Measure Of Overall Survival Research Articles

Are measures and related symptoms of cachexia recorded as outcomes in gastrointestinal cancer chemotherapy clinical trials?

Cachexia is prevalent in gastrointestinal cancers and worsens patient outcomes and chemotherapy compliance. We examined to what extent registered gastrointestinal cancer chemotherapy clinical trials record measures and related symptoms of cachexia as outcomes, and whether these were associated with trial characteristics. Four public trial registries (2012-2022) were accessed for Phase II and/or III randomized controlled pancreatic, gastric, and colorectal cancer chemotherapy trial protocols. Trial outcome measures of overall survival and toxicity/side effects, and those related to cachexia [physical activity, weight/body mass index (BMI), dietary limitations, caloric intake, lean muscle mass] and symptoms (appetite loss, diarrhoea, pain, fatigue/insomnia, constipation, nausea, vomiting, and oral mucositis) were extracted, along with the number and types of performance status and patient-reported outcomes (PROs) tools. Data were summarized descriptively. Chi-square tests examined associations between outcomes and trial characteristics (cancer type, trial location, funding source, PROs tools, and commencement year). Statistical significance was set at P<0.05. We included 540 trial protocols (pancreatic (35.2%), colorectal (33.3%) and gastric (31.5%)), with most trials from Europe (44.1%). Trial lead investigator was from academia (28.3%), industry (27.6%) and government (26.3%). Allied health professional involvement (26.9%) occurred at eligibility. Adjuvant therapy in trials was mainly treatment-related (68.1%). Additional medication included anti-nausea (2.2%) and analgesia (0.9%). Trial protocols mostly recorded overall survival (90.4%) and toxicity (78.9%), and the symptoms appetite loss (26.1%) and diarrhoea (19.1%), with the other symptoms recorded in <10% of the trials. Reporting of physical activity (P=0.001), dietary limitations (P=0.002), lean muscle mass (P=0.027), appetite loss (P<0.001), pain (P=0.001), nausea (P=0.012), and oral mucositis (P=0.049) varied depending cancer type. Toxicity/side effects (P=0.022), physical activity (P<0.001), appetite loss, nausea, and vomiting (all P<0.001), diarrhoea (P=0.010), pain (P=0.001), fatigue/insomnia (P=0.001) varied depending on the trial location. Trial funding was predominantly from private/industry (34.3%) and influenced the reporting of overall survival (P=0.049), weight/BMI (P=0.005), caloric intake (P=0.015), and pain (P=0.031). Performance status and PROs tools were mentioned in 91.2% and 46.3% of the trials, respectively. Trials that incorporated PROs tools were more likely to report cachexia related outcomes, except for overall survival, lean muscle mass, and oral mucositis. The proportion of trials measuring weight/BMI increased with trial commencement year (P=0.04). Cachexia-related outcomes were under-recorded in gastrointestinal cancer chemotherapy trials. As trial patients experience a high symptom burden, cachexia-relevant measures and symptoms should be assessed throughout the trial, and integrated with primary endpoints to support their progress.

UK Stakeholder Perspectives on Surrogate Endpoints in Cancer, and the Potential for UK Real-World Datasets to Validate Their Use in Decision-Making.

Duration of overall survival in patients with cancer has lengthened due to earlier detection and improved treatments. However, these improvements have created challenges in assessing the impact of newer treatments, particularly those used early in the treatment pathway. As overall survival remains most decision-makers' preferred primary endpoint, therapeutic innovations may take a long time to be introduced into clinical practice. Moreover, it is difficult to extrapolate findings to heterogeneous populations and address the concerns of patients wishing to evaluate everyday quality and extension of life. There is growing interest in the use of surrogate or interim endpoints to demonstrate robust treatment effects sooner than is possible with measurement of overall survival. It is hoped that they could speed up patients' access to new drugs, combinations, and sequences, and inform treatment decision-making. However, while surrogate endpoints have been used by regulators for drug approvals, this has occurred on a case-by-case basis. Evidence standards are yet to be clearly defined for acceptability in health technology appraisals or to shape clinical practice. This article considers the relevance of the use of surrogate endpoints in cancer in the UK context, and explores whether collection and analysis of real-world UK data and evidence might contribute to validation.

Structural and Functional Cardiac Parameters in Patients with AL Amyloidosis Correlate with Uptake of the Amyloidophilic Radiotracer Iodine ( 124I) Evuzamitide

Background: The deposition of fibrillar aggregates of monoclonal free light chains in the heart is a characteristic feature of light chain associated (AL) amyloidosis. Cardiac amyloid is the major cause of morbidity and mortality in these patients. Structural and functional sequelae of cardiac amyloidosis can be appreciated clinically using echocardiography, cardiac magnetic resonance imaging, and measurement of serum NT-proBNP and troponins. These measures are not particularly amyloid-specific, and the correlation between parameters derived from these evaluations and amyloid burden remain enigmatic. The iodine-124 labeled peptide (p5+14), iodine ( 124I) evuzamitide, is a novel radiotracer that is being evaluated for the detection of systemic amyloidosis, of any type, by PET/CT imaging. As an amyloid binding peptide, this radiotracer has the potential to serve as a first line diagnostic agent capable of providing whole body semi-quantitative estimation of organ-specific amyloid load. Nascent studies of the relationship between 124I-evuzamitide uptake and established clinical parameters in patients with amyloidosis are underway. Here we report a single site, open label pilot study of 18 ( n=18) patients with AL ( n=8) and ATTR amyloidosis ( n=10) that evaluates the cardiac uptake of 124I-evuzamitide with contemporaneous echocardiographic and serum biomarkers (NCT05968846). Methods: The data described herein was collected as part of an open label single site repeat imaging study that plans to enroll up to 20 ( n=20) patients with AL ( n=10) and ATTR ( n=10) amyloidosis. To date, eight ( n=8) patients with AL and ten ( n=10) with ATTR amyloidosis have undergone 124I-evuzamitide PET/CT imaging with contemporaneous transthoracic echocardiography and assessment of serum NTproBNP within ~30 h of imaging. Patients received 37 or 74 MBq 124I-evuzamitide, and PET/CT imaging was performed at ~5 h post injection. Images were interpreted by a single reviewer, experienced in evaluating this tracer, for positive cardiac uptake. A fully manual 2D region of interest (ROI) analysis was performed encompassing the free left ventricular (LV) wall, LV lumen and interventricular septum (IVS). Blood pool was used as a reference tissue to determine standard uptake value ratios (SUVR mean) and to control for the rate of tracer clearance from the central compartment. Cardiac uptake of radiotracer was compared with free LV wall thickness (cm), IVS thickness (cm), global longitudinal strain (GLS, %), and serum NT-proBNP (pg/mL) measurements. Pearson and Spearman correlations were used to test for associations between variables. Results: Patients with AL amyloidosis were 2012 Mayo Stage I ( n=2/8) or Stage II ( n=6/8). The mean serum NTproBNP was 672.9±762.4 pg/mL (min=98, max=2327). With singular exception, all patients with AL amyloidosis had visually evident cardiac uptake of 124I-evuzamitide in the PET/CT images. In patients with AL amyloidosis ( n=8), the SUVR mean (encompassing the LV, lumen and IVS) correlated strongly with LV thickness (cm) (Pearson r=0.83, p=0.011) and GLS (%) (Pearson r=0.74, p=0.037), but not the IVS thickness (cm) (Pearson r=0.57, p=0.142). In contrast, in patients with ATTR ( n=10), there was no significant correlation of SUVR mean with GLS ( p=0.395), but a moderate significant correlation of SUVR mean with the LV ( p=0.037) and IVS ( p=0.017) thickness was observed. Similarly, in this pilot cohort, we observed a strong positive correlation between serum NTproBNP and cardiac SUVR mean (Pearson r=0.81, p=0.015), but not for patients with ATTR amyloidosis (Pearson r=0.58, p=0.079). Conclusion: Serum NTproBNP is a validated and qualified measure of overall survival for patients with AL amyloidosis (PMID: 27416985). Global longitudinal strain, with or without inclusion of other structural parameters such as left atrial volume, is a strong predictor of survival in patients with AL amyloidosis (PMID: 29111123, PMID: 37143609). PET/CT imaging using 124I-evuzamitide is a promising technique for diagnosing and monitoring AL and other types of amyloidosis. In light of these early results that demonstrate a strong relationship between validated metrics of all cause mortality in patients with AL, larger studies should seek to evaluate similar relationships with some metric of 124I-evuzamitide uptake in the heart, and indeed other organs.

Paclitaxel-coated Devices Improve Outcomes in Patients Presenting With Chronic Limb-Threatening Ischemia

Paclitaxel (PTX)-coated devices decrease restenosis after femoropopliteal artery intervention. Recently, they have been linked to a potential increase in late mortality and amputation based on data of patients predominantly presenting with claudication. Outcome of PTX in patients with chronic limb-threatening ischemia (CLTI) are unknown. The objective of this study was to compare outcome of CLTI patients treated with and without PTX. Patients who underwent femoropopliteal artery interventions for CLTI from January 2016 to October 2020 (n = 35,533; 13,546 treated with PTX) in the Society for Vascular Surgery Vascular Quality Initiative were reviewed. Patients were divided based on PTX exposure and propensity matched to control for differences in symptoms, comorbidities, and perioperative medications. After matching there were 13,528 patients in each cohort. Primary outcome measures of overall survival (OS), limb salvage, freedom from target vessel revascularization (TVR), and freedom from major adverse limb events (MALE) were assessed using Kaplan-Meier survival analysis. After matching there were no significant differences in baseline characteristics. At 2-year follow-up, there was no significant difference in OS between PTX and no-PTX patients (81 vs 80%; P = .07). A significant benefit was observed with PTX treatment in limb salvage (90% vs 87%; P < .001) (Fig 1), freedom from MALE (73% vs 69%; P < .001) (Fig 2), and freedom from TVR (81% vs 78%; P < .001). Multivariable Cox regression analysis confirms that PTX is associated with improved limb salvage (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83; P < .001), freedom from MALE (HR, 0.73; 95% CI, 0.68-0.78; P < .001), and freedom from TVR (HR, 0.72; 95% CI, 0.66-0.79; P < .001), with no difference in OS (HR, 0.95; 95% CI, 1.01-0.88; P = .11). At 2 years, CLTI patients treated with a PTX-coated device demonstrated improved limb salvage, freedom from TVR, and freedom from MALE with no difference in OS. This study suggests that the use of PTX-coated devices may be beneficial to patients presenting with CLTI and are not associated with adverse outcome as suggested by recent meta-analyses.Fig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Long-term demographic changes of deer mouse (Peromyscus maniculatus) populations in a forest landscape with cumulative clearcutting

The deer mouse (Peromyscus maniculatus) is a generalist species and is widespread among the various early-successional forest habitats associated with post-clearcut landscapes. Deer mice seem to occupy clearcuts more than undisturbed late successional forest, at least for abundance, because harvested sites apparently act as dispersal sinks. We investigated the responses in abundance of P. maniculatus populations to cumulative clearcutting of coniferous forests on a landscape that had four independent clearcutting events (Periods 1 to 4) over a 42-year interval from 1979 to 2020 in south-central British Columbia, Canada. We tested three hypotheses (H) that populations of P. maniculatus would (H1) increase in abundance owing to the ongoing availability of early seral post-harvest habitats associated with cumulative clearcutting; (H2) have higher mean abundance, reproduction, and survival in clearcut than forest sites owing to greater food resources; and (H3) occupy clearcut sites as dispersal sinks thereby having lower adult body mass (a proximate measure of condition) and reduced reproductive output than in forest sites.Mean annual abundance of P. maniculatus was highest and similar in Periods 2 and 4 with comparable numbers in Period 1 for the first four post-harvest years of these clearcutting periods. This pattern did not support H1 that P. maniculatus would increase in abundance associated with cumulative clearcutting over the 42-year period. Deer mouse populations reached relatively high densities (range of 23 to 53 per ha) on clearcut sites and these irruptions were likely related to supply of lodgepole pine seed from cones in logging debris. Overall mean abundance of P. maniculatus ranged from 1.4 to 3.6 times higher in clearcut than forest sites, thereby supporting the abundance part of H2. Recruitment, number of successful pregnancies, and breeding young-of-the-year deer mice were all higher in clearcut than forest sites, thereby supporting the reproduction part of H2. However, equivocal measures of overall survival did not support this hypothesis. The general similarity in mean body mass of adult mice between treatment sites and higher reproductive output in clearcut than forest sites did not support H3 that clearcut sites would act as dispersal sinks for deer mice. This study is the first to measure the long-term demographic responses of deer mice to cumulative clearcutting over a coniferous forest landscape. Clearcut sites may provide high-quality habitat for deer mice in this forest landscape.

205: ADJUNCTIVE SURVEILLANCE MODALITIES AND ONCOLOGIC OUTCOME: A REPORT FROM THE ENSURE STUDY

Abstract Background and aim Established and emerging therapies for recurrent esophageal cancer may impact survival and health-related quality-of-life (HRQL), however surveillance protocols after primary curative treatment are inconsistent. Specifically, whether advantages exist for adjunctive surveillance modalities is unknown and was the focus of this study. Methods ENSURE was an international multicenter observational study of consecutive patients undergoing curative-intent surgery for esophageal and esophagogastric junction cancers (2009–2015) across 20 European and North American cancer centers (NCT03461341). The initial report from ENSURE assessed the impact of intensive imaging surveillance on the primary outcome measure of overall survival (OS); secondary outcomes included treatment, disease-specific survival, recurrence pattern, and HRQL. In the present study, multivariable linear, logistic and Cox proportional hazards regression analyses were performed to determine the independent impact of adjunctive surveillance modalities on oncologic outcome. Results Results 4,682 patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy). Routine biochemistry, nutritional profiling, tumor markers, surveillance endoscopy and flexible nasolaryngoscopy were routinely assessed in 37, 33, 15, 19 and 7% of Centers, respectively. Routine biochemistry and tumour markers were associated with reduced risk of symptomatic recurrence, however neither modality was associated with survival benefit. Endoscopic surveillance was independently associated with increased probability of isolated local or anastomotic recurrence (OR1.49 [1.05–2.14]), and reduced probability of symptomatic recurrence (OR0.17 [0.12–0.25]), but not with improved OS. On subgroup analysis, endoscopic surveillance was associated with reduced symptomatic recurrence (OR0.19 [0.12–0.29]) and increased probability of tumour-directed therapy among patients with adenocarcinoma (OR1.65 [1.14–2.38]), but not those with SCC. Endoscopic surveillance was associated with improved OS (HR0.73 [0.55–0.98]) among patients with Barrett’s oesophagus, while flexible nasolaryngoscopy was associated with improved OS among patients with SCC (HR0.19 [0.05–0.80]). Nutritional surveillance was independently associated with increased tumor-directed therapy, improved HRQL (P = 0.015) and OS (HR0.89 [0.80–0.99]), while a multimodal surveillance approach was also associated with improved OS (HR0.83 [0.72–0.95]). Conclusion These data suggest that a multimodal and tailored surveillance approach may improve oncologic outcomes following curative-intent surgery for esophageal and esophagogastric junction cancer. These findings may inform guideline development and shared decision-making with patients.

Immune Cell Infiltrates of the Tumor Microenvironment and Radiosensitivity of Recurrent Glioblastomas and Their Association With Outcome

GBM is a heterogenous tumor with diverse co-existing cell types. However, very little is known of the recurrent GBM (rGBM) microenvironment, and how immune cell infiltrates (ICI) may predict outcome. CIBERSORT provides an estimate of ICI via a gene expression deconvolution algorithm. We have previously validated the radiosensitivity index (RSI) as a measure of overall survival (OS) in primary GBM treated with radiotherapy (RT). In this novel study, we analyzed the presence of ICI, RSI, neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios with respect to outcomes in previously treated rGBMs.From IRB-approved institutional tissue biorepository, we identified patients treated between 2004 - 2012, with rGBM who underwent re-excision and had complete gene expression profiling. Patients with prior low-grade glioma (secondary GBM) were excluded. Gene expression levels were assessed by Affymetrix Hu-RSTA assays. RSI was calculated using the previously published rank-based algorithm. For ICI, the presence and high expression (75%) were used to assess relationships with OS and progression free survival (PFS). For NLR, 2.4 was used based on published data in primary GBM. The 75% of PLR was assessed. Time-to-event analyses were performed with Kaplan-Meier estimates and compared via log-rank test. Associations of factors and outcomes were explored using Cox-regression.A total of 42 rGBM patients were identified, of which 40 (95%) were treated previously by adjuvant RT. Median follow-up from initial GBM diagnosis was 25 (range, 6-119) months and 8 (1-63) months from rGBM re-excision. All patients underwent surgery, 4 (9.5%) received re-irradiation, and 22 (50%) received further treatment under clinical trial. Median PFS was 2.5 (1-18) months after re-excision. Current smoking status (P = 0.04), KPS < 70 (P = 0.01) and age > 50 years (P = 0.01) were poor prognostic factors for OS. Treatment under clinical trial did not affect OS (P = 0.2) or PFS (P = 0.6). Four patients were treated with RT following re-excision. As expected, since RSI is predictive of outcome in RT treated patients, RSI was not predictive of PFS (P = 0.9) or OS (P = 0.6) in the cohort. Among ICI, lack of monocytes (P = 0.05) and presence of resting NK-cells (P = 0.01) adversely affected OS. In addition, high expression (³75%) of neutrophils (P = 0.01) and helper T-cells (P = 0.01) adversely affected OS. No other ICI subtypes were predictive of OS or PFS. Patients with pre-surgery NLR > 2.4 (P = 0.03) and high PLR > 240 (P = 0.04) had significantly worse OS. On multivariate analysis, helper T-cells (HR 0.99; 95% CI 0.98-0.99; P = 0.03), neutrophils (HR 0.43; 95% CI 0.21-0.91; P = 0.02), NLR (HR 0.33; 95% CI 0.11-0.96; P = 0.04) and PLR (HR 0.46; 95% CI 0.21-1.0; P = 0.05) remained significant for OS.Immune activation in previously treated rGBM may have a role in tumor biology affecting survival. The knowledge of ICI and NLR/PLR may serve as a unique risk-stratification and guide clinical decisions.

Correction of redox metabolism and the relationship of markers of systemic chronic inflammation with a measure of overall survival in cancer patients with multiorgan resections

Background. According to the literature, multiorgan resections are carried out with the most radical removal of healthy tissue. Therefore, there is a need for the most favorable preparation of the patient with perioperative therapy to reduce further complications with obtaining improved clinical and pathological prognostic indicators to increase the overall survival. Purpose: correction of redox metabolism based on the data of the oxidative modification of proteins, degree of their catabolic reaction, and data on the enzymatic state and lipid peroxidation in cancer patients with multiorgan resections on the gastrointestinal tract under conditions of perioperative intensive care. Materials and methods. The study involved 117 cancer patients aged 67.6 ± 3.7 years with locally advanced tumor processes of the gastrointestinal tract. Studies have been conducted on the enzymatic state, lipid peroxidation and oxidative modification of proteins, both in terms of the degree of fragmentation of their products in spontaneous and iron-induced reactions, and the level of medium-weight protein molecules. Serum levels of circulating tumor necrosis factor alpha, interleukin-6 and -8 were determined. Survival analysis was performed using the Kaplan-Meier method. Results. The study of patients has shown an improvement in the indicators of oxidative modification of proteins and lipid peroxidation. Survival in cancer patients with multiorgan resections demonstrated dependence on the levels of tumor necrosis factor alpha, interleukin-6 and -8 in the blood serum. Conclusions. Conducting perioperative intensive care makes it possible to reliably restore indicators of the enzymatic state, lipid peroxidation and oxidative protein modification products (on the fourth day and second week, p &lt; 0.05). This gives us grounds for recommending the determination of these parameters in the group of cancer patients and the implementation of metabolic intensive care. In the group of L-ornithine L-aspartate and quercetin combination with povidone, the lowest indicators of systemic chronic inflammation and the best overall survival were found.

Prognostic Impact of Baseline and Delta Tumor Radiomics Features in Patients With Oropharyngeal Cancer (OPC) Treated With Adaptive Image-Guided Radiotherapy (IGRT)

Adaptive IGRT is generally performed to account for mid-treatment changes in tumor volume or patient weight. We investigated the pattern of radiomic features changes and their prognostic value in comparison to well-established clinical variables. Using an IRB-approved single institution database of head and neck cancer patients, we retrospectively identified adult OPC patients who underwent definitive adaptive IGRT between 2012 and 2018. We collected patient, disease, and treatment characteristics, as well as outcomes measures of overall survival (OS) and event-free survival (EFS). All patients underwent contrast-enhanced computed tomography scans for initial and mid-treatment simulation. Primary gross tumor volumes were manually contoured. A total of 145 radiomics features were selected from the following categories: shape, intensity, and second-order features (neighborhood intensity difference ‘NID’, grey-level co-occurrence matrix ‘GLCM’, and grey-level run length matrix ‘GLRLM’) and analyzed using digital gene expression panel software. Second-order features were calculated both in 3D and 2.5D fashions. Pre- and mid-RT values of radiomics features were compared using Wilcoxon signed-rank test with Bonferroni’s correction. Correlation of clinical, pre-RT and delta-radiomic ([mid-pre]/pre) features to OS and EFS was determined using Harrell's concordance index (C-Index) with a preset cut-off >0.7. Statistical analysis was performed using R software. 42 patients were included, with primary tumors located in the base of tongue (n = 23) and tonsil (n = 20). 37 (86%) were HPV positive. Of the mid-RT radiomic features that changed significantly (p<0.05); NID 3D coarseness and contrast, NID 2.5D busyness and coarseness, GLRLM 2.5D, and shape spherical disproportion and surface area density features increased compared to their pre-RT values. In contrast, lower values were noted for other shape features (volume, sphericity, convexity, and compactness, among others), intensity kurtosis, and most GLCM 3D features. For both EFS and OS, radiomics features were more highly correlated than clinical features. For EFS, delta-intensity entropy and mean had the highest correlation (C-index: 0.77 and 0.74, respectively), with no clinical variables demonstrating C-index >0.7. For OS, pre-RT NID 3D complexity outperformed the highest correlated clinical variable of performance status (C-index: 0.78 vs 0.76, respectively). Our analysis consistently showed that pre-RT or delta-radiomic features better correlated to OS and EFS when compared to clinical variables. Temporal tumor radiomics trajectories can provide radiation oncologists with a non-invasive tool to quantify dynamic tumor changes.

Disease-free survival as a measure of overall survival in resected pancreatic endocrine neoplasms.

Overall survival (OS) is considered as the standard measure of outcome in oncology. However, considering that resectable pancreatic neuroendocrine neoplasms (Pan-NENs) usually have a long OS, the feasibility of prospective studies is questionable due to a long follow-up period needed. The primary endpoint was to validate the use of disease-free survival (DFS) as a surrogate measure of OS. The secondary endpoint was to calculate the gain in sample size using DFS instead of OS in hypothetical prospective studies with two parallel groups. A systematic review of studies reporting both OS and DFS in resected Pan-NENs was carried out. Multivariate linear regression analysis was used to evaluate if DFS predicts the OS in patients undergoing radical resection. Monte Carlo simulation was performed to estimate the gain in sample size, supposing the use of DFS instead of OS, to evaluate a hypothetical adjuvant treatment after surgery in a randomized trial. Six studies reporting data about seven cohorts of resected Pan-NENs were included, for a total of 1088 patients. The median OS and DFS were 144 (27–134) and 122 (50–267) months, respectively. There was a significant correlation between DFS and OS (R2 = 0.988; P = 0.035). Monte Carlo simulations showed that the number of patients needed to demonstrate a significant reduction of probability of a ‘target event’ in a hypothetical two-arm group exploring the hypothetical role of adjuvant therapy was reduced using DFS instead OS. This finding supports the legitimacy of using DFS as an acceptable surrogate for OS in surgical clinical trials.

Preoperative imaging characteristics predict poor survival and inadequate resection for left-sided pancreatic adenocarcinoma: a multi-institutional analysis

BackgroundOptimal treatment of pancreatic ductal adenocarcinoma of the neck, body and tail (PDAC-NBT) necessitates R0 surgical resection. Preoperative radiographic identification of patients likely to achieve successful oncologic resection remains difficult. This study seeks to identify preoperative imaging characteristics predictive of non-R0 resections or impaired survival for PDAC-NBT. MethodsPatients at five high-volume centers who underwent resection for PDAC-NBT were retrospectively analyzed. The most immediate preoperative cross-sectional scan was assessed along with outcome measures of overall survival and margin status. Results330 patients were treated between 2001 and 2016. Margin status included 247 R0 (78.2%), 67 R1 (21.2%), and 2 R2 (0.6%). A non-R0 resection predicted worse survival (p = 0.0002). On preoperative imaging, patients with tumors greater than 20 mm, tumor attenuation greater than 70 Hounsfield units, or who demonstrated pancreatic atrophy and/or calcifications also had worse survival (p = 0.010, p = 0.036, p = 0.025 respectively). Patients with tumors interfacing with the splenic artery or vein or extending posteriorly achieved fewer R0 resections (p = 0.0006, p = 0.0004, p = 0.001, respectively). ConclusionPreoperative cross-sectional imaging can identify tumor characteristics associated with poor survival and non-R0 resection. Further investigation is needed to identify the appropriate surgical and treatment modifications necessary to clinically benefit this subset of patients.

A comparison of clinical outcomes between simultaneous integrated boost (SIB) versus sequential boost (SEQ) intensity modulated radiation therapy (IMRT) for head and neck cancer: A meta-analysis.

The optimal intensity modulated radiation therapy (IMRT) technique for head and neck cancer (HNC) has not been determined yet. The present study aimed to compare the clinical outcomes of the simultaneous integrated boost (SIB)-IMRT versus the sequential boost (SEQ)-IMRT in HNC. A meta-analysis of 7 studies involving a total of 1049 patients was carried out to compare the treatment outcomes together with severe acute adverse effects of the SIB-IMRT versus the SEQ-IMRT in HNC patients. Comparison of the SIB-IMRT and SEQ-IMRT showed no significant difference in the measurement of overall survival (OS) (hazard ratio [HR] 0.94; 95% confidence inerval [CI], 0.70-1.27; P = .71), progression free survival (PFS) (HR 1.03; 95% CI, 0.82-1.30; P = .79), locoregional recurrence free survival (LRFS) (HR 0.98; 95% CI, 0.65-1.47; P = .91), and distance metastasis free survival (DMFS) (HR 0.87; 95% CI, 0.50-1.53; P = .63). Moreover, there were no significant differences in adverse effect occurrence between the SIB-IMRT and SEQ-IMRT groups. SIB-IMRT and SEQ-IMRT can provide comparable outcomes in the treatment of patients afflicted by HNC. Both IMRT techniques were found to carry a similar risk of severe acute adverse effect. SIB-IMRT may have advantages due to its convenience and short-course of treatment; however, the optimum fractionation and prescribed dose remained unclear. Furthermore, both IMRT techniques can be advocated as the technique of choice for HNC. Treatment plan should be individualized for patients.

Lower expression of Bax predicts poor clinical outcome in patients with glioma after curative resection and radiotherapy/chemotherapy

BackgroundThe prognosis in patients with gliomas after surgical resection followed by radiotherapy and/or chemotherapy is still very poor. The pro-apoptotic protein Bax, a short-lived protein in cancers, plays important roles in the sensitivity of glioma cells to spontaneous and therapy-induced apoptosis but and its prognostic value in gliomas is unknown.MethodsBy an immunohistochemical method, we determined Bax protein expression from 96 patients with gliomas after curative resection. Two statistical analyses were performed to evaluate the prognostic significance of Bax protein: an independent continuous and a multivariate categorical analysis, with test/validation set-defined cut points, and Kaplan–Meier estimated outcome measures of overall survival (OS) and relapse-free survival (RFS).ResultsBax protein levels in glioblastoma were significantly decreased compared with grade II gliomas. Lower levels of Bax expression confer worse OS (continuous P = 0.025; categorical P = 0.003) and RFS (continuous P = 0.014; categorical P < 0.0001) and negatively correlate with the grades of gliomas. Patients underwent radiotherapy followed by surgical resection showed significantly increased OS (median = 45 vs. 17 months) and RFS (median = 39 vs. 16 months). Patients with higher levels of Bax and radiotherapy showed greatly increased survival rates (median OS = 66 months and median RFS = 105 months). Lower expression of Bax also confers inferior clinical outcome for gliomas patients after chemotherapy with temozolomide (OS and RFS P < 0.0001).ConclusionDecreased expression of Bax correlates with poor clinical outcome in patients with gliomas. We propose that Bax protein levels can be used as a reliable prognostic marker for risk-stratify patients with gliomas after curative resection and radiotherapy and/or chemotherapy.

Preoperative imaging characteristics predict poor survival and inadequate resection for left-sided pancreatic adenocarcinoma: a multi-institutional analysis

Background: Optimal treatment of pancreatic ductal adenocarcinoma of the neck, body and tail (PDAC-NBT) is predicated upon complete surgical resection with negative (R0) margins. However, preoperative identification of patients who may achieve successful resection is difficult. Thus study seeks to identify preoperative imaging characteristics that may serve as prognostic markers associated with non-R0 resection and subsequent poor survival. Methods: Patients at five high-volume pancreatic centers with PDAC-NBT who underwent surgical resection with curative intent were retrospectively analyzed. The most immediate preoperative cross-sectional computed tomography scan was assessed and correlated with the primary outcome measures of overall survival and surgical margins. Results: 330 patients were surgically treated between 2001 and 2016. Of these, 247 underwent R0 (78.2%), 67 R1 (21.2%), and 2 R2 resection (0.6%). A non-R0 resection was significantly associated with worse survival (p = 0.0002). On preoperative imaging, patients with tumors greater than 20 mm, tumor attenuation greater than 70 Hounsfield units, or who demonstrated pancreatic atrophy or calcifications had significantly worse overall survival (p = 0.010, p = 0.036, p = 0.025 respectively). Tumors with any vascular interface with the splenic artery, splenic vein, or both were significantly more likely to undergo non-R0 resection (p = 0.0006, p = 0.0004, p = 0.020, respectively). Posterior extension of the tumor was also associated with non-R0 resection (p = 0.001). Conclusion: Preoperative cross-sectional imaging can identify tumor characteristics which are associated with poor survival and non-R0 resections. These data suggest PDAC-NBT patients with vascular involvement may benefit from aggressive, en-bloc surgical resection, preoperative medical therapy, and regionally directed margin-enhancement techniques.

Phase 3, randomized, double-blind, placebo-controlled study of venetoclax combined with azacitidine versus azacitidine in treatment-naïve patients with acute myeloid leukemia.

TPS7069 Background: Elderly acute myeloid leukemia (AML) is a biologically and clinically distinct disease with a diminished response to chemotherapy, low remission rates, and short disease-free and overall survival. Venetoclax (VEN) is a potent, selective small-molecular inhibitor of BCL-2. In preclinical models, venetoclax has been shown to kill AML cells as a single agent with demonstrated synergistic activity in combination with the DNA methyltransferase inhibitor azacitidine (AZA). Early clinical data from a phase 1b study (NCT02203773) showed that VEN plus AZA had an acceptable safety profile and promising efficacy in treatment-naïve elderly patients with AML. The current phase 3 study continues to evaluate the combination for this AML population. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT02993523) is designed to assess VEN plus AZA compared with placebo plus AZA in treatment-naïve elderly and adult patients with AML who are not eligible for standard induction therapy due to age or comorbidities. Primary objectives of the study are to evaluate if VEN with AZA will improve overall survival (OS) and composite complete remission rate (CR+CRi) versus placebo with AZA. Secondary objectives include event-free survival, CR+CRi rate at the end of Cycle 1, and if combining VEN plus AZA reduces fatigue and improves global health status/quality of life based on patient reported outcomes versus placebo with AZA. Exploratory objectives are to evaluate biomarkers predictive of VEN activity including minimal residual disease negativity rate, and BCL-2 expression and outcome measures of overall survival and complete remission rate, as well as the impact of VEN on additional quality of life measures. Patients will be randomized 2:1 to VEN plus AZA (arm A) or placebo plus AZA (arm B). Patients on arm A will receive once daily 400 mg VEN orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days in a 28-day cycle. Patients on arm B will receive once daily placebo orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days on a 28-day cycle. Study recruitment began in February 2017, with target enrollment of 400 patients. Clinical trial information: NCT02993523.

Biopsy versus partial versus gross total resection in older patients with high-grade glioma: a systematic review and meta-analysis.

Optimal extent of surgical resection (EOR) of high-grade gliomas (HGGs) remains uncertain in the elderly given the unclear benefits and potentially higher rates of mortality and morbidity associated with more extensive degrees of resection. We undertook a meta-analysis according to a predefined protocol and systematically searched literature databases for reports about HGG EOR. Elderly patients (≥60 y) undergoing biopsy, subtotal resection (STR), and gross total resection (GTR) were compared for the outcome measures of overall survival (OS), postoperative karnofsky performance status (KPS), progression-free survival (PFS), mortality, and morbidity. Treatment effects as pooled estimates, mean differences (MDs), or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were determined using random effects modeling. A total of 12 607 participants from 34 studies met eligibility criteria, including our current cohort of 211 patients. When comparing overall resection (of any extent) with biopsy, in favor of the resection group were OS (MD 3.88 mo, 95% CI: 2.14-5.62, P < .001), postoperative KPS (MD 10.4, 95% CI: 6.58-14.22, P < .001), PFS (MD 2.44 mo, 95% CI: 1.45-3.43, P < .001), mortality (RR = 0.27, 95% CI: 0.12-0.61, P = .002), and morbidity (RR = 0.82, 95% CI: 0.46-1.46, P = .514) . GTR was significantly superior to STR in terms of OS (MD 3.77 mo, 95% CI: 2.26-5.29, P < .001), postoperative KPS (MD 4.91, 95% CI: 0.91-8.92, P = .016), and PFS (MD 2.21 mo, 95% CI: 1.13-3.3, P < .001) with no difference in mortality (RR = 0.53, 95% CI: 0.05-5.71, P = .600) or morbidity (RR = 0.52, 95% CI: 0.18-1.49, P = .223). Our findings suggest an upward improvement in survival time, functional recovery, and tumor recurrence rate associated with increasing extents of safe resection. These benefits did not result in higher rates of mortality or morbidity if considered in conjunction with known established safety measures when managing elderly patients harboring HGGs.

Clinical Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study

BackgroundThe availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit. ObjectiveTo provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA. Design, setting, and participantsWe retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel. Outcome measurements and statistical analysisThe independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis. Results and limitationsWe assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences. ConclusionsWe were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy. Patient summaryIt is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent.

Stem cell factor is a novel independent prognostic biomarker for hepatocellular carcinoma after curative resection.

Stem cell factor (SCF), a ligand of c-kit, is a hematopoietic growth factor. Uncontrolled activity of SCF/c-kit signaling pathway contributes to the formation of a variety of human malignancies. In this study, we determined whether SCF expression could risk-stratify patients with hepatocellular carcinoma (HCC) after curative resection. HCC tissues from 160 patients were collected during curative resection and stained with SCF and CD34, a marker for microvessel density (MVD), using immunohistochemistry. Two statistical analyses were performed: an independent continuous and a multivariate categorical analysis, with test/validation set-defined cut points, and Kaplan-Meier estimated outcome measures of overall survival (OS) and relapse-free survival (RFS). We found that higher levels of SCF confer worse OS (continuous P = 0.014; and categorical P = 0.009), and RFS (continuous P = 0.002; categorical P = 0.003) of patients with HCC. SCF varies independently from MVD-CD34, tumor node metastasis, histologic grade, age and gender, and retains prognostic significance when analysed as a categorical variable in a multivariate analysis . We confirmed that MVD-CD34 is also an independent prognostic marker for patients with HCC. The levels of SCF and CD34 showed a positive and significant correlation (P < 0.0001) and double low expression confers superior OS (median = 48 months) and RFS (median = 24 months), whereas double high expression confers shortest RFS (median = 10.5 months) compared with single measurements. The prognostic values of SCF and CD34 were independently determined in this study and we propose that both of them are independent prognostic markers for HCC.

Abstract 5152: Estimating the fraction of a tumor that is killed by a drug.

Abstract We analysed mathematically the progress of thousands of patients enrolled in clinical trials with diagnoses of prostate, renal cell, breast, and thyroid carcinomas and multiple myeloma, treated with cytotoxic and targeted drugs, tumor quantity being measured radiologically or by serum markers (see, e.g., Stein et al Clin Cancer Res. 2011,17, 907-17, for prostate cancer). Treatment often results in reduction of tumor quantity, with subsequent regrowth. In some regression does not occur; in others regrowth is not recorded. All these outcomes are described by a simple mathematical formula (see Eq. (1) below) that describes progress of treatment, yielding the rate of tumor decay, d, and rate of regrowth, g. When regrowth is not seen, g is indistinguishable from zero, as is d if tumor quantity fails to decrease. Parameter g is a surrogate measure of overall survival. Median g values can be used to compare the arms of a clinical trial. In a minority of cases, increase in tumor quantity is delayed for an extended period of time before regrowth occurs, and the simple formula must be modified to include an additional parameter, Ø, the fraction of tumor killed by the drug, see Eq. (2). In a trial of 750 multiple myeloma (MM) patients treated with liposomal doxorubicin plus bortezomib (PLD + B) or bortezomib (B) alone, 114 cases were better fitted by Eq. (2) than by Eq. (1). For these, the median value of Ø was 0.99, meaning that 99% of the tumor was destroyed by drug, only 1% being left to regrow. Were this 1% of tumor to regrow at rate 0.0131 per day (the median for these 114 patients) it would return to the initial tumor quantity, expanding 100-fold, in ln(100)/0.0131 days or 11.5 months. The OS for these patients who died before the study closed was 12.7 (8.9 to 16) months, close to the predicted. If Ø is less than 0.85, and g is larger than 0.02 per day, the predictions of Eqs. 1 and 2 are similar. Slight scatter in the data will not allow a distinction to be made between the models, nor a definitive value of Ø estimated. Nevertheless, aggregating data from numerous patients enables Ø to be estimated for such a data set. Aggregating the data for the 388 MM patients for whom g and/or d but not Ø could be established, Ø was 0.84 for the PLD + B arm and 0.79 for B. To regrow to the initial tumor quantity requires 2.7 doublings for the PLD + B arm and 2.2 for B, a difference that would result in only a trivial increase in OS. However, the difference between the computed tumor growth rates, 0.0019 and 0.0037 for the PLD + B arm and B respectively, would be expected to lead to a noticeable increase in OS were treatment to continue beyond conventional endpoints. Measuring the fraction of tumor killed by a drug, and the rate of growth recovery, can give insight into drug/tumor interactions and guide development of new therapies. Equation 1: f(t) = exp (-d • t) + exp (g • t) -1, exp is the base of the natural logarithms, and f(t) the tumor measurement at time t, normalized to the tumor measurement at day 0; Equation 2: f(t) = Ø • exp (-d • t) + (1-Ø) • exp (g • t)] Citation Format: Wilfred D. Stein, Julia Wilkerson, Elisabet Manasanch, Sen H. Zhuang, Susan E. Bates, Tito Fojo. Estimating the fraction of a tumor that is killed by a drug. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5152. doi:10.1158/1538-7445.AM2013-5152

Carbonic anhydrase-9 expression in head and neck cancer: a meta-analysis

The purpose of the study was to compare CA-9 positivity versus CA-9 negativity in head and neck malignancies and to correlate levels of CA-9 with tumor grade, size, and nodal status. Overall and disease-free survival were also compared for CA-9 positive and negative tumors. A literature search was performed using Medline, Embase, Ovid and Cochrane databases for studies between 1990 and 2009. Carbonic anhydrase IX, CA IX, CA-9, head and neck, and survival were used as search terms. Random-effect meta-analytical techniques were conducted for outcome measures of overall survival and disease-free survival. Sixteen studies matched the selection criteria, reporting on 1,470 patients. Eight hundred and forty two specimens were reported as being CA-9 positive or negative: 512 (60.81%) were CA-9 positive and 330 (39.19%) were CA-9 negative. Nine hundred and eighty specimens had levels of CA-9 expression recorded: 547 (55.82%) had high levels of CA-9 and 433 (44.18%) had low CA-9 levels. Survival was significantly reduced if the tumor was positive for CA-9 (P < 0.0001). Disease-free survival is significantly reduced in patients with CA-9 positive (P = 0.0008) head and neck malignant tumors. The presence of CA-9 in head and neck malignant tumors is associated with reduced overall survival and disease-free survival.