Radiologic response of chemotherapy alone versus radiation and chemotherapy in the treatment of locally-advanced or advanced thymic epithelial tumors.

BACKGROUND: Here, we investigated radiological responses following chemotherapy alone as compared to both radiation/chemotherapy (chemoRT) in patients with thymic epithelial tumors (TETs) who did not receive upfront surgery. METHODS: TETs treated at a tertiary academic cancer center between January 2007 and July 2018 were identified. Patients received chemotherapy or chemoRT as initial therapy and pre- and post-treatment scans were available. Student's t-test, Wilcoxon rank-sum tests, and Cox proportional hazards method were used to compare clinical details and survival between groups. The primary outcome was change in tumor size, which was compared between groups using linear mixed-effects regression models, adjusting for baseline tumor size, age, and histology. RESULTS: A total of 24 of 114 patients with TETs identified met the inclusion criteria. The majority of patients had 67% thymoma (67%, n = 16) and AJCC8 III-IVA disease (58%, n = 14). Median age was 58.5 years (range: 33-76), median initial tumor volume was 187.1 cc (range: 28.7-653.6) and diameter was 8.5 cm (range: 4.5-14.3). Half of the patients received upfront chemotherapy (n = 12: 83% cisplatin/adriamycin/cyclophosphamide) or chemoRT (n = 12: 58% carboplatin/paclitaxel; median RT dose: 63 Gy [range: 60-70 Gy]). At a median imaging follow-up of 15 months (range: 0-86): ChemoRT was associated with increased average radiological response compared to chemotherapy alone (volume: -47.0 cc more, P < 0.001; diameter: -0.8 cm more, P = 0.03). In eight patients who received chemotherapy, 33% saw further tumor shrinkage (median volume: -42.3%, P = 0.03; diameter: -3.0%, P = 0.049) with additional radiation/chemoradiation. Median survival increased for patients ultimately receiving surgery versus those who did not (46 month, range: 16-127 vs. 14 month, range: 6-82; P < 0.01). CONCLUSIONS: ChemoRT produced a greater radiologic response compared to chemotherapy alone in patients with TETs not suitable for upfront resection. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: We found that chemoRT was associated with a greater radiologic response compared to patients who received chemotherapy alone. WHAT THIS STUDY ADDS: What this study adds: In patients with TET not amenable to upfront resection, chemoRT may be a feasible strategy for cytoreduction.

Applying Non-Homogeneous Dose Optimization to Improve Conventionally Fractionated Radiation Plan Quality in Patients with Non-Small Cell Lung Cancer.

PURPOSE: Nonhomogeneous dose optimization (NHDO) is exploited in stereotactic body radiation therapy (SBRT) to increase dose delivery to the tumor and allow rapid dose falloff to surrounding normal tissues. We investigate changes in plan quality when NHDO is applied to inverse-planned conventionally fractionated radiation therapy (CF-RT) plans in patients with non-small cell lung cancer. METHODS AND MATERIALS: Patients with near-central non-small cell lung cancer treated with CF-RT in 2018 at a single institution were identified. CF-RT plans were replanned using NHDO techniques, including normalizing to a lower isodose line, while maintaining clinically acceptable normal tissue constraints and target coverage. Tumor control probabilities were calculated. We compared delivered CF-RT plans using homogenous dose optimization (HDO) versus NHDO using Wilcoxon signed-rank tests. Median values are reported. RESULTS: Thirteen patients were replanned with NHDO techniques. Planning target volume coverage by the prescription dose was similar (NHDO = 96% vs HDO = 97%, P = .3). All normal-tissue dose constraints were met. NHDO plans were prescribed to a lower-prescription isodose line compared with HDO plans (85% vs 97%, P = .001). NHDO increased mean dose to the planning target volume (73 Gy vs 67 Gy), dose heterogeneity, and dose falloff gradient (P < .03). NHDO decreased mean dose to surrounding lungs, esophagus, and heart (relative reduction of 6%, 14%, and 15%, respectively; P < .05). Other normal tissue objectives improved with NHDO, including total lung V40 and V60, heart V30, and maximum esophageal dose (P < .05). Tumor control probabilities doubled from 31.6% to 65.4% with NHDO (P = .001). CONCLUSIONS: In select patients, NHDO principles used in SBRT optimization can be applied to CF-RT. NHDO results in increased tumor dose, reduction in select organ-at-risk dose objectives, and better maintenance of target coverage and normal-tissue constraints compared with HDO. Our data demonstrate that principles of NHDO used in SBRT can also improve plan quality in CF-RT.

Reductions in prostatic doses are associated with less acute morbidity in patients undergoing Pd-103 brachytherapy: Substantiation of the rationale for focal therapy.

PURPOSE: Interest in prostate dose reduction or focal treatment exists due to expected reductions in treatment morbidity. Prior analyses have not generally corroborated relationships between prostate or urethral dose and urinary toxicity after brachytherapy, but such analyses have been performed on cohorts all receiving the same prescribed dose. We analyzed patients treated to differing prescription doses to assess acute urinary morbidity with dose reduction. METHODS AND MATERIALS: Patients treated with Pd-103 to either 125 Gy or 90-100 Gy were compared using the International Prostate Symptom Score (IPSS) at 1-month postimplant. Patients in the 90-100 Gy cohort began external beam radiation therapy after their 1-month assessment; thus, toxicities were measured before contribution from external beam radiation therapy. Patient/treatment characteristics were compared to verify subgroup homogeneity. Dose and change in IPSS 1 month after treatment were assessed using a multivariate linear regression model. RESULTS: One hundred ninety-one and 41 patients were treated with 125 Gy versus 90-100 Gy, respectively. Preimplant and postimplant prostate volumes and initial IPSS were similar between groups. Higher prescription dose and increased pretreatment IPSS were independent predictors of increased 1-month IPSS. In addition, every 10 percentage point additional prostate volume receiving a given dose was associated with increase in IPSS after treatment for the same level of pretreatment IPSS. CONCLUSION: Lower prescription dose and decreased volume of high-dose regions to the prostate correlated with reduced acute urinary morbidity after brachytherapy. Our findings suggest that focal treatment approaches with modest dose reductions to subregions of the prostate may reduce acute morbidity and potentially expand the number of patients eligible for brachytherapy.

Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival.

BACKGROUND: We seek to investigate whether carboplatin-based induction chemotherapy before modern day concurrent chemoradiotherapy (CCRT) improves survival in patients with bulky, locally advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 105 patients with Stage II and III NSCLC treated with definitive CCRT from 2003 to 2013. All patients underwent definitive treatment with weekly platinum-based doublet chemotherapy delivered concurrently with 60-66 Gy of thoracic radiotherapy. Thirty patients who received induction chemotherapy before CCRT had T4 disease, N3 disease, or gross tumor volume (GTV) of >150 cm 3. These patients were compared to those with unresectable disease who received CCRT alone without induction chemotherapy. Statistical analysis included univariate and multivariate methods. RESULTS: Mean follow-up time was 15.6 months. Patients treated with carboplatin based induction chemotherapy demonstrated prolonged overall survival (28.2 vs. 14.2 months, P = 0.04), progression free survival (12.6 vs. 9.0 months, P = 0.02), and distant metastasis free survival (15.8 vs. 10.1months, P = 0.05) compared to those who received CCRT alone without induction chemotherapy. Univariate analysis revealed older age, larger GTV, and squamous pathology as negative prognostic factors. When controlling for these factors, Cox regression analysis indicated a trend toward significantly improved overall survival in the induction cohort (P = 0.10). CONCLUSION: In patients with large tumors or bulky nodal NSCLC, carboplatin-based induction chemotherapy may be an important addition to definitive CCRT in the modern era. Our findings strongly support further investigation induction chemotherapy in this population.

Comparison of Mammographic Changes Across Three Different Fractionation Schedules for Early-Stage Breast Cancer.

PURPOSE: As the use of hypofractionated breast radiation therapy (RT) increases, so will the need for long-term data on post-RT mammographic changes. The purpose of the present study was to longitudinally compare the incidence of common mammographic sequelae seen after breast conserving surgery and RT in patients treated with accelerated partial breast irradiation (APBI), hypofractionated whole breast irradiation (HWBI), and conventionally fractionated whole breast irradiation (WBI). METHODS AND MATERIALS: Patients treated with either APBI or HWBI after breast conserving therapy and with ≥3 mammograms of the treated breast were identified. They were matched 1:1 by age ±5 years to patients treated with WBI. The mammograms were evaluated for common post-RT breast findings by a mammographer who was unaware of the treatment. The outcomes were analyzed using a cumulative logistic regression model; P<.05 indicated statistically significance. RESULTS: Of 89 patients treated with RT from 2006 to 2011, 29 had received APBI, 30 had received HWBI, and 30 had received WBI. Their median age was 60 years (range 33-83). A total of 605 mammograms were evaluated, with a median follow-up of 48 months. The treatment technique did not affect the severity of architectural distortion when the groups were evaluated longitudinally. The likelihood of finding skin thickening decreased with increasing follow-up duration (odds ratio 0.6; P<.001) adjusted for fractionation schemes. No differences were seen with respect to changes in skin thickening, fluid collections, or calcifications among the treatment groups, after adjustment for the follow-up time. The clinical characteristics, including age, race, T stage, and chemotherapy use, were not linked to the likelihood of finding several mammographic phenomena over time. CONCLUSIONS: Although specific post-treatment imaging findings evolved over time, RT fractionation did not alter the relative incidence or severity of architectural distortion, skin thickening, fluid collections, or calcifications. These findings will be useful to both radiologists and radiation oncologists when counseling patients regarding follow-up studies after RT.

Racial Disparities in Hypofractionated Radiotherapy Breast Cancer Clinical Trials.

There is a paucity of data regarding factors affecting enrollment onto radiation oncology clinical trials. The purpose of this study was to determine patients and tumor characteristics that influenced enrollment of breast cancer patients onto hypofractionated breast radiotherapy trials (HBRTs) at a single institution. In this retrospective cohort study, patients enrolled on HBRTs at the Rutgers Cancer Institute of New Jersey (n = 132) were compared with a cohort of breast cancer patients eligible for, but not enrolled onto HBRTs treated during the same time period (n = 132). Charts were retrospectively reviewed to determine patients' demographics, clinico-pathologic factors, and treatment characteristics. Statistical analysis was performed to analyze variables affecting enrollment onto HBRTs between the two groups. Over a 42-month time period, 132 patients treated on HBRTs received 2,475-4,995 cGy over 3 to 15 fractions. When compared with patients treated off trial, there was no statistically significant effect of age, family history, lymph node positivity, tumor grade, estrogen or Her-2 receptor status, use of chemotherapy or hormones, use of brachytherapy, or the site of initial consultation on HBRT enrollment. Non-White women were less likely to enroll in HBRT's when compared with White women (25.7% versus 40.1%, p = 0.0129), though this was found to be a nonsignificant trend when taking stage into consideration on multivariate analysis (OR for lower T-stage: 0.281, p = 0.003, OR 1.839 for white race, p = 0.076). Consistent with previous studies, non-White women were less likely to enroll in HBRTs than White women. However, disease stage accounted for these racial disparities. Further studies must be performed to determine if race is an independent factor determining radiation oncology clinical trial enrollment.

Impact of metformin use on survival in locally-advanced, inoperable non-small cell lung cancer treated with definitive chemoradiation.

BACKGROUND: We investigated survival outcomes in diabetic patients with non-small cell lung cancer (NSCLC) treated with concurrent metformin and definitive chemoradiation. METHODS: This single-institution, retrospective cohort study included 166 patients with NSCLC who were treated definitively with chemoradiation between 1999 and 2013. Of 40 patients who had type II diabetes, 20 (50%) were on metformin, and 20 (50%) were not on metformin. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). Kaplan Meier method and log-rank test were performed in survival analysis. Cox regression was utilized in univariate analysis of potential confounders. RESULTS: Median follow-up was 17.0 months. Compared with non-diabetic patients, diabetic patients on metformin demonstrated similar OS (16.3 vs. 14.3 mo, P=0.23), PFS (11.6 vs. 9.7 mo, P=0.26), LRRFS (14.1 vs. 11.9 mo, P=0.78), and DMFS (13.4 vs. 10.0 mo, P=0.69). Compared with diabetic patients not on metformin, diabetic patients on metformin also exhibited similar OS (14.3 vs. 19.2 mo, P=0.18), PFS (19.7 vs. 10.1 mo, P=0.38), LRRFS (11.9 vs. 15.5 mo, P=0.69), and DMFS (10.0 vs. 17.4 mo, P=0.12). Identified negative prognostic factors on included squamous cell histology, lower performance status, higher T stage, and non-caucasian ethnicity. CONCLUSIONS: No statistically significant differences in survival or patterns of failure were found among the three cohorts in this small set of patients. No statistically significant differences in survival or patterns of failure were found between the three cohorts in this small set of patients. Though it is possible that metformin use may in fact have no effect on survival in NSCLC patients treated with definitive RT, larger-scale retrospective and prospective studies are implicated for clarification.

Optimization of surgical clip placement for breast-conservation therapy.

PURPOSE: The purpose of this study was to determine if seroma cavity visualization could be further improved with placement of gold fiducial markers in each anatomic wall of the seroma cavity compared with placement of surgical titanium clips at the surgeon's discretion. METHODS AND MATERIALS: We identified patients with breast cancer who received breast-conservation surgery. Patients were grouped into 3 categories: patients without clips, patients with titanium clips placed at the discretion of the treating surgeon, and patients with gold fiducial markers directly sutured to each wall of the seroma cavity. Cavity visualization was determined using the cavity visualization score criteria. RESULTS: A total of 262 patients met the criteria for the study; 119 patients did not have surgical clips placed during breast-conservation surgery, 109 patients received surgical titanium clip placement at the surgeon's discretion, and 34 patients received directed placement of gold fiducial markers in each anatomic wall of the seroma cavity. There was improvement in the visualization of the seroma cavity in patients who received directed gold fiducial marker placement in each wall of the seroma cavity compared with titanium clip placement at the surgeon's discretion (P < .05). An association was not identified between the quantity of titanium clips used, the amount of seroma walls with titanium clips present, or the time interval between surgery and radiation therapy planning with cavity visualization when surgical titanium clips were placed at the surgeon's discretion. CONCLUSIONS: The placement of a gold fiducial marker in each of the seroma cavity walls improved visualization of the seroma cavity compared with the placement of titanium clips at the surgeon's discretion. This technique may be utilized in order to assist in planning a seroma boost following whole breast irradiation or in accelerated partial breast irradiation.

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

This study describes our institution's 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 institution's 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.

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.

Differential H3K4 methylation identifies developmentally poised hematopoietic genes.

Throughout development, cell fate decisions are converted into epigenetic information that determines cellular identity. Covalent histone modifications are heritable epigenetic marks and are hypothesized to play a central role in this process. In this report, we assess the concordance of histone H3 lysine 4 dimethylation (H3K4me2) and trimethylation (H3K4me3) on a genome-wide scale in erythroid development by analyzing pluripotent, multipotent, and unipotent cell types. Although H3K4me2 and H3K4me3 are concordant at most genes, multipotential hematopoietic cells have a subset of genes that are differentially methylated (H3K4me2+/me3-). These genes are transcriptionally silent, highly enriched in lineage-specific hematopoietic genes, and uniquely susceptible to differentiation-induced H3K4 demethylation. Self-renewing embryonic stem cells, which restrict H3K4 methylation to genes that contain CpG islands (CGIs), lack H3K4me2+/me3- genes. These data reveal distinct epigenetic regulation of CGI and non-CGI genes during development and indicate an interactive relationship between DNA sequence and differential H3K4 methylation in lineage-specific differentiation.