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.

Does HER2 status influence in the benefit of ramucirumab and paclitaxel as second line treatment of advanced gastro-esophageal adenocarcinoma? Data from the AGAMENON-SEOM registry.

PURPOSE: This study aimed to compare ramucirumab-paclitaxel versus chemotherapy in second-line (2L) advanced gastroesophageal cancer (aGEC) based on HER2 status and analyze prognostic factors. METHODS: The study includes patients from the AGAMENON-SEOM registry with aGEC and known HER2 status who received 2L between 2016 and 2021. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS) and multivariable Cox regression analysis was done to adjust for confounding variables. RESULTS: Of the 552 patients who met the selection criteria, 149 (26.9%) had HER2-positive aGEC, 89 were treated with chemotherapy, and 60 with ramucirumab-paclitaxel, and 403 had an HER2-negative aGEC, 259 were treated with chemotherapy, and 144 with ramucirumab-paclitaxel. In the whole sample, 2L PFS was 3.0 months (95% CI 2.8-3.2), 2L OS, 5.7 months (5.2-6.3), and ramucirumab-paclitaxel versus chemotherapy was associated with increased PFS (HR 0.64, 95% CI 0.53-0.78, p < 0.0001) and OS (HR 0.68, 0.55-0.83, p = 0.0002). Median PFS of ramucirumab- paclitaxel versus chemotherapy was 3.5 vs 2.8 months (HR 0.67, 0.54-0.83, p = 0.0004) in HER2-negative, and 4.7 vs 2.7 months (HR 0.57, 0.40-0.82, p = 0.0031) in HER2-positive aGEC, respectively. Median OS for ramucirumab-paclitaxel versus chemotherapy was 6.6 vs 5 months (HR 0.67, 0.53-0.85, p = 0.0007) in HER2-negative, and 7.4 vs 5.6 months (HR 0.70, 0.53-1.04, p = 0.083) in HER2-positive aGEC, respectively. ECOG-PS, tumor burden, Lauren subtype, and neutrophil-lymphocyte ratio were prognostic factors. CONCLUSIONS: In patients with an aGEC from the AGAMENON-SEOM registry, 2L treatment with ramucirumab-paclitaxel was superior to chemotherapy in PFS, OS and response rate, independent of HER2 status.

Integrative immune transcriptomic classification improves patient selection for precision immunotherapy in advanced gastro-oesophageal adenocarcinoma.

BACKGROUND: Advanced gastro-oesophageal cancer (GEA) treatment has been improved by the introduction of immune checkpoint inhibitors (CPIs), yet identifying predictive biomarkers remains a priority, particularly in patients with a combined positive score (CPS) < 5, where the benefit is less clear. Our study assesses certain immune microenvironment features related to sensitivity or resistance to CPIs with the aim of implementing a personalised approach across CPS < 5 GEA. DESIGN: Through integrative transcriptomic and clinicopathological analyses, we studied in both a retrospective and a prospective cohort, the immune tumour microenvironment features. We analysed the cell types composing the immune infiltrate highlighting their functional activity. RESULTS: This integrative study allowed the identification of four different groups across our patients. Among them, we identified a cluster whose tumours expressed the most gene signatures related to immunomodulatory pathways and immunotherapy response. These tumours presented an enriched immune infiltrate showing high immune function activity that could potentially achieve the best benefit from CPIs. Finally, our findings were proven in an external CPI-exposed population, where the use of our transcriptomic results combined with CPS helped better identify those patients who could benefit from immunotherapy than using CPS alone (p = 0.043). CONCLUSIONS: This transcriptomic classification could improve precision immunotherapy for GEA.

Applicability of Quality Indicators for Appropriate Antibiotic use in Outpatient Parenteral Antimicrobial Therapy (OPAT): A Point Prevalence Survey.

The ability to measure the quality of antibiotic prescription is a critical element in any antimicrobial stewardship programme. The aim of this study was to evaluate the clinimetric properties of 33 quality indicators (QIs) developed to assess Outpatient Parenteral Antimicrobial Therapy (OPAT) and to identify potential room for improvement in a hospital-at-home (HaH) unit. Study performed in a healthcare district in Barcelona, Spain with 260,657 inhabitants, nine primary healthcare centres, a 400-bed acute care teaching hospital, and an HaH unit. We studied 33 QIs on appropriate antibiotic use and classified them as qualitative or quantitative. Quantitative QIs were further categorized as measurable or non-measurable depending on the availability of data in the patients' medical records. Data from 202 OPAT episodes in 192 patients were assessed. Adherence was found for 22 of the 24 qualitative QIs analyzed; the other two showed room for improvement. Four of the nine quantitative indicators were non-measurable. High adherence rates were achieved for QI-17 "The OPAT plan should be documented" (84.65%), QI-26 "The OPAT treatment plan should include choice, dose, frequency, duration and follow-up plan" (79.70%), and QI-33 "The team should document clinical response" (94.55%). Adverse events were documented in just 1.98% of cases (QI-32) and 92.57% patients were classified as alive on discharge (QI-24). The QIs evaluated were applicable to clinical practice and proved useful for identifying areas with room for improvement in our setting and for guiding the design of future interventions with specific objectives.

Cost analysis and critical success factors of the use of oxygen concentrators versus cylinders in sub-divisional hospitals in Fiji.

BACKGROUND: Oxygen is vital in the treatment of illnesses in children and adults, yet is lacking in many low and middle-income countries health care settings. Oxygen concentrators (OCs) can increase access to oxygen, compared to conventional oxygen cylinders. We investigated the costs and critical success factors of OCs in three hospitals in Fiji, and extrapolated these to estimate the oxygen delivery cost to all Sub-Divisional hospitals (SDH) nationwide. METHODS: Data sources included key personnel interviews, and data from SDH records, Ministry of Health and Medical Services, and a non-governmental organisation. We used Investment Logic Mapping (ILM) to define key issues. An economic case was developed to identify the investment option that optimised value while incorporating critical success factors identified through ILM. A fit-for-purpose analysis was conducted using cost analysis of four short-listed options. Sensitivity analyses were performed by altering variables to show the best or worst case scenario. All costs are presented in Fijian dollars. RESULTS: Critical success factors identifed included oxygen availability, safety, ease of use, feasibility, and affordability. Compared to the status quo of having only oxygen cylinders, an option of having a minimum number of concentrators with cylinder backup would cost $434,032 (range: $327,940 to $506,920) over 5 years which would be 55% (range: 41 to 64%) of the status quo cost. CONCLUSION: Introducing OCs into all SDHs in Fiji would reduce overall costs, while ensuring identified critical success factors are maintained. This study provides evidence for the benefits of OCs in this and similar settings.

The development and implementation of an oxygen treatment solution for health facilities in low and middle-income countries.

BACKGROUND: Oxygen reduces mortality from severe pneumonia and is a vital part of case management, but achieving reliable access to oxygen is challenging in low and middle-income country (LMIC) settings. We developed and field tested two oxygen supply solutions suitable for the realities of LMIC health facilities. METHODS: A Health Needs Assessment identified a technology gap preventing reliable oxygen supplies in Gambian hospitals. We used simultaneous engineering to develop two solutions: a Mains-Power Storage (Mains-PS) system consisting of an oxygen concentrator and batteries connected to mains power, and a Solar-Power Storage (Solar-PS) system (with batteries charged by photovoltaic panels) and evaluated them in health facilities in The Gambia and Fiji to assess reliability, usability and costs. RESULTS: The Mains-PS system delivered the specified ≥85% (±3%) oxygen concentration in 100% of 1-2 weekly measurements over 12 months, which was available to 100% of hypoxaemic patients, and 100% of users rated ease-of-use as at least 'good' (90% very good or excellent). The Solar-PS system delivered ≥85% ± 3%) oxygen concentration in 100% of 1-2 weekly measurements, was available to 100% of patients needing oxygen, and 100% of users rated ease-of-use at least very good.Costs for the systems (in US dollars) were: PS$9519, Solar-PS standard version $20 718. The of oxygen for a standardised 30-bed health facility using 1.7 million litres of oxygen per year was: for cylinders 3.2 cents (c)/L in The Gambia and 6.8 c/L in Fiji, for the PS system 1.2 c/L in both countries, and for the Solar-PS system 1.5 c/L in both countries. CONCLUSIONS: The oxygen systems developed and tested delivered high-quality, reliable, cost-efficient oxygen in LMIC contexts, and were easy to operate. Reliable oxygen supplies are achievable in LMIC health facilities like those in The Gambia and Fiji.

Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02).

BACKGROUND: RAS testing is used to select patients with anti-epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p-IGF-1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti-EGFR resistance. MATERIALS AND METHODS: We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12-months progression-free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild-type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFS based on the analysis of clinical and selected biomarkers (α = .05, ß = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. RESULTS: We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left-sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60-0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61-0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61-0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58-0.73, p = .09). CONCLUSION: The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12-month PFS. IMPLICATIONS FOR PRACTICE: This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.

The prognostic value of hTERT expression levels in advanced-stage colorectal cancer patients: a comparison between tissue and serum expression.

AIM: Telomeres are regions of highly repetitive, non-coding DNA located at the termini of chromosomes whose principal function is to maintain the structural stability of these ends. In 90% of human tumours, telomere length is maintained by the expression and activation of telomerase reverse transcriptase. Various studies have demonstrated an increase in telomerase activity in tumour tissue, which suggests its possible prognostic value. The main objective of our study was to study the prognostic value of the expression level of telomerase catalytic component (hTERT) in patients with colorectal cancer (CRC). METHODS: We analysed the prognostic value of the ratio of telomerase expression in tumour tissue to telomerase expression in the adjacent healthy mucosa and the prognostic value of the expression level of hTERT in the serum of patients diagnosed with CRC. As secondary objectives of the study, we (1) analysed the correlation between telomerase expression in the serum and that in the tumour tissue and (2) analysed the relationship between telomerase expression and different clinical parameters. RESULTS: Peripheral blood and tissue samples taken from 48 patients with CRC were analysed. No significant differences were observed in disease-free survival (DFS) or overall survival time (OST) between the groups of patients categorised based on the ratio of telomerase expression between tumour tissue and healthy tissue. The correlation index (Pearson's coefficient) between telomerase levels in the serum and those in tissue was 0.32. Our study of the relationship between telomerase levels in the serum and different clinical variables, such as tumour size, ganglion affectation, preoperative carcinoembryonic antigen levels and stage, revealed a higher telomerase expression level in patients with stage IV CRC. There was no significant association between telomerase expression in tumour tissue and the clinical parameters analysed. CONCLUSIONS: The results obtained in our study do not allow us to propose that the level of telomerase expression be used as a prognostic factor in colorectal cancer. Thus, we cannot consider telomerase expression in the serum as a surrogate marker of its expression in tumour tissue.

Phase II clinical trial with gemcitabine and paclitaxel sequential monotherapy as first-line treatment for advanced non-small-cell lung cancer (SLCG 01-04).

BACKGROUND: In advanced-stage (IIIB or IV) non-small-cell lung cancer (NSCLC), combination chemotherapy has demonstrated response rates of 20% and a 1-year survival rate of 30%. We conducted a multicentre, open-label, nonrandomised phase II trial to determine the efficacy and tolerability of sequential monotherapy with gemcitabine followed by paclitaxel in chemotherapy-naïve patients with advanced NSCLC. MATERIALS AND METHODS: Between December 2002 and July 2004, the Spanish Lung Cancer Group (SLCG) conducted a study in which 34 patients with advanced (stage IIIB or IV) NSCLC received 1200 mg/m(2) of i.v. gemcitabine on days 1, 8 and 15 of each 28-day cycle for a total of 3 cycles followed by 100 mg/m(2) of weekly i.v. paclitaxel for a maximum of 8 weeks. If objective response or stable disease was achieved, 70 mg/m(2) of weekly i.v. paclitaxel was maintained until disease progression was evident or toxic effects were intolerable. Lung Cancer Symptom Scale (LCSS) analysis was performed. Baseline levels of serum VEGF, EGFR, telomerase reverse transcriptase (hTERT) and K-ras mutations were analysed. The primary endpoint was the objective response rate. RESULTS: The median age of the 34 patients who were enrolled was 67 years (range 46-77), but later 8 patients were excluded; 78.8% were men, 81.8% had performance status 1 and also 81.8% had metastatic disease at diagnosis. The objective response rate was 28% (95% CI, 14.2-47.8); the median overall survival was 7.2 months (95% CI, 2.1-12.3) and the median time to progression (TTP) was 3.1 months (95% CI, 2.5-5.3). Grade 3 or 4 drug-related haematological toxicities were observed in 6 patients. Patients with lower baseline serum VEGF levels had significantly longer survival. CONCLUSIONS: Sequential therapy with gemcitabine followed by paclitaxel was well tolerated with a low proportion of grade 3 or 4 adverse events, the absence of unexpected toxicity and with an improvement in quality of life. Unfortunately, the response rate did not meet the minimally required rate of 20% and the study was prematurely closed. VEGF was identified as a poor prognostic factor for TTP and survival.

Retrospective analysis of the prognostic role of p16 protein inactivation in plasma in patients with locally advanced non-small cell lung cancer.

It has been analyzed the frequency of p16 inactivation in 67 blood samples of patients diagnosed with advanced non-small cell lung cancer (NSCLC), to establish the relationship between p16 inactivation and time to progression (TTP) and overall survival (OS), and its relationship with various clinical parameters. This is a retrospective study of 67 patients diagnosed with advanced NSCLC between August 2000 and July 2003 in the Hospital General de Valencia analysing p16 inactivation by assessing in plasma either loss of heterozygosity (LOH) or p16 promoter methylation. The study shows p16 inactivation in 28.3% (either by LOH or by p16 methylation). No significant differences were found between the group with p16 inactivation and the group without p16 inactivation, either in patients' TTP (31 weeks vs. 24 weeks; p=0.7) or in OS (53 weeks vs. 43 weeks; p=0.48). No relationship was found between the state of p16 and the clinical parameters analyzed (stage, ECOG, histology). Despite the fact that p16 is important in NSCLC carcinogenesis, the data obtained in our study do not allow the prognostic impact of this biological marker to be established.

Can the Spanish care system assume the new costs of medications against cancer?

Cancer is a high incidence disease, forcing healthcare systems to assign a significant amount of resources to its treatment. New developments have arisen recently: development of new agents that act at specific steps of cellular differentiation and proliferation and identification of predictive genetic markers which allow sub-groups of patients that will benefit from these agents, alone or in combination with chemotherapy, to be targeted. The majority of new drugs coming to the market combine greater clinical benefit and higher costs. Constraints on healthcare budgets worldwide make it necessary to rationalise the expense by prioritising allocation of available resources to the most efficient interventions, so that the best possible clinical result can be obtained at a reasonable cost and with the best quality of life for the patient. Economic evaluation studies represent the only tool available to scientifically determine the cost-effectiveness of new treatments and the budgetary impact of their introduction to the therapeutic arsenal available for the treatment of cancer.