Neil K. Taunk

Radiation-Induced Heart Disease: Pathologic Abnormalities and Putative Mechanisms

Breast cancer is a common diagnosis in women. Breast radiation has become critical in managing patients who receive breast conserving surgery, or have certain high-risk features after mastectomy. Most patients have an excellent prognosis, therefore understanding the late effects of radiation to the chest is important. Radiation-induced heart disease (RIHD) comprises a spectrum of cardiac pathology including myocardial fibrosis and cardiomyopathy, coronary artery disease, valvular disease, pericardial disease, and arrhythmias. Tissue fibrosis is a common mediator in RIHD. Multiple pathways converge with both acute and chronic cellular, molecular, and genetic changes to result in fibrosis. In this article, we review the pathophysiology of cardiac disease related to radiation therapy to the chest. Our understanding of these mechanisms has improved substantially, but much work remains to further refine radiation delivery techniques and develop therapeutics to battle late effects of radiation.

Chromosomal instability drives metastasis through a cytosolic DNA response

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Prognostic significance of IGF-1R expression in patients treated with breast-conserving surgery and radiation therapy

BACKGROUND Insulin-like growth factor (IGF) receptor is a key receptor in apoptotic protection, cell adhesion, longevity, and transformation into a cancerous cell and can induce malignant changes in the presence of the IGF ligand. Over-expression of IGF-1R has been associated with resistance to radiation. Inhibitors of IGF-1R have been shown to enhance tumor radiation sensitivity and amplify radiation therapy-induced apoptosis. The purpose of this study is to evaluate the prognostic significance of IGF-1R expression in patients with breast cancer treated with breast conserving therapy. MATERIALS AND METHODS Paraffin specimens from 345 women with early stage breast cancer treated with BCT were constructed into tissue microarrays and stained for IGF-1R, COX-2 and p53. The molecular profiles were correlated with clinical-pathologic factors, overall, local, and distant relapse-free survival. The association between IGF-1R, other co-variables, and outcome was assessed. RESULTS IGF-1R over-expression was identified in 197 cases (57%). IGF-1R over-expression was found to be correlated with African-American race (p=0.0233), p53 status (p=0.0082) and COX-2 expression (p<0.0001). While IGF-1R over-expression was associated with lower overall survival (p=0.0224) in node-negative patients, there was no impact of IGF-1R expression on local control. CONCLUSIONS In node-negative patients, patients with high levels of IGF-1R were found to have a significant reduction in overall survival, but no apparent effect on local control. Given the limited published data on IGF-1R in early stage, conservatively treated patients, further studies investigating IGF-1R expression in this cohort are necessary.

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

UNLABELLED Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patients disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small-molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles. The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation. There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases. This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS. IMPLICATIONS FOR PRACTICE Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy.

External beam re-irradiation, combination chemoradiotherapy, and particle therapy for the treatment of recurrent glioblastoma.

SUMMARY Glioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies.

Evaluation of Diabetic Patients with Breast Cancer Treated with Metformin during Adjuvant Radiotherapy

Purpose. The purpose of this study was to evaluate acute locoregional toxicity in patients with breast cancer receiving concurrent metformin plus radiation therapy. Methods and Materials. Diabetic breast cancer patients receiving concurrent metformin and radiation therapy were matched with nondiabetic patients and diabetic patients using an alternative diabetes medication. Primary endpoints included the presence of a treatment break and development of dry or moist desquamation. Results. There was a statistically significant increase in treatment breaks for diabetic patients receiving concurrent metformin when compared to the nondiabetic patients (P value = 0.02) and a trend toward significance when compared to diabetic patients receiving an alternate diabetes medication (P value = 0.08). Multiple logistic regression analysis demonstrated concurrent metformin use as being associated with a trend toward the predictive value of determining the incidence of developing desquamation in diabetic patients receiving radiation therapy compared to diabetic patients receiving an alternate diabetes medication (P value = 0.06). Conclusions. Diabetic patients treated with concurrent metformin and radiation therapy developed increased acute locoregional toxicity in comparison with diabetic patients receiving an alternate diabetes medication and nondiabetic patients. Further clinical investigation should be conducted to determine the therapeutic ratio of metformin in combination with radiation therapy.

Stereotactic body radiotherapy for metastatic spinal sarcoma: a detailed patterns-of-failure study

OBJECTIVE The aim of this study was to report the first detailed analysis of patterns of failure within the spinal axis of patients treated with stereotactic body radiotherapy (SBRT) for sarcoma spine metastases. METHODS Between 2005 and 2012, 88 consecutive patients with metastatic sarcoma were treated with SBRT for 120 spinal lesions. Seventy-one percent of patients were enrolled on prospective institutional protocols. For patients who underwent routine posttreatment total-spine MRI (64 patients, 88 lesions), each site of progression within the entire spinal axis was mapped in relation to the treated lesion. Actuarial rates of local-, adjacent-, and distant-segment failure-free survival (FFS) were calculated using the Kaplan-Meier method. RESULTS The median follow-up for the cohort was 14.4 months, with 81.7% of patients followed up until death. The 12-month actuarial rate of local FFS was 85.9%; however, 83.3% of local failures occurred in conjunction with distant-segment failures. The 12-month actuarial rates of isolated local-, adjacent-, and distant-segment FFS were 98.0%, 97.8%, and 74.7%, respectively. Of patients with any spinal progression (n = 55), only 25.5% (n = 14) had progression at a single vertebral level, with 60.0% (n = 33) having progression at ≥ 3 sites within the spine simultaneously. Linear regression analysis revealed a relationship of decreasing risk of failure with increasing distance from the treated index lesion (R(2) = 0.87), and 54.1% of failures occurred ≥ 5 vertebral levels away. Treatment of the index lesion with a lower biological effective dose (OR 3.2, 95% CI 1.1-9.2) and presence of local failure (OR 18.0, 95% CI 2.1-152.9) independently predicted for distant spine failure. CONCLUSIONS Isolated local- and adjacent-segment failures are exceptionally rare for patients with metastatic sarcoma to the spine treated with SBRT, thereby affirming the treatment of the involved level only. The majority of progression within the spinal axis occurs ≥ 5 vertebral levels away. Thus, total-spine imaging is necessary for surveillance posttreatment.

Short-Interval Retreatment With Stereotactic Body Radiotherapy (SBRT) for Pediatric Neuroblastoma Resulting in Severe Myositis.

We report a severe and not previously reported toxicity after short‐interval retreatment with stereotactic body radiotherapy (SBRT) in a pediatric patient with neuroblastoma. This patient experienced Grade III radiation myositis after treatment with conventional radiation therapy followed by high‐dose SBRT for persistent disease a short interval after the initial radiotherapy course. While SBRT shows outstanding rates of local control in adult disease, data in pediatric cancers are extremely limited. In this report, we discuss the rationale of SBRT in this patients multimodality neuroblastoma treatment, management of the toxicity, and future perspectives on the use of SBRT in pediatric cancer.

Cranial irradiation in adults diagnosed with acute myelogenous leukemia presenting with hyperleukocytosis and neurologic dysfunction

Abstract This study describes our institutions experience using whole brain radiation therapy (WBRT) to treat patients with acute myelogenous leukemia (AML) presenting with hyperleukocytosis. After approval by the institutional review board, we identified patients with AML and hyperleukocytosis using hospital records. The primary endpoints in the study included alleviation of neurological symptoms (or prevention if prophylactic RT was used), overall survival, development of intracranial hemorrhage (ICH) and ≥ grade 3 toxicities using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Eighteen patients received WBRT for the treatment of AML hyperleukocytosis. Thirteen patients received treatment in order to control neurological symptoms. Clinical assessment showed that 12 of 13 patients (92%) achieved resolution of neurological symptoms either concurrent with RT or immediately after RT. The mean overall survival for all of the patients who received WBRT was 14.2 months (95% confidence interval, 5.4–23.0). No patient who received RT experienced ≥ grade 3 toxicity. Two (6%) patients developed ICH following therapy. Our institutions experience demonstrates that WBRT may be utilized as part of multimodality therapy in order to alleviate or prevent neurological symptoms in patients with AML presenting with leukostasis.

Immunotherapy and radiation therapy for operable early stage and locally advanced non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality. Although a significant proportion of patients can be cured with surgery, with or without adjuvant or neoadjuvant chemotherapy and radiation, a significant proportion of patients will fail, particularly distantly. Over fifty percent of patients present with stage IV disease. There are multiple forms of immunotherapy available including T-cell transfer, cytokine therapy, and oncolytic viruses. Checkpoint inhibitors have shown tremendous activity in NSCLC and are currently under intense study given promising data on response. Immunotherapy and radiation therapy (RT) both show significant immune editing activity in NSCLC that may allow the innate and adaptive immune system to help control systemic disease by both radiosensitization and a sustained systemic immune response. Multiple clinical trials are underway exploring the role of adjuvant or neoadjuvant immunotherapy in operable NSCLC. A substantial amount of progress is to be made in terms of optimizing radiation dose and fractionation, immunotherapy type and dose, and integrating both to best realize the benefits of immunotherapy and radiation in operable lung cancer.