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Breast Cancer
Table of Contents
- General Information
- Celluar Classification
- Stage Information
Inflammatory breast cancer
- Treatment Option Overview
- Breast Cancer in Situ
Intraductal carcinoma
- Lobular carcinoma in situ
- Stage I Breast Cancer
Primary therapy
- Adjuvant therapy
- Timing of primary and adjuvant therapy
- Initial surgical management
- Adjuvant therapy
- Stage II Breast Cancer
Primary therapy
- Adjuvant therapy: stage II positive nodes
- Adjuvant therapy: stage II negative nodes
- Timing of primary and adjuvant therapy
- Initial surgical management
- Adjuvant therapy
- Stage III Breast Cancer
Stage IIIA
- Stage IIIB (locally advanced, including inflammatory)
- Stage IV Breast Cancer
- Inflammatory Breast Cancer
- Recurrent Breast Cancer
(Separate summaries containing information on prevention of breast cancer, screening
for breast cancer, breast cancer and pregnancy, and male breast cancer are also available
in PDQ.)
Breast cancer, which is highly treatable by surgery, radiation therapy, chemotherapy,
and hormonal therapy, is most often curable when detected in early stages. Mammography is
the most important screening modality for the early detection of breast cancer. Breast
magnetic resonance imaging is under study as a diagnostic tool.[1]
Prognosis and selection of therapy are influenced by the age of the patient,[2] stage of the disease, pathologic characteristics of the primary
tumor including the presence of tumor necrosis,[3]
estrogen-receptor (ER) and progesterone-receptor (PR) levels in the tumor tissue, and
measures of proliferative capacity, as well as by menopausal status and general health.
Since criteria of menopausal status vary widely, age older than 50 years can be
substituted as a definition of the postmenopausal state. Overweight patients may have a
poorer prognosis.[4] Prognosis may also vary by race, with blacks,
and to a lesser extent Hispanics, having a poorer prognosis than whites.[5] Breast cancer is classified into a variety of cell types, but only
a few of these affect prognosis or selection of therapy. Rarely, the breast may be
involved by other tumors such as melanoma, lymphoma, or sarcoma.
Female relatives of patients with breast cancer may have an increased risk of the
disease. Age-specific risk estimates are available to help counsel these women and to
design screening strategies for them.[6,7]
It is estimated that approximately 5% of all women with breast cancer may have germ-line
mutation(s) in a gene (BRCA1) localized to chromosome 17q21. Their relatives, if carriers
of the BRCA1 mutation(s), may have an increased lifetime risk of breast cancer with many
of the breast cancers occurring prior to age 50 years. Specific mutations of the BRCA1
gene may be more common in certain ethnic groups.[8] Ovarian
cancer risk is also elevated in patients with the BRCA1 mutation.[9]
A second gene, BRCA2, has been localized to chromosome 13q12-13. BRCA2 confers a high risk
of breast cancer and, to a lesser extent, ovarian cancer.[10] As
practical assays are developed and validated, such detectable genetic abnormalities may be
used to screen members of high-risk families.[11-15] Refer to the PDQ summaries on screening for breast cancer and
prevention of breast cancer for more information.
Hormonal contraceptives have been associated with a slight increase in the risk of
breast cancer in a large overview analysis of 54 epidemiologic studies.[16] The relative risk does vary with time from last use; current
users have a relative risk of 1.24. For women who have not taken contraceptives for 1 to 4
years, the risk is 1.16 and for women who have not taken contraceptives for 5 to 9 years,
the risk falls to 1.07. For women who have not taken contraceptives for 10 years, there
appears to be no increased risk of breast cancer.
Patient management following initial suspicion of breast cancer generally includes
confirmation of the diagnosis, evaluation of stage of disease, and selection of therapy.
Diagnosis may be confirmed by aspiration cytology, core needle biopsy with a stereotactic
or ultrasound technique for nonpalpable lesions, or incisional or excisional biopsy. At
the time the tumor tissue is surgically removed, part of it should be processed for
determination of ER and PR levels. Assay procedures are technically demanding, and the
laboratory should use appropriate quality control procedures.[17]
Charcoal, enzyme immunoassay, or enzyme immunocytochemical assays may be done.[18-20]
Although anatomic stage (size of primary tumor, axillary node status) remains an
important prognostic factor,[21-24]
other histologic and biologic characteristics may have predictive value.[25,26] Studies from the National Surgical
Adjuvant Breast and Bowel Project (NSABP) [17] and the
International Breast Cancer Study Group (IBCSG) [27] have shown
that tumor nuclear grade and histologic grade, respectively, are important indicators of
outcome following adjuvant therapy for breast cancer. Morphologically determined tumor
necrosis may be a prognostic variable for early recurrence.[3]
However, the prognostic significance of these pathologic factors outside these study
groups is unclear. In addition, the IBCSG has reported that serial sectioning of
ipsilateral axillary lymph nodes judged to be disease-free after routine histologic
examination reveals micrometastases in 9% of breast cancer patients and may identify a
higher-risk "node-negative" population,[28] confirming
reports by Friedman et al.[29] There is substantial evidence that
ER status and measures of proliferative capacity of the primary tumor (thymidine labeling
index or flow cytometric measurements of S-phase and ploidy) may have important
independent predictive value.[30-33] In
stage II disease, the PR status may have greater prognostic value than the ER status.[34] Tumor microvessel density, c-erbB-2, c-myc, p53 expression, and
peritumoral lymphatic vessel invasion may also be prognostic indicators in patients with
node-negative breast cancer.[35-41]
Several retrospective reviews demonstrate a significantly better disease-free survival
for premenopausal women with breast cancer and positive axillary lymph nodes operated on
during the luteal phase (days 15-36) as compared to those operated on during the
follicular phase (days 0-14) of their menstrual cycle.[42-44] However, several other studies have failed to confirm this
finding or have found opposite results.[45-47]
Because of the inconsistent results of these studies, it would be premature to mandate a
modification in the scheduling of breast cancer operations according to the patient's
menstrual cycle.
Pathologically, breast cancer is frequently a multicentric disease. However, clinical
diagnosis of two or more primary cancers in a single breast is uncommon.[48] Similarly, simultaneous bilateral breast cancer is unusual. It
is more common in patients with infiltrating lobular carcinoma. Patients who have breast
cancer should have bilateral mammography at the time of diagnosis to rule out synchronous
disease. They should also continue to have regular breast physical examinations and
mammography to detect either asynchronous disease in the ipsilateral breast in those
patients treated with breast- conserving surgery and radiation therapy or a second primary
cancer in the contralateral breast.[49] The risk of a primary
breast cancer in the contralateral breast is significant, approximately 1% per year.[26,50] Patient age of less than 55 years at
the time of diagnosis or lobular tumor histology appear to increase this risk to 1.5%.[51] The development of a contralateral breast cancer is associated
with an increased risk of distant recurrence.[52]
Some retrospective studies suggest that perioperative blood transfusion impairs
survival in breast cancer patients.[53] Although other
retrospective studies have not confirmed the association between transfusion and
prognosis,[54] limiting the transfusion of blood to breast cancer
patients whenever medically feasible seems prudent. A modified radical mastectomy rarely
requires blood transfusion if performed by an experienced surgeon, even when combined with
submuscular insertion of an implant to restore breast contour. When breast contour
following modified radical mastectomy is to be restored using a tissue flap, the need for
blood transfusions should be anticipated. Provision for autologous blood transfusions in
that setting is recommended.
Even when standard therapy is effective, patients with breast cancer are appropriately
considered as candidates for clinical trials designed to improve therapeutic results and
decrease the morbidity of treatment. There is convincing evidence from randomized trials
that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests
of liver function do not improve survival or quality of life when compared to routine
physical examinations.[55,56] Even when
these tests permit earlier detection of recurrent disease, patient survival is
unaffected.[56] Based on these data, some investigators feel
acceptable follow-up for asymptomatic patients after completion of their treatment of
stages I-III breast cancer can be limited to physical examination along with annual
mammography. In patients treated with lumpectomy and radiation, the detection of in-breast
recurrence by physical examination and/or mammography can lead to curative mastectomy. In
one series of 30 patients who failed locally after lumpectomy plus radiation therapy and
who underwent salvage mastectomy, no distant recurrences were seen later than 6 years
after initial local failure, and the disease-free survival following salvage mastectomy
was 58% at 5 years and 50% at 10 years.[57-61]
The intensity of follow-up and the appropriateness of screening tests after the completion
of primary treatment of stages I-III breast cancer remain controversial.
Increasingly, hormone replacement therapy (HRT) is prescribed for many postmenopausal
women in the United States both to decrease acute menopausal symptoms and to promote long
term health benefits. More precise quantitation of those latter benefits with current HRT
regimens is presently under study (Women's Health Initiative Trial), but the benefits are
potentially important. A study involving 121,000 nurses has shown that HRT taken for 5
years is associated with a reduced risk of coronary artery disease deaths as well as death
from cancer. After 10 years of HRT, the magnitude of the reduction in risk of death is
partially attenuated due to an increased risk of death in women taking HRT for more than
10 years.[62,63]
With rising numbers of breast cancer survivors, many of whom are entering menopause
prematurely due to adjuvant hormonal or chemotherapy treatment, HRT for these women poses
a dilemma. HRT is generally not used for women with breast cancer because estrogen is a
proven growth factor for most breast cancer cells in the laboratory. However, a review of
the literature makes several pertinent observations based on clinical trials.[64,65] In addition, the prognosis of women
who took HRT before developing breast cancer appears better than that of women with no
such exposure. This may be a result of increased surveillance leading to detection of
tumors at an earlier stage and may not be a result of the HRT.[66]
Neither pregnancy after breast cancer nor the use of oral contraceptive pills before a
diagnosis of breast cancer has been shown to adversely impact survival when controlled for
stage of disease. These findings provide the rationale for prospective clinical trials
testing the impact of HRT on breast cancer recurrence and on the development of new
tumors. Such research is planned in carefully selected women with breast cancer at
relatively low risk of relapse. The routine use of HRT should await these results.[65]
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density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are
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to adjuvant therapy in women with node-positive early breast cancer. New England Journal
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surgical treatment of breast cancer. Lancet 343(8912): 1545-1547, 1994.
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menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet
337(8752): 1261-1264, 1991.
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surgery during menstrual cycle: a 5-year analysis of 385 pre-menopausal women.
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Infiltrating or invasive ductal cancer is the most common cell type, comprising 70%-80%
of all cases.
Lobular carcinoma involves both breasts more frequently than other histologic types.
Inflammatory carcinoma is a clinicopathologic entity characterized by diffuse brawny
induration of the skin of the breast with an erysipeloid edge, usually without an
underlying palpable mass.[1] Radiologically there may be a
detectable mass and characteristic thickening of the skin over the breast. This clinical
presentation is due to tumor embolization of dermal lymphatics with engorgement of
superficial capillaries. Inflammatory carcinoma is classified as T4d.
The following is a list of breast cancer histologic classifications:[1]
carcinoma, NOS (not otherwise specified)
ductal
- intraductal (in situ)
invasive with predominant intraductal component
invasive, NOS
comedo
inflammatory
medullary with lymphocytic infiltrate
mucinous (colloid)
papillary
scirrhous
tubular
other
lobular
- in situ
invasive with predominant in situ component
invasive [2]
nipple
- Paget's disease, NOS
Paget's disease with intraductal carcinoma
Paget's disease with invasive ductal carcinoma
other
- undifferentiated carcinoma
The following are tumor subtypes that occur in the breast, but are not considered to be
typical breast cancers:
cystosarcoma phyllodes
- Cystosarcoma phyllodes is a rare variant of breast cancer generally treated
with wide local excision. Although most patients are cured with such
treatment, the risk of developing local recurrence or metastases is related
to infiltrating margins, degree of stromal mitotic activity, nuclear
pleomorphism, and stromal overgrowth.[3]
angiosarcoma primary lymphoma
References:
- Breast. In: American Joint Committee on Cancer: AJCC Cancer Staging
Manual. Philadelphia: Lippincott-Raven Publishers, 5th ed., 1997, pp 171-180.
- Yeatman TJ, Cantor AB, Smith TJ, et al.: Tumor biology of infiltrating
lobular carcinoma: implications for management. Annals of Surgery 222(4): 549-561, 1995.
- Reinfuss M, Mitus J, Duda K, et al.: The treatment and prognosis of
patients with phyllodes tumor of the breast: an analysis of 170 cases. Cancer 77(5):
910-916, 1996.
This staging system provides a strategy for grouping patients with respect to
prognosis. Therapeutic decisions are formulated in part according to staging categories
but primarily according to lymph node status, estrogen- and progesterone-receptor levels
in the tumor tissue, menopausal status, and the general health of the patient.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM
classification.[1]
-- TNM definitions --
Primary tumor (T):
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ; intraductal carcinoma, lobular carcinoma in situ, or
Paget's disease of the nipple with no associated tumor.
Note: Paget's disease associated with a tumor is classified according to
the size of the tumor.
T1: Tumor 2.0 cm or less in greatest dimension
T1mic: Microinvasion 0.1 cm or less in greatest dimension
T1a: Tumor more than 0.1 but not more than 0.5 cm in greatest dimension
T1b: Tumor more than 0.5 cm but not more than 1.0 cm in greatest dimension
T1c: Tumor more than 1.0 cm but not more than 2.0 cm in greatest dimension
T2: Tumor more than 2.0 cm but not more than 5.0 cm in greatest dimension
T3: Tumor more than 5.0 cm in greatest dimension
T4: Tumor of any size with direct extension to (a) chest wall or (b) skin,
only as described below.
Note: Chest wall includes ribs, intercostal muscles, and serratus
anterior muscle but not pectoral muscle.
T4a: Extension to chest wall
T4b: Edema (including peau d'orange) or ulceration of the skin of the
breast or satellite skin nodules confined to the same breast
T4c: Both of the above (T4a and T4b)
T4d: Inflammatory carcinoma
Regional lymph nodes (N):
NX: Regional lymph nodes cannot be assessed (e.g., previously removed)
N0: No regional lymph node metastasis
N1: Metastasis to movable ipsilateral axillary lymph node(s)
N2: Metastasis to ipsilateral axillary lymph node(s) fixed to one another or
to other structures
N3: Metastasis to ipsilateral internal mammary lymph node(s)
Pathologic classification (pN):
pNX: Regional lymph nodes cannot be assessed (not removed for pathologic
study or previously removed)
pN0: No regional lymph node metastasis
pN1: Metastasis to movable ipsilateral axillary lymph node(s)
pN1a: Only micrometastasis (none larger than 0.2 cm)
pN1b: Metastasis to lymph node(s), any larger than 0.2 cm
pN1bi: Metastasis in 1 to 3 lymph nodes, any more than 0.2 cm and all
less than 2.0 cm in greatest dimension
pN1bii: Metastasis to 4 or more lymph nodes, any more than 0.2 cm and
all less than 2.0 cm in greatest dimension
pN1biii: Extension of tumor beyond the capsule of a lymph node
metastasis less than 2.0 cm in greatest dimension
pN1biv: Metastasis to a lymph node 2.0 cm or more in greatest dimension
pN2: Metastasis to ipsilateral axillary lymph node(s) fixed to one another
or to other structures
pN3: Metastasis to ipsilateral internal mammary lymph node(s)
Distant metastasis (M):
MX: Presence of distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis present (includes metastasis to ipsilateral
supraclavicular lymph nodes)
-- AJCC stage groupings --
-- Stage 0 --
Tis, N0, M0
-- Stage I --
T1,* N0, M0
*T1 includes T1mic
-- Stage IIA --
T0, N1, M0
T1,* N1,** M0
T2, N0, M0
*T1 includes T1mic
**The prognosis of patients with pN1a disease is similar to that of patients
with pN0 disease.
-- Stage IIB --
T2, N1, M0
T3, N0, M0
-- Stage IIIA --
T0, N2, M0
T1,* N2, M0
T2, N2, M0
T3, N1, M0
T3, N2, M0
*T1 includes T1mic
-- Stage IIIB --
T4, Any N, M0
Any T, N3, M0
-- Stage IV --
Any T, Any N, M1
Inflammatory breast cancer
Inflammatory carcinoma is a clinicopathologic entity characterized by diffuse brawny
induration of the skin of the breast with an erysipeloid edge, usually without an
underlying palpable mass. Radiologically there may be a detectable mass and characteristic
thickening of the skin over the breast. The clinical presentation is due to tumor
embolization of dermal lymphatics or to capillary congestion. Inflammatory carcinoma is
classified T4d.
References:
- Breast. In: American Joint Committee on Cancer: AJCC Cancer Staging
Manual. Philadelphia: Lippincott-Raven Publishers, 5th ed., 1997, pp 171-180.
The choice of breast cancer treatment is influenced by tumor stage and estrogen- and
progesterone-receptor levels and by patient age and menopausal status. All newly diagnosed
patients with breast cancer may appropriately be considered as candidates for one of the
numerous ongoing clinical trials designed to improve survival and decrease the morbidity
of current conventional treatment.
A separate summary containing information on breast cancer and pregnancy is also
available in PDQ.
The designations in PDQ that treatments are "standard" or "under
clinical evaluation" are not to be used as a basis for reimbursement determinations.
Carcinoma in situ is classified as either intraductal carcinoma in situ (DCIS) arising
from ductal epithelium or lobular carcinoma in situ (LCIS) arising from the epithelium of
the lobules.[1] With the increasing use of screening mammography,
noninvasive cancers are more frequently diagnosed and now constitute 15%-20% of all breast
cancers. DCIS usually presents as microcalcifications or as a soft-tissue abnormality.[2] There are several histologic subtypes: micropapillary, papillary,
solid, cribriform, and comedocarcinoma. Some evidence suggests that comedocarcinoma may be
more aggressive and associated with a higher probability of microinvasion.[3] LCIS is usually an incidental finding when a biopsy is done for
some other abnormality. Data suggest that LCIS is a risk factor for invasive cancer.[4] Because it may be difficult to distinguish DCIS from atypical
hyperplasia and because certain forms of DCIS may be confused with LCIS, it may be helpful
to obtain a second histopathologic interpretation of the biopsy specimen.
Intraductal carcinoma
The customary treatment of DCIS was previously mastectomy. This treatment results in a
combined local and distant recurrence rate of 1%-2%. Experience with breast-conserving
surgery and radiation therapy suggests that it is a reasonable alternative. Breast cancer
recurrence rates of 9%-21% are seen, and one half of these recurrences are invasive
carcinomas. Salvage of recurrences with mastectomy is feasible, and survival remains
excellent and comparable to primary mastectomy.[5] Although no
randomized comparisons of mastectomy versus breast-conserving surgery plus breast
irradiation have been done, the National Surgical Adjuvant Breast and Bowel Project
(NSABP) study B-17 randomly assigned 818 women with localized DCIS and negative margins
following excisional biopsy to breast irradiation (50 Gy) or no further therapy.[6-8] On both treatment arms, 80% of the
patients were diagnosed by mammography and 70% had small lesions (</= 1.0 centimeter).
In the irradiated group, 8-year event-free survival was improved, due entirely to a
decrease in ipsilateral breast cancers. At 8 years, the cumulative incidence of recurrent
DCIS was reduced by radiation from 13.4% to 8.2% (P = .007), and, more importantly,
occurrence of invasive cancer decreased from 13.4% to 3.9% (P <.001). Overall, 14
deaths (1.1%) from breast cancer have been reported thus far in this trial. The NSABP
investigators concluded that local excision and breast irradiation is an acceptable
alternative to mastectomy for treatment of localized DCIS.
To determine whether patients at high risk for recurrence could be identified, the
NSABP analyzed the pathologic material submitted for central review from 573 of the
original cohort of 818 women randomized in B-17.[9] Only the
absence of clear tumor margins and moderate to marked comedonecrosis were independent
predictors of ipsilateral breast tumor recurrence. However, even among cases with these
risk factors, the rate of recurrence after local excision and irradiation was not
sufficiently increased to make mastectomy necessarily preferable to complete local
excision and irradiation.
In addition to the B-17 randomized study results, several retrospective, nonrandomized
series from single institutions have demonstrated that there is a low ipsilateral
recurrence rate following local excision alone in carefully selected cases. Recurrence and
the occurrence of invasive cancer appear to decrease with the addition of breast
irradiation, even for the lowest-risk lesions, and this knowledge should be factored into
the decision-making process of those choosing excision alone. There is much debate among
pathologists over how to best identify low-risk DCIS lesions. Several pathologic staging
systems have been developed and tested retrospectively, but consensus recommendations have
not been achieved.[10-13] The Van Nuys
Prognostic Index (VNPI) was used to conduct a retrospective analysis of 333 patients
treated with either excision alone or excision and radiation, with a median follow-up of
79 months. The index requires independent, prospective validation prior to its adoption as
a paradigm for treatment.[14]
Patients with nonpalpable lesions and microcalcifications detected on mammography who
are considered for breast-conserving treatment should undergo careful mammographic
evaluation prior to biopsy, followed by needle localization biopsy. Radiography of the
oriented specimen should be performed to confirm that the lesion has been excised and to
direct pathologic sampling. A pathologist should give a careful gross description of the
excised specimen and should ink the specimen margins before sectioning to facilitate
margin evaluation on permanent section. The relation between the calcifications and the
lesion and the distance from the tumor to the inked margins of resection should be
described. Following biopsy, mammography should be repeated to confirm that all suspicious
microcalcifications have been removed. If residual microcalcifications are seen on
post-biopsy mammography, the primary site should be re-excised prior to beginning
radiation therapy. The choice of treatment when there is margin involvement by tumor is a
controversial issue. Frequently, if the original excision reveals positive margins, a
re-excision is done. Then, the extent of disease in the re-excision is evaluated and a
decision is made as to whether radiation therapy or mastectomy is appropriate. A
simultaneous low axillary dissection is not recommended, as positive lymph nodes are
rare.[15] Those patients with invasive disease in whom lymph node
involvement is documented should be managed as described under stage II.
Patients with persistent microscopic involvement of margins after local excision or
with a diagnosis of DCIS and evidence of suspicious, diffuse microcalcifications have
usually been treated with mastectomy. The NSABP has completed accrual to a trial (B-24)
comparing two treatment options for these patients. In this trial, 1,800 women with such
lesions were randomly assigned, following local excision, to receive either irradiation
plus tamoxifen or irradiation plus placebo, but the results are not yet available.
Surgical and radiotherapeutic techniques are extremely important in obtaining an
optimal therapeutic result and satisfactory cosmesis. The availability of specialized
equipment and radiation oncologists with expertise using these techniques should be
considered in the selection of treatment. Radiation side effects that can be minimized
with careful attention to technique include: myocardial damage for left-sided breast
lesions, radiation pneumonitis, arm edema, brachial plexopathy, and the risk of second
malignancies. Sarcomas in the treatment port and secondary leukemias are very rare. One
report suggests an increase in contralateral breast cancer for women under the age of 45
who have received radiation. Modern techniques to minimize radiation dose to the
contralateral breast should be used to keep the absolute risk as low as possible.[16,17]
There is no defined role for chemotherapy for the treatment of DCIS lesions and
hormonal therapy is under clinical evaluation. The NSABP trial B-24 has been completed and
results are awaited.
Lobular carcinoma in situ
LCIS is a controversial term; some prefer to call this lesion "lobular
neoplasia." The lesion is generally widely distributed throughout the breast and is
frequently bilateral. Data suggest that LCIS is a risk factor for invasive cancer.[4] The patient with LCIS has a 25% chance of developing an invasive
cancer (either lobular or, more commonly, infiltrating duct cancer) in either breast
within 25 years. The incidence of subsequent cancer is not related to the extent of focal
areas of LCIS within the breast. The clinical management of the patient with LCIS is
controversial; options include no treatment after biopsy with careful follow-up (physical
examination and mammography) or bilateral prophylactic mastectomies. Axillary lymph node
dissection is not necessary for the in situ lesion. Many physicians favor periodic
examination and mammography without further surgery, provided the patient is aware of the
risk of developing invasive cancer and is also aware of the possibility of developing
metastatic cancer before a clinical diagnosis is established.[18,19] Patients who have undergone local excision for LCIS are eligible
for a large multicenter clinical trial of tamoxifen to prevent development of invasive
cancer.[20]
For patients with either LCIS or DCIS who opt for a total mastectomy, reconstructive
surgery may be used. It may be done at the time of the mastectomy (immediate
reconstruction) or at some subsequent time (delayed reconstruction) in an attempt to
restore the anatomical deficit of the mastectomy.[21-24] Breast contour can be restored either by the submuscular
insertion of an artificial implant (saline-filled) or by a rectus muscle or other flap.
Both procedures offer satisfactory cosmetic results. Insertion of an artificial implant is
a relatively simple procedure. A saline-filled tissue expander can be inserted beneath the
pectoral muscle. Saline is used to expand it during a period of weeks or months until the
desired volume is obtained. The tissue expander is then replaced by a permanent implant.
Rectus muscle flaps, which offer a better cosmetic result, require a considerably more
complicated and prolonged operative procedure, and blood transfusions may be required.
There is no consistent evidence that a silicone implant induces cancer or autoimmune
disease. Problems associated with silicone implants include contracture of the capsule
around the implant causing hardening and pain, rupture of the implant with release of the
silicone gel, and infection.[25-27] In
rare instances, either procedure could make a local recurrence of cancer more difficult to
detect. Following breast reconstruction, radiation therapy can be delivered to the chest
wall and regional nodes either in the adjuvant setting or when local disease recurs.
Although this does not adversely affect outcome, cosmesis may be affected and the
incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[26] The use of silicone implants for breast augmentation may make
the early detection of breast cancer more difficult by obscuring and compressing breast
parenchyma.[25,27,28]
The Food and Drug Administration (FDA) has announced that silicone breast implants will be
available only through controlled clinical studies. Women who wish to undergo
reconstructive surgery following mastectomy will be assured access to those studies.
However, the FDA has placed no restrictions on the use of saline-filled breast implants,
which may constitute a reasonable alternative.
Standard treatment options for intraductal carcinoma (DCIS):[29-34]
- 1. Total mastectomy.
2. Breast-conserving surgery with radiation therapy.
Under clinical evaluation:
- Lumpectomy with radiation therapy with or without tamoxifen. The NSABP has
completed accrual to a trial (B-24) for which women were randomly
assigned, following local resection, to receive either radiation plus
tamoxifen or radiation plus placebo, but the results are not yet available.
Women who opt for local excision alone or lumpectomy with radiation therapy for DCIS
should have careful follow-up with regular mammography and physical examination to detect
asynchronous disease in breast tissue recurring in the ipsilateral breast.[35] Women treated with radiation therapy or mastectomy should also
have regular physical and mammographic examinations of the contralateral breast because of
the risk of a second primary.
Treatment options for lobular carcinoma in situ (LCIS):[36-38]
- 1. Long-term periodic examination with yearly mammography and follow-up after biopsy
without further therapy.[39]
2. A large multicenter clinical trial of tamoxifen to prevent development of invasive
cancer.
3. Bilateral total mastectomy.
References:
- Ariel IM, Cleary JB, Eds.: Breast Cancer - Diagnosis and Treatment. New
York: McGraw-Hill, 1987.
- Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ
of the breast. Annals of Internal Medicine 127(11): 1013-1022, 1997.
- Patchefsky AS, Schwartz GF, Finkelstein SD, et al.: Heterogeneity of
intraductal carcinoma of the breast. Cancer 63(4): 731-741, 1989.
- Fisher ER, Costantino J, Fisher B, et al.: Pathologic findings from
the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Cancer 78(7):
1403-1416, 1996.
- Solin LJ, Fourquet A, McCormick B, et al.: Salvage treatment for local
recurrence following breast-conserving surgery and definitive irradiation for ductal
carcinoma in situ (intraductal carcinoma) of the breast. International Journal of
Radiation Oncology, Biology, Physics 30(1): 3-9, 1994.
- Fisher B, Costantino J, Redmond C, et al.: Lumpectomy compared with
lumpectomy and radiation therapy for the treatment of intraductal breast cancer. New
England Journal of Medicine 328(22): 1581-1586, 1993.
- Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation
therapy for the treatment of intraductal breast cancer: findings from the National
Surgical Adjuvant Breast and Bowel Project B-17. Journal of Clinical Oncology 16(2):
441-452, 1998.
- Amichetti M, Caffo O, Richetti A, et al.: Ten-year results of
treatment of ductal carcinoma in situ (DCIS) of the breast with conservative surgery and
radiotherapy. European Journal of Cancer 33(10): 1559-1565, 1997.
- Fisher ER, Costantino J, Fisher B, et al.: Pathologic findings from
the National Surgical Adjuvant Breast Project (NSABP) protocol B-17. Cancer 75(6):
1310-1319, 1995.
- Page DL, Lagios MD: Pathologic analysis of the National Surgical
Adjuvant Breast Project (NSABP) B-17 trial: unanswered questions remaining unanswered
considering current concepts of ductal carcinoma in situ. Cancer 75(6): 1219-1222, 1995.
- Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the
counterpoint. Cancer 75(6): 1223-1227, 1995.
- Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a
proposal for a new classification. Seminars in Diagnostic Pathology 11(3): 167-180, 1994.
- Silverstein MJ, Poller DN, Waisman JR, et al.: Prognostic
classification of breast ductal carcinoma-in-situ. Lancet 345(8958): 1154-1157, 1995.
- Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for
ductal carcinoma in situ of the breast. Cancer 77(11): 2267-2274, 1996.
- Silverstein MJ, Gierson ED, Colburn WJ, et al.: Axillary
lymphadenectomy for intraductal carcinoma of the breast. Surgery, Gynecology and
Obstetrics 172(3): 211-214, 1991.
- Boice JD, Harvey EB, Blettner M, et al.: Cancer in the contralateral
breast after radiotherapy for breast cancer. New England Journal of Medicine 326(12):
781-785, 1992.
- Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast
due to primary breast irradiation. International Journal of Radiation Oncology, Biology,
Physics 11(3): 485-497, 1985.
- Frykberg ER, Santiago F, Betsill WL, et al.: Lobular carcinoma in
situ of the breast. Surgery, Gynecology and Obstetrics 164(3): 285-301, 1987.
- Ciatto S, Cataliotti L, Cardona G, et al.: Risk of infiltrating
breast cancer subsequent to lobular carcinoma in situ. Tumori 78(4): 244-246, 1992.
- Wolmark N, National Surgical Adjuvant Breast and Bowel Project:
Randomized, Placebo-Controlled Clinical Trial to Determine the Worth of Tamoxifen for
Preventing Breast Cancer (Summary Last Modified 01/98), NSABP-P-1, clinical trial, closed,
09/30/97.
- Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with
immediate breast reconstruction. American Surgeon 52(3): 129-133, 1986.
- Cunningham BL: Breast reconstruction following mastectomy. In:
Najarian JS, Delaney JP, Eds.: Advances in Breast and Endocrine Surgery. Chicago: Year
Book Medical Publishers, 1986, pp 213-226.
- Scanlon EF.: The role of reconstruction in breast cancer. Cancer
68(Suppl 5): 1144-1147, 1991.
- Hang-Fu L, Snyderman RK.: State-of-the-art breast reconstruction.
Cancer 68(Suppl 5): 1148-1156, 1991.
- Council on Scientific Affairs, American Medical Association: Silicone
gel breast implants. Journal of the American Medical Association 270(21): 2602-2606, 1993.
- Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast
reconstruction: clinical results and dosimetry. International Journal of Radiation
Oncology, Biology, Physics 21(2): 339-346, 1991.
- Bridges AJ, Vasey FB: Silicone breast implants: history, safety, and
potential complications. Archives of Internal Medicine 153(23): 2638-2644, 1993.
- Kessler DA, Merkatz RB, Schapiro R: A call for higher standards for
breast implants. Journal of the American Medical Association 270(21): 2607-2608, 1993.
- Stotter AT, McNeese M, Oswald MJ, et al.: The role of limited surgery
with irradiation in primary treatment of ductal in situ breast cancer. International
Journal of Radiation Oncology, Biology, Physics 18(2): 283-287, 1990.
- Bornstein BA, Recht A, Connolly JL, et al.: Results of treating
ductal carcinoma in situ of the breast with conservative surgery and radiation therapy.
Cancer 67(7): 7-13, 1991.
- McCormick B, Rosen PP, Kinne D, et al.: Duct carcinoma in situ of the
breast: an analysis of local control after conservation surgery and radiotherapy.
International Journal of Radiation Oncology, Biology, Physics 21(2): 289-292, 1991.
- Silverstein MJ, Waisman JR, Gierson ED, et al.: Radiation therapy for
intraductal carcinoma. Is it an equal alternative? Archives of Surgery 126(4): 424-428,
1991.
- Schnitt SJ, Silen W, Sadowsky NL, et al.: Ductal carcinoma in situ
(intraductal carcinoma) of the breast. New England Journal of Medicine 318(14): 898-903,
1988.
- Solin LJ, Fowble BL, Yeh I, et al.: Microinvasive ductal carcinoma of
the breast treated with breast-conserving surgery and definitive irradiation.
International Journal of Radiation Oncology, Biology, Physics 23(5): 961-968, 1992.
- Orel SG, Troupin RH, Patterson EA, et al.: Breast cancer recurrence
after lumpectomy and irradiation: role of mammography in detection. Radiology 183(1):
201-206, 1992.
- Walt AJ, Simon M, Swanson GM: The continuing dilemma of lobular
carcinoma in situ. Archives of Surgery 127(8): 904-909, 1992.
- Rosen PP: Lobular Carcinoma In Situ and Intraductal Carcinoma of the
Breast. In: McDivitt RW, Okerman MA, Ozzello L, et al., Eds.: The Breast Book. Baltimore:
Williams and Wilkens, 1984, pp 59-105.
- Osborne MP, Hoda SA: Current management of lobular carcinoma in situ
of the breast. Oncology (Huntington NY) 8(2): 45-49, 1994.
- Jager JJ, Langendijk JA, Dohmen JP, et al.: Mammography in the
follow-up after breast-conserving treatment in cancer of the breast: suitability for
mammographic interpretation, validity and interobserver variation. British Journal of
Radiology 68(811): 754-760, 1995.
Some citations in the text of this section are followed by a level of evidence. The PDQ
editorial boards use a formal ranking system to help the reader judge the strength of
evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels
of evidence summary for more information.
Primary therapy
Stage I breast cancer is often curable with a variety of surgical procedures. However,
10-20 year follow-up of patients managed with surgery alone now reveals that as many as
21% may ultimately relapse.[1] Surgical procedures that conserve a
major portion of the involved breast, followed by radiation therapy, provide tumor control
equivalent to more extensive surgical procedures. The diagnostic biopsy and the surgical
procedure that will be used as initial treatment are often performed as two separate
procedures. After the presence of a malignancy is confirmed and the histology is
determined, treatment options should be discussed with the patient before definitive
therapy is recommended. Estrogen-receptor (ER) and progesterone-receptor (PR) status
should always be determined for the primary tumor.[2]
In many cases, the diagnosis of breast carcinoma using core needle biopsy or fine
needle aspiration cytology or stereotactic core needle biopsy may be sufficient to confirm
malignancy. Core needle biopsy is now used in many centers because it provides a large
enough specimen for immunocytochemical analysis. It is then appropriate to discuss the
therapeutic options to help the patient with the treatment decision. Surgical options
include mastectomy, mastectomy with reconstruction, or breast-conserving surgery (i.e.,
lumpectomy, quadrantectomy) plus radiation therapy. Survival is equivalent with any of
these options as documented in prospective randomized trials.[3-9] Selection of the appropriate therapeutic approach depends on the
location and size of the lesion, breast size, patient age, appearance of the mammogram,
and how the patient feels about preservation of the breast. An axillary lymph node
dissection should be performed for histologic study since approximately one third of
patients with clinically negative nodes will have histologic involvement and would be
candidates for additional treatment as per stage II with positive axillary nodes. Although
most authorities agree that an axillary node dissection in the presence of clinically
negative nodes is a necessary staging procedure, controversy exists as to the extent of
the procedure because of long-term morbidity (arm discomfort and swelling) associated with
an axillary node dissection. Mammographically detected tumors less than or equal to 5
millimeters have an incidence of axillary node involvement ranging from 0%-3%. This low
incidence of nodal involvement may obviate the routine use of axillary dissection in this
group of patients.[10] [Level of evidence: 3iii] Whether entire
areas of potentially lymph-node-bearing tissue should be removed or whether staging can be
accomplished by excision of a specific number of nodes is questioned. In an effort to
decrease the morbidity of axillary lymphadenectomy while maintaining accurate staging,
several investigators have studied lymphatic mapping and sentinel lymph node (SLN) biopsy
in women with invasive breast cancer.[11,12]
SLN is defined as the first node in the lymphatic basin that receives primary lymphatic
flow. Studies have demonstrated the ability of peritumoral injection of technetium-labeled
sulfur colloid alone, or with vital blue dye to identify the SLN in 92% to 98% of
patients. These preliminary reports demonstrate a 97.5% to 100% concordance between SLN
biopsy and complete axillary lymph node dissection. The identification of a SLN without
metastatic disease would obviate the need for complete axillary lymphadenectomy. Larger
trials might confirm these data before this technique is routinely incorporated into the
surgical treatment of breast cancer. Data also suggest that the level of lymph node
involvement (I versus II versus III) does not add independent prognostic information to
the total number of positive axillary nodes.[13] In addition, ER
status, PR status, tumor size, and measures of proliferative capacity (thymidine labeling
index, flow cytometry for measurement of S-phase and ploidy) are highly predictive for
risk of relapse in the node-negative patient.[1,14,15] Some patients with stage I tumors
appear to be at low risk of relapse (for example, those with tumor size less than 1.0
centimeter or with more favorable histologic tumor types, e.g., medullary, mucinous,
papillary, tubular) and may not require postoperative adjuvant hormonal therapy or
chemotherapy.[16-18] High histologic
grade of tumor and high rate of mitosis may identify a high-risk subset of patients with
T1 lesions less than 1.0 centimeter.[19] A review of 20 years'
experience illustrates the prognostic significance of tumor size and histologic grade in
stage I tumors.[20]
Adjuvant therapy
Because a substantial number of patients with node-negative breast cancer ultimately
have disease recurrence, several prospective randomized trials have studied adjuvant
chemotherapy or hormonal therapy in node-negative breast cancer. Early trials using
tamoxifen, including the Nolvadex Adjuvant Trial Organization (NATO) trial [21] and the Scottish trial,[22] suggested
disease-free and overall survival benefit for node-negative patients but data were
inconclusive. A small randomized trial comparing adjuvant chemotherapy with
cyclophosphamide, methotrexate, and fluorouracil (CMF) versus no adjuvant therapy
demonstrated improved disease-free and overall survival for poor-prognosis node-negative
patients treated with CMF.[23,24]
Three large trials by the National Surgical Adjuvant Breast and Bowel Project (NSABP)
have demonstrated significant improvement in disease-free survival after 5 years of
follow-up for ER-negative patients treated with adjuvant chemotherapy (methotrexate,
fluorouracil, and leucovorin) [25,26]
and for ER-positive patients treated with adjuvant tamoxifen.[27]
Both of these large randomized trials demonstrate an early significant benefit for
adjuvant therapy in these groups of node-negative breast cancer patients. In both studies,
premenopausal and postmenopausal patients benefitted. An improvement in overall survival
has been demonstrated at 5 years in postmenopausal ER-negative women treated with
chemotherapy.[28] These trials, coupled with the three earlier
trials and another intergroup adjuvant chemotherapy trial (INT-0011), demonstrated the
efficacy of adjuvant treatment.[29,30]
The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) performed a
meta-analysis of systemic treatment of early breast cancer by hormonal, cytotoxic, or
biologic therapy methods in randomized trials involving 75,000 women with stage I or II
carcinoma who were premenopausal or postmenopausal. In stage I and II postmenopausal women
who were ER-positive, tamoxifen at 20 milligrams daily for at least 2 years (or perhaps
longer) was found to prevent recurrent disease and increase survival, with the benefits of
initial treatment persisting up to 10 years. Some evidence indicates that ER-negative
women could receive similar benefits with tamoxifen treatment.[31]
There is a decreased incidence of carcinoma in the contralateral breast and decreased
cardiovascular mortality in women treated with tamoxifen, based on retrospective analyses.
Cytotoxic chemotherapy in the EBCTCG, usually with CMF for 6-12 months, was shown to
decrease recurrences and increase survival in both premenopausal and postmenopausal women
with stages I and II disease.[26] The role of ovarian ablation in
women younger than 50 years of age was also analyzed. It was found to produce a survival
benefit comparable to that seen with chemotherapy in premenopausal women. This has raised
the question again of whether a portion of the impact of systemic chemotherapy is through
an endocrine mechanism - ovarian ablation. Such a mechanism of action has been postulated
in several trials.[32] In one study, a 12-week chemotherapy
regimen induced menopause less frequently than a 36-week regimen and was associated with
poorer survival.[33] An additional data-derived analysis of
ovarian ablation and chemotherapy postulated an additive effect.[34]
The EBCTCG by an indirect analysis also postulated that there would be an additive effect
of tamoxifen and cytotoxic chemotherapy in postmenopausal women.[31,35] However, individual randomized trials have generally had
inadequate sample sizes to detect the small improvement suggested by the EBCTCG
meta-analysis. Even when restricted to node-positive, ER-positive, premenopausal patients,
a study of 314 patients was unable to detect a benefit for the addition of oophorectomy to
adjuvant chemotherapy.[36] Larger trials testing this concept
have completed enrollment and should be able to address this question more definitively.
An intergroup trial (INT-0142) in the United States, coordinated by the Eastern
Cooperative Oncology Group (E-3193), is evaluating whether oophorectomy is additive to
tamoxifen in node-negative, ER-positive or PR-positive, premenopausal women.[37] The ongoing International Breast Cancer Trial VIII compares
combination CMF with ovarian suppression (CMF versus goserelin versus sequential CMF and
goserelin).[38]
The use of adjuvant tamoxifen has been associated with certain toxic effects. The most
important is the development of endometrial cancer which, in large clinical trials, has
been reported to occur at a rate that is 2-7 times greater than that observed in untreated
women.[39-42] A population-based
observational study of women with breast cancer who took tamoxifen as adjuvant therapy for
2 years showed no increased risk of ovarian or endometrial cancer and a significant
decrease in the risk of developing contralateral breast cancer.[43]
There has been some concern raised about increased risk of gastrointestinal malignancy,
but these findings are tentative and further study is needed.[44]
Adjuvant chemotherapy is associated with several well-characterized side effects that
vary according to the individual drugs used in each regimen. Common side effects include
nausea and vomiting, myelosuppression, alopecia, and mucositis. Less common, but serious,
side effects include heart failure (if an anthracycline is used), thromboembolic events,
and premature menopause.[45]
Adjuvant combinations of tamoxifen and chemotherapy administered concurrently to
enhance efficacy may also have enhanced toxicity. One study randomly assigned
postmenopausal, node-positive, ER-positive women to receive tamoxifen (30 milligrams per
day for 2 years) plus CMF (intravenously for 6 months) (n = 353) or tamoxifen alone (n =
352).[45] Of the women receiving combined chemohormonal therapy,
13.6% developed one or more thromboembolic events compared with 2.6% in the
tamoxifen-alone group (P<.0001). There were also significantly more women on combined
treatment who developed severe thromboembolic events (grade 3-5), most of which (39 of 54)
occurred while women were actually receiving chemotherapy. However, not all studies that
compared concurrent chemotherapy plus tamoxifen with tamoxifen alone have reported rates
as high as these. In NSABP B-16, a study that compared tamoxifen (20 milligrams per day
for 5 years) plus chemotherapy with doxorubicin plus cyclophosphamide (four cycles) with
tamoxifen alone, 4.9% of the women on combined treatment had thromboembolic events versus
2.1% of women on tamoxifen alone.[46]
Results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol
B-14, which evaluated 5 years versus 10 years of adjuvant tamoxifen for early-stage breast
cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with
node-negative, estrogen receptor- positive breast cancers.[47] In
view of the proven benefits of 5 years of adjuvant tamoxifen, this treatment should
continue to be administered whenever appropriate to women with early-stage breast cancer.
The optimal duration of tamoxifen treatment of node-positive patients is unknown. There
are no data to suggest that more than 5 years of tamoxifen is beneficial. Therefore, it
has been recommended that adjuvant tamoxifen be discontinued after 5 years in all
patients. This controversial issue is being studied in ongoing clinical trials.[48,49]
If ER status is used to select adjuvant treatment, the study should be performed in a
well-established, skilled laboratory, and ER-indeterminate patients (either because of
inadequate tissue sample or equivocal results) should be considered separately.
Timing of primary and adjuvant therapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after
breast-conserving surgery was studied in a randomized trial.[50]
Patients received either chemotherapy first (n=122) consisting of CMFP (cyclophosphamide,
methotrexate, fluorouracil, prednisone) plus doxorubicin repeated every 21 days for four
cycles followed by breast irradiation, or breast irradiation first (n=122) followed by the
same chemotherapy. With a median follow-up of 5 years, overall survival was 73% for the
radiation-first group and 81% for the chemotherapy-first group (P=0.11). The 5-year crude
rates of first recurrence by site in the radiation therapy-first and chemotherapy-first
groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or
regional recurrence or both. This difference in the pattern of recurrence was of
borderline significance (P=0.07). Further analyses revealed that differences in recurrence
patterns persisted for most subgroups with the exception of those that had either negative
tumor margins or 1-3 positive lymph nodes. For these two subgroups, sequence assignment
made little difference in local or distant recurrence rates, although the statistical
power of these subgroup analyses is low. Potential explanations for the increase in
distant recurrence noted in the radiation therapy-first group are that chemotherapy was
delayed a median of 17 weeks after surgery and that this group received lower chemotherapy
dosages due to increased myelosuppression.
Two additional randomized trials,[51,52]
while not specifically designed to address the timing of radiation therapy and adjuvant
chemotherapy, do add useful information. In the NSABP B-15 trial, patients undergoing
breast- conserving surgery received either one course of CMF (cyclophosphamide,
methotrexate, fluorouracil; n=194) and then received radiation therapy followed by five
additional cycles of CMF or they received four cycles of AC (doxorubicin,
cyclophosphamide; n=199) followed by radiation therapy. No differences in disease-free
survival, distant disease-free survival, and overall survival were observed between these
two arms. The International Breast Cancer Study Group (IBCSG) trials VI and VII also
varied the timing of radiation therapy with CMF adjuvant chemotherapy.[52] These studies showed that delays in radiation therapy after
surgery from 2 to 7 months had no effect on the rate of local recurrence.
Based on the above studies, delaying radiation therapy for several months after
breast-conserving surgery until the completion of adjuvant chemotherapy appears safe and
may be preferable for patients at high risk of distant dissemination.
Patients on tamoxifen should have follow-up with annual pelvic examinations and have
timely evaluation of all extramenstrual uterine bleeding. Although one retrospective study
raised concern that endometrial cancers in women on tamoxifen (40 milligrams per day) had
a worse outcome and were characterized by higher grade lesions and a more advanced stage
than in women not treated with tamoxifen, other larger studies using standard tamoxifen
doses (20 milligrams per day) have failed to demonstrate this finding.[39,53,54] Similar
to estrogen, tamoxifen produces endometrial hyperplasia which can be a premalignant
change. In a cohort of women without a history of breast cancer randomized to receive
tamoxifen or placebo on the British Pilot Breast Cancer Prevention Trial, 16% of those on
tamoxifen developed atypical hyperplasia at varying times from the start of treatment
(range 3-75 months, median 24 months) while no cases occurred on the control arm.[55] Because of this increase, patients on tamoxifen should have
follow-up pelvic examinations and should be examined if there is any abnormal uterine
bleeding. The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as
screening tools is unclear.[56]
Other toxic effects noted with tamoxifen include thromboembolic phenomena, which
occurred with an increased frequency of approximately 1% in women on the NSABP trial.[28] Clotting factor changes have been reported in controlled studies
of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet
counts have been minimally reduced in patients receiving tamoxifen. The relationship of
these counts to thromboembolic phenomena is not clear.[57]
Patients should be watched for this complication. An additional potential problem is the
development of benign ovarian cysts, which occurred in about 10% of women in one study.[58] Physicians should be aware of this side effect during the annual
pelvic examination that is required for women receiving tamoxifen. The relationship
between tamoxifen and ovarian tumors requires further study.[59]
Short-term toxic effects of tamoxifen in postmenopausal women may include vasomotor
symptoms and gynecologic symptoms (vaginal discharge or irritation).[60]
Clonidine can ameliorate hot flashes in some patients.[61]
Tamoxifen therapy may also be associated with certain beneficial estrogenic effects
including decreased total and low-density lipoprotein levels.[62,63] A large controlled Swedish trial has shown a decreased incidence
of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women
taking tamoxifen for 5 years than in those taking it for 2 years.[64]
In another trial, the risk of fatal myocardial infarction was significantly decreased in
patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery
alone.[63] In NSABP B-14, there was not a statistically
significant difference in the number of deaths from coronary heart disease in patients
receiving tamoxifen versus placebo.[65] The NSABP B-14 trial has
also shown a decrease in heart disease deaths in women who have taken tamoxifen for 5
years.[65] There are now three large controlled trials that have
shown a decrease in heart disease.[63-65]
Controlled studies have associated long-term tamoxifen use with preservation of bone
mineral density of the lumbar spine in postmenopausal women.[66-68] In premenopausal women, there may be decreased bone mineral
density.[69] Ophthalmologic toxic effects have been reported in
patients receiving tamoxifen; such patients who complain of visual problems should be
assessed carefully.[70,71] Because the
teratogenic potential of tamoxifen is unknown, contraception should be discussed with
patients who are premenopausal or of childbearing age and are candidates for treatment
with this drug. The usual tamoxifen dosage is 10 milligrams twice daily, but evidence
suggests that 20 milligrams once daily is bioequivalent.[72]
Treatment options:
Standard:
Initial surgical management
The surgical procedure for initial treatment depends on the location and size of the
lesion, analysis of the mammogram, breast size, patient age, and how the patient feels
about preservation of the breast. The primary advantage of breast-conserving surgery
(i.e., lumpectomy) plus radiation therapy is cosmesis with breast preservation. Long-term,
prospective, randomized studies indicate that survival is equivalent with either modified
radical mastectomy or breast- conserving surgery plus radiation therapy.[3-9] All histologic types of invasive breast
cancer may be well-treated with breast-conserving surgery plus radiation therapy.[73] The rate of local recurrence in the breast varies with the
surgical technique used (lumpectomy, quadrantectomy, segmental mastectomy, and others). It
is lowest with extensive local resections such as quadrantectomy [9]
and highest with gross total excision.[7] The risk of in- breast
recurrence is higher in patients younger than 35 years of age. The use of adjuvant
therapy, whether chemotherapy or hormonal therapy, lowers the risk for in-breast
recurrence.[3,9]
There is debate as to whether completely clear microscopic margins are necessary.[74-76] Investigators have shown that in
patients with positive, close, or unknown margins after an excisional biopsy, large tumors
(T2 lesions), positive axillary nodes, tumors with an extensive intraductal component [77], detectability of the tumor by palpation, and lobular histology
correlate with a higher likelihood of finding persistent tumor on re-excision. Patients
whose tumors have these characteristics may benefit from a more generous initial excision
to avoid the need for a re-excision.[78,79]
Surgical and radiotherapeutic techniques are extremely important in obtaining an
optimal therapeutic result and satisfactory cosmesis. Radiation therapy consists of
external-beam radiation to the entire breast. Some of the randomized trials have employed
a boost to the primary site,[7,8] others
have not.[3] A randomized trial from Lyon has shown that a 10 Gy
boost reduces the risk of early local recurrence (3.6% versus 4.5%, p=0.044).[80][Level of evidence: 1iiDii] If a boost is used, it can be given
either with an interstitial radioactive implant or by external-beam radiation, generally
with electrons. Axillary radiation may not be required in patients who have had axillary
dissections.[81,82] In patients with
four or more positive nodes, the addition of supraclavicular radiation results in low
rates of supraclavicular nodal recurrence.[81,82] Radiation side effects that can be minimized with careful
attention to technique include myocardial damage for left-sided breast lesions, radiation
pneumonitis, arm edema, brachial plexopathy, and the risk of second malignancies. Sarcomas
in the treatment field and secondary leukemias are very rare. One report suggests an
increase in contralateral breast cancer for women younger than 45 years of age who have
received chest wall irradiation after mastectomy.[83] There is no
increased risk of contralateral breast cancer for women 45 years of age and older who
receive radiation therapy.[84] Modern techniques to minimize the
radiation dose to the contralateral breast should be used to keep the absolute risk as low
as possible.[85] In nonsmokers, the risk of lung cancer as a
result of radiation exposure during treatment of breast cancer is minimal when modern
dosimetry techniques are used. Smokers, however, may have an increased risk of lung cancer
in the ipsilateral lung.[86]
Women who opt for radiation therapy should be followed carefully with regular
mammography and physical examination to detect asynchronous disease in remaining breast
tissue in the ipsilateral breast.[87,88]
Women treated with radiation therapy or mastectomy should also have regular physical and
mammographic examinations of the contralateral breast because of the risk of a second
primary tumor. Women who have initially undergone radiation and who develop a primary
tumor in the contralateral breast may be treated with breast- conserving surgery plus
radiation therapy for this second tumor with excellent cosmetic results. The development
of a contralateral breast cancer is associated with an increased risk of distant
recurrence.[89]
Breast-conserving surgery alone without radiation has been compared with
breast-conserving surgery followed by radiation in four prospective randomized trials.[3,9,90-92] All of the trials demonstrate a higher in-breast recurrence rate
overall with breast-conserving surgery alone. No subset has been identified that did not
benefit from the addition of radiation. In a report of the NSABP-B06 trial, distant
disease-free survival was worse in the node- negative group treated with lumpectomy
alone.[3]
Proposals have been made to treat elderly patients with tamoxifen alone and with no
surgery. This approach has unacceptably high local recurrence rates and outside of a
clinical trial setting should be used only in patients who are not candidates for
mastectomy or for breast-conserving surgery plus radiation therapy or for those who refuse
these options.[93-95] A study is
underway in which patients treated with lumpectomy plus tamoxifen are randomly assigned to
receive or not to receive radiation therapy.[96] One report
showed that treatment with lumpectomy and radiation in women 65 years of age and older
produces survival and freedom-from-recurrence rates similar to those of women younger than
65 years of age.[97]
For patients who opt for a total mastectomy, reconstructive surgery may be used. It may
be done at the time of the mastectomy (immediate reconstruction) or at some subsequent
time (delayed reconstruction) in an attempt to restore the anatomical deficit of the
mastectomy.[98-101] Breast contour can
be restored either by the submuscular insertion of an artificial implant (saline-filled)
or by a rectus muscle or other flap. Both procedures offer satisfactory cosmetic results.
Insertion of an artificial implant is a relatively simple procedure. A saline-filled
tissue expander can be inserted beneath the pectoral muscle. Saline is used to expand it
during a period of weeks or months until the desired volume is obtained. The tissue
expander is then replaced by a permanent implant. Rectus muscle flaps, which offer a
better cosmetic result, require a considerably more complicated and prolonged operative
procedure, and blood transfusions may be required. There is no convincing evidence that a
silicone implant induces cancer or autoimmune disease. Problems associated with silicone
implants include contracture of the capsule around the implant causing hardening and pain,
rupture of the implant with release of the silicone gel, and infection.[102-104] In rare instances, either
procedure could make a local recurrence of cancer more difficult to detect. Following
breast reconstruction, radiation therapy can be delivered to the chest wall and regional
nodes either in the adjuvant setting or when local disease recurs. Although this does not
adversely affect outcome, cosmesis may be affected and the incidence of capsular fibrosis,
pain, or the need for implant removal may be increased.[103] The
use of silicone implants for breast augmentation may make the early detection of breast
cancer more difficult by obscuring and compressing breast parenchyma.[102,104,105]
The Food and Drug Administration (FDA) has announced that silicone breast implants will be
available only through controlled clinical studies. Women who wish to undergo
reconstructive surgery following mastectomy will be assured access to those studies.
However, the FDA has placed no restrictions on the use of saline-filled breast implants,
which may constitute a reasonable alternative.
The surgical procedures include:
- 1. Breast-conserving surgery (lumpectomy, quadrantectomy, or segmental mastectomy) with
separate axillary node dissection and radiation therapy to the breast.[3,9]
2. Modified radical or total mastectomy with axillary dissection.[9,106,107]
Adjuvant therapy
- 1. For suitable ER-negative patients, adjuvant chemotherapy with a proven effective
regimen.[23,25] There is continuing
controversy concerning the routine use of adjuvant chemotherapy in all patients with
ER-negative, node-negative cancers. Patients with a poor prognosis (manifested by poor
nuclear differentiation, tumor necrosis, and tumor size greater than 2.0 centimeters) are
reasonable candidates for adjuvant chemotherapy. A number of studies have been reported,
however, that indicate that a group of patients with small tumors who probably would not
benefit from adjuvant chemotherapy could be identified. These include patients with more
favorable histologic types of breast cancer, with tumors less than 1.0 centimeter in size,
and with diploid tumors with less than a 6%-10% fraction of cells in S phase.[1]
2. For ER-positive patients, adjuvant chemotherapy [25,29] or tamoxifen (20 milligrams daily).[27,28]
In completed trials, adjuvant therapy was initiated within 6 weeks of surgery. Whether
adjuvant therapy is effective if initiated at a later time is unknown.
Under clinical evaluation:
- 1. Studies of the value of more aggressive adjuvant chemotherapy for subsets of patients
with unfavorable prognostic factors.[108,109]
2. No adjuvant therapy for selected subsets of patients with favorable prognostic factors.
3. Studies of the role of ovarian ablation or suppression for premenopausal ER-positive
patients.[110,111]
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influencing cosmetic outcome and complication risk after conservative surgery and
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- Holland R, Connolly JL, Gelman RS, et al.: The presence of an
extensive intraductal component following a limited excision correlates with prominent
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- Jardines L, Fowble B, Schultz D, et al.: Factors associated with a
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- Boice JD, Harvey EB, Blettner M, et al.: Cancer in the contralateral
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- Storm HH, Andersson M, Boice JD, et al.: Adjuvant radiotherapy and
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- Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast
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- Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation
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- Jager JJ, Langendijk JA, Dohmen JP, et al.: Mammography in the
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- Veronesi U, Luini A, Del Vecchio M, et al.: Radiotherapy after
breast-preserving surgery in women with localized cancer of the breast. New England
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- Clark RM, McCulloch PB, Levine MN, et al.: Randomized clinical trial
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Some citations in the text of this section are followed by a level of evidence. The PDQ
editorial boards use a formal ranking system to help the reader judge the strength of
evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels
of evidence summary for more information.
Primary therapy
Stage II breast cancer is curable with a range of accepted surgical procedures.
Surgical approaches that conserve a portion of the breast, followed by radiation therapy,
can provide survival rates equivalent to more extensive surgery. The diagnostic biopsy and
surgical procedure that will be used as primary treatment should be performed as two
separate procedures. After the presence of a malignancy is confirmed and histology is
determined, treatment options should be discussed with the patient before a definitive
therapeutic procedure is recommended. Estrogen-receptor (ER) and progesterone-receptor
(PR) protein status should be determined for the primary tumor.[1]
In many cases, the diagnosis of breast carcinoma using core needle biopsy or fine
needle aspiration cytology may be sufficient to confirm malignancy. It is then appropriate
to discuss the therapeutic options to help the patient with the treatment decision. The
surgeon may then proceed with a single, sequential procedure that includes biopsy, frozen
section confirmation of carcinoma, and the surgery elected by the patient.
Surgical options include mastectomy, mastectomy with reconstruction, or breast-
conserving surgery (i.e., lumpectomy) plus radiation therapy. Survival is equivalent with
any of these options as documented in randomized prospective trials.[2-8] Selection of the appropriate therapeutic approach depends on the
location and size of the lesion, analysis of the mammogram, breast size, patient age, and
how the patient feels about preserving the breast. An axillary lymph node dissection
should be done for staging purposes. In the situation of clinically positive nodes, the
axillary dissection may have some local therapeutic benefit.
Radiation therapy can decrease local-regional recurrence in this group even among those
who receive adjuvant chemotherapy.[9-11]
Postoperative chest wall radiation therapy after mastectomy should not be given routinely
to node- positive women. It should be considered in selected patients who are thought to
be in a high-risk group for local-regional failure. The improvement in local regional
control has been evident for many years. In some trials of combined chemotherapy and
radiation with prolonged follow-up, an overall survival advantage has emerged. In the
Danish Breast Cancer Cooperative Group protocol 82b, 1708 premenopausal women who were
node-positive, or T3 N0, or had skin or pectoral fascial invasion, were randomized to
receive either cyclophosphamide plus methotrexate plus fluorouracil (CMF) and radiation,
or CMF alone after mastectomy. At 10 years, local regional recurrence (9% versus 32%,
p<0.001) and overall survival (54% versus 45%, p<0.001) favored the combined arm.[12][Level of evidence: 1iiA] A similar but smaller trial from
British Columbia of 318 premenopausal node-positive women, with 15-year follow- up, showed
an overall survival benefit of 54% versus 46% (p=0.07).[13][Level
of evidence: 1iiA] Patients at highest risk include those with four or more positive
nodes, with grossly evident extracapsular nodal extension, or with involved or very close,
deep margins of resection. Patients at somewhat lower risk include those with one to three
involved nodes in whom other features such as large primary tumor size and/or adverse
tumor prognostic factors, including extensive lymphatic/vascular space invasion, should be
assessed to determine the level of risk of chest or regional nodal recurrence before
postoperative radiation can be recommended. The indications for postoperative chest wall
radiation therapy are undergoing reassessment.
An update of a meta-analysis of all randomized trials using radiation therapy after
mastectomy, which included earlier results from the Danish and British Columbia trials,
reported a decrease in deaths as a result of breast cancer in patients who received
radiation therapy.[14] However, an increase in non- breast cancer
deaths was seen in patients who received radiation, particularly in older women. This may
be related to an increase in cardiac mortality which could potentially be modified by
attention to minimization of volume of heart in the radiated fields.[15]
No increased cardiac mortality was seen in either the Danish or the British Columbia
trials.[12,13]
Adjuvant therapy: stage II positive nodes
Adjuvant combination chemotherapy has been found to prolong the disease-free interval
and survival for pre- and postmenopausal patients with positive nodes.[16] The standard duration of administration of such chemotherapy
does not exceed 6 months. For node-positive, postmenopausal women with
hormone-receptor-positive tumors, adjuvant hormonal therapy with tamoxifen prolongs
disease-free interval and overall survival. In this setting, tamoxifen should be given for
at least two years. Cyclophosphamide plus doxorubicin (CA) and cyclophosphamide,
methotrexate, and fluorouracil (CMF) seem to produce similar results in terms of
disease-free survival in both premenopausal and postmenopausal patients, but there are
differences in toxicity that may influence the choice of regimen.[17]
Long term follow-up of women who received cyclophosphamide-containing adjuvant
chemotherapy for treatment of breast cancer indicates that the incidence of other solid
tumors and secondary leukemia is not much higher than that in the general population.[18] In a trial by the National Surgical Adjuvant Breast and Bowel
Project (NSABP-B-16), node-positive women 50-59 years of age who were PR-positive and
women 60 years of age and older irrespective of receptor status had improved disease-free
and overall survival when treated with tamoxifen and chemotherapy (doxorubicin plus
cyclophosphamide) compared to those treated with tamoxifen alone.[19]
A report from the Eastern Cooperative Oncology Group (ECOG), comparing CMFP and CMFPT to
surgery alone in node-positive postmenopausal patients, demonstrated disease-free survival
benefit for CMFP chemotherapy in ER-negative patients, but overall survival was not
prolonged at the time of analysis. CMFPT, given for 1 year, failed to improve either
disease-free or overall survival compared to surgery alone. ER-positive women experienced
no benefit on either regimen.[20] A Southwest Oncology Group
(SWOG) study of node-positive, postmenopausal, ER-positive women compared tamoxifen alone
to CMFVP and CMFVP + tamoxifen. CMFVP alone or in combination with tamoxifen was not
superior to tamoxifen alone. In both the SWOG and ECOG studies, the small number of
patients entered into these studies may have limited the ability to detect small but
important differences. Another small study has indicated that disease-free survival may be
increased with prolonged therapy with tamoxifen and one year of CMFVP chemotherapy.[21,22] A multicenter study comparing CMF
with FEC (which includes epirubicin, an anthracycline similar to doxorubicin) in
premenopausal women shows no difference in overall survival or in relapse-free survival
between the two treatment groups at 4.5 years.[23] The optimal
timing of initiation of adjuvant therapy is uncertain. One study addressed the use of
perioperative adjuvant chemotherapy in node-positive patients. It showed no advantage in
disease-free survival when a single cycle of perioperative chemotherapy was given in
addition to standard therapy initiated 4 weeks after surgery.[24]
A single cycle of immediate postoperative chemotherapy alone was inferior.[25] With regard to duration of therapy, the 10-year survival rate
for both premenopausal and postmenopausal women receiving either six or twelve cycles of
CMF has been shown to be identical.[9]
Adjuvant therapy: stage II negative nodes
Patients with stage IIA, node-negative breast cancer (T2 N0 M0) generally have a lower
risk of recurrence than node-positive patients. Relapse may be related to a number of
factors, including tumor size. In an analysis of patients with T2 N0 M0 breast cancer,
there was a 33% chance of recurrence at 20 years for patients with T = 2.1-3.0 centimeters
compared to 44% for T = 3.1-5.0 centimeters.[26] Because a
substantial number of patients with node-negative breast cancer ultimately have disease
recurrence, several prospective randomized trials have studied adjuvant chemotherapy or
hormonal therapy in node-negative breast cancer. Early trials, including the Nolvadex
Adjuvant Trial Organization (NATO) trial [27] and the Scottish
trial,[28] suggested disease-free and overall survival benefit
for node-negative patients but data were inconclusive. A small randomized trial comparing
adjuvant chemotherapy with CMF versus no adjuvant therapy showed improved disease-free and
overall survival for poor-prognosis node-negative patients treated with CMF.[27-29]
Two large trials by the NSABP have demonstrated substantial improvement in disease-free
survival after four years follow-up for ER-negative patients treated with chemotherapy
(methotrexate, fluorouracil, and leucovorin) [30] and for
ER-positive patients treated with tamoxifen.[31] Both of these
large randomized trials demonstrate an early substantial benefit for adjuvant therapy in
these groups of node-negative breast cancer patients, although an improvement in overall
survival has not been demonstrated. In both studies, pre- and postmenopausal patients
benefitted. These trials, coupled with the three earlier trials and another intergroup
adjuvant chemotherapy trial (INT-0011), demonstrated the efficacy of adjuvant treatment.[32,33]
The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) performed a
meta-analysis of systemic treatment of early breast cancer by hormonal, cytotoxic, or
biologic therapy methods in randomized trials involving 75,000 women with stage I or II
carcinoma who were pre- or postmenopausal. In stage I and II postmenopausal women who were
ER-positive, tamoxifen at 20 milligrams daily for at least 2 years (or perhaps longer) was
found to prevent recurrent disease and increase survival, with the benefits of initial
treatment persisting up to 10 years. Some evidence indicates that ER-negative,
postmenopausal women could receive similar benefits with tamoxifen treatment.[34] There is a decreased incidence of carcinoma in the contralateral
breast and decreased cardiovascular mortality in women treated with tamoxifen. Cytotoxic
chemotherapy in the EBCTCG, usually with CMF for 6-12 months, was shown to decrease
recurrences and increase survival in both premenopausal and postmenopausal women with
stages I and II disease.[16,34] The role
of ovarian ablation in women younger than 50 years of age was also analyzed. It was found
to produce a survival benefit comparable to that seen with chemotherapy in premenopausal
women. This has raised the question again of whether a portion of the impact of systemic
chemotherapy is through an endocrine mechanism - ovarian ablation. Such a mechanism of
action has been postulated in several trials.[35] In one study, a
12-week chemotherapy regimen induced menopause less frequently than a 36-week regimen and
was associated with poorer survival.[36] An additional
data-derived analysis of ovarian ablation and chemotherapy postulated an additive effect.
In the only direct comparison of CMF versus ovarian ablation, disease-free and overall
survival rates were identical in 332 premenopausal women with stage II disease.[37] It has been postulated that there should be an additive effect
of tamoxifen and cytotoxic chemotherapy in postmenopausal women.[34,16] Clinical trials that address these issues are ongoing.
The use of adjuvant tamoxifen has been associated with certain toxic effects. The most
important is the development of endometrial cancer which, in large clinical trials, has
been reported to occur at a rate that is 2-7 times greater than that observed in untreated
women.[38-41] Because of this, patients
on tamoxifen should be followed with annual pelvic examinations and have timely evaluation
of all abnormal uterine bleeding. Although one retrospective study raised concern that
endometrial cancers in women on tamoxifen (40 milligrams per day) had a worse outcome and
were characterized by higher grade lesions and a more advanced stage than in women not
treated with tamoxifen, other larger studies using standard tamoxifen doses (20 milligrams
per day) have failed to demonstrate this finding.[38,42,43]
Similar to estrogen, tamoxifen produces endometrial hyperplasia which can be a
premalignant change. In a randomized cohort of patients on tamoxifen or placebo, recruited
from the British Pilot Breast Cancer Prevention Trial, 16% of those on tamoxifen developed
atypical hyperplasia at varying times from the start of treatment (range 3-75 months,
median 24 months) while no cases occurred on the control arm.[44]
The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening
tools is unclear.[45]
Adjuvant chemotherapy is associated with several well-characterized side effects that
vary according to the individual drugs used in each regimen. Common side effects include
nausea and vomiting, myelosuppression, alopecia, and mucositis. Less common, but serious,
side effects include heart failure (if an anthracycline is used), thromboembolic events,
and premature menopause.[46]
Adjuvant combinations of tamoxifen and chemotherapy administered concurrently to
enhance efficacy may also have enhanced toxicity. One study randomly assigned
postmenopausal, node-positive, ER-positive women to receive tamoxifen (30 milligrams per
day for 2 years) plus CMF (intravenously for 6 months) (n = 353) or tamoxifen alone (n =
352).[46] Of the women receiving combined chemohormonal therapy,
13.6% developed one or more thromboembolic events compared with 2.6% in the
tamoxifen-alone group (P<.0001). There were also significantly more women on combined
treatment who developed severe thromboembolic events (grade 3-5), most of which (39 of 54)
occurred while women were actually receiving chemotherapy. However, not all studies that
compared concurrent chemotherapy plus tamoxifen with tamoxifen alone have reported rates
as high as these. In NSABP B-16, a study that compared tamoxifen (20 milligrams per day
for 5 years) plus chemotherapy with doxorubicin plus cyclophosphamide (four cycles) with
tamoxifen alone, 4.9% of the women on combined treatment had thromboembolic events versus
2.1% of women on tamoxifen alone.[19] If combined therapy is
selected, whether tamoxifen should be given concurrently or following the completion of
chemotherapy is also unknown. An Intergroup U.S. Study (INT-0100) has directly posed this
question (tamoxifen alone versus cyclophosphamide, doxorubicin, and fluorouracil [CAF] and
concurrent tamoxifen versus CAF followed by tamoxifen). [22]
Results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol
B-14, which evaluated 5 years versus 10 years of adjuvant tamoxifen for early-stage breast
cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with
node-negative, estrogen receptor- positive breast cancers.[47] In
view of the proven benefits of 5 years of adjuvant tamoxifen, this treatment should
continue to be administered whenever appropriate to women with early-stage breast cancer.
However, the new data suggest that more than 5 years of adjuvant treatment is not
warranted in routine clinical practice in this patient population. For node-positive
patients, there are no data to suggest that more than 5 years of tamoxifen is beneficial.
Therefore, it has been recommended that adjuvant tamoxifen be discontinued after 5 years
in all patients. This issue is being studied in ongoing clinical trials.
If ER status is used to select adjuvant treatment, the study should be performed in a
well-established, skilled laboratory, and ER-indeterminate patients (either because of
inadequate tissue sample or equivocal results) should be considered separately.
Timing of primary and adjuvant therapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after
breast-conserving surgery was studied in a randomized trial.[48]
Patients received either chemotherapy first (n=122) consisting of CMFP (cyclophosphamide,
methotrexate, fluorouracil, prednisone) plus doxorubicin repeated every 21 days for four
cycles followed by breast irradiation or breast irradiation first (n=122) followed by the
same chemotherapy. With a median follow-up of 5 years, overall survival was 73% for the
radiation-first group and 81% for the chemotherapy-first group (P=0.11). The 5-year crude
rates of first recurrence by site in the radiation therapy-first and chemotherapy-first
groups, respectively, were 5% and 14% for local recurrence and 32% and 20% for distant or
regional recurrence or both. This difference in the pattern of recurrence was of
borderline significance (P=0.07). Further analyses revealed that differences in recurrence
patterns persisted for most subgroups with the exception of those that had either negative
tumor margins or 1-3 positive lymph nodes. For these two subgroups, sequence assignment
made little difference in local or distant recurrence rates, although the statistical
power of these subgroup analyses is low. Potential explanations for the increase in
distant recurrence noted in the radiation therapy-first group are that chemotherapy was
delayed a median of 17 weeks after surgery and that this group received lower chemotherapy
dosages due to increased myelosuppression.
Two additional randomized trials,[17,49]
while not specifically designed to address the timing of radiation therapy and adjuvant
chemotherapy, do add useful information. In the NSABP B-15 trial, patients undergoing
breast- conserving surgery received either one course of CMF (cyclophosphamide,
methotrexate, fluorouracil; n=194) and then received radiation therapy followed by five
additional cycles of CMF or they received four cycles of AC (doxorubicin,
cyclophosphamide; n=199) followed by radiation therapy. No differences in disease-free
survival, distant disease-free survival, and overall survival were observed between these
two arms. The International Breast Cancer Study Group (IBCSG) trials VI and VII also
varied the timing of radiation therapy with CMF adjuvant chemotherapy.[49] These studies showed that delays in radiation therapy after
surgery from 2 to 7 months had no effect on the rate of local recurrence.
Based on the above studies, delaying radiation therapy for several months after
breast-conserving surgery until the completion of adjuvant chemotherapy appears safe and
may be preferable for patients at high risk of distant dissemination. Other toxic effects
noted with tamoxifen include thromboembolic phenomena, which occurred with an increased
frequency of approximately 1% in women in the NSABP trial.[32]
Clotting factor changes have been reported in controlled studies of prolonged tamoxifen
use at standard doses; antithrombin III, fibrinogen, and platelet counts have been
minimally reduced in patients receiving tamoxifen. The relationship of these counts to
thromboembolic phenomena is not clear.[50] Patients should be
watched for this complication. An additional potential problem is the development of
benign ovarian cysts, which occurred in about 10% of women in one study.[51] Physicians should be aware of this side effect during the annual
pelvic examination that is required for women receiving tamoxifen. The relationship
between tamoxifen and ovarian tumors requires further study.[52]
Short-term toxic effects of tamoxifen in postmenopausal women may include vasomotor
symptoms and gynecologic symptoms (vaginal discharge or irritation).[53]
Clonidine can ameliorate hot flashes in some patients.[54]
Tamoxifen therapy may also be associated with certain beneficial estrogenic effects,
including decreased total and low-density lipoprotein levels.[55,56] A large controlled Swedish trial has shown a decreased incidence
of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women
taking tamoxifen for 5 years than in those taking it for 2 years.[57]
In another trial, the risk of fatal myocardial infarction was significantly decreased in
patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery
alone.[56] Controlled studies have associated long-term tamoxifen
use with preservation of bone mineral density of the lumbar spine in postmenopausal
women.[58-60] In premenopausal women,
there may be decreased bone mineral density.[61] Ophthalmologic
toxic effects have been reported in patients receiving tamoxifen; such patients who
complain of visual problems should be assessed carefully.[62]
Because the teratogenic potential of tamoxifen is unknown, contraception should be
discussed with patients who are premenopausal or of childbearing age and are candidates
for treatment with this drug. The usual tamoxifen dosage is 10 milligrams twice daily, but
evidence suggests that 20 milligrams once daily is bioequivalent.[63]
Treatment options:
Standard:
Initial surgical management
The surgical procedure for initial treatment depends on the location and size of the
lesion, analysis of the mammogram, breast size, patient age, and how the patient feels
about preservation of the breast. The primary advantage of breast-conserving surgery
(i.e., lumpectomy) plus radiation therapy is cosmesis with breast preservation. Long-term,
prospective, randomized studies indicate that survival is equivalent with either modified
radical mastectomy or breast- conserving surgery plus radiation therapy.[2-8] All histologic types of invasive breast
cancer may be well-treated with breast-conserving surgery plus radiation therapy.[64] The rate of local recurrence in the breast varies with the
surgical technique used. It is lowest with extensive local resections such as the
quadrantectomy [7] and highest with gross total excision.[3] The risk of in-breast recurrence is higher in patients younger
than 35 years of age. The use of adjuvant therapy, whether chemotherapy or hormonal
therapy lowers the risk for in-breast recurrence.[2,7]
There is debate as to whether completely clear microscopic margins are necessary.[65-67] A group from the Joint Center for
Radiation Therapy and other investigators have used extensive intraductal component (EIC)
as a histopathologic marker to determine extent of resection.[68-72] If EIC is prominently present in grossly normal adjacent breast
tissue, a more extensive resection to remove residual intraductal carcinoma is performed.
If this would leave a cosmetically unacceptable result, a mastectomy is done. Other
investigators have shown that in patients with positive, close, or unknown margins after
an excisional biopsy, large tumors (T2 lesions), positive axillary nodes, detectability of
the tumor by palpation, and lobular histology correlate with a higher likelihood of
finding persistent tumor on re-excision. Patients whose tumors have these characteristics
may benefit from a more generous initial excision to avoid the need for a re-excision.[73,74]
Surgical and radiotherapeutic techniques are extremely important in obtaining an
optimal therapeutic result and satisfactory cosmesis. Radiation therapy consists of
external-beam radiation to the entire breast. Some of the randomized trials have employed
a boost to the primary site,[3,8] others
have not.[2] A randomized trial from Lyon has shown that a 10 Gy
boost reduces the risk of early local recurrence (3.6% versus 4.5%, p=0.044).[75][Level of evidence: 1iiDii] If a boost is used, it can be given
either with an interstitial radioactive implant or by external-beam radiation, generally
with electrons. Axillary radiation may not be required in patients who have had axillary
dissections.[76,77] In patients with
four or more positive nodes, the addition of supraclavicular radiation results in low
rates of supraclavicular nodal recurrence.[76,77] Radiation side effects that can be minimized with careful
attention to technique include myocardial damage for left-sided breast lesions, radiation
pneumonitis, arm edema, brachial plexopathy, and the risk of second malignancies. Sarcomas
in the treatment field and secondary leukemias are very rare. One report suggests an
increase in contralateral breast cancer for women younger than 45 years of age who have
received chest wall radiation after mastectomy.[78] There is no
increased risk of contralateral breast cancer for women 45 years of age and older who
receive radiation therapy.[79] Modern techniques to minimize the
radiation dose to the contralateral breast should be used to keep the absolute risk as low
as possible.[80] In nonsmokers, the risk of lung cancer as a
result of radiation exposure during treatment of breast cancer is minimal when modern
dosimetry techniques are used. Smokers, however may have an increased risk of lung cancer
in the ipsilateral lung.[81]
Women who opt for radiation therapy should be followed carefully with regular
mammography and physical examination to detect recurrent or asynchronous disease in
remaining breast tissue in the ipsilateral breast.[82,83] In patients treated with lumpectomy and radiation, detection of
in-breast recurrence by physical examination and/or mammography can lead to curative
mastectomy. In one series of 30 patients who had a local recurrence in the breast after
lumpectomy plus radiation therapy and who underwent salvage mastectomy, no distant
recurrences were seen later than 6 years after initial local failure, and the disease-free
survival following salvage mastectomy was 58% at 5 years and 50% at 10 years.[84-88] Women treated with radiation therapy
or mastectomy should also have regular physical and mammographic examinations of the
contralateral breast because of the risk of a second primary tumor. Women who have
initially undergone radiation and who develop a primary tumor in the contralateral breast
may be treated with breast-conserving surgery plus radiation therapy for this second tumor
with excellent cosmetic results. The development of a contralateral breast cancer is
associated with an increased risk of recurrence.[89]
Breast-conserving surgery alone without radiation has been compared with
breast-conserving surgery followed by radiation in four prospective randomized trials.[2,7,90,91] All of the trials demonstrate a higher in-breast recurrence rate
overall with breast-conserving surgery alone. No subset has been identified that did not
benefit from the addition of radiation. In a report of the NSABP-B06 trial, distant
disease-free survival was worse in the node- negative group treated with lumpectomy
alone.[2]
Proposals have been made to treat elderly patients with tamoxifen alone and with no
surgery. This approach has unacceptably high local recurrence rates and outside of a
clinical trial setting should be used only in patients who are not candidates for
mastectomy or for breast-conserving surgery plus radiation therapy or for those who refuse
these options.[92,93] A study is
underway in which patients treated with lumpectomy plus tamoxifen are randomly assigned to
receive or not to receive radiation therapy.[94] One report
showed that treatment with lumpectomy and radiation in women 65 years of age and older
produces survival and freedom-from-recurrence rates similar to those of women younger than
65 years of age.[95]
For patients who opt for a total mastectomy, reconstructive surgery may be used. It may
be done at the time of the mastectomy (immediate reconstruction) or at some subsequent
time (delayed reconstruction) in an attempt to restore the anatomical deficit of the
mastectomy.[96-99] Breast contour can be
restored either by the submuscular insertion of an artificial implant (saline-filled) or
by a rectus muscle or other flap. Both procedures offer satisfactory cosmetic results.
Insertion of an artificial implant is a relatively simple procedure. A saline-filled
tissue expander can be inserted beneath the pectoral muscle. Saline is used to expand it
during a period of weeks or months until the desired volume is obtained. The tissue
expander is then replaced by a permanent implant. Rectus muscle flaps, which offer a
better cosmetic result, require a considerably more complicated and prolonged operative
procedure, and blood transfusions may be required. There is no convincing evidence that a
silicone implant induces cancer or autoimmune disease. Problems associated with silicone
implants include contracture of the capsule around the implant causing hardening and pain,
rupture of the implant with release of the silicone gel, and infection.[100-102] In rare instances, either
procedure could make a local recurrence of cancer more difficult to detect. Following
breast reconstruction, radiation therapy can be delivered to the chest wall and regional
nodes either in the adjuvant setting or when local disease recurs. Although this does not
adversely affect outcome, cosmesis may be affected and the incidence of capsular fibrosis,
pain, or the need for implant removal may be increased.[101] The
use of silicone implants for breast augmentation may make the early detection of breast
cancer more difficult by obscuring and compressing breast parenchyma.[100,102,103]
The Food and Drug Administration (FDA) has announced that silicone breast implants will be
available only through controlled clinical studies. Women who wish to undergo
reconstructive surgery following mastectomy will be assured access to those studies.
However, the FDA has placed no restrictions on the use of saline-filled breast implants,
which may constitute a reasonable alternative.
The surgical procedures include:
- 1. Breast-conserving surgery (lumpectomy, quadrantectomy, or segmental mastectomy) with
separate axillary node dissection and radiation therapy to the breast.[2,7]
2. Modified radical or total mastectomy with axillary dissection.[7,104,105]
Radiation therapy to the chest wall and regional nodes should be considered for
patients at high risk of local-regional recurrence, including those with known residual
disease or four or more involved nodes.
Adjuvant therapy
- 1. Following the treatment used to control local disease, adjuvant combination
chemotherapy is given to reduce the rate of recurrence and improve survival in pre- and
postmenopausal node-positive patients. Many different drug regimens have been developed.
Numerous studies have shown that combination chemotherapy is superior to single-agent
treatment, and single-agent adjuvant chemotherapy should be avoided outside a clinical
trial. The drug combinations listed have been tested and provide therapeutic benefit. Not
all have been compared to an untreated control group in prospective randomized trials.[106]
CMF: cyclophosphamide + methotrexate + fluorouracil.[107,108]
Various recognized combinations of cyclophosphamide, doxorubicin, and fluorouracil.[109]
CA +/- tamoxifen: cyclophosphamide + doxorubicin +/- tamoxifen.[17,19]
Dose intensity: Retrospective analyses have indicated that the intensity of dose delivery
may be important in the clinical outcome. The results of one study suggest that drug doses
should not be reduced arbitrarily.[110] Dose intensity is
expressed in milligrams per square meter per week. Analyses of trials using a combination
of drugs have, in general, given equal weight to the "effective drugs" and have
assigned a zero value if a given "standard drug" is not used in a particular
regimen. Therefore, there is some degree of subjectivity to these analyses. Nevertheless,
using such analyses, response rate (in advanced breast cancer) and freedom from relapse
(in stage II breast cancer) have increased with increasing dose intensity. The steepest
relationship between dose intensity and outcome has been observed at dose intensities of
less than 0.8. Physicians should avoid arbitrary reductions in dose intensity.[111-113] One clinical trial has evaluated
the use of actual versus ideal body weight in patients receiving chemotherapy. Obese
patients treated at doses appropriate for their actual weight had no greater toxicity.[114]
- 2. Following the treatment used to control local disease, adjuvant endocrine therapy
with tamoxifen alone is given to reduce the rate of recurrence and improve survival in
postmenopausal patients with lymph node involvement and positive hormone receptors.
Tamoxifen, either alone or combined with chemotherapy, prolongs disease-free survival when
administered for 24 months as adjuvant therapy to postmenopausal women with axillary lymph
node metastases. In a large trial of 3887 postmenopausal women with node-positive and
node-negative breast cancer randomized to receive either 2 or 5 years of adjuvant
tamoxifen, the longer duration of tamoxifen appeared to improve disease-free and overall
survival.[115]
3. In node-negative patients:
For ER-negative patients or ER-positive patients with large tumors, adjuvant chemotherapy
with a proven effective regimen.[29,30]
For ER-positive patients, adjuvant chemotherapy [30,32] or tamoxifen (20 milligrams daily)[31,41].
Data from the NSABP-B-16 protocol indicate that patients 50 years of age and older who
have hormonally responsive, node-positive tumors treated with chemotherapy (AC) and
tamoxifen had a significantly increased disease-free and overall survival when compared
with patients given tamoxifen alone. There was no apparent drug interaction between
chemotherapy and tamoxifen.[19]
In completed trials, adjuvant therapy was initiated within 6 weeks of surgery. Whether
adjuvant therapy is effective if initiated at a later time is unknown.
Under clinical evaluation:
- 1. Data indicate that primary (neoadjuvant) chemotherapy does allow breast-conserving
therapy in patients whose lesion and breast size would not otherwise have allowed this
option.[116-118] This NSABP study also
reported a significantly decreased incidence of positive nodes in patients receiving
preoperative therapy compared to postoperative chemotherapy. Preliminary reports, however,
do not show a disease-free survival or overall survival benefit with preoperative
chemotherapy.[119]
2. Clinical trials of high-dose chemotherapy with bone marrow transplantation in women
with more than 10 positive lymph nodes and in those with four to nine positive lymph
nodes.[120,121]
3. While substantial advances have been made in the past 5 years, the search for optimal
adjuvant therapy continues to evolve for all subsets of patients. For this reason, all
patients and their physicians are strongly encouraged to participate in controlled
clinical trials. [122-125]
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Adjuvant Tamoxifen with vs without Radiotherapy Following Lumpectomy for Carcinoma of the
Breast No Greater Than 2 cm with Clinically Negative Axillary Nodes in Women Age 70 and
Over (Summary Last Modified 08/97), CLB-9343, clinical trial, active, 07/15/94.
- Solin LJ, Schultz DJ, Fowble BL: Ten-year results of the treatment of
early-stage breast carcinoma in elderly women using breast-conserving surgery and
definitive breast irradiation. International Journal of Radiation Oncology, Biology,
Physics 33(1): 45-51, 1995.
- Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with
immediate breast reconstruction. American Surgeon 52(3): 129-133, 1986.
- Cunningham BL: Breast reconstruction following mastectomy. In:
Najarian JS, Delaney JP, Eds.: Advances in Breast and Endocrine Surgery. Chicago: Year
Book Medical Publishers, 1986, pp 213-226.
- Scanlon EF.: The role of reconstruction in breast cancer. Cancer
68(Suppl 5): 1144-1147, 1991.
- Hang-Fu L, Snyderman RK.: State-of-the-art breast reconstruction.
Cancer 68(Suppl 5): 1148-1156, 1991.
- Council on Scientific Affairs, American Medical Association:
Silicone gel breast implants. Journal of the American Medical Association 270(21):
2602-2606, 1993.
- Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast
reconstruction: clinical results and dosimetry. International Journal of Radiation
Oncology, Biology, Physics 21(2): 339-346, 1991.
- Bridges AJ, Vasey FB: Silicone breast implants: history, safety, and
potential complications. Archives of Internal Medicine 153(23): 2638-2644, 1993.
- Kessler DA, Merkatz RB, Schapiro R: A call for higher standards for
breast implants. Journal of the American Medical Association 270(21): 2607-2608, 1993.
- Fisher B, Redmond C, Fisher ER, et al.: Ten-year results of a
randomized clinical trial comparing radical mastectomy and total mastectomy with or
without radiation. New England Journal of Medicine 312(11): 674-681, 1985.
- Martin JK, van Heerden JA, Taylor WF, et al.: Is modified radical
mastectomy really equivalent to radical mastectomy in treatment of carcinoma of the
breast? Cancer 57(3): 510-518, 1986.
- Jones SE, Moon TE, Bonadonna G, et al.: Comparison of different
trials of adjuvant chemotherapy in stage II breast cancer using a natural history data
base. American Journal of Clinical Oncology 10(5): 387-395, 1987.
- Tancini G, Bonadonna G, Valagussa P, et al.: Adjuvant CMF in breast
cancer: comparative 5-year results of 12 versus 6 cycles. Journal of Clinical Oncology
1(1): 2-10, 1983.
- Bonadonna G, Brusamolino E, Valagussa P, et al.: Combination
chemotherapy as an adjuvant treatment in operable breast cancer. New England Journal of
Medicine 294(8): 405-410, 1976.
- Buzdar AU, Kau SW, Smith TL, et al.: Ten-year results of FAC
adjuvant chemotherapy trial in breast cancer. American Journal of Clinical Oncology 12(2):
123-128, 1989.
- Wood WC, Budman DR, Korzun AH, et al.: Dose and dose intensity of
adjuvant chemotherapy for stage II, node-positive breast carcinoma. New England Journal of
Medicine 330(18): 1253-1259, 1994.
- Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant
chemotherapy trials in stage II breast cancer. Journal of Clinical Oncology 4(8):
1162-1170, 1986.
- Focan C, Andrien JM, Closon MT, et al.: Dose-response relationship
of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective
randomized trial. Journal of Clinical Oncology 11(7): 1253-1263, 1993.
- Hryniuk WM: Average relative dose intensity and the impact on design
of clinical trials. Seminars in Oncology 14(1): 65-74, 1987.
- Rosner GL, Hargis JB, Hollis DR, et al.: Relationship between
toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results
from Cancer and Leukemia Group B study 8541. Journal of Clinical Oncology 14(11):
3000-3008, 1996.
- Swedish Breast Cancer Cooperative Group: Randomized trial of 2
versus 5 years of adjuvant tamoxifen in postmenopausal early-stage breast cancer.
Proceedings of the American Society of Clinical Oncology 15: A-171, 126, 1996.
- Bonadonna G, Veronesi U, Brambilla C, et al.: Primary chemotherapy
to avoid mastectomy in tumors with diameters of three centimeters or more. Journal of the
National Cancer Institute 82(19): 1539-1545, 1990.
- Powles TJ, Hickish TF, Markris A, et al.: Randomized trial of
chemoendocrine therapy started before or after surgery for treatment of primary breast
cancer. Journal of Clinical Oncology 13(3): 547-552, 1995.
- Fisher B, Brown A, Mamounas E, et al.: Effect of preoperative
chemotherapy on local-regional disease in women with operable breast cancer: findings from
National Surgical Adjuvant Breast and Bowel Project B-18. Journal of Clinical Oncology
15(7): 2483-2493, 1997.
- Fisher B, Brown A, Mamounas E, et al.: Effect of preoperative
therapy for primary breast cancer (BC) on local-regional disease, disease-free survival
(DFS) and survival (S): results from NSABP B-18. Proceedings of the American Society of
Clinical Oncology 16: A-449, 127a, 1997.
- Peters WP, Cancer and Leukemia Group B: NCI HIGH PRIORITY CLINICAL
TRIAL --- Phase III Randomized Comparison of High-Dose Chemotherapy with Autologous Marrow
and Peripheral Stem Cell Support vs Standard-Dose Chemotherapy Following Adjuvant
Chemotherapy in Women with Stage II/IIIA Breast Cancer with at Least 10 Positive Axillary
Nodes (Summary Last Modified 09/98), CLB-9082, clinical trial, closed, 05/29/98.
- Tallman MS, Eastern Cooperative Oncology Group: NCI HIGH PRIORITY
CLINICAL TRIAL --- Phase III Randomized Study of Adjuvant CAF
(Cyclophosphamide/Doxorubicin/Fluorouracil) vs Adjuvant CAF Followed by Intensification
with High-Dose Cyclophosphamide/Thiotepa plus Autologous Stem Cell Rescue in Women with
Stage II/III Breast Cancer At High Risk of Recurrence (Summary Last Modified 09/98),
EST-2190, clinical trial, active, 08/07/91.
- Henderson IC, Cancer and Leukemia Group B: Phase III Randomized
Study of Adjuvant CA (Cyclophosphamide/Doxorubicin) Comparing Standard- vs Intermediate-
vs High-Dose Doxorubicin, with vs without Subsequent Paclitaxel, in Women with
Node-Positive Breast Cancer (Summary Last Modified 08/97), CLB-9344, clinical trial,
closed, 04/16/97.
- Figlin RA, Southwest Oncology Group: Phase III Randomized Study of
Adjuvant Chemotherapy with High-Dose Doxorubicn/Cyclophosphamide vs Doxorubicin Followed
by Cyclophosphamide in Women with High-Risk Breast Cancer and 0-3 Positive Nodes (Summary
Last Modified 07/97), SWOG-9313, clinical trial, closed, 05/02/97.
- Cobleigh MA, Eastern Cooperative Oncology Group: Phase III
Randomized Double-Blind Study of Adjuvant Tamoxifen/Fenretinide vs Tamoxifen/Placebo in
Postmenopausal Women with Receptor-Positive Breast Cancer and Involved Axillary Lymph
Nodes (Summary Last Modified 06/98), E-EB193, clinical trial, active, 10/04/95.
- Mamounas T, National Surgical Adjuvant Breast and Bowel Project:
Phase III Randomized Study of Paclitaxel vs No Further Chemotherapy Following
Doxorubicin/Cyclophosphamide for Resected Node-Positive Breast Cancer (Summary Last
Modified 07/98), NSABP-B-28, clinical trial, closed, 05/22/98.
- Misset JL, di Palma M, Delgado M, et al.: Adjuvant treatment of
node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and
vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a
16-year median follow-up duration. Journal of Clinical Oncology 14(4): 1136-1145, 1996.
- Bianco AR, De Placido S, Gall C, et al.: Adjuvant therapy with
tamoxifen in operable breast cancer: 10 year results of the Naples (GUN) study. Lancet
2(8620): 1095-1099, 1988.
- Rivkin SE, Green S, Metch B, et al.: Adjuvant CMFVP versus melphalan
for operable breast cancer with positive axillary nodes: 10-year results of a Southwest
Oncology Group Study. Journal of Clinical Oncology 7(9): 1229-1238, 1989.
Stage III (locally advanced) breast cancer is further classified into stage IIIA and
stage IIIB disease. Stage IIIA disease is often operable when axillary lymph nodes are
mobile. However, if the lymph nodes are fixed or if the tumor is very large, neoadjuvant
chemotherapy is indicated to shrink the tumor before surgery.
Stage IIIA
Treatment options:
Standard:
- 1. In operable cases, one of the following surgical procedures for initial treatment:
Modified radical mastectomy.
Radical mastectomy.
2. Because of the high risk of local recurrence for this stage, radiation therapy should
be considered as part of the overall treatment plan: Postoperative external-beam
irradiation to the chest wall. A boost can be given if clinically indicated for positive
or close margins.
3. Chemotherapy regimens with or without hormones are given in conjunction with the above
surgical and radiotherapeutic procedures. Chemotherapy can be given prior to surgery in
cases where primary resection is not feasible or is technically difficult. Some equally
effective combination chemotherapy regimens commonly used are:
CMF: cyclophosphamide + methotrexate + fluorouracil.[1]
CAF: cyclophosphamide + doxorubicin + fluorouracil.[2,3]
CA: cyclophosphamide + doxorubicin.[4]
Under clinical evaluation:
- 1. Clinical trials evaluating the role of combination chemotherapy with or without
hormonal manipulation are ongoing.[5,6]
Preliminary data indicate that neoadjuvant preoperative chemotherapy may allow breast
conservation therapy in patients whose lesion and breast size would not have allowed this
option.[7-9]
2. High-dose chemotherapy with hematopoietic stem cell support.
Stage IIIB (locally advanced, including inflammatory)
The treatment of inflammatory breast cancer is similar to options for stage IIIB or IV
breast cancer.[10,11]
In stage IIIB breast cancer, initial surgery is generally limited to biopsy. Removal of
residual tumor may be performed if a good response is achieved with chemotherapy with or
without radiation therapy.
Treatment options:
Standard:
- 1. Core needle biopsy, fine-needle aspiration or incisional biopsy for diagnosis and
receptor protein assay followed by preoperative chemotherapy. If the patient has a good
response, local therapy with surgery and/or irradiation is recommended. If the response is
poor, palliative radiation therapy may be recommended.
2. Chemotherapy regimens with or without hormones are given in conjunction with the above
surgical and radiotherapeutic procedures. Chemotherapy can be given prior to surgery in
cases where primary resection is not feasible or is technically difficult. Commonly used
chemotherapy regimens include:
CMF: cyclophosphamide + methotrexate + fluorouracil.
CAF: cyclophosphamide + doxorubicin + fluorouracil.
CA: cyclophosphamide + doxorubicin.
3. If combination chemotherapy is contraindicated, pretreatment with tamoxifen may be
recommended for patients whose tumors are positive for estrogen- and progesterone-receptor
proteins.
Under clinical evaluation:
- 1. Phase II studies evaluating newly developed chemotherapeutic or biologic agents may
be considered for patients whose local disease is not controllable by standard measures.
2. High-dose chemotherapy with hematopoietic cell support.
References:
- Tancini G, Bonadonna G, Valagussa P, et al.: Adjuvant CMF in breast
cancer: comparative 5-year results of 12 versus 6 cycles. Journal of Clinical Oncology
1(1): 2-10, 1983.
- Buzdar AU, Kau SW, Smith TL, et al.: Ten-year results of FAC adjuvant
chemotherapy trial in breast cancer. American Journal of Clinical Oncology 12(2): 123-128,
1989.
- Buzdar AU, Smith TL, Powell KC, et al.: Effect of timing of initiation
of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Research
and Treatment 2(2): 163-169, 1982.
- Fisher B, Redmond C, Fisher ER, et al.: A summary of findings from
NSABP: trials of adjuvant therapy. In: Jones SE, Salmon SE, Eds.: Adjuvant Therapy of
Cancer IV. New York: Grune and Stratton, Inc., 1984, pp 185-194.
- Mamounas T, National Surgical Adjuvant Breast and Bowel Project: Phase
III Randomized Study of Paclitaxel vs No Further Chemotherapy Following
Doxorubicin/Cyclophosphamide for Resected Node-Positive Breast Cancer (Summary Last
Modified 07/98), NSABP-B-28, clinical trial, closed, 05/22/98.
- Henderson IC, Cancer and Leukemia Group B: Phase III Randomized Study
of Adjuvant CA (Cyclophosphamide/Doxorubicin) Comparing Standard- vs Intermediate- vs
High-Dose Doxorubicin, with vs without Subsequent Paclitaxel, in Women with Node-Positive
Breast Cancer (Summary Last Modified 08/97), CLB-9344, clinical trial, closed, 04/16/97.
- Bonadonna G, Veronesi U, Brambilla C, et al.: Primary chemotherapy to
avoid mastectomy in tumors with diameters of three centimeters or more. Journal of the
National Cancer Institute 82(19): 1539-1545, 1990.
- Sener SF, Imperato JP, Khandekar JD, et al.: Achieving local control
for inflammatory carcinoma of the breast. Surgery, Gynecology and Obstetrics 175(2):
141-144, 1992.
- Smith IE, Walsh G, Jones A, et al.: High complete remission rates with
primary neoadjuvant infusional chemotherapy for large early breast cancer. Journal of
Clinical Oncology 13(2): 424-429, 1995.
- Moore MP, Ihde JK, Crowe JP, et al.: Inflammatory breast cancer.
Archives of Surgery 126(3): 304-306, 1991.
- Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality
treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson
Cancer Center. Cancer Chemotherapy and Pharmacology 40(4): 321-329, 1997.
Stage IV breast cancer is often responsive to treatment with durable complete
remissions attainable in 10%-20% of patients, although long disease-free survival
indicative of cure is rare.[1-3]
Surgical procedures are generally limited to those that will permit the determination
of histology and estrogen-receptor (ER) and progesterone-receptor (PR) levels. Control of
local disease is usually achieved with either surgery or radiation therapy. External-beam
irradiation also has a major role in the palliation of symptoms, particularly pain caused
by bone metastases. A separate summary containing information on bone metastases is also
available in PDQ.
Appropriate patients should be considered for available trials studying the role of
bisphosphonates in reducing skeletal morbidity in those with bony metastases. Results of
randomized trials of pamidronate and clodronate in patients with bony metastatic disease
show decreased skeletal morbidity in patients receiving this class of drugs.[4,5] The majority of patients with stage IV
breast cancer will respond to a standard chemotherapy regimen used as initial treatment.
However, all eligible patients with stage IV breast cancer should be considered for
ongoing clinical trials designed to improve therapeutic results in this disease.[6,7] For patients with disease progression
after an anthracycline-containing regimen, paclitaxel and docetaxel have produced
clinically useful responses. In studies of refractory metastatic breast cancer, response
rates to these agents have ranged from 6% to 48% for paclitaxel and from 53% to 57% for
docetaxel. However, these agents are associated with substantial toxicity, including
severe neutropenia, fever, complete alopecia, stomatitis, myalgia, neuropathy, asthenia,
and rare cases of allergic reactions. In addition, docetaxel can cause cumulative
dose-related fluid retention and symptomatic pleural effusions.[8-11]
Treatment options:
Standard:
- 1. A biopsy to determine histology and ER and PR levels. External-beam radiation therapy
or a palliative mastectomy may be recommended to control local disease.
2. If visceral disease is minimal or absent and ER and PR status is positive, hormonal
therapy is an excellent first treatment.
Tamoxifen or oophorectomy can be used for premenopausal patients.[12,13]
For patients who relapse following a period of response or prolonged stability on initial
hormone therapy, either megestrol acetate (40 milligrams four times per day), anastrozole
(1 milligram daily), or letrozole (2.5 milligrams) can be valuable palliative treatment.[14,15] Megestrol is associated with weight
gain, which may be an undesirable side effect.
3. If visceral disease is present or ER and PR status is negative, one of the following
combination chemotherapy regimens will produce equivalent results:
CMF: cyclophosphamide + methotrexate + fluorouracil.[16]
CAF: cyclophosphamide + doxorubicin* + fluorouracil.[17]
CA: cyclophosphamide + doxorubicin.*[18]
*The potential for doxorubicin-induced cardiotoxicity should be considered in the
selection of chemotherapeutic regimens for an individual patient. Recognized risk factors
for cardiac toxicity include advanced age, prior chest- wall irradiation, prior
anthracycline exposure, hypertension, diabetes, and known underlying heart disease. The
cardioprotective drug dexrazoxane has been shown in controlled studies to decrease the
risk of doxorubicin-induced cardiac toxicity. The use of this agent has permitted patients
to receive greater cumulative doses of doxorubicin and allowed patients with cardiac risk
factors to receive doxorubicin.[19-22]
Dexrazoxane has a similar protective effect in patients receiving epirubicin.[23] The risks of cardiac toxicity may also be reduced by
administering doxorubicin as a continuous intravenous infusion.[24]
Under clinical evaluation:
- 1. If visceral disease is absent and ER and PR status is positive, clinical trials
evaluating the role of hormonal therapy should be considered as first treatment.[25]
2. If visceral disease is present or ER and PR status is negative, clinical trials
evaluating the role of combination chemotherapy with and without hormonal therapy should
be considered as first treatment.
3. Phase II studies evaluating newly developed chemotherapeutic or biologic agents should
also be considered.[8-11,26-28]
4. High-dose chemotherapy with hematopoietic stem cell support.[29-31]
References:
- Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in
advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. Journal of
Clinical Oncology 5(10): 1534-1545, 1987.
- Tannock IF: Treating the patient, not just the cancer. New England
Journal of Medicine 317(24): 1534-1535, 1987.
- Dhodapkar MV, Ingle JN, Cha SS, et al.: Prognostic factors in elderly
women with metastatic breast cancer treated with tamoxifen: an analysis of patients
entered on four prospective clinical trials. Cancer 77(4): 683-690, 1996.
- Hortobagyi GN, Theriault RL, Porter L, et al.: Efficacy of pamidronate
in reducing skeletal complications in patients with breast cancer and lytic bone
metastases. New England Journal of Medicine 335(24): 1785-1791, 1996.
- Paterson AH, Powles TJ, Kanis JA, et al.: Double-blind controlled
trial of oral clodronate in patients with bone metastases from breast cancer. Journal of
Clinical Oncology 11(1): 59-65, 1993.
- Livingston RB, Southwest Oncology Group: NCI HIGH PRIORITY CLINICAL
TRIAL --- Phase III Randomized Comparison of Marrow Ablation with STAMP V (High-Dose
CTX/TSPA/CDBCA) and Autologous Stem Cell Rescue vs Standard Chemotherapy in Patients with
Poor-Prognosis Advanced Breast Carcinoma (Summary Last Modified 08/93), SWOG-9115,
clinical trial, closed, 01/01/94.
- Taylor CW, Southwest Oncology Group: Phase III Randomized Comparison
of Surgical Oophorectomy vs Medical Oophorectomy with Goserelin in Premenopausal Women
with Metastatic, ER-Positive or PR-Positive Carcinoma of the Breast (Summary Last Modified
02/95), SWOG-8692, clinical trial, closed, 07/15/95.
- Seidman AD, Reichman BS, Crown JP, et al.: Paclitaxel as second and
subsequent therapy for metastatic breast cancer: activity independent of prior
anthracycline response. Journal of Clinical Oncology 13(5): 1152-1159, 1995.
- Gianni L, Munzone E, Capri G, et al.: Paclitaxel in metastatic breast
cancer: a trial of two doses by a 3-hour infusion in patients with disease recurrence
after prior therapy with anthracyclines. Journal of the National Cancer Institute 87(15):
1169-1175, 1995.
- Ravdin PM, Burris HA, Cook G, et al.: Phase II trial of docetaxel in
advanced anthracycline-resistant or anthracenedione-resistant breast cancer. Journal of
Clinical Oncology 13(12): 2879-2885, 1995.
- Valero V, Holmes FA, Walters RS, et al.: Phase II trial of docetaxel:
a new, highly effective antineoplastic agent in the management of patients with
anthracycline-resistant metastatic breast cancer. Journal of Clinical Oncology 13(12):
2886-2894, 1995.
- Ingle JN, Krook JE, Green SJ, et al.: Randomized trial of bilateral
oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer.
Journal of Clinical Oncology 4(2): 178-185, 1986.
- Goldberg RM, Loprinzi CL, O'Fallon JR, et al.: Transdermal clonidine
for ameliorating tamoxifen-induced hot flashes. Journal of Clinical Oncology 12(1):
155-158, 1994.
- Jonat W, Howell A, Blomqvist C, et al.: A randomised trial comparing
two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol
acetate in postmenopausal patients with advanced breast cancer. European Journal of Cancer
32A(3): 404-412, 1996.
- Marty M, Gershanovich M, Campos B, et al.: Letrozole, a new potent,
selective aromatase inhibitor (AI) superior to aminoglutethimide (AG) in postmenopausal
women with advanced breast cancer (ABC) previously treated with anti-estrogens.
Proceedings of the American Society of Clinical Oncology 16: A-544, 156a, 1997.
- Tormey DC, Gelman R, Band PR, et al.: Comparison of induction
chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group trial.
Cancer 50(7): 1235-1244, 1982.
- Smalley RV, Lefante J, Bartolucci A, et al.: A comparison of
cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate,
5-fluorouracil, vincristine and prednisone (CMFVP) in patients with advanced breast
cancer: a Southeastern Cancer Study Group project. Breast Cancer Research and Treatment
3(2): 209-220, 1983.
- Tranum BL, McDonald B, Thigpen T, et al.: Adriamycin combinations in
advanced breast cancer: a Southwest Oncology Group study. Cancer 49(5): 835-839, 1982.
- Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al.: ICRF-187 permits
longer treatment with doxorubicin in women with breast cancer. Journal of Clinical
Oncology 10(1): 117-127, 1992.
- Piga A, Francini G, Pein F, et al.: Cardioprotection by Cardioxane
(dexrazoxane) in breast cancer patients at increased risk for anthracycline induced
cardiotoxicity. Proceedings of the American Association for Cancer Research 34: A-1359,
228, 1993.
- Swain SM, Whaley FS, Gerber MC, et al.: Delayed administration of
dexrazoxane provides cardioprotection for patients with advanced breast cancer treated
with doxorubicin-containing therapy. Journal of Clinical Oncology 15(4): 1333-1340, 1997.
- Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with
dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. Journal of
Clinical Oncology 15(4): 1318-1332, 1997.
- Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter
randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no
cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer.
Journal of Clinical Oncology 14(12): 3112-3120, 1996.
- Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity
of doxorubicin administered by continuous intravenous infusion in combination chemotherapy
for metastatic breast carcinoma. Cancer 63(1):37-45, 1989.
- Rubens RD, Tinson CL, Coleman RE, et al.: Prednisolone improves the
response to primary endocrine treatment for advanced breast cancer. British Journal of
Cancer 58(5): 626-630, 1988.
- Brandt SJ, Peters WP, Atwater SK, et al.: Effect of recombinant human
granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after
high-dose chemotherapy and autologous bone marrow transplantation. New England Journal of
Medicine 318(14): 869-876, 1988.
- Perez JE, Machiavelli M, Leone BA, et al.: Ifosfamide and
mitoxantrone as first-line chemotherapy for metastatic breast cancer. Journal of Clinical
Oncology 11(3): 461-466, 1993.
- Margolin KA, Doroshow JH, Akman SA, et al.: Effective initial therapy
of advanced breast cancer with fluorouracil and high-dose, continuous infusion calcium
leucovorin. Journal of Clinical Oncology 10(8): 1278-1283, 1992.
- Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with
hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized
trial. Journal of Clinical Oncology 13(10): 2483-2489, 1995.
- Kennedy MJ: High-dose chemotherapy of breast cancer: is the question
answered? Journal of Clinical Oncology 13(10): 2477-2479, 1995.
- Stadtmauer EA, Eastern Cooperative Oncology Group: NCI HIGH PRIORITY
CLINICAL TRIAL --- Phase III Randomized Comparison of Conventional CMF Maintenance vs
High-Dose Combination Chemotherapy plus Autologous Bone Marrow and Peripheral Stem Cell
Rescue in Women with Metastatic Breast Cancer Responding to Conventional Induction
Chemotherapy (Summary Last Modified 08/98), E-PBT01, clinical trial, closed, 12/23/97.
The treatment of inflammatory breast cancer is similar to options for stage IIIB or IV
breast cancer.[1]
References:
- Moore MP, Ihde JK, Crowe JP, et al.: Inflammatory breast cancer. Archives
of Surgery 126(3): 304-306, 1991.
Some citations in the text of this section are followed by a level of evidence. The PDQ
editorial boards use a formal ranking system to help the reader judge the strength of
evidence linked to reported results of a therapeutic strategy. Refer to the PDQ levels of
evidence summary for more information.
Recurrent breast cancer is often responsive to therapy although treatment is rarely
curative at this stage of the disease. Radiation therapy has a major role in the
palliation of locally recurrent disease and symptoms such as pain due to bone metastases.
A separate summary containing information on bone metastases is also available in PDQ. The
estrogen-receptor (ER) and progesterone-receptor (PR) levels at the time of recurrence and
previous treatment should be considered in selecting therapy. ER levels may change at time
of recurrence.[1] In one study, 36% of estrogen-receptor positive
tumors lost receptor positivity when remeasured at time of recurrence. If ER and PR status
is unknown or positive, then the site(s) of recurrence, disease-free interval, response to
previous treatment, and menopausal status are useful in selecting chemotherapy or hormonal
therapy.[2]
The results of one long-term trial indicate that between 10% and 20% of patients will
have locally recurrent disease in the breast between 1 and 9 years after breast
conservation surgery plus radiation therapy.[3] The patient's age
alone (younger than or older than 65 years) is not an independent predictor of response to
or toxicity from doxorubicin-based chemotherapy.[4] Local
recurrence is usually the harbinger of widespread disease but, in a subset of patients,
may be the only site of recurrence. For patients in this subset, surgery and/or radiation
therapy may be curative.[5-7] Patients
with chest wall recurrences of less than 3 centimeters, axillary and internal mammary node
recurrence (not supraclavicular, which has a poorer survival), and a greater than 2-year
disease-free interval prior to resection have the best chance for prolonged survival.[7] The 5-year disease-free survival rate (i.e., without further
local or distant relapse) in one series of such patients was 25%, with a 10-year rate of
15%.[5] The locoregional control rate was 57% at 10 years.
The prognosis following breast cancer recurrence after lumpectomy plus radiation
therapy is much better than that following chest-wall recurrence after mastectomy. Only
9%-25% of patients undergoing lumpectomy plus radiation therapy will be found to have
distant metastases or locally extensive disease preventing mastectomy at the time of
recurrence. In one series of 30 patients who had a local recurrence in the breast after
lumpectomy plus radiation therapy and who underwent salvage mastectomy, no distant
recurrences were seen later than 6 years after initial local failure, and the disease-free
survival following salvage mastectomy was 58% at 5 years and 50% at 10 years.[8-12]
All patients with recurrent breast cancer should be considered candidates for one of
the ongoing clinical trials testing newly developed chemotherapeutic and biologic agents
in phase II studies. For patients with recurrence after an anthracycline-containing
regimen, paclitaxel has been approved by the Food and Drug Administration (FDA) for
second-line therapy and docetaxel received formal approval by the FDA.[13]
Treatment options:
Standard:
- 1. If visceral disease is absent or is not bulky and confined to one organ (e.g.,
nodular pulmonary metastases) in an asymptomatic patient, and ER and PR status is positive
or unknown:
Tamoxifen or oophorectomy (or chemical castration with LHRH agonists) for premenopausal
patients.[14]
Tamoxifen for postmenopausal patients.
2. Surgery and/or radiation therapy if recurrence is localized or visceral.[5,15]
3. Patients who respond to additive hormonal therapy and then relapse should be considered
for other forms of hormonal therapy such as those therapies in (1) above not previously
used or:
Progesterone therapy with megestrol acetate at a dose of 160 milligrams per day.[16]
Anastrozole at a dose of 1 milligram per day.[17]
Androgen therapy for pre- and postmenopausal patients.
LHRH agonists for premenopausal patients.
Corticosteroids.
Aminoglutethimide.[18,19]
Aromatase inhibitors anastrozole [17,20]
or fadrozole (the latter of which will soon be available).[21]
Selected patients with an initial response to hormone therapy, generally those with soft
tissue disease and/or hormone-receptor-positive disease, may have a response to withdrawal
of the hormonal therapy of an average duration of ten months, at which time another
hormonal therapy can be instituted.[22]
4. If visceral disease is present and ER and PR status is negative:
CMF: cyclophosphamide + methotrexate + fluorouracil.[23]
CAF: cyclophosphamide + doxorubicin* + fluorouracil.[24]
CA: cyclophosphamide + doxorubicin.[25]
For patients with disease progression after an anthracycline-containing regimen,
paclitaxel and docetaxel have produced significant second-line responses. In studies of
refractory metastatic breast cancer, response rates to these agents have ranged from 6% to
48% for paclitaxel and from 53% to 57% for docetaxel. However, these agents are associated
with substantial toxicity, including severe neutropenia, fever, complete alopecia,
stomatitis, myalgia, neuropathy, asthenia, and rare cases of allergic reactions. In
addition, docetaxel can cause cumulative dose-related fluid retention and symptomatic
pleural effusions.[26-29] Vinorelbine
has also demonstrated activity in patients who relapse after treatment with an
anthracycline-containing regimen [30] and has been effective in
producing palliation as first- and second-line treatment in advanced breast cancer.[31]
*The potential for doxorubicin-induced cardiotoxicity should be considered in the
selection of chemotherapeutic regimens for an individual patient. Recognized risk factors
for cardiac toxicity include advanced age, prior chest- wall irradiation, prior
anthracycline exposure, hypertension, diabetes, and known underlying heart disease. The
cardioprotective drug dexrazoxane has been shown in controlled studies to decrease the
risk of doxorubicin-induced cardiac toxicity. The use of this agent has permitted patients
to receive greater cumulative doses of doxorubicin and allowed patients with cardiac risk
factors to receive doxorubicin.[32,33]
The risks of cardiac toxicity may also be reduced by administering doxorubicin as a
continuous intravenous infusion.[34]
Under clinical evaluation:
- 1. If visceral disease is absent, ER and PR status is positive or unknown, and the
disease-free interval is long, clinical trials evaluating the role of hormonal therapy
such as administration of tamoxifen to premenopausal women should be considered.[14,35,36]
2. For patients with recurrences after an initial response to hormonal manipulation,
clinical trials evaluating combination chemotherapy with or without hormonal manipulation
or new hormonal therapies should be considered.
3. If visceral disease is present, ER and PR status is negative, or the disease-free
interval is less than 2 years, clinical trials evaluating combination chemotherapy or
newly developed chemotherapeutic agents, including taxanes, and biologic agents should be
considered.[26-29,37-39]
4. In patients with a localized chest wall recurrence who have received prior radiation,
hyperthermia could be considered in conjunction with re- irradiation at selected centers
with hyperthermia experience. In a prospective, randomized trial, hyperthermia and
radiation had an enhanced local response rate when compared to radiation therapy alone
(57% versus 31%). There was no effect on survival.[40][Level of
evidence: 1iiDiii]
5. For metastatic disease, high-dose chemotherapy with autologous bone marrow
transplantation has been associated with a high response rate, although responses are
generally not of long duration.[41-44]
This treatment is under evaluation. Patients considered candidates for this approach
should consider enrollment in the PBT-1 trial, a nationwide NCI-sponsored trial comparing
high-dose chemotherapy with standard maintenance chemotherapy in patients sensitive to
standard chemotherapy.[45]
6. New antiestrogens may have fewer toxic effects than tamoxifen.[46,47].
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Date Last Modified: 09/98
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