Breast Radiation and the Heart: Cardiac Toxicity and Cardiac Avoidance.

The purpose of this invited review is to discuss the most recent and relevant outcome studies assessing the risk of late cardiac toxicity in women treated with radiotherapy for breast cancer and to describe the evidence-based technical factors associated with late cardiac toxicity. This review will also discuss the common radiation techniques for reducing radiation dose to the heart, which will lead to better outcomes and lower rates of late toxicity that can cause morbidity and mortality in women who have been cured of their breast cancer.

Precision Medicine for Breast Cancer: The Paths to Truly Individualized Diagnosis and Treatment.

Precision medicine in oncology seeks to individualize each patient's treatment regimen based on an accurate assessment of the risk of recurrence or progression of that person's cancer. Precision will be achieved at each phase of care, from detection to diagnosis to surgery, systemic therapy, and radiation therapy, to survivorship and follow-up care. The precision arises from detailed knowledge of the inherent biological propensities of each tumor, rather than generalizing treatment approaches based on phenotypic, or even genotypic, categories. Extensive research is being conducted in multiple disciplines, including radiology, pathology, molecular biology, and surgical, medical, and radiation oncology. Clinical trial design is adapting to the new paradigms and moving away from grouping heterogeneous patient populations into limited treatment comparison arms. This review touches on several areas invested in clinical research. This special issue highlights the specific work of a number of groups working on precision medicine for breast cancer.

Intraoperative Radiotherapy for Breast Cancer.

Intraoperative radiotherapy (IORT) for early stage breast cancer is a technique for partial breast irradiation. There are several technologies in clinical use to perform breast IORT. Regardless of technique, IORT generally refers to the delivery of a single dose of radiation to the periphery of the tumor bed in the immediate intraoperative time frame, although some protocols have performed IORT as a second procedure. There are two large prospective randomized trials establishing the safety and efficacy of breast IORT in early stage breast cancer patients with sufficient follow-up time on thousands of women. The advantages of IORT for partial breast irradiation include: direct visualization of the target tissue ensuring treatment of the high-risk tissue and eliminating the risk of marginal miss; the use of a single dose coordinated with the necessary surgical excision thereby reducing omission of radiation and the selection of mastectomy for women without access to a radiotherapy facility or unable to undergo several weeks of daily radiation; favorable toxicity profiles; patient convenience and cost savings; radiobiological and tumor microenvironment conditions which lead to enhanced tumor control. The main disadvantage of IORT is the lack of final pathologic information on the tumor size, histology, margins, and nodal status. When unexpected findings on final pathology such as positive margins or positive sentinel nodes predict a higher risk of local or regional recurrence, additional whole breast radiation may be indicated, thereby reducing some of the convenience and low-toxicity advantages of sole IORT. However, IORT as a tumor bed boost has also been studied and appears to be safe with acceptable toxicity. IORT has potential efficacy advantages related to overall survival related to reduced cardiopulmonary radiation doses. It may also be very useful in specific situations, such as prior to oncoplastic reconstruction to improve accuracy of adjuvant radiation delivery, or when used as a boost in higher risk patients to improve tumor control. Ongoing international clinical trials are studying these uses and follow-up data are accumulating on completed studies.

ACR Appropriateness Criteria® Ductal Carcinoma in Situ.

Ductal carcinoma in situ (DCIS) is a breast neoplasm with potential for progression to invasive cancer. Management commonly involves excision, radiotherapy, and hormonal therapy. Surgical assessment of regional lymph nodes is rarely indicated except in cases of microinvasion or mastectomy. Radiotherapy is employed for local control in breast conservation, although it may be omitted for select low-risk situations. Several radiotherapy techniques exist beyond standard whole-breast irradiation (ie, partial-breast irradiation [PBI], hypofractionated whole-breast radiation); evidence for these is evolving. We present an update of the American College of Radiology (ACR) Appropriateness Criteria® for the management of DCIS. The ACR Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions, which are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria local-regional recurrence (LRR) and salvage surgery-breast cancer.

Although both breast-conserving surgery and mastectomy generally provide excellent local-regional control of breast cancer, local-regional recurrence (LRR) does occur. Predictors for LRR include patient, tumor, and treatment-related factors. Salvage after LRR includes coordination of available modalities, including surgery, radiation, chemotherapy, and hormonal therapy, depending on the clinical scenario. Management recommendations for breast cancer LRR, including patient scenarios, are reviewed, and represent evidence-based data and expert opinion of the American College of Radiology Appropriateness Criteria Expert Panel on LRR.The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel.The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

The impact of the size of nodal metastases on recurrence risk in breast cancer patients with 1-3 positive axillary nodes after mastectomy.

PURPOSE: Use of postmastectomy radiation therapy (PMRT) in breast cancer patients with 1-3 positive nodes is controversial. The objective of this study was to determine whether the size of nodal metastases in this subset could predict who would benefit from PMRT. METHODS AND MATERIALS: We analyzed 250 breast cancer patients with 1-3 positive nodes after mastectomy treated with contemporary surgery and systemic therapy at our institution. Of these patients, 204 did not receive PMRT and 46 did receive PMRT. Local and regional recurrence risks were stratified by the size of the largest nodal metastasis measured as less than or equal to 5 mm or greater than 5 mm. RESULTS: The median follow-up was 65.6 months. In the whole group, regional recurrences occurred in 2% of patients in whom the largest nodal metastasis measured 5 mm or less vs 6% for those with metastases measuring greater than 5 mm. For non-irradiated patients only, regional recurrence rates were 2% and 9%, respectively. Those with a maximal nodal size greater than 5 mm had a significantly higher cumulative incidence of regional recurrence (P=.013). The 5-year cumulative incidence of a regional recurrence in the non-irradiated group was 2.7% (95% confidence interval [CI], 0.7%-7.2%) for maximal metastasis size of 5 mm or less, 6.9% (95% CI, 1.7%-17.3%) for metastasis size greater than 5 mm, and 16% (95% CI, 3.4%-36.8%) for metastasis size greater than 10 mm. The impact of the maximal nodal size on regional recurrences became insignificant in the multivariable model. CONCLUSIONS: In patients with 1-3 positive lymph nodes undergoing mastectomy without radiation, nodal metastasis greater than 5 mm was associated with regional recurrence after mastectomy, but its effect was modified by other factors (such as tumor stage). The size of the largest nodal metastasis may be useful to identify high-risk patients who may benefit from radiation therapy after mastectomy.

Accelerated partial breast irradiation: a review and description of an early North American surgical experience with the intrabeam delivery system.

BACKGROUND: Targeted intraoperative radiation therapy (IORT) as an alternative to whole breast irradiation (WBI) has been described for patients with early-stage breast cancer. The randomized phase III TARGiT trial demonstrated similar recurrence rates to WBI and a lower overall toxicity profile on short-term follow-up. We report on our early North American surgical experience using the Intrabeam radiotherapy delivery system and review the current literature. METHODS: Prospectively gathered estrogen receptor-positive, clinically node-negative patients with invasive breast cancer < 3 cm receiving IORT using the Intrabeam system were reviewed. IORT-related effects and early postoperative outcome were assessed. A literature review was also performed. RESULTS: Forty-two patients (median age 71 years) underwent lumpectomy, sentinel lymph node (SLN) biopsy, and concurrent IORT from January 2011 to July 2011. Ninety-one percent of patients had invasive ductal histology with a median tumor size of 1.0 cm. This review highlights the patient selection criteria, describes commercially available accelerated partial breast irradiation (APBI) treatment options, and discusses outcomes for the variety of APBI techniques currently utilized in clinical practice as well as an institutional review of our early surgical experience using the Intrabeam radiotherapy delivery system. CONCLUSIONS: While a variety of APBI techniques are currently available for clinical use, our early North American operative experience with IORT shows it is well tolerated with low morbidity. Delivery of IORT adds moderate operative time and may require creating subcutaneous tissue fl aps. The addition of WBI may be necessary in situations for positive residual margins or microscopic nodal disease in patients who do not undergo additional surgery.

Time-course of arm lymphedema and potential risk factors for progression of lymphedema after breast conservation treatment for early stage breast cancer.

The objective of this study was to describe the progression of arm lymphedema (ALE) after the initial presentation among patients receiving breast conservation therapy for early stage breast cancer and to identify potential risk factors contributing to ALE progression. The study sample was the 266 stage I or II breast cancer patients with documented ALE who underwent breast conservation therapy that included lumpectomy, axillary staging followed by radiation therapy. ALE were graded according to a difference of 0.5-2 cm (mild), 2.1-3 cm (moderate), and >3 cm (severe) in the circumference between the upper extremities for the treated and untreated sides. ALE at presentation was scored as mild, moderate, and severe in 109 (41%), 125 (47%), and 32 (12%) patients, respectively. One third of patients with ALE progressed to a more severe grade of lymphedema at 5 years of follow-up. Age older than 65 years at the time of breast cancer treatment was associated with higher risk of ALE progression when compared 65 year age or younger (p = 0.04). The patients who had regional lymph node irradiation including posterior axillary boost were at higher risk of lymphedema progression than the patients treated with whole breast irradiation only (p = 0.001). Progression of ALE is a common occurrence. The current study provides support for the utility of routine arm measurements after breast cancer treatment to facilitate timely diagnosis and treatment of ALE.

ACR Appropriateness Criteria® local-regional recurrence (LR) and salvage surgery: breast cancer.

Despite the success of both breast conserving surgery and mastectomy, some women will experience a local-regional recurrence (LRR) of their breast cancer. Predictors for LRR after breast-conserving therapy or mastectomy have been identified, including patient, tumor, and treatment-related factors. The role of surgery, radiation, and chemotherapy as treatment has evolved over time and many patients now have the potential for salvage after LRR. This review of LRR of breast cancer and management recommendations, including the use of common clinical scenarios, represents a compilation of evidence-based data and expert opinion of the American College of Radiology Appropriateness Criteria Expert Panel on local-regional recurrence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Validating fiducial markers for image-guided radiation therapy for accelerated partial breast irradiation in early-stage breast cancer.

PURPOSE: Image-guided radiation therapy (IGRT) may be beneficial for accelerated partial breast irradiation (APBI). The goal was to validate the use of intraparenchymal textured gold fiducials in patients receiving APBI. METHODS AND MATERIALS: Twenty-six patients were enrolled on this prospective study that had three or four textured gold intraparenchymal fiducials placed at the periphery of the lumpectomy cavity and were treated with three-dimensional (3D) conformal APBI. Free-breathing four-dimensional computed tomography image sets were obtained pre- and posttreatment, as were daily online megavoltage (MV) orthogonal images. Intrafraction motion, variations in respiratory motion, and fiducial marker migration were calculated using the 3D coordinates of individual fiducials and a calculated center of mass (COM) of the fiducials. We also compared the relative position of the fiducial COM with the geometric center of the seroma. RESULTS: There was less than 1 mm of intrafraction respiratory motion, variation in respiratory motion, or fiducial marker migration. The change in seroma position relative to the fiducial COM was 1 mm ± 1 mm. The average position of the geometric seroma relative to the fiducial COM pretreatment compared with posttreatment was 1 mm ± 1 mm. The largest daily variation in displacement when using bony landmark was in the anteroposterior direction and two standard deviations (SD) of this variation was 10 mm. The average variation in daily separation between the fiducial pairs from daily MV images was 3 mm ± 3 mm therefore 2 SD is 6 mm. CONCLUSION: Fiducial markers are stable throughout the course of APBI. Planning target volume margins when using bony landmarks should be 10 mm and can be reduced to 6 mm if using fiducials.

ACR appropriateness criteria(®) ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) describes a wide spectrum of non-invasive tumors which carry a significant risk of invasive relapse, thus prevention of local recurrence is vital. For appropriate patients with limited disease, management with breast conserving surgery (BCS) followed by whole-breast radiation (RT) is supported by multiple Phase III studies, but mastectomy may be appropriate in selected patients. Omission of RT may also be reasonable in some patients, though which criteria are to be utilized remain unclear, and the existing data are contradictory with limited follow-up. Various RT techniques such as boost to the tumor bed, partial breast radiation or hypofractionated, whole-breast RT are increasingly utilized but the data to support their use specifically in DCIS is limited. Tamoxifen also increases local control for ER + DCIS, adding to the complexity of the local treatment management. This article reviews the existing scientific evidence, the controversies surrounding local management, and clinical guidelines for DCIS based on the group consensus by the ACR Breast Expert Panel. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR appropriateness criteria® locally advanced breast cancer.

Locally advanced breast cancer (LABC) is a disease that is heterogeneous in its presentation, potentially curable, and generally necessitating multidisciplinary management. Radiation therapy (RT) plays an important role in the management of LABC. The integration of radiation with surgery, chemotherapy, and sometimes breast reconstruction can be complex. The American College of Radiology Appropriateness Criteria Breast Committee aims to provide guidance for the management of a variety of LABC cases. The American College of Radiology Appropriateness Criteria is evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is either lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® conservative surgery and radiation--stage I and II breast carcinoma: expert panel on radiation oncology: breast.

Breast conservation is a safe and effective alternative to mastectomy for the majority of women with early-stage breast cancer. Adjuvant radiation therapy lowers the risk of recurrence within the breast and also confers a survival benefit. Although acute side effects of radiation therapy are generally well tolerated; efforts are ongoing to minimize the long-term side effects of radiation, most prominently atherosclerotic heart disease. Efforts to minimize radiation therapy are also underway. They include omitting treatment altogether in the elderly and using accelerated, hypofractionated whole-breast irradiation, and accelerated partial-breast irradiation. Several randomized studies are ongoing to determine the efficacy, safety, and appropriate patients for these shorter treatments.

Cardiac morbidity and mortality in women with ductal carcinoma in situ of the breast treated with breast conservation therapy.

Left-sided breast irradiation has been associated with increased risk of cardiac morbidity and mortality in some studies. This study examines the cardiac toxicity of irradiation in left- versus right-sided patients with ductal carcinoma in situ (DCIS). The medical records of 129 patients with DCIS treated with breast conservation therapy (BCT) at the Moffitt Cancer Center from 1986 to 2002 were reviewed and data regarding subsequent breast cancer and cardiac events were recorded. There were 59 left-sided and 70 right-sided patients treated. Mean age was 55 years. At 8 years, there was no significant difference observed between right- and left-sided breast cancer patients in the development of coronary artery disease, myocardial infarction, congestive heart failure, arrhythmia, valvular disease, cardiomyopathy, or cardiac-related death. Among those patients with left-sided breast cancer, 13.5% of patients developed a cardiovascular event compared to 7% of right-sided patients (p = 0.25). The overall survival at 8 years was 96% and the relapse-free survival was 85%. There were no significant differences in cardiac mortality or morbidity between right- and left-sided DCIS patients treated with BCT. Longer follow-up will be required to ascertain whether late events are more prevalent in left-sided patients.

Assessment of organ motion in postoperative endometrial and cervical cancer patients treated with intensity-modulated radiation therapy.

PURPOSE: Intensity-modulated radiation therapy (IMRT) may be useful to reduce toxicity in gynecologic cancer patients requiring postoperative pelvic irradiation. This study was undertaken to quantify vaginal wall organ motion during the course of postoperative pelvic irradiation using pelvic IMRT. METHODS AND MATERIALS: Twenty-two consecutive patients treated with postoperative pelvic IMRT on helical tomotherapy had fiducial markers placed at the vaginal apex prior to simulation then daily megavoltage computed tomography (CT) scans for positioning. The daily positions of the fiducials were registered and measured in reference to the initial CT scan to quantify the degree of vaginal wall organ motion during the entire course of therapy. RESULTS: The total motion of the fiducials center of mass (COM) was a median of 5.8 mm (range, 0.6-20.2 mm), and 95% of all COM positions fell within 15.7 mm of their original position. Directional margins of 3.1 mm along the right-left axis, 9.5 mm along the superoinferior axis, and of 12.1 mm along the anteroposterior axis encompassed the vaginal fiducials in 95% of treatments. Mean organ deformation for all patients was 3.9 mm, (range, 0-27.5 mm; standard deviation, 3.1 mm), with significant distortions of greater than 10 mm in 17% of secondary image sets. CONCLUSIONS: These data suggest a planning target volume margin of 16 mm will account for maximal organ motion in the majority of gynecologic patients undergoing postoperative pelvic IMRT, and it may be possible to incorporate directional motion into the planning target volume margin.

Accelerated partial breast irradiation: potential roles following breast-conserving surgery.

BACKGROUND: Multiple randomized trials comparing mastectomy to lumpectomy and whole breast irradiation (WBI) have shown equivalent survival outcomes in early-stage breast cancer. WBI requires a treatment course of several weeks, which has resulted in limited access to breast-conserving therapy in certain populations. A shorter accelerated course of partial breast irradiation (APBI) has been investigated recently. METHODS: This article reviews the current medical literature, including randomized trials and prospective institutional studies of APBI and the current recommendations regarding the use of this emerging technique. RESULTS: Several APBI techniques have been developed, including brachytherapy and external beam methods. The longest follow-up data are available for multicatheter interstitial brachytherapy, a technique that is not commonly used. Other methods, including balloon brachytherapy and external beam three-dimensional conformal techniques, have limited follow-up that shows similar local control rates to whole breast irradiation in highly selected patients. Guidelines for the appropriate use of APBI have been published. CONCLUSIONS: While APBI may increase access to breast conservation therapy for some women with early-stage breast cancer, follow-up data demonstrating the efficacy of this relatively new treatment approach are limited. Therefore, strict evidence-based selection criteria should be applied when evaluating patients who may be appropriate for APBI.