Robert W. Mutter

Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy

PURPOSE To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. METHODS AND MATERIALS Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. RESULTS Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. CONCLUSIONS For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted.

Benefits, risks, and safety of external beam radiation therapy for breast cancer.

Breast cancer is a common and complex disease often necessitating multimodality care. Breast cancer may be treated with surgical resection, radiotherapy (RT), and systemic therapy, including chemotherapy, hormonal therapy, and targeted therapies, or a combination thereof. In the past 50 years, RT has played an increasingly significant role in the treatment of breast cancer, resulting in improvements in locoregional control and survival for women undergoing mastectomy who are at high risk of recurrence, and allowing for breast conservation in certain settings. Although radiation provides significant benefit to many women with breast cancer, it is also associated with risks of toxicity, including cardiac and pulmonary toxicity, lymphedema, and secondary malignancy. RT techniques have advanced and continue to evolve dramatically, offering increased precision and reproducibility of treatment delivery and flexibility of treatment schedule. This increased sophistication of RT offers promise of improved outcomes by maintaining or improving efficacy, reducing toxicity, and increasing patient access and convenience. A review of the role of radiation therapy in breast cancer, its associated toxicities and efforts in toxicity reduction is presented.

Radiation oncology in Africa: improving access to cancer care on the African continent.

Radiation Oncology in Africa: Improving Access to Cancer Care on the African Continent Brandon J. Fisher, DO,* Larry C. Daugherty, MD,y John P. Einck, MD,{ Gita Suneja, MD,x Mira M. Shah, MD,k Luqman K. Dad, MD,{ Robert W. Mutter, MD, J. BenWilkinson, MD,** and Arno J. Mundt, MDz *Gamma West Cancer Services, Salt Lake City, Utah; yMayo Clinic, Jacksonville, Florida; zMoores Cancer Center, University of California San Diego, San Diego, California; xAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; kHenry Ford Health System, Detroit, Michigan; {Anne Arundel Medical Center, Annapolis, Maryland; Mayo Clinic, Rochester, Minnesota; and **Willis-Knighton Health System/LSU Health Science Center, Shreveport, Louisiana

Why Target the Globe?: 4-year report (2009-2013) of the Association of Residents in Radiation Oncology Global Health Initiative

Departments of Radiation Oncology, *DeCesaris Cancer Institute, Anne Arundel Medical Center, Annapolis, Maryland, yHenry Ford Health Systems, Detroit, Michigan, zMayo Clinic, Rochester, Minnesota, xWashington University in St. Louis School of Medicine, St. Louis, Missouri, kKarmanos Cancer Center, Detroit Medical Center, Detroit, Michigan, {University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, **Gamma West Cancer Services, Ogden, Utah, yyMemorial Sloan-Kettering Cancer Center, New York, New York, and zzThe University of Texas, MD Anderson Cancer Center, Houston, Texas

Once-daily radiation therapy for inflammatory breast cancer.

PURPOSE Inflammatory breast cancer (IBC) is a rare and aggressive breast cancer variant treated with multimodality therapy. A variety of approaches intended to escalate the intensity and efficacy of radiation therapy have been reported, including twice-daily radiation therapy, dose escalation, and aggressive use of bolus. Herein, we examine our outcomes for patients treated with once-daily radiation therapy with aggressive bolus utilization, focusing on treatment technique. METHODS AND MATERIALS A retrospective review of patients with nonmetastatic IBC treated from January 1, 2000, through December 31, 2010, was performed. Locoregional control (LRC), disease-free survival (DFS), overall survival (OS) and predictors thereof were assessed. RESULTS Fifty-two women with IBC were identified, 49 (94%) of whom were treated with neoadjuvant chemotherapy. All underwent mastectomy followed by adjuvant radiation therapy. Radiation was delivered in once-daily fractions of 1.8 to 2.25 Gy (median, 2 Gy). Patients were typically treated with daily 1-cm bolus throughout treatment, and 33 (63%) received a subsequent boost to the mastectomy scar. Five-year Kaplan Meier survival estimates for LRC, DFS, and OS were 81%, 56%, and 64%, respectively. Locoregional recurrence was associated with poorer OS (P<.001; hazard ratio [HR], 4.1). Extracapsular extension was associated with worse LRC (P=.02), DFS (P=.007), and OS (P=.002). Age greater than 50 years was associated with better DFS (P=.03). Pathologic complete response was associated with a trend toward improved LRC (P=.06). CONCLUSIONS Once-daily radiation therapy with aggressive use of bolus for IBC results in outcomes consistent with previous reports using various intensified radiation therapy regimens. LRC remains a challenge despite modern systemic therapy. Extracapsular extension, age ≤50 years, and lack of complete response to chemotherapy appear to be associated with worse outcomes. Novel strategies are needed in IBC, particularly among these subsets of patients.

Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Homologous recombination (HR) DNA repair‐deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51‐based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole‐exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large‐scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi‐allelic loss‐of‐function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR‐proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi‐allelic alterations in the HR pathway to deliver a precision medicine‐based approach to select patients for therapies targeting tumour‐specific DNA repair defects. Copyright

Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports

PURPOSE The feasibility of proton postmastectomy radiation therapy in patients reconstructed with expanders has not been previously reported, limiting treatment options. We analyzed the dosimetric impact of the metallic port contained within expanders on intensity modulated proton therapy (IMPT) and report our techniques and quality control for treating patients in this setting. METHODS AND MATERIALS Twelve patients with the same expander model underwent 2-field IMPT as part of a prospective registry. All planning dosimetry was checked with an in-house graphic processing unit--based Monte Carlo simulation. Proton ranges through the expander were validated using a sample implant. Dosimetric impact of setup metallic port position uncertainty was evaluated. Pre- and posttreatment photographs were obtained and acute toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS Nine patients had bilateral skin-sparing mastectomy with bilateral tissue expander reconstruction, and 3 patients had unilateral skin-sparing mastectomy and reconstruction. The left side was treated in 10 patients and the right side in 2. Target coverage and normal tissue dose uncertainties resulting from the expander were small and clinically acceptable. The maximum physician-assessed acute radiation dermatitis was grade 3 in 1 patient, grade 2 in 5 patients, and grade 1 in 6 patients. CONCLUSIONS Postmastectomy IMPT in breast cancer patients with expanders is feasible and associated with favorable clinical target volume coverage and normal tissue sparing, even when taking into account treatment uncertainties; therefore, these patients should be eligible to participate in clinical trials studying the potential role of proton therapy in breast cancer. We caution, however, that institutions should carry out similar analyses of the physical properties and dosimetric impact of the particular expanders used in their practice before considering IMPT.

In Reply to Yang and Guo

lymph node only accounted for 10% of positive lymph nodes in breast cancer (3, 4). Therefore, we postulate that clinical recurrence in the posterior triangle would be reduced only if we give an adequate radiation dose to the medial SCV subclinical disease. An SCV radiation field with photon beam angled 10 -15 away from the spinal cord was used to treat the axillary and periclavicular nodes in early clinical trials, the Danish 82b and 82c studies (5-7). If the field design was simulated on a “standard patient” with a 6-MV photon beam, we found that only the medial SCV region was covered by the 95% isodose line (Fig. 1b). However, in the combined analysis of locoregional recurrence in these 2 studies after 18-year follow-up (8), the periclavicular recurrence only accounted for 2.2% in the radiation group with 1538 cases. Thus, the true recurrence in the posterior triangle was scarce in the high-risk patients with prophylactic irradiation focused only on the medial SCV region. Given the above analysis, we think the authors’ suggestion is suitable for patients with N3c at initial diagnosis or with SCV nodal macrometastases at recurrence. However, it could be enough to cover medial SCV subclinical disease for postoperative adjuvant radiation therapy.

Carbon fiducial image-guidance increases the accuracy of lumpectomy cavity localization in radiation therapy for breast cancer

PURPOSE We investigated the feasibility and accuracy of using carbon fiducials to localize the lumpectomy cavity with 2-dimensional kV imaging for early stage breast cancer radiation therapy. METHODS AND MATERIALS Carbon fiducials were placed intraoperatively in the periphery of the lumpectomy cavity. Nine patients received whole breast irradiation with a boost, and 2 patients received 3-dimensional conformal partial breast irradiation. A total of 89 fractions were assessed for setup errors relative to a predefined gold standard, cone beam computed tomography (CBCT) match to the lumpectomy cavity, using the following 4 setup methods: (1) Align skin tattoos with lasers; (2) match bone with 2-dimensional-2-dimensional (2D/2D) kV onboard imaging (OBI); (3) match the whole breast with CBCT; and (4) match carbon fiducials with 2D/2D kV OBI. The margin for the planning target volume (PTV) was calculated by 2 standard deviations of the setup errors, and compared among the 4 setup methods. Setup errors for patients treated with free breathing and patients with deep inspiration breath hold were also compared. RESULTS The carbon fiducials were sufficiently visible on OBI for matching and introduced minimal artifacts. Of the 4 alignment methods, 2D/2D OBI match to fiducials resulted in the smallest setup errors. The PTV margin was 12 mm for aligning skin tattoos using lasers, 9.2 mm for matching bone on OBI, 6.5 mm for matching breast on CBCT, and 3.5 mm for matching fiducials on 2D/2D OBI. Compared with free breathing, deep inspiration breath hold generally reduced the standard deviations of the setup errors, but further investigation would be needed. CONCLUSIONS Matching to carbon fiducials increased the localization accuracy to the lumpectomy cavity. This reduces residual setup error and PTV margins, facilitating tissue sparing without diminishing treatment efficacy.

Cardiovascular Concerns in BRCA1 and BRCA2 Mutation Carriers

Purpose of reviewBRCA1 and BRCA2 mutation carriers can be at increased cardiovascular risk. The goal of this review is to provide information about factors associated with increased cardiovascular risk, methods to prevent cardiovascular toxicities, and recommended screening guidelines.Recent findingsBRCA1/2 mutation carriers who are diagnosed with cancer are often exposed to chemotherapy, chest radiotherapy, and/or HER2 directed therapies, all of which can be cardiotoxic. In addition, BRCA1/2 carriers often undergo prophylactic salpingoopherectomies, which may also increase cardiovascular risks.SummaryUnderstanding the potential for increased cardiovascular risk in individuals with a BRCA1 or BRCA2 mutation, as well as gold standard practices for prevention, detection, and treatment of cardiac concerns in this population, is important.