The most frequently used regimen is doxorubicin and cyclophosphamide given for three months or cyclophosphamide, methotrexate, and fluorouracil given for six months. The efficacy of the two regimens is similar they differ in that doxorubicin and cyclophosphamide are more likely to cause alopecia and vomiting, whereas cyclophosphamide, methotrexate, and fluorouracil are more likely to cause nausea, myelosuppression, and ovarian failure. A meta-analysis of randomized trials of adjuvant chemotherapy showed that regimens containing doxorubicin were slightly superior to regimens consisting of cyclophosphamide, methotrexate, and fluorouracil.

Taxanes such as paclitaxel and docetaxel are being incorporated into adjuvant regimens on the basis of their antitumor activity in advanced breast cancer and the absence of cross-resistance with doxorubicin.Both of these taxanes can cause hypersensitivity reactions, peripheral neuropathy, myalgias, and arthralgias, and docetaxel can cause fluid accumulation. Glucocorticoids and histamine-receptor antagonists administered before the taxane can ameliorate these side effects. The administration of four cycles of paclitaxel after doxorubicin and cyclophosphamide was associated with a statistically significant survival advantage in a study involving women with node-positive breast cancer,and the Food and Drug Administration (FDA) has recently approved paclitaxel for this indication. Further information on the efficacy and side effects of taxanes will be available from the results of ongoing and recently completed randomized trials. At this time, there are insufficient data to recommend the use of taxanes in women with node-negative breast cancer.

Myelosuppression

A small-to-moderate reduction in the white-cell count often occurs 10 to 14 days after each cycle of adjuvant chemotherapy. In most women, the white-cell count improves before the next treatment cycle. The incidences of fever, absolute neutrophil counts below 500 per cubic millimeter, and life-threatening infections are 2 percent or less, and no deaths have been reported. Guidelines for the administration of hematopoietic growth factors do not support their routine use to prevent febrile neutropenia or to allow an increase in the dose intensity of the chemotherapeutic regimen in women with breast cancer who are receiving adjuvant chemotherapy.

Nausea and Vomiting

The majority of women with breast cancer treated with adjuvant chemotherapy have mild or moderate nausea and vomiting, but these symptoms are severe in less than 5 percent of women. Drugs that prevent nausea and vomiting include serotonin-receptor antagonists, such as ondansetron, metoclopramide, glucocorticoids, and phenothiazines; new drugs (e.g., an antagonist to substance P) are being developed.Lorazepam, a benzodiazepine, is given to reduce anxiety during adjuvant chemotherapy and is often helpful in women with anticipatory nausea and vomiting. Oral delta-9-tetrahydrocannabinol (dronabinol), the active ingredient in marijuana, is more effective in controlling nausea than placebo or phenothiazines. It causes hallucinations, depression, or intoxication in 23 percent to 81 percent of patients with cancer, and surveys of oncologists suggest that they prefer other antiemetic drugs and rarely prescribe dronabinol.There are few data on the antiemetic efficacy of smoking marijuana; anecdotal reports suggest it is effective, particularly among those who have previously smoked it. The incidences of severe oropharyngeal mucositis or stomatitis and of diarrhea requiring intravenous-fluid therapy or hospitalization are low for regimens of cyclophosphamide and doxorubicin but may be higher when the regimen includes fluorouracil.

Neurologic Toxicity

The taxanes cause both sensory and motor peripheral neuropathy. The neuropathy is usually mild to moderate, and the severity is related to the individual dose, cumulative dose, and schedule of administration. There are currently no effective means to prevent or treat taxane-induced neuropathy, but early recognition and a subsequent delay or reduction in the dose improve the symptoms in most cases. Taxanes often cause mild-to-moderate myalgias and arthralgias that usually respond to nonsteroidal antiinflammatory drugs or codeine-containing analgesic drugs. In severe cases, a short course of glucocorticoids may be helpful.

Weight Gain

The majority of women with breast cancer who are treated with cyclophosphamide, methotrexate, and fluorouracil gain weight. The average weight gain ranges from 2 to 6 kg; the gain tends to be at the upper end of this range in women who are premenopausal, those who are treated with a prolonged regimen (12 months vs. 6 months), and those who are also receiving prednisone.Women treated with doxorubicin and cyclophosphamide gain less weight than those given cyclophosphamide, methotrexate, and fluorouracil. The postulated causes of weight gain include decreased physical activity, ovarian failure, increased food consumption, and a reduced basal metabolic rate. Weight gain may adversely affect the quality of life and has been associated with higher rates of recurrent cancer in some, but not all, studies.

Ovarian Failure

Age and the duration of adjuvant chemotherapy are the primary determinants of ovarian failure. Treatment with cyclophosphamide, methotrexate, and fluorouracil for six months results in permanent ovarian failure in 70 percent of women over 40 years of age and in 40 percent of younger women. The median time to the onset of ovarian failure is shorter in older women than in younger women (2 to 4 months vs. 6 to 16 months), and ovarian failure is less likely to be reversible in older women (in about 10 percent vs. up to 50 percent). The rate of permanent ovarian failure is lower with regimens of doxorubicin and cyclophosphamide than with cyclophosphamide, methotrexate, and fluorouracil.The rate of ovarian failure among women treated with taxane-containing regimens is not known.

Chemotherapy-induced ovarian failure may have short-term and long-term consequences for health. Menopausal symptoms, including hot flashes, vaginal dryness, dyspareunia, depression, and sleep disturbances, are often reported by women with breast cancer and are severe in up to one third of them. Ovarian failure may increase the risk of osteoporosis and possibly of cardiovascular disease. Long-term data on fractures in women with chemotherapy-induced ovarian failure are unavailable. However, early menopause is a risk factor for osteoporosis. Treatment with bisphosphonates mitigates bone loss in women with breast cancer and chemotherapy-induced ovarian failure.Women who have chemotherapy-induced ovarian failure should have adequate dietary intakes of calcium and vitamin D and should perform weight-bearing exercise regularly and have their bone density evaluated.

The administration of estrogen to women with breast cancer for the relief of menopausal symptoms and for the long-term prevention of osteoporosis and possibly heart disease is controversial, because supplemental estrogen may increase the risk of disease progression or the development of a new primary breast cancer. However, an increasing body of data highlights the potential benefits and absence of adverse effects of estrogen in women who have had breast cancer.Until the results of randomized trials are available, caution should be exercised in prescribing estrogen for such women, and nonhormonal treatments for hot flashes, such as selective serotonin-reuptake inhibitors or bisphosphonates for the prevention of osteoporosis, should be considered.

Cardiac Toxicity

Doxorubicin directly damages the myocardium and can cause cardiomyopathy. Risk factors for doxorubicin-related myocardial damage include a high cumulative dose of the drug, an older age at the time of treatment, preexisting heart disease, a history of mediastinal (cardiac) irradiation, and the coadministration of paclitaxel or trastuzumab. Continuous infusions or low-dose weekly infusions are associated with a lower risk of damage than are bolus infusions. When the total dose of doxorubicin is limited to 240 to 300 mg per square meter of body-surface area, the incidence of clinically important cardiomyopathy is less than 1 percent.

Congestive heart failure, ventricular tachycardia, and sudden death have been reported in survivors of childhood cancer years after treatment with doxorubicin or other anthracyclines. Thus far, no such delayed cardiac events have been noted in women in whom the cumulative dose of doxorubicin was less than 300 mg per square meter.In one study of women with breast cancer, however, 8 percent of those previously treated with doxorubicin had echocardiographic evidence of systolic dysfunction or a reduced left ventricular ejection fraction without cardiac dilatation, as compared with less than 1 percent of women previously treated with cyclophosphamide, methotrexate, and fluorouracil.Whether such subclinical systolic dysfunction eventually results in clinically overt cardiac problems is unknown.

Cardiomyopathy develops in approximately 3 percent of women with advanced breast cancer who are treated with trastuzumab.When trastuzumab is given concurrently with doxorubicin, the incidence of cardiac toxicity increases to 18 percent.

Second Cancers

There is little evidence that the risk of second cancers is increased among women who receive cyclophosphamide, methotrexate, and fluorouracil. There is less information on the risk of second cancers among women treated with doxorubicin-containing regimens, and there is no information on the risk with regimens that contain taxanes. The risks of chemotherapy-induced acute myeloid leukemia and myelodysplasia are dependent on the specific alkylating drug, the cumulative dose, and the duration of treatment. Registry data show that treatment with cyclophosphamide, methotrexate, and fluorouracil for 6 months is associated with a risk of acute myeloid leukemia or myelodysplasia that is increased by a factor of approximately two, or about 5 excess cases per 10,000 treated patients at 10 years. The risk of acute myeloid leukemia or myelodysplasia with standard doses of doxorubicin-containing adjuvant chemotherapy is no higher or is only slightly higher than that in the general population.However, among women receiving both chemotherapy and radiation treatment, the risk of leukemia may be higher.

Unlike the leukemia associated with alkylating agents, that associated with doxorubicin is monocytic, involves a specific cytogenetic abnormality (11q23), and develops within a few years after treatment, without prior myelodysplasia in some cases.

Fatigue and Quality of Life

Many women with breast cancer who are receiving adjuvant chemotherapy have fatigue, and about two thirds of them rate the level of fatigue as moderate or severe.The cause of the fatigue is poorly understood; possible contributing factors include anemia, vasomotor symptoms that cause sleep disturbance, and depression. There are insufficient data to support the use of erythropoietin to relieve fatigue in women receiving adjuvant chemotherapy. The fatigue appears to resolve after treatment. In a survey of nearly 2000 women with breast cancer who were evaluated three years after adjuvant treatment, the level of fatigue was similar to that of age-matched normal women.

Measurements of the quality of life also worsen during adjuvant chemotherapy but improve after the cessation of treatment. In several studies, the overall quality of life, the presence or absence of depression, and body image did not differ significantly between women with breast cancer who had been treated with adjuvant chemotherapy, tamoxifen, or both and women who had not received such treatment or age-matched normal women. In addition, ethnicity was not associated with significant differences in the overall quality of life.However, specific symptoms are associated with specific treatments. In one study, for example, the frequency of sexual dysfunction was higher in women who received chemotherapy, whereas vasomotor symptoms occurred more often in women who received tamoxifen.

Vaginal dryness and dyspareunia are common in breast-cancer survivors, especially among women who receive chemotherapy. Topical estrogen therapy relieves these symptoms, but its use is associated with the same issues as oral estrogen therapy in these women. In one study, polycarbophil-based vaginal lubricant and placebo were equally effective in relieving vaginal dryness and dyspareunia.

Cognitive Dysfunction

Preliminary studies suggest that cognitive dysfunction may occur after adjuvant chemotherapy. Two or three years after treatment, problems with memory, concentration, and language were more frequent in women who had received chemotherapy than in similar women who had not received such treatment or in women without breast cancer. These cognitive problems did not appear to be associated with a worsening of the quality of life, fatigue, or depression. The mechanism of cognitive dysfunction is unknown, but it has been postulated that a direct effect of chemotherapy or diminished estrogen secretion resulting from ovarian failure has a role.