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    Breast:

    Anatomy The mammary gland lies over the pectoralis major muscle and extends from the second to the

    sixth rib in the vertical plane and from the sternum to the anterior or midaxillary line. The mamma

    consists of glandular tissue arranged in multiple lobes composed of lobules connected in ducts,areolar tissue, and blood vessels. A network of lymphatics is formed over the en tire surface of the chest, neck, and abdomen and

    becomes dense under the areola.

    Natural History As breast cancer grows, it travels along the ducts, eventually breaking through the basement

    membrane of the duct to invade adjacent lobules, ducts, fascial strands,mammary fat, and skin. Itthen spreads through the breast lymphatics and into the peripheral lymphatics; tumor can invadeblood vessels.

    axillary nodal metastases; hematogenous metastases to the lungs, pleura, bone, brain, eyes,liver, ovaries, and adrenal and pituitary glands occurs, even with mall tumors.

    Clinical Presentation Most patients with carcinoma in situ, a painless or slightly tender breast mass or have an

    abnormal screening mammogram.

    mammography only

    Pathologic Classification The World Health Organization has classified proliferative conditions and tumors of the breast as

    benign mammary dysplasias, benign or apparently benign tumors,carcinoma, sarcoma,carcinosarcoma, and unclassified tumors . The American Joint Committee on Cancer hasdeveloped an alternate system.

    Intraductal carcinoma or ductal carcinoma in situ (DCIS) is a noninvasive lesion with five histologicsubtypes: comedo, solid, cribriform, papillary, and micropapillary.

    Lobular carcinoma in situ (LCIS) is a noninvasive proliferation of abnormal epithelial cells in thelobules of the breast.

    Invasive (infiltrating) ductal carcinoma,

    Prognostic FactorsIntrinsic Factors

    Tumor size and clinical stage are strong prognostic factors influencing local recurrence, nodal anddistant metastases, and survival.

    Results of tumor excision and breast irradiation are equivalent in patients with infiltrating lobular orinfiltrating ductal carcinoma.

    The incidence of local recurrence is greater and survival decreased with higher nuclear grade,vascular invasion, inflammatory infiltrate, and undifferentiation and necrosis of the tumor.

    Tumor location in the breast does not affect prognosis.

    Extrinsic (Host) Factors Young age may be a risk factor for breast recurrence in conservation surgery and irradiation; high

    tumor grade, and a major mononuclear cell reaction, Black women are commonly diagnosed with more advanced stages of breast cancer than white

    women. Although it was believed in the past that pregnancy after the diagnosis of breast cancer was

    associated with a worse prognosis, recent evidence suggests the opposite.

    General ManagementDuctal Carcinoma In Situand Lobular Carcinoma In Situ

    Patients with LCIS also have a propensity to develop invasive lesions. DCIS that presents as a large mass (greater than 2.5 cm) has a significantly higher potential for

    occult invasion, multicentricity, axillary lymph node metastases, and local recurrence than

    nonpalpable lesions, as well as worse survival.Treatment of Ductal Carcinoma In Situ total mastectomy or breast-conserving surgery, with or (in selected patients) without irradiation.

    Treatment of Lobular Carcinoma In Situ Treatment options for LCIS include complete local excision of the lesion and close follow-up,

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    ipsilateral total mastectomy or, bilateral mastectomies, and hormonal manipulation ininvestigational protocols.

    The breast is treated with doses of 50 Gy and the axillary/supraclavicular lymph nodes with 50 Gy,with a boost of 10 to 15 Gy to the axillary fossa.

    Radiation Therapy Techniques for the Intact BreastTreatment Volume

    The entire breast and chest wall should be included in the irradiated volume, along with a smallportion of underlying lung.

    Radiopaque surgical clips placed at the margin of the tumor bed may assist in defining thetarget volume.

    When combined with a supraclavicular portal, the upper margin of the portal is placed at thesecond intercostal space (angle of Louie).

    If the regional lymph nodes are not to be irradiated, the upper margin of the portals should beplaced at the head of the clavicle to include the entire breast (Fig. 2).

    If no internal mammary portal is used, the medial margin should be 1 cm over the midline. If aninternal mammary field is used, the medial tangential portal is located at the lateral margin of the

    internal mammary field (Fig. 2). The lateral/posterior margin should be placed 2 cm beyond all palpable breast tissue. The inferior margin is drawn 2 to 3 cm below the inframammary fold. Irradiation in the prone position has been proposed for patients with large, pendulous breasts.

    Doses and Beams Minimal tumor doses of approximately 50 Gy are delivered to the entire breast in 5 to 6 weeks

    (1.8- to 2.0-Gy tumor dose daily, 5 weekly fractions). Minimum doses of 46.8 Gy (1.8-Gy dailyfraction) are preferred for patients with large, pendulous breasts or when irradiation is combinedwith chemotherapy.

    X-ray energies of 4 to 6 MV are preferred to treat the breast. Photon energies greater than 6 MVmay underdose superficial tissues beneath the skin surface, but higher-energy photons may be

    helpful in large breasts to decrease the integral breast dose-

    Boost to Tumor Site The indications for boost irradiation are strongly supported by the pathologic findings Boost doses range from 10 to 20 Gy, depending on the size of the tumor and status of excision

    margins.Irradiation of Regional LymphaticsSupraclavicular Lymph Nodes

    If only the apex of the axilla is treated (after modified radical mastectomy or axillary dissection),the inferior border of the supraclavicular field is the first or second intercostal space.

    The medial border is 1 cm across the midline, extending upward, following the medial border ofthe sternocleidomastoid muscle to the thyrocricoid groove.

    The lateral border is a vertical line at the level of the anterior axillary fold. The humeral head is blocked as much as possible without compromising coverage of the high

    axillary lymph nodes (Fig. 33-2). This field is angled approximately 15 to 20 degrees laterally tospare the spinal cord.

    The low axilla is treated only when there is extracapsular tumor or if axillary dissection is notperformed. The supraclavicular field is modified so that the inferior border comes down to split thesecond rib (angle of Louie), and the lateral border is drawn to just block falloff across the skin ofthe anterior axillary fold.

    Total dose to the supraclavicular field is 46 Gy at 2 Gy per day (calculated at 3-cm depth) in 5fractions per week; an alternative schedule is 50.4 Gy in 1.8-Gy fractions.

    Axillary Lymph Nodes The medial border of this field is drawn to allow 1.5 to 2 cm of lung to show on the portal film. The

    inferior border is at the same level as the inferior border of the supraclavicular field; the lateralborder just blocks falloff across the posterior axillary fold. The superior border splits the clavicle,and the superior-lateral border shields or splits the humeral head.

    The dose to the midplane of the axilla from the supraclavicular field is calculated at a pointapproximately 2 cm inferior to the midportion of the clavicle.

    The dose to the midplane of the axilla is supplemented by a posterior axillary field. Additional dose to the axilla midplane is administered to complete 46 to 50 Gy (2 Gy daily). When indicated, a boost of 10 to 15 Gy is delivered with reduced portals.

    Internal Mammary Lymph Nodes The benefit of treating internal mammary lymph nodes is unresolved, since clinical failures at this

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    site are very rare. The medial border of the internal mammary field is the midline. The lateral border is usually 5 cm

    lateral to the midline; the superior border abuts the inferior border of the supraclavicular field; andthe inferior border is at the xiphoid.

    If only the internal mammary nodes are treated, the superior border of the field is at the superiorsurface of the head of the clavicle. The field is set with an oblique incidence to match the medial

    tangential portal. The dose to the internal mammary field (45 to 50 Gy at 1.8 to 2.0 Gy per day) is calculated at apoint 4 to 5 cm beneath the skin surface. CT scans of the chest are very helpful in determiningdose-prescription depth.

    To spare underlying lung, mediastinum, and spinal cord, 12- to 16-MeV electrons are preferred fora portion of the treatment. The usual proportion is 14.4 Gy delivered with 4- to 6-MV photons and30.6 to 35.6 Gy with electrons (1.8 Gy daily).

    Timing of Irradiation after Conservation Surgery The optimal sequence for combining breast-conserving surgery, irradiation, and chemotherapy for

    patients with T1, T2, and selected T3 breast cancer is unknown. At present, it is generally agreed that irradiation optimally should be started within 6 weeks from

    breast surgery for patients not receiving chemotherapy and within 16 weeks for those treated withadjuvant chemotherapy.

    Sequelae of TherapyRadical Mastectomy

    A comprehensive article detailed the following complications in 1,198 patients after radicalmastectomy: death (1.2%), skin flap necrosis (36%), hematoma under the flap (4%), serumcollection under the flap (40%), wound dehiscence (3%), chest wound infection (14%), loss ofskin graft (32%), arm edema (31%), pneumothorax (6%), and infection of the donor site (8%)

    Conservation Surgery and Irradiation The most frequent complications associated with conservation surgery and irradiation are arm or

    breast edema, breast fibrosis, painful mastitis or myositis, pneumonitis, and rib fracture (seen inapproximately 10% of patients).

    Apical pulmonary fibrosis occasionally is noted when the regional lymph nodes are irradiated.Symptomatic pneumonitis is infrequent and may be related to the volume of lung irradiated.

    Breast: Locally Advanced (T3 and T4), Inflammatory, and Recurrent TumorsClinical or pathologic findings of locally advanced carcinoma at presentation include the following: tumorsize greater than 5 cm; clinically or pathologically positive axillary lymph nodes; tumor of any size withdirect extension to ribs, intercostal muscles, or skin; edema (includingpeau d'orange), ulceration of skinof breast, or satellite skin nodules confined to the same breast; inflammatory carcinoma (T4d); andmetastases to ipsilateral internal mammary lymph nodes or ipsilateral axillary lymph nodes fixed to oneanother or other structures.

    Locally Advanced (T3 and T4) Tumors Locally advanced breast cancer may evolve from a mass to infiltration of the deep lymphatics of

    dermis, causing edema of the skin. More pronounced edema (peau d'orange) usually indicatessuperficial and deep lymphatic involvement.

    Fixation of the skin over the tumor and localized redness occur, followed by ulceration andinfiltration of overlying skin.

    Skin retraction may be caused by tumor invasion of Cooper's ligament. Further extensive involvement includes satellite nodules and carcinoma en cuirasse, in which the

    skin becomes plaque-like and yellowish, red, or gray. Lymphatic spread to axillary, internal mammary, or supraclavicular lymph nodes frequently occurs. Common initial sites of hematogenous spread are, in order, bone, lung, and pleura.

    Inflammatory Carcinoma Clinical definition of inflammatory carcinoma is the presence of warmth, erythema, and peau

    d'orange in the involved breast. The pathologic criterion is the presence of tumor emboli in the dermal lymphatics.

    Diagnostic Workup Physical examination must give special attention to documenting locoregional extent of tumor and

    checking potential sites of spread. Laboratory studies include a complete blood cell count, serum chemistry profile, and full liver

    function tests. If liver function values are abnormal, a computed tomography (CT) scan of the abdomen

    should be obtained.

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    If anemia, leukopenia, or thrombocytopenia is present, bone marrow biopsy is necessary. Radiographic studies include chest x-ray, bone scans, and plain radiographs of symptomatic

    regions or suspicious areas of increased uptake on bone scans. If neurologic symptoms suggest cerebral metastases, a contrast-enhanced CT scan or

    gadolinium-enhanced magnetic resonance imaging scan of the brain should be obtained.

    Prognostic Factors Factors associated with increased local recurrence include larger, more diffuse tumors, presence

    of edema, and number of involved axillary nodes. Patients without estrogen/progesterone receptors have a significantly lower survival rate, and are

    not likely to respond to hormonal therapy. Her-2-neu overexpression is associated with poor prognosis. Tumor and axillary nodal response to neoadjuvant chemotherapy is an indicator for disease-free

    survival.

    General Management multiagent chemotherapy plays a primary role in the treatment of these patients. Radiation therapy and surgery each have important roles in optimizing locoregional tumor control. Surgery should be performed on all patients with technically resectable disease. Borderline

    resectable and unresectable locally advanced breast cancers have been treated with irradiationalone.

    Neoadjuvant chemotherapy (with or without hormone therapy) before surgical resection andirradiation plays a prominent role.

    Radiation Therapy TechniquesIrradiation of the Inoperable Breast

    Patients with technically inoperable tumors should be irradiated to the breast, supraclavicularnodes, and axillary nodes.

    Treatment of the ipsilateral internal mammary lymph nodes may be indicated if medial chest wall/breast disease is present or if there is clinical or radiographic involvement of the internalmammary node chain.

    The breast is treated with photons through tangential fields with borders similar to those used inearly breast cancer, ensuring that all potential tumor-bearing tissues are adequately covered.

    Irradiation of the Chest Wall

    Irradiation of the chest wall after mastectomy can be accomplished with tangential photon fields(as in the intact breast) or with appositional electron beams. Bolus is necessary over the entire field for part of the treatment, and should be added to the scar

    alone for an additional part of the treatment. Several electron-beam techniques can be used as an alternative to tangential photon treatment;

    the simplest is a single appositional field using 6- to 12-MeV electrons. CT scans assist indetermining the thickness of the chest wall to select the optimal electron-beam energy.

    Field BordersAnatomic landmarks defining the field borders for treatment of breast/chest wall tangentials,supraclavicular nodes, internal mammary nodes, and axilla are similar to those used to treat early breastancer.Matchline Technique

    Many methods have been used to achieve an ideal match of the anterior-oblique supraclavicular-field caudal edge and the cephalad edge of the tangential field.

    A nondivergent supraclavicular-field edge is achieved by blocking the inferior half of the field. Various methods achieve a nondivergent edge from the tangential beams, including blocking and

    table angulation with collimator angulation combined.Doses

    Total dose to the entire breast or chest wall is 50 Gy in 1.8- to 2.0-Gy daily fractions. If surgery is not feasible, the breast should be given an additional 10 to 25 Gy with external

    irradiation (electrons or photons). This should be performed with shrinking fields or with aniridium-192 implant to a total dose of 75 to 80 Gy. The boost dose is determined by the volume ofresidual disease.

    In patients with close or positive margins, a boost of 10 to 15 Gy is given to a reduced volume with"minitangential" photon or appositional electron beam portals.

    Internal mammary nodes, supraclavicular fossa nodes, and axillary nodal areas should receive 45to 50 Gy over 5 to 6 weeks if no macroscopic tumor is present.

    Any gross nodal disease should be boosted with an additional 10 to 15 Gy using a reducedappositional electron beam field.

    Postmastectomy Radiation Therapy In general, postmastectomy irradiation is recommended for lesions larger than 5 cm in diameter;

    any skin, fascial, or skeletal muscle involvement; poorly differentiated tumors; positive or close

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    surgical margins (less than 3 mm); lymphatic permeation; matted lymph nodes; two or morepositive axillary lymph nodes; or gross extracapsular tumor extension.

    Adjuvant irradiation can be effectively given before, concurrent with, or after chemotherapy. Doses for subclinical disease in electively treated areas is 50 Gy in 1.8- to 2.0-Gy fractions. Bolus frequently is used in the mastectomy scar and for 50% of treatments to the chest wall. For close or positive margins, an additional 10 to 15 Gy is administered with reduced fields.

    Locoregional Recurrence After Mastectomy Locoregional recurrence after mastectomy is recurrent cancer in the bone, muscle, skin, or

    subcutaneous tissue of the chest wall. Regional involvement may include lymph nodes in the axilla, supraclavicular, or infraclavicular

    region; ipsilateral internal mammary lymph nodes; or retropectoral lymph nodes. Locoregional recurrences may be isolated or concomitant with distant metastases; complete

    restaging workup is mandatory. Patients developing locoregional recurrence may be treated with a combination of irradiation,

    surgery, systemic therapy, or hyperthermia. Surgical management may consist of local excision for purposes of debulking or may be extensive,

    as in chest wall resection. A second issue in the treatment of isolated locoregional recurrences is elective irradiation of the

    chest wall and regional lymphatics to prevent second recurrences in these sites. Irradiation doses of 50 Gy are given to electively treated areas and to areas where recurrent

    tumors have been completely excised. For unresected lesions smaller than 3 cm, 60 to 65 Gy should be given; larger masses require 65

    to 75 Gv .