Prospective observational trial of low-dose skin electron beam therapy in mycosis fungoides using a rotational technique.

INTRODUCTION: Low-dose total skin electron beam therapy provides a durable treatment response for skin lesions caused by cutaneous T-cell lymphoma. We prospectively assessed the durability of response and quality of life for patients receiving low-dose total skin electron beam therapy using a novel rotational technique and dosing regimen. METHODS: Patients completed baseline Skindex-29 quality-of-life surveys and had baseline Modified Severity-Weighted Assessment Tool score recorded. Patients received 12 Gy in 12 fractions with a dual-field rotational technique. The primary outcome was overall response rate, with the secondary outcomes being time to treatment response, duration of clinical benefit, and quality-of-life change. RESULTS: We enrolled 20 patients and recorded an overall response rate of 90%. The median time to treatment response was 6.5 weeks. The baseline Modified Severity-Weighted Assessment Tool score was 55.6 and it declined to a median of 2.2 at last follow-up (P < .001). The median duration of clinical benefit was 21 months. There was a decline in the Skindex-29 total score and every subdomain when each follow-up visit was compared (P = .004). CONCLUSIONS: This prospective study demonstrated a very high overall response rate and improvement in skin-related quality of life. Low-dose rotational total skin electron beam therapy can be implemented routinely in clinical practice.

Childhood cancer survivors: The integral role of the cardiologist and cardiovascular imaging.

IMPORTANCE: With 80% of childhood cancer survivors (CCS) alive 30 years after diagnosis, preventable causes of death, such as cardiovascular disease resulting from initial cancer therapy, becomes an important metric. This leads to a more pronounced role for cardiologists in the care of CCS. OBSERVATIONS: While routine cardiovascular screening has been traditionally performed by the hematologist/oncologist or primary care provider, our understanding of cardiovascular disease in CCS has advanced. The measurement of left ventricular ejection fraction (LVEF) can now be complemented with additional assessments of strain, LV mass, right ventricular function, diastolic function, valve function, the pericardium, coronary perfusion, and biomarkers. Risk factor modification, prophylaxis, and timing of treatment are also critical. CONCLUSIONS AND RELEVANCE: Early cardiovascular screening and treatment in asymptomatic CCS can be nuanced and complex. As a result, there is a renewed opportunity for the cardiologist to play an integral role in the care of CCS. KEY POINTS: Question/Purpose: Review cardiovascular disease and the role of the cardiologist in the care of asymptomatic childhood cancer survivors (CCS). FINDINGS: Cardiovascular care in CCS benefits from a multi-faceted approach that does not overly rely on LVEF. Meaning: Adequate screening and treatment of cardiovascular disease in asymptomatic CCS may often be optimized by the involvement of a cardiologist.

Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma.

BACKGROUND AND OBJECTIVES: Lymphopenia associated with chemoradiotherapy predicts prognosis in esophageal carcinoma. The purpose of our study was to evaluate alterations in hematologic measures of inflammation during chemoradiation. METHODS: We performed an observational study evaluating adults treated with chemoradiation in the neoadjuvant or definitive setting for stage II-III esophageal carcinoma. Multivariable logistic regression evaluated predictors of pathologic response. Survival was analyzed by time-varying multivariable Cox proportional hazards regressions. RESULTS: A total of 94 patients were included with median follow-up of 1.6 years. Elevated neutrophil:lymphocyte ratio (NLR) was predictive of incomplete pathologic response to neoadjuvant chemoradiation (OR, 1.07; P = .0030) as well as shorter distant metastasis-free survival (HR, 1.01; P = .0369) and reduced overall survival (HR, 1.01; P = .0448). An NLR > 5.55 in week two of chemoradiation predicted shorter overall survival (P = .0070). Upon adjusted analysis, NLR was independently associated with reduced probability of complete pathologic response (OR, 0.80; P = .0291), as well as poor histologic response to neoadjuvant chemoradiation (OR, 1.05; P = .0303), shorter disease-free survival (HR, 1.02; P = .0077), and reduced overall survival (HR, 1.02; P = .0070). CONCLUSIONS: Dynamic time-dependent changes in NLR during chemoradiation predict response, relapse, metastasis, and survival in esophageal carcinoma. Prospective validation is warranted.

Assessing the Accuracy and Reliability of AI-Generated Medical Responses: An Evaluation of the Chat-GPT Model.

Background: Natural language processing models such as ChatGPT can generate text-based content and are poised to become a major information source in medicine and beyond. The accuracy and completeness of ChatGPT for medical queries is not known. Methods: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes/no) or descriptive answers. The physicians then graded ChatGPT-generated answers to these questions for accuracy (6-point Likert scale; range 1 - completely incorrect to 6 - completely correct) and completeness (3-point Likert scale; range 1 - incomplete to 3 - complete plus additional context). Scores were summarized with descriptive statistics and compared using Mann-Whitney U or Kruskal-Wallis testing. Results: Across all questions (n=284), median accuracy score was 5.5 (between almost completely and completely correct) with mean score of 4.8 (between mostly and almost completely correct). Median completeness score was 3 (complete and comprehensive) with mean score of 2.5. For questions rated easy, medium, and hard, median accuracy scores were 6, 5.5, and 5 (mean 5.0, 4.7, and 4.6; p=0.05). Accuracy scores for binary and descriptive questions were similar (median 6 vs. 5; mean 4.9 vs. 4.7; p=0.07). Of 36 questions with scores of 1-2, 34 were re-queried/re-graded 8-17 days later with substantial improvement (median 2 vs. 4; p<0.01). Conclusions: ChatGPT generated largely accurate information to diverse medical queries as judged by academic physician specialists although with important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Accuracy and Reliability of Chatbot Responses to Physician Questions.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency. Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information. Design, Setting, and Participants: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes or no) or descriptive answers. The physicians then graded the chatbot-generated answers to these questions for accuracy (6-point Likert scale with 1 being completely incorrect and 6 being completely correct) and completeness (3-point Likert scale, with 1 being incomplete and 3 being complete plus additional context). Scores were summarized with descriptive statistics and compared using the Mann-Whitney U test or the Kruskal-Wallis test. The study (including data analysis) was conducted from January to May 2023. Main Outcomes and Measures: Accuracy, completeness, and consistency over time and between 2 different versions (GPT-3.5 and GPT-4) of chatbot-generated medical responses. Results: Across all questions (n = 284) generated by 33 physicians (31 faculty members and 2 recent graduates from residency or fellowship programs) across 17 specialties, the median accuracy score was 5.5 (IQR, 4.0-6.0) (between almost completely and complete correct) with a mean (SD) score of 4.8 (1.6) (between mostly and almost completely correct). The median completeness score was 3.0 (IQR, 2.0-3.0) (complete and comprehensive) with a mean (SD) score of 2.5 (0.7). For questions rated easy, medium, and hard, the median accuracy scores were 6.0 (IQR, 5.0-6.0), 5.5 (IQR, 5.0-6.0), and 5.0 (IQR, 4.0-6.0), respectively (mean [SD] scores were 5.0 [1.5], 4.7 [1.7], and 4.6 [1.6], respectively; P = .05). Accuracy scores for binary and descriptive questions were similar (median score, 6.0 [IQR, 4.0-6.0] vs 5.0 [IQR, 3.4-6.0]; mean [SD] score, 4.9 [1.6] vs 4.7 [1.6]; P = .07). Of 36 questions with scores of 1.0 to 2.0, 34 were requeried or regraded 8 to 17 days later with substantial improvement (median score 2.0 [IQR, 1.0-3.0] vs 4.0 [IQR, 2.0-5.3]; P < .01). A subset of questions, regardless of initial scores (version 3.5), were regenerated and rescored using version 4 with improvement (mean accuracy [SD] score, 5.2 [1.5] vs 5.7 [0.8]; median score, 6.0 [IQR, 5.0-6.0] for original and 6.0 [IQR, 6.0-6.0] for rescored; P = .002). Conclusions and Relevance: In this cross-sectional study, chatbot generated largely accurate information to diverse medical queries as judged by academic physician specialists with improvement over time, although it had important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Radiation-Induced Peripheral Neuropathy After Thoracic Stereotactic Ablative Radiotherapy: Case Report.

Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for medically inoperable patients with early stage NSCLC. Because of its noninvasive nature and favorable toxicity profile, the use of SABR continues to expand for eligible patients. We present here two uncommon cases of peripheral neuropathy secondary to SABR-induced injury to recurrent laryngeal and phrenic nerves, resulting in unilateral vocal cord and diaphragmatic paralysis, respectively.

Estimating the Practice-Level and National Cost Burden of Treatment-Related Prior Authorization for Academic Radiation Oncology Practices.

PURPOSE: Prior authorization (PA) imposes significant time burdens on radiation oncology practices, but its financial impact has not been characterized. We used time-driven activity-based costing (TDABC) to assess the cost burden of treatment-related PA events at an academic radiation oncology practice. We then estimated annual costs for an academic practice and academic practices nationally. METHODS AND MATERIALS: Using internal analyses, we created TDABC process maps for treatment-related PA events at an academic radiation oncology practice. Using published compensation data, internal workhour estimates, and supervisory requirements, we calculated the cost of each PA event and annual costs. Using data from the 2017 American Society for Radiation Oncology Workforce Survey and the 2018 American Society for Radiation Oncology Prior Authorization Survey, we estimated annual PA costs for academic medical centers nationally. RESULTS: We successfully created TDABC process maps for treatment-related PA events at an academic radiation oncology practice. There were significant time and cost burdens for all events (range: 51-95 minutes, $28-$101 US dollars [USD]), with significant increases when peer-to-peer discussion was required (range: 92-95 minutes, $75-$101 USD). Annual treatment-related PA departmental costs were estimated to be $491,989 USD, with approved treatments accounting for the majority (94%; $463,027 USD). Nationally, annual treatment-related PA costs were estimated to be $40,125,848 USD, with approved treatments accounting for the majority (86%; $34,632,620 USD). CONCLUSION: TDABC can be used to estimate the cost burden of PA events. These burdens are significant and translate into massive organizational costs. Our national estimates highlight the tremendous cost of PA for academic radiation oncology practices, with the majority of costs related to approved treatments.

The Role of Thoracic Radiation Therapy Dosing in the Treatment of Limited-Stage Small Cell Lung Cancer: A Study Based on the National Cancer Database.

Purpose: Small cell lung cancer (SCLC) is a highly fatal disease, but its treatment has remained relatively unchanged for decades. Randomized clinical trials evaluating radiation therapy (RT) dosing and fractionation have yielded mixed results on overall survival (OS). Methods and Materials: We identified 2261 patients with limited-stage (LS) SCLC undergoing definitive RT at 1.5, 1.8, and 2.0 Gy dose per fraction, concurrently with chemotherapy, between 2004 and 2015 within the National Cancer Database. Overall survival (OS) was evaluated using the Kaplan-Meier method, and Cox proportional hazards regression was used to investigate whether there was any survival difference among patients who received hyperfractionated, twice-daily RT at 1.5 Gy per fraction (HF1.5) and once-daily, standard fractionation RT at 1.8 Gy (SF1.8) or 2.0 Gy (SF2.0) per fraction. Subgroup analyses by age, sex, race, time to RT, facility type, and Charlson comorbidity index were also performed. Results: All stage median OS rates for HF1.5, SF1.8, and SF2.0 Gy groups were 21.6, 18.9, and 19.4 months, respectively (log-rank P = .0079). Multivariate analyses adjusting for demographic factors, socioeconomic status, tumor characteristics, and year of diagnosis showed SF1.8 (hazard ratio [HR] = 1.30, 1.03-1.63) and SF2.0 (HR = 1.20, 1.00-1.45) was associated with worse 1-year survival compared with HF1.5. This association was more evident in stage IIb-stage III than stage I to stage IIa patients. Propensity score-weighted analysis showed similar results. Stratified analyses showed the significant associations were confined to male or black patients, those aged >65 years, with 1 comorbidity, who had waited >60 days to start RT or were treated at an academic medical center. Conclusions: Analyses of real-world treatment outcome data showed that receiving hyperfractionated, twice-daily RT was associated with improved survival among patients with LS-SCLC compared with standard, once-daily fractionation regimens at 1 year after diagnosis, particularly for subsets of patients. Some associations retained statistical significance 3 years postdiagnosis.

Practical demonstration of time bias with administration of adjuvant therapy in lung cancer.

PURPOSE/BACKGROUND: Immortal time bias (ITB) can hinder appropriate interpretations of studies administering adjuvant therapies. Given the increase in National Cancer Data Base (NCDB) analyses evaluating postoperative radiation therapy (PORT) as an adjuvant therapy, we sought to practically demonstrate the effects of ITB by performing a series of simulated NCDB analyses. METHODS: A simulated NCDB analysis was performed to examine how the reported benefit of PORT in stage III non-small cell lung cancer (NSCLC) may change with adjustment for ITB utilizing sequential land mark analysis (SLMA) and time dependent Cox (TDC) modeling. RESULTS: On the simulation analysis of 6440 NSCLC patients, we found that the omission of PORT without ITB adjustment was associated with an increased risk of death (HR 1.17, p < 0.0001). After performing a sequential LMA, the detrmient of omitting PORT continued to decrease until it was no longer significant at 8 months, HR 1.05 (p = 0.09). With the TDC model, although still significant, the relative benefit of PORT decreased, to a HR of 1.07 (p = 0.02). CONCLUSIONS: Immortal time bias can alter the results of survival analyses if not carefully accounted for. Adjusting for this bias is essential for accurate data interpretation and to better quantify the impact and effect size of adjuvant therapies such as PORT.

Application of an automatic, uncertainty model-guided, target-generating algorithm to lung stereotactic body radiotherapy.

PURPOSE: This work evaluated a new radiotherapy target-generating framework (the αTarget algorithm) for creating internal target volumes for lung SBRT. METHODS: Nineteen patients previously treated with definitive intent SBRT to the lung were identified from a clinical database. For each patient's 4DCT simulation scan, deformable image registration was used between phases of the scan in order to generate voxelized models of motion for 35 individual gross tumor volumes. These motion models were then used with a new implementation of a previously described target-generating algorithm to create new internal target volumes (αITVs). The resulting αITVs were analyzed with respect to their volume and the coverage they provided each tumor voxel per that voxel's motion model. The clinically used ITVs were similarly analyzed, and were then compared to the αITVs using paired Student's t-tests. In addition, isotropic margins were added to the αITVs in order to determine the largest margin magnitude that could be added without exceeding the volume of the clinical ITVs. RESULTS: The αITVs increased the target coverage provided to each tumor's 5th-percentile-most-covered-voxel an average of 50.3% compared to the clinical ITVs (p < 0.0001). At the same time, the αITVs had volumes that were, on average, 31.4% smaller (p < 0.0001). The differences in volume were large enough that, on average, an extra 2 mm isotropic margin could be added to the αITV before it had a volume greater than the clinical ITV. CONCLUSIONS: The αTarget algorithm can generate more effective lung SBRT internal target volumes that provide greater coverage with smaller volumes. In combination with numerous other advantages of the framework, this effectiveness makes the αTarget algorithm a powerful new method for advanced IGRT or adaptive radiotherapy techniques.

Monte Carlo study on dose distributions from total skin electron irradiation therapy (TSET).

Total skin electron therapy (TSET) has been used to treat mycosis fungoides since the 1950s. Practitioners of TSET rely on relatively crude, phantom-based point measurements for commissioning and treatment plan dosimetry. Using Monte Carlo simulation techniques, this study presents whole-body dosimetry for a patient receiving rotational, dual-field TSET. The Monte Carlo codes, BEAMnrc/DOSXYZnrc, were used to simulate 6 MeV electron beams to calculate skin dose from TSET. Simulations were validated with experimental measurements. The rotational dual-field technique uses extended source-to-surface distance with an acrylic beam degrader between the patient and incident beams. Simulations incorporated patient positioning: standing on a platform that rotates during radiation delivery. Resultant patient doses were analyzed as a function of skin depth-dose coverage and evaluated using dose-volume-histograms. Good agreement was obtained between simulations and measurements. For a cylinder with a 30 cm diameter, the depths that dose fell to 50% of the surface dose was 0.66 cm, 1.15 cm and 1.42 cm for thicknesses of 9 mm, 3 mm and without an acrylic scatter plate, respectively. The results are insensitive to cylinder diameter. Relatively uniform skin surface dose was obtained for skin in the torso area although large dose variations (>25%) were found in other areas resulting from partial beam shielding of the extremities. To achieve 95% mean dose to the first 5 mm of skin depth, the mean dose to skin depth of 5-10 mm and depth of 10-15 mm from the skin surface was 74% (57%) and 50% (25%) of the prescribed dose when using a 3 mm (9 mm) thickness scatter plate, respectively. As a result of this investigation on patient skin dose distributions we changed our patient treatments to use a 3 mm instead of a 9 mm thickness Acrylic scatter plate for clinically preferred skin depth dose coverage.

Radiation Therapy Adherence Among Patients Experiencing Homelessness.

PURPOSE: Radiation therapy is a valuable, yet time- and resource-intense therapy. Patients experiencing homelessness (PEH) face many barriers related to the timely receipt of radiation therapy. Owing to a paucity of data regarding cancer treatment and homelessness, clinicians have a limited evidence base when recommending therapy to PEH. This study was performed to evaluate adherence to radiation therapy treatment regimens in PEH with cancer. METHODS AND MATERIALS: The study cohort was primarily derived from the Vanderbilt University Medical Center Homeless Health Services program. Patients in the Homeless Health Services program with radiation oncology visits were identified by query of the electronic medical record. Manual chart review was performed to gather standard treatment parameters and data describing missed appointments. A comparison group of patients not experiencing homelessness (non-PEH) was generated by aggregating appointment data for all other patients receiving similar treatments at Vanderbilt University Medical Center during multiple, consecutive years. RESULTS: In the study, 3408 PEH were identified, of whom 48 underwent radiation oncology consultation. Thirty-two were prescribed at least 1 course of radiation therapy, for a total of 54 unique courses. Out of these courses, 34 (62.9%) were completed as prescribed without delay, 12 (22.2%) were completed with delay(s), and 8 (14.8%) were not fully completed. Although the PEH cohort had significantly higher rates of delayed and undelivered fractions, the proportion of delayed or incomplete courses was not significantly different from the comparison group of non-PEH, particularly for courses with 10 or fewer fractions. Reasons for missed appointments for PEH were variable. CONCLUSIONS: This is the first publication describing adherence to radiation therapy in PEH. Our data suggest that PEH are as likely as non-PEH to complete a course of radiation therapy, albeit with more treatment interruptions. When treatment courses of >10 fractions are expected, PEH may benefit from more hypofractionated regimens, provided they have equivalent clinical efficacy to longer regimens. Documenting reasons for missed appointments will be essential to further understanding the needs of PEH. This study serves as a foundation for further analysis regarding homelessness and radiation therapy.

Circulating Tumor DNA as a Biomarker of Radiographic Tumor Burden in SCLC.

INTRODUCTION: Blood-based next-generation sequencing assays of circulating tumor DNA (ctDNA) have the ability to detect tumor-associated mutations in patients with SCLC. We sought to characterize the relationship between ctDNA mean variant allele frequency (VAF) and radiographic total-body tumor volume (TV) in patients with SCLC. METHODS: We identified matched blood draws and computed tomography (CT) or positron emission tomography (PET) scans within a prospective SCLC blood banking cohort. We sequenced plasma using our previously developed 14-gene SCLC-specific ctDNA assay. Three-dimensional TV was determined from PET and CT scans using MIM software and reviewed by radiation oncologists. Univariate association and multivariate regression analyses were performed to evaluate the association between mean VAF and total-body TV. RESULTS: We analyzed 75 matched blood draws and CT or PET scans from 25 unique patients with SCLC. Univariate analysis revealed a positive association between mean VAF and total-body TV (Spearman's ρ = 0.292, p < 0.01), and when considering only treatment-naive and pretreatment patients (n = 11), there was an increase in the magnitude of association (ρ = 0.618, p = 0.048). The relationship remained significant when adjusting for treatment status and bone metastases (p = 0.046). In the subgroup of patients with TP53 variants, univariate analysis revealed a significant association (ρ = 0.762, p = 0.037) only when considering treatment-naive and pretreatment patients (n = 8). CONCLUSIONS: We observed a positive association between mean VAF and total-body TV in patients with SCLC, suggesting mean VAF may represent a dynamic biomarker of tumor burden that could be followed to monitor disease status.

Dosimetric analysis of lymphopenia during chemoradiotherapy for esophageal cancer.

BACKGROUND: Lymphopenia during chemoradiation (CRT) for esophageal cancer (EC) can adversely affect clinical outcomes. We sought to explore an association between lymphopenia and dosimetric parameters during CRT for EC. METHODS: After IRB approval, we retrospectively reviewed 54 patients treated with either definitive or neoadjuvant CRT for EC. Absolute lymphocyte count was recorded weekly during CRT up and graded according to the common terminology of adverse events (CTCAE) version 4.0. Dose volume histograms (DVH) parameters were collected based on vertebral body, body dose, dose to peripheral lymphocytes, and spleen. Logistic regression correlated Grade 4 toxicity with DVH parameters and linear regression analysis correlated absolute lymphocyte nadir counts with DVH parameters. Receiver operator curves (ROC) were constructed to define dosimetric thresholds. RESULTS: There were a total of 21 Grade 4 events (38.8%) of lymphopenia. Increasing vertebral volume receiving ≥10 Gy (OR 1.1, P=0.04), ≥20 Gy (OR 1.1, P=0.03), ≥30 Gy (OR 1.1, P=0.012), or mean body dose (OR 1.04, P=0.032) were correlated with Grade 4 lymphopenia on multivariable logistic regression. The dosimetric parameters most predictive of Grade 4 toxicity via a ROC analysis included absolute vertebral volume receiving 10 Gy >289 cc, 20 Gy ≥270 cc, and vertebral volumes receiving 30 Gy ≥197 cc. On multivariable linear regression increasing volume receiving 20 Gy (Beta -0.004, P=0.001), 30 Gy (Beta -0.005, P=0.0046), and mean body dose (Beta -0.002, P=0.001) all correlated with absolute lymphocyte nadir. CONCLUSIONS: Lymphopenia, a known negative prognostic factor in EC, is closely correlated with the volume of vertebral bodies receiving radiation during CRT for EC. Dosimetric sparing of the vertebral bodies may result in better outcomes.

Immortal Time Bias in National Cancer Database Studies.

PURPOSE: In studies evaluating the benefit of adjuvant therapies, immortal time bias (ITB) can affect the results by incorrectly reporting a survival advantage. It does so by including all deceased patients who may have been planned to receive adjuvant therapy within the observation cohort. Given the increase in National Cancer Database (NCDB) analyses evaluating postoperative radiation therapy (PORT) as an adjuvant therapy, we sought to examine how often such studies accounted and adjusted for ITB. METHODS AND MATERIALS: A systematic review was undertaken to search MEDLINE and EMBASE from January 2014 until May 2019 for NCDB studies evaluating PORT. After appropriate exclusion criteria were applied, 60 peer-reviewed manuscripts in which PORT was compared with postoperative observation or maintenance therapy were reviewed. The manuscripts were reviewed to evaluate whether ITB was accounted for, the method with which it was adjusted for, impact factor, year of publication, and whether PORT was beneficial. RESULTS: Of the 60 publications reviewed, 23 studies (38.3%) did not include an adjustment for ITB. Most studies that did adjust for ITB employed a single landmark (LM) time (n = 31), 4 used a sequential landmark analyses, and 2 used a time-dependent Cox model. In 23 of 31 studies (74.2%) that did adjust for ITB via a single LM time, the rationale behind why the specified LM time was chosen was not clearly explained. There was no relationship between adjusting for ITB and year of publication (P = .074) or whether the study was published in a high-impact journal (P = .55). CONCLUSIONS: Studies assessing adjuvant radiation therapy by analyzing the NCDB are susceptible to ITB, which overestimates the effect size of adjuvant therapies and can provide misleading results. Adjusting for this bias is essential for accurate data representation and to better quantify the impact of adjuvant therapies such as PORT.

Mean cardiopulmonary dose and vertebral marrow dose differentially predict lineage-specific leukopenia kinetics during radiotherapy for esophageal cancer.

BACKGROUND AND PURPOSE: Lymphopenia is associated with poor outcomes in esophageal cancer (EC) patients undergoing chemoradiotherapy (CRT). We hypothesized that radiation dose to marrow (central) vs. circulating (peripheral) leukocytes (WBCs) may have unique effects on WBC counts and clinical outcomes in EC. MATERIALS AND METHODS: Weekly and 90-day post-CRT blood cell counts were evaluated for 46 patients with stage II-III EC treated with CRT. Thoracic vertebral volume spared (TVS) radiation was extracted from dose volume histograms (DVH). Mean cardiopulmonary dose (mCPD) was calculated as mean dose to the volumetric sum of heart, lungs, and great vessels as a surrogate for circulating blood pool. Linear and logistic regression identified associations between dosimetric variables and hematologic toxicities (HT). Repeated measures ANOVA tested associations between cell count trends and clinical predictors. RESULTS: WBCs and platelets reached nadir at week 6 of CRT. On multivariate analysis, mCPD was associated with lower WBC and neutrophil nadirs (p < 0.05). TVS5-40 Gy were associated with higher lymphocyte nadirs (all p < 0.05). Repeated measures ANOVA revealed an interaction effect of sex on absolute lymphocyte trend as well as age (<67 vs. >67) and diabetes on normalized lymphocyte trend (all p < 0.015). CONCLUSIONS: mCPD and volume of thoracic marrow spared radiation differentially predict lineage-specific leukopenias during CRT for EC. mCPD is significantly associated with lower total WBC and neutrophil nadirs. In contrast, greater thoracic marrow spared radiation is associated with mitigation of lymphopenia during CRT. Clinical factors such as sex, age, and diabetes may be associated with a more rapid decline in hematologic counts during treatment.

Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice.

CDC25A phosphatase activates multiple cyclin-dependent kinases (CDK) during cell cycle progression. Inactivation of CDC25A by ubiquitin-mediated degradation is a major mechanism of DNA damage-induced S-G(2) checkpoint. Although increased CDC25A expression has been reported in various human cancer tissues, it remains unclear whether CDC25A activation is a critical rate-limiting step of carcinogenesis. To assess the role for CDC25A in cell cycle control and carcinogenesis, we used a Cdc25A-null mouse strain we recently generated. Whereas Cdc25A(-/-) mice exhibit early embryonic lethality, Cdc25A(+/-) mice show no appreciable developmental defect. Cdc25A(+/-) mouse embryonic fibroblasts (MEF) exhibit normal kinetics of cell cycle progression at early passages, modestly enhanced G(2) checkpoint response to DNA damage, and shortened proliferative life span, compared with wild-type MEFs. Importantly, Cdc25A(+/-) MEFs are significantly resistant to malignant transformation induced by coexpression of H-ras(V12) and a dominant negative p53 mutant. The rate-limiting role for CDC25A in transformation is further supported by decreased transformation efficiency in MCF-10A human mammary epithelial cells stably expressing CDC25A small interfering RNA. Consistently, Cdc25A(+/-) mice show substantially prolonged latency in mammary tumorigenesis induced by MMTV-H-ras or MMTV-neu transgene, whereas MMTV-myc-induced tumorigenesis is not significantly affected by Cdc25A heterozygosity. Mammary tissues of Cdc25A(+/-);MMTV-neu mice before tumor development display less proliferative response to the oncogene with increased tyrosine phosphorylation of CDK1/2, but show no significant change in apoptosis. These results suggest that Cdc25A plays a rate-limiting role in transformation and tumor initiation mediated by ras activation.

Stereotactic body radiotherapy versus conventional radiotherapy for early-stage small cell lung cancer.

PURPOSE: This study was designed to compare survival outcomes for non-surgically managed T1-T2N0M0 small cell lung cancer (SCLC) who received either stereotactic body radiation therapy (SBRT) or conventionally fractionated radiotherapy (CFRT) using the National Cancer Data Base (NCDB). METHODS: The was queried between 2004-2015 for patients with T1-T2N0M0 SCLC. Patients must have been treated with curative intent SBRT or CFRT (delivered daily or twice daily, 45-70 Gy) with or without chemotherapy. The primary outcome was overall survival (OS). A subset analysis of patient receiving chemotherapy was also performed. A propensity score matched (PSM) analysis was performed to compare OS among patients who received chemotherapy. RESULTS: We evaluated 1378 patients in the general cohort. Multivariable Cox regression analysis(MVA) in the general cohort revealed that SBRT was significantly associated with improved survival (HR 0.68, p<0.001) along with receipt of chemotherapy (HR 0.63, p <0.001). SBRT patients were less likely to receive chemotherapy compared to CFRT patients (p<0.01). In the chemotherapy subset, of 1096 patients, on MVA, there was a trend in favor of the SBRT group (HR 0.73; p=0.06). A 3:1 PSM analysis on the chemotherapy subset found similar results on MVA with a trend in favor of SBRT (p=0.06). CONCLUSION: Patients with T1-2N0M0 SCLC treated with SBRT regimens incorporating chemotherapy had comparable outcomes to concurrent chemoradiotherapy using standard fractionation. Treatment paradigms for T1-2N0M0 SCLC incorporating SBRT warrant further exploration and should incorporate chemotherapy.

Before or After: Evolving Neoadjuvant Approaches to Locally Advanced Non-Small Cell Lung Cancer.

The treatment of patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) is one of the most challenging and controversial areas of thoracic oncology. This heterogeneous group is characterized by varying tumor size and location, the potential for involvement of surrounding structures, and ipsilateral mediastinal lymph node spread. Neoadjuvant chemotherapy, administered prior to definitive local therapy, has been found to improve survival in patients with stage IIIA (N2) NSCLC. Concurrent chemoradiation has also been evaluated in phase III studies in efforts to improve control of locoregional disease. In certain instances, a tri-modality approach involving concurrent chemoradiation followed by surgery, may offer patients the best chance for cure. In this article, we provide an overview of the trials evaluating neoadjuvant therapy in patients with stage IIIA (N2) NSCLC that have resulted in current practice strategies, and we highlight the areas of uncertainty in the management of this challenging disease. We also review the current ongoing research and future directions in the management of stage IIIA (N2) NSCLC.