Clinical Study 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 ( value = 0.02) and a trend toward significance when compared to diabetic patients receiving an alternate diabetes medication ( 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 ( 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

Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer

Purpose To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). Methods and Materials In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. Results The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], –0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, –0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. Conclusions With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease

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

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer

PURPOSE: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes. METHODS AND MATERIALS: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. RESULTS: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P \u3c .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P \u3c .0001. CONCLUSIONS: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens

Planning comparison of intensity modulated radiation therapy delivered with 2 tangential fields versus 3-dimensional conformal radiotherapy for cardiac sparing in women with left-sided breast cancer.

PURPOSE: In women with unfavorable thoracic anatomy undergoing left breast radiation therapy (RT) after breast-conserving surgery, a significant volume of the heart may receive high-dose radiation, which has been shown previously to be associated with increased late cardiac morbidity and mortality. Use of intensity modulated radiation therapy (IMRT) has been proposed to reduce cardiac dose in these patients. We compared cardiac exposure from IMRT delivered from 2 opposed fields and 3-dimensional conformal radiation therapy (3DCRT) plans employing simple heart blocks. METHODS AND MATERIALS: Fourteen patients with left-sided breast cancer treated with breast-conserving surgery and RT were identified to have unfavorable cardiac anatomy, defined as maximum heart depth (MHD) ≥1.0 cm within the unblocked opposed tangential fields. 3DCRT plans utilized dynamic wedges, segments, and custom heart blocks designed by the treating physician. Tangent IMRT plans were optimized to reduce cardiac dose while maintaining planning target volume (PTV) coverage equal to that achieved with the 3DCRT plan. We generated tangential field plans with complete heart block (CHB) or no heart block (NHB) for comparison. Plans were normalized to deliver 46 Gy to the PTV. Dose to the heart, PTV, and lumpectomy cavity were compared. RESULTS: Mean MHD was 1.44 cm (1.0-1.86 cm). There was no significant difference in PTV receiving \u3e95% of the prescription dose between 3DCRT and IMRT, as intended. Mean V30 to the heart was 0% for CHB plans, 1.7% for 3DCRT plans, 1.8% for IMRT plans, and 3.3% for NHB plans, respectively. There was no significant difference in heart V30 for 3DCRT and IMRT plans (P = .8). IMRT plans delivered 256 total monitor units compared with 201 in 3DCRT plans (P \u3c .01). CONCLUSIONS: Inverse-planned tangent IMRT does not reduce high-dose radiation to the heart compared with 3DCRT, incorporating a simple heart block in women with left-sided cancer and unfavorable cardiac anatomy when PTV coverage was equalized for both plans. In select patients with early-stage breast cancer and unfavorable thoracic anatomy, 3DCRT with heart block may be sufficient to adequately protect the heart from high-dose radiation

Stereotactic Radiation for Oligometastatic and Oligoprogressive Stage IV Breast Cancer: A Case-Based Review

For decades, the distant progression of breast cancer has been the purview of systemic therapy alone or with low to moderate-dose radiation therapy intended for the palliation of symptomatic metastases. However, for decades there have been anecdotes of long-term disease-free survival with more aggressive local treatment of one or more metastases. The hypothesis of oligometastases is that the treatment of a clinically limited number of distant metastases can change the natural history of stage IV breast cancer. The advance in the technology of stereotactic body radiation (SBRT) has made it more possible to offer a non-invasive, yet potentially disease-modifying, metastases-directed ablative treatment in place of surgery or a palliative radiation regimen. Although there are promising local control and survival outcomes in phase I/II trials, there is still a lack of phase III evidence of ablative SBRT results showing any change in the natural history of metastatic breast cancer. Limited oligometastases may call for an ablative approach with SBRT when definitive long-term local control is needed for the best palliation against symptomatic progression in challenging locations. Some oligometastases that have progression on a certain systemic regimen, while others remain stable or in remission, may also be treated with SBRT in the hopes of prolonging the use of that regimen. Whether SBRT should represent the standard management for stage IV breast cancer of a limited number or of limited progression requires confirmation by phase III data. This review will discuss the data from key clinical trials as it applies to decision making in typical clinical cases considered for potentially ablative SBRT for oligometastases or oligoprogression

Radiation-induced heart disease: Pathologic abnormalities and putative mechanisms

© 2015 Taunk, Haffty, Kostis and Goyal. 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