CHAPTER 13 Radiation Therapy Effects and Considerations

For more than 100 years, the treatment of breast cancer was exclusively surgical. The paradigm of breast malignancy management was eventually challenged by several landmark breast preservation trials, which led to the wide acceptance of treatment of most stage I and II breast cancer patients with whole-breast irradiation following tumor excision. In 1973, in Milan, Italy, women with clinically localized breast carcinoma were randomly assigned treatment with total mastectomy or breast conservation therapy (BCT) with partial mastectomy (quadrantectomy) and whole-breast irradiation. By 1980, a total of 701 patients were randomized and treated. In the United States, a similar trial was initiated in 1976. The National Surgical Adjuvant Breast Project B-06 (NSABP B-06) randomized 2163 women with T1–T2 and N0–N1 breast cancer to one of three treatments: total mastectomy, segmental mastectomy, or segmental mastectomy and radiation therapy (RT). In 2002, the results of both studies, with 20 years of follow-up, were published in the New England Journal of Medicine. The results of both trials supported the use of BCT as equally effective compared to mastectomy, in that disease-free survival and overall survival were not adversely affected by preserving the breast. The importance of the status of margins was stressed in NSABP B-06. These two studies and many subsequent international and multi-institutional trials led to a consensus statement by the National Cancer Institute in June 1990 recommending BCT as preferable to mastectomy in appropriately selected patients.¹^–⁵

PATIENT SELECTION FOR BREAST CONSERVATION THERAPY

Most women diagnosed with nonmetastatic, localized tumors are candidates for BCT. Contraindications for BCT include multicentricity, diffuse microcalcifications, pregnancy, prior chest radiation, and persistently positive margins after multiple re-excisions. Relative contraindications for BCT include collagen vascular disease (e.g., scleroderma) and large tumor size relative to the size of the breast. (Neoadjuvant chemotherapy may convert some initially ineligible patients into suitable BCT candidates.)

BREAST PRESERVING WHOLE-BREAST IRRADIATION (THREE-DIMENSIONAL NON-INTENSITY–MODULATED RADIATION THERAPY OR FORWARD PLANNING TECHNIQUE)

The patient is examined at consultation, paying special attention to the patient’s breast size, location of the tumor, and any wound issues. Pathology and imaging studies are reviewed. Patients requiring chemotherapy often receive a full course of systemic treatment before radiation. Before RT starts, a mammogram of the involved breast may be obtained. This will serve as a baseline study for follow-up mammograms. Case 1 in this chapter is an illustration of the potential utility of preradiation mammography. Questionable abnormalities need to be worked up before initiation of RT.

Simulation Process

Imaging studies and pathology are reviewed in conjunction with design of the radiation fields. The requirement for reproducible positioning of the patient may involve the creation of custom immobilizing molds or breast or wing boards and the use of nets or other techniques. A treatment planning CT is performed. The entire breast, lung volumes, and heart (for left-sided tumors) are imaged. The surgical scars are wired and marked. The setup points are marked on the skin.

Treatment Planning

The computerized treatment planning process starts with the radiation oncologist outlining the volumes of interest (tumor bed, heart, lungs). The physicist or dosimetrist then creates an optimal arrangement of the tangential fields to cover the breast with a uniform isodose distribution (Figure 1). The dose-volume histograms are created, and the plan is reviewed and approved by the radiation oncologist. The patient is brought in for port films (Figure 2) and visual check of the fields on the skin to ensure a reproducible setup.

FIGURE 1 Isodose (indicated by the colored outlines) distribution diagram for a patient after lumpectomy for right breast cancer shows uniform distribution of the isodoses, avoiding hot spots and conforming to the chest wall contours, thus minimizing radiation exposure of the underlying lung. A large postoperative fluid collection can be seen in the lateral breast.

FIGURE 2 A weekly port film is obtained to verify the reproducibility of the setup (patient and breast positioning and radiation field coverage) and is checked by the radiation oncologist for quality assurance.

Daily Treatments

The typical course of treatment usually takes 6 to 7 weeks. Radiation treatments are given daily (5 days a week). At least once a week, port films are reviewed to ensure accuracy of the setup.

Tumor Bed Boost

Studies have shown that a boost dose of about 1600 cGy to the tumor bed improves local control. Radiation oncologists use the findings on physical examination, as well as pretreatment imaging studies, and correlate these with the pathology and operative reports to design the volume of tissue to be included in the boost. The patient is placed on a simulation table in a position to even out the surface of the skin over the tumor bed. The volume is outlined and marked with a wire (Figure 3). Ultrasound or CT is obtained to verify the coverage of the tumor bed and to calculate the energy of the electron beam necessary to adequately treat the surgical bed. Once the coverage is approved by the radiation oncologist, a custom lead alloy cut-out is created. The optimal energy of the electron beam is selected to adequately cover the depth of the postsurgical bed, without extending into underlying structures.⁶^–⁸

FIGURE 3 CT treatment planning imaging for boost dosing the tumor bed. A, A wire has been placed by the radiation oncologist on the skin overlying the lumpectomy site, and the patient’s left lateral breast lumpectomy site is scanned to verify that the surgical bed is encompassed by the wire (arrow), here depicted on a volume rendered view of the CT data. B, CT planning images, from above to below, with the wire in place on the skin overlying the lumpectomy bed, with the patient in a predetermined treatment position.

WHOLE-BREAST IRRADIATION USING INTENSITY-MODULATED RADIATION THERAPY (IMRT) OR FORWARD TREATMENT PLANNING TECHNIQUE

The continuing search for improved delivery of the conformal dose of radiation to the breast, while protecting the underlying structures and minimizing exposure of the contralateral breast, led to development of treatment planning algorithms using IMRT. Based purely on dosimetry, the superiority of treatment plans created using IMRT or forward planning technique (without wedges, using multiple-shaped fields) over threedimensional conformal opposed tangential fields (using wedges to compensate for uneven breast contours) is readily evident (Figure 4). The dose to the breast is more uniform, there is less of a “hot spot,” and the isodose curves are concave, conforming to the shape of the underlying chest wall. The dose to the ipsilateral lung can thus be reduced, and in cases of left breast treatment, the heart can be spared to a greater extent.

FIGURE 4 A, IMRT process showing five different segments for a single tangential field. The dose is modified using multileaf collimation (indicated by red and white shading) to selectively expose areas to be treated or protect underlying structures. B, CT view of the resulting IMRT generated isodoses, showing better uniformity than achievable with traditional techniques. A postoperative fluid collection is seen in the medial breast.

These dosimetric advantages are no longer just hypothetical, but are observed clinically. There is growing evidence suggesting that IMRT is the best technique available for treatment of the whole breast.

There are challenges associated with implementation of a breast cancer IMRT program on a routine basis. The planning and quality assurance processes are extensive, and the treatment time is longer (not an insignificant factor in a busy department). The patients tolerate treatment better, with less acute skin toxicity. Reduction in long-term toxicity is expected. Further efforts to improve the therapeutic index of RT (optimal dosing to the target volume and maximal protection of the surrounding tissues) involve alternative patient setup (prone), breath-hold and deep inspiration technique, and use of different fractionation. To further spare the surrounding tissues, techniques of partial-breast RT using IMRT have been developed. Partial-breast irradiation is being tested against whole-breast treatment in the ongoing NSABP B-39/Radiation Therapy Oncology Group (RTOG) 0413 study.⁹^–¹¹

TREATMENT OF LYMPH NODES

The optimal management of axillary and supraclavicular nodal basins is an area of ongoing research and debate. It is accepted and proven that involvement of more than three lymph nodes with metastases requires RT to the axilla and supraclavicular region. RT reduces axillary recurrence and improves survival. The Southwest Oncology Group (SWOG) S9927 (RTOG 99–15) study was designed to evaluate the benefit of axillary RT in patients with one to three positive lymph nodes. Unfortunately, the trial closed because of poor patient accrual. The decision whether to give RT to the regional lymphatics in patients with one to three involved lymph nodes must be individualized and based on careful weighing of the pathology and review of the risk-to-benefit relation issues with the patient.

The radiation of axillary lymph nodes can be achieved with either inclusion of the level I and II lymph nodes in the tangential fields (if the CT simulation confirms good coverage and if the lung and heart can be spared) or use of a separate oblique field matched inferiorly to the upper border of the tangential breast fields. Depending on the patient’s anatomy, the use of an additional posterior axillary boost (PAB) field may be required. Coverage of the supraclavicular region depends on the available information delineating the exact location of the nodal basin and the brachial plexus (Figure 5).¹²^–¹⁴

FIGURE 5 A, Supraclavicular and axillary field setup to cover the lymphatics, while protecting midline neck structures and the humeral head by use of oblique fields and blocks, here using multileaf collimation (indicated by the cross-hatched areas). B, CT view of left anterior oblique (LAO) field covering the right supraclavicular and axillary lymph node basins in the same patient, demonstrating sparing of midline structures (trachea, esophagus, cervical spine) while covering the lymphatic basins. Isodose depths can be modified with use of varying photon energies or opposed posterior axillary boost fields.

Internal Mammary Lymph Node Radiation Therapy

Primary lymphatic drainage into the internal mammary (IM) lymph nodes may occur in 17% to 25% of tumors located in medial, 29% in central, and 27% in lower outer quadrants of the breast. Information from lymphoscintigraphy or positron emission tomography (PET), CT, or MRI, if available, can help in localization of IM lymph nodes. Treatment of IM lymph nodes is individualized and dependent on many factors (Figure 6). Central, medial, or lower outer quadrant breast tumors with multiple positive axillary lymph nodes may require treatment of the IM lymph nodes. However, isolated IM failure is uncommon. The most commonly involved IM lymph nodes are in the second, third, and first interspaces, in that order. The potential for increased cardiopulmonary toxicity warrants caution. Published treatment guidelines give no definitive recommendation for routine treatment of IM lymph nodes and leave this decision to the discretion of the treating radiation oncologist.^15,¹⁶

FIGURE 6 A, CT treatment planning images of a postmastectomy patient at high risk for internal mammary lymph node (IMLN) involvement, showing the position of the IMLN (red dots on left and middle images), which are covered by the isodoses, indicated by the colored outlines. B, Port film of same patient, showing the IMLN outlined (red shaded area). The lung protection afforded by multileaf collimation is outlined as well (red and white shaded area). C, Sagittal CT reconstruction of the same patient showing the isodose distributions from the supraclavicular, axillary, and chest wall–internal mammary contributions. The upper IMLN location is again designated by the red shaded area.

POST MASTECTOMY RADIATION THERAPY

Currently, postmastectomy RT is indicated in patients with large tumors (≥5 cm), involvement of four lymph nodes or more, close or positive margins, and sometimes multicentric tumors. A Danish study reported in the New England Journal of Medicine in 1997 on results of a trial in which 1708 women with stage II to III breast cancer were treated with mastectomy and then randomized to either eight cycles of Cytoxan, methotrexate, 5-fluorouracil (CMF) chemotherapy and chest wall and regional lymphatic RT, or nine cycles of CMF chemotherapy and no RT. After 114 months of median follow-up, the locoregional failure rate was 9% in the arm treated with RT, compared with 32% without RT. The 10-year overall survival rates were 54% and 45%, respectively. A Canadian study, also reported in the New England Journal of Medicine in 1997, reported results of a trial of 318 premenopausal node-positive patients after mastectomy who were randomized to undergo either CMF chemotherapy and RT or CMF chemotherapy alone. The arm treated with chemotherapy and RT received three cycles of CMF, followed by RT, followed by another three cycles of CMF. After 150 months of median follow-up, there was a 33% reduction in recurrences, a 17% improvement in disease-free survival, and a 29% reduction in breast cancer–related mortality.

A more recent report reviewed data from five randomized studies, including NSABP B-15, B-16, B18, B-22 and B-25. A total of 5758 node-positive patients enrolled in these studies were treated with mastectomy and chemotherapy, with or without tamoxifen, but no RT. The median follow-up was 11.1 years. The cumulative incidence of isolated locoregional failure was 12.2%, compared with 19.8% for locoregional failure with or without distant failure and 43.3% for distant failure alone as a first event. The cumulative incidence rates of locoregional failure (with or without distant failure) increased with greater axillary nodal involvement, from 13% for one to three nodes involved, to 24.4% for four to nine involved nodes, to 31.9% for more than 10 involved nodes. Similarly, with increasing tumor size, the cumulative incidence rates of locoregional failure (with or without distant failure) increased from 14.9% for tumors smaller than 2 cm, to 21.3% for tumors 2.1 to 5 cm, and up to 24.6% for tumors larger than 5 cm.

These reports from Denmark and Canada and from review of the NSABP data indicate that postmastectomy RT improves local control, but, more importantly, also improves survival.

As the use of postmastectomy RT has increased, so have concerns regarding the effect of RT on reconstructive tissue, implants, and the overall cosmetic treatment outcome. The Therapeutic Index of Loco/Regional Treatment must first account for optimal tumor control, while resulting in the best cosmetic outcome. It is not just cosmesis that is at stake. Development of implant encapsulation can be painful. Fat necrosis can be difficult to differentiate from tumor recurrence and often leads to biopsy, causing patients anxiety. Development of infection or seromas in the reconstructed breast may lead to the removal of transplanted or implanted tissue. Although all these adverse outcomes can occur without use of RT, the incidence does increase with exposure of transplanted tissue or implanted devices to radiation. It is thus extremely important that any patient with even a remote possibility of needing postmastectomy RT be thoroughly evaluated by the whole team to select the best surgical option.¹⁷^–²¹

POSTMASTECTOMY RADIATION AND BREAST RECONSTRUCTION

Before mastectomy, patients should undergo an extensive consultation with review of the available reconstructive options. Clinically staged patients who are not expected to require postmastectomy RT are excellent candidates for immediate reconstruction. There are many factors that need to be taken into account while selecting the best surgical reconstruction option. Tumor-related considerations include the tumor size and location, multifocality or multicentricity, lymph node involvement, and chest wall fixation. Patient-related factors include body habitus, medical conditions affecting tissue healing (e.g., collagen vascular diseases), prior chest RT, the location of prior breast surgery scars, smoking history, and prior or planned chemotherapy. Patients with larger tumors (>5 cm), more than three lymph nodes involved, or close margins will require postmastectomy RT. Reconstructive surgery in this population of patients has to be planned carefully. Optimal approaches and timing of reconstruction are the subjects of ongoing discussion and continuing evolution. At many institutions, the anticipated need for postmastectomy RT is a relative contraindication to immediate breast reconstruction using implants. Delayed immediate reconstruction is a viable option in management of patients at high risk for needing postmastectomy RT. During mastectomy, tissue expanders are placed. While the patient is recovering from surgery and, if applicable, undergoing chemotherapy, tissue expansion is achieved by ongoing repetitive injections of saline. This process must be completed before the simulation and radiation treatment planning process can begin (Figure 7).²¹

FIGURE 7 Illustration of the potential impact of immediate delayed reconstruction on the RT planning process. This patient had bilateral mastectomy with immediate delayed reconstruction, but needed RT on the left. A, Treatment planning was attempted, but the right expansion resulted in excessive exposure of the right chest wall. The patient was sent back to the plastic surgeon for right expander deflation, which resulted in a more desirable isodose distribution (B).

Transverse rectus abdominis myocutaneous (TRAM) flap reconstruction surgery should be delayed if possible, until after completion of the full course of radiation. This allows for an optimal cosmetic outcome ^22,²³ and improved technical coverage with the radiation fields.^24,²⁵

LOCOREGIONAL TREATMENT OF BREAST CANCER IN THE ERA OF NEOADJUVANT CHEMOTHERAPY

Neoadjuvant chemotherapy was initially given in an effort to improve respectability, with planned subsequent mastectomy, to patients with bulky tumors and lymph nodes. Concerns that preoperative chemotherapy would increase postoperative complications and delay adjuvant RT and additional chemotherapy did not materialize.

Management of lymph nodes was and continues to be one of the major challenges of neoadjuvant chemotherapy. It has been demonstrated that the information from sentinel lymph node sampling and axillary dissection performed after completion of chemotherapy correlates well with overall prognosis. The role of sentinel lymph node sampling and axillary dissection in the postchemotherapy setting was reviewed in a meta-analysis, with an overall accuracy of 95%.

In an attempt to reduce false-negative sentinel lymph node findings after neoadjuvant chemotherapy, many surgeons favor routine sentinel lymph node sampling before initiation of chemotherapy. Positive sentinel lymph node biopsy would lead to completion axillary dissection, before or after chemotherapy. Pathology from prechemotherapy sentinel lymph node biopsy is used by the radiation oncologist to plan the extent of the radiation fields.^26,²⁷

NEOADJUVANT CHEMOTHERAPY TO ATTEMPT BREAST PRESERVATION

Once the safety and efficacy of neoadjuvant chemotherapy followed by mastectomy was established, its potential use in converting a mastectomy patient into a BCT candidate was tested. Randomized trials of neoadjuvant chemotherapy, followed by lumpectomy, were initiated. The largest study, NSABP B-18, reviewed results of 1523 patients with stage I to IIIB disease. The analysis showed equal median overall survival (69% versus 70%) and local recurrence rates (10.7% versus 7.6%) after preoperative and postoperative chemotherapy, respectively. Higher rates of BCT (68% versus 60%) were achieved in patients treated with neoadjuvant chemotherapy.

The increasing use of neoadjuvant chemotherapy for BCT necessitates even closer cooperation of the multidisciplinary team managing these patients. Unless there are obvious microcalcifications to mark the tumor, the lesion needs to be marked with a clip either before or within the first two cycles of chemotherapy. This is usually done with ultrasound or mammography guidance. In patients who reach clinical complete remission, these clips will guide the surgeon in planning the lumpectomy and the radiation oncologist in planning the extent of the tumor bed boost.²⁸

RADIATION THERAPY IN THE MANAGEMENT OF DUCTAL CARCINOMA IN SITU

In the era of routine screening mammography, the diagnosis of ductal carcinoma in situ (DCIS) has become a frequent clinical presentation. Management with aggressive surgery has been largely replaced with breast preservation surgery, followed by RT to the breast. There is considerable confusion as to the optimal management, especially for the low-risk patient (low-grade, small tumors, negative margins). There are advocates of lumpectomy alone as a sole treatment.

Three randomized studies comparing tumor resection (with clear margins) with or without RT reported a strong beneficial effect of RT on local recurrence rates, but no effect on overall survival. Chemoprevention with tamoxifen further protects the involved, as well as the contralateral, breast. The technique of RT is the same as that for invasive tumors. There is no need for treatment of lymph nodes, although sentinel lymph node biopsy may be indicated in high-grade or large tumors.²⁹^–³¹

INFLAMMATORY BREAST CANCER

One of the most aggressive and dramatic presentations of breast malignancy is the clinically evident inflammatory breast carcinoma (IBC). The classic presentation leaves little doubt as to the diagnosis, and pathologic confirmation often is a formality. However, there are patients whose diagnosis of IBC is based on histology, rather than the clinical picture. Dermal lymphatic tumor invasion, the histologic hallmark of IBC, may or may not give rise to the clinically characteristic “inflammatory” presentation. Patients with less typical presentations usually undergo workup with mammography, ultrasound, MRI, and biopsy. Once the histologic diagnosis is made, further workup and management are directed toward excluding metastatic disease and initiating systemic chemotherapy as soon as possible. No attempt is made to preserve the breast in patients with IBC. A multimodality team approach to planning the treatment schedule allows for the most expeditious timing of the different components of treatment. The original tumor location is an important parameter in planning postchemotherapy and postmastectomy RT. Imaging studies obtained before and (if available) after chemotherapy assist the radiation oncologist in designing the optimal postmastectomy isodose distribution. Patients with IBC need RT to the regional lymph nodes as part of comprehensive treatment planning. Inclusion of IM lymph nodes is based on review of clinical, imaging, and pathologic information and on the technical feasibility of treatment with the patient’s anatomy and scar location.

EVOLUTION OF RADIATION THERAPY IN BREAST CONSERVATION THERAPY

Until recently, BCT was synonymous with the use of whole-breast radiation, after primary tumor removal with lumpectomy, with clear resection margins. Partial-breast RT, in which lumpectomy is followed by less than whole-breast radiation, has been developed in recent years and parallels trends in breast cancer treatment toward less aggressive diagnostic and treatment methods (e.g., sentinel node sampling over axillary dissection, percutaneous over excisional biopsy for diagnosis). Partial-breast RT can be accomplished by brachytherapy, IMRT, and more recently, use of CyberKnife robotic radiosurgery.

Rationale and Options for Partial Breast Radiation

Numerous randomized trials ³²^–³⁵ comparing whole-breast radiation after tumor excision to tumor excision alone have shown that most breast tumors recur in the tumor cavity. Additionally, these trials have shown that the risk for recurrence outside the tumor cavity is similar whether or not whole-breast radiation was given. This suggests that additional radiation given outside the tumor cavity may not be of additional benefit to patients.

Breast brachytherapy has been traditionally used to treat the lumpectomy cavity as a “boost” following external whole-breast RT. Many centers in recent years have adopted the use of accelerated partial breast RT, either with interstitial needle implants, balloon catheters, or even three-dimensional conformal external RT as the sole radiation treatment modality following breastconserving surgery. By decreasing the volume of breast tissue that needed irradiation, higher radiation doses could be administered per fraction to the tumor bed. This shortened treatment times to 1 week, decreasing the burden for patients when compared with the need for daily travel for whole-breast radiation, which typically lasts 5 to 7 weeks.

Patients are potential candidates for accelerated partial breast RT if they have stage 0, I, or II tumors, a single tumor less than 3 cm in maximal dimension, minimal nodal involvement, and clear surgical margins. Typically, partial-breast radiation is delivered twice a day, with treatments given at least 6 hours apart, for a total of 10 fractions.

Interstitial breast brachytherapy alone has been successfully used at some U.S. centers for more than 10 years following breast-conserving surgery. A trial was started by Vicini and colleagues in 1993 using brachytherapy as the only radiation treatment modality for patients following breastconserving surgery.^36,³⁷ By 2001, 120 patients were enrolled in this trial. Four patients developed local recurrence at a median follow-up of 82 months. During 1997 to 2000, 100 patients were enrolled in an RTOG prospective phase I/II study of breast brachytherapy. At a median follow-up of 2.7 years, most patients experienced only mild treatment-related toxicities.³⁸

In 2002, the U.S. Food and Drug Administration approved the Proxima Therapeutics MammoSite balloon catheter for intracavitary high-dose-rate breast brachytherapy (Figure 8). Seventy patients were initially enrolled in a prospective multicenter trial evaluating the safety of the MammoSite balloon catheter. Subsequent evaluation of 43 patients eligible for the therapy revealed only mild to moderate self-limited side effects.³⁹ Advantages of the balloon catheter are that it is easier to place in the cavity, placement is more reproducible, and patient comfort is improved. Only a single catheter needs to be temporarily placed in the lumpectomy cavity, as opposed to 10 to 20 catheters with traditional interstitial implants. However, the balloon needs to “conform” properly to the tumor cavity and optimal dosimetry could be problematic if a large air pocket develops along the periphery of the cavity. In addition, balloon catheters may not be appropriate for tumors near the skin surface. A more recent addition to the partial-breast RT armamentarium is the SAVI device, which allows a radiation oncologist to selectively direct radiation through up to 7 catheter channels, allowing more tailored manipulation of the isodose (Figure 9). The Contura multilumen balloon catheter combines features of these partial-breast RT devices, with multiple offset lumens around a balloon, also allowing dose-shaping opportunities to minimize skin and rib doses (Figure 10).