Home: Educational Supplement: Appendix

Side Effects of Chemotherapy and
Combined Chemohormonal Therapy

Eric P. Winer, M.D.

The decision to receive chemotherapy (or concurrent chemohormonal therapy) involves careful consideration of both the potential benefits of therapy and the possible risks. The side effects associated with chemotherapy to treat breast cancer are substantial, and include some common short-term effects (usually present during the period of treatment) as well as the possibility of late toxicity. These side effects vary, depending on the specific agents used in the adjuvant regimen as well as the size of the dose and the duration of treatment. There is also considerable variability across individuals, but our ability to predict which patients will have more severe toxicity is very limited. This review will focus on the short- and long-term toxicity seen with the most commonly used adjuvant chemotherapy (and chemohormonal) regimens, including CMF, CAF, CEF, AC, and AC followed by T [C=cyclophosphamide, M=methotrexate, F=fluorouracil, A=doxorubicin, E=epirubicin, and T=paclitaxel].

Short-Term Side Effects

For the purposes of this review, the short-term side effects of chemotherapy occur during the course of treatment and resolve (in some cases gradually) with the completion of therapy. The most common forms of toxicity include emesis (nausea and vomiting), neutropenia with risk of febrile neutropenia, alopecia, mucositis, neuropathy, and fatigue (Fisher, Anderson, Wickerham, et al., 1997; Levine, Bramwell, Pritchard, et al., 1998; Henderson, Berry, Demetri, et al., 1998). With the exception of neuropathy, most side effects resolve promptly upon the completion of treatment. In recent years, fatigue has been recognized as an important toxicity of chemotherapy. Mild to moderate fatigue is frequent with adjuvant chemotherapy, but it has generally not been reported as part of the toxicity assessment in clinical trials. For this reason, it is difficult to compare the severity of fatigue across regimens. Table 1 lists the other side effects rated on a 0, +, ++, and +++ scale, based on the frequency and severity of the toxicity.

Thromboembolic complications can also be seen with chemotherapy regimens (Levine, Gent, Hirsh, et. al., 1988). The risk of thromboembolic events appears to be increased when chemotherapy and hormonal therapy are administered concurrently.

Long-Term Side Effects

For most patients and clinicians, the long-term side effects of chemotherapy are of greater concern than the acute short-term effects (Burstein, Winer, 2000). Among the late or chronic effects of chemotherapy, those of greatest concern include (1) premature menopause; (2) weight gain; (3) cardiac toxicity from anthracyclines; (4) secondary leukemia; and (5) cognitive dysfunction. Each of these late effects is considered separately.

Premature Menopause

For premenopausal women with breast cancer, the possibility of experiencing treatment-induced ovarian failure is a major concern (Burstein, Winer, 2000; Bines, Oleske, Cobleigh, 1996). It is beyond the scope of this review to comment on the potential benefits of ovarian failure in relation to cancer recurrence. There is little question, however, that premature ovarian failure results in a number of undesired consequences, including infertility, sexual difficulties, accelerated bone loss, and increased risk of vascular disease. The risk of ovarian failure with chemotherapy is related to the age of the woman, the specific chemotherapy agents used, and the cumulative dose. Cyclophosphamide and doxorubicin are among the agents most often associated with ovarian failure, although a treatment course limited to four cycles of AC is more often associated with preservation of ovarian function than either 6 months of CMF or FAC. Some women will experience periods of ovarian suppression during the course of treatment and in the months following therapy, with restoration of ovarian function after a variable time interval. To what extent a course of chemotherapy may decrease fertility in women who maintain or resume regular menstrual cycles after treatment is unknown. Also unknown is whether women who complete chemotherapy with intact ovarian function will ultimately experience menopause at a younger age than they would have in the absence of chemotherapy.

Weight Gain

Weight gain is a well-recognized complication of chemotherapy (Demark-Wahnefried, Winer, Rimer, 1993). In general, weight gain has been more pronounced in premenopausal than in postmenopausal women. The mechanism of weight gain is uncertain, but it does not appear to be a consequence of excess intake. It is unclear to what extent long-term weight gain is a problem after a course of chemotherapy. To what extent weight gain can be modified through behavioral intervention is also unknown.

Cardiac Dysfunction

The widespread use of anthracyclines has raised concern about the potential for cardiac dysfunction following adjuvant therapy. In most doxorubicin-containing regimens, the cumulative dose of doxorubicin is in the range of 240-360 mg/M 2 . With these cumulative doses, the risk of clinical congestive heart failure following therapy is thought to be less than 1 percent (Shan, Lincoff, Young, 1996; Valagussa, Zambetti, Biasi, et al., 1994). There are rare patients who present with congestive heart failure with doses in this range. Although higher cumulative doses of epirubicin are used in epirubicin-containing regimens, this anthracycline is less cardiotoxic than doxorubicin on a mg to mg basis. To date, long-term followup of patients treated with anthracyclines in the adjuvant setting is limited. In a recent report, more than 300 women who were a median of 10.8 years from diagnosis underwent cardiac evaluation, including an echocardiogram (Gianni, Zambetti, Moliterni, 1999). Women who had received anthracyclines in the adjuvant setting did not have clinical symptoms of cardiac dysfunction, but a higher proportion of women who had received anthracyclines compared to those who had CMF alone were reported to have a borderline or decreased left ventricular ejection fraction.

Secondary Leukemia

Breast cancer patients treated with adjuvant chemotherapy have a slightly increased risk of leukemia. With CMF-type regimens, the increased risk appears to be negligible (Curtis, Boice, Stoval, et al., 1992; Tallman, Gray, Bennett, et al., 1995). Anthracycline-based regimens are associated with a greater risk, though still of relatively small magnitude. In a series of patients treated with FAC at the M.D. Anderson Cancer Center, the risk of leukemia at 10 years was estimated to be 1.5 percent. The median time to diagnosis of leukemia was 66 months (Diamandidou, Buzdar, Smith, et al., 1996). Recent reports from the NSABP (B-22 and B-25) have also indicated an increased risk of acute myelogenous leukemia and myelodysplastic syndrome in women treated with AC (standard dose doxorubicin with standard or dose-intensified cyclophosphamide) (Fisher, Anderson, Wickerham, et al., 1997; Fisher, Anderson, DeCillis, et al., 1999).

Cognitive Dysfunction

Recent reports have suggested that chemotherapy—both high dose and standard dose therapy—may be associated with cognitive dysfunction (Brezden, Phillips, Abdolell, et al., 2000; van Dam, Schagen, Muller, et al., 1998). The studies have not been definitive, however, and additional research is needed to determine if cognitive difficulties are a consequence of adjuvant chemotherapy.

Summary

In summary, adjuvant chemotherapy (with or without concurrent hormonal therapy ) is associated with a range of acute forms of toxicity which generally resolve once treatment has been completed. With the exception of premature menopause, long-term toxicity is generally quite rare. However, these uncommon late effects need to be considered in making decisions about adjuvant therapy, particularly when a patient is at low risk of disease recurrence and the absolute benefit of treatment is of small magnitude. Further research is needed to characterize fully the spectrum of late forms of toxicity following adjuvant chemotherapy.

References

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Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000;18:2695–701. Abstract.

Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Eng J Med 2000;343:1086–94. No Abstract Available.

Burstein HJ, Winer EP. “Reproductive Issues.” In: Harris JR, Lippman ME, Morrow M, Osborne CK (ed.): Diseases of the Breast, second edition. New York: Lippincott, 2000, 1051–9. No Abstract Available.

Curtis RE, Boice JD Jr, Stovall M, Bernstein L, Greenberg RS, Flannery JT, et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Eng J Med 1992;326:1745–51. Abstract.

Demark-Wahnefried W, Winer EP, Rimer BK. Why women gain weight with adjuvant chemotherapy for breast cancer. J Clin Oncol 1993;11:1418–29. Abstract.

Diamandidou E, Buzdar AU, Smith TL, Frye D, Witjaksono M, Hortobagyi GN. Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 1996;14:2722-30. Abstract.

Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, et al. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 1997;15:1858–69. Abstract.

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Gianni L, Zambetti M, Moliterni A. Cardiac sequelae in operable breast cancer after CMF + doxorubicin + irradiation. Proc Am Soc Clin Oncol 1999;18:255. Abstract.

Henderson IC, Berry D, Demetri G, et al. Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive breast cancer. Proc Am Soc Clin Oncol 1998;17:390A. Abstract.

Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Eng J Med 1988;318:404–7. Abstract.

Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 1998;16:2651–8. Abstract.

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Valagussa P, Zambetti M, Biasi S, Moliterni A, Zucali R, Bonadonna G. Cardiac effects following adjuvant chemotherapy and breast irradiation in operable breast cancer. Ann Oncol 1994;5:209–16. Abstract.

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