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Background: The role of systemic tumor immune environment (STIE) is unclear in hepatocellular carcinoma (HCC). This study aimed to exam the cells in the STIE, their changes after transarterial chemoembolisation (TACE), stereotactic body radiotherapy (SBRT), and immunotherapy (IO) and explore their significance in the treatment response of patients with unresectable HCC. Methods: This is a prospective biomarker study of patients with unresectable HCC. The treatment was sequential TACE, SBRT (27.5–40 Gy/5 fractions), and IO. The treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) by magnetic resonance imaging (MRI) after 6 months of treatment. Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts, including leukocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and platelets. Peripheral blood samples were collected at baseline and after TACE, SBRT, and IO for T-lymphocyte subtyping by flow cytometry. Generalized estimation equation was employed for longitudinal analyses. Results: A total of 35 patients with unresectable HCC were enrolled: 23 patients in the exploratory cohort and 12 in the validation cohort. STIE circulating cells, especially lymphocytes, were heterogenous at baseline and changed differentially after TACE, SBRT, and IO in both cohorts. SBRT caused the greatest reduction of 0.7 × 109/L (95 % CI: 0.3 × 109/L–1.0 × 109/L, P < 0.001) in lymphocytes; less reduction was associated with significantly better treatment response. The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+ T cells (P = 0.010), type 1 T helper (Th1) cells (P = 0.007), and Th1/Th17 ratios (P = 0.001) were significantly higher in responders, while regulatory T (Treg) cells (P = 0.002), Th17 cells (P = 0.047), and Th2/Th1 ratios (P = 0.028) were significantly higher in non-responders. After treatment with TACE, SBRT and IO, T-lymphocyte lineage also changed differentially. More reductions were observed in CD25+CD8+ T cells and CD127+CD8+ T cells after SBRT in non-responders, while increases in natural killer T (NKT) cells after SBRT (10.4% vs. 3.4 %, P = 0.001) and increases in the lymphocyte counts were noted during IO in responders. Conclusions: STIE cells are significant for treatment response, can be reshaped differentially after TACE, SBRT, and IO. The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25+CD8+ T cells, CD127+CD8+ T cells, and NKT cells, which also have significant effects on the ultimate treatment response after TACE-SBRT-IO (ClinicalTrails.gov identifier: GCOG0001/NCT05061342).

Introduction: Anti-programmed cell death 1 (PD-1) immunotherapy is the standard of care for metastatic NSCLC but many tumors develop resistance. We hypothesized that combining a T-cell agonist such as varlilumab (anti-CD27 antibody) with checkpoint inhibition may be synergistic and this synergy may be potentiated further by using targeted radiation (RT). Methods: We conducted an open-label, single-center, phase I trial (NCT04081688) to determine the safety and clinical benefit of the atezolizumab and varlilumab in combination with palliative RT in patients with advanced or metastatic NSCLC with progression on prior programmed cell death ligand 1therapy. On day 1 of each 21-day cycle, patients received varlilumab followed by atezolizumab on day 2. RT to a lung lesion was administered between cycle 1 and cycle 2. Results: A total of 15 patients were enrolled (one patient did not start treatment). The median age was 64 years; 10 patients were female. Eight patients (57%) had at least one treatment-related adverse event (AE) and 7 (50%) had at least one grade III or worse treatment-related AE. There was only one grade III immune-related AE requiring steroids (1 diarrhea and colitis); there were no treatment-related deaths. Of the 12 patients evaluable for efficacy, three patients had stable disease (2 with stable disease > 4 mo) and the clinical benefit rate was 25%. The median progression-free survival was two months and the median overall survival was 6.4 months. Conclusions: Varlilumab in combination with atezolizumab and RT was safe and well tolerated; no additional signal was identified for toxicity. Clinical activity for the combination was modest with 25% of patients with stable disease as the best response.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0–2; n = 66), CCI intermediate (3–4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs

Purpose: Margin-negative (R0) resection is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC). Pre-operative multi-agent chemotherapy alone (MAC) or MAC followed by pre-operative radiotherapy (MAC + RT) may be used to improve resectability and potentially survival. However, the optimal pre-operative regimen is unknown. Methods: Patients with non-metastatic PDAC from 2006 to 2016 who received pre-operative MAC or MAC + RT before oncologic resection were identified in the National Cancer Database. Univariable and multivariable (MVA) associates with R0 resection were identified with logistic regression, and survival was analyzed secondarily with the Kaplan Meier method and Cox regression analysis. Results: 4,599 patients were identified (MAC: 3,109, MAC + RT: 1,490). Compared to those receiving MAC, patients receiving MAC + RT were more likely to have cT3-4 disease (76% vs 64%, p

Background: Neoadjuvant therapy (NAT) for T1/T2 pancreatic adenocarcinoma (PDAC) prior to pancreaticoduodenectomy remains controversial. We compared positive margin rates in patients with clinical T1&T2 tumors who did and did not receive NAT. Methods: The National Cancer Database (NCDB) found clinical T1&T2 PDAC patients who underwent pancreaticoduodenectomy from 2004 to 2014. Univariate and multivariate regression determined factors associated with a positive margin and survival. Results: 9795 patients underwent surgery for clinical T1 or T2 pancreatic head adenocarcinoma. 8472 patients had data regarding use of neoadjuvant and adjuvant therapies; of which, 774 (9.1%) received NAT and 435 (5.1%) received both chemotherapy and radiation therapy. NAT was found to lower positive margin rates from 21.8 to 15.5% (p

Purpose: We examined long-term clinical outcomes among patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) treated at our institution with definitive thoracic chemoradiation therapy (CRT) and local therapy to all oligometastatic lesions. Methods and Materials: A retrospective review identified 38 patients with synchronous oligometastatic NSCLC (≤3 metastatic lesions) who were treated with definitive CRT to the primary tumor and regional lymph nodes between 1999 and 2017 at our institution. Of the 38 patients, 27 patients (71%) received induction chemotherapy, all of whom responded or stabilized with initial systemic therapy before consideration of CRT. Most patients received chemotherapy concurrently with radiation therapy (n = 32; 84%) and local therapy to the metastatic disease site(s) (n = 34; 89%). We assessed patterns of progression or failure, overall survival (OS), progression-free survival (PFS), and toxicities. Results: The median follow-up duration was 54.9 months. Most patients (84%) presented with N2 to N3 disease. The brain or central nervous system was the most common site of disease progression and occurred in 16 of 28 patients (57%) experiencing any progression and 10 of 16 patients (63%) who initially presented with brain oligometastases. Median OS was 21.1 months (95% confidence interval [CI], 15.6-49.0 months), and median PFS 9.7 months (95% CI, 8.2-14.4 months). The 1-, 2-, and 4-year OS rates were 75.7%, 45.0%, and 33.7%, respectively. On multivariate analysis, both locoregional progression (hazard ratio: 5.8; 95% CI, 2.2-15.0; P = .0003) and distant progression (hazard ratio: 6.0; 95% CI, 2.3-15.4; P = .0002), when treated as time-dependent covariates, were associated with inferior OS. Grade ≥3 esophagitis occurred in 9% and grade ≥3 pneumonitis in 5% of patients with evaluable data. Conclusions: Patients with synchronous oligometastatic NSCLC and a high regional nodal burden treated with definitive thoracic CRT experienced favorable survival outcomes and low toxicity. At our institution, treating oligometastatic disease with CRT after systemic therapy is incorporated into the treatment plan from the onset of therapy, and we monitor the neuraxis closely for progression during and after treatment. Future research should focus on novel treatment combinations, such as immunotherapy or targeted systemic therapy as appropriate to further improve tumor control and survival.

Purpose: Although the association of marital status with outcomes for patients with cancer has been widely studied, the mechanisms underpinning the protective effect of marriage are still not fully understood. The social support that marriage imparts is often discussed as an explanation for why patients with cancer who are married have better outcomes. Social support has been difficult to objectively quantify. Accompaniment of the patient at physician visits may be more meaningful than marital status itself. This study investigated the effect of caregiver presence at physician visits on treatment tolerance and outcome in patients undergoing chemoradiation therapy (CRT) for esophageal cancer. Methods and Materials: Patients who received a diagnosis of esophageal cancer who underwent CRT from January 1, 2005, to January 1, 2016, as part of their curative-intent management were retrospectively reviewed. Data collected included the patients’ marital status, caregiver presence at each physician visit, baseline performance status, serum albumin values and leukocyte values throughout treatment, patient weight values throughout treatment, tumor response to therapy, and overall survival. Patients were divided into 2 groups based on frequency of caregiver presence at physician visits (

Purpose: This study aimed to evaluate whether the coronavirus disease of 2019 (COVID-19) pandemic resulted in treatment delays in patients scheduled for or undergoing brachytherapy. Methods and Materials: A retrospective cohort study was conducted across 4 affiliated sites after local institutional review board approval. The eligibility criteria were defined as all patients with cancer whose treatment plan included brachytherapy during the COVID-19 pandemic from February 24, 2020 to June 30, 2020. Treatment delays, cancellations, alterations of fractionation regimens, and treatment paradigm changes were evaluated. Results: A total of 47 patients were eligible for the analysis. Median patient age at the time of treatment was 62 years (interquartile range, 56-70 years). Endometrial, cervical, and prostate cancers were the most common sites included in this analysis. Three patients (6.4%) with cervical cancer were diagnosed with COVID-19 during the course of their treatment. Interruptions of external beam radiation therapy (EBRT), cancellations of EBRT, cancellations of brachytherapy, and treatment delays due to COVID occurred in 5 (10.6%), 3 (6.4%), 8 (17%), and 9 (19%) patients, respectively. The mean and median number of days delayed for patients who experienced treatment interruptions were 16.3 days (standard deviation: 13.9 days) and 14 days (interquartile range, 5.75-23.75 days), respectively. For patients with cervical cancer, the mean and median overall treatment times defined as the time from the start of EBRT to the end of brachytherapy were 56 and 49 days, respectively. Conclusions: Despite the challenges the health care system faced during the pandemic, most patients with cancer were safely treated with minor treatment delays and interruptions. Long-term follow up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.

Introduction: Malignant pleural mesothelioma (MPM) is a rare malignancy with a poor prognosis. While treatment with a platinum-based chemotherapy is the standard of care, many patients have rapid progression of disease with a median overall survival of ~12 months. Limited data exist about the genomic alterations associated with MPM and their clinical implications. Methods: We report genomic alterations and clinical data for 17 patients with MPM who had next generation sequencing performed. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier method. Results: Median age at diagnosis was 70 years (range 55–85), and 47% of the patients were male. The most common genomic alterations in the 17 patients were NF2 (53%), BAP1 (41%), CDKN2A (41%) and TP53 (29%). The median OS was 10.8 months. When stratified by mutational status, patients had better median OS if they had a BAP1 alteration compared to TP53 alteration (median OS 14.5 vs 7.2 months). Median PFS with first-line chemotherapy was 7 months (SD ± 3.3). However, patients with TP53 mutations had worse PFS with chemotherapy with median of only 3.9 months. Tumor mutation burden (TMB) was available for 12 patients and all had low TMB (range 1 to 8.1 mutation/Mb). Median PFS with immunotherapy was poor with at 1.5 months (SD ±0.4) and there was no significant difference in PFS with immunotherapy based on molecular profile. Conclusion: Our study has identified that TP53 confers worse survival and response to platinum chemotherapy compared to BAP1. Overall PDL1 expression and TMB is low in patients with MPM resulting in limited benefit from single agent PD-1/PD-L1 agent.