Cytotoxic chemotherapy for breast cancer
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Breast cancer can develop into disseminated disease, thought to result from undetectable micrometastases present at the time of initial treatment, and increasing attention has therefore been given to systemic therapies, which can eradicate these deposits before they become clinically significant.
Cytotoxic chemotherapeutic agents work by interfering with the ability of cancerous cells to divide. Nearly all chemotherapy treatment regimens used in breast cancer involve two or more agents used together. Combination chemotherapy capitalises on the fact that different drugs act in different ways; and studies have shown that two or more drugs used together increase the chances of killing more cells. [1]
Cytotoxic chemotherapy has become established as one of the major therapeutic modalities in breast cancer. However, as with radiotherapy, the cytotoxic agents affect all actively dividing cells in the body, both cancerous and healthy. This produces unpleasant side effects, such as nausea, vomiting, alopecia, and occasionally more serious affects including neutropenia and cardiotoxicity. [2,3,4] Chemotherapy will also cause ovarian failure, resulting in amenorrhoea in a substantial proportion of pre-menopausal women, depending upon the treatment regimen used [5,6]. It is thought that at least part of the benefits achieved with chemotherapy in pre-menopausal women could be due to their additional ‘endocrine’ effects, i.e. manifested through chemical ovarian ‘ablation’.
Chemotherapy is administered in a series of cycles with rests in between successive cycles to help minimise side effects as well as to allow time for cells in the patient’s normal tissues to recover. The number of cycles varies depending on the agents used, typically four to six cycles are employed within a course of chemotherapy.
There are several different types of cytotoxic agent used to treat breast cancer. The main ones are alkylating agents, antimetabolites and cytotoxic antibiotics. Most, if not all, cytotoxic agents target dividing cells at the point in the cell cycle when DNA is replicated or the cell undergoes division; termed the S phase ( Figure 1 ).
Figure 1: The S phase - the point of action of chemotherapeutic agents in the cell cycle.
Adjuvant chemotherapy of early breast cancer
In early breast cancer, chemotherapy is most usually applied as adjuvant treatment following local excision of the tumour, with the aim of preventing the proliferation of secondary metastases. [7]
Adjuvant combination chemotherapy is the systemic treatment of choice in lymph node-positive patients with ER-negative tumours, irrespective of menopausal status, and may be considered as an option in addition to endocrine therapy in patients with ER-positive tumours. Conventionally, lymph node-negative patients were not considered for chemotherapy as it was widely believed that the disease was confined entirely to the breast and, therefore, would most likely be cured by local treatment. However, several large clinical trials showed significant improvements in disease free survival in these patients. Additional studies have shown that adjuvant chemotherapy significantly alters the natural history of breast cancer in lymph node-negative patients, prolonging the time to recurrence. [8,9]
Chemotherapy can also be given before surgery. Neoadjuvant chemotherapy may be employed to shrink the size of the tumour and allow more breast-conserving types of surgery to be undertaken or more complete excision of very large tumours. [10,11,12]
Chemotherapy in advanced breast cancer
Cytotoxic therapy tends to be used in most patients with advanced breast cancer at some stage. This may be as first-line therapy in patients with ER-negative tumours, or at a later stage in patients with initially ER-positive tumours, which eventually fail to respond to endocrine interventions. The median duration of response to a chemotherapy regimen in advanced breast cancer usually ranges from 6 to 12 months, which is generally less than that observed with hormonal therapies. Use of one chemotherapy regimen may be successfully followed by a sequence of different regimens as progression occurs.
References
- Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992 Jan 11;339(8785):71-85.
- Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumours: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8: 1483–1496.
- Weiss HD, Walker MD, Wiernik PH. Neurotoxicity of commonly used antineoplastic agents (second of two parts). N Engl J Med 1974 Jul 18;291(3):127-133
- Partridge AH, Burstein HJ, Winer EP. Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J Natl Cancer Inst Monogr 2001;(30):135-4
- Erratum in: J Natl Cancer Inst 2002 Jun 5;94(11):866
- Padmanabhan N, Wang DY, Moore JW, Rubens RD. Ovarian function and adjuvant chemotherapy for early breast cancer. Eur J Cancer Clin Oncol 1987 Jun;23(6):745-8
- Bines J, Oleske DM, Cobleigh MA.Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996 May;14(5):1718-29
- Osborne CK, Ravdin PM. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast, 2nd edition. Philadelphia: Lippincott, Williams and Wilkins, 2000:599-632.
- Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998 Sep 19;352(9132):930-42
- Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 2001 Sep 15;19(18):3817-27
- Smith IE, Jones AL, O’Brien MER, et al. Primary medical (neoadjuvant) chemotherapy for operable breast cancer. Eur J Cancer 1993; 29A: 1796–1799.
- Bonadonna G, Valagussa P, Zucali R, Salvadori B. Primary chemotherapy in surgically resectable breast cancer. CA Cancer J Clin 1995; 45: 227–243.
- Calais G, Berger C, Descamps P, et al. Conservative treatment feasibility with induction chemotherapy, surgery and radiotherapy for patients with breast carcinoma larger than 3cm. Cancer 1994; 74: 1283–1288.
