The acute toxicities of adjuvant systemic therapy of early breast cancer are significant but generally well tolerated and are easily justified given the potential benefit. The toxicities of chemotherapy can be divided into those of the CMF-like regimens and those of the doxoru-bicin regimens. All chemotherapies used as adjuvant treatment cause significant myelosup-pression, with leukopenia generally clinically more significant than anemia or thrombocy-topenia. In the NSABP trials of classic CMF x 6, the incidence of neutropenia less than 2,000 was ~ 10 percent and severe infection about 1 percent.21 With AC x 4, it is 4 percent severe neutropenia and 2 percent severe infec-tion.21 With 6 months of CAF, the risk of leukopenia and infection is higher. Thrombocy-topenia is seen in less than 1 percent of patients in most regimens.21 Doxorubicin-containing regimens are more emetogenic than CMF; however, the incidence of severe vomiting is rapidly dropping with the introduction of serotonin antagonists. Alopecia is nearly universal with doxorubicin and is seen in about 40 percent of CMF patients.21 Diarrhea is rarely seen with either regimens; the use of serotonin antagonist antiemetics is associated with constipation (and mild headache). Cystitis is seen in about 1 percent of patients receiving cyclophosphamide-containing regimens and correlates with longer durations of therapy.21 Other rare side effects of both regimens include mucositis, thromboem-bolic events, and, for doxorubicin, extravasation skin ulceration.
The most common chronic chemotherapy toxicity is the cessation of menses and induction of menopause in premenopausal women. This is more common with 6 months of CMF (and CAF) than with AC x 4. In one study, amenorrhea was seen in 68 percent of women on CMF and 34 percent of women on AC.60 Symptomatic cardiomyopathy is a rare complication seen with doxorubicin-containing regimens. The risk is less than 1 percent with cumulative doxorubicin doses less than 350 mg/M2.61 The cumulative dose with AC x 4 is 240/m2; with CAF, it is 360/m2. The risk is increased with age, left chest wall irradiation, and prior heart disease. Chemotherapy agents are carinogenic in experimental systems. Nev ertheless, the incidence of second malignancies has been low. The ECOG estimated the risk of secondary leukemia or myelodysplasia after its CMF adjuvant regimens to be less than 0.2 percent similar to that of the general population.62 Bonadonna could find no increased risk of malignancy in long-term follow-up of his adjuvant CMF patients.63 The M.D. Anderson Hospital, in reviewing its adjuvant doxorubicin programs, found the risk of secondary leukemia or myelodysplasia to be 0.2 to 0.5 percent.64 There is some suggestion that concomitant high-dose cyclophosphamide may increase the doxoru-bicin leukemia risk.65 Other than menopause in younger women, long-term complications of adjuvant chemotherapy are infrequent.
Tamoxifen is a selective estrogen receptor modular (SERM) and so may be antiestrogenic or estrogenic, depending on its interaction with the individual tissue receptor. Its toxicity profile reflects this duality. The most common acute tamoxifen side effects are menopausal symptoms. In the NSABP trial B-14, hot flashes were seen in about two-thirds of patients, about a third had weight gain, fluid retention, and vaginal discharge, and a quarter experienced nausea, and weight loss.35 Irregular menses were seen in a fourth of pre-menopausal women.35 The only significant acute toxicities were rare thromboembolic events: deep vein thrombosis in 0.8 percent and pulmonary embolus in 0.4 percent. Mood swings and depression are unusual. Very-high-dose tamoxifen may cause retinal changes, but these are rarely seen with conventional doses. There are reports of cataracts in patients on the drug.66 In a large review of ocular toxicity from the NSABP, there were no cases of vision-threatening eye toxicity with tamoxifen.66
There is an increased risk of developing uterine cancer in women receiving tamoxifen (2/1,000/y of therapy versus 1/1,000/y in control).67 In the 1995 meta-analysis, 10 years after breast surgery, women on 5 years of the drug had a 1.1 percent risk of uterine malignancy compared with 0.3 percent for those who did not receive the drug.31 Furthermore, most reported cases were early stage and highly cur-able,68,69 although fatal cases of uterine cancer have been reported.70 In contrast to the uterine cancer effects are thoses of tamoxifen on the development of contralateral breast cancer. Multiple studies have found that tamoxifen given to prevent recurrence of previous breast cancer significantly decreases the risk of developing new contralateral breast cancer.68 The 1995 overview found a 47 percent decrease in the risk of contralateral malignancy in women receiving 5 years of the drug.31 This effect of tamoxifen was confirmed by the Breast Cancer Prevention Trial (NSABP P-1), which found a virtually identical decrease in the development of new breast cancers in high risk women without a history of the disease.71 This effect would suggest that even in women with a history of receptor-negative breast cancer, tamoxifen might be considered not to prevent recurrence but to decrease the risk of new malignancy.
Other beneficial effects of adjuvant tamox-ifen include an estrogenic-like decrease in bone loss in postmenopausal women,72-74 decrease in cholesterol,75 and, in some studies, decreased cardiac mortality.76-78 Overall, the risk/benefit ratio strongly favors tamoxifen's use as adjuvant therapy for hormone receptor-containing early-stage breast cancer.
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