Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Bayesian interpretation of immunotherapy trials with dynamic treatment effects.

INTRODUCTION: The mechanism of action of immune checkpoints inhibitors hinders the writing of rational statistical analysis plans for phase III randomised clinical trials (RCTs) because of their unpredictable dynamic effects. The purpose is to illustrate the advantages of Bayesian reporting of treatment efficacy analysis in immunotherapy RCTs, in contrast to frequentist reporting. METHOD: Fourteen RCTs (one with two pairwise comparisons) that failed to achieve their primary objective (overall survival, OS) were selected. These RCTs were reanalysed using Bayesian Cox models with dynamic covariate coefficients and time-invariant models. RESULTS: The RCTs that met inclusion criteria were 7 lung cancer trials, various other tumours, with antiPD1, antiPDL1 or antiCTLA4 therapies. The minimum detectable effect (δS) was superior to the true benefit observed in all cases, in conditions of non-proportional hazards. Schoenfeld tests indicated the existence of PH assumption violations (p<0.05) in 6/15 cases. The Bayesian Cox models revealed a probability of benefit >79% in all the RCTs, with the therapeutic equivalence hypothesis unlikely. The OS curves diverged after a median of 9.1 months. Since the divergency, no non-proportionality was evinced in 13/15, while the Wald tests achieved p<0.05 in 12/15 datasets. In all cases, the Bayesian Cox models with dynamic coefficients detected fluctuations of the hazard ratio, and increased 2-year OS was the most likely hypothesis. CONCLUSION: We recommend progressively implementing Bayesian and dynamic analyses in all RCTs of immunotherapy to interpret and assess the credibility of frequentist results.

Is advanced esophageal adenocarcinoma a distinct entity from intestinal subtype gastric cancer? Data from the AGAMENON-SEOM Registry.

BACKGROUND: Advanced esophageal adenocarcinoma (EAC) is generally treated similarly to advanced gastroesophageal junction (GEJ-AC) and gastric (GAC) adenocarcinomas, although GAC clinical trials rarely include EAC. This work sought to compare clinical characteristics and treatment outcomes of advanced EAC with those of GEJ-AC and GAC and examine prognostic factors. PATIENTS AND METHODS: Participants comprised patients with advanced EAC, intestinal GEJ-AC, and GAC treated with platin and fluoropyrimidine (plus trastuzumab when HER2 status was positive). Overall and progression-free survival were estimated using the Kaplan-Meier method. Cox proportional hazards regression gauged the prognostic value of the AGAMENON model. RESULTS: Between 2008 and 2019, 971 participants from the AGAMENON-SEOM registry were recruited at 35 centers. The sample included 67.3% GAC, 13.3% GEJ-AC, and 19.4% EAC. Pulmonary metastases were most common in EAC and peritoneal metastases in GAC. Median PFS and OS were 7.7 (95% CI 7.3-8.0) and 13.9 months (12.9-14.7). There was no difference in PFS or OS between HER2- and HER2+ tumors from the three locations (p > 0.05). Five covariates were found to be prognostic for the entire sample: ECOG-PS, histological grade, number of metastatic sites, NLR, and HER2+ tumors treated with trastuzumab. In EAC, the same variables were prognostic except for grade. The favorable prognosis for HER2+ cancers treated with trastuzumab was homogenous for all three subgroups (p = 0.351) and, after adjusting for the remaining covariates, no evidence supported primary tumor localization as a prognostic factor (p = 0.331). CONCLUSION: Our study supports the hypothesis that EAC exhibits clinicopathological characteristics, prognostic factors, and treatment outcomes comparable to intestinal GEJ-AC and GAC.

Critical reappraisal of phase III trials with immune checkpoint inhibitors in non-proportional hazards settings.

BACKGROUND: The dynamic effects of immune checkpoint inhibitors (ICIs) are a challenge when designing and analysing data in non-proportional hazards (PH) scenarios. Herein, we present the risk of making type II errors, affecting pharmacotherapeutic development when methods that assume constant effects are applied. PATIENTS AND METHODS: Individual patient data from six clinical trials (KEYNOTE-062/061, IMvigor211, CA184-143 y CheckMate-057/037) were extracted. The most relevant time-varying effects were examined using the Royston-Parmar spline model (RPSM), time-driven analyses and weighted log-rank and Renyi tests. RESULTS: The RPSM yields an appropriate fit in non-PH contexts, enabling dynamic descriptions of the hazard rate, and time-varying differences of overall survival (OS)/progression-free survival. In the KEYNOTE-061, CheckMate-057 and 037 trials, 12-, 18-, and 24-month OS rates were higher with immunotherapy (differences of some 10%) (P-value <0.05). In KEYNOTE-062, CA184-043 and IMvigor-211 trials, OS rate differences were significant for past 20 months. Flemming-Harrington and Renyi tests with late weighting (e.g. with ρ-value = 0 and γ-value = 1) captured the existence of significant differences on all curves. The Cox models and log-rank tests were inefficient at detecting the effect. CONCLUSION: This analysis highlights the risk of declaring studies with ICIs negative, despite associating substantial OS benefits. Effort and consensus are needed with respect to methodology to design and evaluate trials with ICIs in non-PH settings.

Does active smoking worsen Covid-19?

Probably it does.

Multistate Models: Accurate and Dynamic Methods to Improve Predictions of Thrombotic Risk in Patients with Cancer.

Research into cancer-associated thrombosis (CAT) entails managing dynamic data that pose an analytical challenge. Thus, methods that assume proportional hazards to investigate prognosis entail a risk of misinterpreting or overlooking key traits or time-varying effects. We examined the AGAMENON registry, which collects data from 2,129 patients with advanced gastric cancer. An accelerated failure time (AFT) multistate model and flexible competing risks regression were used to scrutinize the time-varying effect of CAT, as well as to estimate how covariates dynamically predict cumulative incidence. The AFT model revealed that thrombosis shortened progression-free survival and overall survival with adjusted time ratios of 0.72 and 0.56, respectively. Nevertheless, its prognostic effect was nonproportional and disappeared over time if the subject managed to survive long enough. CAT that occurred later had a more pronounced prognostic effect. In the flexible competing risks model, multiple covariates were seen to have significant time-varying effects on the cumulative incidence of CAT (Khorana score, secondary thromboprophylaxis, high tumor burden, and cisplatin-containing regimen), whereas other predictors exerted a constant effect (signet ring cells and primary thromboprophylaxis). The model that assumes proportional hazards was incapable of capturing the effect of these covariates and predicted the cumulative incidence in a biased way. This study evinces that flexible and multistate models are a useful and innovative method to describe the dynamic effect of variables associated with CAT and should be more widely used.

Surgery for metastases for esophageal-gastric cancer in the real world: Data from the AGAMENON national registry.

INTRODUCTION: The effect of surgery for metastases in patients with esophagogastric cancer is unknown, given the lack of randomized clinical trials; likewise, the criteria for selecting eligible patients remain to be determined. METHODS: This registry evaluates the results of patients with advanced adenocarcinoma of the stomach, distal esophagus, or gastro-esophageal junction from 32 centers. To assess selection criteria and prognostic factors, a state arrival extended Markov proportional hazards (PH) model was used. RESULTS: 1792 subjects were analyzed, 5% of whom (n = 92) underwent surgery for metastasis. The most common surgeries were peritoneal (29%), hepatic (24%), and distant lymph nodes (11%). Subjects chosen for metastasectomy had higher survival rates, HR 0.34 (95% CI, 0.06-0.80, p = 0.021). Patients who underwent surgery had a mOS since metastasectomy of 16.7 months (95% CI, 12.5-22.4). The 1- and 3-year relapse rates following R0 resection were 58% and 65%, respectively. Median time since R0 metastasectomy until relapse was 8.4 months (95% CI, 7.6-23.7). The 3-year OS after surgery was 30.6% (95% CI, 19.3-40.4). Duration of chemotherapy prior to surgery (months) increased mortality (HR 1.04 [95% CI, 1.01-1.07]), p = 0.009. The only significant interaction involved the use of anti-HER2 therapy. CONCLUSION: The AGAMENON registry suggests that subjects with limited metastatic disease, selected on a clinical basis, can benefit from early surgeries. Prospective trials are needed to confirm these data.

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry.

BACKGROUND: The choice of chemotherapy in HER2-negative gastric cancer is based on centre's preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS). METHODS: We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2-3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of 'treatment-by-histology' interaction, was used to estimate treatment effect. RESULTS: Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525-0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054-1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49-0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50-0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46-0.88), P=0.046. CONCLUSIONS: As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.

Konjac glucomannan/xanthan gum enzyme sensitive binary mixtures for colonic drug delivery.

The polysaccharide konjac glucomannan (KGM) is degraded in the colon but not the small intestine, which makes it potentially useful as an excipient for colonic drug delivery. With xanthan gum (XG) KGM forms thermoreversible gels with hitherto unexplored biodegradation properties. In this work, rheological measurements of KGM and KGM/XG systems incubated with and without Aspergillus niger beta-mannanase (used to mimic colonic enzymes) showed that KGM was degraded by the enzyme even when interacting with XG. Tablets with KGM/XG/sucrose matrices that varied in accordance with a simplex design and bore diltiazem as a typical highly soluble drug load were prepared by wet granulation, and in most cases were found to possess satisfactory mechanical strength and exhibit slow, nearly zero-order drug release. Drug release from these tablets remained zero-order, but was accelerated (presumably due to degradation of KGM), in the presence of A. niger beta-mannanase at concentrations equivalent to human colonic conditions. However, marked differences between Japanese and American varieties of KGM as regards degree of acetylation and particle size led to significant differences in swelling rate and drug release between formulations prepared with one and the other KGM: whereas a formulation with Japanese KGM released its entire drug load within 24h in the presence of beta-mannanase, only 60% release was achieved under the same conditions by the corresponding formulation with American KGM, suggesting that with this KGM it will be necessary to optimize technological variables such as compression pressure in order to achieve suitable porosity, swelling rate, and drug release. To sum up, the results of this study suggest that sustained release of water-soluble drugs in the colon from orally administered tablets may be achieved using simple, inexpensive formulations based on combinations of KGM and XG that take the variability of KGM characteristics into account.

Konjac glucomannan and konjac glucomannan/xanthan gum mixtures as excipients for controlled drug delivery systems. Diffusion of small drugs.

Konjac glucomannan (KGM), alone or in combination with xanthan gum (XG), was evaluated as main component of systems capable of controlling the diffusion of small molecules with a view of their use in drug delivery. To provide the study with enough general character, KGM batches were obtained from the three main areas of excipient harmonization (Europe, USA and Japan). The rheological evaluation at physiological temperature of KGM (0.5%, w/v) aqueous dispersions, with or without XG at different ratios, showed significant variability among the three KGMs owing to differences in the acetylation degree. The Japanese and European varieties of KGM synergically interact with XG giving rise to gel formation; the synergism being maximum at a 1:1 ratio. By contrast, the American KGM does not show such effect forming only viscous solutions. Drug diffusion coefficients of theophylline and diltiazem HCl, with different molecular size and net charge, were evaluated in systems containing KGM/XG ratio 1:1. KGM/XG systems were more efficient than the XG alone dispersion for controlling drug diffusion of small molecules because of the gel formation. These results point out the potential of mixtures of some KGM types with XG to develop delivery systems capable of maintaining physical integrity and drug release control for up to 8-h period.

Characterization of diffusion of macromolecules in konjac glucomannan solutions and gels by fluorescence recovery after photobleaching technique.

Konjac glucomannan (KGM) is a neutral polysaccharide with interesting properties as gelling agent and thickener. Its peculiar biodegradability, being not degradable in the small intestine but degradable by the anaerobic human intestinal bacteria, turn it into a promising candidate for colonic drug delivery systems. In this study aqueous systems (0.5%, w/v,) of KGM from three different origins and their mixtures with xanthan gum (XG) (1:1) were evaluated as regards their rheological properties and the diffusion coefficients and mobile fraction of macromolecules (dextrans of different molecular weight). Rheological data illustrate the synergism between KGM and XG at a stoichiometric relationship 1:1. Moreover, fluorescence recovery after photobleaching (FRAP) data indicate that diffusion of probes through the polysaccharide systems cannot be completely explained by the macroscopic properties of the medium but it is related to their molecular size and as a consequence to a sieving mechanism. The strong differences between KGM from different suppliers suggest the convenience of establishing specifications for this material in order to use it as pharmaceutical excipient.