`The New England Iournal of Medicine
`
`
`
`
`
`Review Article
`
`Drug Therapy
`
`ALASTAIR 1.}. WOOD, M.D., Editor
`
`TREATMENT OF BREAST CANCER
`
`GABRIEL N. HORTOBAGYI, M.D.
`
`REAST cancer is a major public health prob—
`lem worldwide. Management of breast cancer
`was last 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 make it 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.2)3 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.3 Similar decreases in mortality were recently
`reported in Sweden and the United Kingdomfl)5
`The incidence of breast cancer increases with age,
`although the rate 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)9 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.”13 About 5 to 10
`percent of all 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.12
`
`BIOLOGY
`
`The recent identification and cloning of BRCA1
`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 I, 1998
`
`breast cancer.14)15 Germ—line mutations in these two
`
`genes are associated with a 50 to 85 percent lifetime
`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.16 All breast cancers
`have somatic genetic abnormalities. In sporadic breast
`cancer, abnormalities have been identified in several
`genes (including 1753, bcl-Z, c-myc, and c-myb),1Z18
`and in some cancers normal genes or gene products
`(HER—Z/nm and cyclin D1) are overexpressed. How—
`ever, the number and types of mutations necessary
`for the development of sporadic breast cancer are not
`known.
`
`Many factors 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 a and fl,
`and insulin—like growth factors I and II), and vari—
`ous cytokines and lymphokines influence 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.20 The recognition that these factors influence
`the growth and dissemination of breast cancer has
`provided new targets for therapeutic and preventive
`intervention.”23 Breast cancer also induces neo—
`
`vascularization, which, in turn, facilitates the meta—
`static process.23 Metastatic spread is not a random
`mechanical phenomenon but requires systematic in—
`teraction among breast 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 women over the age of
`50 years (Table I)25 and probably also in women be—
`tween the ages of 40 and 50 years.26 The American
`Cancer Society and the National Cancer Institute rec—
`ommend annual screening mammography for wom—
`en older than 40 years who have a standard risk of
`breast cancer.26)27 In women from high—risk families,
`
`
`
`The New England Journal of Medicine
`Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on December 5, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
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`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`
`

`

`DRUG THERAPY
`
`
`
`TABLE 1. BENEFIT OF SCREENING MAMMOGRAPHY
`ACCORDING TO AGE.*
`
`STUDY
`
`DURATION OF
`FOLLOW-UP
`
`SCREENING
`INTERVAL
`
`RELATIVE RISK OF DEATH
`FROM CANCER
`(95% CDT
`
`AGE
`50774 YR
`
`AGE
`40749 YR
`
`yr
`
`10
`12
`12
`12
`7
`10
`
`mo
`
`24
`18724
`24733
`24733
`12
`12
`
`Edinburgh
`Malmo
`Kopparberg
`Ostergotland
`Canada
`Health Insurance
`Plan
`
`0.8 (0671.1) 0.8 (0.5715)
`0.9 (0671.2) 0.5 (0271.2)
`0.8 (0570.9) 0.8 (0471.4)
`0.8 (0671.0)
`1.3 (0.8723)
`1.0 (0.6715)
`1.4 (0872.2)
`0.7 (0571.0) 0.8 (0571.2)
`
`1.0 (0572.0)
`0.6 (0471.1)
`28
`8
`Stockholm
`0.9 (0571.6) 0.7 (0372.0)
`18
`7
`Gothenburg
`
`Overall 0.8 (0770.9) 0.9 (0871.1) 7 7
`
`
`
`*Data are modified from Tables 2 and 3 in Kerlikowske et al.,25 with the
`permission of the publisher.
`TRelative risks are for women who underwent mammographic screening
`as compared with those who did not. C1 denotes confidence interval.
`
`especially those with BRCAI or BRCAZ 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.28)29
`Twenty years ago, incisional or excisional biopsies
`were the standard methods for confirming the diag—
`nosis; today, fine—needle aspiration30 or core needle
`biopsy31 is the standard. Ultrasound— guided core nee—
`dle biopsy, stereotactic biopsy,32 and magnetic reso—
`nanceidirected biopsy have become important dir
`agnostic tools, especially for women with suspicious
`but nonpalpable breast masses. The use of large—core
`needle—biopsy techniques increases the pathologist’s
`ability to characterize the lesion.33
`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.37 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 women with 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,39 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.40 Noninvasive (in situ) ductal and lobular
`breast cancer can also be treated adequately with
`lumpectomy and radiotherapyfllfl2
`
`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,43 and it 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 dye is 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 node that has taken
`up the dye or radioactive substance (i.e., the senti—
`nel node) is excised.44 If it is histologically negative,
`the rest of the axillary lymph nodes are 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—
`center trial.45 The positive predictive value of a suc—
`cessful sentinel—node biopsy approaches 100 per—
`cent, whereas its negative predictive value exceeds
`95 percent.44A5 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
`tumor for nuclear or histologic grade, kinetics of cell
`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 Iournal of Medicine
`
`Study
`
`IGR
`
`Milan
`
`NSABP
`
`NCI
`
`EORTC
`
`Pooled
`data
`
`
`
`0.0
`
`Favors Breast-
`Conserving Therapy
`
`1.0
`0.5
`1.5
`4— —>
`Odds Ratio
`
`2.0
`
`2.5
`
`Favors
`Mastectomy
`
`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,35 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).
`
`Radiotherapy
`
`Radiotherapy is an integral part of breast—conserv—
`ing treatment?“8 A recent randomized trial showed
`that administering chemotherapy before radiotherapy
`resulted in higher survival rates when both chemo—
`therapy and radiotherapy were given postoperativelyfl6
`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.“50 For that reason and
`because of its 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).“52 These results have re—
`newed interest in postmastectomy radiotherapy.
`
`
`
`976
`
`~ October 1, 1998
`
`
`
`TABLE 2. TENeYEAR CANCERaFREE 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 Columbia51
`Cancer, free survival
`Overall survival
`Danish Breast Cancer
`Cooperative Group52
`<0.001
`48
`34
`Cancerefree survival
`<0.001
`54
`45
`Overall survival
`
`4 1
`54
`
`5 6
`64
`
`0.007
`0.07
`
`318
`
`1708
`
`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.53'56 Current knowledge is based on about
`400 trials including more than 220,000 women.
`Hormonal therapy and chemotherapy added to local
`
`The New England Journal of Medicine
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`

`DRUG THERAPY
`
`treatment favorably 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
`some the benefit is marginal. The indications for sys—
`temic adjuvant therapy are shown in Table 3.
`For adjuvant therapy, combination chemotherapy is
`more effective than single—drug therapy, reducing the
`annual risk of death by about 20 percent.53 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 about five years,
`rather than one to three years, and when it is given
`to women with estrogen—receptor—positive tumors.54
`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.57
`
`Preoperative Chemotherapy
`
`Chemotherapy is 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—
`ports5358 have indicated that close to 90 percent of
`primary operable tumors decrease in size by more
`than 50 percent after chemotherapy,
`thus making
`lumpectomy a possibility for many women who would
`
`
`
`otherwise have required a mastectomy. In terms of
`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 was inferior to treatment for four
`
`to six months, whereas treatment with a single com—
`bination—chemotherapy regimen, such as cyclophos—
`phamide, methotrexate, and fiuorouracil (CMF), for
`longer than six months was no more effective than
`treatment for four to six months.535559 The combi—
`
`nations used most often are fiuorouracil, doxorubicin,
`and cyclophosphamide (FAC); fluorouracil, epirubi—
`cin, and cyclophosphamide (FEC); doxorubicin and
`cyclophosphamide (AC); and CMF. 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.60 In premenopausal women, ovarian
`ablation has a substantial benefit, equivalent to that
`of combination chemotherapy or tamoxifen.53)56 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.53555659 Therefore,
`
`
`
`TABLE 3. INDICATIONS FOR ADIUVANT SYSTEMIC THERAPY AFTER SURGERY IN WOMEN
`WITH OPERABLE BREAST CANCER.
`
`TYPE OF DISEASE
`
`ADJUVANT THERAPY |NDIcATED*
`
`None
`
`Breast cancer without evidence Of invasion
`Noninvasive breast cancer (ductal or lObular carcinoma in 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 21 cm in largest
`diameter
`Invasive carcinoma 23 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
`
`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
`Hormonal
`therapy consists Of tamoxifen or ovarian ablation (either surgical or chemical).
`
`The New England Journal of Medicine
`Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on December 5, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`Volume 339 Number 14
`
`~
`
`977
`
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`

`The New England Iournal of Medicine
`
`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 randomized trials should help to determine the
`efficacy of high—dose regimens and new therapeutic
`agents as curative treatments in breast cancerfil)62
`
`Locally Advanced and Inflammatory 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.63)64 In more than 65 percent
`of such women, the tumors shrink by more than 50
`
`
`
`percent with preoperative chemotherapy. Most previ—
`ously inoperable tumors become operable, and some
`become amenable to breast—conserving therapy.64
`Limited data suggest that adjuvant chemotherapy and
`hormonal
`therapy are indicated after preoperative
`chemotherapy and regional treatment.65 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.63)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 of life are the main goals of treatment. It
`is important to use all 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 of life (Fig. 2).
`
`Diagnosis
`
`Frequent testing to identify recurrences and me—
`tastases in order to institute aggressive treatment has
`not altered the clinical course of women with meta—
`
`
`
`TABLE 4. SELECTION OF ADIUVANT SYSTEMIC THERAPY FOR WOMEN WITH OPERABLE
`PRIMARY BREAST CANCER AND INDICATIONS FOR ADIUVANT TREATMENT.
`
`CHARACTERISTICS OF PATIENT AND TUMOR
`ESTROGENERECEIYTOR
`STATUS
`
`AGE
`
`LEVEL 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
`
`ChemOtTerapy
`Hormonal therapy
`or
`ChemOtTerapy
`or
`Chemotherapy and Tormonal therapy
`Chemotherapy and Tormonal therapy
`or
`Investigational therapies
`Chemotherapy and Tormonal therapy
`ChemOtTerapy
`Tamoxifen
`or
`Chemotherapy and Tormonal therapy
`Chemotherapy and Tormonal therapy
`or
`Investigational therapies
`AnyUnknown Chemotherapy and Tormonal therapy
`
`
`
`
`
`
`
`*Chemotherapy consists Of fluorouracil, doxorubicin, and cyclophosphamide (FAC); doxorubicin
`and cyclophosphamide (AC); or cyclophosphamide, methotrexate, and fluorouracil
`Hormonal
`therapy consists Of tamoxifen or ovarian ablation (either surgical or chemical).
`
`978
`
`~ October 1, 1998
`
`The New England Journal of MediCine
`Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on DeCember 5, 2014. For personal use only. No other uses without permission.
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`
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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
`
`Fi rst—line chemotherapy
`
`No progression
`of disease
`
`Progression
`of disease
`
`No progression
`of disease
`
`Progression
`of disease
`
`
`
`Second—line hormonal therapy
`
`Progression
`of disease
`
`No progression
`of disease
`
` Third—line hormonal therapy
`
`
`
`Second—line chemotherapy
`
`No progression
`of disease
`
`Progression
`
`of disease Third—line chemotherapy
`
`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.69)70 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
`
`women with limited and non—life—threatening dis—
`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)}5672 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 hormonal in—
`tervention often have a response to a second after the
`first becomes ineffective.72 Some women may thus
`
`The New England Journal of Medicine
`Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on December 5, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`Volume 339 Number 14
`
`~
`
`979
`
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`

`

`
`The New England Iournal of Medicine
`
`
`
`TABLE 5. GUIDELINES FOR SURVEILLANCE OF WOMEN WITH OPERABLE BREAST CANCER
`AFTER THE COMPLETION OF PRIMARY TREATMENT.*
`
`PROCEDURE
`
`FREQUENCY
`
`Education of patient about symptoms and signs
`of recurrence
`History and physical examination
`
`At the completion of therapy and as needed
`
`Every 3 to 6 months for the first 3 years, every
`6 to 12 months for the next 2 years, then
`annually
`Monthly
`
`Breast selfaexamination
`Mammography
`Contralateral
`1psilateral (remaining breast after lumpectomy)
`Other recommended cancerascreening proceduresT
`Complete blood count, automated bloodachemistry
`studies, assays for serum tumor markers (carcinoa
`embryonic antigen, CA2729, CA1573)
`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.71
`TOther recommended procedures are pelvic examination with Pap smear, rectal examination, fecal
`occultablood 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
`symptoms and 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?”3 For second—line hormonal treatment of
`women with receptor—positive tumors, the probability
`of an Objective response ranges from 10 percent to
`20 percent,74 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
`(CMF or FAC). Fifty to 80 percent of women have
`an Objective response to FAC, and 40 to 60 percent
`have an Objective response to CMF.75 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 postradia
`anon)
`Ovarian ablation after antiestroa
`gens; antiestrogens after ovarian
`ablation
`
`Aromatase inhibitors
`
`Progestins
`Progestins
`Third line
`
`Fourth line Androgens Androgens or estrogens
`
`
`
`toxicity. In a recent meta—analysis of randomized trials,
`anthracycline—containing combinations were superi—
`or tO CMF.76 1n the past 10 years, several new drugs
`have become available for the management of breast
`cancer (Table 7).62)67 Among these, vinorelbine, a
`third—generation vinca alkaloid,77 and the taxanes
`(paclitaxel and docetaxel)78 are the most prominent.
`Vinorelbine, paclitaxel, and docetaxel given alone re—
`sult in response rates similar to those associated with
`CMF as first—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.79 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 hormonal therapy followed by first—line
`chemotherapy is changing rapidly.”82 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.81)82 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—
`came available, 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)83)84
`
`980
`
`October 1, 1998
`
`The New England Journal of Medicine
`Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on December 5, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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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
`
`%
`
`19754
`
`127 39
`
`18 7 63
`
`18 7 3 3
`
`25746
`
`13768
`
`20 7 36
`
`18752
`
`Hormonal
`Antiestrogens
`Toremifene (Fareston)
`Raloxifene (Evista)
`
`Idoxifene
`Faslodex (ICI 182,780)
`Aromatase inhibitors
`Formestane
`Anastrozole (Arimidex)
`Letrozole (Femara)
`Vorozole
`Exemesmne
`Cytotoxic
`Anthrapyrazoles
`Losoxantrone
`Anthracyclines
`Liposomal doxorubicin (D 99)
`Purine analogues
`Gemcitabine (Gemzar)
`Taxanes
`Docetaxel (Taxotere)
`
`Paclitaxel (Taxol)
`
`Thymidylate synthase inhibitors
`Capecitabine
`
`Raltitrexed (Tomudex)
`UFT
`Vinca alkaloids
`Vinorelbine (Navelbine)
`
`Commercially available
`Approved by the FDA for osteoporosis;
`in phase 3 trials
`In phase 3 trials for metastatic breast cancer
`In phase 3 trials for metastatic breast cancer
`
`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
`
`Commercially available for lung cancer; in phase 3
`trials as adjuvant therapy and for metastatic breast
`CQHCCI'
`
`
`*FDA denotes Food and Drug Administration, and UFT uracil7ftorafur.
`
`Bone is the most common site 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 therapy re—
`duce pain and the incidence of complications, and
`they prolong survival free of bone—related events.85
`
`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).86)87 Two types of high—dose regi—
`mens have been studied. In one, a single cycle of a
`high—dose combination of cytotoxic drugs (