Clinical factors associated with mortality within three months after radiosurgery of asymptomatic brain metastases from non-small cell lung cancer.

PURPOSE: Routine brain MRI surveillance frequently diagnoses small, asymptomatic brain metastases from non-small cell lung cancer (NSCLC) that are effectively treated with stereotactic radiosurgery (SRS). A subset of patients, however, may die prior to the onset of symptoms. This study identifies clinical features that distinguish neurologically-asymptomatic NSCLC brain metastases patients that die prior to routine 3 month follow-up after SRS. METHODS: Retrospective chart review from 2007 to 2017 identified 18 patients with neurologically-asymptomatic NSCLC brain metastases who died < 3 months after SRS. Twenty-eight additional patients meeting criteria and surviving > 6 months after SRS were identified. Clinical factors were examined to determine characteristics correlated with survival using cox proportional hazards and nominal logistic regression models. Logistic regression models using salient factors were trained with 10-fold cross-validation and compared to the graded prognostic assessment (GPA) and score index of radiosurgery (SIR) using the AUC from receiver operant characteristic curves. RESULTS: The median survival following SRS was 1.4 and 9.2 months for the < 3 months and > 6 months groups, respectively. Age, number of brain metastases, and Karnofsky performance status were associated with overall survival while gender and interval between primary cancer and first brain metastasis diagnoses were associated with < 3 months and > 6 months survival, respectively. Models using GPA and SIR performed poorly compared to preliminary metrics generated in this study for prognosis of both < 3 months and > 6 months survival. CONCLUSION: Physicians require data to provide high-value, cost-conscious health care. Clinical metrics can screen patients with asymptomatic NSCLC brain metastases likely to die prior to the standard screening interval and observation could be considered.

Feasibility of optimizing intensity-modulated radiation therapy plans based on measured mucosal dose adjacent to dental fillings and toxicity outcomes.

We prospectively investigated the feasibility of IMRT treatment plan optimization based on dosimeter measurements of lateral tongue mucosal dose adjacent to the dental fillings and evaluated dose-toxicity relationship and factors affecting oral mucositis (OM) in head and neck cancer patients. Twenty-nine head and neck cancer patients with metallic dental fillings who were scheduled to undergo fractionated external beam radiation therapy (RT) ± chemotherapy were enrolled. The lateral tongue dose was measured and if the calculated dose for the entire treatment was ≥35 Gy, a re-plan was generated to reduce the lateral tongue mucosal dose. OM was graded weekly according to Common Terminology Criteria for Adverse Events version 4.0 and the patients completed the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer. The result showed that it was not feasible to optimize the IMRT plan based on measured tongue dose in most of the patients who needed re-plan as re-planning compromised the target coverage in 60% of these patients. The duration of grade (Gr) 2 OM was correlated with measured lateral tongue dose (P = 0.050). Concurrent cetuximab was significantly associated with faster onset of Gr2 OM than concurrent cisplatin (P = 0.006) and with longer duration of OM (P = 0.041) compared to concurrent cisplatin or IMRT-alone. The pattern of reported pain over time was significantly different for each treatment type (RT and cetuximab, RT and cisplatin and RT-alone) and depending on the dose level (P = 0.006). In conclusion, optimizing the IMRT plan based on measured lateral tongue dose was not feasible. Measured lateral tongue dose was significantly correlated with longer duration of OM ≥Gr2, and concurrent cetuximab was associated with earlier onset and longer duration of OM ≥Gr2.

The long-term prognostic value of the Q wave criteria for prior myocardial infarction recommended in the universal definition of myocardial infarction.

BACKGROUND: We sought to characterize the prognostic value of the third universal definition of myocardial infarction (UDMI) and ≥40msec Q wave criteria. METHODS: We evaluated hazard ratios (HR) with 95% confidence intervals (CI) for cardiovascular (CV) death for computerized Q wave measurements from the electrocardiograms of 43,661 patients collected from 1987 to 1999 at the Palo Alto VA. There were 3929 (9.0%) CV deaths over a mean follow-up of 7.6 (±3.8) years. RESULTS: The risk of CV death for Q waves ≥40msec in any two contiguous leads in any lead group was equivalent to or higher than that for contiguous UDMI Q waves, with HR 2.44 (95% CI 2.15-4.11) and HR 2.42 (95% CI (2.18-3.42), respectively. CONCLUSIONS: The UDMI Q wave criteria do not provide an advantage over ≥40msec Q waves at predicting CV death.

Are the QRS duration and ST depression cut-points from the Seattle criteria too conservative?

BACKGROUND: Screening athletes with ECGs is aimed at identifying "at-risk" individuals who may have a cardiac condition predisposing them to sudden cardiac death. The Seattle criteria highlight QRS duration greater than 140 ms and ST segment depression in two or more leads greater than 50 µV as two abnormal ECG patterns associated with sudden cardiac death. METHODS: High school, college, and professional athletes underwent 12 lead ECGs as part of routine pre-participation physicals. Prevalence of prolonged QRS duration was measured using cut-points of 120, 125, 130, and 140 ms. ST segment depression was measured in all leads except leads III, aVR, and V1 with cut-points of 25 µV and 50 µV. RESULTS: Between June 2010 and November 2013, 1595 participants including 297 (167 male, mean age 16.2) high school athletes, 1016 (541 male, mean age 18.8) college athletes, and 282 (mean age 26.6) male professional athletes underwent screening with an ECG. Only 3 athletes (0.2%) had a QRS duration greater than 125 ms. ST segment depression in two or more leads greater than 50 µV was uncommon (0.8%), while the prevalence of ST segment depression in two or more leads increased to 4.5% with a cut-point of 25 µV. CONCLUSION: Changing the QRS duration cut-point to 125 ms would increase the sensitivity of the screening ECG, without a significant increase in false-positives. However, changing the ST segment depression cut-point to 25 µV would lead to a significant increase in false-positives and would therefore not be justified.

Limitations of Current AHA Guidelines and Proposal of New Guidelines for the Preparticipation Examination of Athletes.

OBJECTIVE: To examine the prevalence of athletes who screen positive with the preparticipation examination guidelines from the American Heart Association, the AHA 12-elements, in combination with 3 screening electrocardiogram (ECG) criteria. DESIGN: Observational cross-sectional study. SETTING: Stanford University Sports Medicine Clinic. PARTICIPANTS: Total of 1596 participants, including 297 (167 male; mean age, 16.2 years) high school athletes, 1016 (541 male; mean age, 18.8 years) collegiate athletes, and 283 (mean age, 26.3 years) male professional athletes. MAIN OUTCOME MEASURES: Athletes were screened using the 8 personal and family history questions from the AHA 12-elements. Electrocardiograms were obtained for all participants and interpreted using Seattle criteria, Stanford criteria, and European Society of Cardiology (ESC) recommendations. RESULTS: Approximately one-quarter of all athletes (23.8%) had at least 1 positive response to the AHA personal and family history elements. High school and college athletes had similar rates of having at least 1 positive response (25.9% vs 27.4%), whereas professional athletes had a significantly lower rate of having at least 1 positive response (8.8%, P < 0.05). Females reported more episodes of unexplained syncope (11.4% vs 7.5%, P = 0.017) and excessive exertional dyspnea with exercise (11.1% vs 6.1%, P = 0.001) than males. High school athletes had more positive responses to the family history elements when compared with college athletes (P < 0.05). The percentage of athletes who had an abnormal ECG varied between Seattle criteria (6.0%), Stanford criteria (8.8%), and ESC recommendations (26.8%). CONCLUSIONS: Many athletes screen positive under current screening recommendations, and ECG results vary widely by interpretation criteria. CLINICAL RELEVANCE: In a patient population without any adverse cardiovascular events, the currently recommended AHA 12-elements have an unacceptably high rate of false positives. Newer screening guidelines are needed, with fewer false positives and evidence-based updates.

Patterns and prognosis of all components of the J-wave pattern in multiethnic athletes and ambulatory patients.

BACKGROUND: Despite recent concern about the significance of the J-wave pattern (also often referred to as early repolarization) and the importance of screening in athletes, there are limited rigorous prognostic data characterizing the 3 components of the J-wave pattern (ST elevation, J waves, and QRS slurs). We aim to assess the prevalence, patterns, and prognosis of the J-wave pattern among both stable clinical and athlete populations. METHODS: We retrospectively studied 4,041 electrocardiograms from a multiethnic clinical population from 1997 to 1999 at the Veterans Affairs Palo Alto Health Care System. We also examined preparticipation electrocardiograms of 1,114 Stanford University varsity athletes from 2007 to 2008. Strictly defined criteria for components of the J-wave pattern were examined. In clinical subjects, prognosis was assessed using the end point of cardiovascular death after 7 years of follow-up. RESULTS: Components of the J-wave pattern were most prevalent in males; African Americans; and, particularly, athletes, with the greatest variations demonstrated in the lateral leads. ST elevation was the most common. Inferior J waves and slurs, previously linked to cardiovascular risk, were observed in 9.6% of clinical subjects and 12.3% of athletes. J waves, slurs, or ST elevation was not associated with time to cardiovascular death in clinical subjects, and ST-segment slope abnormalities were not prevalent enough in conjunction with them to reach significance. CONCLUSIONS: J waves, slurs, or ST elevation was not associated with increased hazard of cardiovascular death in our large multiethnic, ambulatory population. Even subsets of J-wave patterns, recently proposed to pose a risk of arrhythmic death, occurred at such a high prevalence as to negate their utility in screening.

Resting ST amplitude: prognosis and normal values in an ambulatory clinical population.

BACKGROUND: There is limited data describing ST segment amplitude in apparently healthy, asymptomatic populations. We analyzed ST amplitude in the standard resting electrocardiogram (ECG) in a large, multiethnic, stable, clinical population. METHODS: We evaluated computerized ST amplitude measurements from the resting ECGs of 29,281 ambulatory outpatients collected between 1987 and 1999 at the Palo Alto, VA. With the PR interval as the isoelectric line, both elevation criteria (≥0.1 mV, ≥0.15 mV, and ≥0.2 mV) and depression criteria (≤-0.05 mV or ≤-0.1 mV), were applied. Cox-Hazard survival analysis techniques were used to demonstrate in which leads ST amplitude displacement was associated with cardiovascular (CV) death. To create a cohort without ECG patterns clearly associated with disease, we excluded ECGs with inverted T waves, wide QRS, or diagnostic Q waves and coded the remaining "normal" ECGs for ST elevation and depression to determine a normal range. RESULTS: The only ST amplitudes that were significantly and independently associated with time to CV death when adjusted for age, gender, and ethnicity were ST depression in all of the lateral leads (I, V4 -V6 ). When isolated to the inferior leads, (II and AVF), no ST amplitude criteria were associated with CV death. Among the "normal ECG" subgroup the precordial leads exhibited the greatest median ST amplitudes and the most significant differences between the leads, genders and ethnicities. CONCLUSIONS: Significant differences in ST amplitude were present in the precordial leads according to gender and ethnicity. This was particularly apparent when amplitude threshold were set for comparisons. Our findings provide the normal range for ST amplitude that when exceeded, should raise clinical concern.

Spectrum of ST amplitude: athletes and an ambulatory clinical population.

BACKGROUND AND PURPOSE: To augment data guiding thresholds for myocardial ischemia and cardiac risk, we studied resting ST amplitude in ambulatory patients and collegiate athletes. METHODS: We analyzed 4041 ECGs from ambulatory visits at the Veterans Affairs in Palo Alto, California from 1997 to 1999 and 1114 screening ECGs from Stanford University athletes in 2007-2008. Using the PR interval as the isoelectric line and >95µV and<-45µV (visually equivalent to 1mm and 0.5mm) to define ST elevation and depression, ST amplitude was measured at QRS-end. RESULTS: ST elevation was most prevalent in males, African Americans, and athletes (87% of male athletes in anterior leads). ST depression was rare in athletes and, among patients, associated with time to cardiovascular death in lateral leads (age-adjusted HR of 1.9, p<0.001). CONCLUSIONS: ST amplitude differs by gender, age, race, and athletic status, which should be considered when developing guidelines for ECG interpretation.

Automated model versus treating physician for predicting survival time of patients with metastatic cancer.

OBJECTIVE: Being able to predict a patient's life expectancy can help doctors and patients prioritize treatments and supportive care. For predicting life expectancy, physicians have been shown to outperform traditional models that use only a few predictor variables. It is possible that a machine learning model that uses many predictor variables and diverse data sources from the electronic medical record can improve on physicians' performance. For patients with metastatic cancer, we compared accuracy of life expectancy predictions by the treating physician, a machine learning model, and a traditional model. MATERIALS AND METHODS: A machine learning model was trained using 14 600 metastatic cancer patients' data to predict each patient's distribution of survival time. Data sources included note text, laboratory values, and vital signs. From 2015-2016, 899 patients receiving radiotherapy for metastatic cancer were enrolled in a study in which their radiation oncologist estimated life expectancy. Survival predictions were also made by the machine learning model and a traditional model using only performance status. Performance was assessed with area under the curve for 1-year survival and calibration plots. RESULTS: The radiotherapy study included 1190 treatment courses in 899 patients. A total of 879 treatment courses in 685 patients were included in this analysis. Median overall survival was 11.7 months. Physicians, machine learning model, and traditional model had area under the curve for 1-year survival of 0.72 (95% CI 0.63-0.81), 0.77 (0.73-0.81), and 0.68 (0.65-0.71), respectively. CONCLUSIONS: The machine learning model's predictions were more accurate than those of the treating physician or a traditional model.

The role of Glial cell derived neurotrophic factor in head and neck cancer.

Glial cell-derived neurotrophic factor (GDNF) is reported to promote the survival of neurons and salivary gland regeneration after radiation damage. This study investigated the effect of GDNF on cell migration, growth, and response to radiation in preclinical models of head and neck squamous cell carcinoma (HNSCC) and correlated GDNF expression to treatment outcomes in HNSCC patients. Our ultimate goal is to determine whether systemic administration of GDNF at high dose is safe for the management of hyposalivation or xerostomia in HNSCC patients. Three HPV-positive and three HPV-negative cell lines were examined for cell migration, growth, and clonogenic survival in vitro and tumor growth assay in vivo. Immunohistochemical staining of GDNF, its receptors GFRα1 and its co-receptor RET was performed on two independent HNSCC tissue microarrays (TMA) and correlated to treatment outcomes. Results showed that GDNF only enhanced cell migration in two HPV-positive cells at supra-physiologic doses, but not in HPV-negative cells. GDNF did not increase cell survival in the tested cell lines post-irradiation. Likewise, GDNF treatment affected neither tumor growth in vitro nor response to radiation in xenografts in two HPV-positive and two HPV-negative HNSCC models. High stromal expression of GDNF protein was associated with worse overall survival in HPV-negative HNSCC on multivariate analysis in a combined cohort of patients from Stanford University (n = 82) and Washington University (n = 189); however, the association between GDNF gene expression and worse survival was not confirmed in a separate group of HPV-negative HNSCC patients identified from the Cancer Genome Atlas (TCGA) database. Based on these data, we do not believe that GNDF is a safe systemic treatment to prevent or treat xerostomia in HNSCC and a local delivery approach such as intraglandular injection needs to be explored.

Predicting Survival for Patients With Metastatic Disease.

PURPOSE: This prospective study aimed to determine the accuracy of radiation oncologists in predicting the survival of patients with metastatic disease receiving radiation therapy and to understand factors associated with their accuracy. METHODS AND MATERIALS: This single-institution study surveyed 22 attending radiation oncologists to estimate patient survival. Survival predictions were defined as accurate if the observed survival (OS) was within the correct survival prediction category (0-6 months, >6-12 months, >12-24 months, and >24 months). The physicians made survival estimates for each course of radiation, yielding 877 analyzable predictions for 689 unique patients. Data analysis included Stuart's Tau C, logistic regression models, ordinal logistic regression models, and stepwise selection to examine variable interactions. RESULTS: Of the 877 radiation oncologists' predictions, 39.7% were accurate, 26.5% were underestimations, and 33.9% were overestimations. Stuart's Tau C showed low correlation between OS and survival estimates (0.3499), consistent with the inaccuracy reported in the literature. However, results showed less systematic overprediction than reported in the literature. Karnofsky performance status was the most significant predictor of accuracy, with greater accuracy for patients with shorter OS. Estimates were also more accurate for patients with lower Karnofsky performance status. Accuracy by patient age varied by primary site and race. Physician years of experience did not correlate with accuracy. CONCLUSIONS: The sampled radiation oncologists have a 40% accuracy in predicting patient survival. Future investigation should explore how survival estimates influence treatment decisions and how to improve survival prediction accuracy.

Impact of Accuracy of Survival Predictions on Quality of End-of-Life Care Among Patients With Metastatic Cancer Who Receive Radiation Therapy.

PURPOSE:: For patients treated with palliative radiation, we examined the association between life expectancy predictions by radiation oncologists and aggressive end-of-life care. MATERIALS AND METHODS:: We included decedents from a study that assessed the ability of oncologists to predict survival of patients with metastatic cancer who received radiation. We identified patients who died within 12 months of study enrollment to assess accuracy of predictions. Aggressive end-of-life care was defined by the National Quality Forum, ASCO Quality Oncology Practice Initiative metrics, and advanced radiation modalities in the last month of life. Survival predictions were categorized as follows: correct (< 12 months), 12 to 18 months, 18 to 24 months, and more than 24 months. We assessed association between prediction and aggressive end-of-life care using a generalized estimation equation. RESULTS:: Of 489 decedents, we identified 467 encounters with survival estimates. Overall, 156 decedents (32%) met at least one metric of aggressive end-of-life care. Factors associated with aggressive end-of-life care included younger age, female sex, primary cancer diagnosis, no brain metastases, and private insurance. In each encounter when an oncologist predicted survival, 363 predictions (78%) were correct (< 12 months), 54 (11%) incorrectly predicted 12 to 18 months, 27 (6%) predicted 18 to 24 months, and 23 (5%) predicted more than 24 months. Compared with patients who had encounters that had correct survival predictions, patients predicted to live more than 24 months were more likely to meet at least one metric of aggressive end-of-life care (odds ratio, 2.55; 95% CI, 1.09 to 5.99; P = .03). CONCLUSION:: Inaccurate survival predictions by oncologists are associated with more aggressive end-of-life care for patients with advanced cancer.

Increases in Serial Pretreatment 18F-FDG PET-CT Metrics Predict Survival in Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy.

PURPOSE: Quantitative changes in positron emission tomography with computed tomography imaging metrics over serial scans may be predictive biomarkers. We evaluated the relationship of pretreatment metabolic tumor growth rate (MTGR) and standardized uptake value velocity (SUVV) with disease recurrence or death in patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS: Under institutional review board approval, we retrospectively identified patients who underwent positron emission tomography with computed tomography at diagnosis and staging and simulation for SABR. Two cohorts underwent SABR between November 2005 to October 2012 (discovery) and January 2012 to April 2016 (validation). MTGR and SUVV were calculated as the daily change in metabolic tumor volume and maximum standardized uptake value, respectively. Cox proportional hazard models identified predictors of local, regional, and distant recurrence and death for the combined cohort. MTGR and SUVV thresholds dichotomizing risk of death in the discovery cohort were applied to the validation cohort. RESULTS: A total of 152 lesions were identified in 143 patients (92 lesions in 83 discovery cohort patients). In multivariable models, increasing MTGR trended toward increased hazard of distant recurrence (hazard ratio, 6.98; 95% confidence interval, 0.67-72.61; P = .10). In univariable models, SUVV trended toward risk of death (hazard ratio, 11.8, 95% confidence interval, 0.85-165.1, P = .07). MTGR greater than 0.04 mL/d was prognostic of decreased survival in discovery (P = .048) and validation cohorts (P < .01). CONCLUSIONS: MTGR greater than 0.04 mL/d is prognostic of death in patients with non-small cell lung cancer treated with SABR. Increasing SUVV trends, nonsignificantly, toward increased risk of recurrence and death. MTGR and SUVV may be candidate imaging biomarkers to study in trials evaluating systemic therapy with SABR for patients at high risk of out-of-field recurrence.

Automated Survival Prediction in Metastatic Cancer Patients Using High-Dimensional Electronic Medical Record Data.

BACKGROUND: Oncologists use patients' life expectancy to guide decisions and may benefit from a tool that accurately predicts prognosis. Existing prognostic models generally use only a few predictor variables. We used an electronic medical record dataset to train a prognostic model for patients with metastatic cancer. METHODS: The model was trained and tested using 12 588 patients treated for metastatic cancer in the Stanford Health Care system from 2008 to 2017. Data sources included provider note text, labs, vital signs, procedures, medication orders, and diagnosis codes. Patients were divided randomly into a training set used to fit the model coefficients and a test set used to evaluate model performance (80%/20% split). A regularized Cox model with 4126 predictor variables was used. A landmarking approach was used due to the multiple observations per patient, with t0 set to the time of metastatic cancer diagnosis. Performance was also evaluated using 399 palliative radiation courses in test set patients. RESULTS: The C-index for overall survival was 0.786 in the test set (averaged across landmark times). For palliative radiation courses, the C-index was 0.745 (95% confidence interval [CI] = 0.715 to 0.775) compared with 0.635 (95% CI = 0.601 to 0.669) for a published model using performance status, primary tumor site, and treated site (two-sided P < .001). Our model's predictions were well-calibrated. CONCLUSIONS: The model showed high predictive performance, which will need to be validated using external data. Because it is fully automated, the model can be used to examine providers' practice patterns and could be deployed in a decision support tool to help improve quality of care.

The role of bone marrow and spleen irradiation in the development of acute hematologic toxicity during chemoradiation for esophageal cancer.

PURPOSE: The purpose of this study was to determine the impact of splenic and thoracic bone marrow irradiation on hematologic toxicity in the setting of chemoradiation therapy for esophageal cancer. METHODS AND MATERIALS: We analyzed 60 patients with carcinoma of the distal esophagus or gastroesophageal junction who received concurrent chemoradiation in the preoperative or definitive setting. Dosimetric and volumetric parameters were calculated for the spleen, thoracic spine, and posterior ribs. The primary endpoint was grade ≥3 hematologic toxicity (HT3+). Associations were assessed using logistic and linear regression models. RESULTS: Twenty-one patients (35%) experienced HT3+, including 18 patients with leukopenia and 5 with thrombocytopenia. Higher spleen V5-V20 was correlated with a lower risk of HT3+ on multivariable analysis (odds ratio: 0.83 per 10 cm3 increase in V10; P = .013). A dose-dependent decrease in spleen volume was observed after radiation therapy, and a greater decrease was independently associated with a lower risk of HT3+ (odds ratio: 0.93 per 1% volume decrease; P = .014). Dosimetric parameters of the thoracic spine were not significantly associated with HT3+. CONCLUSIONS: A greater decrease in spleen size after radiation therapy and a higher spleen V5-V20 were independently associated with a lower risk of severe hematologic toxicity. Splenic irradiation may mitigate leukopenia associated with chemoradiation therapy.

Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) Utilizing Free-Text Clinical Narratives.

We propose a deep learning model - Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) for estimating short-term life expectancy (>3 months) of the patients by analyzing free-text clinical notes in the electronic medical record, while maintaining the temporal visit sequence. In a single framework, we integrated semantic data mapping and neural embedding technique to produce a text processing method that extracts relevant information from heterogeneous types of clinical notes in an unsupervised manner, and we designed a recurrent neural network to model the temporal dependency of the patient visits. The model was trained on a large dataset (10,293 patients) and validated on a separated dataset (1818 patients). Our method achieved an area under the ROC curve (AUC) of 0.89. To provide explain-ability, we developed an interactive graphical tool that may improve physician understanding of the basis for the model's predictions. The high accuracy and explain-ability of the PPES-Met model may enable our model to be used as a decision support tool to personalize metastatic cancer treatment and provide valuable assistance to the physicians.

Albumin and Neutrophil-Lymphocyte Ratio (NLR) Predict Survival in Patients With Pancreatic Adenocarcinoma Treated With SBRT.

PURPOSE: To determine if pretreatment nutritional status and inflammatory markers correlate with survival in patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: We retrospectively reviewed 208 patients with newly diagnosed, locally advanced pancreatic adenocarcinoma treated with SBRT at our institution from 2002 to 2014. Laboratory values were collected before SBRT, including hemoglobin, platelets, albumin, red blood cell, white blood cell, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and tumor markers CA 19-9 and CEA. Patients were followed every 3 months with computed tomography (CT) and/or positron emission tomography-CT imaging to monitor for local recurrence and overall survival (OS). RESULTS: Median follow-up after SBRT was 7.5 months (interquartile range, 4.6 to 12.0 mo) for all patients. Median OS for patients with NLR>5 compared with NLR≤5 was 6.9 and 8.5 months, respectively (P=0.0057). On univariate analysis, receipt of chemotherapy (P=0.05, hazard ratio [HR]=0.69), increased albumin (P=0.002, HR=0.64), increased red blood cell (P=0.05, HR=0.75), increased lymphocyte count (P=0.002, HR=0.66), decreased CEA (P=0.01, HR=0.96), and NLR≤5 (P=0.01, HR=0.65) correlated with improved OS. On multivariate analysis, higher albumin (P=0.03, HR=0.70), receipt of chemotherapy (P=0.007, HR=0.56), and NLR≤5 (P=0.02, HR=0.66) correlated with better survival. CONCLUSIONS: Preradiotherapy low albumin levels and NLR>5 correlate with decreased survival in patients with locally advanced pancreatic adenocarcinoma treated with SBRT, indicating the prognostic value of systemic inflammatory markers (such as NLR) and a role of nutritional supplementation to improve outcomes in these patients. Further investigation is warranted.

Improved Metastasis- and Disease-Free Survival With Preoperative Sequential Short-Course Radiation Therapy and FOLFOX Chemotherapy for Rectal Cancer Compared With Neoadjuvant Long-Course Chemoradiotherapy: Results of a Matched Pair Analysis.

PURPOSE: To compare treatment and toxicity outcomes between a phase 2 institutional trial of near total neoadjuvant therapy (nTNT) for locally advanced rectal cancer and a similar historical control cohort treated at Washington University in St. Louis with the current US standard of care, defined as neoadjuvant chemoradiotherapy (NCRT), total mesorectal excision (TME), and adjuvant FOLFOX chemotherapy; to expand the comparison to an additional institution, patients treated with similar NCRT at Stanford University were included. METHODS AND MATERIALS: Sixty-nine patients with cT3-4N0-2M0 rectal adenocarcinoma enrolled on the Washington University in St. Louis phase 2 study of nTNT were included for analysis. Patients treated at the same institution with conventional NCRT and adjuvant FOLFOX were matched for exact cTNM stage. Forty-one patients treated with NCRT at Stanford University were included in a second analysis. Kaplan-Meier analysis with log-rank test was used to compare local control, distant metastasis-free survival, disease-free survival, and overall survival. RESULTS: Median follow-up was 49 and 54 months for nTNT and NCRT, respectively. Pathologic complete response and T-downstaging rates were 28% versus 16% (P=.21) and 75% versus 41% (P<.001) in the nTNT and NCRT cohorts, respectively. Three-year disease-free survival (85% vs 68%, P=.032) was significantly better in the nTNT group. Actuarial 3-year local control (92% vs 96%, P=.36) and overall survival (96% vs 88%, P=.67) were similar. The Stanford cohort had significantly lower clinical stage. After controlling for clinical stage, age, tumor location, institution, and number of chemotherapy cycles, nTNT treatment remained significantly associated with lower risk of recurrence (P=.006). CONCLUSIONS: Patients treated with nTNT had higher T-downstaging and superior distant metastasis-free survival and disease-free survival compared with conventional NCRT when matched for tumor location and exact cTNM stage. Near total neoadjuvant therapy remained a significant multivariate predictor for improved outcome when including patients treated with NCRT at another institution.

Hematologic Nadirs During Chemoradiation for Anal Cancer: Temporal Characterization and Dosimetric Predictors.

PURPOSE: Pelvic bone marrow (BM) constraints may offer a means to reduce the toxicity commonly associated with chemoradiation for anal cancer. We conducted a bi-institutional analysis of dose-volume metrics in a time-sensitive fashion to devise practical metrics to minimize hematologic toxicity. METHODS AND MATERIALS: Fifty-six anal cancer patients from 2 institutions received definitive radiation therapy (median primary dose of 54 Gy) using intensity modulated radiation therapy (IMRT, n=49) or 3-dimensional (3D) conformal therapy (n=7) with concurrent 5-fluorouracil (5-FU) and mitomycin C. Weekly blood counts were retrospectively plotted to characterize the time course of cytopenias. Dose-volume parameters were correlated with blood counts at a standardized time point to identify predictors of initial blood count nadirs. RESULTS: Leukocytes, neutrophils, and platelets reached a nadir at week 3 of treatment. Smaller volumes of the pelvic BM correlated most strongly with lower week 3 blood counts, more so than age, sex, body mass index (BMI), or dose metrics. Patients who had ≥750 cc of pelvic BM spared from doses of ≥30 Gy had 0% grade 3+ leukopenia or neutropenia at week 3. Higher V40 Gy to the lower pelvic BM (LP V40) also correlated with cytopenia. Patients with an LP V40 >23% had higher rates of grade 3+ leukopenia (29% vs 4%, P=.02), grade 3+ neutropenia (33% vs 8%, P=.04), and grade 2+ thrombocytopenia (32% vs 7%, P=.04) at week 3. On multivariate analysis, pelvic BM volume and LP V40 remained associated with leukocyte count, and all marrow subsite volumes remained associated with neutrophil counts at week 3 (P<.1). CONCLUSIONS: Larger pelvic BM volumes correlate with less severe leukocyte and neutrophil nadirs, suggesting that larger total "marrow reserve" can mitigate cytopenias. Sparing a critical marrow reserve and limiting the V40 Gy to the lower pelvis may reduce the risk of hematologic toxicity.

Severe Chest Wall Toxicity From Cryoablation in the Setting of Prior Stereotactic Ablative Radiotherapy.

We present the case of a 42-year-old woman with metastatic synovial sarcoma of parotid origin, treated definitively with chemoradiation, who subsequently developed oligometastatic disease limited to the lungs. She underwent multiple left and right lung wedge resections and left lower lobectomy, followed by right lower lobe stereotactic ablative radiotherapy (SABR), 54 Gy in three fractions to a right lower lobe lesion abutting the chest wall. Two years later, she was treated with cryoablation for a separate right upper lobe nodule abutting the chest wall. Two months later, she presented with acute shortness of breath, pleuritic chest pain, decreased peripheral blood O2 saturation, and productive cough. A computed tomography (CT) scan demonstrated severe chest wall necrosis in the area of recent cryoablation that, in retrospect, also received a significant radiation dose from her prior SABR. This case demonstrates that clinicians should exercise caution in using cryoablation when treating lung tumors abutting a previously irradiated chest wall. Note: Drs. Loo and Shah contributed equally as co-senior authors.