Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

12. Breast

Daniela Addeo

Breast Cancer – Highlights

Key Recent Clinical Studies

Stillie et al. (J Med Imag Rad Oncol 2011) reported that Field-in-Field (FiF) forward-planned RT gave lower mean heart and contralateral breast dose compared to inverse-planned IMRT using five or nine fields in the treatment of left-sided breast cancer patients. FiF also showed a comparable homogeneity index for the whole-breast PTV. (PMID 21696567)

New Treatment Delivery Options

Morganti et al. (J App Clin Med Phys 2011) demonstrated that postoperative breast cancer patients had better homogeneity of dose distribution with forward-planned IMRT, irrespective of breast size or supraclavicular nodal irradiation.

FIGURE 12-6. Illustration of a six-copolanar inverse IMRT whole-breast plan that minimizes dose to the heart.

• Breast cancer is the most common malignancy in women in the United States. The estimated number of new cases diagnosed in 2012 is 229,060. While incidence has been rising in the recent decades in United States, mortality has been declining with 17% of diagnosed patients dying of breast cancer in 2012.1

1. ANATOMY

• The mammary gland lies over the pectoralis major muscle and extends from the second to the sixth rib craniocaudally, and from the sternum to near the midaxillary line.

• The breast parenchyma is intermixed with connective tissue, which has a rich vascular and lymphatic network and is supported by fibrous septae known as Cooper ligaments. These septae connect the breast parenchyma to the overlying skin and the pectoralis fascia. These supporting structures can be affected by tumors and lead to skin dimpling.

• The predominant lymphatic drainage of the breast is to axillary lymph nodes. The axilla has three levels, based on the relationship of the lymph node regions to the pectoralis minor muscle. Level I axilla is caudal and lateral to the muscle, level II is beneath the muscle, and level III (also known as the infraclavicular region) is cranial and medial to the muscle. A standard axillary lymph node dissection resects the tissue and lymph nodes within levels I and II. The axillary lymph nodes continue underneath the clavicle to become the supraclavicular lymph nodes.

• Breast lymphatics can also drain directly into the internal mammary lymph node chain (IMC) usually limited to the first three interspaces. The internal mammary lymph nodes are intrathoracic structures located in the parasternal space. Breast cancers that develop in the medial, central, or lower breast more commonly drain to the IMC compared to breast cancer occurring in the lateral and upper quadrants (see Fig. 12-1).2

2. NATURAL HISTORY

2.1. Breast Cancer Development

• Breast cancer develops as a consequence of changes in epithelial cells and complex interactions between epithelial cells and the microenvironment. Some, but not all, breast cancers pass through a series of conditions ranging from atypical ductal hyperplasia (ADH), to noninvasive ductal carcinoma in situ (DCIS), and finally to invasive breast cancer. Many breast cancers develop in the absence of DCIS, suggesting that the ordered progression through the traditional biological spectrum is not required. Typical patterns of spread for breast cancer by T stage are illustrated in Figure 12-2.

• The progression rate of DCIS to invasive breast cancer is difficult to estimate and likely dependent on the grade of the lesion.

• Lobular carcinoma in situ (LCIS) has historically been felt to be more of a marker for breast cancer risk than a true premalignant condition for invasive breast cancer development, and the risk of ipsilateral and contralateral cancer is roughly equivalent.

• The kinetics of breast cancer evolution is heterogeneous, with some tumors being rather indolent, while others, such as inflammatory breast cancer, with rapid onset of symptoms and rapid progression.

• Risk factors for the development of breast cancer include

º Genetic: germline mutations in BRCA1, BRCA2, p53, PTEN

º Family History: positive family history of breast or ovarian cancer

º Estrogenic: nulliparity, late first pregnancy, early menarche, late menopause, postmenopausal estrogen/progesterone replacement

º Dietary: moderate or heavy alcohol use

º Pathology: personal history of prior breast cancer, DCIS, LICS, and ADH

2.2. Breast Cancer Progression

Invasive breast cancers can metastasize to regional lymph nodes (axillary, supraclavicular, and internal mammary nodal regions) or to distant sites at any point in their development history.

• Risk factors associated with increased incidence of spread to regional lymph nodes and distant sites include

º Primary tumor size (the risk of metastases is low for tumors under 1 cm in size)

º Primary tumor grade

º Presence of lymphovascular space invasion

º Nonfavorable histology (i.e., not tubular, medullary, or mucinous)

º Triple-negative tumors

3. STAGING SYSTEM

• All patients with breast cancer are staged using TNM staging system. In 2010, the American Joint Committee on Cancer implemented changes/additions of the TNM staging for breast cancer and generated the 7th edition of the TNM classification.3

• Pathological staging system is used for patients treated with surgery first, whereas for patients treated with chemotherapy before surgery (neoadjuvant chemotherapy) the clinical staging system is applied.

FIGURE 12-1. Lymphatic drainage of the right breast. (A) Most lymph drains to the axillary lymph nodes. (B) The red arrows indicate the direction of lymph flow from the axillary lymph nodes to the right lymphatic duct. (From Moore KL, Dalley AF. Clinically Oriented Anatomy, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 1999.)

FIGURE 12-2. Patterns of spread for breast cancer. The primary cancer invades in various directions, which are color-coded vectors (arrows) representing stage of progression. Tis, yellow; T1, green; T2, blue; T3, purple; T4, red; and metastatic, black. (Reprinted from Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:213. Modified from Agur AMR, Dalley AF, eds. Grant’s Atlas of Anatomy, 12th edition. Philadelphia: Lippincott Williams & Wilkins, 2009.)

3.1. Primary Tumor

Tumor stage is denoted as follows: Tis: DCIS or LCIS; T0: no evidence of primary tumor; T1: invasive disease up to 2 cm; T2: 2–5 cm; T3: larger than 5 cm; T4: tumor of any size with direct extension to the chest wall and/or the skin (ulceration or skin nodules), with subcategories: T4a: fixation to chest wall, T4b: involvement of skin, T4c: both, T4d: inflammatory breast cancer.

3.2. Regional Lymph Nodes (N)

Lymph node classification criteria differ depending on whether the nodes are clinically (cN) or pathologically (pN) assessed.

• Clinical N1 is described as suspicious mobile ipsilateral level I, II axillary lymph nodes; clinical N2 is defined as fixed or matted axillary lymph nodes or clinically detected ipsilateral internal mammary nodes (IMN) in the absence of clinically evident axillary node metastases; clinical N3 includes infraclavicular or supraclavicular lymphadenopathy or clinically detected ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases.

• Pathologic classification of regional lymph nodes include pN0 defined as no histologic regional lymph node metastasis; pN1, micrometastases, or metastases in one to three axillary lymph nodes; pN2, metastases in four to nine axillary lymph nodes; pN3, metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes.

º Patients are considered to have M1 (stage IV) breast cancer if metastases were detectable before neoadjuvant therapy, regardless of their status after neoadjuvant treatment. M0 is defined as absence of distant metastases based on clinical or radiographic evidence: cM0(i+) when no clinical or radiographic evidence of distant metastases is present, but deposits of molecularly or microscopically detected tumor cells are found in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases; M1 is defined as distant detectable metastases determined by clinical and radiographic means or histologically proven larger than 0.2 mm.

º An important change made to the T, N, and M categories in the 7th edition of the staging system for breast cancer involves the definition of ypTNM nomenclature used for cases where systemic and/or radiation therapy are given before surgery (neoadjuvant setting). The posttreatment ypT is the largest contiguous focus of invasive cancer as defined histopathologically. Posttreatment nodal metastases no greater than 0.2 mm are classified as ypN0(+).

4. CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

• Most patients with carcinoma in situ, T1, and T2 breast cancers present with an abnormal screening mammogram or have a painless or slightly tender palpable breast mass.

• Locally advanced breast cancer can arise from a tumor that has been present for a long period of time which grows within the breast and spreads to nearby areas including lymph nodes, skin, and muscles or can present as a rapidly growing breast mass with or without redness, swelling, and peau d’orange. The latter is commonly referred to as inflammatory breast cancer.

• Metastases can occur through lymphatic or hematogenous spread; the former involves the axillary, internal mammary or supraclavicular nodes and the latter causes spread to bone, lung, pleura, liver, and brain.

• All patients should undergo workup that includes

º History and physical exam

º Diagnostic bilateral mammogram and ultrasound. Ultrasonography, which has a sensitivity of 73% and specificity of 95%, is helpful in differentiating cysts from solid tumors.

º Tissue diagnosis: Biopsy of the palpable breast lesion and palpable regional adenopathy and nonpalpable lesions detected on imaging studies and needle localization with radiographic techniques.

º Estrogen (ER) and progesterone receptor (PR) status on both invasive and noninvasive breast cancers as well as assay to assess overexpression of Her-2Neu is obtained.

º Breast magnetic resonance imaging (MRI) is optional and can be done when the breast is mammographically dense to evaluate extent of disease in the presence of multifocal or multicentric disease and for diagnosis of questionable findings seen on physical examination, mammography, or ultrasound.

º CBC, serum chemistry profile including liver function tests and alkaline phosphatase.

• In patients with stage 0, I, or II disease, the incidence of abnormal bone scan is approximately 2% and it is not routinely obtained unless there is localized bone pain or elevated alkaline phosphatase.

• For more advanced tumors, computed tomography (CT) scans of chest, abdomen, and bone will diagnose or rule out distant metastases. Alternatively, a positron emission tomography (PET)/CT scan can be obtained, but is considered optional at this time.1

• If neurologic symptoms suggest cerebral metastases, a contrast-enhanced CT scan or, for better diagnosis, gadolinium-enhanced MRI scan of the brain should be obtained.

5. MANAGEMENT

• The management of breast cancer depends on prognostic factors including stage, histologic type, nuclear and architectural grade, differentiation, tumor hormone receptor content (ER, PR, HER2-Neu receptors), Ki-67, presence of lympho-vascular invasion, menopausal status at the time of diagnosis, and comorbid conditions.

• Management usually consists of a combination of local-regional surgery, radiotherapy (RT), and systemic treatment including cytotoxic chemotherapy, endocrine therapy, biologic agents.

• The following chapter will focus on local-regional management with RT and the application of intensity-modulated radiotherapy (IMRT).

5.1. Local-Regional Management of Stage 0, I, and II Breast Cancer

5.1.1. Stage 0 (TisN0M0)

• Mastectomy and lumpectomy with negative margins followed by breast RT offer equal overall and cause-specific survival and represent options for treatment of pure DCIS. This equivalence has been demonstrated by four randomized trials with long follow-up of 10–20 years. If tumor cells are positive for ER, hormonal therapy is added for additional benefit in decreasing ipsilateral breast recurrence as well as contralateral breast cancer diagnosis.

• RT administered after lumpectomy decreases invasive and noninvasive recurrences by 50% to 60% in the treated breast.

5.1.2. Early Stage—I and II Breast Cancer (T1,T2/N0, N1mic, N1/M0; T3 N0 M0)

• Treatment options for early breast cancer include mastectomy with sentinel node biopsy/axillary node dissection or breast conserving therapy (BCT) consisting of lumpectomy, sentinel lymph node biopsy/axillary node dissection followed by breast irradiation.

• Six randomized trials with mature data of 10 to more than 20 years follow-up revealed equivalence between mastectomy and BCT regarding cause-specific survival and overall survival. Clinical trials also showed that RT added to lumpectomy reduces tumor recurrence in the treated breast by two-thirds compared to lumpectomy alone, with no effect on overall survival by individual trials.

• The most recent Early Breast Cancer Trialist’s Group (EBCTG) individual patient meta-analysis showed that adding RT to breast conserving surgery significantly reduces the breast cancer–specific mortality by 3.8% for pN0 patients and 8.5% for pN+ patients with an overall improvement in survival of 4.4% at 15 years.4

• With well-established benefit, radiation is a recommended component of BCT.

• Chemotherapy and/or hormonal therapy are incorporated into the management in selected patients. RT usually follows chemotherapy completion, whereas hormonal therapy is in general started after the course of RT is finished.

5.1.3. Radiation Therapy Doses for Whole-Breast Radiation

• Traditionally, in postoperative setting RT has been administered to the entire breast in daily fractions for 5 weeks followed by additional boost dose to the tumor bed for 1–1.5 weeks.

• In general, radiation doses to the entire breast consist of 45–50 Gy in 1.8–2.0 Gy/fraction, 5 days/week. Photons with energies of 4 to 6 MV (<10 MV) are preferred to treat the breast. Wedges (dynamic or static) or compensating filters have been used to achieve a uniform dose distribution within the breast (ideally <7% dose variance across the target volume).

• The boost to the tumor bed, when necessary, can be administered using electrons or photon beams for additional 10–16 Gy in 2 Gy fractions, 5 days/week.

• In recent years, shorter radiation courses of RT have been investigated. Treating the entire breast with hypofractionated accelerated schemes was found in selected patients to be comparable with traditional 6–7 weeks regimen in achieving local control, cosmetic results, and survival.

• A common fractionation scheme applied to the whole breast accelerated treatment is whole breast dose of 42.5 Gy in 2.66 Gy/fraction for 16 days treatment.5

• Table 12-1 illustrates published randomized trials of standard versus hypofractionated whole-breast regimens. Tumor bed boost was not administered in the Canadian (Wheelan) protocol, while the other protocols were left at the discretion of treating physician.

• An American Society for Therapeutic Radiation Oncology (ASTRO) task force performed a systematic literature review of hypofractionated whole-breast RT.6

• A set of criteria was generated for short RT course eligibility as following:

º age 50 years or older at diagnosis

º pathological stage T1–T2 N0

º no systemic chemotherapy administration

º dose variation along the central axis of 93% to 107%

5.2. Accelerated Partial-Breast Irradiation

• To further shorten the course of RT, the lumpectomy cavity only can be treated using large dose per fraction administered to smaller volumes with acceptable toxicity. The rationale of this approach is the observation that most recurrences occur in the same quadrant with initial location of the tumor.

• A panel of experts selected by ASTRO generated a consensus of patient eligibility for partial-breast RT administration (see Table 12-2) based on review of 4 randomized trials and 38 retrospective studies.7Single-arm, single-institution published studies revealed that selected, low-risk patients treated with accelerated partial-breast irradiation (APBI) had a breast cancer recurrence of 3% to 5% at 2–8 years follow-up.

• Although a variety of fractionated schemes have been studied, the most frequent partial-breast radiation dose used outside a clinical trial, administered using either mammosite balloon or external beam RT, is 38.5 Gy in 10 fractions (3.85 Gy per fraction), 2 fractions per day, with interfraction interval of at least 6 hours. At the time this chapter was written, there were three open phase III, randomized trials that compared whole-breast radiation therapy with APBI (see Table 12-3).

• Until results of these randomized trials are available, ASTRO consensus statement of selection criteria for APBI should be applied outside of clinical trials.

5.3. Radiation Therapy Techniques for Treatment of the Whole Breast

• Early planning of radiation treatment used two-dimensional (2D) approach, with isodose distribution being visualized in only one plane (central axis). CT scan–based simulation brought improvement in treatment planning allowing visualization and adjustments of dose distribution through the entire breast. This has implications in clinical outcome as has been demonstrated that dose homogeneity within the breast and technical methods to improve it influence clinical outcomes of toxicity and cosmesis.

5.3.1. Treatment Volume

• With patient in supine position, the tangent fields have the following borders:

º The upper margin is placed at the head of the clavicle.

º The lateral/posterior margin is placed 2 cm beyond palpable breast tissue (usually at the midaxillary line or anterior extend of the latissimus dorsi muscle that can be visualized on CT slices).

º The inferior margin is placed 2 cm below the inframammary fold or below the mammary gland for pendulous breast.

º The medial margin is placed at the anterior midline chest.

• Other treatment positions have been introduced in practice to improve dosimetry in patients with large, pendulous breasts, like lateral decubitus position to flatten the breast contour.

• More popular technique is treatment in prone position on a special prone breast board with the treated breast positioned vertically to gravity, away from the chest wall.

• Figure 12-3 illustrates tangent treatment fields projected on patient’s body with borders as described.

5.3.2. IMRT for Breast Treatment

• Improvement in therapeutic ratio of breast irradiation has been achieved with CT-based, three-dimensional (3D) planning methods. IMRT offers additional potential dosimetric benefit in maximizing target coverage and tumor control, while minimizing toxicity to the treated breast and surrounding normal structures.

• IMRT has been used for breast cancer treatment to improve dose homogeneity within the treated breast with subsequent reduction in toxicity and improvement in cosmesis and to minimize the dose received by surrounding normal tissues with subsequent decrease of acute and long-term toxicity.811

FIGURE 12-3. Tangential treatment fields for whole-breast irradiation.

• Two IMRT techniques have been applied:

º inverse IMRT planning that involves contouring normal structures (e.g., lungs, heart, and contralateral breast) and delineating target volumes. Inverse planning optimization is used to determine the beams (number, direction, aperture, and weights) in order to fulfill the normal structures and target volumes dose constraints.

º forward IMRT planning methods in which conventional tangent fields are set and the planner modulates the number and position of multileaf collimator (MLC) segments within the fields to optimize the uniformity of dose distribution. Initially, medial and lateral tangent fields are conventionally designed to cover the treated breast with a nondivergent posterior field edge. The dose distribution is first obtained with the dose normalized to a conventional point located at the interface between the breast tissue and pectoralis major muscle at approximately midseparation in the central plane. Adjustments to field weighting are performed. Segments of MLC are inserted in the tangent fields until the dose uniformity is maximized. This method does not have the goal to generate steep dose gradients to protect critical surrounding structures as inverse planning has. Forward planning is achieved either with dynamic MLC (dMLC) or with “field-in-field” (FiF) static MLC (sMLC) segments within the tangent fields, treated sequentially in step and shoot fashion.

• There is limited data on comparison of different IMRT methods in whole-breast RT. A retrospective dosimetric review of planning CT scans of 10 patients with left-sided breast cancer treated with whole-breast RT was published.12For each patient three plans were generated: FiF forward plan and two inverse IMRT plans of five and nine fields, with a prescribed dose (PD) of 50 Gy. When compared to inverse-planning IMRT, the FiF resulted in lower mean dose to the heart and contralateral breast and comparable dose homogeneity and coverage within the target volume.

• IMRT planning applications for breast irradiation include

º whole-breast treatment—in prone and supine positions

º whole breast with concomitant tumor bed boost

º partial-breast treatment (APBI)

º breast and regional lymph node regions (axillary, supraclavicular, internal mammary) treatment

º chest wall RT after mastectomy

The latter two applications will be reviewed in Section 5.4.

• Whole-breast IMRT: Published experience of IMRT application for whole-breast RT has shown not only good feasibility but also improvement in outcome compared to 2D planning methods. Table 12-4illustrates accumulated results of whole-breast IMRT.1221

5.3.2.1 Target Volumes for Breast IMRT Planning

• Breast CTV: Includes the glandular breast tissue visualized on CT slices, limited anteriorly within 5 mm from the skin, posteriorly by the anterior surface of the chest wall–pectoralis, serratous anterior muscles excluding boney thorax and lung. Medially it extends to the ipsilateral edge of the sternum (sternal–rib junction) and laterally to the anterior border of the latissimus dorsi muscle.

• Breast Planning Target Volume (PTV): Breast CTV + 7 mm 3D uniform expansion (always exclude heart).

• Breast PTVeval is used for dose-volume histogram (DVH) analysis and is limited anteriorly to 5 mm under the skin (in order to remove the build-up region) and posteriorly to the muscle–ribs interface.

• Lumpectomy Gross Tumor Volume (GTV) includes the excision cavity volume, architectural distortion seen on the simulation CT, seroma, and surgical clips.

• Lumpectomy CTV is lumpectomy GTV + 1 cm, 3D expansion. Posteriorly it is limited by the anterior surface of the chest wall (pectoralis major, serratous muscles) unless known involvement.

• Both lumpectomy volumes should be limited anteriorly to 5 mm from skin.

5.3.2.2 Normal Structure Volumes

• Both lungs are outlined, as well as the heart from the apex to the bifurcation of the pulmonary artery (excluding pericardial fat) and contralateral breast.

• Figure 12-4 illustrates breast CTV and lumpectomy GTV contours in supine treatment position.

• Figure 12-5 illustrates breast CTV contours at different levels in prone treatment position.

5.3.2.3 Suggested Dose Constraints

• Target volumes coverage:

º Breast PTVeval: ≥95% of the breast PTVeval should receive 95% of PD. Maximal point dose: ≤110% of the whole-breast PD.

º Lumpectomy CTV: 100% of the lumpectomy CTV should receive the PD.

º Normal structures (PD of 50 Gy to entire breast):

º Contralateral breast: maximum dose to contralateral breast should be ≤3.30 Gy.

º Ipsilateral lung: ≤20% of the ipsilateral lung should receive ≥20 Gy; ≤40% of the ipsilateral lung should receive ≥10 Gy; ≤55% of the ipsilateral lung should receive ≥5 Gy.

º Contralateral lung: ≤15% of the contralateral lung should receive 5 Gy or more.

º Heart: ≤5% of the whole heart should receive ≥20–25 Gy for left-sided breast cancers and 0% of the heart should receive ≥25 Gy for right-sided breast cancers.

FIGURE 12-4. Breast CTV (green) and lumpectomy GTV (red) contours in supine treatment position.

º ≤35% of the whole heart should receive ≥10 Gy for left-sided breast cancers and ≤15% of the heart should receive ≥10 Gy for right-sided breast cancers.

º Mean heart dose should be ≤5 Gy.

º Thyroid: maximum point dose should be <3% of the PD.

• Figures 12-6 and 12-7 illustrate a six-field coplanar inverse IMRT whole-breast plan that minimizes dose to the heart.

• Forward IMRT plans are set by placing conventional tangent field boundaries. A plan is generated as described above and optimized to improve dose homogeneity. If target volume is not covered properly or the doses to normal structures are unacceptable, the tangent fields are adjusted accordingly and a new optimized plan is generated.

• Concomitant tumor bed/lumpectomy boost and whole-breast RT are attractive applications of IMRT planning as they reduce the duration of radiation course.

FIGURE 12-5. Breast CTV contours at different levels in prone treatment position.

• Table 12-5 illustrates reported studies of simultaneous integrated boost.2227

• Data published based on single-institution experience revealed tolerable acute toxicity, excellent local control, and good to excellent cosmesis in more than 95% of the patients using hypofractionated radiation course to whole breast with concomitant boost.

• RTOG 1005 Protocol was launched in the United States and is randomizing patients to compare standard fractionation to a hypofractionated regimen of 15 fractions consisting of concomitant treatment of the entire breast and the tumor bed boost. Planned to enroll 2,312 patients, the objectives of this study are to evaluate the efficacy, toxicity, and cosmetic results of the short radiation course compared to the traditional approach.

• IMRT-MC2 Trial is a prospective multicenter trial initiated in Europe randomizing patients with early breast cancer after surgery to either conventional RT (whole-breast irradiation with consecutive boost) or whole-breast IMRT with integrated boost. The goal is to recruit 502 patients and the primary objectives are cosmetic results and local recurrence rates.

FIGURE 12-6. Six-field inverse IMRT.

• In the setting of integrated tumor bed boost, the target volumes and normal tissues are delineated as described in the previous section and target coverage has the same parameters. In addition, a lumpectomy PTV is defined by expanding CTV lumpectomy by 7 mm. PTVeval used for DVH analysis is created from lumpectomy PTV by limiting the volume within 5 mm from the skin surface and anterior border of the chest wall/pectoralis muscle.

• Dose constraints for a PD of 15 fractions, 2.7 Gy/fraction (to entire breast: 40.5 Gy) and 3.2 Gy/fraction for the tumor bed (48 Gy), as used in RTOG 1005 Protocol are as follows:

º Ideally, at least 95% of the breast PTVeval and lumpectomy PTVeval should receive 95% of the PD.

º Contralateral breast: The maximum dose to contralateral breast should be ≤2.64 Gy.

º Ipsilateral lung: ≤20% of the ipsilateral lung should receive ≥16 Gy, ≤40% of the ipsilateral lung should receive ≥8 Gy, ≤55% of the ipsilateral lung should receive ≥4 Gy.

º Contralateral lung: ≤15% of the contralateral lung should receive 4 Gy or more.

º Heart: ≤5% of the whole heart should receive ≥20 Gy for left-sided breast cancers, and 0% of the heart should receive ≥20 Gy for right-sided breast cancers.

º ≤35% of the whole heart receives ≥8 Gy for left-sided breast cancers and ≤15% of the heart receives ≥8 Gy for right-sided breast cancers.

º Mean heart dose should be ≤4 Gy.

º Thyroid: maximum point dose should be <3% of the PD.

FIGURE 12-7. Isodose line (blue) representing 4,500 cGy that covers the breast CTV (red volume).

5.3.3. IMRT for Accelerated Partial-Breast Irradiation

• Interstitial brachytherapy and mammosite balloon brachytherapy have been used to treat the breast tissue around the lumpectomy site.28,29

• External beam partial-breast irradiation is appealing to practical use due to ease of administration.

• Applying IMRT for partial-breast RT is an alternative to 3D conformal external radiotherapy (3DCRT) with the potential to further decrease normal tissue exposure to significant dose of radiation. For a recent review, see Njeh et al.24

• Table 12-6 illustrates relevant published studies of APBI using IMRT.3032

• For APBI, target volumes and normal structures are drawn in the same manner as described in the above section.

º Lumpectomy GTV includes the excision cavity volume, architectural distortion seen on the simulation CT, seroma, and surgical clips.

º Lumpectomy CTV is lumpectomy GTV + 1.5 cm 3D expansion. Posteriorly it is limited by the anterior surface of the chest wall (pectoralis major, serratus muscle) and anteriorly 5 mm from skin.

º Lumpectomy PTV is lumpectomy CTV + 7 mm 3D expansion (excludes heart).

º Lumpectomy PTV Eval is lumpectomy PTV with exclusion of the part outside the ipsilateral breast and the first 5 mm under the skin, as well as expansion beyond the posterior extent of breast tissue. Lumpectomy PTV Eval is the structure used for DVH constraints and analysis.

• Figure 12-8 illustrates breast CTV (blue contour), lumpectomy CTV (red area), and lumpectomy PTVeval (green).

• Figure 12-9 illustrates isodose lines for the above patient treated using partial-breast IMRT plan according to RTOG 0413 fractionation and constraints.33,34 Yellow is the 95% and light blue is the 80% isodose line.

• Suggested dose constraints:

º Lumpectomy PTVeval coverage: 95% of the volume to receive 95% of the PD.

º Uninvolved normal breast: <60% whole breast (breast CTV) should receive ≥50% of the PD; <35% of the breast should receive the PD.

º Contralateral breast: <3% of the PD to any point.

º Ipsilateral lung: <15% of the lung receives 30% of the PD.

º Contralateral lung: <15% of the lung receives 5% of the PD.

FIGURE 12-8. Breast CTV (blue contour), lumpectomy CTV (red area), and lumpectomy PTVeval (green).

FIGURE 12-9. Isodose lines for partial-breast IMRT plan according to RTOG 0413 fractionation and constraints. Yellow is the 95% and light blue is the 80% isodose line.

º Heart right-sided lesions: <5% volume receives >5% of the PD.

º Heart left sided lesions: <40% volume receives >5% of the PD.

º Thyroid: maximum point dose should be <3% of the PD.

• At present time RTOG Protocol 0413, a randomized multi-institutional trial comparing partial-breast with whole-breast RT for early breast cancer patients is still accruing patients.

5.4. Locoregional Advanced Breast Cancer, Stage III

(T0,T1,T2/N2, T3/N1,N2, T4/N0,N1,N2, Any T/N3, M0)

• Patients with locally advanced breast cancer who underwent upfront mastectomy followed by adjuvant chemotherapy should receive postoperative RT when at least one of the following pathological factors are present:

º pathologically four or more positive axillary lymph nodes

º breast mass of T4 stage or pathologically 5 cm or larger, especially if there is lymphovascular invasion or,

º positive resection margins or close margins (<1 mm), even if the nodes are negative and tumor is smaller than 5 cm

• if 1–3 axillary nodes are involved, adjuvant radiation is administered to selected patients.3537 Although there is no definite consensus, adjuvant radiation should be considered if more than 15% to 20% nodes removed are positive, for high-grade tumors,38 Ki-67 level is higher than 20% with extensive vascular invasion.39

• Chemotherapy before surgical resection is a common approach for locally advanced breast cancer. Studies evaluating Adriamycin, Cytoxan (AC) chemotherapy pre- or postoperatively showed that there is no difference in overall survival; however, with neoadjuvant chemotherapy, more patients can undergo BCT.40,41

• NSABP-27 trial has shown that the addition of a taxane to AC chemotherapy results in better complete pathologic response and disease-free survival than AC alone.25,42

• Radiation therapy administered to selected group of patients after mastectomy improves locoregional control and according to a recent meta-analysis long-term overall survival.4

• When chemotherapy is administered in neoadjuvant setting, before mastectomy, indications for RT have been identified taking into consideration prechemotherapy tumor characteristics as well as final pathologic stage. At least one of the following criteria should be present:

º clinical stage T3,T4, clinical stage III disease, stage IV (ipsilateral supraclavicular nodal disease) regardless of response to chemotherapy43,44

º patients with clinical stage I and II, who pathologically were found with four or more positive nodes and tumor larger than 5 cm

º presence of positive pathologic margins

5.4.1. Radiation Therapy Doses

• The chest wall usually receives a dose of 50 to 50.4 Gy in 1.8 to 2 Gy fractions. Additional dose of 10 Gy at 2 Gy per fraction is optional and is administered to the mastectomy surgical scar. Bolus, when used, is applied for 50% of treatments to the chest wall.

• IMN, supraclavicular fossa nodes, and axillary nodal areas when treated should receive a dose of 45 to 50 Gy over 5–6 weeks. Additional boost for microscopic or gross residual disease is administered with reduced fields, for 10 to 20 Gy.

5.4.2. Postmastectomy Radiation Therapy Conventional Technique

5.4.2.1. Irradiation of the Chest Wall

• Irradiation of the chest wall after mastectomy can be accomplished with tangential photon fields (as in the intact breast) of 6 to 10 MV energy or with appositional electron beams. CT scans assist in determining the thickness of the chest wall to select the optimal electron-beam energy.

5.4.2.2. Field Borders

• Anatomic landmarks defining field borders for treatment of chest wall are similar to those used to treat early breast cancer with tangent fields.

• An asymmetric-jaws technique and beam-split technique of all portals along the central-axis plane placed at the level of the lower aspect of the clavicle head uses one isocenter to treat the opposed tangential photon breast fields, supraclavicular and posterior axillary fields45 (see Fig. 12-10). There is no need for couch movement in order to achieve a precise single matchline between the tangents and supraclavicular field. Collimation and blocking at the matchline can be necessary. Placement of the matchline between the supraclavicular field and the tangent fields caudal to the clavicular head improves coverage of the level III axilla/axillary apex lymph nodes, as revealed by a dosimetric study published by Garg et al.46

FIGURE 12-10. Skin projections for supraclavicular and tangent fields, with single isocenter technique.

• Inclusion of IMN in treatment fields is recommended when the nodes are clinically positive, but elective irradiation is still debatable. The Danish and British Columbia randomized studies showed that postmastectomy RT (including internal mammary chain) improved overall survival.3537 However, the contribution of internal mammary irradiation to this benefit is unknown.

• Results of a prospective randomized trial evaluating possible benefits of adding IMN irradiation to chest wall, axilla, and supraclavicular regions were published in 2009. Total of 1,334 postmastectomy patients with positive axillary nodes and/or inner/ central located tumors were enrolled. With 10 years follow-up, there was no difference in survival by adding IMN RT.47

• Three prospective randomized trials evaluating the role of IMN irradiation are being conducted in Europe and Canada with results not available at this time.

• When treated, IMNs are included in tangential ports, that are wider superiorly, for the first three intercostal spaces (deep tangents).

• Alternatively, an electron IMN field is matched to the medial tangent and supraclavicular fields, extending inferiorly to encompass the first three intercostal spaces. The width of the IMN field is usually 5–6 cm, and the beam energy is chosen based on the depth of the nodal chain, as visualized on CT images.48

• Figure 12-10 illustrates skin projections for supraclavicular and tangent fields, with single isocenter technique.

5.4.3. Postmastectomy Radiation Therapy—IMRT

• IMRT can be applied for chest wall treatment as forward static or dynamic field in field technique for more homogenous chest wall coverage. When single isocenter, beam-split technique is used, the opposed tangent fields are not collimated and lung blocks are placed to shape the fields. Forward IMRT will give zero fluence for the blocked area and will maximize dose homogeneity. The setup is easier, avoiding collimation and blocking at the matchline.

• There is limited published data on the role of multifield inverse-planned IMRT for chest wall and regional lymph nodes (see Chui et al.55). Results of dosimetric studies of IMRT application for treatment of the chest wall and regional nodes are illustrated in Table 12-8.

• Inverse IMRT planning involves contouring CTV, PTV, and organs at risk, and dose volume constraints are defined. Dose objectives and dose priorities are entered in the planning system. Plans are generated and optimized and consist of complex multiple-beam arrangement, with different angles. Guidelines for breast, supraclavicular, axillary, and internal mammary nodes contouring are included in Table 12-7 and Figure 12-11; a more detailed description is found on RTOG website (Atlas for Breast Cancer Treatment).

5.4.3.1. Volume Definition

• The CTV depends on the extent of the area to be treated and includes the chest wall and regional lymph node groups with the boundaries described in Table 12-7. The postmastectomy chest wall extends between the lower aspect of the clavicle head, inframammary fold (contralateral breast), ipsilateral border of the sternum, anterior aspect of the ribs, intercostal muscles, and anterior border of the latissimus muscle.

• Figure 12-12 illustrates right (A) and left (B) side CTV contours in transverse plane.

• PTV is defined as CTV with 7 mm and PTVeval is as described in the above sections.

5.4.3.2. Suggested Dose Constraints

• For a PD of 50 Gy in 25 treatments to the chest wall, internal mammary, and supraclavicular and axillary nodal regions, the following are suggestions for dose constraints:

º 95% of PTVeval should receive 95% of the PD

º If possible, ≤5% of the whole heart should receive ≥30 Gy, ≤10 % of whole heart should receive >20 Gy, with a mean dose of <8 Gy.

º Ipsilateral lung: ≤20% of the ipsilateral lung should receive ≥20 Gy, ≤40% of the ipsilateral lung should receive ≥15 Gy, ≤55% of the ipsilateral lung should receive ≥5 Gy, with a mean of <15 Gy. More stringent requirements are set for contralateral lung: ≤10% of the volume should receive 5 Gy or more and ≤5% of the volume should receive 20 Gy or more.

º Contralateral breast should receive no more than 10 Gy to 10% of the volume with a maximum point dose of 15 Gy.

º Thyroid: <30% volume should receive >30 Gy.

º Spinal cord dose: should receive <30 Gy.

• Figure 12-13A,B illustrates coronal and transverse isodose distribution for an IMRT plan that included in the target volume the chest wall, internal mammary, supraclavicular and axillary regions.

FIGURE 12-11. RTOG contours for the regional lymph nodes of the breast. Each figure corresponds to the nodes listed in Table 12-7. In the images second from top and at the bottom, there is a long purple contour. This outlines chestwall structures.

6. CONCLUSIONS

• In an effort to improve dosimetry and decrease normal structure doses, complex techniques have been adopted for radiation treatment of breast cancer. These techniques include forward dynamic or static field in field IMRT and inverse-planning IMRT.

• Published data revealed that IMRT technology improves dose homogeneity in the treated breast. This leads to reduced acute dermatitis (both in severity and duration). Some of the studies with longer follow-up showed decrease in fibrosis of the breast and improved cosmesis.

• IMRT offers advantages compared to 3DCRT in sparing normal tissues when the RT course consists of integrated boost and partial-breast techniques. IMRT planning can achieve reduction of dose to the heart, lungs, and contralateral breast. These dosimetric benefits are method-dependent and the actual clinical benefit is to be proven on long follow-up.

FIGURE 12-12. (A) Right side post-mastectomy CTV contours in transverse plane.

FIGURE 12-12. (B) left side postmastectomy CTV contours in transverse plane.

FIGURE 12-13. Coronal (A) and transverse (B) isodose distribution for IMRT; target volume included chest wall, internal mammary, and supraclavicular and axillary regions. Green: 4,500 cGy isodose line; red: PTVeval.

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