Declarations of Independence: How Embedded Multicollinearity Errors Affect Dosimetric and Other Complex Analyses in Radiation Oncology.

The statistical technique of multiple regression, commonly referred to as "multivariable regression," is often used in clinical research to quantify the relationships between multiple predictor variables and a single outcome variable of interest. The foundational theory underpinning multivariable regression assumes that all predictor variables are independent of one another. In other words, the effect of each independent variable is measured by its contribution to the regression equation while all other variables remain unchanged. In the presence of correlations between two or more variables, however, it is impossible to change one variable without a consequent change in the variable(s) it is linked to. This condition, known as "multicollinearity," can introduce errors into multivariable regression models by affecting estimates of the regression coefficients that quantify the relationship between individual predictor variables and the outcome variable. Errors that arise due to violations of the multicollinearity assumption are of special interest to radiation oncology researchers. Because of high levels of correlation among variables derived from points along individual organ dose-volume histogram (DVH) curves, as well as strong intercorrelations among dose-volume parameters in neighboring organs, dosimetric analyses are particularly subject to multicollinearity errors. For example, dose-volume parameters for the heart are strongly correlated not only with other points along the heart DVH curve but are likely also correlated with dose-volume parameters in neighboring organs such as the lung. In this paper, we describe the problem of multicollinearity in accessible terms and discuss examples of violations of the multicollinearity assumption within the radiation oncology literature. Finally, we provide recommendations regarding best practices for identifying and managing multicollinearity in complex data sets.

Evaluation of Adjuvant Chemotherapy Survival Outcomes Among Patients With Surgically Resected Pancreatic Carcinoma With Node-Negative Disease After Neoadjuvant Therapy.

Importance: Neoadjuvant therapy (NAT) is rarely associated with a complete histopathologic response in patients with pancreatic ductal adenocarcinoma (PDAC) but results in downstaging of regional nodal disease. Such nodal downstaging after NAT may have implications for the use of additional adjuvant therapy (AT). Objectives: To examine the prognostic implications of AT in patients with node-negative (N0) disease after NAT and to identify factors associated with progression-free (PFS) and overall survival (OS). Design, Setting, and Participants: A retrospective review was conducted using data from 2 high-volume, tertiary care academic centers (University of Pittsburgh Medical Center and the Medical College of Wisconsin). Prospectively maintained pancreatic cancer databases at both institutes were searched to identify patients with localized PDAC treated with preoperative therapy and subsequent surgical resection between 2010 and 2019, with N0 disease on final histopathology. Exposures: Patients received NAT consisting of chemotherapy with or without concomitant neoadjuvant radiation (NART). For patients who received NART, chemotherapy regimens were gemcitabine or 5-fluoururacil based and included stereotactic body radiotherapy (SBRT) or intensity-modulated radiation therapy (IMRT) after all intended chemotherapy and approximately 4 to 5 weeks before anticipated surgery. Adjuvant therapy consisted of gemcitabine-based therapy or FOLFIRINOX; when used, adjuvant radiation was commonly administered as either SBRT or IMRT. Main Outcomes and Measures: The association of AT with PFS and OS was evaluated in the overall cohort and in different subgroups. The interaction between AT and other clinicopathologic variables was examined on Cox proportional hazards regression analysis. Results: In this cohort study, 430 consecutive patients were treated between 2010 and 2019. Patients had a mean (SD) age of 65.2 (9.4) years, and 220 (51.2%) were women. The predominant NAT was gemcitabine based (196 patients [45.6%]), with a median duration of 2.7 cycles (IQR, 1.5-3.4). Neoadjuvant radiation was administered to 279 patients (64.9%). Pancreatoduodenectomy was performed in 310 patients (72.1%), and 160 (37.2%) required concomitant vascular resection. The median lymph node yield was 26 (IQR, 19-34); perineural invasion (PNI), lymphovascular invasion (LVI), and residual positive margins (R1) were found in 254 (59.3%), 92 (22.0%), and 87 (21.1%) patients, respectively. The restricted mean OS was 5.2 years (95% CI, 4.8-5.7). On adjusted analysis, PNI, LVI, and poorly differentiated tumors were independently associated with worse PFS and OS in N0 disease after NAT, with hazard ratios (95% CIs) of 2.04 (1.43-2.92; P < .001) and 1.68 (1.14-2.48; P = .009), 1.47 (1.08-1.98; P = .01) and 1.54 (1.10-2.14; P = .01), and 1.90 (1.18-3.07; P = .008) and 1.98 (1.20-3.26; P = .008), respectively. Although AT was associated with prolonged survival in the overall cohort, the effect was reduced in patients who received NART and strengthened in patients with PNI (AT × PNI interaction: hazard ratio, 0.55 [95% CI, 0.32-0.97]; P = .04). Conclusions and Relevance: The findings of this cohort study suggest a survival benefit for AT in patients with N0 disease after NAT and surgical resection. This survival benefit may be most pronounced in patients with PNI.

Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab After Concurrent Chemoradiotherapy for NSCLC.

Introduction: Durvalumab after concurrent chemoradiation (CCRT) for NSCLC improves survival, but only in a subset of patients. We investigated the effect of severe radiation-induced lymphopenia (sRIL) on survival in these patients. Methods: Outcomes after CCRT (2010-2019) or CCRT followed by durvalumab (2018-2019) were reviewed. RIL was defined by absolute lymphocyte count (ALC) nadir in samples collected at end of CCRT; sRIL was defined as nadir ALC less than 0.23 × 109/L (the lowest tertile). Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Cox proportional hazard modeling evaluated associations between clinical variables and survival. Results: Of 309 patients, 192 (62%) received CCRT only and 117 (38%) CCRT plus durvalumab. Multivariable logistic regression analysis indicated that sRIL was associated with planning target volume (OR = 1.002, p = 0.001), stage IIIB disease (OR = 2.77, p = 0.04), and baseline ALC (OR = 0.36, p < 0.01). Durvalumab extended median PFS (23.3 versus 14.1 mo, p = 0.003) and OS (not reached versus 30.8 mo, p < 0.01). sRIL predicted poorer PFS and OS in both treatment groups. Among patients with sRIL, durvalumab did not improve survival (median = 24.6 mo versus 18.1 mo CCRT only, p = 0.079). On multivariable analyses, sRIL (OR = 1.81, p < 0.01) independently predicted poor survival. Conclusions: Severe RIL compromises survival benefits from durvalumab after CCRT for NSCLC. Measures to mitigate RIL after CCRT may be warranted to enhance the benefit of consolidation durvalumab.

Lymphocyte Depletion Rate as a Biomarker of Radiation Dose to Circulating Lymphocytes During Fractionated Partial-Body Radiation Therapy.

Purpose: Radiation causes exponential depletion of circulating lymphocyte populations; in turn, radiation-induced lymphopenia is associated with worse survival for many solid tumors, possibly owing to attenuated antitumor immune responses. Identifying reliable and reproducible methods of calculating the radiation dose to circulating immune cells may facilitate development of techniques to reduce the risk and severity of radiation-induced toxic effects to circulating lymphocytes. Methods and Materials: Patient-specific lymphocyte loss rates were derived from a clinical data set including 684 adult patients with solid tumors. Multivariable linear regression was used to model the relationship between the lymphocyte loss rate and physical parameters of the radiation plan that determine circulating blood dose. Results: During partial-body radiation, lymphocyte loss rates are determined by physical parameters of the radiation plan that reflect radiation exposure to circulating cells, including target volume size, dose per fraction squared, and anatomic site treated. Differences in observed versus predicted lymphocyte loss rates may be partly explained by variations in concurrent chemotherapy regimens. Conclusions: We describe a novel method of using patient-specific lymphocyte loss kinetics to approximate the effective radiation dose to circulating lymphocytes during focal fractionated photon radiation therapy. Clinical applications of these findings include the early identification of patients at particularly high risk of severe radiation-induced lymphopenia based on physical parameters of the radiation therapy plan.

Neoadjuvant Radiotherapy After (m)FOLFIRINOX for Borderline Resectable Pancreatic Adenocarcinoma: A TAPS Consortium Study.

BACKGROUND: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. METHODS: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. RESULTS: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). CONCLUSIONS: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.

Tumor Size Differences Between Preoperative Endoscopic Ultrasound and Postoperative Pathology for Neoadjuvant-Treated Pancreatic Ductal Adenocarcinoma Predict Patient Outcome.

BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.

The association of age with acute toxicities in NRG oncology combined modality lower GI cancer trials.

PURPOSE: Expected toxicity from chemoradiation (CRT) is an important factor in treatment decisions but is poorly understood in older adults with lower gastrointestinal (GI) malignancies. Our objective was to compare acute adverse events (AAEs) of older and younger adults with lower GI malignancies treated on NRG studies. METHODS: Data from 6 NRG trials, testing combined modality therapy in patients with anal or rectal cancer, were used to test the hypothesis that older age was associated with increased AAEs. AAEs and compliance with protocol-directed therapy were compared between patients aged ≥70 and < 70. Categorical variables were compared across age groups using the chi-square test. The association of age on AAEs was evaluated using a covariate-adjusted logistic regression model, with odds ratio (OR) reported. To adjust for multiple comparisons, a p-value <0.01 was considered statistically significant. RESULTS: There were 2525 patients, including 380 patients ≥70 years old (15%) evaluable. Older patients were more likely to have worse baseline performance status (PS 1 or 2) (23% vs. 16%, p = 0.001), but otherwise baseline characteristics were similar. Older patients were less likely to complete their chemotherapy (78% vs. 87%, p < 0.001), but had similar RT duration. On univariate analysis, older patients were more likely to experience grade ≥ 3 GI AAEs (36% vs. 23%, p < 0.001), and less likely to experience grade ≥ 3 skin AAEs (8% vs. 14%, p = 0.002). On multivariable analysis, older age was associated with grade ≥ 3 GI AAE (OR 1.93, 95% CI: 1.52, 2.47, p < 0.001) after adjusting for sex, race, PS, and disease site. CONCLUSIONS: Older patients with lower GI cancers who underwent CRT were less likely to complete chemotherapy and had higher rates of grade 3+ GI AAEs. These results can be used to counsel older adults prior to treatment and manage expected toxicities throughout pelvic CRT.

Higher Radiation Dose to the Immune Cells Correlates with Worse Tumor Control and Overall Survival in Patients with Stage III NSCLC: A Secondary Analysis of RTOG0617.

Background: We hypothesized that the Effective radiation Dose to the Immune Cells (EDIC) in circulating blood is a significant factor for the treatment outcome in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: This is a secondary study of a phase III trial, NRG/RTOG 0617, in patients with stage III NSCLC treated with radiation-based treatment. The EDIC was computed as equivalent uniform dose to the entire blood based on radiation doses to all blood-containing organs, with consideration of blood flow and fractionation effect. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and local progression-free survival (LPFS). The EDIC-survival relationship was analyzed with consideration of clinical significant factors. Results: A total of 456 patients were eligible. The median EDIC values were 5.6 Gy (range, 2.1-12.2 Gy) and 6.3 Gy (2.1-11.6 Gy) for the low- and high-dose groups, respectively. The EDIC was significantly associated with OS (hazard ratio [HR] = 1.12, p = 0.005) and LPFS (HR = 1.09, p = 0.02) but PFS (HR = 1.05, p = 0.17) after adjustment for tumor dose, gross tumor volume and other factors. OS decreased with an increasing EDIC in a non-linear pattern: the two-year OS decreased first with a slope of 8%/Gy when the EDIC < 6 Gy, remained relatively unchanged when the EDIC was 6-8 Gy, and followed by a further reduction with a slope of 12%/Gy when the EDIC > 8 Gy. Conclusions: The EDIC is a significant independent risk factor for poor OS and LPFS in RTOG 0617 patients with stage III NSCLC, suggesting that radiation dose to circulating immune cells is critical for tumor control. Organ at risk for the immune system should be considered during RT plan.

Radiation-Induced Lymphopenia Risks of Photon Versus Proton Therapy for Esophageal Cancer Patients.

PURPOSE: To assess possible differences in radiation-induced lymphocyte depletion for esophageal cancer patients being treated with the following 3 treatment modalities: intensity-modulated radiation therapy (IMRT), passive scattering proton therapy (PSPT), and intensity-modulated proton therapy (IMPT). METHODS AND MATERIALS: We used 2 prediction models to estimate lymphocyte depletion based on dose distributions. Model I used a piecewise linear relationship between lymphocyte survival and voxel-by-voxel dose. Model II assumes that lymphocytes deplete exponentially as a function of total delivered dose. The models can be fitted using the weekly absolute lymphocyte counts measurements collected throughout treatment. We randomly selected 45 esophageal cancer patients treated with IMRT, PSPT, or IMPT at our institution (15 per modality) to demonstrate the fitness of the 2 models. A different group of 10 esophageal cancer patients who had received PSPT were included in this study of in silico simulations of multiple modalities. One IMRT and one IMPT plan were created, using our standards of practice for each modality, as competing plans to the existing PSPT plan for each patient. We fitted the models by PSPT plans used in treatment and predicted absolute lymphocyte counts for IMRT and IMPT plans. RESULTS: Model validation on each modality group of patients showed good agreement between measured and predicted absolute lymphocyte counts nadirs with mean squared errors from 0.003 to 0.023 among the modalities and models. In the simulation study of IMRT and IMPT on the 10 PSPT patients, the average predicted absolute lymphocyte count (ALC) nadirs were 0.27, 0.35, and 0.37 K/µL after IMRT, PSPT, and IMPT treatments using Model I, respectively, and 0.14, 0.22, and 0.33 K/µL using Model II. CONCLUSIONS: Proton plans carried a lower predicted risk of lymphopenia after the treatment course than did photon plans. Moreover, IMPT plans outperformed PSPT in terms of predicted lymphocyte preservation.

Patient-Specific Lymphocyte Loss Kinetics as Biomarker of Spleen Dose in Patients Undergoing Radiation Therapy for Upper Abdominal Malignancies.

PURPOSE: Radiation therapy (RT)-induced lymphopenia (RIL) is linked with inferior survival in esophageal and pancreatic cancers. Previous work has demonstrated a correlation between spleen dose and RIL risk. The present study correlates spleen dose-volume parameters with fractional lymphocyte loss rate (FLL) and total percent change in absolute lymphocyte count (%ΔALC) and suggests spleen dose constraints to reduce RIL risk. METHODS AND MATERIALS: This registry-based study included 140 patients who underwent RT for pancreatic (n = 67), gastroesophageal (n = 61), or biliary tract (n = 12) adenocarcinoma. Patient-specific parameters of lymphocyte loss kinetics, including FLL and %ΔALC, were calculated based on serial ALCs obtained during RT. Spearman's rho was used to correlate spleen dose-volume parameters with %ΔALC, end-treatment ALC, and FLL. Multivariable logistic regression was used to identify predictors of ≥grade 3 and grade 4 RIL. RESULTS: Spleen dose-volume parameters, including mean spleen dose (MSD), all correlated with %ΔALC, end-treatment ALC, and FLL. Controlling for baseline ALC and planning target volume (PTV), an increase in any spleen dose-volume parameter increased the odds of developing ≥grade 3 lymphopenia. Each 1-Gy increase in MSD increased the odds of ≥grade 3 RIL by 18.6%, and each 100-cm3 increase in PTV increased the odds of ≥grade 3 lymphopenia by 20%. Patients with baseline ALC < 1500 cells/µL had a high risk of ≥grade 3 RIL regardless of MSD or PTV. FLL was an equally good predictor of ≥grade 3 lymphopenia as any spleen dose-volume parameter. CONCLUSIONS: In patients undergoing RT for upper abdominal malignancies, higher spleen dose is associated with higher per-fraction lymphocyte loss rates, higher total %ΔALC, and increased odds of severe lymphopenia. Spleen dose constraints should be individualized based on baseline ALC and PTV size to minimize RIL risk, although our findings require validation in larger, ideally prospective data sets.

A Pancreatic Cancer Multidisciplinary Clinic Eliminates Socioeconomic Disparities in Treatment and Improves Survival.

AIMS: National studies have demonstrated disparities in the treatment and survival of pancreatic cancer patients based on socioeconomic status (SES). This study aimed to identify specific differences in perioperative management and outcomes based on patient SES and to study the role of a multidisciplinary clinic (MDC) in mitigating any variations. METHODS: The study analyzed patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma in a large hospital system. The patients were categorized into groups of high and low SES and whether they were managed by the authors' pancreatic cancer MDC or not. The study compared differences in disease characteristics, receipt of multimodality therapy, perioperative outcomes, and recurrence-free and overall survival. RESULTS: Of the 162 low-SES patients and 119 high-SES patients, 54% were managed in the MDC. Outside the MDC, low-SES patients were less likely to receive neoadjuvant chemotherapy and had less minimally invasive surgery, a longer OR time, less enhanced recovery participation, and more major complications (p < 0.05). No SES disparities were observed among the MDC patients. Despite similar tumor characteristics, the low-SES patients had inferior median overall survival (21 vs 32 months; p = 0.005), but the MDC appeared to eliminate this disparity. Low SES correlated with inferior survival for the non-MDC patients (17 vs 32 months; p < 0.001), but not for the MDC patients (24 vs 25 months; p = 0.33). These findings persisted in the multivariable analysis. CONCLUSION: A pancreatic cancer MDC standardizes treatment decisions, eliminates disparities in surgical outcomes, and improves survival for low-SES patients.

Circulating Lymphocyte Counts Early During Radiation Therapy Are Associated With Recurrence in Pediatric Medulloblastoma.

PURPOSE: Decreased peripheral lymphocyte counts are associated with survival after radiation therapy (RT) in several solid tumors, although they appear late during or after the radiation course and often correlate with other clinical factors. Here we investigate if absolute lymphocyte counts (ALCs) are independently associated with recurrence in pediatric medulloblastoma early during RT. METHODS AND MATERIALS: We assessed 202 patients with medulloblastoma treated between 2000 and 2016 and analyzed ALC throughout therapy, focusing on both early markers (ALC during week 1 - ALCwk1; grade 3+ Lymphopenia during week 2 - Lymphopeniawk2) and late markers (ALC nadir). Uni- and multivariable regressions were used to assess association of clinical and treatment variables with ALC and of ALC with recurrence. RESULTS: Thirty-six recurrences were observed, with a median time to recurrence of 1.6 years (range, 0.2-10.3) and 7.1 years median follow-up. ALC during RT was associated with induction chemotherapy (P < .001), concurrent carboplatin (P = .009), age (P = .01), and high-risk status (P = .05). On univariable analysis, high-risk disease (hazard ratio = 2.0 [1.06-3.9]; P = .03) and M stage≥1 (hazard ratio = 2.2 [1.1-4.4]) were associated with recurrence risk, as was lower ALC early during RT (ALCwk1, hazard ratio = 0.28 [0.12-0.65]; P = .003; Lymphopeniawk2, hazard ratio = 2.27 [1.1-4.6]; P = .02). Neither baseline ALC nor nadir correlated with outcome. These associations persisted when excluding carboplatin and pre-RT chemotherapy patients, and in the multivariable analysis accounting for confounders lymphocyte counts remained significant (ALCwk1, hazard-ratio = 0.23 [0.09-0.57]; P = .002; Lymphopeniawk2, hazard-ratio = 2.3 [1.1-4.8]; P = .03). CONCLUSIONS: ALC during weeks 1 and 2 of RT was associated with recurrence, and low ALC is an independent prognostic factor in medulloblastoma. Strategies to mitigate the risk of radiation-induced lymphopenia should be considered.

Outcomes of Neoadjuvant Chemotherapy Versus Chemoradiation in Localized Pancreatic Cancer: A Case-Control Matched Analysis.

BACKGROUND: Neoadjuvant therapy is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). It is unknown whether neoadjuvant chemoradiotherapy is more effective than chemotherapy (NCRT vs. NAC). We aim to compare pathological and survival outcomes of NCRT and NAC in patients with PDAC. PATIENTS AND METHODS: Single-center analysis of PDAC patients treated with NCRT or NAC followed by resection between December 2008 and December 2018 was performed. Average treatment effect (ATE) was estimated after case-control matching using Mahalanobis distance nearest-neighbor matching. Inverse probability weighted estimates (IPWE)-based ATE was estimated for disease-free survival (DFS) and overall survival (OS). RESULTS: Among the 418 patients (mean age 66.8 years, 51% female) included in the study, 327 received NAC and 91 received NCRT. NCRT patients had higher rates of locally advanced disease, number of neoadjuvant chemotherapy cycles, more chemotherapy regimen crossover (gemcitabine and 5-FU based), and were more likely to undergo open surgical procedures and/or vascular resection (all p < 0.05). After matched analysis, NCRT was associated with a significant reduction in lymph node positive disease [ATE = (-)0.24, p = 0.007] and lymphovascular invasion [ATE = (-)0.20, p = 0.02]. While NCRT was associated with significantly improved DFS by 9.5 months (p = 0.006), it did not affect OS by IPWE-based ATE after adjusting for adjuvant therapy (ATE = 5.5 months; p = 0.32). CONCLUSION: Compared with NAC alone, NCRT is associated with improved pathologic surrogates and disease-free survival, but not overall survival in patients with PDAC.

Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons.

BACKGROUND: We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM). METHODS: Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79-0.94) for the final G3+L prediction model. CONCLUSIONS: Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.

Demographic factors associated with missed follow-up among solid tumor patients treated at a large multi-site academic institution.

Aim: To identify demographic predictors of patients who miss oncology follow-up, considering that missed follow-up has not been well studies in cancer patients. Methods: Patients with solid tumors diagnosed from 2007 to 2016 were analyzed (n = 16,080). Univariate and multivariable logistic regression models were constructed to examine predictors of missed follow-up. Results: Our study revealed that 21.2% of patients missed ≥1 follow-up appointment. African-American race (odds ratio [OR] 1.33; 95% CI: 1.17-1.51), Medicaid insurance (OR 1.59; 1.36-1.87), no insurance (OR 1.66; 1.32-2.10) and rural residence (OR 1.78; 1.49-2.13) were associated with missed follow-up. Conclusion: Many cancer patients miss follow-up, and inadequate follow-up may influence cancer outcomes. Further research is needed on how to address disparities in follow-up care in high-risk patients.

Baseline Karnofsky performance status is independently predictive of death within 30 days of intracranial radiation therapy completion for metastatic disease.

INTRODUCTION: For patients with brain metastases, palliative radiation therapy (RT) has long been a standard of care for improving quality of life and optimizing intracranial disease control. The duration of time between completion of palliative RT and patient death has rarely been evaluated. METHODS: A compilation of two prospective institutional databases encompassing April 2015 through December 2018 was used to identify patients who received palliative intracranial radiation therapy. A multivariate logistic regression model characterized patients adjusting for age, sex, admission status (inpatient versus outpatient), Karnofsky Performance Status (KPS), and radiation therapy indication. RESULTS: 136 consecutive patients received intracranial palliative radiation therapy. Patients with baseline KPS <70 (OR = 2.2; 95%CI = 1.6-3.1; p < 0.0001) were significantly more likely to die within 30 days of treatment. Intracranial palliative radiation therapy was most commonly delivered to provide local control (66% of patients) or alleviate neurologic symptoms (32% of patients), and was most commonly delivered via whole brain radiation therapy in 10 fractions to 30 Gy (38% of patients). Of the 42 patients who died within 30 days of RT, 31 (74%) received at least 10 fractions. CONCLUSIONS: Our findings indicate that baseline KPS <70 is independently predictive of death within 30 days of palliative intracranial RT, and that a large majority of patients who died within 30 days received at least 10 fractions. These results indicate that for poor performance status patients requiring palliative intracranial radiation, hypofractionated RT courses should be strongly considered.

Radiosurgery dose reduction for brain metastases on immunotherapy (RADREMI): A prospective phase I study protocol.

INTRODUCTION: Up to 20% of patients with brain metastases treated with immune checkpoint inhibitor (ICI) therapy and concomitant stereotactic radiosurgery (SRS) suffer from symptomatic radiation necrosis. The goal of this study is to evaluate Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) on six-month symptomatic radiation necrosis rates. METHODS: This study is a prospective single arm Phase I pilot study which will recruit patients with brain metastases receiving ICI delivered within 30 days before SRS. All patients will be treated with RADREMI dosing, which involves SRS doses of 18 Gy for 0-2 cm lesions, 14 Gy for 2.1-3 cm lesions, and 12 Gy for 3.1-4 cm lesions. All patients will be monitored for six-month symptomatic radiation necrosis (defined as a six-month rate of clinical symptomatology requiring steroid administration and/or operative intervention concomitant with imaging findings consistent with radiation necrosis) and six-month local control. We expect that RADREMI dosing will significantly reduce the symptomatic radiation necrosis rate of concomitant SRS + ICI without significantly sacrificing the local control obtained by the present RTOG 90-05 SRS dosing schema. Local control will be defined according to the Response Assessment in Neuro-Oncology (RANO) criteria. DISCUSSION: This study is the first prospective trial to investigate the safety of dose-reduced SRS in treatment of brain metastases with concomitant ICI. The findings should provide fertile soil for future multi-institutional collaborative efficacy trials of RADREMI dosing for this patient population. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04047602 (registration date: July 25, 2019).