`The New England Journal of Medicine
`
`
`
`
`
`
`
`Review Article
`
` breast cancer.'4!5 Germ-line mutations in these two
`
`Drug Therapy
`
`ALASTAIR J.J. Woop, M.D., Editor
`
`TREATMENT OF BREAST CANCER
`
`GasrieL N. Hortosacyli, M.D.
`
`REAST cancer is a major public health prob-
`lem worldwide. Management of breast cancer
`waslast reviewed in the Journal in 1992.1 The
`accumulation of new biologic information, the re-
`sults of recent clinical trials, and the availability of
`new diagnostic and therapeutic tools makeit appro-
`priate to review the subject again.
`
`EPIDEMIOLOGY
`
`The incidence of breast cancer in the United States
`has been increasing gradually for the past three dec-
`ades.23 It was estimated that 181,600 new cases of
`breast cancer were diagnosed in the United States in
`1997 and that 44,190 people would die of breast
`cancer during the same year. However, incidence and
`mortality have recently leveled off and even decreased
`slightly. Similar decreases in mortality were recently
`reported in Sweden and the United Kingdom.4§
`The incidence of breast cancer increases with age,
`although therate of increase slows after menopause.®”
`Early menarche, late menopause, and nulliparity in-
`crease the risk of breast cancer. Atypical lobular or
`ductal hyperplasia also increases the risk, and benign
`breast disease does so marginally.8° Other risk factors
`are early exposure to ionizing radiation, long-term
`postmenopausal estrogen-replacement therapy, and
`alcohol consumption. The most important risk factor
`is a family history of breast cancer.'!°1% About 5 to 10
`percent ofall breast cancers occur in high-risk families,
`and there are several familial breast cancer syndromes,
`including the breast—ovarian cancer syndrome, the
`Li-Fraumeni syndrome, and Cowden’s disease.!?
`
`BIOLOGY
`
`The recent identification and cloning of BRCAI
`and BRCA2 has expanded our knowledge of familial
`
`From the Department of Breast Medical Oncology, University of Texas
`M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 56, Houston,
`TX 77030, where reprint requests should be addressed to Dr. Hortobagyi.
`©1998, Massachusetts Medical Society.
`
`974
`
`- October 1, 1998
`
`genes are associated with a 50 to 85 percentlifetime
`risk of breast cancer, ovarian cancer, or both. Tests
`for these mutations exist, and research efforts to
`develop comprehensive genetic screening and coun-
`seling programs are ongoing.!¢ All breast cancers
`have somatic genetic abnormalities. In sporadic breast
`cancer, abnormalities have been identified in several
`genes (including p53, bel-2, c-myc, and c-myb) 178
`and in some cancers normal genes or gene products
`(HER-2/nen and cyclin D1) are overexpressed. How-
`ever, the number and types of mutations necessary
`for the development of sporadic breast cancer are not
`known.
`Manyfactors that stimulate or inhibit growth influ-
`ence the growth and proliferation of breast-cancer
`cells.19 Gonadal steroid hormones (estrogens, pro-
`gestins, and androgens), growth factors (epidermal
`growth factor, transforming growth factors @ and B,
`and insulin-like growth factors I and II), and vari-
`ous cytokines and lymphokinesinfluence the behav-
`ior and phenotypic expression of breast cells. For in-
`stance, production of parathyroid hormone-—related
`protein, prostaglandin E, or interleukin-6 by the tu-
`mor leads to the development of osseous metasta-
`ses.2° The recognition that these factors influence
`the growth and dissemination of breast cancer has
`provided new targets for therapeutic and preventive
`intervention.2)24 Breast cancer also induces neo-
`vascularization, which, in turn, facilitates the meta-
`static process.8 Metastatic spread is not a random
`mechanical phenomenon but requires systematic in-
`teraction amongbreast cells, stroma, and surround-
`ing normal tissue at both primary and metastatic
`sites.24 Adhesion molecules,
`local mediators, hor-
`mones, and growth factors must all act for metasta-
`ses to develop. On the basis of this new informa-
`tion, diagnosis and treatment have changed. Many
`new cytotoxic and hormonal agents have emerged
`from new biologic concepts and are being devel-
`oped for clinical use.
`
`DIAGNOSTIC APPROACHES
`
`Systematic screening by means of mammography
`and clinical examination results in early diagnosis of
`breast cancer and a 25 to 30 percent decrease in mor-
`tality due to breast cancer in womenover the age of
`50 years (Table 1)?5 and probably also in women be-
`tween the ages of 40 and 50 years.26 The American
`Cancer Society and the National CancerInstitute rec-
`ommend annual screening mammography for wom-
`en older than 40 years who have a standard risk of
`breast cancer.2627 In women from high-risk families,
`
`The New England Journal of Medicine
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`
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`
`
`
`DRUG THERAPY
`
`
`
`TABLE 1. BENEFIT OF SCREENING MAMMOGRAPHY
`ACCORDING TO AGE.*
`
`Stupy
`
`DURATION OF
`FoLttow-up
`
`SCREENING
`INTERVAL
`
`ReLative Risk oF DEATH
`FROM CANCER
`(95% CI)t
`
`AGE
`50-74 YR
`
`AGE
`40-49 yr
`
`yr
`
`10
`12
`12
`12
`7
`10
`
`mo
`
`24
`18-24
`24-33
`24-33
`12
`12
`
`Edinburgh
`Malmé
`Kopparberg
`Ostergotland
`Canada
`Health Insurance
`Plan
`
`0.8 (0.6-1.1) 0.8 (0.5-1.5)
`0.9 (0.6-1.2) 0.5 (0.2-1.2)
`0.8 (0.5-0.9) 0.8 (0.4-1.4)
`0.8 {0.6-1.0)
`1.3 (0.8-2.3)
`1.0 (0.6-1.5)
`1.4 (0.8-2.2)
`0.7 (0.5-1.0) 0.8 (0.5-1.2)
`
`1.0 (0.5-2.0)
`0.6 (0.4-1.1)
`28
`8
`Stockholm
`0.9 (0.5-1.6) 0.7 (0.3-2.0)
`18
`7
`Gothenburg
`
`Overall 0.8 (0.7-0.9) 0.9 (0.8-1.1) — —
`
`
`
`*Data are modified from Tables 2 and 3 in Kerlikowske et al.,2® with the
`permission of the publisher.
`tRelative risks are for women who underwent mammographic screening
`as compared with those who did not. CI denotes confidence interval.
`
`especially those with BRCAor BRCA2 mutations,
`screening should start at 25 years of age, or 5 years
`earlier than the earliest age at which breast cancer
`was diagnosed in a family member. Substantial techni-
`cal improvements have been made in screening mam-
`mography, and additional improvements are expected
`to result from digital mammography. Breast mag-
`netic resonance imaging and technetium-99m sesta-
`mibi imaging are under evaluation and may further
`increase our capability for early diagnosis.?8.?9
`Twenty years ago, incisional or excisional biopsies
`were the standard methods for confirming the diag-
`nosis; today, fine-needle aspiration?® or core needle
`biopsy*! is the standard. Ultrasound-guided core nee-
`dle biopsy, stereotactic biopsy,?2 and magnetic reso-
`nance—directed biopsy have become important di-
`agnostic tools, especially for women with suspicious
`but nonpalpable breast masses. The use oflarge-core
`needle-biopsy techniques increases the pathologist’s
`ability to characterize the lesion.
`THERAPY
`
`Primary Breast Cancer
`In some women breast cancer is a local disease
`without distant spread. Such early breast cancers are
`usually diagnosed by screening mammography and
`are highly curable with local or regional treatment
`alone.34 However, most women with primary breast
`cancer have subclinical metastases, and in a high per-
`centage of those treated with apparently curative
`surgery (with or without radiotherapy), distant me-
`tastases ultimately develop.35.36
`
`
`
`Local and Regional Treatment
`
`Radical mastectomy has been largely discontinued
`and is seldom, if ever, indicated today.3?7 Random-
`ized trials have established that for most women
`with early breast cancer, lumpectomy (wide excision
`of the tumor with preservation of the breast) with
`radiotherapy is the preferred treatment (Fig. 1),38
`and up to 50 percent of womenwith early breast can-
`cer in the United States are now treated in this way.
`However, there are marked geographic variations in
`the use of this treatment in the United States,3? sug-
`gesting that patients’ preferences and physicians’
`choices often override medical criteria in the selec-
`tion of treatment. Radiotherapy, an integral part of
`breast-conserving treatment, is inappropriately with-
`held from some women, especially those older than
`65 years.4° Noninvasive (in situ) ductal and lobular
`breast cancer can also be treated adequately with
`lumpectomy and radiotherapy.4
`
`Axillary Lymph-Node Dissection
`
`The probability of recurrence is higher for wom-
`en with histologically positive axillary lymph nodes
`and increases with each additional positive node.
`Axillary lymph-node dissection provides prognostic
`information but has minimal therapeutic benefit or
`none, especially in women with clinically negative
`axillary lymph nodes,*andit is responsible for most
`of the morbidity associated with breast surgery.
`Therefore, there is increasing interest in developing
`alternative methods to obtain prognostic informa-
`tion. Sentinel-lymph-node mapping is a procedure
`in which a radioactive substance or a blue dyeis in-
`jected into the area around the tumor; a short time
`later, the lower ipsilateral axilla is explored through
`a small incision and the lymph nodethat has taken
`up the dye or radioactive substance(i.e., the senti-
`nel node) is excised.*4 If it is histologically negative,
`the rest of the axillary lymph nodesare also likely
`to be negative.
`In expert hands,
`this procedure
`identifies the sentinel node in more than 90 percent
`of women. Elsewhere in this issue of the Journal,
`Krag et al. report similar results in a large multi-
`centertrial. The positive predictive value of a suc-
`cessful sentinel-node biopsy approaches 100 per-
`cent, whereas its negative predictive value exceeds
`95 percent.*445 Many patients with clinically nega-
`tive axillary lymph nodes could be spared an axillary
`dissection if the sentinel node was found to be neg-
`ative.
`An alternative approach is to analyze the primary
`tumorfor nuclear or histologic grade, kinetics ofcell
`growth and division, hormone-receptor expression,
`markers of invasive or metastatic capability, or blood-
`vessel content. A combination of these prognostic
`markers might provide an acceptable substitute for
`the information derived from axillary lymph-node
`examination. Until these newer techniques are vali-
`
`Volume 339 Number 14
`
`-
`
`975
`
`The New England Journal of Medicine
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`
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`
`
`The New England Journal of Medicine
`
`Study
`
`IGR
`
`Milan
`
`NSABP
`
`NCI
`
`EORTC
`
`Pooled
`
`Favors Breast- —<|——__———___» Favors
`
`Conserving Therapy
`Odds Ratio
`Mastectomy
`
`0.0
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`2.5
`
`Figure 1. Individual and Pooled Odds Ratios for Survival at 10 Years in Women with Breast Cancer
`Treated by Breast-Conserving Therapy as Compared with Mastectomy.
`Breast-conserving therapy consisted of breast-conserving surgery plus radiation. The horizontal bars
`indicate 95 percent confidence intervals. For the pooled data, the odds ratio is 0.9 (95 percent confi-
`dence interval, 0.8 to 1.0). IGR denotes Institut Gustave—Roussy, NSABP National Surgical Adjuvant
`Breast and Bowel Project, NCI National Cancer Institute, and EORTC European Organization for
`Research and Treatment of Cancer. Adapted from Fisher, with the permission of the publisher.
`
`dated, axillary dissection remains the standard of care
`for all women with invasive breast cancer or large non-
`invasive tumors (>2.5 cm).
`
`TABLE 2. TEN-YEAR CANCER-FREE SURVIVAL AND OVERALL
`SURVIVAL AMONG WOMEN TREATED WITH CHEMOTHERAPY
`WITH OR WITHOUT RADIOTHERAPY AFTER MASTECTOMY.
`
`STUDY AND OUTCOME
`
`No. oF
`SUBJECTS
`
`PERCENT SURVIVING
`CHEMOTHERAPY
`AND
`CHEMOTHERAPY RADIOTHERAPY
`
`P
`VALUE
`
`British Columbia*!
`Cancer-free survival
`Overall survival
`Danish Breast Cancer
`Cooperative Group*?
`<0.001
`48
`34
`Cancer-free survival
`
`
`
`45 54Overall survival <0.001
`
`318
`
`1708
`
`41
`54
`
`56
`64
`
`0.007
`0.07
`
`data
`
`
`Radiotherapy
`
`Radiotherapy is an integral part of breast-conserv-
`ing treatment.#438 A recent randomized trial showed
`that administering chemotherapy before radiotherapy
`resulted in higher survival rates when both chemo-
`therapy and radiotherapy were given postoperatively.*¢
`Postmastectomy radiotherapy reduces the inci-
`dence of local and regional recurrences by 50 to 75
`percent, but in most randomized trials, and accord-
`ing to a meta-analysis, this reduction was not accom-
`panied by increased survival.*”°° For that reason and
`becauseofits potential for long-term adverse effects,
`radiotherapy after mastectomy is indicated only for
`women at high risk for local or regional recurrence
`(patients with large tumors invading the skin of the
`breast or the chest wall or those with many positive
`axillary lymph nodes). However, in two recent, long-
`term randomized studies of high-risk premenopausal
`women with breast cancer treated with modern radio-
`therapy techniques and chemotherapy or with che-
`motherapy alone, there were fewer local and regional
`recurrences and overall survival was significantly bet-
`ter among the women treated with radiotherapy and
`chemotherapy (Table 2).552 These results have re-
`newedinterest in postmastectomy radiotherapy.
`
`Systemic Hormone Therapy or Chemotherapy
`
`The optimal treatment for women with primary
`breast cancer involves multiple methods and includes
`systemic therapy with hormonal agents, combina-
`tion chemotherapy, or both. Over the past 25 years,
`various aspects of systemic therapy have been stud-
`ied in many randomized trials, and there have been
`four overviews of data from the available random-
`ized trials.535° Current knowledgeis based on about
`400 trials including more than 220,000 women.
`Hormonal therapy and chemotherapy added to local
`
`976
`
`October 1, 1998
`
`The New England Journal of Medicine
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`
`
`DRUG THERAPY
`
`lumpectomya possibility for many women who would otherwise have required a mastectomy. In terms of
`
`treatmentfavorably alter the natural history of breast
`cancer. The reduction in the rates of recurrence and
`death persists beyond 15 years for all forms of sys-
`temic treatment. Most women with primary breast
`cancer have sufficient residual
`risk after regional
`therapy to benefit from systemic therapy, but for
`somethe benefit is marginal. The indications for sys-
`temic adjuvant therapy are shown in Table 3.
`For adjuvant therapy, combination chemotherapyis
`more effective than single-drug therapy, reducing the
`annual risk of death by about 20 percent.5? Although
`the effects of combination chemotherapy are more
`marked in women younger than 60 years, especially
`those who are premenopausal when therapy is begun,
`its effectiveness has been clearly demonstrated up to
`the age of 69 years. Adjuvant tamoxifen therapy sig-
`nificantly reduces the risks of recurrence and death
`in women in all age groups. The benefit is greater
`when tamoxifen is administered for aboutfive years,
`rather than one to three years, and whenit is given
`to women with estrogen-receptor—positive tumors.4
`Recent analyses suggest that women with estrogen-
`receptor—negative tumors should not be treated with
`hormonal therapy. Treatment for more than five years
`is no more effective than treatment for five years.”
`
`Preoperative Chemotherapy
`
`Chemotherapyis usually administered after surgery
`in women with operable breast cancer. However, for
`women with large operable tumors, preoperative che-
`motherapy may have some advantages. Several re-
`ports®?*8 have indicated that close to 90 percent of
`primary operable tumors decrease in size by more
`than 50 percent after chemotherapy,
`thus making
`
`survival, there is no apparent advantage to preoper-
`ative chemotherapy as compared with postoperative
`chemotherapy.
`
`Duration of Chemotherapy
`
`In several trials, combination treatment for less
`than three months wasinferior to treatment for four
`to six months, whereas treatment with a single com-
`bination-chemotherapy regimen, such as cyclophos-
`phamide, methotrexate, and fluorouracil (CMF), for
`longer than six months was no more effective than
`treatment for four to six months.5355.59 The combi-
`nations used most often are fluorouracil, doxorubicin,
`and. cyclophosphamide (FAC); fluorouracil, epirubi-
`cin, and cyclophosphamide (FEC); doxorubicin and
`cyclophosphamide (AC); and CME These combina-
`tions are administered intermittently at intervals of
`three to four weeks. Six cycles of FAC or FEC (dura-
`tion, 18 to 24 weeks), six cycles of CMF (duration,
`18 to 24 weeks), or four cycles of AC (duration, 12
`to 16 weeks) are considered standard therapy. A recent
`report of the preliminary results of a large random-
`ized trial suggested that the addition of four cycles
`of paclitaxel (duration, 12 to 16 weeks) to four cycles
`of AC improved both disease-free survival and overall
`survival
`rates.©° In premenopausal women, ovarian
`ablation has a substantial benefit, equivalent to that
`of combination chemotherapy or tamoxifen.53.5¢ This
`benefit persists for 15 years after treatment.
`
`Combination Chemotherapy and Hormone Therapy
`
`The combination of tamoxifen (or ovarian abla-
`tion for premenopausal women) and chemotherapy
`is more effective than either alone.53.55,56.59 Therefore,
`
`
`
`TABLE 3. INDICATIONS FOR ADJUVANT SYSTEMIC THERAPY AFTER SURGERY IN WOMEN
`WITH OPERABLE BREAST CANCER.
`
`Type OF DISEASE
`
`ADJUVANT THERAPY INDICATED*
`
`Breast cancer without evidence ofinvasion
`Noninvasive breast cancer (ductal or lobular carcinomain situ)
`Breast cancer with evidence of invasion, but negative axillary
`lymph nodes
`Microinvasive breast cancer (<1 mm in largest diameter)
`Invasive ductal or lobular carcinoma <1 cm in largest
`diameter
`Invasive carcinoma <3 cm in largest diameter with favorable
`histologic findings (pure tubular, mucinous, or papillary)
`Invasive ductal or lobular carcinoma #1 cm in largest
`diameter
`Invasive carcinoma #3 cm in largest diameter with favorable
`histologic findings (pure tubular, mucinous, or papillary)
`Invasive breast cancer with positive axillary lymph nodes
`Chemotherapy, hormonal
`All tumors, regardless of size or histologic findings
`therapy, or both
`
`None
`
`None
`None
`
`None
`
`Chemotherapy, hormonal
`therapy, or both
`Chemotherapy, hormonal
`therapy, or both
`
`*Chemotherapy consists of fluorouracil, doxorubicin, and cyclophosphamide (FAC); doxorubicin
`and cyclophosphamide (AC); or cyclophosphamide, methotrexate, and fluorouracil (CMF). Hormonal
`therapy consists of tamoxifen or ovarian ablation (either surgical or chemical).
`
`The New England Journal of Medicine
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`
`Volume 339 Number 14
`
`-
`
`977
`
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`
`
`The New England Journal of Medicine
`
`of such women,the tumors shrink by more than 50 percent with preoperative chemotherapy. Most previ-
`
`the combination of chemotherapy and tamoxifen is
`recommended, especially for women with a high risk
`of recurrent disease. There is substantial agreement
`about the choice of optimal adjuvant therapy once it
`has been determined that a woman might benefit
`from this intervention (Table 4).
`
`Dose-Intensive and High-Dose Chemotherapy Regimens
`
`In dose-intensive regimens, chemotherapy is ad-
`ministered in conventional doses but at shorter inter-
`vals; in high-dose regimens, chemotherapy is given
`in doses higher than conventional doses. Although
`preliminary results with these regimens are encour-
`aging, there is no evidence from randomized trials
`that either type of regimen is more effective than
`standard-dose adjuvant chemotherapy or than che-
`motherapy and hormonal therapy combined. Ongo-
`ing randomizedtrials should help to determine the
`efficacy of high-dose regimens and new therapeutic
`agents as curative treatments in breast cancer.o.2
`
`Locally Advanced andInflammatory Breast Cancer
`
`Stage III breast cancer includes tumors larger than
`5 cm in the largest diameter, tumors of any size with
`direct invasion of the skin of the breast or the chest
`wall, and any tumors with fixed or matted axillary
`lymphadenopathy. Women with stage III or locally
`advanced breast cancer should be treated with pre-
`operative chemotherapy or hormonal therapy, sur-
`gery, and radiotherapy.®64 In more than 65 percent
`
`ously inoperable tumors becomeoperable, and some
`become amenable to breast-conserving therapy.%
`Limited data suggest that adjuvant chemotherapy and
`hormonal
`therapy are indicated after preoperative
`chemotherapy and regional treatment.® Excellent lo-
`cal control can be achieved in 80 to 90 percent of
`women, and about 30 percent of women with stage
`IIIB tumors (tumors with direct invasion of the skin
`of the breast or the chest wall) or inflammatory breast
`cancer remain free of cancer after 10 years.%.66
`Metastatic Breast Cancer
`
`The clinical course of metastatic breast cancer is
`variable; this heterogeneity results in large variations in
`growth rate and responsiveness to systemic therapy.
`Chemotherapy, hormonal therapy, radiotherapy, and
`limited surgery are all used in the treatment of wom-
`en with metastatic breast cancer,°” although the
`overwhelming majority of these women will die of
`their disease.68 Therefore, optimal palliation and pro-
`longation oflife are the main goals of treatment. It
`is important to useall available treatments to obtain
`maximal control of symptoms, prevent serious com-
`plications, and prolong life with minimal disruption
`of the woman’s lifestyle and quality oflife (Fig. 2).
`
`Diagnosis
`
`Frequent testing to identify recurrences and me-
`tastases in orderto institute aggressive treatment has
`not altered the clinical course of women with meta-
`
`
`
`TABLE 4. SELECTION OF ADJUVANT SYSTEMIC THERAPY FOR WOMEN WITH OPERABLE
`PRIMARY BREAST CANCER AND INDICATIONS FOR ADJUVANT TREATMENT.
`
`CHARACTERISTICS OF PATIENT AND TUMOR
`ESTROGEN-RECEPTOR
`STATUS
`
`AGE
`
`Levet oF Risk
`
`ADJUVANT SYSTEMIC THERAPY*
`
`
`
`<50 yr
`
`Negative
`Positive
`
`Any
`Low
`
`Positive
`
`Moderate or high
`
`250 yr
`
`Unknown
`Negative
`Positive
`
`Any
`Any
`Low
`
`Positive
`
`Moderate or high
`
`Chemotherapy
`Hormonal therapy
`or
`Chemotherapy
`or
`Chemotherapy and hormonal therapy
`Chemotherapy and hormonal therapy
`or
`Investigational therapies
`Chemotherapy and hormonal therapy
`Chemotherapy
`Tamoxifen
`or
`Chemotherapy and hormonal therapy
`Chemotherapy and hormonal therapy
`or
`Investigational therapies
`Unknown Chemotherapy and hormonal therapy Any
`
`
`
`
`
`*Chemotherapy consists of fluorouracil, doxorubicin, and cyclophosphamide (FAC); doxorubicin
`and cyclophosphamide (AC); or cyclophosphamide, methotrexate, and fluorouracil (CMF). Hormonal
`therapy consists of tamoxifen or ovarian ablation (either surgical or chemical).
`
`978
`
`- October 1, 1998
`
`The New England Journal of Medicine
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`DRUG THERAPY
`
`Diagnosis of metastatic breast cancer
`
`Determination of site and extent of disease
`Assessment of hormone-receptor status,
`disease-free interval, age, and menopausal status
`
`Hormone-responsive disease
`No life-threatening disease
`
`Hormone-unresponsive or
`life-threatening disease
`
`First-line hormonal therapy
`
`First-line chemotherapy
`
`No progression
`of disease
`
`Progression
`of disease
`
`
`
`Second-line hormonal therapy
`
`No progression
`of disease
`
`Progression
`of disease
`
`Second-line chemotherapy
`
`No progression
`of disease
`
`Progression
`
`
`
`
`of disease Third-line chemotherapy
` women with limited and non-—life-threatening dis-
`
`Response
`
`No response
`
`Progression
`of disease
`
`No progression
`of disease
`
`Third-line hormonal therapy
`
`Response
`
`No response
`
`Figure 2. Optimal Palliative Therapy for Women with Metastatic Breast Cancer.
`
`static breast cancer. Most recurrences or metastases
`are diagnosed on the basis of symptoms and physical
`findings, and extensive biochemical testing or imag-
`ing contributes little.%%7° Guidelines for surveillance
`of asymptomatic women are shown in Table 5.71
`Treatment
`
`Once metastatic breast cancer becomes evident, it
`is appropriate to determine the extent and location of
`metastases. An overall therapeutic strategy is then
`developed on the basis of age, disease-free interval,
`hormone-receptor status, and extent of disease. For
`
`ease, especially those who have no symptoms,are eld-
`erly, or have estrogen-receptor—positive tumors, hor-
`monal therapy is the initial treatment of choice (Fig.
`2).°672 There has been a quiet revolution in hormonal
`therapy. Ablative endocrine procedures have been re-
`placed by specific, well-tolerated hormonal treatments
`(antiestrogens, aromatase inhibitors, gonadotropin-
`releasing—hormone analogues, and progestins) (Table
`6). Women who have a response to one hormonalin-
`tervention often have a response to a secondafter the
`first becomes ineffective.”2 Some women may thus
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`
`TABLE 5. GUIDELINES FOR SURVEILLANCE OF WOMEN WITH CPERABLE BREAST CANCER
`AFTER THE COMPLETION OF PRIMARY TREATMENT.*
`
`PROCEDURE
`
`FREQUENCY
`
`Education of patient about symptomsand signs
`of recurrence
`History and physical examination
`
`At the completion of therapy and as needed
`
`Every 3 to 6 monthsforthefirst 3 years, every
`6 to 12 months for the next 2 years, then
`annually
`Monthly
`
`Breast self-examination
`Mammography
`Contralateral
`Ipsilateral (remaining breast after lumpectomy)
`Other recommended cancer-screening procedurest
`Complete blood count, automated blood-chemistry
`studies, assays for serum tumor markers (carcino-
`embryonic antigen, CA2729, CA15-3)
`Not recommended
`Radionuclide bone scanning; imaging of the chest,
`abdomen,pelvis, or brain
`
`
`Annually
`Annually
`Annually or every 2 years
`Not recommended
`
`* Guidelines are from the American Society of Clinical Oncology?!
`t Other recommended procedures are pelvic examination with Pap smear, rectal examination, fecal
`occult- blood testing, and examination of the skin.
`
`benefit from three or four hormonal therapies in se-
`quence and have a good quality of life with minimal
`symptomsand side effects for several years. Twenty
`to 35 percent of women with metastatic breast can-
`cer have an objective response to the initial hormonal
`therapy.”278 For second-line hormonal treatment of
`women with receptor-positive tumors, the probability
`of an objective response ranges from 10 percent to
`20 percent,” and another 15 to 30 percent of women
`may have stable disease for six months or longer. Ta-
`ble 6 describes the preferred sequence of current
`hormonal options.
`Eventually, in most women, metastatic breast can-
`cer becomes refractory to hormonal treatment, at
`which time the women should receive chemotherapy
`(CMEor FAC). Fifty to 80 percent of women have
`an objective response to FAC, and 40 to 60 percent
`have an objective response to CME’5 Both regimens
`provide substantial palliation with tolerable levels of
`
`
`
`TABLE 6. HORMONAL THERAPIES FOR WOMEN WITH
`METASTATIC BREAST CANCER.
`
`ORDER OF
`THERAPY
`
`First line
`
`Second line
`
`PREMENOPAUSAL WOMEN
`
`PosTMENOPAUSAL WOMEN
`
`Antiestrogens or ovarian ablation Antiestrogens
`(chemical, surgical, or postradi-
`ation)
`Ovarian ablation after antiestro-
`gens; antiestrogensafter ovarian
`ablation
`
`Aromatase inhibitors
`
`Progestins
`Progestins
`Third line
`
`Fourth line Androgens Androgensor estrogens
`
`980
`
`October 1, 1998
`
`
`
`toxicity. In a recent meta-analysis of randomizedtrials,
`anthracycline-containing combinations were superi-
`or to CME”In the past 10 years, several new drugs
`have becomeavailable for the management of breast
`cancer (Table 7).o267 Among these, vinorelbine, a
`third-generation vinca alkaloid,7”? and the taxanes
`(paclitaxel and docetaxel)’8 are the most prominent.
`Vinorelbine, paclitaxel, and docetaxel given alonere-
`sult in responserates similar to those associated with
`CMFasfirst-line treatment. Combinations of tax-
`anes and anthracyclines result in responses in 40 to
`94 percent of women in first-line treatment and
`complete remissions in 12 to 41 percent.”? The du-
`rations of remission and times to progression after
`treatment with doxorubicin—paclitaxel or doxorubi-
`cin—docetaxel combinations are similar to those af-
`ter therapy with CMF or FAC.
`The approach to metastatic breast cancer that pro-
`gresses after hormonaltherapy followed byfirst-line
`chemotherapy is changing rapidly.8°8? Today,
`the
`taxanes and vinorelbine are the second-line and third-
`line treatments of choice, respectively, and we know
`that taxane-containing salvage regimens improve over-
`all survival.882 Another area of progress has been
`the treatment of anthracycline-resistant breast can-
`cer, defined as disease that progresses during treat-
`ment with a regimen containing an anthracycline
`(doxorubicin or a related drug). Before taxanes be-
`cameavailable, the response rates in women with tu-
`mors resistant to anthracyclines (as second-line or
`third-line treatment) were less than 10 percent, and
`their overall survival was less than six months. Now,
`with the availability of taxanes, the response rates in
`these women range from 30 percent to 40 percent
`and survival for 10 to 12 months is customary.81:84.84
`
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`DRUG THERAPY
`
`
`
`TABLE 7. NEW AGENTS FOR SYSTEMIC THERAPY IN WOMEN
`WITH METASTATIC BREAST CANCER.*
`
`AGENT
`
`STAGE OF CLINICAL DEVELOPMENT
`
`RESPONSE
`RATE
`
`%
`
`Hormonal
`Antiestrogens
`Commercially available
`Toremifene (Fareston)
`Approved by the FDA for osteoporosis;
`Raloxifene (Evista)
`in phase3trials
`Idoxifene
`In phase 3 trials for metastatic breast cancer
`Faslodex (ICI 182,780)
`In phase 3 trials for metastatic breast cancer
`Aromatase inhibitors
`Formestane
`Anastrozole (Arimidex)
`Letrozole (Femara)
`Vorozole
`Exemestane
`Cytotoxic
`Anthrapyrazoles
`Losoxantrone
`Anthracyclines
`Liposomal doxorubicin (D 99)
`Purine analogues
`Gemcitabine (Gemzar)
`Taxanes
`Docetaxel (Taxotere)
`
`Commercially available in Europe
`Commercially available; in phase 3 trials
`Commercially available; in phase 3 trials
`In phase 3 trials for metastatic breast cancer
`In phase 3 trials for metastatic breast cancer
`
`In phase 3 trials for metastatic breast cancer
`
`In phase 3 trials for metastatic breast cancer
`
`Commercially available for pancreatic cancer; in
`phase 3 trials for metastatic breast cancer
`
`Commercially available; in phase 3 trials as adjuvant
`therapy and for metastatic breast cancer
`Commercially available; in phase 3 trials as adjuvant
`therapy and for metastatic breast cancer
`
`Commercially available; in phase 3 trials for
`metastatic breast cancer
`In phase 3 trials for metastatic breast cancer
`In phase 3 trials for metastatic breast cancer
`
`19-54
`
`12-39
`
`18-63
`
`18-33
`
`25-46
`
`13-68
`
`20-36
`
`18-52
`
`Paclitaxel (Taxol)
`
`Thymidylate synthase inhibitors
`Capecitabine
`
`Raltitrexed (Tomudex)
`UFT
`Vinca alkaloids
`Vinorelbine (Navelbine)
`
`Commercially available for lung cancer; in phase 3
`trials as adjuvant therapy and for metastatic breast
`cancer
`
`
`*FDA denotes Food and Drug Administration, and UFT uracil—ftorafur.
`
`Bone is the most commonsite of metastases in
`breast cancer, and bone metastases are the cause of
`substantial morbidity and complications. Bisphos-
`phonates (pamidronate and clodronate [clodronic ac-
`id]) added to chemotherapy or hormonal therapyre-
`duce pain and the incidence of complications, and
`they prolong survival free of bone-related events.®
`
`High-Dose Chemotherapy
`
`The development of techniques to harvest, store,
`and reinfuse autologous hematopoietic stem cells and
`the availability of hematopoietic growth factors have
`allowed the evaluation of very-high-dose chemothera-
`peutic regimens (given at doses 2 to 20 times as high
`as standard doses).8687 Two types of high-dose regi-
`mens have been studied. In one, a single cycle of a
`high-dose combination of cytotoxic drugs (usua