Postmastectomy Breast Cancer Radiation Therapy

Epidemiology

Locally advanced breast cancer encompasses a heterogeneous group of patients, including those with advanced primary tumor size, extensive or widespread nodal disease, and inflammatory breast cancer. In 2013, 30 to 40% of patients diagnosed with breast cancer had regional lymph node involvement, and 10% of patients had a primary tumor 5 centimeters or greater in size. Unlike most other malignancies, the prognosis for patients with locally advanced disease is favorable, with 5-year breast cancer-specific survival ranging from 78% to 90%.[1]

Treatment / Management

Indications for PMRT

Several large randomized trials have demonstrated a clinical benefit with the addition of postmastectomy radiation therapy in patients with high-risk diseases.[2] A large meta-analysis performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) pooled individual patient data from 22 randomized trials comparing mastectomy, with or without adjuvant radiation therapy, and found that among patients with 4 or more positive notes, PMRT reduced locoregional recurrence by 19% which translated into a 9% reduction in breast cancer mortality [3]. The 2 largest studies included in this meta-analysis, the Danish collaborative group trials, randomized pre-and post-menopausal women with high-risk breast cancer, defined as any positive axillary lymph nodes, tumor size greater than 5 cm, or skin invasion, to undergo adjuvant chemotherapy with or without postmastectomy radiation therapy.[2] These trials both showed an improvement in disease-free and overall survival with the addition of postmastectomy radiation therapy by approximately 10%, irrespective of tumor size or the number of lymph nodes involved. Therefore, the National Cancer Center Network (NCCN) recommends postmastectomy radiation therapy for patients with greater than or equal to 4 positive nodes.(A1)

Current controversies in PMRT

Less than 4 positive lymph nodes

Despite earlier trials showing a consistent survival advantage for all node-positive patients, the validity of these findings among patients with less than 4 positive lymph nodes is often debated. The main criticisms of these trials were the use of less effective systemic therapies (ie, taxanes, dose-dense chemotherapy scheduling, HER2 targeted agents, and prolonged use of hormonal therapy were not consistently used) and inadequate axillary lymph node dissections. Furthermore, several other studies suggest the rate of locoregional recurrence among patients with 1 to 3 positive nodes is low [4][5]. An earlier study by Katz et al included over a thousand patients treated with mastectomy without adjuvant radiation and reported a locoregional failure rate of only 10% for a woman with 1 to 3 positive nodes. However, in the presence of other pathologic features, such as large tumor size, invasion of the skin/nipple, and close/positive margins, the risk of LRR was higher [5]. A more recent analysis of more than 600 patients with 1 to 3 positive nodes enrolled on a randomized chemotherapy trial reported a 6.5% versus 2.5% rate of locoregional first recurrence after total mastectomy for those treated with or without postmastectomy radiation therapy, respectively [6]. A more modern series from the Cleveland Clinic reported a less than 10% locoregional failure rate among patients with 1 to 3 positive lymph nodes treated with mastectomy and chemotherapy without radiation [7].(A1)

Given the conflicting data, the NCCN recommends postmastectomy radiation therapy should be “strongly considered” in patients with 1 to 3 positive lymph nodes while also taking into account other clinical characteristics (ie, age, comorbidities, life expectancy), pathologic risk factors (ie tumor size, the ratio of positive lymph nodes, tumor grade, LVSI), and biologic tumor makeup (ie, hormonal receptor status and targetable mutations). These recommendations align with recently updated postmastectomy radiation therapy guidelines by a joint panel of the American Societies of Clinical, Radiation, and Surgical Oncology [8]. An ongoing, randomized trial in Europe (P88 MRC/EORTC BIG 2-04 SUPREMO) is evaluating the role of postmastectomy radiation therapy in intermediate-risk patients, including those with 1 to 3 positive nodes, by randomizing patients to receive postmastectomy radiation therapy or not.

T3N0

A similar controversy exists among node-negative patients with large primary tumor size (greater than 5 cm) [9]. Isolated locoregional failure was as low as 7% among patients with T3N0 disease treated with mastectomy alone or with adjuvant systemic therapy in 5 NSABP chemotherapy trials [9]. Furthermore, a recent SEER analysis of 568 patients who received postmastectomy radiation therapy for T3N0 breast cancer showed no improvement in overall survival compared to a case-matched control analysis [10]. However, the risk of locoregional recurrence is higher in the presence of high-risk pathologic features, including LVSI, high tumor grade, close/positive margins, and premenopausal status, which again implies a subset of patients who may benefit from postmastectomy radiation therapy [11].(A1)

Complete nodal response after neoadjuvant chemotherapy

Current recommendations for postmastectomy radiation therapy are based on the clinical stage before initiation of any therapy. However, an excellent/complete pathologic response to neoadjuvant chemotherapy in either the nodes or the breast is associated with a significantly decreased risk of locoregional recurrence [12]. As a result, many argue these patients are effectively down-staged to a lower risk category and thus may no longer derive a significant benefit from postmastectomy radiation therapy [13]. This is the subject of an ongoing randomized controlled trial, NSABP B-51 (NCT01872975), in which patients with initial biopsy-proven positive lymph nodes (N1) that have a complete pathologic response to neoadjuvant chemotherapy are randomized to comprehensive regional nodal RT or chest wall radiation only. However, both NCCN and professional societies currently state there is not enough evidence to support the omission of postmastectomy radiation therapy in these patients [8].(A1)

Internal mammary node coverage

If internal mammary nodes (IMNs) are involved (ie, pathologically enlarged on CT and metabolically active on PET), they should be included in the radiation field. Elective IMN coverage is somewhat controversial. In the earlier postmastectomy radiation therapy trials, the radiation portal encompassed all draining lymphatics of the breast, including the axillary, supraclavicular, and internal mammary nodal (IMN) chain [2]. However, several studies have demonstrated an extremely low incidence of IMN nodal positivity and clinical IMN recurrence [14]. Furthermore, the inclusion of the IMN chain within the radiation field comes at the expense of increased doses to the heart and lungs, resulting in a potentially greater risk of long-term toxicity. (A1)

Several large trials have evaluated the volume of elective nodal irradiation (ENI) volume to include in patients with centrally/medially located tumors, positive lymph nodes, or node-negative patients with high-risk disease after mastectomy [15]. Studies from France and Denmark specifically addressed the benefit of internal mammary node irradiation (IMNI) by comparing outcomes of patients treated with a whole breast, chest wall radiation, supraclavicular, and axillary apex with or without IMNI [23][16]. While the French study was randomized, the Dutch study allocated IMNI only to patients with right-sided disease and omitted IMNI in left-sided disease to save the dose to the heart. The Dutch study reported a small but significant 2.5% improvement in breast cancer-specific survival for right-sided breast cancer patients allocated to IMNI [17]. In contrast, the French randomized trial failed to show a survival benefit [18]. Another large randomized trial, EORTC 22922, evaluated comprehensive nodal irradiation (including IMN) compared to standard breast radiation alone in patients with high-risk node-negative, central/medially located tumors, or positive lymph nodes. This study demonstrated a 3% improvement in disease-free survival and a 2% reduction in breast cancer mortality; however, only about one-fourth of these patients had undergone mastectomy [15].(A1)

In summary, comprehensive lymph node coverage has yielded mixed results but may offer a small improvement in disease-free and possibly even breast cancer-specific survival. Given the insufficient evidence, a multidisciplinary expert panel on post-mastectomy management suggests that if comprehensive nodal radiation is recommended, the radiation treatment field should include the IMN, supraclavicular, and apical axillary regions, as well as the chest wall [8].

Postmastectomy radiation therapy after implant/tissue expander

Postmastectomy radiation therapy after breast reconstruction has been associated with increased rates of capsular contracture, reconstructive failures, revision surgeries, and overall worse cosmetic outcomes [19]. The timing of the breast reconstruction (ie, immediate versus delayed) and type of breast reconstruction (ie, autologous versus implant-based) are important considerations that require an informative discussion with the patient and multi-disciplinary team before surgery.(B2)

Most often, implant reconstruction occurs in 2 phases, with the placement of a tissue expander followed by a permanent implant. Several studies evaluating the optimal sequence of 2-phase reconstruction with radiotherapy have demonstrated higher rates of reconstructive failures ranging from 32% to 40% when radiation was delivered to the tissue expander compared to radiation directed at the permanent implant [20]. Interestingly, a prospective study from the Mastectomy Reconstruction Outcomes Consortium (MROC) found no difference in major complication rates between tissue-expander versus implant-directed radiotherapy and reported an overall failure rate of 10% [21]. Therefore, patients who elect to undergo immediate expander/implant reconstruction should be carefully evaluated to determine the potential need for postmastectomy radiation therapy and should be thoroughly counseled regarding the risks in the setting of breast reconstruction.(A1)

Radiation Oncology

Simulation and Treatment Volumes

Patients are simulated in the supine position with their arms raised above their heads. Immobilization devices, such as a wingboard with a vacuum bag, can support the arms and neck and replicate the same position during daily treatments. The head is turned up and away from the treated breast to remove the chin from the beam divergence. The mastectomy scar is often delineated with a radio-opaque marker to make sure the entire scar is included in the radiation plan. The medial, lateral (mid-axillary line), superior (caudal edge of the clavicle), and inferior (1 to 2 cm below the inframammary line) field borders can also be delineated with a radio-opaque marker to guide initial beam placement. For patients with left-sided breast cancer, deep-inspiratory breath hold, a technique in which patients are instructed to hold their breath for 20 to 30 seconds at peak inspiration, can often increase the distance between the heart and chest wall, thus lowering the cardiac dose. If this technique is considered, testing a patient’s ability to perform this exercise should be done during simulation. Several contouring atlases are available for chest wall and nodal delineation, including the Radiation Therapy Oncology Group (RTOG) [22] and RADCOMP (NCT02603341), among others [16]. For lymph node volume delineation, contouring guidelines differ slightly regarding anatomical reference points and vessel-based approaches.

General volume delineation guidelines for the chest wall

• The chest wall clinical target volume (CTV) should be contoured to the muscle-rib interface to include the pectoralis muscles and the entire scar plus margin. The cranial border extends to the caudal border of the clavicular head, which is clinically determined based on markers placed at the time of simulation and using the contralateral breast as a guide. The lateral border typically extends to the mid-axillary line and the medial border to the sternal-rib junction to avoid crossing the midline.
• If image guidance is used during treatments, the chest wall planning target volume (PTV) is created by expanding the CTV by 0.5 cm. Otherwise, the CTV to PTV expansion ranges from 0.5 to 1 cm. To ensure chest wall dose, the PTV can extend into the ribs about 2 mm.

General volume delineation guidelines for lymph nodes

• Axillary levels 1 through 3 are demarcated relative to the pectoralis minor muscle, axillary vessels in which level 1 lies lateral and inferior, level 2 lies posterior, and level 3 lies superior-medial.
• The supraclavicular (SCV) lymph nodes lie superior to level 3 and commence just caudal to the cricoid cartilage. SVC nodes extend inferiorly to the caudal edge of the clavicular head, laterally to the lateral edge of the sternocleidomastoid or junction of the 1 rib with the clavicle, and medially, it excludes the thyroid and trachea. 
• If treating the internal mammary nodes with IMRT, the first 3 intercostal spaces should be contoured. 
• When using image guidance, PTV for the lymph nodes is generated by expanding the CTV by 0.5 cm.

Radiation Planning Technique

Patient anatomy, target volume, dose constraints, and physician preference are used to determine the optimal radiation technique. Below is a description of various radiation techniques.

3D conformation radiation therapy (3DCRT)

The most commonly used treatment technique for PMRT is a forward-planned technique using photons called 3D conformation radiation therapy (3DCRT). The dosimetrist and radiation oncologist often use 3 to 5 beams to treat the chest wall and regional lymphatics. To create a customized plan for each patient, the dosimetrist and radiation oncologist work together to determine the best beam angle, field size, blocks, beam energy, and weighting. The radiation field setup for a typical plan is discussed below:

• The chest wall is treated with 2 opposing tangential fields. The superior field edge of the tangential fields is often just below the clavicular head, and the inferior field edge of the supraclavicular field (discussed below). The tangents should be placed at an angle to avoid the contralateral breast and minimize the dose to the heart and lungs, ideally with less than 1 cm (or no heart) in the field and less than 2 cm of the lung in the field.
• The supraclavicular and Level 3 lymph node volumes are treated with a single oblique anterior supraclavicular field, often angled 10 to 15 degrees away from the midline, to avoid overlapping the spinal cord and esophagus. The multileaf collimator blocks the acromioclavicular joint and part of the humeral head. The beam's energy can be adjusted so that the 45 Gray (Gy) line reaches the posterior edge of the lymph node volumes. An optional posterior axillary “boost” field may be added to increase deep axillary coverage or to reduce hot spots from a single anterior field.
• A direct matched electron or photon field can cover the internal mammary chain. Alternatively, the tangents can be partially widened superiorly to cover the top 3 intercostal spaces encompassing the internal mammary nodes. 
•  An even, non-divergent match line between the tangential chest wall beams and the anterior supraclavicular beam is generated by using a half-beam block (one isocenter technique) or by angling the couch (couch-kick) to create a horizontal match line between the tangential and supraclavicular field edges (2 isocenter technique).

Intensity-modulated radiation therapy (IMRT)

Intensity-modulated radiation therapy (IMRT) is generally considered when heart or lung dose-volume constraints with 3DCRT planning are unmet. IMRT is an inverse planning technique using photons. This means that after the target and normal structures are contoured, the dosimetrist enters the goals of coverage and limits to normal structures, and the radiation treatment planning system runs to optimize the plan. IMRT typically involves a greater number of beams compared to 3DCRT. Volumetric modulated therapy (VMAT) is the IMRT technique that employs continuous arcs during treatment. While VMAT can be very conformal, it does result in the expansive spread of low dose to a larger volume of normal structures compared to a 3DCRT plan due to the exit dose of the photon beam arc.

Intensity-modulated proton therapy (IMPT)

Protons are heavy ions that deposit the maximum dose at a specific distance in tissue (Bragg Peak), after which no dose is deposited into the tissue. In other words, there is no exit dose when using proton therapy, resulting in possibly less dose to normal tissues and, therefore, has the potential to reduce long-term side effects. This contrasts photon beams with an entry and exit dose [23]. Clinical experience with proton therapy for postmastectomy radiation therapy primarily involves patients with left-sided lesions or those that require regional nodal irradiation (RNI) [24]. Reported mean heart dose, mean heart V5, and mean lung V20 from select studies are less than or equal to 1 Gy, 3% to 7%, and 13% to 28% [24][25]. Proton treatment planning involving the chest wall and lymphatics commonly employs 2 enface proton beams to cover the targets. The treatment planning system then optimizes the plan and accounts for uncertainties pertaining to dose calibration using Hounsfield units (HU) and proton end range. Comparison of conventional photon versus proton radiation in comprehensive breast irradiation is an area of ongoing research. A nationwide randomized trial, RADCOMP (NCT02603341), is actively accruing patients with locally advanced breast cancer who require RNI after either mastectomy or breast conservation surgery to receive either photon or proton therapy. The primary endpoint of this study is a reduction in major cardiovascular events at 10 years. Other assessment endpoints include long-term disease control, survival, and quality of life.

Radiation Dosing and Fractionation

Conventional dosing for PMRT is 50-50.4 Gy in 1.8-2.0 Gy per fraction (25-28 total fractions) to the chest wall and 45-50 Gy in 1.8-2.0 Gy per fraction (25 total fractions) to the regional lymph nodes. Hypofractionation, which involves giving a larger daily dose over a shorter period (fewer total fractions), is an active area of research in the post-mastectomy setting to reduce treatment costs and increase patient convenience. The Alliance Group is currently evaluating the effect of hypofractionated PMRT in breast reconstruction, with the primary endpoint being the 2-year reconstructive complication rate (NCT03414970). In this study, patients with stage IIA-IIIA breast cancer who have undergone mastectomy and breast reconstruction are randomized to receive either standard daily radiation therapy for 5 to 6 weeks or daily radiotherapy given over a shortened course of 3 to 4 weeks. Further dose hypofractionation for postmastectomy radiation therapy is being explored in the United Kingdom (FAST-Forward). This phase III, multicenter, randomized controlled trial (FAST-Forward) is evaluating 2 different 5-fraction PMRT dosing regimens (27 Gy or 26 Gy in 5 fractions) compared to standard control (40.05 Gy in 15 fractions). 

Since photons require tissue interaction to build up the dose, the dose at the skin surface is lower than the dose at the target. A chest wall bolus may be used to increase the skin dose for patients who have an increased risk of chest wall recurrence (ie, large tumors, positive/close margins, inflammatory breast cancer). In general, a 0.5 cm tissue equivalent bolus can be used every other day to increase the skin to 85% of the prescription dose, or in cases of inflammatory breast cancer, a daily bolus can be used to ensure the skin dose reaches 95% of the prescribed dose. Alternatively, a single sheet of brass bolus (2-sheet thickness for inflammatory/T4 tumors) can be used daily and is equivalent to 0.5 cm tissue equivalent bolus every other day. A mastectomy scar boost to 10 to 16 Gy in 5 to 8 fractions is considered in the presence of close (less than 2 mm) or positive margins, and for inflammatory breast cancer, however, a boost is generally avoided in patients planned for reconstruction if they don’t have other risk factors for recurrence. 

Plan Evaluation

Radiation oncologists work with dosimetrists to customize the plan to the patient’s anatomy and targets using the abovementioned options. The radiation oncologist then evaluates the plan to assess the adequacy of target coverage while minimizing the dose to the lung, heart, and other nearby tissues using the dose-value recommendations.

Complications

Radiation Toxicity

In general, postmastectomy radiation therapy is very well tolerated, and patients can continue their normal routine. It does not lead to decreased immunity or feelings of illness, and patients are not radioactive; therefore, they are safe to be around other people. Adverse effects or toxicity associated with postmastectomy radiation therapy is discussed in terms of acute and chronic.

Acute Toxicity

Acute toxicity is generally defined as occurring during and within 3 months of radiation treatment. The most common adverse effects include fatigue, temporary sore throat, and radiation dermatitis. Radiation dermatitis gradually develops as more radiation treatments are delivered. It can include skin erythema, hyperpigmentation, rash, and dryness followed by moist desquamation. Skin toxicity may peak in intensity 1 to 2 weeks after the end of treatment. Patients are advised to keep their skin moisturized during radiation to help with the daily healing of healthy skin tissue. Other topical agents like aloe, hydrocortisone, or silver sulfadiazine can help with burning, itching, and desquamation of the skin. If a patient develops large confluent areas of moist desquamation, hydrogel or hydrocolloid dressings can be applied. The skin should be monitored regularly for signs and symptoms of infection. A skin bolus is typically removed during brisk erythema or moist desquamation. Generally, the skin is well healed 2 to 4 weeks after treatment, although some patients have residual long-term skin hyperpigmentation and subcutaneous fibrosis throughout the treatment field.

Chronic Toxicity

Common chronic or long-term toxicity associated with postmastectomy radiation therapy includes hyperpigmentation and fibrosis of the chest wall, affecting cosmetic outcomes after reconstruction (breast implant). Other potential long-term toxicities include minor risks of radiation pneumonitis (higher when treating comprehensive lymph nodes), rib fracture, arm lymphedema, radiation-induced heart disease (RIHD) (particularly for left-sided treatments), hypothyroidism (if treating supraclavicular region), and an extremely low risk of secondary malignancy. The management of arm lymphedema and the risk of RIHD is discussed in more detail below. Chronic arm lymphedema is a very challenging complication of postmastectomy radiation therapy, and thus, prevention and early intervention are key. Early signs of lymphedema include swelling, limb heaviness, aching, tightness, and fatigue. The risk of lymphedema after axillary RT ranges from 11% to 15% at 1 to 5 years post-treatment and is significantly higher in the setting of prior axillary dissection [26]. Lymphedema education, compression sleeves, compression pumps, regular exercise, and personal preventive measures have been shown to reduce the incidence of breast cancer-related lymphedema [27].

The most worrisome late side effect of postmastectomy radiation therapy is the increased risk of cardiac disease. Data to support dose-volume constraints for normal tissues are limited. The ongoing national randomized trial, RADCOMP, recommends general dose-volume constraints. An early landmark trial by Darby et al demonstrated a linear correlation between dose to the heart and rate of major coronary events. In this analysis, for every 1 Gy increase in mean dose to the heart, the relative rate of major coronary events increased by 7.4% and was observed as early as 5 years and continued up to 20 years after treatment [28]. However, this risk is thought to be less with more modern radiation techniques. A more recent analysis of individual patient data published between 2010 and 2015 reported average whole lung and heart doses of 5.7 Gy and 4.4 Gy, respectively [29]. Among patients treated before the year 2000, the risk of cardiac mortality was increased (RR 1.3), corresponding to a 4% increased incidence of cardiac mortality per Gy mean heart dose.

Proton beam therapy may reduce the dose to the heart and lungs, particularly when treating comprehensive lymph nodes. There have been several dosimetric comparison studies between 3D conformal, IMRT, and proton beam therapy and comparisons of passive scatter and pencil beam technology [30]. These studies have shown a reduction in dose to the heart and lung with proton therapy, particularly when IMNs are treated; however, the clinical impact of this dose reduction is unknown. An ongoing randomized trial, RADCOMP (NCT02603341), evaluates these dose effects by randomizing patients who require comprehensive nodal irradiation to receive either proton or photon therapy, with the primary endpoint being a reduction in late cardiac mortality. Deep inspiratory breath hold is another technique to reduce the radiation dose to the heart by creating lung airspace between the chest wall and mediastinum.