| Contents | Previous | Next |
By Barbara Bolinger, Pharm. D. |
Christy Russell, M.D. |
In the United States, breast cancer is the most common cancer in women accounting for nearly one-third of all their malignancies.1 It is the second leading cause of cancer-related deaths for all American females, and the leading cause for women between the ages of 15 and 54. The scope and gravity. of the problem are easily seen in the 1996 statistics for the US:
Due to improved methods of detection, reports of breast cancer increased steadily at 1-2% per year since 1960, but the mortality rate has remained stable for the last 50 years. This is due most likely to early intervention and improved methods of treatment. Because of the high incidence, even small improvements in the efficacy of treatment are important and may represent tens of thousands of lives saved every year.
As a result of the high failure rates that have been associated with therapies that treat the disease locally or regionally, there has been a concerted effort to find better treatments—or combinations of treatments—that would increase the cure rates of both primary and metastaric breast cancer.
This article will review current oncology recommendations, the status o-adjuvant systemic therapies, and emerging factors that may significantly alter the future management of the disease. (The term adjuvant therapy refers IL anticancer drugs or hormones given after surgery and/or radiation to help prevent recurrence of the cancer.)
The causes of breast cancer are unknown, but some factors associate with its increased incidence are more widely accepted than others. For example the risk becomes greater as individuals grow older. A family history of breast cancer is also an important risk factor, especially if the cancer occurred both in the mother and a sister and developed before menopause. Women who began menstruation at an early age, or entered menopause late in life, o-never gave birth, or had a first pregnancy after age 30 are at higher risk Although there is some controversy about the relationship between breast cancer and the use of birth control pills, evidence favors the position that women in general are not predisposed to the disease for this reason. The various groups mentioned above, however, may be at greater risk.
There are three main screening methods used to detect breast cancer breast self-examination (BSE), clinical physical examination, and imaging techniques—primarily mammography. About 90% of all palpable breast cancer-are said to be detected by the patient, but the percentage detected by screening procedures such as mammography is increasing.
Current guidelines published by the American Cancer Society (see Table 1) recommend a monthly self-examination for women 20 and older. A breast examination by a physician should be performed at least every 3 years beginning at age 20, with an initial mammogram at age 40. For women with a family history of breast cancer, the first mammogram should be done at an earlier age. Annual mammograms and physical examinations are recommended for women 40 and older. Evidence indicates that early detection using these screening methods leads to a substantial reduction in mortality.
| Table 1: American Cancer Society Screening Recommendations | ||
|---|---|---|
| Breast Self Exam (BSE) | 20 years and older | Monthly |
| Clinical Physical Exam | 20 - 40 years | Every 3 years |
| 40 and over | Every year | |
| Mammography | 40 years of age | Baseline and yearly |
Most breast cancers are first discovered when a nodule is found during a physical examination or screening mammography2. The only proven way to determine whether either a palpable or nonpalpable breast lesion is cancerous is through tissue diagnosis by means of biopsy. Removing the tissue necessary for diagnosis by fine-needle aspiration is less invasive than excisional biopsy, and this has now become the routine procedure preferred by many surgeons.'
After the diagnosis of breast cancer is made, the treatment options include surgical procedures such as segmental resection or modified radical mastectomy, radiotherapy, hormone therapy, and chemotherapy.
| Table 2: Definitions for Breast Cancer Staging | |
|---|---|
| Tumor | |
| T1S | Carcinoma in situ (intraductal carcinoma, tabular) |
| TO | No evidence of primary tumor |
| T1 | Tumor 2 cm in greatest dimension |
| T2 | Tumor >2cm but <5cm in greatest dimension |
| T3 | Tumor >5cm in greatest dimension |
| T4 | Tumor of any size with direct extension into chest wall or skin |
| Nodes | |
| N0 | No regional lymph node metastases |
| N1 | Metastases to movable ipsilateral axillary node(s) |
| N2 | Metastases to ipsilateral axillary lymph node(s), fixed to one another or other structures |
| Metastases | |
| M0 | No distant metastases |
| M1 | Metastases to movable ipsilateral axillary node(s), metastases to ipsilateral axillary lymph node(s), fixed to one another or other structures, of metastases to ipsilateral internal mammary lymph node(s); distant metastases |
The staging process assesses prognostic factors and the presence of metastases and aids in the selection of postsurgical therapy. The number of microscopic malignant nodes out of the total number of nodes sampled is the single most predictable indicator of long-term prognosis. The routine use of serum tumor markers, however, has not vet been shown to be of value in breast cancer prognosis.3
The clinical staging system of the International Union Against Cancer (UICC) is based on the TNM (tumor, nodes, metastases) system (see Tables 2 and 3)2 and has now gained universal acceptance.
| Table 3: Classification of Breast Cancer Stages5 | |
|---|---|
| Stage 0: | T1S, N0, M0 |
| Stage I: | T1, N0, M0 |
| Stage IIA: | T0, N1, M0 |
| Stage IIB: | T2, N1, M0 or T3, N0, M0 |
| Stage IIIA: | T0, N2, M0, or T1, N2, M0 or T2, N2, M0 or T3, N1 or N2, M0 |
| Stage IIIB: | T4, any N, MO or any T, N3 |
| Stage IV: | Any T, any N, M1 |
There are a number of tumor characteristics that may be prognostic factors for stage I or stage II breast cancer. One of the most common characteristics that affects the risk of recurrence, regardless of initial node status, is estrogen receptor (ER) content. The ER content of a specimen is evaluated at the time of tumor removal. In general, patients with ER-positive and/or PR (progesterone receptor-positive tumors seem to have a better prognosis, even if advanced disease is present.
Survival rates in patients with metastatic disease vary with the location and type of metastases. Women with osseous (bone) and cutaneous (skin) metastases may survive for several years. Whereas those with lymphangitic metastases of the lung and /or extensive liver metastases have a mean survival duration of only three to six months.3
The treatment of breast cancer has changed somewhat over the last two decades, but very little progress has been made. The surgical treatment of the disease in its early stage consists of either total or partial mastectomy (lumpectomy), with an associated lymph node dissection. Partial mastectomy is usually followed by radiation therapy to prevent local recurrence. Whenever possible, partial mastectomy is chosen to conserve breast tissue.
Adjuvant systemic therapies, whether hormonal or cytotoxic, have become part of the standard treatment for primary breast cancer. Studies of these therapies generally report the percentage of women with a positive response (where response is defined as tumor shrinkage or lack of disease progression). Results of systemic therapies were summarized and issued as a series of recommendations (see Table 4)4 based on the Fourth International Conference on Adjuvant Therapy of Primary Breast Cancer. These recommendations indicate that adjuvant tamoxifen therapy may be more effective in women over the age of 50, while adjuvant cytotoxic therapy has its greatest impact on younger women.
| Table 4: Recommendations on Adjuwant Therapy of Primary Breast Cancer4 | |
|---|---|
| GROUP | ADJUVANT THERAPY |
| PATIENTS WITH MODE-NEGATIVE TUMORS | |
| Low risk of recurrence | |
| Premenopausal | None or tamoxifen |
| Postmenopausal | None or tamoxifen |
| Elderly | None |
| Intermediate risk of recurrence | |
| Postmenopausal | Tamoxifen |
| Elderly* | Tamoxifen |
| High risk of recurrence | |
| Premenopausal, hormone-receptor positive | Chemotherapy, with or without tamoxifen |
| Premenopausal, hormone-receptor negative | Chemotherapy |
| Postmenopausal, hormone-receptor positive | Tamoxifen, with or without chemotherapy |
| Postmenopausal, hormone-receptor negative | Chemotherapy, with or without tamoxifen |
| Elderly | Tamoxifen (chemotherapy in selected cases) |
| PATIENTS WITH MODE-NEGATIVE TUMORS | |
| Premenopausal, hormone-receptor positive | Chemotherapy, with or without tamoxifen |
| Premenopausal, hormone-receptor negative | Chemotherapy |
| Postmenopausal, hormone-receptor positive | Tamoxifen, with or without chemotherapy |
| Postmenopausal, hormone-receptor negative | Chemotherapy, with or without tamoxifen |
| Elderly, hormone-receptor positive | Tamoxifen |
| Elderly, hormone-receptor negative | Chemotherapy (if tolerated), with or without tamoxifen |
| *>70 years of age | |
The use of hormone therapy has increase since more sophisticated hormone-receptor assays have become available, and new types treatments have been introduced. The therapies of the past, such as major surgery, have given way in many cases to treatment with antietrogens, progestins , and aromatase inhibitors (see Table 5) Choosing which hormonal therapy is best for particular patient depends on the patient’s response and tolerance of side effects.
| Table 5: Hormonal Therapy | |||
|---|---|---|---|
| CLASS | DRUG | DOSE | SIDE EFFECTS |
| Antiestrogen | Tamoxifen | 20 mg daily | Weight gain, vaginal bleeding, hot flashes, DVT, nausea, and vomiting |
| Progestin | Megestrol | 40 mg 4 times daily | Fluid retention, weight gain, and hot flashes |
| LHRH Agonists | Leuprolide | 3.75 mg IM Depot | Edema, pain, hot flashes, and asthenia |
| Goserelin | 3.6 mg IM Depot | Hypercalcemia, vaginal bleeding, hot flashes, pain, and lethargy | |
| Aromatase Inhibitor | Anastrozole | 1 mg daily | Asthenia, nausea, headache, hot flashes, and back pain |
The antiestrogen tamoxifen has been shown to delay tumor recurrence and prolong the survival of postmenopausal women. Tamoxifen blocks the release of two potent factors, growth factor beta and the insulin-like growth factor I (IGF-1), which slows tumor growth.3 Tamoxifen is also effective as adjuvant therapy in premenopausal women with breast cancer that is ER-positive.
The standard therapeutic dose of tamoxifen is 20 mg/day orally, and should be continued for a minimum of two years or until the disease progresses. Toxicity from tamoxifen is usually mild and transient, with the most common side effects being weight gain, vaginal bleeding (endometrial hyperplasia), skin rash, hot flashes, deep vein thrombosis, thrombocytopenia, hypercalcemia, nausea, vomiting, and the progression of cataracts.
Another hormonal therapy that is available the semisynthetic progestin megestrol acetate. The commonly used therapeutic dosage is 160 mg/day in divided oral doses. Randomized trials have confirmed that for patients who have not had prior endocrine therapy, megestrol acetate therapeutically equivalent to tamoxifen. However, the response rate is low (<10%) if megestrol acetate is used after two or three other hormone treatments.5 Toxicity with this therapy is also mild and transient, and side effects include fluid retention, weight gain, and hot flashes
Leutinizing hormone-releasing hormone (LHRH) agonises such as leuprolide and goserelin decrease follicle stimulating hormone and leutinizing hormone excretion and may have a direct effect on breast cancer. The LHRH agonists are effective in premenopausal women with metastanc disease. They are easy to administer as a once monthly depot injection and have minimal toxicity.
The newest addition to the hormone therapy family is the aromatase inhibitor anastrozole. It is indicated for use in postmenopausal women whose disease has progressed following tamoxifen therapy. The recommended dose is 1 mg taken orally once a day.
Patients with estrogen-receptor negative diseases that doesn't respond to tamoxifen probably will not respond to anastrozole therapy either. When compared to treatment with megestrol acetate, more than 60% of patients responded for longer than six months when given anastrozole, and more than 15% responded for longer than 12 months. There was no difference in efficacy between the two treatments.6 The most commonly reported side effects included weakness (16%), nausea (1S%), headache (13%), hot flashes (12%), and bone or joint pain (10.7%). Diarrhea was more common with anastrozole than with megestrol acetate.
Cytotoxic chemotherapy is the treatment of choice for patients who have hormone refractory tumors or whose tumors become hormone-resistant.7 The cytotoxic agents most commonly used in the adjuvant treatment of breast cancer are cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and doxorubicin (A) used in combination (see Table 6)5. These combinations are associated with therapeutic response rates of 50-70%. Regimens that include doxorubicin have been shown to produce higher overall and complete response rates and longer durations of response and survival.
| Table 6: Effective Combination Chemotherapy Regimens Commonly Used to Treat Breast Cancer5 | ||||
|---|---|---|---|---|
| Regimen | Dose (mg.m2) |
Route | Day(s) of Treatment | Recycle |
| CMF (P) Cyclophosphamide | 100 | PO | 1 to 14 | |
| Methotrexate | 40 (60) | I.V. | 1 and 8 | 4 wks |
| Fluorouracil | 600 (700) | I.V. | 1 and 8 | |
| Prednisone | (40) | (PO) | (1 to 14) | |
| CMF Cyclophosphamide | 600 | I.V. | 1 | |
| Methotrexate | 40 | I.V. | 1 | 3 wks |
| Fluorouracil | 600 | I.V. | 1 | |
| CMF Cyclophosphamide | 600 | I.V. | ||
| Methotrexate | 40 | I.V. | 1 and 8 | 4 wks |
| Fluoiouracil | 600 | I.V. | 1 and 8 | |
| CA Cyclophosphamide | 200 | PO | 3 to 6 | 3-4 wks |
| Doxorubicin | 40 | I.V. | 1 | |
| AC Doxorubicin | 45 | I.V. | 1 | 3 wks |
| Cyclophosphamide | 500 | I.V. | 1 | |
| FAC Flurouracil | 500 | I.V. | 1 and 8 | |
| Doxorubicin | 50 | I.V. | 1 | 4 wks |
| Cyclophosphamide | 500 | I.V. | 1 | |
A reasonable approach to determining which combination of agents is best suited to a particular patient is to use CMF combinations for low-risk patients (those with good prognostic factors), and FAC or AC with higher risk groups8.
The adverse effects of chemotherapy regimens are still a major concern. Table 7 summarizes the early toxic effects and the average frequency for the two most common chemotherapeutic regimens5. Significant hair loss occurs in fewer than 10% of patients, but is to be expected when a doxorubicin-based regimen is employed.
| Table 7: Acute and Late Toxicity From Commonly Used Adjuvant Chemotherapy Combinations5 | ||
|---|---|---|
| Texicity | CMF (%) | FAC or AC (%) |
| Acute Vomiting | >90 | >90 |
| Oral Mucositis | <10 | |
| Marked Alopecia | 10 | >90 |
| Leukopenia* | 10 | 25 |
| Thrombocytopenia | <10 | <5 |
| Conjunctivitis | 30 | |
| Cystitis | 15 | <5 |
| Delayed Amenorrhea | 70 | 80 |
| Congestive Heart Failure | 0 | 1-2 |
| Late Acute Leukemia | <1 | <1 |
| * < 2500/mm3 <7575,000/mm3 (Data are averages derived from the published literature) |
||
Approximately one-third of patients complain of anticipatory nausea and/or vomiting. Weight gain during adjuvant chemotherapy has been consistently documented in at least half of the women receiving this therapy, with an average weight gain of 3-4 kg. Major delayed toxic effects include irreversible amenorrhea (<40 years: 40%; >40 years: 95%). Doxorubicin-based treatments have a 1-2% incidence of congestive heart failure if the cumulative lifetime dose does not exceed 300-350 mg/m". The risk of heart failure increases dramatically if this dose is exceeded.
When first-line chemotherapy becomes ineffective and metastatic disease progresses, second-line agents are employed. These are either single-agent therapies or combinations not previously used. The new combinations may include vinca alkaloids (vincristine, vinblastine), mitomycin, mitoxantrone, etoposide, cisplatin, carboplatin, and thiotepa.
The response rate from the use of this type of combination therapy usually approaches 20-25%, and this type therapy usually remains effective for a shorter time. New agents such as taxanes, the new vinca alkaloid vinorelbine, and topoisomerase inhibitors, which prevent tumor growth through a different mechanism than older drugs, have provided a much-needed boost to the chemotherapeutic armamentarium (see Table 8).
| Table 8: New Second Line Agents in Breast Cancer | ||
|---|---|---|
| Class | Drug | Dose (mg/m2) |
| Taxanes | Paditaxel | 135-250 I.V. over 3 hours |
| Docetaxel | 60- 100 I.V over 1 hour | |
| Vinca Alkaloid | Vinorelbine * | 30 Slow I.V.P. |
| Topoisomerase I Inhibitor | # Topotecan | 1.5 I.V. over 30 min. X 5 days |
| # Irinotecan (CPT 11) | 125 I. V. over 90 min | |
| * Unlabeled use # Not FDA approved for breast cancer |
||
Paclitaxel, a taxane that disrupts microtubules and cell division, is one of the newest single-agent chemotherapeutic options available for refractory disease. The response rate in patients with minimal prior chemotherapy is well above 50%, but a decrease in that response rate has been noted depending on the amount of previous chemotherapy the patient has undergone. Patients in the latter category still show a 2 3 % response rate, even where there is doxorubicin resistance.9
Paclitaxel doses ranging from 135-250 mg/m2 have been used and infused over three hours. All patients should be premedicated before pacilaxtel is administered to prevent severe hypersensitivity reactions. The manufacturer recommends dexamethasone (TV or PO), IV diphenhydramine and IV cimetidine 30-60 minutes prior to administration. Neither optimal dosage and treatment schedules nor combination therapies have been defined.
Docetaxel is the second taxane to be developed. A partial response rate of 41% and a complete response (no detection of tumor) rate of 2% have been noted for this drug, with a median duration of response of 6 months and a median time to progression of 4 months. Median survival time was 10 months.10
The recommended dosage for docetaxel is 60-100 mg/m2 given over 1 hour every three weeks. Longer infusion times have caused mucositis (mouth sores) and more severe neutropenia (lowering of white blood cells). Neutropenic nadirs usually occur on day 8, with recovery by day 21.
Side effects of docetaxel include grade 4, or severe, neutropenia (75-90% of patients); febrile neutropenia (0-22%); grade 1 to 3, or mild to moderate, hair loss (80%); and fluid retention (40%) seen as weight gain, edema or pleural effusions. Fluid retention is related to increased capillary permeability, and is treated with dexametha-sone (8 mg orally twice a day), beginning the day before and continuing 3 days after the infusion of docetaxel. Patients with neutrophil counts of less than 500 cells/mm3 for more than one week or severe peripheral neuropathy should have subs quent doses decreased to 75-55 mg/m, or the treatment discontinued.
Vinorelbine, a vinca alkaloid, is a new addition that offers the potential of less neurotoxicity than vincristine or vinblastine. Response rates in patients without prior therapy are 40-60%, whereas response rates in patients with prior therapy are 20-30%. Vinorelbine is given as an IV infusion into a large, central vein. However, improper administration (outside the central vein) may result in local tissue damage.
The topoisomerase I inhibitors topotecan and irinotecan (CPT 11) have shown promise in the treatment of metastatic breast cancer. These agents, although not FDA-approved for this use, have had encouraging results in phase I trials.
The development of new and effective cytotoxic agents over the last three years and the formulation of original and exciting treatment approaches hold promise in the fight against primary and metastatic breast cancer. There is a growing understanding of the hormonal regulation of breast cancer cell proliferation, which has led to new avenues of research, particularly toward the ability to bind monoclonal antibodies to specific receptors. These receptors play an important role in the development and growth of mammary carcinoma by producing diffusible products that enhance the growth of breast cancer cells. This new understanding of growth regulation may play an important role in the development of therapies that target tumor expansion by interfering specifically with the factors that control their growth.