more fatigue, and more hair loss compared to 5-FU. When irinotecan is combined with 5-FU and leucovorin (FOLFIRI), the most common side effect is diarrhea. Patients should call their healthcare provider immediately if severe diarrhea develops.
Oxaliplatin — Oxaliplatin can cause numbness and tingling of the hands and feet, and this is more likely with longer durations of therapy. This drug can also cause an unusual sensitivity to cold temperatures. This can result in painful spasms of the throat while inhaling cold air or ingesting cold liquids. Patients should not drink cold fluids in the several days surrounding their oxaliplatin infusions, avoid inhaling cold air, and avoid exposing the hands and feet to cold when possible.
Avastin — Avastin can rarely cause an allergic reaction. If the reaction is severe, the drug may need to be stopped. Because there is a small risk that Avastin can impair wound healing, surgery should be avoided for at least four weeks before and after Avastin (if possible) to avoid this potential side effect.
Avastin may also cause bleeding or, uncommonly, perforation of the bowel during treatment. It can also increase blood pressure or cause protein in the urine. Close monitoring is necessary to detect these problems early so that they can be effectively treated.
There is an increased risk of blood clots for patients using Avastin in combination with 5-FU. Approximately 5 percent of patients have serious events such as strokes and heart attacks during therapy. The risk appears to be highest in patients with prior heart problems, and in those over the age of 65.
Erbitux — Erbitux can cause allergic reactions slightly more frequently than Avastin. If severe, treatment with Erbitux may be stopped. Patients will be closely monitored for allergic reactions during and after their infusion.
Other side effects include a skin rash that resembles acne, and low blood levels of magnesium. Low magnesium levels can cause weakness, heart rhythm abnormalities, and lead to low levels of other components of the blood, such as potassium and calcium.
Vectibix — Vectibix can also cause allergic reactions which, if severe, may require that drug treatment be stopped. Other side effects are similar to those with Erbitux, including skin rash, which may be severe and accompanied by infection, and low blood levels of magnesium.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The American Gastroenterological Association
(www.gastro.org)
The American College of Gastroenterology
(www.acg.gi.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Goldberg, RM, Fleming, TR, Tangen, CM, et al. Surgery for recurrent colon cancer: Strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 1998; 129:27.
2. Adam, R, Delvart, V, Pascal, G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644.
3. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls.asp.
4. Kemeny, N, Huang, Y, Cohen, AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039.
5. Goldberg, RM, Sargent, DJ, Morton, RF, et al. A randomized controlled trial of Fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23.
6. Tournigand, C, Andre, T, Achille, E, et al. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. J Clin Oncol 2004; 22:229.
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