Metastatic breast cancer is a devastating problem, with only a small percentage of patients surviving 5 years or longer. In 1999, about 45,000 women died of metastatic breast cancera mortality statistic that has not changed appreciably in decades. The median survival after the detection of distant metastases is about 3 years for all patients and about 2 years for patients whose disease is endocrine refractory. Thus, metastatic breast cancer remains an essentially incurable disease.
Until recently, little progress had been made in treatment. However, the development of newer endocrine, chemotherapeutic, and, most recently, biological agents, may lead to modest but definite improvements in these grim statistics. Except for clinical trials that use high-dose therapies, palliation remains the major goal of therapy.
Nevertheless, several highly debated, controversial treatment-related issues remain. These include: (1) whether initial treatment should consist of endocrine therapy or chemotherapy; (2) whether combination chemotherapy (polychemotherapy) is superior to single-agent chemotherapy; (3) the optimal sequence of administration of chemotherapeutic agents and regimens; (4) whether dose intensification is superior to standard-dose treatment; and (5) what constitutes the optimal duration of treatment.
The most important therapeutic issue is whether treatment is being initiated with curative or palliative intent. Despite the aggressive trimodality efforts of medical oncology, radiation oncology, and surgical oncology, almost all patients with metastatic breast cancer eventually succumb to the disease. Physicians and patients should discuss and clarify the intent of treatment and decide how they wish to navigate the delicate balance among relief of symptoms, prolongation of survival, and toxicity.
An awareness of the natural history of untreated breast cancer is also important. In a series of 250 patients with breast cancer who opted for no treatment at diagnosis, median survival was 2.7 years, and 10% of patients lived 10 years or longer. These data indicate that, in a small percentage of patients, breast cancer may behave as a chronic disease, even without treatment.
Prolonged remissions have been well documented in patients treated with endocrine therapy. In one study of 156 patients treated with tamoxifen(Drug information on tamoxifen) (Nolvadex) for estrogen receptorpositive metastatic breast cancer, 15% were alive and 7.6% were progression free after 5 years.
The potential for cure using state-of-the-art polychemotherapy is well illustrated by a review of 1,581 patients with metastatic breast cancer treated between 1973 and 1982 with a doxorubicin(Drug information on doxorubicin)-containing induction regimen followed by cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil) (CMF) maintenance therapy. Complete responses occurred in 16.6% of patients, but only 3.1% remained in complete remission for more than 5 years. With a median follow-up of 16 years, only 1.6% (26 of the 1,581 initial patients) were still alive and disease free. Favorable characteristics of these remarkable long-term survivors included younger age, premenopausal status, good performance status, and a low tumor burden at the time of treatment. These sobering statistics are characteristic of the results of current chemotherapeutic regimens used in the metastatic setting.
Is it better to initiate treatment with endocrine therapy or chemotherapy? Two randomized trials have addressed this question. In the first trial, 339 postmenopausal women with metastatic breast cancer, 75% of whom had unknown hormone receptor status, were randomized to receive tamoxifen alone, tamoxifen and concurrent cyclophosphamide and Adriamycin (CA), or CA alone. Although the response rates ranged from 51% in patients treated with tamoxifen plus CA to 22% in those given tamoxifen alone, overall survival rates were virtually identical among the three groups. Of the tamoxifen treated patients, 35% responded to CA as a second-line therapy. In no subgroup was initial chemotherapy associated with superior survival when compared with endocrine therapy.
A similar trial compared initial therapy with CMF vs tamoxifen in patients 65 years of age and older. Complete and partial response rates were 45% for patients treated with tamoxifen and 38% for those given CMF, with median response durations of 10.4 and 7.9 months, respectively. Overall survival data favored tamoxifen as initial therapy, even in estrogen receptornegative patients.
Currently, most patients with receptor-positive invasive breast cancer receive systemic therapy with tamoxifen at the time of initial diagnosis, and it is uncertain as to whether such patients may do as well with initial endocrine therapy in the metastatic setting. In our view, patients who relapse within 1 to 2 years after the initiation of adjuvant tamoxifen or oophorectomy are more likely to benefit from chemotherapy than from further endocrine therapy, but this decision is unlikely to have any major effect on survival. In all other patients, with the exception of patients with rapidly progressive visceral metastatic disease, initial treatment in the metastatic setting should consist of endocrine therapy.
In patients who are receptor positive and seriously ill, chemotherapy combined with endocrine therapy is a reasonable option so as to maximize the patients chance for a rapid response. Numerous trials comparing concurrent chemotherapy and endocrine therapy with chemotherapy alone have failed to show a survival benefit for combined treatment.
Endocrine therapies should be continued indefinitely in patients with stable disease and until disease progression in responding patients. Individuals who have displayed stable disease for 4 to 6 months or longer should be observed for a withdrawal response at the time of disease progression and prior to initiation of further therapies. Agents that should be considered for hormonal therapy are described below.
Selective Estrogen Receptor Modulators
There is major interest in the development of new selective estrogen receptor modulators (SERMs). Tamoxifen, the first SERM widely available for the treatment of breast cancer, has demonstrated efficacy in both the metastatic and adjuvant settings and has served as the prototype for the development of newer SERMs.
The search for the ideal SERM continues. This agent should have estrogen antagonistic effects on breast and endometrial tissues (less breast and endometrial cancer), estrogen agonistic effects on the hypothalamus (cessation or decrease in vasomotor symptoms), skeleton (maintenance of bone density), and liver (lowering of cholesterol), and no effect on the coagulation system. To date, no agent has met all of these goals.
Toremifene(Drug information on toremifene) (Fareston) is currently available for the treatment of metastatic breast cancer and appears to have less estrogen agonistic effects on the endometrium compared with tamoxifen. In the metastatic setting, toremifene offers no advantages over tamoxifen.
Raloxifene(Drug information on raloxifene) (Evista) has been approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis in postmenopausal women and may decrease the risk of breast cancer. Although raloxifene has shown activity in patients with metastatic breast cancer, no trials have directly compared it with tamoxifen or other hormonal agents. As a result, raloxifene should not be used in patients with metastatic breast cancer outside of a clinical trial.
Other SERMs, including droloxifene and idoxifene, are unlikely to be associated with a better therapeutic index than available agents. Newer SERMs with potentially superior therapeutic indices are currently in clinical trials.