The contemporary systemic treatment of metastatic breast cancer involves the sequential selection and delivery of hormonal therapies and cytotoxic chemotherapies. The available therapies for metastatic breast cancer are rarely curative, although high rates of response and modest prolongation of survival may be achieved in association with varying degrees of treatment-related toxicity. Therefore, selection of appropriate therapy requires a reasoned consideration of the likelihood of benefit from therapy balanced with the impact of the therapy on the patients quality of life. Unfortunately, relatively little objective evidence is available regarding the impact of most systemic therapies on the quality of life of patients with metastatic breast cancer.
The quality of life in patients with cancer has many dimensions (Table 1). A number of reliable and valid instruments have been developed to measure quality of life in patients with cancer, and some have been specifically developed to assess quality of life in patients with breast cancer.[2-7] None of the available instruments has been universally accepted. These instruments include:
- Time Without Symptoms and Toxicity (TWiST)
- Quality of Time Without Symptoms and Toxicity (Q-TWist)
- Quality-Adjusted Life Year (QALY), Quality of Well Being (QWB)
- Cancer Rehabilitation Evaluation System (CARES)
- European Organization for Research and Treatment of Cancer QLQ-C30
- Functional Assessment of Cancer Therapy (FACT)
- Functional Living IndexCancer (FLIC)
- Selby Linear Analogue Self-Assessment (LASA) scale
- Rotterdam Symptom Check List (RSCL).
All of these instruments require time and resources to administer and expertise to analyze. As a result, the use of the quality of life instruments has been limited primarily to research studies involving women with local-regional breast cancer. Even in the research setting, few randomized clinical trials have incorporated quality of life assessments other than the use of measurements of physical performance by the Karnofsky or Eastern Cooperative Oncology Group (ECOG [Zubrod, World Health Organization]) scales.[8,9] Instruments that efficiently and comprehensibly measure quality-of-life will be required before routine quality of life measurements will be used in the nonresearch setting.
In the absence of formal quality-of-life assessments in clinical trials, the clinician must balance antitumor activity, performance status, and the usual toxicity measures (eg, nausea, myelosuppression, asthenia) as surrogates for quality of life associated with each specific systemic therapy.
The hormonal therapies have the quality-of-life advantages of limited and usually non-threatening acute toxicity, rare chronic toxicity, need for infrequent visits to health care providers, oral administration, and, in appropriately selected patients, response and duration of response rates equivalent to the cytotoxic agents. Tamoxifen (Nolvadex) remains the most commonly used first-line hormonal agent and has a favorable and acceptable toxicity profile. New estrogen antagonists (toremifene [Fareston], droloxifene) appear to have therapeutic indices similar to those of tamoxifen, although further study is needed before firm conclusions may be made.[10,11] The recent addition of new aromatase inhibitors (anastrozole [Arimidex], letrozole [Femara]) for the treatment of postmenopausal women provides increased ease of administration, decreased acute and chronic toxicity, and excellent rates of response in comparison with aminoglutethimide (Cytadren) and many of the other second- and third-line hormonal agents.[12-14]
A number of cytotoxic agents have activity in the treatment of metastatic breast cancer. The active single agents differ substantially in their toxicity profiles, although the dose-limiting toxicity is usually myelosuppression. Combination chemotherapy regimens are usually used for first-line cytotoxic treatment of metastatic breast cancer. When cytotoxic agents are used in combination regimens, the toxicity experienced is a combination of that observed with the single agents. Because of their additive nature, the most frequently used combinations (eg, CMF [cyclophosphamide/methotrexate/5-fluorouracil], CAF [cyclophosphamide/Adriamycin/5-fluorouracil]/FAC, CEF [cyclophosphamide/epirubicin/5-fluorouracil]) have similar rates of response and toxicities.
Response Predicts Quality of Life
An early study addressed the quality of life of women with metastatic breast cancer using a linear analogue self-assessment scale. This study compared the quality of life of women with metastatic breast cancer randomized to receive hormonal therapy versus combination chemotherapy with cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin), 5-fluorouracil (5-FU) and vincristine (Oncovin). A total of 25 parameters of quality of life were measured, and, as expected, patients receiving cytotoxic therapy experienced more alopecia, nausea, vomiting, and constipation than those treated with hormonal maneuvers. However, there was a trend toward improved well-being in patients receiving cytotoxic therapy that became statistically significant by week 11 of therapy. This study was initiated prior to the availability of reliable hormone receptor determinations that would have selected a cohort of women who are likely to respond to hormonal therapy (Table 2). Thus, the objective response rate was higher in the cytotoxic therapy group. The improved well-being with cytotoxic therapy was related to the achievement of an objective response. Thus, achievement of an objective response appears to be a strong predictor of quality of life despite the acute toxicity of cytotoxic therapy.
A trial in women with metastatic breast cancer compared treatment with continuous versus intermittent CMF plus prednisone or doxorubicin plus cyclophosphamide chemotherapy. Patients in the continuous arm received chemotherapy until progression of disease, while those in the intermittent arm received three cycles of chemotherapy and then received additional chemotherapy only at the time of progression. Continuous chemotherapy was associated with higher rates of response and superior time to progression. There was a trend toward superior survival with continuous treatment. Surprisingly, both patient and physician assessments of patient quality of life were superior for those patients receiving continuous therapy. This confirms findings from the earlier study of Baum et al that response is associated with improved quality of life.
Another trial incorporating a quality-of-life assessment compared two dose levels of CMF in patients with metastatic breast cancer. Higher dose CMF compared with lower dose CMF was associated with improved rates of response, improved median survival, and more vomiting, myelosuppression, conjunctivitis, and alopecia. The quality of life assessment demonstrated similar scores for both the higher and lower dose CMF regimens, although most scores favored the higher dose regimen. Thus, the higher dose CMF regimen appeared to produce superior palliation compared with the lower dose CMF regimen.
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