MB BMedSci MRCPI
Guy’s and St Thomas’ Hospital
The incidence and prevalence of breast cancer are both rising, increasing the numbers of women undergoing treatment. The goals of anticancer treatment in breast cancer are prevention, adjuvant treatment, and dealing with metastases.
Studies suggest that preventive measures are effective in reducing the incidence of breast cancer. One trial randomising between tamoxifen and placebo administration showed a 45% reduction in the incidence of breast cancer in the tamoxifen group.(1) Other trials have failed to show an effect.(2)
The current sequence of treatment for women diagnosed with early breast cancer is surgery, chemotherapy and radiotherapy, followed by endocrine therapy where appropriate. Surgery is the most important initial step to control the disease. Tumours and regional lymph nodes are excised. Radical radiotherapy is administered to achieve optimal local control.
Despite good local control, breast cancer can recur. Metastatic spread is presumed to be due to small clusters of cells, which escape from the primary tumour and travel to other organs. Eventually, these cells proliferate and cause established distant disease.
Much attention has been paid to the concept of eradicating micrometastatic cells before they become clinically significant. This is achieved with chemotherapy and hormone therapy postoperatively, known as adjuvant treatment. Intuitively this is a sensible approach, on the assumption that smaller cell clusters are more likely to respond to therapy than large tumour masses. Evidence exists to support the idea that adjuvant chemotherapy improves the long-term survival of patients,(1) with impact on both overall survival and disease-free survival.(3)
Many women present late and have established spread at the time of diagnosis. Others develop metastatic disease some time after their adjuvant treatment. The main sites of metastatic breast cancer are bone, liver, lung and brain.
The philosophy of treatment of metastatic breast cancer is different from that in the postoperative setting. Patients are offered treatment to suppress the cancer and control symptoms, rather than being treated with the hope of eradicating the disease. The expectations and the intensity of the treatment differ from adjuvant treatment. Palliation of symptoms and quality of life are more important goals than prolongation of life per se.
Chemotherapy is utilised for patients with early disease as well as those with widespread cancer. Many drugs have shown antitumour activity in breast cancer (see Table 1). Anthracyclines and taxanes are the most active agents.
Combination regimens are employed in the adjuvant setting. One problem in treating cancer is resistance. Cancer cells overcome the mechanisms of action of the drug, develop a means of survival and proliferate once again. In combination chemotherapy, drugs are chosen with different mechanisms of action. It is more difficult for the tumour to evolve multiple forms of resistance simultaneously. Drugs are also ideally combined in polychemotherapy with nonoverlapping toxicities, so that higher doses of individual drugs can be used.
Two regimens commonly used in the UK are FEC (5-fluorouracil [FU] 600–700mg/m(2) intravenous [iv], plus epirubicin 60–70mg/m(2) iv, plus cyclophosphamide 600–700mg/m(2) iv; repeated every three weeks to a total of six cycles), and CMF (cyclophosphamide 100mg/m(2)/day days 1–14 orally, plus methotrexate 40mg/m(2) iv days 1 and 8, plus 5-FU 600mg/m(2) iv days 1 and 8; repeated every four weeks to a total of six cycles).
Single-agent treatment is frequently employed in metastatic disease. Combination regimens are also used, but increasingly patients will have received combination chemotherapy as adjuvant treatment. The anthracycline epirubicin is often used. Doses commence at 75–90mg/m(2), every three weeks. The initial dose depends on the general condition of the patient and the serum bilirubin level.
Anthracyclines are cardiotoxic, and so cumulative doses are monitored. Taxanes are also used. Paclitaxel is administered on a weekly basis, and docetaxel three times weekly. The efficacy and safety of anthracycline–taxane combinations have been established in metastatic disease. The role of taxanes in the adjuvant setting is uncertain.(4) As a consequence, their use in combination adjuvant chemotherapy is under investigation.
Acute toxicity of chemotherapy
Toxicity of chemotherapy is largely predictable. The balance between the potential benefit of treatment and risks of adverse effects must be assessed for each individual. The reduction in tumour bulk in metastatic disease should not be offset by toxicity and unpleasant side-effects (see Table 2).
Emesis potential differs. 5HT-3 serotonin antagonists such as granisetron are used as premedication for highly emetogenic drugs. Steroids and domperidone are also commonly used. Mucositis/stomatitis occurs and can lead to malnutrition in severe cases. Epithelial regrowth can be improved with drugs such as sucralfate. Antiseptic mouthwashes can reduce superinfection.
Myelosuppression (anaemia, thrombocytopenia
Anthracyclines and taxanes reduce the number of neutrophils. Rarely, life-threatening sepsis occurs. Patients have nadir neutrophils checked during treatment, and prophylactic broad-spectrum antibiotics can be administered. Chemotherapy is delayed or reduced if recurrent neutropenia or sepsis occurs.
Varies between regimens and can be prevented in some cases by wearing a scalp-cooling device during the administration of the anthracycline or taxane.
Bronchospasm and hypotension can occur with taxanes, accompanied by fluid retention, which can be prevented by premedication with steroids and/or antihistamines.
Usually mediated via small nonmyelinated nerve fibres, and is reversible for many drugs once the treatment is discontinued.
High-dose chemotherapy (HDC)
HDC was developed to reduce the relapse rate in breast cancer. It has also been used in metastatic disease. Patients’ stem cells are harvested. High doses of cytotoxic drugs are administered. Tumour cells are killed and bone marrow obliterated. The stem cells are returned (autologous stem cell transplant) and engrafted. The bone marrow recovers. Intensive inpatient supportive care is required. The results of randomised trials of HDC are conflicting. In a study published in 1993, therapy-related mortality was 12%.(5) By 1997, HDC emerged as an effective regimen with occasional toxicity.(6)
There have been allegations of data tampering from one South African centre, which claimed to show a significant survival advantage. A US team did an onsite review of records and found the treatment details to be at great variance from the data presented at two international meetings. Scientific misconduct was later admitted.(7) Great unease exists regarding HDC. Although evaluations are ongoing, many centres do not advocate its use.
In the next issue the author will look at other pharmacological treatments for breast cancer, including endocrine manipulation.
- Fisher B, et al. Tamoxifen for the prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-88.
- Powles T, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen chemoprevention trial. Lancet 1998;352:98-101.
- EBCTCG. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930-42.
- Davidson NE, Wolff AC. The use of anthracyclines and taxanes for adjuvant therapy of breast cancer. Breast 2001;10 Suppl 3:90-5.
- Peters WP, et al. High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11:1132-43.
- Gianni AM, et al. Efficacy, toxicity, and applicability of high-dose sequential chemo as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes. J Clin Oncol 1997;15:2312-21
- Weiss RB, et al. High-dose chemo for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet 2000;355:999-1003.
Devita VT, Rosenberg SA, Hellman S. Cancer: principles and practice of oncology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001.
Skeel RT. Handbook of cancer chemotherapy. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 1999.