Difference In Median Survival Research Articles

Immunophenotypic correlates and response to first-line pembrolizumab among elderly patients with PD-L1-high (≥ 50%) non–small cell lung cancer.

9054 Background: Older age is associated with increased levels of systemic inflammation and altered immunosurveillance in cancer. Whether aging correlates with a distinct immunophenotype or impacts clinical outcomes to first-line pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of ≥50% is unclear. Methods: We performed a retrospective analysis of patients with NSCLC. Multiplexed immunofluorescence (mIF) for CD8+, PD-1+, PD-1+CD8+ and FOXP3+ was performed to explore tumor immunophenotype. Clinical outcomes were analyzed on a separate cohort of patients with PD-L1-high (TPS of ≥50%) NSCLC (negative for sensitizing genomic alterations in EGFR and ALK) who received treatment with first-line pembrolizumab. Variables demonstrating a univariate signal of association of p < 0.1 were included in the multivariate model. The results were compared in patients < 80 vs ≥80 years old. Results: Among 541 patients with NSCLCs profiled by mIF, the median age was 67 (28-90). When comparing patients < 80y (n = 497) to ≥80y (n = 44), there was no difference in median CD8+ T cells/mm2 (171 vs 148; p = 0.69), PD-1+ immune cells/mm2 (81.1 vs 87.2; p = 0.95), or PD-1+CD8+ T cells/mm2 (18.0 vs 13.1; p = 0.56). NSCLCs from patients ≥80y had a higher median of intratumoral-associated FOXP3+ T cells/mm2 (63.6 vs 91.1; p = 0.03). In a cohort of 271 patients with PD-L1 ≥50% who received first-line pembrolizumab, baseline clinicopathological characteristics were balanced in the < 80y (n = 225) vs ≥80y (n = 46) groups in terms of sex, tobacco use, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), histology, presence of potentially targetable driver mutations (KRAS, MET, BRAF, HER2, RET), and PD-L1 TPS distribution (50-89% vs ≥90%). Compared to patients < 80y, patients ≥80y had no difference in objective response rate (ORR 39.1% vs 28.2%; p = 0.22) or median progression-free survival (mPFS 6.0 vs 3.0 months; p = 0.16). However, patients ≥80y had a shorter median overall survival (mOS 25.7 vs 7.6 months; p = 0.02), and this result remained significant after adjusting for ECOG-PS. Among those who experienced disease progression on pembrolizumab, patients ≥80y were significantly less likely to receive any second-line systemic therapy compared to patients < 80y (55.6% vs 30.8%; p = 0.008). Conclusions: In patients with NSCLC and PD-L1 ≥50%, the ORR and mPFS to first-line pembrolizumab were similar between patients < vs ≥80 years old. OS was shorter among patients ≥80y, potentially reflecting lower use of second-line therapy in elderly patients after progression on pembrolizumab. The immunophenotypic correlates of NSCLC in older patients need further investigation.

Comparison between preoperative chemoradiation versus neoadjuvant chemotherapy with postoperative radiation for extremity soft-tissues sarcomas.

e23527 Background: Extremity soft-tissues sarcomas are a rare entity that represent 1% of solid tumors in adults. Surgery is the main treatment and limb sparing resection with adjuvant radiotherapy (RT) is associated with good local control. However, high rates of distant relapses motivated the evaluation of adjuvant systemic treatment protocols. We aim to compare survival rates between two cohorts of patients treated with two different preoperative protocols. Methods: An observational comparative cohort study were carried out. Two cohorts of patients with high grade, larger then 5.0 cm, and non-metastatic soft tissue sarcomas of extremities, treated with two distinct preoperative institutional protocols, in two different periods of time, were compared. Group 1 included patients treated in the period from January, 1995 to December, 2004, when patients with high risk extremities soft tissue sarcomas were submitted to preoperative radiation therapy (a total dose of 30 Gy) concomitant with doxorubicin (60 mg/m2); this protocol included adjuvant chemotherapy with doxorubicin and ifosfamide. Group 2 included patients treated in the period from April, 2005 to July, 2012, when our group changed the preoperative protocol to neoadjuvant chemotherapy without radiation, with four cycles doxorubicin (60 mg/m2 per cycle) and ifosfamide (9.000 mg/m2 per cycle), followed by surgery, and postoperative radiation. Data from the group 1 were retrospectively collected, and data from group 2 were from our prospective database. Results: Eighty-eight patients were included (37 in group 1 and 51 in group 2). There were no statistical differences between the groups with regards to age, gender, location and tumor size. Predominant histological subtypes were synovial sarcoma (27.3%), pleomorphic sarcoma (15.9%), leiomyosarcoma (11.4%) and liposarcoma (8%). Relapses occurred in 60.5% of patients, most in the lungs (48.1%). Amputation rates were 14.3% in the group 1 and 4.5% in the group 2. Five-year local recurrence free survival was 81.7% for the group 1 and 91.7% for the group 2. There was no difference in median overall survival when comparing group 1 and 2 (47 versus 78 months, respectively; IC 95 3.967 – 132.033; p = 0.49), but our data showed higher recurrence free survival in group 2 (19 versus 132 months; IC 95 5.9 – 60.09; p = 0.025, respectively). Among patients from the group 2, whom presented less than 10% of viable tumor cells in the surgical specimens (good responders), no local or distant recurrences have occurred. Conclusions: In our retrospective analysis, neoadjuvant chemotherapy was associated with greater recurrence free survival in patients with high-grade extremity soft tissue sarcomas as compared to neoadjuvant chemoradiation. For patients with high risk of distant relapse, neoadjuvant chemotherapy should be considered after a multidisciplinary discussion.

Automated imaging-based prognostication (IPRO) for stage I non-small cell lung cancer using deep learning applied to computed tomography.

e20575 Background: Computed tomography (CT) imaging is used to inform staging and treatment decisions for stage I non-small cell lung cancer (NSCLC) patients. We have previously used deep learning applied to pretreatment CTs to generate an imaging-based prognostication (IPRO) score that automatically quantifies mortality risk and stratifies patients beyond tumor, node, metastasis (TNM) substages. Here we present validation data of its prognostic impact. Methods: We developed a fully automated deep learning model, IPRO, designed to process a CT scan, localize the 36cm3 space centered on the lungs, and learn prognostic imaging features to predict mortality risk. IPRO was trained on pretreatment CTs acquired from 1,696 patients treated for NSCLC at a tertiary care center between 2004 and 2018. We withheld 20% of the cases for validation, including 162 patients that were diagnosed with stage I NSCLC by clinical staging. We evaluated IPRO’s ability to stratify stage I NSCLC patients into mortality risk quintiles using the Cox proportional hazards model and assessed differences in median overall survival (mOS). Results: Of the 162 stage I NSCLC patients in the validation set, the mOS was 68.5 months (95% CI 66.7-69.6), 85 (52.5%) were male, and 125 (77.2%) were diagnosed with stage IA. Of these, 111 patients received surgery, 40 received radiotherapy (RT), 9 received surgery + adjuvant systemic therapy (ST), and 2 patients received surgery + ST + RT. According to IPRO, the patients predicted to have the highest risk had significantly increased 5-year mortality compared to those predicted to have the lowest risk (OR 8.4, 95% CI 2.4-29.2, p < 0.01); median survival 48.0 months and 69.5 months, respectively. Conclusions: Deep learning applied to pretreatment CTs provides personalized prognostic insights for stage I NSCLC beyond current TNM staging. [Table: see text]

Survival Is Worse in Patients Completing Immunotherapy Prior to SBRT/SRS Compared to Those Receiving It Concurrently or After.

Purpose/ObjectivesThe abscopal effect could theoretically be potentiated when combined with immunomodulating drugs through increased antigen production. The optimal dosing and schedule of radiotherapy with immunotherapy are unknown, although they are actively investigated in laboratory and clinical models. Clinical data in patients treated for metastatic disease with both modalities may guide future studies.Materials and MethodsThis is a single-institution retrospective review of all patients treated with stereotactic body radiotherapy (SBRT)/stereotactic radiosurgery (SRS) and immunomodulating therapy within 6 months before or after SBRT/SRS for metastatic cancer. Clinical and tumor characteristics were recorded, as well as SBRT/SRS details, immunotherapy details, and survival. Log-rank tests on Kaplan–Meier curves for overall survival (OS) that were calculated from the end of SBRT/SRS were used in univariate analysis and Cox proportional hazards regression for multivariate analysis.ResultsA total of 125 patients were identified who met the inclusion criteria; 70 received SBRT, and 57 received SRS. Eighty-three patients were treated for non-small cell lung cancer, 7 patients for small cell lung cancer, and 35 patients for other cancers, with the most common one being melanoma. Fifty-three percent of patients received nivolumab, 29% pembrolizumab, 13% atezolizumab, 5% other. Twenty percent received immunotherapy before SBRT/SRS, 39% during SBRT/SRS, 41% after. Eighty-six patients had died by the time of the analysis; the median OS for the whole cohort was 9.7 months. Patients who had completed immunotherapy prior to SBRT/SRS had worse OS than those who received concurrent therapy or immunotherapy after SBRT/SRS, with a difference in median OS of 3.6 months vs. 13.0 months (p = 0.010) that was retained on multivariate analysis (p = 0.011). There was no significant difference in OS between patients receiving SRS vs. SBRT (p = 0.20), sex (p = 0.53), age >62 years (p = 0.76), or lung primary vs. others (p = 0.73) on univariate or multivariate analysis. When comparing before/concurrent to after/concurrent administration, there is a difference in survival with after/concurrent survival of 8.181 months and before survival of 13.010 months, but this was not significant (p = 0.25).ConclusionsOS appears to be worse in patients who complete immunotherapy prior to SBRT/SRS compared to those receiving it concurrently or after. The design of this retrospective review may be prone to lead time bias, although the difference in median survival is longer than the 6-month window before SBRT/SRS and could only account for part of this difference. Further analysis into causes of death and toxicity and prospective studies are needed to confirm the results of this analysis.

Reliability analysis of exonic-breakpoint fusions identified by DNA sequencing for predicting the efficacy of targeted therapy in non-small cell lung cancer

BackgroundDiverse genomic breakpoints of fusions that localize to intronic, exonic, or intergenic regions have been identified by DNA next-generation sequencing (NGS), but the role of exonic breakpoints remains elusive. We investigated whether exonic-breakpoint fusions could predict matched targeted therapy efficacy in non-small cell lung cancer (NSCLC).MethodsNSCLC samples were analyzed by DNA NGS, RNA NGS, immunohistochemistry (IHC), and fluorescence in situ hybridization.ResultsUsing DNA NGS, kinase fusions were identified in 685 of 7148 (9.6%) NSCLCs, with 74 harboring exonic-breakpoint fusions, mostly anaplastic lymphoma kinase (ALK) fusions. RNA NGS and IHC revealed that 11 of 55 (20%) exonic-breakpoint fusions generated no aberrant transcript/protein, possibly due to open reading frame disruption or different gene transcriptional orientations. Four cases of genomic-positive but RNA/protein-negative fusions were treated with matched targeted therapy, but progressive disease developed within 2 months. Nevertheless, 44 of 55 (80%) exonic-breakpoint fusions produced chimeric transcripts/proteins, possibly owing to various alternative splicing patterns, including exon skipping, alternative splice site selection, and intron retention. Most of these genomic- and RNA/protein-positive fusion cases showed a clinical response to matched targeted therapy. Particularly, there were no differences in objective response rate (P = 0.714) or median progression-free survival (P = 0.500) between intronic-breakpoint (n = 56) and exonic-breakpoint ALK fusion subtypes (n = 11) among ALK RNA/protein-validated patients who received first-line crizotinib.ConclusionsExonic-breakpoint fusions may generate in-frame fusion transcripts/proteins or not, and thus are unreliable for predicting the efficacy of targeted therapy, which highlights the necessity of implementing RNA or protein assays for functional validation in exonic-breakpoint fusion cases.

Impact of Histological Features on Adjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Carcinoma.

This study evaluated the efficacy of adjuvant chemotherapy (AC) for intraductal papillary mucinous carcinoma (IPMC). We retrospectively analyzed patients who underwent pancreatectomy for invasive IPMC from January 2007 to June 2020. We evaluated outcomes of AC in the entire cohort and in patients with known prognostic factors. A total of 51 patients with invasive IPMC underwent surgery, of which 35 received AC. In the entire cohort, there was no significant difference in median overall survival (OS) between the AC and surgery alone (SA) group [hazard ratio (HR)=0.54; p=0.232]. For patients with poorly differentiated adenocarcinoma, median OS was significantly longer in the AC group (HR=0.27; p=0.022). For patients with lymph node metastasis, median OS was significantly higher in the AC group (HR=0.07; p<0.001). AC may be effective for selected invasive IPMC patients.

60P Machine learning based on blood biomarkers predicts fast progression in advanced NSCLC patients treated with immunotherapy

Fast progression (FP) represents a detrimental situation for advanced non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) therapy. We here aimed to develop an advanced NSCLC-specific predictive framework for identification of clinical FP using machine learning (ML) methods based on blood test biomarkers. We extracted atezolizumab-treated patients from 4 multicenter clinical trials, namely OAK, BIRCH, POPLAR and FIR. FP was defined as either a ≥50% increase in the sum of largest diameters within 6 weeks or death due to disease progression within 12 weeks. The patients of the OAK trial were taken for for model training, and the patients of the other trials were used for independent validation. By using 21 pretreatment laboratory test variables, seven ML approaches including the LASSO, GLM, SVM, Decision Tree model (DT), the Random Forest model (RF), the eXtreme Gradient Boosting model (XGB), and the Generalized Boosted Regression Models (GBM), a prediction model for FP was developed. The performance was evaluated using the receiver operating characteristic (ROC) curve and the precision-recall curve. The prevalence of FP was 7.6% (118 of 1546) in all atezolizumab treated patients. The most important variables for the prediction model were: C-Reactive Protein (CRP), Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), Lymphocyte-Neutrophil-Monocyte Ratio (LMR), Lactate Dehydrogenase (LDH), and Alanine Transaminase (ALT). The XGBoost method with 6 biomarkers demonstrated a robust performance: Area under the ROC Curve (AUC) were 0.8433, 0.6602, and 0.7978 in the training cohort (OAK) and validation cohort 1 (BIRCH) and 2 (merged POPLAR and FIR), respectively. In addition, the absolute difference in median survival between the FP and non-FP groups was significant for both progression-free survival (PFS) and overall survival (OS) (P <0.001). The identified ML method-based, 6 blood biomarkers including, the XGBoost method allow discrimination of FP in advanced NSCLC patients before ICI therapy, which should improve personalized therapeutic decision-making in ICI therapy for NSCLC.

Clinicopathological features of HER2 positive metastatic colorectal cancer and survival analysis of anti-HER2 treatment

BackgroundWe aimed to investigate response and prognostic factors in patients with human epidermal growth factor receptor 2 (HER2) positive metastatic colorectal cancer (mCRC) and compare the curative effect on patients who received different therapy regimens (including chemotherapy and chemotherapy combined with targeted drugs).MethodsWe retrospectively analyzed all HER2 positive mCRC patients treated at Peking University Cancer Hospital between September 2011 and February 2021. We divided 63 HER2 positive mCRC into group A and group B according to the use of trastuzumab or not. Besides, we assigned four subgroups according to the first-line therapies of KRAS/NRAS/BRAF WT patients. The Kaplan–Meier estimator was used to calculate PFS and OS. Univariable analysis and Cox proportional hazards models were used to analyze the association between clinicopathological features and survival outcomes.ResultsAmong 63 patients, 54 (85.7%) were KRAS/NRAS/BRAF wild-type (WT). Univariate analysis showed that the male sex, primary lesions in the right colon, simultaneous metastasis, and unresectable primary lesions were significant risk factors for poor survival of HER2 positive mCRC (P < 0.05). Using Cox proportional hazards models, we found that the two factors of gender and resection of primary lesions were independent prognostic factors (P < 0.05). The median PFS and median OS of HER2-positive patients with mCRC who received first-line treatment were 8.4 months [95% confidence interval (CI): 5.0–11.7] and 48.2 months (95% CI: 23.5–72.8), respectively. The log-rank test revealed a significant difference in median OS survival between group A and group B (χ2 = 5.852, P = 0.016), and the two groups were divided according to the use or absence of trastuzumab treatment. In KRAS/NRAS/BRAF WT patients, there was a significant difference in median PFS and median OS between the fourth group patients (chemotherapy plus trastuzumab) and each of the other three groups (P < 0.05).ConclusionsThe two factors of gender and resection for primary lesion may be independent prognostic factors of advanced HER2 positive colorectal cancer patients. For patients with HER2-positive mCRC, patients in the chemotherapy combined with trastuzumab group have better efficacy than those without trastuzumab.

Graft Survival in Pediatric Heart Retransplantation Can Rival Primary Heart Transplantation

<h3>Purpose</h3> Pediatric heart re-transplantation (re-HTx) has been associated with poorer graft survival when compared to first-time pediatric heart transplants (primary-HTx). Identification of patients who are more likely to benefit from re-HTx could aid clinicians in selecting patients for surgery. <h3>Methods</h3> The United Network for Organ Sharing (UNOS) database was queried to identify patients who underwent re-HTx from 1987 to 2020 and were less than 18-years-old at the time of their primary-HTx. This cohort was propensity matched with a set of primary-HTx patients based on several prognostic indicators. <h3>Results</h3> There were a total of 9,993 primary-HTx and 782 re-HTx. After matching, median graft survival [months (95% CI)] was longer for primary-HTx [129 (116 - 149)] than it was for re-transplants [109 (92 - 126)] with a hazard ratio [HR (95% CI)] of 1.21 (1.1 - 1.4, <i>p</i> = 0.0083). The difference in primary-HTx and re-HTx median graft survival was no longer statistically significant if the interval between primary-HTx and re-HTx was greater than 12 months (HR 1.15 [1.0 - 1.3], <i>p</i> = 0.0602), if re-HTx took place between the ages of 3 to 13 (HR 1.07 [0.89 - 1.3], <i>p</i> = 0.474), or if there were no episodes of acute rejection within the first year of primary-HTx (HR 0.99 [0.75 - 1.3], <i>p</i> = 0.962). If re-HTx took place within 12 months of primary-HTx, median survival dropped to 15 months (3 - 41) with a HR of 2.32 (1.7 - 3.2). <h3>Conclusion</h3> Graft survival is significantly shorter following re-HTx when compared to primary-HTx. However, there are multiple patient cohorts in which re-tx survival is equivalent to primary HTx survival (e.g. patients more than one year out from primary-HTx). Conversely, patients requiring a re-HTx within the first year of their primary-HTx have an abysmal graft survival and re-HTx for these patients may not be prudent. Further study to identify cohorts where re-HTx should and should not be pursued is needed.

Effect and Tolerability of Immunotherapy in Patients with NSCLC with or without Brain Metastasis.

Simple SummaryImmune checkpoint inhibitors (ICIs) are increasingly used in the treatment of non-small cell lung cancer (NSCLC). Most randomized clinical trials have excluded patients with brain metastasis (BM), and real-life patients with NSCLC who receive ICIs are not routinely scanned with magnetic resonance imaging (MR-C) of the brain prior to ICI. This means that there are no prospective data available on the prevalence of BM or on the rate of intracranial response (ICR) attributable to ICIs. To evaluate this along with the impact of BM on quality of life and overall survival, we used MR-C as a screening tool in 159 ICI-eligible patients with advanced NSCLC prior to first ICI. At the time of ICI initiation, 28% of patients had BM. Of those who received ICI without additional early local radiotherapy or surgery, 50% had intracranial response at their first MR-C assessment. Long-term survival of patients with BM was comparable to those without.Sparse data exist on immune checkpoint inhibition (ICI) in NSCLC patients with brain metastasis (BM), especially for those with no local therapy (LT) (whole brain radiation therapy (WBRT), stereotactic RT (SRT) or neurosurgery) preceding ICI. Our aims were to investigate the prevalence of BM, rate of intracranial response (ICR), and survival and quality of life (QoL) in real-life patients with advanced NSCLC undergoing palliative ICI. This was a prospective non-randomized study (NCT03870464) with magnetic resonance imaging of the brain (MR-C) performed at baseline resulting in a clinical decision to administer LT or not. ICR evaluation (MR-C) at week 8–9 (mRECIST criteria) for group A (LT) and group B (untreated) was assessed. Change in QoL was assessed using EQ-5D-5L. Of 159 included patients, 45 (28%) had baseline BM. Median follow-up was 23.2 months (IQR 16.4–30.2). Of patients in group A (21) and B (16), 16/37 (43%) had symptomatic BM. ICR was 8/21, 38% (complete or partial response) for group A versus 8/16, 50% for group B. No statistical difference in median overall survival of patients with BM (group A: 12.3 (5.2-NR), group B: 20.5 months (4.9-NR)) and without (22.4 months (95% 16.2–26.3)) was obtained. Baseline QoL was comparable regardless of BM, but an improved QoL (at week 9) was found in those without BM. Patients with NSCLC and BM receiving ICI had long-term survival comparable to those without BM.

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study

The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis. In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs >3) and aged (<75 vs ≥75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting. Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection). Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing. Sanofi.

Duchenne muscular dystrophy gene expression is an independent prognostic marker for IDH mutant low-grade glioma

Alterations in the expression of the Duchenne muscular dystrophy (DMD) gene have been associated with the development, progression and survival outcomes of numerous cancers including tumours of the central nervous system. We undertook a detailed bioinformatic analysis of low-grade glioma (LGG) bulk RNAseq data to characterise the association between DMD expression and LGG survival outcomes. High DMD expression was significantly associated with poor survival in LGG with a difference in median overall survival between high and low DMD groups of over 7 years (P = < 0.0001). In a multivariate model, DMD expression remained significant (P = 0.02) and was an independent prognostic marker for LGG. The effect of DMD expression on overall survival was only apparent in isocitrate dehydrogenase (IDH) mutant cases where non-1p/19q co-deleted LGG patients could be further stratified into high/low DMD groups. Patients in the high DMD group had a median overall survival time almost halve that of the low DMD group. The expression of the individual DMD gene products Dp71, Dp71ab and Dp427m were also significantly associated with overall survival in LGG which have differential biological effects relevant to the pathogenesis of LGG. Differential gene expression and pathway analysis identifies dysregulated biological processes relating to ribosome biogenesis, synaptic signalling, neurodevelopment, morphogenesis and immune pathways. Genes spanning almost the entirety of chromosome 1p are upregulated in patients with high overall DMD, Dp71 and Dp427m expression which worsens survival outcomes for these patients. We confirmed dystrophin protein is variably expressed in LGG tumour tissue by immunohistochemistry and, overall, demonstrate that DMD expression has potential utility as an independent prognostic marker which can further stratify IDH mutant LGG to identify those at risk of poor survival. This knowledge may improve risk stratification and management of LGG.

Clinical application of gelatin sponge microparticles-transcatheter arterial chemoembolization combined with synchronous antigen-presenting dendritic cell sequential reinfusion for treatment of advanced large liver cancer: A single-center, prospective, non-randomized, controlled trial.

To assess the clinical efficacy and safety of gelatin sponge microparticles-transcatheter arterial chemoembolization (GSMs-TACE) plus synchronous antigen-presenting dendritic cell (DC) sequential reinfusion for advanced large liver cancer (LC).Patients with large LC were assigned to the experimental (combined sequential DC therapy) or control group. All patients received standardized GSMs-TACE. In the experimental group, 60 mL of peripheral blood was collected for in vitro culture of DCs (10–14 days). Then, intravenous reinfusion was conducted 3 times within 10, 20, and 30 days after surgery. Adverse reactions during the treatment were recorded and evaluated. The overall survival, transcatheter arterial chemoembolization frequency, and physical score (PS) were calculated.The median survival time of the experimental group was significantly longer than that of the control group. There were significant differences in median progression-free survival between the 2 groups (P < .05) and the objective effective rate at 1 and 6 months and 1 year (P < .05), but not 2 years (P > .05). The PSs of 2 groups were significantly improved at 1 month after GSMs-TACE, with more obvious improvement in the experimental group (P < .05).GSMs-TACE plus synchronous DC sequential reinfusion significantly prolonged the median survival time, improved the tumor response rate and PS, prolonged progression-free survival, and reduced intervention frequency. GSMs-TACE plus synchronous DC sequential reinfusion treatment is suitable for comprehensive treatment of patients with advanced larger LC in China.

Treatment outcomes of patients with metastatic prostate cancer and co-morbid diabetes mellitus.

113 Background: In metastatic castrate resistant prostate cancer (mCRPC) there is a lack of studies that explore the interaction of comorbidities on treatment outcomes, which presents a challenge in choosing the right drug. In patients with diabetes mellitus, two common therapies, enzalutamide (ENZ) and abiraterone (ABI) have different effectiveness due to different mechanisms of action and because ABI requires co-administration of prednisone. Thus, in this study, we aim to assess the survival of patients with comorbid diabetes treated with ENZ and ABI. Methods: Patients treated with AA or ENZ for mCRPC from September 10, 2014, to June 2, 2017 were identified within the Veterans Health Administration. For these patients, presence of diabetes or complicated diabetes was determined using the Charlson method from the International Classification of Diseases (ICD) 9/10 codes. A Kaplan–Meier time to event analysis and the cox proportional hazards modeling was used to analyze the data with the latter including covariates such as age, Charlson Comorbidity Index, body-mass index, treatment with bone-directed therapy, black race, and baseline PSA at start of treatment with ENZ or ABI. Results: We identified 5822 patients treated for mCRPC, of which 2202 had diabetes and were treated using either ENZ (n = 1041) or ABI (n = 1161). Median survival of patients with diabetes treated with ENZ was 3 months longer than in patients treated with ABI (23.8 vs. 20.8, p = 0.002 by log-rank). In 3620 patients without diabetes, no significant difference in median survival (24.7 vs. 22.7 months, p = 0.065) was seen between ENZ (n = 1463) and ABI (n = 2157). In a multivariable model, ENZ was associated with improved survival in patients with diabetes (adjusted HR 0.87, 95% CI 0.79-0.97) and in patients without diabetes (adjusted HR 0.90, 95% CI 0.83-0.98). Conclusions: ENZ was associated with improved 3-month median survival in patients with diabetes compared to ABI in unadjusted analyses. Additionally, in adjusted analyses the cox proportional model also showed significantly better survival in mCRPC patients treated with ENZ both with and without diabetes, although the findings are more robust for patients with diabetes. The cause of these differences is unknown, so there may be differences in efficacy and adverse events between the two agents in real-world use. Further assessment of patient outcomes with comorbid disease is appropriate to improve care of patients with advanced prostate cancer.

Impact of care fragmentation in patients receiving neoadjuvant chemotherapy and radical cystectomy for bladder cancer.

468 Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC). However, the impact of care fragmentation on the outcomes of patients receiving NAC and RC for MIBC is not well defined. Methods: The National Cancer Database was queried for adult (≥18 years old) patients with cT2-T4aN0M0 urothelial carcinoma of the bladder receiving NAC followed by RC between 2004 and 2017. Patients were dichotomized based on whether they received fragmented care (FC, defined as receiving NAC at a different facility from RC) or integrated care (IC, defined as receiving NAC and RC at a single facility). Descriptive statistics were used to characterize the two groups based on demographic and therapeutic profiles. Overall survival was compared between patients who received FC versus IC. Statistical analyses include Chi-squared tests, t-tests, Kaplan-Meier with log-rank test, and Cox regression analysis. Results: A total of 5054 patients received NAC followed by RC: 1848 (36.6%) received FC and 3206 (63.4%) received IC. Greater travel distance, private insurance, and treatment at a community cancer program were associated with FC whereas age, sex, race, median income, education level, rurality, and comorbidity burden were not. While patients who received FC had a longer time to initiation of NAC (40 vs. 37 days, p&lt; 0.001), there was no significant difference in median overall survival (OS) (84.3 vs. 92.8 months, p= 0.37). On multivariable Cox regression analysis, age, comorbidity burden, stage, lymphovascular invasion, and surgical margins were associated with OS, while FC was not (hazard ratio: 1.03; 95% confidence interval 0.94-1.13; p= 0.51). Conclusions: Although care fragmentation was associated with a slight delay in the initiation of NAC, long-term survival rates were similar between the FC and IC groups.[Table: see text]

Neoadjuvant Stereotactic Body Radiotherapy After Upfront Chemotherapy Improves Pathologic Outcomes Compared With Chemotherapy Alone for Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma Without Increasing Perioperative Toxicity

BackgroundPatients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT).MethodsPatients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes.ResultsOf 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%; p < 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months; p = 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%; p < 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%; p < 0.001), negative nodes (59% vs 42%; p < 0.001), and pathologic complete response (7% vs 0%; p = 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (p < 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (p = 0.81).ConclusionsDespite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.

POS-732 QUALITY OF LIFE AND ONE-YEAR SURVIVAL OF PATIENTS WITH KIDNEY FAILURE IN A RESOURCE LIMITED SETTING

In 2017, 1.2million people died due to kidney failure making it the 12th leading cause of death globally. This position has risen from 17th over the past three decades. The global burden of kidney failure is most felt in Resource Limited Settings (RLS) such as Uganda in Sub-Saharan Africa (SSA). In most of SSA, patients never receive renal replacement therapy due to limited accessibility or proximity to these services and of those initiated onto dialysis, 85% will discontinue it due to cost limitations to maintain healthcare expenditure thus leading to premature death. The objective of this study was to determine the survival and changes in Quality of Life (QOL) of kidney failure patients receiving care in a tertiary hospital in Uganda over a one-year period. Patients aged ≥18 years with kidney failure were recruited from the renal outpatients’ clinic, hemodialysis unit and inpatient ward of tertiary hospital in Uganda, and followed up for 12months. Survival rates were calculated using the Kaplan Meier method and factors associated with survival analysed with the log rank test. Quality of life was calculated using the Kidney Disease and Quality of Life-Short Form (KDQOL-SF™) version 1.3 questionnaire. Scores less than 50 were considered to be indicative of poor QOL. Data was analysed for 335 patients recruited into the study. 216 (64%) patients were on Conservative Management (CM) while 119 (34%) were on Hemodialysis (HD). Overall, one-year survival was 26.6%; 95%CI (21.8 – 31.2). There was no statistically significant difference in median survival of patients on CM (7.6 months) in comparison to those on HD (8 months) (p-value 0.3984). Male sex and distance from the hospital were significantly associated with shorter survival HR 1.38 (CI 1.04-1.83) while belonging to a protestant faith improved survival HR 0.64 (CI 0.48-0.88). Quality of life scores changed significantly for 13 out of 19 subdomains of the KDQOL-SF™. Subdomain scores that changed the most included- Social support; 75.6 ±29.2 at baseline to 27.7 ±19.4 at one year (p-value <0.001), and Effects of kidney disease 54± 20 to 70± 23 (p-value <0.001). All three composite summary scores; -mental health, physical health and kidney disease specific, showed statistically significant increases but remained less than 50 throughout the one-year follow up. Survival is dismal for patients with kidney failure with no survival or QOL advantage offered by HD in comparison to CM in this setting. Male sex and residence far from the hospital were associated with reduced survival and protestant faith improved survival despite poor QOL scores and a marked decline in social support over the one-year period. To improve patient outcomes in RLS, health systems need to increase accessibility and affordability of specialist renal services including; trained human resources and renal replacement therapy options, as well as integrate spiritual support, financial literacy and social support services into existing care practices.

Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial.

The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported. In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial. Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer. Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer.

Day 30 SUVmax predicts progression in patients with lymphoma achieving PR/SD after CAR T-cell therapy

AbstractAbout 70% of patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel) and who achieve a partial response (PR) or stable disease (SD) on the day 30 (D30) positron emission tomography (PET)–computed tomography (CT) scan progress; however, the factors that are predictive of progression are unknown. This a retrospective study of patients with LBCL who were treated with axi-cel at MD Anderson Cancer Center between January of 2018 and February of 2021. Among 50 patients with D30 PR/SD, 13 (26%) converted to a complete response (CR). Among 95 patients with a D30 CR, 72 (76%) remained in CR. On univariate analysis, the only day −5 characteristic associated with conversion from D30 PR/SD to subsequent CR was a higher platelet count (P = .05). The only D30 factor associated with conversion from D30 PR/SD to subsequent CR was a lower maximum standardized uptake volume (SUVmax; P < .001); all patients with D30 SUVmax ≥ 10 progressed. After a median follow-up of 12 months, no significant difference in median progression-free survival was observed between patients who converted from D30 PR/SD to subsequent CR and those who had been in CR since D30 (P = .19). Novel predictive and prognostic markers based on tissue biopsy and noninvasive diagnostic assays are needed to more effectively identify these patients and characterize the biology of their residual disease.

Efficacy and safety of ramucirumab and docetaxel in previously treated patients with squamous cell lung cancer: a multicenter retrospective cohort study.

Ramucirumab plus docetaxel (RAM/DOC) therapy is currently the standard for previously treated advanced non-small cell lung cancer (NSCLC), irrespective of histology. However, in the clinical trial, only the first-line platinum-based chemotherapy refractory patients were enrolled and the eligible criteria was strict to avoid hemoptysis, especially in squamous cell NSCLC (Sq). Thus, the efficacy and safety data on ramucirumab for Sq in real-world settings after immune checkpoint inhibitors monotherapy or combination therapy approved as novel first-line therapy is lacking. We retrospectively analyzed previously treated patients with advanced NSCLC who underwent RAM/DOC therapy at four institutions. Clinical data on the initiation of RAM/DOC were collected from medical records. Treatment outcomes were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Incidence of pulmonary hemorrhage was assessed according to the Common Terminology Criteria for Adverse Events version 5.0. Overall, 237 patients with NSCLC were included and 38 (16%) had squamous cell carcinoma. There were no significant differences in median progression-free survival and overall survival between Sq and non-Sq patients (5.8months vs. 4.3months, P = 0.0937; 15.2months vs. 13.4months, P = 0.714, respectively). Of all patients, 13 (5%) developed pulmonary hemorrhage. According to histological analysis, there was no significant difference in pulmonary hemorrhage proportion between Sq and non-Sq cohorts (2/38 vs. 11/199, respectively, P = 0.947). For previously treated patients with Sq, the efficacy and safety of RAM/DOC therapy were confirmed in a real-world setting and were similar to non-Sq.