A.D. Currey

Tracheoesophageal Fistula Associated with Bevacizumab 21 Months after Completion of Radiation Therapy

To the Editor: We present a case of a 48-year-old man with stage IIIa non-small cell lung cancer treated with preoperative concurrent chemotherapy and radiation therapy (RT). Two years later, he was treated with salvage bevacizumab and chemotherapy and developed a fatal tracheoesophageal fistula (TEF). The patient had a RUL mass and mediastinoscopy-proven right paratracheal lymphadenopathy. He was treated with definitive RT (66 Gy) and weekly carboplatin and paclitaxel. Maximum esophageal dose was 68.1 Gy. Absolute volume receiving 68 Gy was 0.03 (Figure 1). Eight weeks later, he had a right upper lobectomy with lymph node dissection, pT1N0M0. Residual mass was necrotic with rare tumor cells. Seventeen months after diagnosis, he had biopsy-proven chest wall recurrence. Computed tomography showed progressive RUL collapse, although no mediastinal mass. He was treated with carboplatin, gemcitabine, and bevacizumab. Fourteen days after cycle 1, he was diagnosed with RLL pneumonia. Twenty-three days later, he had progressive dysphagia and cough. Swallow study showed a TEF. Chest computed tomography confirmed erosion of the posterior wall of the distal trachea, mediastinal air, oral contrast within the pleural space, and a tracheoesophageal mass (Figure 2). Mediastinal recurrence was suspected, although not histologically confirmed. An esophageal stent was placed with symptomatic relief. One month later, bronchoscopy and esophagogastroduodenoscopy showed complete erosion of the esophagus and posterior tracheal wall from the cricoid cartilage to carina. Biopsies were negative. The patient died of pneumonia several days later. Acute esophageal toxicity is a common side effect of RT and predicts for late toxicity.1Esophageal dose in this case was acceptable by published parameters. The patient had minimal acute esophageal toxicity. Severe late complications were not anticipated. Bevacizumab is associated with gastrointestinal complications, including TEF.2–5 A drug warning was issued in April 2007 after formation of three TEF in 29 patients treated on a phase II study with concurrent thoracic RT, chemotherapy, and bevacizumab.4 TEF occurred during maintenance bevacizumab. Six other cases of TEF with concurrent RT and bevacizumab for lung and esophageal cancer have been reported. TEF formation has also been reported in head and neck cancer with bevacizumab and concurrent chemoradiotherapy.2 Although delayed gastrointestinal complications associated with bevacizumab after RT are described for colorectal cancer, delayed TEF in patients with lung cancer have not been widely reported. Disclosure: Dr. Choong is a consultant for Genentech. The other authors declare no conflicts of interest. Address for correspondence: Elizabeth Gore, MD, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226. E-mail: egore@mcw.edu Copyright

Influence of patient, physician, and hospital characteristics on the receipt of guideline-concordant care for inflammatory breast cancer.

PURPOSE Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer for which treatments vary, so we sought to identify factors that affect the receipt of guideline-concordant care. METHODS Patients diagnosed with IBC in 2004 were identified from the Breast and Prostate Cancer Data Quality and Patterns of Care Study, containing information from cancer registries in seven states. Variation in guideline-concordant care for IBC, based on National Comprehensive Cancer Network (NCCN) guidelines, was assessed according to patient, physician, and hospital characteristics. RESULTS Of the 107 IBC patients in the study without distant metastasis at the time of diagnosis, only 25.8% received treatment concordant with guidelines. Predictors of non-concordance included patient age (≥70 years), non-white race, normal body mass index (BMI 18.5-25 kg/m(2)), patients with physicians graduating from medical school >15 years prior, and smaller hospital size (<200 beds). IBC patients survived longer if they received guideline-concordant treatment based on either 2003 (p=0.06) or 2013 (p=0.06) NCCN guidelines. CONCLUSIONS Targeting factors associated with receipt of care that is not guideline-concordant may reduce survival disparities in IBC patients. Prompt referral for neoadjuvant chemotherapy and post-operative radiation therapy is also crucial.

Adaptive Replanning to Account for Lumpectomy Cavity Change in Sequential Boost After Whole-Breast Irradiation

PURPOSE To evaluate the efficiency of standard image-guided radiation therapy (IGRT) to account for lumpectomy cavity (LC) variation during whole-breast irradiation (WBI) and propose an adaptive strategy to improve dosimetry if IGRT fails to address the interfraction LC variations. METHODS AND MATERIALS Daily diagnostic-quality CT data acquired during IGRT in the boost stage using an in-room CT for 19 breast cancer patients treated with sequential boost after WBI in the prone position were retrospectively analyzed. Contours of the LC, treated breast, ipsilateral lung, and heart were generated by populating contours from planning CTs to boost fraction CTs using an auto-segmentation tool with manual editing. Three plans were generated on each fraction CT: (1) a repositioning plan by applying the original boost plan with the shift determined by IGRT; (2) an adaptive plan by modifying the original plan according to a fraction CT; and (3) a reoptimization plan by a full-scale optimization. RESULTS Significant variations were observed in LC. The change in LC volume at the first boost fraction ranged from a 70% decrease to a 50% increase of that on the planning CT. The adaptive and reoptimization plans were comparable. Compared with the repositioning plans, the adaptive plans led to an improvement in target coverage for an increased LC case (1 of 19, 7.5% increase in planning target volume evaluation volume V95%), and breast tissue sparing for an LC decrease larger than 35% (3 of 19, 7.5% decrease in breast evaluation volume V50%; P=.008). CONCLUSION Significant changes in LC shape and volume at the time of boost that deviate from the original plan for WBI with sequential boost can be addressed by adaptive replanning at the first boost fraction.

Patient-reported outcomes in patients with nonmelanomatous skin cancers of the face treated with orthovoltage radiation therapy: a cross-sectional survey.

Patients confronted with various treatment options for the treatment of nonmelanomatous skin cancers in visible areas of the face may not be fully informed of the expected outcomes associated with treatment. Radiation therapy may be particularly advantageous in treating lesions in which surgical resection would risk poor cosmetic outcomes. Results from several large series demonstrate local recurrence rates of <10% with the use of radiation therapy (1-4). Despite reports of local control rates comparable to those associated with surgical resection, few studies have addressed cosmetic endpoints following radiation therapy. No studies have assessed patient-reported outcomes. The purpose of the survey was to evaluate patient-reported outcomes following orthovoltage radiation therapy for skin cancers of the face (SCF).

Reducing the Human Burden of Breast Cancer: Advanced Radiation Therapy Yields Improved Treatment Outcomes.

Radiation therapy is an important modality in the treatment of patients with breast cancer. While its efficacy in the treatment of breast cancer was known shortly after the discovery of x‐rays, significant advances in radiation delivery over the past 20 years have resulted in improved patient outcomes. With the development of improved systemic therapy, optimizing local control has become increasingly important and has been shown to improve survival. Better understanding of the magnitude of treatment benefit, as well as patient and biological factors that confer an increased recurrence risk, have allowed radiation oncologists to better tailor treatment decisions to individual patients. Furthermore, significant technological advances have occurred that have reduced the acute and long‐term toxicity of radiation treatment. These advances continue to reduce the human burden of breast cancer. It is important for radiation oncologists and nonradiation oncologists to understand these advances, so that patients are appropriately educated about the risks and benefits of this important treatment modality.

Cutaneous Metastasis due to Breast Cancer in a Patient with Primary Biliary Cirrhosis: A Case Report

Background: Breast cancer is the most common solid tumor to cause cutaneous metastases. These are incurable and the treatment goal is geared toward local control with surgical excision, radiation, and chemotherapy. However, treatment can be challenging in subjects with end-stage liver disease and a multidisciplinary approach is warranted. Case Report: In this case report, we present a 61-year-old female with primary biliary cirrhosis and human epidermal growth factor-2 (HER-2)-positive breast cancer, who subsequently developed cutaneous metastases. We briefly describe the treatment challenges due to underlying end-stage liver disease, and an exceptional response to trastuzumab and nab-paclitaxel. Conclusion: A multidisciplinary approach to local control and attenuated doses of nab-paclitaxel and trastuzumab suggest a durable response to HER-2-positive breast cancer with cutaneous metastasis. Subjects with end-stage liver disease pose unique challenges and toxicities, warranting additional research and drug development for less hepatotoxic antineoplastic agents.

Deep Inspiration Breath Hold: Techniques and Advantages for Cardiac Sparing During Breast Cancer Irradiation

Historically, heart dose from left-sided breast radiotherapy has been associated with a risk of cardiac injury. Data suggests that there is not a threshold for the deleterious effects from radiation on the heart. Over the past several years, advances in radiation delivery techniques have reduced cardiac morbidity due to treatment. Deep inspiration breath hold (DIBH) is a technique that takes advantage of a more favorable position of the heart during inspiration to minimize heart doses over a course of radiation therapy. In the accompanying review article, we outline several methods used to deliver treatment with DIBH, quantify the benefits of DIBH treatment, discuss considerations for patient selection, and identify challenges associated with DIBH techniques.

Management of the axilla after neo-adjuvant chemotherapy for breast cancer: Sentinel node biopsy and radiotherapy considerations

Preoperative or neo‐adjuvant chemotherapy in the management of breast cancer is a treatment approach that has gained in popularity in recent years. However, it is unclear if the treatment paradigms often employed for patients treated with surgery first hold true for those treated with preoperative chemotherapy. The role of sentinel node biopsy and the data supporting its use is different for those with clinically negative and clinically positive nodes prior to chemotherapy. For clinically node‐negative patients, sentinel node biopsy after neo‐adjuvant chemotherapy may be appropriate. For those node‐positive patients whose axillary disease resolves clinically, the false‐negative rate of the sentinel node biopsy is high. However, there are measures that can reduce that rate. After surgery, the radiation oncologist is often faced with complicated decisions surrounding the optimal radiotherapy in this setting. Tailoring radiation plans based on chemotherapy response holds promise and is the subject of ongoing clinical trials. In the accompanying article, we review the current literature on both surgery and radiation in axillary management and describe the interplay between these two treatment modalities. This highlights the need for multidisciplinary management in making treatment decisions for patients treated in this manner.

Evolving rationale for post-mastectomy radiation

Devastating local recurrences (LR) of breast cancer after mastectomy are a challenging problem as old as the procedure itself. The role of post-mastectomy radiation (PMRT) to prevent such recurrences has been extensively studied and prospective randomized studies of PMRT were conducted as early as the 1940’s. Obtaining optimal benefit from PMRT depends on three factors: (1) treatment technique avoiding late radiation toxicity; (2) appropriate systemic therapy; and (3) selection of patients with a risk of recurrence high enough to justify treatment. In the 1990’s, integration of these factors into practice resulted in the publication of two prospective trials from the Danish Breast Cancer Cooperative Group and a third from British Columbia demonstrating that PMRT not only reduces the risk of LR, but also confers a survival advantage. Most of the patients treated on these studies had lymph node positive disease. These studies, and subsequent meta-analyses, confirmed a role for PMRT in node positive patients. The Early Breast Cancer Trialists’ Cooperative Group (EBCTCG) published a meta-analysis of 22 trials of PMRT, and confirmed the benefit of treatment for those with lymph node positive disease. However, for patients who had an axillary dissection and no radiotherapy, the LR rate was 1.4%, and radiation therapy did not improve that recurrence risk. Several publications have suggested that there is a subset of node-negative patients who are at high risk of LR, and might benefit from PMRT. A pooled analysis of the International Breast Cancer Study Group, demonstrated that for node-negative premenopausal patients with high risk features, the cumulative incident risk of LR with or without distant metastasis was 15-19%, depending on tumor size. This exceeded the risk for some patients with 1-3 positive lymph nodes and equaled the risk for patients with 4 or more nodes positive and low risk factors. The factors that most significantly increased the risk for these women were vascular invasion and tumor size. Jagsi et al. reported a strikingly high 10-year LR risk of 40.6% for node-negative patients who had three high risk factors including premenopausal status, tumor size >2 cm, and lymphovascular invasion (LVI). Similar findings of recurrence risks approaching 20% in high risk node-negative patients have been reported. This LR risk is comparable to the recurrence risks of 20.3% and 32.1% reported in the EBCTCG for patients with 1-3 and 4 or more positive nodes, respectively, following mastectomy alone. The latter are a group of patients who routinely receive PMRT. Most patients in these high risk node-negative series had T1-T2 tumors, with only a few having T3N0 disease. These and other studies were summarized in a meta-analysis reported by Rowell, and identified that for patients with node-negative breast cancer, LVI, grade 3 tumor, and premenopausal status or age <50 were all predictors of recurrence. The presence of multiple factors increased recurrence risk substantially. The retrospective analysis reported by Poppe et al. adds to this growing body of evidence suggesting that for younger patients, LVI is an important factor predicting recurrence. They report the experience of two institutions and demonstrate that for patients under 40 years old, patients with LVI had a 10-year freedom from LR of 72%. Again, in this high risk node-negative cohort, the LR risk approaches or exceeds that in some patients with positive nodes who routinely receive PMRT. Furthermore, they demonstrate the effectiveness of PMRT in reducing this risk in that they observed no LRs in the women who received PMRT. Understanding the biological underpinnings of breast cancer behavior and recurrence patterns has recently increased substantially. For patients undergoing breast-conserving treatment, molecular subtypes of breast cancer such as Luminal A, Luminal B, and Basal-like cancers differ in their associated rates of LR. Similarly, for patients treated on the Danish Breast Cancer Cooperative Group studies of PMRT, receptor status (as a surrogate for molecular subtypes) predicted for different risks for LR. In the newly released 8th edition of the American Joint Commission on Cancer (AJCC) staging manual, these biologic factors have been incorporated into a new AJCC Prognostic Stage Group. Abdulkarim et al., found that triple negative, node-negative breast cancer patients treated with breast conserving therapy had lower rates of LR than patients treated with mastectomy. They, as well as others have suggested that patients with triple negative T1-T2 tumors might benefit from PMRT. However, the impact of PMRT in patients with different molecular subtypes has been variable and at times, counter-intuitive. In the Danish studies, patients with hormone receptor positive disease derived the greatest benefit from PMRT despite higher recurrence rates among those with triple negative breast cancer. In Selz’s et al. study of 699 patients with node-negative breast cancer, molecular subtype had no predictive value for LR. Instead, only the proliferative index of Ki-67 predicted for recurrence. Even when those patients received PMRT, there was no improvement in the rate of LR. On the contrary, a phase III study published by Wang et al. randomized 681 women with triple negative breast cancer to mastectomy and chemotherapy alone vs chemotherapy and PMRT. Most of these patients (83.5%) were node negative. While LR rates were not reported, 5-year recurrence-free survival was improved with PMRT (88.3% vs 74.6%), as was 5-year overall survival (90.4% vs 78.7%). Another indicator of tumor biology that may soon help determine benefit from PMRT is tumor response to preoperative DOI: 10.1111/tbj.12836

Racial and Socioeconomic Disparities Are More Pronounced in Inflammatory Breast Cancer Than Other Breast Cancers

Inflammatory breast cancer (IBC) is a rare yet aggressive form of breast cancer. We examined differences in patient demographics and outcomes in IBC compared to locally advanced breast cancer (LABC) and all other breast cancer patients from the Breast and Prostate Cancer Data Quality and Patterns of Care Study (POC-BP), containing information from cancer registries in seven states. Out of 7,624 cases of invasive carcinoma, IBC and LABC accounted for 2.2% (N = 170) and 4.9% (N = 375), respectively. IBC patients were more likely to have a higher number (P = 0.03) and severity (P = 0.01) of comorbidities than other breast cancer patients. Among IBC patients, a higher percentage of patients with metastatic disease versus nonmetastatic disease were black, on Medicaid, and from areas of higher poverty and more urban areas. Black and Hispanic IBC patients had worse overall and breast cancer-specific survival than white patients; moreover, IBC patients with Medicaid, patients from urban areas, and patients from areas of higher poverty and lower education had worse outcomes. These data highlight the effects of disparities in race and socioeconomic status on the incidence of IBC as well as IBC outcomes. Further work is needed to reveal the causes behind these disparities and methods to improve IBC outcomes.