Breast cancer

BREAST

CANCER

ABSTRACT.-Breast cancer will affect 1 out of 10 women in the United States and cause 27 deaths per 100,000 women per year. The etiology remains unknown, but the incidence correlates with genetic as well as environmental factors. Screening programs have been shown to prolong the survival by early detection compared with control populations but remain underutilized by physicians and patients. Breast disease can be evaluated by physical examination and mammography and a definitive diagnosis made by needle aspiration, needle biopsy, or excisional biopsy. This allows the patient to participate in the decision regarding mastectomy vs. conservative surgery plus radiation therapy. These two approaches have equivalent survival in selected patients. Patients with locally advanced, nonmetastatic disease benefit from a multidisciplinary approach using preoperative chemotherapy and postoperative radiation therapy. This approach has allowed less disfiguring surgery and improved survival. Preinvasive carcinoma is diagnosed more frequently with the increased use of screening mammography. Local therapy options include simple mastectomy, local excision plus radiation, or local excision alone. The natural history and results of therapy in preinvasive disease are evolving as more data are accumulated. Systemic adjuvant therapy is recommended for all node-positive patients and most nodenegative patients with invasive cancer. The specific modality (hormonal or cytotoxic) varies with the subgroup involved. Treatment of metastatic disease to palliate symptoms and prolong survival includes the use of local therapies (surgery and radiation) and hormonal and cytotoxic agents. Most patients benefit, but cure has been unobtainable. Newer approaches utilizing high-dose chemotherapy and bone marrow supDM,

Febmry1990

67

port with growth tion are currently

factors or autologous being explored.

transplanta-

IN BRIEF Breast cancer deaths in the United States are estimated at 42,~~ per year. One out of 10 U.S. women develops breast cancer. The resources required to diagnose and treat breast cancer are enormous, especially when screening programs and breast biopsies are taken into account. The management of the disease requires expertise from radiologists, surgeons, orthopedic surgeons, neurosurgeons, radiotherapists, and medical oncologists. Risk factors for the development of breast cancer include family history, reproductive history, nutrition and body size, benign breast disease, ionizing radiation, alcohol, and other malignancies. A familial type of breast cancer with an autosomal dominant type of inheritance does exist. Oncogenes have been found in breast cancer specimens. Their role in carcinogenesis, prognosis, and response to therapy is currently unknown. Because the presence of these genes in other malignancies has been of great importance, further study is warranted. Hormone receptors, particularly estrogen receptor protein (ERPI and progesterone receptor protein (PRP), have been studied in breast cancer and are now routinely measured. These measurements have prognostic and therapeutic implications. Newer growth factors such as epidermal growth factor IEGF), transforming growth factor 01 (TGF+x) and transforming growth factor p (TGF-j3) have been studied in tissue culture of breast cancer cell lines. Screening programs for breast cancer are illustrated by the Health Insurance Plan of Greater New York (HIP) programs and the Breast Cancer Detection Demonstration Project (BCDDP). These projects demonstrated that earlier detection and improved survival could be achieved by breast self-examination (BSE), physical examination by a physician, and mammography. Screening programs are underutilized, however, due to inadequate physician support, reimbursement by insurance companies, and education of the public, particularly the socioeconomically disadvantaged. Breast disease due to benign or malignant conditions can manifest itself as pain or a mass. Breast biopsy is indicated for a mammographic abnormality suggesting a malignancy or for a solid mass on physical examination. Biopsy techniques include fine needle aspiration (FNA), needle core, needle localization, and excisional or incisional biopsy. Pathologically most breast cancers are duct cell carcinomas, whereas a minority are lobular carcinomas. Both histologies may 68

DM,

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1990

present as noninvasive lesions: duct cell carcinoma in situ or lobular carcinoma in situ. Pathologic factors that influence prognosis include histology presence of necrosis, lymphatic or vascular invasion, nuclear grade, hormonal receptor status, proliferative index, and the amount of aneuploidy. Inflammatory breast cancer and Paget’s disease of the breast represent special conditions. Inflammatory breast cancer is characterized by erythematous, edematous skin changes caused pathologically by intradermal lymphatic obstruction by carcinoma. It is a form of advanced local disease and usually has early systemic spread. Paget’s disease is characterized by nipple scaling or erosion and is associated with an underlying ductal malignancy. Staging is done for prognostic reasons and to allow comparisons in clinical studies and takes into account clinical as well as pathologic findings. The tumor, nodal, and distant metastases (TNM) system employed by the American Joint Committee on Cancer &ICC) and the International Union Against Cancer (UICC) allows for stage groupings 0 through IV, which correlate with survival. Local and regional therapy for breast cancer uses surgical and radiation therapy to abolish cancer in the breast, on the chest wall, or in the regional lymphatics. The surgical options include mastectomy with or without axillary nodal dissection or conservative surgery (lumpectomy, quadrantectomy, partial mastectomy) with or without axillary dissection and with or without radiation therapy. Conservative surgery with radiation therapy has been shown to provide survival equivalent to modified radical mastectomy in selected patient groups. For larger cancers, modified radical mastectomy is the standard procedure. Advanced cancers can best be managed with a multidisciplinary approach using preoperative chemotherapy and postoperative radiation therapy. Treatment for preinvasive carcinomas includes excision, excision plus radiation, and simple mastectomy. No standard approach for noninvasive breast cancer has developed at this time. Adjuvant radiation given after modified radical mastectomy has not been shown to increase survival but does improve local control. In patients at high risk for local recurrence, it should be considered. Adjuvant systemic therapy is indicated for almost all node-positive and many node-negative patients. Controversy surrounds the use and type of therapy in node-positive postmenopausal groups where survival has not been clearly shown to be influenced by therapy. Aggressive lesions in the node-negative group benefit from chemotherapy. Small favorable lesions with negative nodes remain an unknown and are the subject of current investigations. The type of chemotherapy given and durations longer than 6 months do not seem critical. fiehabilitation and reconstruction are extremely important and should be addressed from the time of diagnosis. Immediate or early DA4,Febmary1990

69

reconstruction is increasingly accepted because it does not hinder follow-up care. Rehabilitation, both physical and psychologic, requires time but is best initiated early. Therapy for metastatic cancer can improve symptoms and prolong life. It involves the use of hormonal manipulations, cytotoxic agents, and radiation therapy based on sites of metastases, menopausal status of the patient, presence or absence of hormone receptors in the cancer, and previous therapy. Cure is not usually achievable. New approaches are taking advantage of the use of bone marrow growth factors or autologous marrow support to allow highdose therapy and may provide cures.

70

D~,Februwy

1990

\ /’ &

Lc

1

Laura F. Hutchins, M.D., graduated from the University of Arkansas for Medical Sciences &JAMS) in 1977. She did a residency in internal medicine and a s-year fellowship in hematology/oncology at UAnilS. She is currently an Associate Professor of Medicine in the Division of Hematology/ Oncology at the University of Arkansas for Medical Sciences in Little Rock, Arkansas.

Ralph Broadwater, Jr., M.D., is Assistant Professor of Surgery at the University qf Arkansas for Medical Sciences in Little Rock, Arkansas. He completed medical school and his general surgery residency at the University of Arkansas for Medical Sciences. He completed a Z-year surgicaloncolony fellowship at the University of Texas M.D. Anderson Cancer Center in Houston, Texas in 1988.

Nicholas P. Lang, M.D., began his medical education at the University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas. Afrer graduating from UAMS, he did a general surgery residency at University Hospital, Little Rock. Following a fellowship at the National Cancer Institute, he returned to the Department of Surgery at LAMS where he is Associate Professor of Surgery, Director of Surgical Endoscopy, and Associate Program Director for the Surgical Residency.

Ann Maners, M.D., is an Assistant Professor in the Division of Radiation Oncology at the University of Arkansas for Medical Sciences. Her clinical practice is based at the Central Arkansas Radiation Therapy Institute. Dr. Maners completed her graduate and postgraduate medical training at the Medical University of South Carolina. DM,

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Marinelle Bowie, B.S.N., R.N.P., O.C.N., received her B.S.N. degree at the University of Arkansas College of Nursing in 1972. At the University of Arkansas for Medical Sciences (UAMS) she was Head Nurse on a general surgery unit. Since 1975, she has been an Oncology Nurse Practitioner in Surgical Oncology at UAMS, working primarily with breast cancer. Ms. Bowie is currently the Associate Director of Nursing at the Arkansas Cancer Research Center.

Kent C. Westbrook, M.D., graduated from the University of Arkansas College of Medicine in 19ti5. He did a residency at the University of Arkansas and then a 2-year fellowship in surgical oncology at M.D. Anderson Hospital and Tumor Institute in Houston, Texas. He has been on the faculty at the University of Arkansas since 1972 and is currently Professor of Surgery, Associate Dean of the College of Medicine, and Director of the Arkansas Cancer Research Center. 72

LAW, February

1990

BFWAST

EXTENT

CANCEK

OF PROBLEM

Nearly every woman in America will, at some time, think that she has breast cancer. The breast, being under hormonal control, undergoes continuous changes throughout the life of a woman. Frequently, these changes result in localized alterations in the consistency of the breast. Any “lump” represents a potential cancer. In addition, the extensive public education on breast cancer and improved screening have heightened public awareness. Screening mammography is being done on a wider basis, and women receive letters stating, “An abnormality has been detected on your mammogram. You should contact your physician immediately.” Patients usually interpret this to read, “You have breast cancer and will be dead within a year.” The increased awareness of the incidence of breast cancer, the frequency of physical abnormalities in the breast, and the sensitivity of screening mammography all have combined to make every woman aware of her personal risk of developing breast cancer. In 1989, there will be about 140,000 new cases of breast cancer in women and about 1,200 new cases of breast cancer in men in the United States. Breast cancer is the most common malignancy in women, excluding skin cancer. The mortality from breast cancer has changed little over the last 40 years. The death rate has hovered at about 27 deaths per 100,000 women per year, producing approximately 42,000 deaths in 1989. Breast cancer is the second most common cause of cancer deaths in women, having been surpassed by lung cancer in 1987. The total cost of the care of women with breast cancer in our society is enormous in terms of time, effort, and money. About 1 million breast biopsies are done annually to discover the 140,000 new cases of breast cancer. Nearly all of the 140,000 new cases will require surgery or surgery plus radiotherapy for local control. More than 100,000 women will receive adjuvant systemic treatment in 1989. Probably 50,000 patients will relapse with metastatic disease in 1989. Nearly all of these will die of their cancer. The treatment of breast cancer involves most medical specialties. 1244, rebnmy1990

73

Primary care physicians are usually involved in the early recognition. Radiologists facilitate detection and staging, surgeons are involved in diagnosis and treatment, radiation therapists provide treatment, and medical oncologists provide adjuvant treatment and coordinate the overall treatment plan. Many other specialists, such as neurosurgeons and orthopedic surgeons, are involved in the management of disseminated disease. Hence, in any medical center, the management of breast cancer involves many specialists working together in an effort to provide early detection, proper treatment of primary disease, and optimal treatment of systemic disease. BIOLOGY ETIOLOGY

The cause of breast cancer is multifactorial.l-” Known predisposing factors are summarized in Table 1 and include family history,4-6 reproductive history,7’ ’ nutrition and body size,g-ll benign breast disease,l” I3 ionizing radiation,14, I5 alcohol,1”-18 and other malignancies.’ Women with first-degree relatives with breast cancer may have a twofold to threefold excess risk. The number of first-degree

TABLE

1.

Predisposing Increased

Factors

to Breast

Risk

First-degree family Early menarche Late menopause

Decreased

Not Associated Increased Risk

Risk

history

Nulliparity First pregnancy after 35 yr High fat diet Obesity Proliferative benign breast disease _ Ionizing radiation Alcohol EndometrialJ ovarian, 01 colon cancer

74

Cancer

Late menarche Early menopause castration Early first term

or pregnancy

? Low fat diet Ideal body weight

No alcohol

-

Cigarette smoking Augmentation mammaplasty Blood pressure medication Caffeine

DM,

February1990

With

relatives, young age at diagnosis, and bilateral disease increase the risk of cancer. Second-degree relatives are at the same risk as the general population6, ls A familial type of breast cancer exists that appears to have an autosomal dominant pattern of inheritanceP Care must be taken in labeling families as having the autosomal dominant type of familial breast cancer since the nonautosomal dominant disease is so common, and families tend to share common environmental factors resulting in clustering of cases. The incidence of breast cancer seems to correlate with the lifetime number of menstrual cycles and increases in women with long menstrual histories. Nulliparous women are at greater risk than multiparous women, and women with more than four pregnancies carried for more than 6 months have less risk than women with fewer than four pregnancies. Term pregnancy at a younger age decreases the risk of breast cancer, but a first pregnancy at age 35 years or older is associated with a higher risk of breast cancer than the nulliparous state.7 Early menarche, late menopause, and no pregnancies increase the risk, whereas early castration decreases the risk.’ Estrogen levels have been shown to be higher in obese women. Obese postmenopausal women can have premenopausal levels of estrogen present continuously. This may partially explain why women with large body size, and particularly those with obesity late in life, are at increased risk for postmenopausal development of breast cancer.zo’21 A high-fat diet, especially saturated fats, has been reported to predispose to breast cancer.31’22-25 Five percent of patients with benign breast disease have proliferative lesions such as ductal and lobular hyperplasia and have an increased risk of developing an invasive carcinoma. Histologic atypia denotes higher risk. Typical fibrocystic disease and other nonproliferative breast lesions are not predisposing conditions but may result in increased numbers of biopsies because of abnormal physical examinations.l’, l3 Ionizing radiation is a known carcinogen for the breast, with a dose response and a delayed response similar to that seen in other tumor models. There is an increased incidence of breast cancer in survivors of the atomic bomb, those treated with radiation for mastitis, and those with multiple fluoroscopies for tuberculosis.34’1” Several recent studies have suggested an association between moderate alcohol intake (1 to 2 oz/day) and an increased risk of breast cancer. However, information regarding the importance of age and the onset of ethanol consumption as well as type of beverage consumed is conflicting.‘6-18, 26--28 There has been controversy over exogenous estrogen therapy in the form of oraI contraceptives,2s-34 as we11 as postmenopausal replacement estrogen”5P40 and the risk of breast cancer. Conclusions

DM,February1990

75

of published epidemiologic studies have been faulted because of the heterogeneous populations studied with regard to age, type of estrogen preparation, dose, schedule, and use of concomitant progesterone.41, 42 Kecent studies examining both oral contraceptives and postmenopausal replacement therapy continue to report conflicting information.4”-45 Prospective large studies may answer these questions, but for now, clinical judgment will be required for an individual patient. Patients with significant breast cancer risk should not receive replacement therapy. Continued concern for the general population exists on at least a theoretical basis since higher numbers of menstrual cycles correlate with an increased risk of breast cancer, and postmenopausal replacement is designed to mimic normal monthly cycles. Cigarette smoking does not appear to increase the risk of breast carcinoma.46p48 Augmentation mammaplasty does not increase the risk of breast carcinoma.49p53 Blood pressure medications, phenothiazines, and other drugs that increase prolactin levels have not been shown to increase the risk for breast cancer.“, 53 Caffeine also has no predisposing effect on breast cancer but may play a role in the development of benign breast disease.54-56 BIOLOGIC

MECHANISMS

Molecular

Biologic

OF BREAST

GROWTH

Factors

Tissue culture cell lines have indicated a genetic basis for some malignancies in animals and humans. Chronic myelogenous leukemia and Burkitt’s lymphoma stand as clear examples. An abnormal chromosomal function results in activation of a gene that produces a growth factor to stimulate the growth of its own cells (autocrine) or other cells (paracrine or endocrine) in an uncontrolled fashion. This gene in its original site with low activity is termed a proto-oncogene. As a group, these proto-oncogenes bear homology to the RNA retroviruses for which they are named. They are thought to be necessary for normal human growth and development. When these genes are activated or inactivated at an inappropriate time, malignant transformation can occur, and these genes are then called oncogenes. Breast carcinoma cells from biopsy specimens have been found to contain c-?-as-Ha, c-myc, c-erbB2, HER-Z/nezz, and int-2 oncogenes.57-5g The incidence of these oncogenes has not correlated with known prognostic factors.60 However, HER-2/neu has recently been reported as a predictor of survivaL6* With additional information, it is hoped that more specific therapy may be targeted toward the exact molecular abnormality found in each patient’s cancer. Much work must be done, but banked pathologic specimens from large clinical trials should aid in this research. 76

U&f, February

1990

Hormone

Receptors

and

Growth

Factors

Normal breast tissue grows and develops through a complex interaction of hormones and growth factors. Some of the proteins found in breast carcinoma cells function as hormone receptors and are useful clinically as indicators of prognosis and response to therapy. They function like most other hormone receptors. A specific hormone binds to a specific receptor, initiating a signal to the nucleus. This signal may result in cell division or the production of additional hormones or receptors. In the case of breast ductal cells, activation of the estrogen receptor protein (ERP) by estrogen has been thought to lead to the production of the progesterone receptor protein (PRP; Fig 11."' More recently, other protein receptors that may have a great impact on the proliferation of these cells have been described.63 Androgen receptors, growth hormone receptors, insulin-like growth factor receptors, epidermal growth factor (EGF) receptors, glucocorticoid receptors, transforming growth factor CY(TGF-a) receptors, and transforming growth factor p (TGF-P) receptors all have been discovered (Fig 2). The exact interaction of these receptors and hormones is not clear. Some may function in permissive normal regulation, and others may have an important role in the malignant process. 64-67 There is evidence in cell culture that EGF and TGF-(x may be increased or induced by physiologic doses of estrogen in ERP-positive cell culture lines.68 This effect is blocked by pretreatment of the cells

u r

d

nuclear fi processing

nrowth

\ // \

/

FIG 1. Breast cancer cell. Biochemical mechanism of estrogen action in human breast cancer cells. E, estrogen; ER, estrogen receptor; PgR, progesterone receptor. (From Osborne CK: Receptors, in Harris JR, Hellman S, Henderson IC, et al [eds]: Breast Diseases. Philadelphia, JB Lippincott Co, 1987, pp 210-232. Used by permission.)

DM,l%bmary1990

77

EGF

FIG 2. Breast cell. Potential hormonal rnteractrons with breast eprthelral cells. E, estrogen; fR, estrogen receptor; A, androgens; AR, androgen receptor; G, glucocorticoids; GR, glucocorticoid receptor; Pg, progesterone; PgR, progesterone receptor; Pr, prolactin; GH, growth hormone; LR, lactogenic receptor; I, insulin; IR, insulin receptor; IGF, insulin-like growth factor; IGF-R, insulin-like growth factor receptor: EGF, epidermal growth factor; EGF-R, hormones; TR, thyroid hormone receptor. epidermal growth factor receptor; T3+ thyroid (From Osborne CK: Receptors, in Harris JR, Hellman S, Henderson IC, et al [eds]: Breast Diseases. Philadelphia, JB Lippincott Co, 1987, pp 210-232. Used by permission.)

with tamoxifen (an ERP blocker).65 The production of TGF-(x is increased in ERP-negative cell lines independent of estrogen or tamoxifen. 6g~71 Levels of TGF-o have also been found to be increased in body fluids of patients with metastatic disease from breast cancer as well as other types of cancers.72 Further patient evaluation will be required to determine the clinical value of this observation. Early attempts at blocking the receptor for TGF-a with the expectation of decreased growth have not been successful.73 Transforming growth factor p has been shown to decrease growth of both ERP-positive and ERP-negative cell lines.74-76 The best studied of hormone factors are the ERPs and PRPs, which mediate growth of ductal and lobular cells, respectively. Receptor assays are widely performed and reported clinically. The assay generally requires 1 gm of cancer handled as fresh tissue, which is frozen and stored at -70°C and shipped on dry ice. Estrogen receptor levels reported as positive correlate with a positive response to hormonal therapy. Positive results are more commonly seen in older patients (>50 years of age) who are usually postmenopausal. Premenopausal patients have higher levels of PRPs, possibly due to induction by higher circulating estrogen levels. The therapeutic response to hormone manipulation (e.g., adrenalectomy, 78

DM,

February

1990

hypophysectomy, high-dose estrogens, tamoxifen, androgensl is 50% to 70% in the ERP-positive tumors and less than 10% in ERP-negative tumors. Therefore, hormone receptor information frequently influences therapeutic recommendations.62 SCRE’ENPNG

FOR

BREAST

CANCER

Screening is defined as an effort to detect disease in an asymptomatic patient. It permits treatment before irreversible damage has occurred and, with breast cancer, implies that cure is possible. We will review the screening techniques, evaluate the Health Insurance Plan of Greater New York (HIP) and Breast Cancer Detection Demonstration Project (BCDDPJ studies, and discuss current recommendations for screening. BHEAST

SELF-EXAIMINATION

Breast self-examination (BSE) has several characteristics that make it appealing as a screening tool. First, the examination can be done in privacy as part of a daily routine in the home. Second, the examination has a low initial cost for training and no long-term costs. Third, training using didactic sessions plus models of breasts containing various lumps requires a short time. The high level of public interest seen during the Arkansas Division of the American Cancer Society’s 1989 Breast Check Project accented the importance of BSE. During a 4-month time span, 52,000 women attended BSE training sessions. Finally, BSE should be better than physician examination because of increased frequency (monthly vs. annually) and because women can better detect abnormalities in their own breasts. A study by Turner et al. suggests that this benefit does occur since women trained in BSE had more cancers smaller than 2 cm at biopsy (54% vs. 24%).77 PHYSICAL

EXAMINATION

Physical examination of the breast by a physician remains an important detection method for breast cancer. Physical examination was the only method that detected some breast cancers in the HIP and in the BCDDP (45% and 7%, respectively). However, physical examination as a screening device is limited by cost and lack of sensitivity. Mammography can detect much earlier breast cancers than physical examination. Minimal cancers (intraductal, in situ, and invasive
DM,

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79

TABLE Cancer

2. Detection

by Mammography

and

Physical Physical

Mammogram HIP BCDDP All canceis Minimal cancers

Only

(%)

Examination Examination Only i% 1

Physical Examination and Mammogram i% I

33

45

22

40

7 4

53 40

56

IX’L‘IMMOGRAPHY

Because mammography can detect nonpalpable breast cancers, it should benefit patients through earlier detection and improved survival. Both the HIP and the BCDDP demonstrated these benefits. Despite these advantages, negative aspects to screening mammography remain. Cost is an important disadvantage. More than 30 million women over age 50 years need annual screening. With prices ranging from $30 to $150 for mammography, the total cost ranges from 0.9 to 4.5 billion dollars annually. For maximum benefit, mammography must be performed yearly. Radiolo@ units are not currently available to perform 30 million mammograms annually. With such constraints on cost and availability, recommended annual screening may not be possible for every woman. Safety is another potential negative factor. Specifically, how many new cancers will be caused by the annual screening mammogram after age 50 years compared with the number of cancers detected? The report of the Committee on the Biological Effect of Ionizing Radiation suggested that annual mammography delivering 0.44 rad would induce 53 new cancers over the lifetime of 100,000 women screened.78 This compares to the 6,500 “natural” cancers potentially detected by screening mammography. Current techniques have reduced radiation exposure from 0.44 rad at the time of the study to 0.03 rad now, further reducing the risk. In addition, the American College of Radiology has a mammography unit certification program that evaluates each unit’s performance to ensure low dosage and quality mammography. Thus, screening mammography is currently safe. Recent changes in film quality and technique have increased the detection of breast abnormalities. Along with earlier detection of cancer, many previously unrecognized abnormalities that may require biopsy are also being detected. The improvements in mammography technique that occurred between the HIP (1963) and the BCDDP (19721 produced such an effect that the biopsy rate was four times higher (8% vs. 2%) in the BCDDP than in the HIP.7g A second concern is the decreasing proportion of cancers detected in the biopsy specimens removed for a mammographic abnormality. The 80

DM,

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1990

BCDDP found an overall 18.5% cancer detection rate, whereas unscreened patients have a 20% to 30% rate. The percentage of abnormal biopsy results was only 6% for women 3.5 to 39 years of age in the BCDDP. The concern for unnecessary biopsies arose at our hospital where our percentage of abnormal biopsy results was 3.5% for needle localizationdirected biopsies precipitated by more sensitive mammography equipment. Modification of biopsy indications has improved our results since that time.” Physician support for mammographic screening is varied. Although the American Cancer Society (ACS) and the National Cancer Institute (NC11 have strongly supported breast cancer screening, the average physician has not adopted their recommendations. A national survey funded by the Ohio Division of the ACS found 41’70 of physicians agreed with ACS mammography guidelines; however, only 11% actually followed the guidelines.“l The reasons given for disagreement with ACS guidelines included “too expensive” (39% 1, “too much radiation exposure” (25%), and “low yield” (16%). With such high physician noncompliance, some effort is needed to change behavior. The ACS has begun a national project to increase physician and patient awareness of the value of BSE and screening mammography. Even this project will not solve all the problems, as figures from Arkansas illustrate. In our state, 285,000 women over age 50 years need screening. Our Breast Check Project resulted in 56,000 women receiving BSE training and 5,000 women having screening mammograms. Forty-four unsuspected cancers were detected. In addition, a statewide mammography certification program was instituted and two new mammography units opened. Despite these programs, thousands of women received neither screening nor education in BSE. One of the barriers to mammography screening occurs with the economically disadvantaged. Our initial impression was that cost ($50) prevented some women from participating. However, offering free mammograms produced no response. This occurred because the women did not understand what a mammogram was, so they had no interest in getting one at any price. This response reinforces the perceived need for better public education. RESULTS OF THE YORK STUDY

HEALTH

INSURANCE

PLAN

OF GREATER

NEW

In 1963, the HIP started a randomized trial to see if periodic screening with mammography and physical examination would reduce breast cancer mortality. A study group of 31,000 women aged 40 to 64 years was to receive initial screening examination, followed by three annual examinations. A matched control group of 31,000 women from the same prepaid medical group practice plan would DA4,February1990

81

receive their usual medical care. One third of the study group refused screening, and only one half received all four screenings. Despite this problem, after 5 years of follow-up, 39 breast cancer deaths occurred in the study group compared with 63 among the controls (38% reduction).‘” To the credit of the HIP study designers, a substantial reduction in mortality continues to be observed. At the 18year point, 126 breast cancer deaths have occurred in the study group compared with 163 in the controls (23% reduction). This trial inspired the ACS and the NC1 to organize the BCDDP to confirm the HIP study on a large scale by enlisting cooperation from the medical profession and the public. RESULTS PROJECT

OF THE

BRE4ST

CANCER

DETECTION

DEMONSTRATION

In 1972, the ACS funded 12 centers to perform annual physical examinations and mammography on 5,000 women in each center. The NC1 expanded the program to 29 centers that were to enroll 10,000 women each. By 1975, the program included 29 centers at 27 locations that had enrolled more than 280,000 women aged 35 to 74 years. The women received a medical history, a physical examination, mammography, and thermography. In addition, each participant attended a BSE class and received instructions to practice BSE monthly. Each woman received annual screening four times after the initial visit. The criticisms leveled at this project included the lack of a control group, the screening of younger women (150 years) and the cancer induction risks of repeated mammograms. In addition to these concerns, the role of lead time bias (the bias of detecting tumors earlier than usual case finding) and length time bias must be considered. The BCDDP was a demonstration project, not a research study. Despite the absence of a control group, the massive size of the data base and the length of follow-up produced many significant observations. Reports on initial results of the HIP study indicated that mortality gains were occurring only for women more than 50 years of age.“” Controversy developed concerning the value of screening mammography in younger wornens The apparent lack of benefit for women less than 50 years of age and the postulated risks of mammography formed the basis for these concerns. A review of BCDDP screening performed at that time led to a change of policy in late 1976 that restricted the use of mammography in women less than 50 years of age to those at high risk based on personal history family history and physical examination. Efforts to reduce the radiation exposure of mammography were intensified by the controversy. As a result, the current dose per mammogram was lowered from an average 0.44 rad to 0.03 rad. This 82

DA4, February

1990

tenfold reduction in the radiation exposure reduced the projected risk so that this controversy is moot. During the five annual screenings 4,257 women of 280,000 screened had 4,485 primary breast cancers discovered. The survival analysis concerns data on 4,240 women since follow-up was not available on 17 participants. The prevalence yield (first screen) in women with screening-detected cancers was almost equal to the total yield (incidence) for the next three screenings. The observed 5-, B-, and lo-year cumulative survival percentages, allowing for 1 year’s lead time (actually the 6-, 9-, and II-year rates), were 87%, 80%, and 75%, respectively. Comparison of survival data from the BCDDP and the HIP study demonstrated similar relative survival rates at 5 years (88%). However, for years 8 and 10 the BCDDP rates were higher (83% vs. 80% and 80% vs. 72%). The survival advantage for the BCDDP patients persisted even when invasive cancer only from the BCDDP was compared with all cancer detected in the HIP. When compared with the NC1 Surveillance, Epidemioloa and End Results (SEER) program from 1977 to 1982, the B-year survival rates for total invasive cancers from the BCDDP was 81% vs. 65% for the NCI SEER.85 The result is a 46% reduction of cancer deaths in the BCDDP. When compared with SEER data, a definite benefit in 5-year survival rates occurred for all invasive cancers diagnosed in women less than age 50 years (BCDDP 87% vs. SEER 74%). Another method used to address this question involved comparing the survival figures for women diagnosed in the BCDDP from ages 40 to 49 years with those for women diagnosed from ages 50 to 59 years. This yields survival figures that are very similar at 5, 8, and 10 years (89% vs. 87%, 83% vs. 81%, and 80% vs. 76% 1. These data contrast with HIP data where there was no reduction in breast cancer deaths in study women who were less than 50 years of age at diagnosis. Both a lead-time and a length-time bias must be considered when these data are analyzed. To adjust for lead-time bias, subtract 1 year from the survival figures to correct for detecting the cancers earlier in their natural course. This adjustment reflects the convention used in analyzing the HIP data. By contrasting survival rates for cancers found at initial screening with rates for cancers found at later screenings, one can evaluate the role of length-time bias. Cancer detected on the first examination may be slow growing (prevalence cases), whereas cancers found at later screenings may be fast growing (incidence cases). Comparison of the survival rates for prevalence cases vs. incidence cases yielded 85% vs. 85% and 80% vs. 82Y0 at 5 and 8 years, respectively. Thus, the length-time bias is very small. Thermography was dropped from screening by the BCDDP because it added nothing to the physical examination and mammograDM,

February1990

83

phy. Improvements in mammography techniyue produced an increase from 33W in the HIP to 50% in the BCDDP of cancers detected by mammography alone. There was an even greater drop in the category of physical examination alone detection from 45% in the HIP to 7% in the BCDDP. Improvement in mammography also produced a tenfold drop in radiation exposure and a four-fold increase in the biopsy rate. In addition, this increased sensitivity resulted in a decrease in the rate of cancer detected in removed tissue from the 20% to 30% seen in unscreened patients to an overall rate of 18.5% and only 6% in women aged 3.5 to 39 years.

The American Cancer Society recommends that breast cancer detection use three modalities: BSE, physical examination, and manmography (Table 3). DIAGNOSIS

OF BREAST

ABNORMALITIES

The breast is a complex organ composed of skin, subcutaneous tissue, fatty tissue, and branching ductal and glandular structures. Various diseases that affect these structures can produce a palpable mass. In addition, the physiologic changes associated with the menstrual cycle can cause abnormalities of the breast that produce a three-dimensional mass. Hence, breast masses can arise from (11 diseases of the skin or supporting structures, (2) physiologic and hormonal changes within the breast, and (3) neoplasms of the breast. The four most common causes of breast masses in young women are (1) fibroadenoma, (2) fibrocystic disease, (3) carcinoma, and (4) fat necrosis. Any patient who has a complaint reFerable to the breast and is more than 30 years of age should have the breast evaluated by mam-

TABLE

3.

American

Cancer

BSE Breast physical examination Mammography

84

Societv

Kecommendations

for Cancer

Detection

20

Monthly

X-40 >40

Every Yearly

35 40-50 >50

Baseline Eve1y 2 yr Yearly

DM,

February

3 yr

19YO

mography. In general, mammography is more reliable in older patients with fatty breasts than in young women with dense breasts.86 Mammographic signs of breast cancer include the following: (1) irregular breast mass, (2) breast mass smaller on mammography than on physical examination, (3) nipple retraction, (4) increased stromal density noted on sequential examination, and (5) calcifications. In addition to establishing a diagnosis, mammography can also aid in planning the proper surgical procedure for the breast biopsy procedure. A mammogram also serves as a baseline comparison for the opposite breast.

PAIN Mastodynia frequently presents as moderately severe pain occurring just before the menstrual period. It is usually diffuse but may be localized to one breast or to one area within a breast. When localized, it tends to be in the upper outer quadrant. Mastodynia is most frequently associated with fibrocystic disease. The clinical course of fibrocystic disease suggests that hormone imbalance is responsible for the pathology. The process is never present until the breast develops, is fairly common during the active menstrual life span, and usually ceases at the time of menopause. The symptoms are cyclic in nature and are accentuated in the latter part of the menstrual cycle.

Patients find 90% of breast masses through self-examination or accidental contact. When a breast mass is identified at physical examination, it should be accurately delineated as to (1) location; (2) size, shape, and consistency; (3) fixation to adjacent tissue; and (4) presence of tenderness or pain. Any skin or nipple alterations should be noted. The correct diagnosis can frequently be made regarding a breast mass based only on history and physical examination.

BREASTBIOPSY Breast biopsy is indicated for a mammographic abnormality that suggests malignancy or for a mass that is palpable on physical examination. The type of biopsy used depends on the mass size and characteristics. The types of biopsy are (1) fine needle aspiration IFNA), (2) core needle biopsy, (3) incisional biopsy, and (4) excisional biopsy. A special type of open (excisional) biopsy is the needle localization biopsy, which is used when a mammographic abnormality is not associated with a palpable mass. Since mammography will miss DM,

FebruarylYYO

85

approximately 10% to 15% of breast cancers, a biopsy should be performed on any solid three-dimensional mass within the breastx7 Fine

Needle

Aspiration

Using a Z&gauge needle, pathologists are frequently able to diagnose breast cancer with cytology. Results of FNA can be used as the basis for mastectomy when the physical examination and mammographic abnormalitY coincide with the cytologic diagnosis. The accuracy of FNA is quite good in experienced hands. However, many of the large series have at least one case of false positive cancer diagnosis. For this reason, many surgeons will not depend on FNA as the only biopsy prior to mastectomy. Needle

Core

Biopsy

A core needle biopsy (Tru-cut) provides the pathologist with sufficient tissue to make a histologic diagnosis of cancer. A Tru-cut needle biopsy can be performed under local anesthesia in the outpatient setting. This is the method of choice when breast cancer is suspected and a mass is palpable of sufficient size to allow the physician to take a core biopsy. Care should be taken to direct the point of the needle away from or parallel to the chest wall rather than toward the chest wall. Lesions less than 1 cm are not appropriate for core needle biopsy due to difficulty in localization. In a setting where the physical examination and mammogram suggest malignancy, a normal core biopsy result must be confirmed with open biopsy. Excisional

Biopsy

Excisional biopsy is the standard biopsy technique for clinically benign lesions or for clinically malignant lesions less than 2 cm in diameter. This term indicates the complete removal of the abnormal tissue. Excisional biopsy may be performed under either local or general anesthesia and is usually done as an outpatient procedure. Needle

Localization

Biopsy

Needle localization biopsy is a two-stage procedure. The localization is performed in the radiology department. A mammogram is obtained on the patient, and the mammographic abnormality is localized in a compression plate in the craniocaudal view. Superficial local anesthesia is used to permit a needle-wire assembly placement in the breast. A confirmatory craniocaudal view mammogram is obtained. If the mammographic abnormality is in good alignment with the needle in the craniocaudal view, a follow-up go-degree mediolatera1 view is performed to confirm the appropriate depth of the needle placement. A second wire insertion is performed if the mammographic lesion is not within 1 cm of the wire tip. 86

DA4, February1990

A progress note is made with a diagram detailing the exact relationship of the localizing device to the mammographic abnormality and is sent to the operating room with the mammograms. General anesthesia is usually used for the biopsy. The needle is identified through an appropriate incision and the suspicious area removed. A specimen radiograph is taken to confirm the removal of the abnormal tissue. If there is any question of adequate removal, a postbiopsy mammogram is indicated. Incisional

Biopsy

of Advanced

Lesions

Incisional biopsy means removal of only a portion of a mass or abnormality. This method is used for large malignant lesions and diffuse areas of abnormality that blend into adjacent tissue (fibrocystic change or disease). PATHOLOGY IhWASlVE

CARCINOiM4

The pathologic evaluation of breast lesions serves to establish the histologic diagnosis and extent of involvement, thereby aiding prognosis assessment. The histologic diagnosis is based on the normal breast structures, which consist of a network of differentially sized ducts, with glandular structures that are present during pregnancy. Factors believed to influence prognosis include histology, the presence of necrosis, lymphatic or vascular invasion, nuclear grade, hormone receptor status, proliferative index, amount of aneuploidy, presence or absence of oncogenes, and perhaps presence or absence of elevated growth factors and are discussed later on. Infiltrating ductal carcinoma is the most common histology. Other histologic patterns can occur alone or with infiltrating ductal carcinoma (Table 4). The prognosis according to histology is worse for infiltrating ductal carcinoma, followed by invasive lobular carcinoma.

TABLE Histologic Infiltrating Mcdulhy Mutinous Tubular

4. Types duct

NOS*

70%-80% 5% 2% 2%

Adenocystic Papillary Carcinosarcoma

0.1% 0.3% 0.1%

Lobular ‘NOS

UA4, February

1990

5% = not otherwise

specilied.

87

The remaining types are less common but, in general, have a better prognosis.8’ Special situations seen clinically and histologically include Paget’s disease of the breast, inflammatory breast cancer, and lobular carcinoma. Paget’s disease presents clinically with a history of scaling, itching, bleeding, or drainage of some type from the nipple for extended periods of time prior to presentation. A palpable lesion in that breast occurs only one third of the time, and the underlying tumor may be invasive or intraductal (see later discussion). Histologically, the nipple epithelium contains tumor cells. Prognosis is determined by the extent of the cancer in the breast and nodes. Inflammatory breast carcinoma presents with red, edematous skin, induration, and erythema, which is caused by intradermal lymphatic invasion by tumor cells. This tumor is almost always associated with regional and distant metastases, which give it a poor prognosis. Loblllar carcinoma arises from the terminal ducts and lobules and has a high incidence of prior, concurrent, or subsequent contralateral involvement (6% to 28% 1. The metastatic sites of disease differ from those of infiltrating ductal carcinoma by having a predilection for the meninges, abdominal serosal surfaces, gastrointestinal (GI) tract, ovaries, and uterus.8Y Rare histologies reported include adenocystic carcinoma, carcinosarcomas, squamous cell carcinomas, carcinoma with osseous or cartilaginous stroma, basal cell carcinomas, and lipid-rich carcinomas. Nonepithelial tumors include fibrosarcomas, leiomyosarcoma, and lymphomas. The prognosis for the sarcomas is generally poor, with rapid development of distant metastases. The remaining histologies are so rare that prognoses are unreliable. The remaining pathologically determined factors having prognostic value independent of stage include the presence of tumor necrosis, vascular or lymphatic invasion,‘” ERP and PRP,” nuclear grade, percent cells in S phase,” and presence of aneup10idy.y”~‘“2 Some studies suggest that there is excellent prognostic concurrence among nuclear grade, presence of aneuploidy, and percent S phase.‘“” The determination of nuclear grade has the advantage of not requiring specialized equipment such as flow cytometry or thymidine labeling. However, there is no generalized agreement that these parameters are equivalent, and there has not yet been agreement that the flow cytometry results are comparable across the board. The determination of the ERP and PRP levels is common practice and should be attempted for all primary tumors. Other than staging, the hormone receptor status (ERP and PRP) results remain the most reliable and predictable factor influencing prognosis. Other factors are likely to become more important as 88

DM,

February1990

techniques improve planned prospective NONINVASIVE

BHEAST

and additional information studies is accumulated.

from

ongoing

and

CAHCINOMA

As “with invasive carcinoma, the noninvasive lesions may be divided broadly into ductal and lobular categories. The terminology for these lesions, however, has not been consistent. In situ carcinoma (ductal and lobular) and intraductal carcinoma are the most common terms and refer to lesions that histologically appear as their invasive counterparts do but do not show invasion through the basement membrane by light microscopy. They probably represent the step between atypical hyperplasia and invasive carcinoma. Our knowledge of the natural history and incidence of ductal carcinoma in situ (DCIS) is evolving. The incidence as reported in pathologic specimens is frequently dependent on the type of patient enrolled in the study. Today, most cases of DCIS are found on biopsy for clustered calcifications seen on screening mammography. Up to 22% of patients with carcinoma detected on screening mammography have in situ lesions. A palpable mass is usually not present. Ductal carcinoma in situ has the same age distribution as invasive carcinoma. Axillary nodal status has been variably reported, depending on the criteria used to classily the primary tumor, but is rare. Only 1% of patients treated by mastectomy for noninvasive carcinoma will die of metastatic disease. Data on hormone receptor status are also scant due to the fact that the small tumor size makes obtaining enough tissue for the assay difficult. The progression of these lesions to carcinoma is also questioned, with some suggesting that it is a marker lesion rather than a direct precursor of invasive carcinoma. However, most older studies indicate that about 30% of patients with DCIS treated only by excisional biopsy will develop invasive cancer. This is usually in the area of the previous biopsy.“” 8g Lobular carcinoma in situ (LCIS) comprises 30% to 50% of noninvasive breast carcinomas. It is nonpalpable and does not produce calcifications on mammography and frequently is found adjacent to a benign lesion that precipitated the biopsy. Multicentricity is common (>30%), and the opposite breast is affected in up to 50% of patients. Since it is clinically nondetectable, the incidence in the opposite breast is influenced by the type and number of biopsies. There has been doubt as to whether or not LCIS proceeds to invasive carcinoma or serves as a marker for a higher chance of invasive carcinoma elsewhere in the breast. About 25% to 30% of patients treated by excision only develop invasive carcinoma. Most cancers that develop are invasive ductal carcinoma, and nearly one half occur in the opposite breasts8’ ” DM,February1990

89

STAGING The staging of cancer provides prognostic information and improves our knowledge of the natural history of cancer and the effect of therapy. The scientific study of cancer in humans would be imaccurate staging information to describe the possible without groups of patients being studied and to allow comparison of like groups from different studies. Staging for breast cancer can be clinical or pathologic. Older clinical staging systems such as the Manchester Staging System and the Columbia Clinical Classification have been replaced by a system jointly agreed on by the AJCC and the LJICC. This system employs descriptions of the tumor (T), lymph nodes (N), and distant metastases (M). For breast cancer, the regional lymph nodes include the ipsilateral axillary, internal mammary, and pectoral nodes. All others are considered distant metastases. In this staging system, the clinical staging information is derived from physical examination, operative findings, and some pathologic findings. Pathologic staging requires excision of the primary with no gross involvement of margins and removal of at least six low-level axillary lymph nodes. The primary tumor definitions are as follows: TX: TO: Tis: Tl:

T2: T3: T4:

T4a: T4b: T4c: T4d:

Inadequate information to assess primary tumor. No primary cancer. Carcinoma in situ. Primary <2 cm. Tla: CO.5 cm. Tlb: >0.5 but l cm but c2.0 cm. Primary >2 cm but <5 cm. Primary >5 cm. Primary of any size with direct extension to the chest wall (ribs, intercostal muscles, and anterior serratus muscle but not the greater pectoral muscle). Extension to the chest wall. Edema, ulceration, or metastases to the skin of the ipsilateral breast. Roth T4a and T4b. Inflammatory carcinoma.

Regional NX: NO: Nl:

so

lymph

node involvement

includes:

Inadequate information for assessment. No carcinoma in lymph nodes. Carcinoma present in movable ipsilateral

node or nodes.

DM,

February

1990

N2: N3:

Carcinoma Carcinoma

Distant

present in fixed or matted ipsilateral axillary nodes. in ipsilateral internal mammary nodes.

metastases

are designated:

MX: tnadequate information for assessment. MO: Absence of distant metastases. Ml: Distant metastases. The pathologic nated:

classification

of lymphatic

involvement

is desig-

pNX: lnadequate information or material for assessment. pN0: Absence of regional nodal metastases. pN1: Carcinoma present in movable ipsilateral axillaly nodes. pNla: Metastases CO.2 cm. pNlb: Metastases >0.2 cm. pNlbi: l-3 lymph nodes involved with any of the metaslatic lesions >O.Z cm but all <2 cm. pNlbii: >4 lymph nodes involved with any metastatic lesions >0.2 cm but all <2 cm. pNlbiii: Invasion of carcinoma beyond the capsule of the lymph node but <2 cm in diameter. pNlbiv: Metastatic carcinoma in lymph node >2 cm in diameter. pN2: Involvement of fixed axillary lymph nodes. pN3: Involvement of ipsilateral internal mammary nodes. Stages are derived by grouping levels of TNM characteristics as seen in Table 5. This has been updated since 1983 with the notable change of TSNOMO from stage III to stage II because updated survival information showed this group to have survival closer to stage II than to groups in stage III.lo4 LOCAL AND CANCER

REGIONAL

TREATMENT

OF PRIMARY

BREAST

The surgical management of breast cancer is now based on a more rational scientific basis. Randomized clinical trials designed to resolve areas of controversy in surgical management and to address biologic questions about cancer of the breast have changed current thoughts about breast cancer.

DM,February1990

91

TABLE Stage

5. Grouping’ Stage 0 Tis Stage I Tl stage

Stage Stage

IIA

IIB IIIA

TO Tl 1‘2 T2 T3

NO NO Nl

MO MO MO

Nlt NO Nl NO

MO MO MO MO MO

TO ‘I‘1 ‘TZ 1‘3

N2 N2 NZ Nl,

TTTB T4 Any Stage IV Any

Any N3 Any

stago

T T

N2 N N

OH, Henson DE, Hutter NV, et al: Manual ,for Stasing of Cancel; Lippincott Co, 1988, p 147. Used by permission. *The prognosis of patients with pNla is similar to lhal of patients with pN0. *hOr~l

Keahrs

SURGICAL

MO MO MO MO MO Ml ed 3. Phikdclphia,

JB

OPTIONS

In the past, surgical management of breast cancer was based on the halstedian concept of tumor spread; breast cancer was thought to spread sequentially from the breast to the regional lymphatics and then systemically. Radical mastectomy was designed to remove the breast and the regional lymphatics before the tumor spread systemically. In spite of this aggressive approach, patients still died from distant disease. Experience with less radical procedures yielded no difference in survival when compared with radical mastectomy.lo5 Because of this experience, a randomized trial was designed by the National Surgical Adjuvant Breast Project (NSABP) to (1) determine the appropriate surgical management of cancer of the breast, (2) evaluate the role of radiotherapy following mastectomy, and (3) ask questions about the biology of breast cancer. This trial, NSABP B-04, randomized 1,765 patients between 1971 and 1975. Patients with clinically normal axillary lymph nodes were randomized to receive either radical mastectomy, total mastectomy with radiation, or total mastectomy alone. Patients who subsequently developed axillary metastasis had axillary dissection (Pig 3). Median follow-up is now more than 10 years and shows no survival advantage with any treatment group (Table 6).lofi This convincingly demonstrated that radical mastectomy had no advantage over less radical procedures in improving patient survival. The results of this trial changed the practice patterns of general surgeons; radical mastectomy is uncommonly per92

DM,

February1990

Trial

Design

NSAPB

1 Clinical --~.

B-04

Examination

Trial

i

-I,

/N.dh:egatire/

positive lymph

Node

Positive

axillary nodes

1 axillary dissection

FIG 3. Design

of NSABP

B-04

trial

formed, and modified radical mastectomy is the standard procedure for cancer of the breast.lo7 In NSABP B-04, the addition of radiotherapy to surgical resection did not improve survival or distant recurrence rates. There was an improvement in local control when radiation was added, but this did not translate into a survival benefit. In summary, this trial demonstrated that radical local management of cancer of the breast did not improve survival. Neither removal of the regional lymph nodes nor axillary irradiation improved survival. This trial challenged the halstedian concept of tumor spread. Breast cancer was seen to frequently be a systemic disease from the outset; consequently, aggressive surgical procedures would not improve cure rates, and systemic treatment in the adjuvant setting would be necessary. TABLE Results

6. of NSABP

B-04

Trial*

Procedure Kadical Total

Nfl. mastectomy

mastectomy

and

radiation Total mastectomy ‘Average

DM,

Callow-up

February

survival

(70)

Disease-free Survival (W j

Local Recurrence

654

58

47

6

646

59

48

1

365

54

42

8

1% J

120 mo.

1990

93

As surgeons changed their approach to breast cancer, even less radical procedures were performed. In Canada and Europe, breast cancer was often treated with radiation alone, preserving the breast.l” Removal of the tumor with preservation of the breast became a rational option. Several large randomized clinical trials that address whether patients can be treated with breast conservation have been completed. From 1973 to 1980, the Milan Tumor Institute randomized 701 patients with primary breast cancer to receive either radical mastectomy or quadrantectomy, axillary dissection, and radiation. All patients with abnormal axillary lymph nodes were treated with adjuvant chemotherapy. To date, no difference in survival or disease-free survival has been noted.lo9 The NSABP also conducted a trial to evaluate breast conservation, protocol B-06. This trial randomized 2,163 patients between 1976 and 1984. Patients were randomized between three groups: (1) segmental mastectomy with axillary dissection, (2) segmental mastectomy with axillary dissection and radiation, and (3) total mastectomy with axillary dissection (Fig 4). There are 1,855 evaluable patients, with an average follow-up of over 39 months. No advantage has been seen between the three groups in survival, disease-free survival, or distant disease-free survival (Fig 5).l*’ In the segmental mastectomy group, there were more local recurrences in the group who did not receive radiation compared with those who received radiation (28% vs. SW), but there was no difference in survival. These studies have shown that selected patients with breast cancer can have breast conservation without compromising survival. In spite of local-regional control of breast cancer, patients develop distant metastasis and die from their disease. At one time, some sur-

Trial

Design Clinical

NSABP Examination

B-06

-1

Segmental Mastectomy Axillary*dissection + Breast Irradiation

FIG 4. Design 94

of NSABP

B-06

trial. DA4, February

1990

DISEASE

FREE

SURVIVAL

DISTANT

YEAR0 12 3 4 50 .q,GAT 0 586 520 356 212 121 67 586 RISK A 625 554 382 241 149 88 625 dO"'"STED FOR NO OF POS NODES

DISEASE FREE SURVIVAL

12 523 370 556 384

3 221 246

4 128 151

50 67 586 88 625

SURVIVAL

I2 532 558

398 406

3 253 266

4 148 168

5 6, 98

FIG 5. Results of NSABP B-06 plus breast irradiation. randomized clinical trial ment of breast cancer.

trial. TM = total mastectomy; SM + RTx = segmental mastectomy (From Fisher B, Bauer M, Margolese R, et al: Five year results of a comparing total mastectomy with or without radiation in the treatN Engl J I\/led 1985; 312:665-673. Used by permission.)

geons believed that even more radical surgery would cure these patients? Operations were designed to remove the internal mammary lymph nodes (extended radical mastectomy). These more radical procedures have not resulted in improved survival rates and are not commonly performed. With the results of clinical trials and the current understanding of the biology of breast cancer, the surgeon has several logical alternatives to manage the patient with localized breast cancer. Management of Stage Z and ZZBreast Cancer Selecting the best option for the patient with localized cancer of the breast is a complex decision. There are several treatment options, and the final decision should be based on information obtained from the patient, physical examination, biopsy, and mammogram. The standard therapy for localized breast cancer is modified radical mastectomy (simple mastectomy and axillary dissection). This procedure removes the breast and axillary lymph nodes. The greater pectoral muscle is preserved, and the lesser pectoral muscle may be removed or divided and left in place.“” In selected patients, breast conservation may be a rational alternative to mastectomy. Patients are candidates for breast conservation if they meet specific criteria. These criteria try to ensure that patients who have breast conservation have .(l) survival equivalent to modified mastectomy, (2) low risk of local recurrence in the breast, and (3) a good cosmetic result. This procedure has been standardized and consists of removal of the lesion with a l-cm margin of normal breast tissue (Fig 6).11” Axillary dissection is performed through a DM,

February

1990

95

RECOMMENDED

NON RECOMMENDED

FIG 6. Recommended surgical technique for breast Shibata H, et al: The technique of segmental section: A syllabus from the National Surgical 1987; 102:828-834. Used by permission.)

conservation. (From Margolese R, Poisson H, mastectomy [lumpectomy] and axillary disAdluvant Breast Project Workshops. Surgery

separate incision so that the cosmetic result is optimal. In spite of having a small tumor, some patients may not be candidates for breast conservation. Contraindications to breast conservation surgery are listed in Table 7. Schnitt et al. have looked at risk factors for local recurrence following breast conservation114’ I’S Patients who have a marked component of intraductal breast cancer adjacent to the invasive tumor have a very high incidence of recurrence within the breast (39% ). In addition, many patients (36%) who have margins of resection involved with cancer will develop recurrence within the breast and should have reexcision with negative margins or modified radical mastectomy. It is important to note that other studies have not confirmed this finding and that recurrence within the breast is usually well managed by mastectomy. Whether local recurrence following breast conservation treatment significantly decreases survival is unknown. 96

DM,February1990

TABLE

7.

Kelalive Contraindications Conservation Therapy Tumor

>3

to Breast

cm

Large tumor in a relatively small breast Lymphatic or vascular invasion Subareolar tumor Marked adjacent intraductal component Inadequate radiotherapy support Patient who desires Large axillaly nodes Multifocal disease Multiple

areas

mastectomy

of suspicious

calcilication

on

mammogram

Any treatment decision should be made with the patient as an informed participant. Current biopsy techniques, such as PNA and core needle biopsy (Tru-cut), usually allow the surgeon to diagnose the cancer without the need for open surgical biopsy. Treatment options can be discussed with the patient before surgery, and appropriate consultations can be obtained before surgery with the radiation therapist, plastic surgeon, and medical oncologist. With careful patient selection and radiation therapy techniques, survival rates should be equivalent whether breast conservation or modified mastectomy is performed. Local recurrence rates with either procedure should be less than 6%. Management of the A,xilla Surgical management of the axilla is controversial. One position is that axillary dissection and axillary nodal information are not needed since most women will be referred for adjuvant chemotherapy, regardless of their nodal status. In addition, surgical removal of the axillary lymph nodes does not improve patient survival. Although most women will be referred for adjuvant treatment, knowledge of the axillary lymph node status remains the most important prognostic variable in predicting patient survival. For this reason, axillary dissection is still recommended so that patients can be appropriately staged and stratified for clinical trials, and accurate information can be given to the patient regarding her prognosis. Certainly, clinical involvement of level II or level III lymph nodes at the time of surgery mandates their removal with the specimen. The perioperative management of patients undergoing breast cancer surgery is straightforward. The procedures are done after general anesthesia; the average operating time is between 1.5 and 2 hours. Two closed-suction drains are placed to evacuate any fluid collection. With appropriate patient education, patients may be disDA4,Pebruaz-y

1990

97

charged with drains in place, usually 2 to 3 days following surgery. Complete pathologic staging should be performed after histologic examination of the surgical specimen. Management

of Locally

Advanced

Breast

Cancer

In spite of early diagnosis and screening programs, some patients still present with locally advanced breast cancer. In the past, these patients were not managed surgically. Haagensen developed his grave signs to indicate a group of patients in whom surgical therapy could not be expected to achieve any real benefit (Table 8). Surgical management of these advanced lesions reyuired large resections involving chest wall, peripheral nerves, and blood vessels. Skin grafts were required for adequate closure. In spite of radical local-regional treatment, patients usually died from their disease; less than 25% were alive at 5 years. Fortunately, breast cancer is one of the solid tumors most responsive to systemic chemotherapy. As the natural history of advanced breast cancer has been defined, early aggressive systemic therapy has been used to control micrometastases, reduce tumor bulk, and allow for more limited procedures for local contro1.116’ ‘17 When combination chemotherapy with doxorubicin iAdriamycin)based regimens are used, tumor response rates are seen in 80% of patients. Approximately 10% of patients will have a complete response with chemotherapy. This combination approach with chemotherapy prior to surgery has resulted in (1) improved survival rates, (2) marked tumor responses, and (3) mastectomy for local control without the need for wide chest wall resections or skin graft closure (Fig 7). Our approach to the patient with locally advanced breast cancer is summarized in Figure 8. This approach is based on the rationale TABLE

8.

Haagensen’s Edema

Criteria

of more

than

of Inoperability one

third

of breast

Satellite nodules Inflammatory carcinoma Edema of the arm Supraclavicular metastases Parasternal metastases Distant metastases The presence of two or more following signs: Ulceration of the skin

of the

Edema of less than one third of breast Chest wall fixation Axillruy nodes more than 2.5 cm Fixed

98

axillary

nodes

DM,Februuy1990

FIGa. This advanced primary cancer demonstrates with chemotherapy and radiation.

the marked

response

that

can

be achieved

that these patients are at gravest risk from their systemic disease; thcrcfore, systemic treatment is indicated immediately. In addition, it takes advantage of high response rates that allow surgical resection without complicated procedures or the need for skin grafting. A small group of patients will not respond to therapy, and surgical resection cannot be performed. These patients receive radiotherapy following their systemic therapy. A group of patients will have a

Management

of Locally

complete

Advanced

staging

for

Breast

Cancer

metastasis

biobsy (dx,

hormone

receptors,

induction response __--l _

__

_-

flow

cytometry)

chemotherapy ---

A

.

. __-

no response ---_. --

-.--

.-._.

__ -.

mastectomy

radiation

1 CTX

I CTX radiation

1

therapy

therapy

reassess

for

1 mastectomy

FIG 8. Management uM,

February

of locally 1990

advanced

breast

cancer. 99

complete response following combination chemotherapy, and radiation may be used in place of mastectomy. The timing of radiation following surgical resection is controversial. Our approach is lo continue systemic therapy following surgical resection for the full course of lreatment. Radiation is added following completion of systemic therapy. Using this approach, we have not seen a problem with local failures. Survival rates with aggressive preoperative chemotherapy are improved, with S-year survivals approaching 50%. il&WAGEMENT

OF RECURRENCE

Kecurrent disease of the chest wall or axilla following surgery indicates failure of the initial local therapy. More important, il usuaily indicates that the tumor is biologically aggressive. Patients who have local or regional recurrence should have systemic therapy in addition to management of the local recurrence. Localized recurrence in the skin or chest wall is usually managed with surgical excision plus radiotherapy. Disease that would require extensive chest wall resection is treated with preoperative chemotherapy and radiation. Recurrent disease or new disease in the axilla is best managed by axillary dissection. If the patient is believed to be unresectable by clinical examination, the lesion is managed with radiation therapy. Following axillary dissection, radiation therapy is added for (1) evidence of extranodal disease, (~1 incomplete excision, or (31 multiple lymph nodes involved with tumor. Supraclavicular lymph node disease is best managed by radiation therapy. If a combined approach is used, control of local-regional disease can be achieved for the majority of patients.ll” “’ ik!ANAGEMENT

OF PREIW!lVE

CANCER

As screening mammography utilization has increased and the quality of mammography has improved, more patients are presenting with preinvasive cancers. In some series, this percentage is as high as 25% of all breast cancers now being treated. The management of preinvasive lesions is highly controversial. The natural history of these lesions is poorly understood; most data do not address these early lesions that have been detected only by mammography. The most common preinvasive cancer is intraductal cancer or DCIS. Based on follow-up studies, it appears that DCIS is multicentric in approximately 50% of patients, DCIS is a unilateral problem, and more than 30% of patients will subsequently develop an invasive carcinoma in the area of involvement. At the time of diagnosis, less than 1% of patients will have axillary metastasis 120,1Zl 100

DM,

February

1990

Based on this information, rational surgical options are as follows: mastectomy, (2) local excision plus radiation, and (3) local excision alone. There is no need for axillary dissection. Treatment should be based on physical examination (difficulty of evaluating the breast), degree of intraductal component on biopsy, and extent of mammographic abnormalities. Patients with breasts that are difficult to evaluate or have multifocal disease on biopsy or mammography should have simple mastectomy as their treatment. If possible, the best approach to these patients is to enroll them in the NSABP B-17 trial. This trial randomizes patients to receive local excision vs. excision plus radiation therapy. As noted earlier, the other noninvasive lesion frequently found on biopsy of mammographic abnormalities is LCIS. This lesion is also multicentric but frequently involves both breasts. Invasive carcinoma occurs in 15% of patients at the time of diagnosis of LCIS. About 30% of patients diagnosed as having LCIS develop invasive carcinoma if followed. This occurs equally in both breasts and is often invasive duct cell carcinoma. ‘I’herefore, LCIS is a marker for high risk of developing invasive cancer in both breasts. For this reason, treatment options are complicated. Like DCIS, the incidence of lymph node metastasis is low, less than 1%. The incidence of developing invasive carcinoma is approximately 1% to 2% per year that the patient is folloWed.lZZz 123 Rational approaches to managing these patients are as follows: (1) local excision (biopsy of an abnormal breast) with careful follow-up of both breasts, or (2) bilateral mastectomy. Treatment decisions should take into account the amount of difficulty in examining the breasts on physical examination, the degree of mammographic abnormality, family history of breast cancer, age, and the patient’s desires. As screening programs increase, discovery of these preinvasive lesions will only increase. Physicians are encouraged to enroll these patients in clinical trials so that the natural history can be determined and decisions made on a more rational basis. (1) simple

RADIATION

THERAPY

Radiation With Conservative Surgery In the use of definitive radiation and conservative surgery, the major criterion for patient selection is the ability to do an adequate resection with an acceptable cosmetic outcome. Patients eligible for this treatment are those with clinical stage 1 or II disease (Tl or T2, NO or Nl). Relative contraindications to definitive irradiation include masses in the subareolar area, large lesions relative to breast size, patients with multifocal cancer, multiple suspicious clusters of calcifications, large axillary nodes, or unavailability for follow-up. UM,

kkbmuy

1990

101

Radiation Techniques.-Three to 6 weeks following surgery, as wound healing permits, postoperative irradiation can begin. The entire breast is treated with tangential opposed radiation fields to a dose of 4,500 to 5,000 rad over 5 to 6 weeks. This technique minimizes radiation dose to underlying thoracic structures. Doses more than 5,000 rad to the whole breast may result in unacceptable fibrosis and should not be used in the treatment of early stage disease. Often a boost dose of radiation with either electrons or interstitial radiation is given to the biopsy site. In patients who are at high risk for locally recurrent nodal disease, the lymph node drainage areas may also be treated. Definitive irradiation for breast cancer is generally well tolerated. The most common side effect is mild fatigue. Skin changes are generally transient. Long-term side effects include radiation pneumonitis, rib fractures, and arm paresthesias, but they are uncommon.1z4 Postoperative

Radiation

Therapy

Following

Mastectomy

Radiation after mastectomy has largely gone out of favor. Although several studies indicate that postoperative radiation has no effect on overall survival, lz5, lz6 it has been shown to reduce the rate of localregional recurrence.127’ lz8 Patients with advanced local disease benefit from postoperative irradiation by achieving superior local control. Whether overall survival may be improved in selected groups of patients is a question that has not been completely resolved.“” The prevalent use of adjuvant chemotherapy makes it difficult to gather clear information on this question. ROLE

OF RECONSTRUCTION

AND

REBAl3ILITATION

Advances in plastic surgery have made breast reconstruction a viable option in many patients. In selected patients, breast reconstruction is a better alternative than breast conservation, resulting in a better cosmetic result with less chance of recurrence. There are two basic methods of breast reconstruction. The most common approach uses local tissues with a subpectoral placement of a tissue expander, followed by a prosthesis. The alternative approach is accomplished with a myocutaneous flap (Fig 9). The two most common flaps are the latissimus dorsi myocutaneous flap and the transverse rectus abdominis myocutaneous flap. The major question in reconstruction is appropriate timing of breast reconstruction. Oncologic surgeons worry that immediate reconstruction may complicate the patient’s course should local or regional recurrence occur. However, reconstruction has not been shown to increase recurrence. In one study, there were no local recurrences in stage I patients before 2 years following mastectomy.“” 102

DM,

Fdxuary

1930

FIG 9. Excellent cosmetic neous flap.

result

following

breast

reconstruction

with

a latisslmus

dorsi

myocuta-

For this reason, there is probably no medical basis to delay reconstruction in patients who desire reconstruction. Some plastic surgeons believe that patients do better psychologically (accept a less than perfect result) and may do better physically (actually have a better result) if reconstruction is delayed for several months. We believe that reconstruction may be offered to most patients either at the time of surgery or later. We do not recommend immediate or early reconstruction in patients with advanced local disease or a very high risk of recurrence. Mastectomy is a safe procedure, having a mortality of less than 0.5%. The incidence of seroma formation (a fluid collection underneath the flap or in the axilla) ranges from 20% to 35%. Wound infection, necrosis, or both occur in approximately 5% of patients. These complications may delay the institution of systemic therapy until they are resolved. Rehabilitation is an important part of the management of patients with breast cancer and should encompass both physical and psychologic concerns. Physical rehabilitation generally occurs over a short period of time. In the initial postoperative period, women are encouraged to use the affected arm but to limit shoulder movement and avoid abduction of the shoulder. Prior to discharge, patients are evaluated by a physical therapist and instructed on range of motion exercises. Following removal of the drains, the formal exercise program is initiated and should be continued until preoperative range of motion is achieved. For most women, this will take 3 to 6 weeks. Patients are reassessed 1 month postoperatively for shoulder mobility, and if this is inadequate, physical therapy is used for further instruction and treatment. Women are informed about the physical sensations that occur during the 3 to 6 months following mastectomy. The chest wall and DA4, February

1990

103

inner aspect of the upper extremity are initially numb but soon develop alterations in feeling that range from prickling to occasional severe ache. A startling sensation for most women is the occurrence of phantom breast pain. An explanation of the normalcy of these sensations usually reassures women and helps them deal with these temporary but frightening changes. Breast self-examination should be emphasized in the rehabilitation process. The immediate postoperative period is not an effective time to stress this, but it can be done 4 to 6 weeks postoperatively when healing has occurred. Physical rehabilitation is not complete until the patient has achieved a satisfactory cosmetic recovery. For most women, this will involve obtaining an external breast prosthesis. Women can use a lightweight filler to restore breast shape as soon as they can comfortably wear a bra, usually after the drains are removed. They are encouraged to obtain a fitted prosthesis as soon as the incision is well healed. The extensive variety of prostheses, ranging in cost from $50 to $1,000, assures that most women can be fitted economically and cosmetically to provide acceptable breast replacement. Information regarding reconstruction should be available at the time of diagnosis and plastic surgery consultation obtained early in all patients who are interested in reconstruction. Psychologic rehabilitation may take longer to achieve but should be addressed early in the treatment of breast cancer. Frank discussion of treatment options should include the patient’s spouse, partner, or family whenever possible. All patients should be visited by an American Cancer Society Reach to Recovery volunteer following surgery. There are several benefits from this patient-to-patient encounter. The volunteer brings a lightweight breast form that can be used in the immediate postoperative period, she demonstrates the range of motion exercises, and she can provide realistic suggestions for dealing with specific problems. These volunteers do not discuss treatment but give patients an encouraging example of successful recovery. There are other support programs available that provide psychologic and physical support, such as Y-Me or Encore. Most women find it helpful to talk with someone who has experienced the same problem and should have the opportunity to do so. However, these groups should not replace open discussion with their physician regarding psychologic concerns. Women are assessed for psychologic adaptation as well as physical and cosmetic recovery. Return to preoperative activities, social and sexual, is a good measure of psychologic healing. Some women desire or require therapeutic intervention in the form of counseling and are referred to the appropriate resource. 104

D&i‘, February

1990

SYSTEMIC

ADJUVANT

THERAPY

Failure of standard surgery and radiation to cure patients with breast cancer and the failure of systemic treatment for gross recurrence to cure led to the application of systemic therapy in the perioperative period. Animal data also support early use of chemotherapy. in the initial trials, the question seemed simple, “Does a therapy known not to cure patients in the grossly metastatic phase of the disease improve survival if given at a time when metastases are microscopic in size?” Today, after thousands of patients, herculean efforts, and millions of dollars, this question is only partially answered, and more questions have arisen. First, mature, meaningful data from a breast cancer adjuvant study must include follow-up at a time that has allowed for the biology of this cancer to be expressed. Positive results have disappeared between the Z-year and lo-year data reports of many studies. In addition, the regular utilization of reliable assays for ERPs and PRPs has been available for only about 10 years, and most of the mature trials reporting on the effects of adjuvant therapy lack this information on a significant number of patients. Biologic factors believed to alter results of adjuvant therapy are tumor mass (primary and number of lymph nodes), hormone receptor status, histologic grade, age, and menopausal status. Nonbiologic factors include timing of initiation of therapy and dose intensity when chemotherapy is used.13’, 13’ The drug combination and duration of therapy have not been shown to be major determinants. The relative importance of these factors is very controversial and in part serves as the basis for much of the disagreement surrounding the interpretation of the studies already completed. NODE-POSITIVE

STUDIES

Adjuvant chemotherapy for breast cancer began in 1958 when the NSABP gave 2 days of thiotepa beginning in the operating room. Eight hundred and twenty-six patients were studied, and at 10 years there was a disease-free survival (DFS) and overall survival (OS) advantage for the treatment group. Another larger study was reported by Nissen-Meyer in which 1,136 women were randomized to receive or not to receive 6 days of intravenous (Iv) cyclophosphamide postoperatively, and at 17 years of follow-up there was a DFS and OS advantage for the treatment group.88 Following these early studies, a stepwise series of studies have been completed, all aimed at identifying a superior treatment regimen and progressing from short-term perioperative therapy to longer (1 to 2 years) single-agent postoperative therapy to multidrug

postoperative therapy. Most of these reported prospectively randomized studies have shown DFS or OS advantages for all patients or, more commonly, for subgroups (divided by age, hormone status, menopausal status, number of axillary nodes, and histologic grade) .132,lx3 The analysis of this mountain of data has provided controversial conclusions from statisticians and oncologists throughout the world. A tabulated summary of some of the randomized reported studies is listed in Tables 9 through 11.155 In 1985, the NC1 held and published results of a consensus conference designed to analyze these studies and form conc1usions.15B Their conclusions based on the studies included were: 1. Premenopausal, node positive, any ERP/PKP: Combination chemotherapy should become standard care. 2. Premenopausal, node negative: Combination chemotherapy is not standard care but should be considered for high-risk patients. 3. Postmenopausal, node positive, hormone positive: Tamoxifen is the treatment of choice. 4. Postmenopausal, node positive, hormone negative: Chemotherapy may be given but would not be considered standard care. 5. Postmenopausal, negative nodes, any hormone status: No indication for adjuvant therapy, but in high-risk groups it may be considered. 6. Optimal therapy has not been defined for any subset, and all patients and physicians are encouraged to participate in clinical trials. The conclusions of this conference have not been universally accepted. The statistical methods for all of the trials on which the consensus was based have been questioned.ls7 In the node-positive group, there is little controversy surrounding the premenopausal subgroup in which almost all studies show a positive result of therapy, and the issues for current trials have centered on optimizing therapeutic results and decreasing morbidity. Postmenopausal groups serve as one of the main topics of controversy. Results with chemotherapy have not been consistent, and the majority of studies have not shown a significant survival advantage. Lippman’5” points out that although the tamoxifen studies are more uniform in dose and schedule, and almost uniform in duration,1”9-1”4 the chemotherapy regimens for analysis during the consensus conference were quite heterogenous. Several of the studies have been criticized for automatic dose reductions based on age alone, and studies that have more dose-intense regimens did show improvement in postmenopausal as well as premenopausal groups. As will be discussed, in the node-negative stud106

DA4,Febmayl990

TABLE

9.

Published Randomized

Studies in Which Patients With HistologicaUy Involved Lymph Nodes To Receive Prolonged Chemotherapy or Local Therapy Alone*

Accrual

Japanla4 Ellis-Fischell”S

1962-1976 1963-1972 1972-1975

MMC 2 C Thiotepa L-PAM

9 12 24

551’ 167 343

1973-1975 1974- 1977 1975

CMF LMFP CMFV

12 6 6

Guy’s/Manchester’4” ManchestedGuy’s’4’ Heidelberg’4z Stockholm/Gottland’4”

1975-1979 1976-1983 1976 1976-1982

W. Midlandsl” Glasgow”” Denmark’4fi

1976-1984 1976- 1982 1977-1982

L-PAM CMF LF CMF CMF-AV

1% 12 24 12 6

386 240* 291* 370 327

Oxford’47 ECOG14’ UWAsia14” Ludwigl”

1977 1978-1981 1978 1978-1981

CMF CMF or C L-PAM ? MF CMFP +- T

13 12 24 1%

322 1,029s: 273 22411

CMF CMFPT CMF, Vlb

18 12 36

399 50311 241

Viennaz51

Drug(sH

No. of Patients Entered

Group/Institution

NSABP=” MilanIs Osako &vis~j’~~ English multicentc?’

y,

Duration of Therapy imo.1

Were

+ BCG

100 331’ 462

*From Henderson IC: Primary treatment of breast cancer, in Harris JR, Hellman S, Henderson IC, et al (edsl: Breast /&eases. Philadelphia, JB Lippincott Co, 1987, pp 324-353. Used by permission. tThiotepa = N,N’N”-triethylenethiophosphoramide; F = 5.fluomuracil; C = Lyclophosphamide; M = methotrexate; L = chlorambucfi; Vlb = vinblastine; P = prednisone; MMC = mitomycin C; T = tamoxifen; L-PAM = L-phenylalanine mustard; A = doxorubicin; V = vincristine. “Some node-negative patients are included. 5Only premenopausal patients are entered. llOnly postmenopausal patients are included.

ies in which postmenopausal patients did not receive dose reduction because of age, the results were the same as in the premenopausal group. When looked at by biologic parameters such as thymidine labeling reflecting growth rate, subgroups with a high labeling index had prolonged DFS when treated with chemotherapy compared with a control group. Those patients with low labeling indices had no improvement in survival when treated. These results were the same in premenopausal and postmenopausal groups. NODE-NEGATIVE

STUDIES

On May 16, 1988, the NC1 issued a clinical alert describing the results of three randomized studies conducted on patients with nodenegative breast cancer. The follow-up was 3 to 4 years for all three studies. DM,February1990

107

TABLE

10.

Results of Trials Were Randomized

in Which Premenopausal Women With to Prolonged Chemotherapy or Local

Histologically Positive Therapy Only?

Nodes

Survival OV%Lll

Disease-free No. of Patients

Trial NSABP”’ Milanls7

Follow-up

120

JJenmark14” osako’53 G/M L-PAMI~” M/G CMF14’ W. Midlands144 Glasgow14” Oxford*47 Heidelberg14’

@id*

Trend

10 10 6

189 1,029 60 156 168

5 5 5 5

228 ND 117 62

P Value

+

0.026

+ + + + +

0.0005 0.001 0.64

ND +

0.02 0.0% 02 ND

+ ND ND ND ND +

ND NS 0.2

+

P value

+ +

0.14 0.0% O.OlY

+

4 5 1.5

Trend

ND ND ND 0.5 NS ND

0 ND

‘From Henderson IC: Primary treatment of breast cancer, in Harris JR, Hellman S, Henderson IC, et al iedsl: Breast Diseases. Philadelphia, JR Lippincott Co, 1987, pp 324-353. Used by permission. KM, MG = Guy’s and Manchester Hospital; ND = no data; ND = no date; NS = not significant; + = disease-free or overall survival of treated patients superior to control group. *Date of longest follow-up shown on actuarial disease-free or survival curves for this group of patients.

TABLE

11.

Results of Trials Were Randomized

in Which Postmenopausal Women With to Prolonged Chemotherapy or Local

Histologically Positive Therapy Only*?

Disease-f?ee Trial

No. of Patients

Follow-up

i.yryri*

Trend

Nodes

Overall

P Value

Trend

P Value

NSARP1’= Milan’37 Stockholm/Gottland143 Osakols”

229 197 331 58

10 10 7 5

+ + +

0.49 0.32 0.01 0.57

+ + ND

0.80 0.89 0.36 ND

LudwigIs W. Midlands144 M/G CMF=

463 234 153

5 5 5

+ +

<0.0001 0.37 0.2

+ ND ND

0.76 ND ND

G/M l,-PAM1“ Oxford-” ECOG*@ HeidelbergI*’

214 156 224 21

5 5 4 1.5

+ 0 0 +

0.39 NS 0.09 NS

ND 0 ND

ND NS 0.82 ND

*From Henderson IC: Primaly treatment of breast cancer, in Harris JR, Hellman S, Hendsrson IC, et al (eds): BreastDiseases. Philadelphia, JB Lippincott Co, 1987, pp 324-353. Used by permission. tG/M, M/G = Guy’s and Manchester Hospitals; ND = no data; NS = not significant, precise P value not given; + = disease-free or overall survival of treated group superior to control group. *Date of longest follow-up show on actuarial disease-free or suwivaI curves for this group of patients.

108

DA4,Februaryl990

In the NSABP B-13 study, ERP-negative premenopausal and postmenopausal patients were randomized between observation and 13 4-week cycles of methotrexate, citrovorum factor, and 5fluorouracil. At 4 years, 80% of the treated group and 71% of the control group were alive and disease free.165 In the NSAPB B-14 study, ERP-positive premenopausal and postmenopausal patients were randomized to placebo or 10 mg of tamoxifen twice daily for 5 years. At 4 years of median follow-up, 82% of the tamoxifen group and 77% of the placebo group are alive and disease-free.lfifi The Intergroup Study (INT-DOll) initiated by the Eastern Cooperative Oncology Group and joined by the Southwest Oncology Group and the Cancer and Leukemia Group B randomized premenopausal and postmenopausal ERP-negative and ERP-positive patients with tumors greater than 3 cm to observation or 6 months of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone. At 3 years’ median follow-up, the treated group had 84% disease-free survival compared with 67% in the control group.167 These data have not reached full maturity, and as yet no survival differences have been demonstrated. The alert has fueled an already controversial area, raising questions as to which patient subgroups and which tumor characteristics predict the need for adjuvant treatment .16’, 16’ There is no general agreement, but the second-generation node-negative trials are aimed at developing better information concerning the biology and natural history of this disease to better enable the physician and patient to make these decisions. RECOMMENDATIONS Although many studies have been completed and the NC1 consensus as well as a more recent analysis have been published, recommendations for patients must be individualized. In each case the risk factors for metastatic disease must be weighed against the morbidity and cost of adjuvant therapy and followed by a mutual decision made by the physician and patient.ls” In general, all patients should be entered on clinical trials, and there is almost no patient for whom a trial would not be available. More intensive therapy and preoperative (neoadjuvant) therapy are currently being tested for node-positive groups,170-17Z whereas biologic questions concerning natural history and prognostic variables are being examined in node-negative trials. Concluding that our past therapy is “standard” may contribute to inertia in moving forward toward better results. For patients who do not qualify or refuse adjuvant trials, the conclusions of the Consensus Conference and the Clinical Alert can serve as guidelines. DM,

February1990

109

TREATMENT

OF METASTATIC

BREAST

CANCER

RATIONALE

Treatment of metastatic breast cancer is designed to alleviate or prevent suffering and prolong life. Cure has not been possible with our current therapies. Survival is variable after the development of metastatic disease, with median survival ranging from 11 to 24 months, 5-year survival of 5% to X3%, and some patients (5%) living for 10 to 15 years with metastatic disease. The prognosis is dependent on site or sites of relapse, with bone better than visceral relapse and single-site better than multiple-site relapse. The longer the disease-free survival, the better the prognosis, and those with hormonepositive tumors have a longer survival than those with hormone-negative tumors.173J 174 Sites of metastatic disease listed in order of frequency include bone, lung, pleura, liver, soft tissue, and central nervous system. Any site can be involved, including the GI tract and meninges.88 The approach to patients with metastatic disease has not changed significantly in recent years. Diagnostic tools have improved with computed tomography and magnetic resonance imaging providing much more sensitive studies of the brain, spinal cord, and liver. Radionuclear bone scans remain the most sensitive tool for evaluating bone metastases in most patients. For the usual patient, the sites of metastatic disease, hormone receptor status, presence or absence of symptoms, and past therapies will indicate the approach to metastatic sites. Since cure is not currently achievable, the strategy should be to give the simplest, least toxic treatment that will achieve the desired goal while carefully watching for known potentially debilitating progression that would require a change in therapy. Certain factors are known: 1. Brain and spinal cord metastases are generally unaffected by systemic hormone or chemotherapy, but may rarely respond to systemic therapy.17’ 2. Rapidly growing liver or lung metastases are not effectively treated by hormone therapy. 3. Radiation therapy is effective for local problems. 4. The presence of hormone receptors predicts a 60% to 70% chance of response to hormonal therapy, and the absence of receptors predicts a 90% failure rate of hormone therapy.88’ 17’ 5. The combination of chemotherapy and hormone therapy has not consistently shown a change in survival, although the combination may alter the response rate.177-181 6. Combination chemotherapy has a superior response rate when compared with single-agent therapy.18” ls3 110

DM,

February1990

RADIATION

THERAPY

FOR METASTATZC

BREAST

CANCER

Radiation is an important modality in the treatment of symptomatic metastatic disease. The most common indication for treatment is painful bone metastases. Approximately 90% of patients treated will obtain significant pain relief.lS4 Radiation is also an important modamy in the palliative treatment of metastatic brain lesions, spinal cord lesions,ls5’ ls6 eye-orbit lesions,187 and nodal metastases. Radiation to treat painful hepatic lesionsl” or symptomatic thoracic metastasislss can also be beneficial in certain circumstances. SYSTEMZC

THERAPY

An approach to metastatic disease is illustrated in Figure 10. The sites involved influence the type and sequence of therapy.

Metastases

Noted

Delineate Site Involved (CT Head, ? CT, Liver, Bone Scan)

Evaluate for Clinical

Trial

/-

Enter TTrial

No trial available d

Failed Visceral

’ + l1 ERPERP Minimal disease

Hormonal

ERP- -

Chemotherapy

therapy

FIG 10. Approach

to therapy

DA4, February1990

for metastatic

drsease 111

This information, along with the ERP value, guides initial therapy. Patients should be evaluated for eligibility in clinical trials early. These trials are important for continued improvement in therapy foI all concerned but may also offer a treatment advantage for individual patients by providing agents not otherwise available. Since prior therapy may make patients ineligible for many of these trials, the decision to participate should be considered before initiation of therapy. Hormonal Therapy Patients who are ERP positive or who are elderly with metastatic disease involving bone, soft tissue, and non-life-threatening visceral organ involvement should be considered for hormonal manipulation. Oophorectomy was the first systemic approach taken for metastatic breast cancer and remains an initial option in premenopausal patients.1g0-1g2 Tamoxifen,1s3-1s7 a competitive ERP blocker, may be used in nonoophorectomized patients, but controversy exists concerning the appropriate dose and the ability of the ovary to eventually overcome the blockage by producing higher levels of estrogen.7Y8’ lgy There may be other unrecognized factors since patients failing tamoxifen may respond to oophorectomy. The new LH-FSH agonist Zoladex”’ may obviate the need for oophorectomy, but confirmation studies are not complete. Other modalities include adrenalectomy,zo1 hypophysectomy, diethylstilbestrol, androgens, progestins,“’ and aminoglutethimide.203--205 The response to hormonal manipulation is not significantly different among the options available. Therefore, the initial choice should be tailored to the specific patient with convenience, toxicity, and cost in mind. The time to response varies, but an adequate trial may take 8 weeks. An initial flare of the disease may be seen, including hypercalcemia, and should be treated by withholding the agent and cautiously restarting. There is also a therapeutic benefit noted on withdrawal of an agent that should be taken advantage of if possible. Rapid progression or lack of initial response may indicate the need for chemotherapy.“‘” Cytotoxic Chemotherapy The chemotherapeutic agents that have activity in breast cancer, listed in order of activity, include: doxorubicin,Z07’208 cyclophosphamide, &fluorouracil, methotrexate, vincristine, vinblastine, and mitothat has activity when used together but mycin C .‘Os A combination not alone is etoposide-cisplatin.“10 Mitoxantrone is also an active agent that has recently been approved for use.“” Combination therapy has a higher response rate and perhaps 112

DM,

February

1990

longer survival than sequential single-agent commonly used combinations are:

therapy?l’

The most

1. “Cooper”: cyclophosphamide, 2 mg/kg/day orally; methotrexate, 0.7 mg/kg/week intravenously for 8 weeks; 5-fluorouracil, 12 mg/kg/week for 8 weeks and then every other week; vincristine, 3’5 Fg/kg/week for 4 to 5 weeks; and prednisone, 0.75 mg/kg/ day, reduced by one half every 10 days to 5 mg/day for 3 weeks. 2. CMF: cyclophosphamide, 100 mg/m” orally from day 1 to 14; methotrexate, 30 to 40 mg/m” intravenously on days 1 and 8; and 5-fluorouracil, 400 to 600 mg/m’ intravenously on days 1 and 8; all repeated every 28 days. 3. FAC: 5-fluorouracil, 400 mg/m’ intravenously on days 1 and 8; doxorubicin, 40 mg/m” intravenously on day 1; and cyclophosphamide, 400 mg/mz intravenously on day 1; all repeated every 28 days. Almost all treatment can be given on an outpatient basis.” Numerous other combinations exist, but none provides a far superior response. New areas of investigation involve the use of combination chemotherapy and hormone therapy in a sequential administration to biologically recruit cancer cells into a more susceptible growth phase for better cell kill by the chemotherapy. Drug dose, most commonly limited by myelosuppression, is being markedly escalated when used in combination with autologous marrow transplant or with growth factors that stimulate marrow production.213-215 Complications and Terminal Care If cure is not to be achieved, providing the best quality of life is important. This means different things to different people. Some patients find that a ‘no therapy” approach is unacceptable from a physical as well as a psychologic standpoint. Others fear side effects of therapy more than complications of their cancer and refuse medical intervention. Most patients and their families have difficulty in separating symptoms caused by treatment from those caused by the cancer, and the physical changes caused by therapy (e.g., alopecia, skin changes, mastectomy) also may have a strong emotional impact. All of these factors should be considered when one is caring for patients. Complications known to cause tremendous morbidity include pathologic bone fractures, brain metastases, spinal cord compression, and hypercalcemia. Other complications can occur but are seen with less frequency in breast cancer patients. Anticipation of these problems can help guide the use of imaging techniques, laboratory tests and specific radiation therapy or surgery for fractures or DM,

February1990

113

central nervous system disease, or medication and hydration for hypercalcemia. Control of pain and nausea has improved, and even better antiemetics are on the horizon. The use of continuous IV or epidural morphine has allowed outpatient control of pain that has previously been difficult to control. Control of symptoms should be the major determinant in recommending therapy if cure is not achievable. FOLLOW

UP OF THE

PATIENT

WITH

BREAST

CANCER

Optimal management of the patient with breast cancer requires a multidisciplinary approach. Most patients are seen initially by the surgeon for a breast mass or abnormal mammogram. We believe that all patients with cancer should be seen by the medical oncologist and radiotherapist prior to surgery. Only with input from all three disciplines can the best treatment decision be made for each patient . Patients should have mammograms of the contralateral breast yearly and routine physical examination of the remaining breast, axillae, mastectomy incision, chest wall, and abdomen. It is our practice to follow patients at 3-month intervals for the first 2 years, 6month intervals for the next 2 years, and then at yearly intervals. If the medical oncologist is allowed to order all tests, duplication and increased costs are kept to a minimum. The surgeon’s attention is directed to rehabilitation, identification of local or regional failure, or the development of a new primary cancer in the opposite breast. SUMMARY

Our understanding of breast cancer has evolved due to advances in tumor biology and the results of randomized clinical trials. In spite of the fact that breast cancer is frequently a systemic disease, local-regional control is achieved by surgery in the majority of patients. Selected patients are candidates for breast conservation. Patients who present with advanced local tumors may have successful management with combined therapy. As screening mammography increases, more noninvasive lesions have been identified. Breast cancer is a great burden for our society and for the health care system. It is a greater burden for those who have it. We must do all we can to cure those who can be cured and provide understanding care for those who cannot. REFERENCES 1. Brinton screening 114

LA, Williams program

RR, Hoover participants.

RN, et al: Breast cancer risk factors J Natl Cancer Inst 1979; 62:37-43. DM,

among

February1990

2. MacMahon B, Cole P, Brown J: Etiology of human breast cancer: A review. J Nat1 Cancer Inst 1973; 5021-42. 3. Miller AB, Bulbrook KD: The epidemiology and etiology of breast cancer. N Engl J Med 1980; 20:1246-1248. 4. Newman B, Austin, MA, Lee M, et al: Inheritance of human breast cancer: Evidence for autosomal dominant transmission in high-risk families. Proc Nat1 Acad Sci USA 1988; 85:3044-3048 5. Pathak S, Goodacre A: Specific chromosome anomalies and predisposition to human breast, renal cell and colorectal carcinoma. Cancer Genet Cytogenet 1986; 19:29-36. 6. Anderson DE: A genetic study of human breast cancer. J Nat1 Cancer Inst 1972; 48:10291034. 7. Pathak DK, Speizer FE, Willett WC, et al: Parity and breast cancer risk: Possible effect on age at diagnosis. Int J Cancer 1986; 37:21-25. 8. White E: Projected changes in breast cancer incidence due to trend toward delayed childbearing. Am J Public Health 1987; 77(4):495-497. 9. Irwin KL, Lee NC, Peterson HB, et al: Hysterectomy, tubal sterilization and the risk of breast cancer. Am J Epidemiol 1988; 127(6):1192-1201. 10. Marchand LL, Kolonel LN, Earle ME, et al: Body size at different periods of life and breast cancer risk. Am J Epidemiol 1988; 128:137-152. 11. Newman SC, Miller AB, Howe GR: A study of the effect of weight and dietary fat on breast cancer survival time. Am J Epidemiol 1986; 123:767-774. 12. Black MM, Barclay THC, Cutler SJ, et al: Association of atypical characteristics of benign breast lesions with subsequent risk of breast cancer. Cancer 1972; 29:338-343. 13. Manse1 RE: Benign breast disease and cancer risk: New perspectives. Ann NY Acad Sci 1986; 464:364366. 14. McGregor DH, Land CE, Choi K, et al: Breast cancer incidence among atomic bomb survivors, Hiroshima and Nagasaki, 1950-69. J Nat1 Cancer Inst 1977; 59:799-811. 15. Shore RE, Hempelmann LH, Kowaluk E, et al: Breast neoplasms in women treated with x-rays for acute postpartum mastitis. J Nat1 Cancer Inst 1977; 59:813-822. 16. Harvey EB, Schairer C, Brinton LA, et al: Alcohol consumption and breast cancer. J Nat1 Cancer Inst 1987; 78:657-661. 17. Stamper MJ, Colditz GA, Willet WC: Alcohol intake and risk of breast cancer. Compre Ther 1988; 14:8-15. 18. Longnecker MP, Berlin JA, Orza MJ, et al: A meta-analysis of alcohol consumption in relation to risk of breast cancer. JAMA 1988; 260:652-656. 19. Ottman R, King MC, Pike MC, et al: Practical guide for estimating risk for familial breast cancer. Lancet 1983; 2:556-558. 20. Hislop TG, Coldman AJ, Elwood JM, et al: Relationship between risk factors for breast cancer and hormonal status. Int J Epidemiol 1986; 1.5:469-476. 21. Ota DM, Jones LH, Jackson GL, et al: Obesity, non-protein-bound estradiol levels, and distribution of estradiol in the sera of breast cancer patients. Cancer 1986; 57:558-562. 22. Hirahuta T, Shigematsu T, Nomura AMY, et al: Occurrence of breast cancer in relation to diet and reproductive history: A case-control study in Fukuoka, Japan. Nat1 Cancer Inst Monogr 1988; 69:187-190. 23. Verrault R, Brisson J, Deschenes L, et al: Dietary fat in relation to prognostic indicators in breast cancer. J Nat1 Cancer Inst 1988; 80:819-825. 24. Tornberg SA, Holm LE, Carstensen JM: Breast cancer risk in relation to seDM,February1990

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25.

26. 27. 28. 29. 30.

31. 32. 33. 34. 35.

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