Introduction
This section covers palliative therapy of disseminated disease incurable by surgery (stage IV).

Radiotherapy
Palliative radiotherapy may be advised for primary treatment of locally advanced cancers with distant metastases to control ulceration, pain, and other manifestations in the breast and regional nodes. Irradiation of the breast and chest wall and the axillary, internal mammary, and supraclavicular nodes should be undertaken in an attempt to cure locally advanced and inoperable lesions when there is no evidence of distant metastases. A small number of patients in this group are cured in spite of extensive breast and regional node involvement.

Palliative irradiation is of value also in the treatment of certain bone or soft tissue metastases to control pain or avoid fracture. Radiotherapy is especially useful in the treatment of isolated bony metastasis, chest wall recurrences, brain metastases, and acute spinal cord compression.

Hormone & Targeted Therapy
Disseminated disease may shrink - or grow less rapidly - after endocrine therapy such as administration of hormones (eg, estrogens, androgens, progestins; see

Table 17-5); ablation of the ovaries, adrenals, or pituitary; or administration of drugs that block hormone receptor sites (eg, antiestrogens) or drugs that block the synthesis of hormones (eg, aromatase inhibitors). Hormonal manipulation is usually more successful in postmenopausal women even if they have received estrogen replacement therapy. Treatment should be based on the presence of estrogen receptor protein in the primary tumor or metastases. The rate of response is nearly equal in premenopausal and postmenopausal women with ER-positive tumors. A favorable response to hormonal manipulation occurs in about one-third of patients with metastatic breast cancer. Of those whose tumors contain estrogen receptors, the response is about 60% and perhaps as high as 80% for patients whose tumors contain progesterone receptors as well. Because only 5-10% of women whose tumors do not contain estrogen receptors respond, they should not receive hormonal therapy except in unusual circumstances, eg, in an older patient who cannot tolerate chemotherapy. Because the quality of life during a remission induced by endocrine manipulation is often superior to a remission following cytotoxic chemotherapy, it is usually best to try endocrine manipulation first in cases in which the estrogen receptor status is unknown. Additionally, women with ER-positive tumors who fail hormone therapy or experience progression should be placed on a different form of hormonal manipulation. Women who have failed tamoxifen and gone on to a third-generation aromatase inhibitor have shown equal if not better response than those who respond to tamoxifen. When receptor status is unknown but the disease is progressing rapidly or involves visceral organs, however, endocrine therapy is rarely successful, and introducing it may waste valuable time.

In addition to radiotherapy, bisphosphonate therapy has shown excellent results in delaying and reducing skeletal events in women with bony metastases. Bisphosphonates are also sometimes used in conjunction with aromatase inhibitors to decrease the potential bony events associated with those drugs. Further research is being conducted examining the utility of bisphosphonates in conjunction with other therapies and in early breast cancer treatment.

In general, only one type of therapy should be given at a time unless it is necessary to irradiate a destructive lesion of weight-bearing bone while the patient is on another regimen. The regimen should be changed only if the disease is clearly progressing. This is especially important for patients with destructive bone metastases, since changes in the status of these lesions are difficult to determine radiographically. A plan of therapy that would simultaneously minimize toxicity and maximize benefits is often best achieved by hormonal manipulation.

The choice of endocrine therapy depends on the menopausal status of the patient. Women within 1 year of their last menstrual period are arbitrarily considered to be premenopausal, whereas women whose menstruation ceased more than a year ago are postmenopausal. If endocrine therapy is the initial choice, it is referred to as primary hormonal manipulation; subsequent endocrine treatment is called secondary or tertiary hormonal manipulation.

Trastuzumab is a monoclonal antibody that binds to HER-2/neu receptors on the cancer cell and has been shown to be highly effective in HER-2/neu-expressive cancers. In metastatic disease, for patients with HER-2/neu oncogene overexpression, trastuzumab has been shown to increase survival when combined with AC or paclitaxel. Ongoing studies are evaluating trastuzumab in combination with others for adjuvant chemotherapy regimens.

A. The Premenopausal Patient

1. Primary Hormonal Therapy - The potent antiestrogen tamoxifen is the endocrine treatment of choice in the premenopausal patient. Tamoxifen is usually given orally in a dose of 20 mg daily. There is no significant difference in survival or response between tamoxifen therapy and bilateral oophorectomy. Tamoxifen is by far the most common and preferred method of hormonal manipulation for both premenopausal and postmenopausal women. The average remission is about 12 months. Tamoxifen can be given with little morbidity and few side effects. Toremifene, a tamoxifen analogue, is currently available and has similar side effects but is less likely to cause uterine cancer. Controversy continues about whether a response to tamoxifen is predictive of probable success with other forms of endocrine manipulation.

Bilateral oophorectomy is less desirable than primary hormonal manipulation in premenopausal women because tamoxifen is so well tolerated. Oophorectomy can be achieved rapidly and safely by surgery, however, or if the patient is a poor operative risk, by irradiation of the ovaries. Chemical ovarian ablation using a gonadotropin-releasing hormone analogue can also be utilized. Oophorectomy presumably works by eliminating estrogens, progestins, and androgens, which stimulate growth of the tumor.

2. Secondary or Tertiary Hormonal Therapy - Although patients who do not respond to tamoxifen or oophorectomy should be treated with cytotoxic drugs, those who respond and then relapse may subsequently respond to another form of endocrine treatment (

Table 17-5). The initial choice for secondary endocrine manipulation has not been clearly defined.

Patients who improve after oophorectomy but subsequently relapse should receive tamoxifen or an aromatase inhibitor. If one fails, the other may be tried but is not likely to succeed. Megestrol acetate may be considered. Megestrol is a progestational agent. Both drugs cause less morbidity and mortality than surgical adrenalectomy, can be discontinued once the patient improves, and are not associated with the many problems of postsurgical hypoadrenalism, so that patients who require chemotherapy are more easily managed. Adrenalectomy or hypophysectomy used in the past induced regression in 30-50% of patients who previously responded to oophorectomy, but these procedures are rarely done today. Pharmacologic hormonal manipulation has in large part replaced these invasive procedures. Toremifene has shown no added value in women whose tumors no longer respond to tamoxifen. Aromatase inhibitors are of value in patients who responded to tamoxifen or oophorectomy but then progress.

B. The Postmenopausal Patient

1. Primary Hormonal Therapy - Tamoxifen, 20 mg daily, or anastrozole, 1 mg daily, is the initial therapy of choice for postmenopausal women with metastatic breast cancer amenable to endocrine manipulation. Anastrozole (an aromatase inhibitor) has fewer side effects than tamoxifen, the former therapy of choice, and is at least equally as effective. The main side effects of tamoxifen are nausea, vomiting, skin rash, and hot flushes. Rarely, it may induce hypercalcemia in patients with bony metastases. The main side effects of anastrozole are similar but lower in incidence; however, osteoporosis can occur.

2. Secondary or Tertiary Hormonal Therapy - Postmenopausal patients who do not respond to tamoxifen or anastrozole should be given cytotoxic drugs such as CMF or AC. Postmenopausal women who respond initially to tamoxifen or anastrozole but later manifest progressive disease may be crossed over. Aromatase inhibitors have been available for the treatment of advanced breast cancer in postmenopausal women who fail tamoxifen treatment. Recent trials comparing an aromatase inhibitor, anastrozole, with tamoxifen suggest that the former is just as effective and has fewer side effects. Aromatase inhibitors recently have achieved the status of primary hormonal therapy in postmenopausal women. Clinical trials have proved the efficacy of anastrozole and toremifene for such purposes. Androgens have many toxicities and should rarely be used. As in premenopausal patients, neither hypophysectomy nor adrenalectomy is still being performed.