Chemonaive Patients Research Articles

Phase I Clinical Trial on Pleural Mesothelioma Using Neoadjuvant Local Administration of Paclitaxel-Loaded Mesenchymal Stromal Cells (PACLIMES Trial): Study Rationale and Design.

Background and rationale. Pleural mesothelioma (PM) is a rare and aggressive neoplasm that originates from the pleural mesothelium and whose onset is mainly linked to exposure to asbestos, which cannot be attacked with truly effective therapies with consequent poor prognosis. The rationale of this study is based on the use of mesenchymal stromal cells (MSCs) as a vehicle for chemotherapy drugs to be injected directly into the pathological site, such as the pleural cavity. Study design. The study involves the use of a conventional chemotherapeutic drug, Paclitaxel (PTX), which is widely used in the treatment of different types of solid tumors, including PM, although some limitations are related to pharmacokinetic aspects. The use of PTX-loaded MSCs to treat PM should provide several potential advantages over the systemically administered drug as reduced toxicity and increased concentration of active drug in the tumor-surrounding context. The PACLIMES trial explores the safety and toxicity of the local administration of Paclimes in chemonaive patients, candidates for pleurectomy. The secondary objective is to find the effective Paclimes dose for subsequent phase II studies and to observe and record the antitumor activity. Future direction. The experimental pre-clinical background and rationale are discussed as well.

Risk Stratification According to Baseline and Early Change in Neutrophil-to-Lymphocyte Ratio in Advanced Non-Small Cell Lung Cancer Treated with Chemoimmunotherapy: A Multicenter Real-World Study.

Chemoimmunotherapy is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, data on clinical predictive factors remain scarce. We aim to identify clinical biomarkers in patients undergoing chemoimmunotherapy. This multicenter, real-world cohort study included chemonaive patients who underwent chemoimmunotherapy between December 2018 and May 2022. Multivariate analysis was used to determine associations between survival outcomes and patient background, including baseline neutrophil-to-lymphocyte ratio (NLR) and its dynamic change (ΔNLR). To further investigate the clinical significance of NLR, patients were classified based on their peripheral immune status, defined by a combination of NLR and ΔNLR. The study included 280 patients with 30.1 months of median follow-up. Multivariate analysis revealed that older individuals, poor performance status, tumor proportion score < 1%, liver metastasis, baseline NLR ≥ 5, and ΔNLR ≥ 0 independently correlated significantly with shorter progression-free and overall survival (OS). Patients with high peripheral immune status (defined as NLR <5 and ΔNLR < 0) significantly improved long-term survival (2-year OS rate of 58.3%), whereas those with low peripheral immune status (defined as NLR ≥ 5 and ΔNLR ≥ 0) had extremely poor outcomes (2-year OS rate of 5.6%). Safety profiles did not differ significantly in terms of severe adverse events and treatment-related death rates despite the patients' peripheral immune status (P = 0.46 and 0.63, respectively). Our study provides real-world evidence regarding clinical prognostic factors for the efficacy of chemoimmunotherapy. The combined assessment of baseline NLR and ΔNLR could facilitate the identification of patients who are likely to achieve a durable response from chemoimmunotherapy.

Health-Related Quality of Life and Economic Analysis of Olanzapine Versus Aprepitant in Preventing Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy in Malaysia

ObjectivesOlanzapine has been shown to be effective in preventing chemotherapy-induced nausea and vomiting (CINV) after highly emetogenic chemotherapy (HEC); however, there is limited work on the impact of CINV on health-related quality of life (HRQoL) and the comparative cost-effectiveness of CINV prophylaxis in the Malaysian context. Therefore, this study was conducted to determine the HRQoL using EQ-5D-5L and the cost-effectiveness of olanzapine compared with aprepitant for CINV prophylaxis in Malaysia using data from a local study. MethodsFifty-nine chemo-naive patients receiving either olanzapine or aprepitant were randomly recruited and completed the EQ-5D-5L before and day 5 after HEC. HRQoL utility scores were analyzed according to the Malaysian valuation set. The economic evaluation was conducted from a healthcare payer perspective with a 5-day time horizon. Quality-adjusted life days (QALD) and the rate of successfully treated patients were used to measure health effects. The incremental cost-effectiveness ratio is assessed as the mean difference between groups’ costs per mean difference in health effects. A one-way sensitivity analysis was performed to assess variations that might affect outcomes. ResultsAprepitant and olanzapine arms’ patients had comparable baseline mean HRQoL utility scores of 0.920 (SD = 0.097) and 0.930 (SD = 0.117), respectively; however, on day 5, a significant difference (P value = .006) was observed with mean score of 0.778 (SD = 0.168) for aprepitant and 0.889 (SD = 0.133) for olanzapine. The cost per successfully treated patient in the aprepitant arm was 60 times greater than in the olanzapine arm (Malaysian Ringgit [MYR] 927 vs MYR 14.83). Likewise, the cost per QALD gain in the aprepitant arm was 36 times higher than in the olanzapine arm (MYR 57.05 vs MYR 1.57). Incremental cost-effectiveness ratio of MYR −937.00 (USD −200.98) per successfully treated patient and MYR −391.84 (USD −85.43) per QALD gained for olanzapine compared with the aprepitant-based regimen. ConclusionsAn olanzapine-based regimen is a cost-effective therapeutic substitution in patients receiving HEC in Malaysia.

Characteristics of nausea and its impact on health-related quality of life in cisplatin-treated patients receiving dexamethasone-sparing prophylaxis: an analysis of the LUNG-NEPA study.

We investigated the intensity and duration of nausea as well as its impact on health-related quality of life among cisplatin-treated patients who participated in a study of dexamethasone (DEX)-sparing regimens based on NEPA (netupitant/palonosetron). This retrospective analysis included chemo-naive patients from a trial evaluating non-inferiority of DEX on day 1 (DEX1 arm) combined with NEPA, compared with the same regimen with DEX administered on days 1-4 (DEX4; reference arm) following cisplatin (≥ 70mg/m2) administration. Nausea intensity was self-rated using a four-point Likert scale. Extended nausea duration was considered ≥ 3days within the 5days post-chemotherapy. Patients completed the Functional Living Index-Emesis (FLIE) questionnaire on day 6. In the DEX1 arm, more patients (20/76) experienced acute nausea, influencing the outcome of delayed nausea (38/76). During days 1 to 5, 51.3% (39/76) and 39.5% (30/76) of patients experienced nausea in the DEX1 and DEX4 arms, respectively (P = 0.192). Of these, 43.6% and 60% reported moderate-to-severe nausea, respectively, in the DEX1 and DEX4 arms (P = 0.200), while 74.4% and 56.7% of patients experienced extended nausea duration (P = 0.122). Similar between-arm rates of nauseated patients reported an impact on daily life (79.5% vs. 70%; P = 0.408). In analyses stratified for antiemetic regimen, moderate-to-severe nausea or extended nausea duration was associated with an impact on daily life (P ≤ 0.001). Despite the higher incidence, there was no suggestion of any strong adverse effect of NEPA plus single-dose DEX on the characteristics of nausea as well as its impact on daily life in patients with cisplatin-induced nausea. Further prospective controlled study is warranted. ClinicalTrials.gov identifier: NCT04201769. Registration date: 17/12/2019.

Prognostic and predictive significance of inflammatory markers in patients with locally advanced unresectable and metastatic pancreatic cancer treated with first-line chemotherapy FOLFIRINOX or Gemcitabine/Nabpaclitaxel.

Advanced pancreatic ductal adenocarcinoma (PDAC) remains adisease with adismal prognosis, significantly limited therapeutic options, and few innovative drugs. Inflammation plays asignificant role in the development and progression of PDAC. Systemic inflammatory indexes reflect the anti-tumor inflammatory capacity of and are of prognostic and predictive value in the treatment of patients with PDAC. In our retrospective study, we investigated the prognostic and predictive significance of inflammatory markers in chemonaive patients with locally advanced unresectable pancreatic cancer (LAPC) and metastatic pancreatic cancer (mPDAC), in relation to progression-free survival (PFS) and overall survival (OS). Survival analysis was conducted using the Kaplan-Meier method with log-rank tests in univariate analysis. We used multivariate Cox regression analysis to determine the impact of inflammatory markers on survival time. The present clinical study included 46 patients with LAPC and mPDAC treated with FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) or GEM/Nab-P (gemcitabine/nab-paclitaxel) as first-line chemotherapy regimens. Performance status (PS) ECOG 0-1, neutrophil-to-lymphocyte ratio (NLR)≤2.09 and the prognostic nutritional index (PNI)≥49.09 were associated with significantly longer OS in the analyzed patient cohort, Multivariate analysis confirmed PS, NLR and PNI as independent prognostic factors for OS. In our cohort of patients with advanced PDAC, PS, NLR and PNI were confirmed as independent prognostic factors for OS (Tab. 9, Fig. 2, Ref. 82). Text in PDF www.elis.sk Keywords: pancreatic cancer, inflammatory markers, tumor microenvironment, chemotherapy.

Favorable Outcomes of Splenic Marginal Zone Lymphoma in an International Study of 934 Patients with Long Follow-up

Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale international real-world data studies are critical to evaluate outcomes of different treatment interventions and to understand the natural history of SMZL in the rituximab-era. Methods: Adult patients with SMZL diagnosed between Jan 1 st 2000 and Dec 31 st 2018 were identified using regional/nationwide population-based registries or hospital registries in Europe, the UK, North America, and Australia. Medical records and pathology reports from eligible patients were reviewed locally by clinicians with specialty experience in hemato-oncology. SMZL cases were required to meet the diagnostic criteria by Matutes et al. Detailed data on clinico-pathological features, comorbidities, treatments (including treatment intention), treatment responses and survival outcomes were entered in a central study database. Overall survival (OS) was defined as time from diagnosis until death from any cause or censoring at last follow-up unless stated otherwise. Event-free survival (EFS) was defined as the time from diagnosis until histological transformation, initiation of new chemotherapy or death from any cause. Survival probabilities were estimated using the Kaplan-Meier estimator. Cumulative risk of transformation was estimated with death as a competing risk. Primary endpoints were 10-year OS and 5-year EFS respectivly. Results: A total of 934 patients from 25 sites were included. Median age at diagnosis was 68 years (IQR 60-76) and 54% were female. Bone marrow involvement was present in 96% (564/590) of those assessed, anemia (Hb &amp;lt;12g/dL for women or &amp;lt;13g/dL for men) in 58%, LDH &amp;gt;UNL in 46%, lymphocytosis (&amp;gt;5 x10 9/L) in 34%, and B-symptoms in 34%. Treatment data were available for 97% of patients. Median follow-up was 9.1 years (range 0-23). Watch and wait was the initial strategy in 28% and 88% of patients received at least one line of treatment during follow-up with the most common being splenectomy (45%), immuno-chemotherapy (19%) or rituximab monotherapy (8%). Fifteen percent received “other” treatments (i.e., combinations of listed therapies and/or radiation). The overall response rate to first-line treatment was 88% (95%CI: 85-90%) with 61% (95%CI: 57-64%) achieving CR. Second line (2L) therapy was needed in 34% during follow-up, 3L in 20% and 4L+ in 9%. The 5-year EFS and OS for all patients were 61% (95%CI: 57-65%) and 77% (95%CI: 74-80%) respectively. The 10-year OS and lymphoma-specific mortality (with non-SMZL deaths as competing risk) estimates were 60% (95%CI: 57-64%) and 11% (95%CI: 9-14%) respectively. The 5-year OS after 2L and 3L were 61% (95%CI: 55-68%) and 51% (95%CI: 42-61%) respectively (figure 1). The 10-year cumulative risk of histological transformation was 17% (95%CI: 13-21%), with 5-year post-transformation OS of 42% (32-54%). At the time of transformation, 60% were chemo-naive and 52% had never been treated for SMZL. The 5-year OS for chemo-naive patients with transformation was 54% (95%CI: 41-71%) versus 24% (95% CI: 13-44%) for transformations after (immuno)chemotherapy (p = 0.01). When comparing patients intended for treatment in first line with splenectomy (n=312) versus rituximab (n=70), patients treated with splenectomy more frequently presented with extra-hilar lymphadenopathy (35% vs 18%), splenomegaly (92% vs 87%) and anemia (64% vs 48%). OS was similar for the two groups (Figure 2, p = 0.53). The 5-year EFS were 63% (95%CI: 57-68%) and 64% (95%CI: 54-77%), respectively (p = 0.31). Conclusions: To date, this is the largest real-world study of SMZL with detailed treatment and outcome data. The study shows that histological transformation was not uncommon with 10-year risk of 17%. However, outcomes for the entire cohort were excellent irrespective of initial treatment and both OS and EFS were similar after first line rituximab versus splenectomy. Long-term survival remained relatively high even following multiple lines of therapy.

High-grade serous ovarian carcinoma, the "Achiles' hill" for clinicians and molecular biologists: a molecular insight.

High-grade serous ovarian carcinoma (HGSOC), the deadliest ovarian cancer, alone accounts for 90% of all its subtypes. Characterized by hallmark mutation of TP53, HGSOC show diverse molecular etiology. HGSOC can arise from both ovarian epithelium as well as the fimbrial epithelium of the fallopian tube. Ovulation induced reactive oxygen species, follicular fluid associated growth factor induced stemness, deregulation of hormone receptors like ER, FSHR, AR and hormones like FSH, LH, prolonged ovulation cycle, use of oral contraceptives are agonists of HGSOC while parity, breastfeeding provide protective effect from HGSOC development. Apart from a generic TP53 mutation, mutation of BRCA1/2, RAD51, BRIP1, PALB2, CHEK2, RAD50 etc., were reportedly associated with development of HGSOC. Epigenetic events like methylation of RASSF1A of RAS signaling pathway,OR51L1, OR51I1, OR51F1 etc. has been reported in HGSOC. Micro-RNAs like miR-1290, miR 27-a-3p miR23a, miR205 were reportedly upregulated in HGSOC. Amongst its cognate subtypes viz. differentiated, immunoreactive, mesenchymal, and proliferative, mesenchymal, and proliferative show worst prognosis. A system biology approach showed five major altered pathways in HGSOC, namely, RB, PI3K/RAS, NOTCH, HRR and FOXM1 signaling. For chemonaive patients, drugs that helps in efflux of reduced glutathione or prevent the redox coupling of GSH-GSSG, like Cisplatin, could be considered as the best therapeutic choice for HGSOC. For patients with BRCA1/2 mutations, PARP inhibitors alone or with Bevacizumab can be effective. Immune checkpoint inhibitors could be effective against immunoreactive subtypes. Identification of genes deregulated in chemoresistance could provide better insights in dealing with the disease.

Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

Docetaxel Plus Ramucirumab With Primary Prophylactic Pegylated Granulocyte-Colony Stimulating Factor Support for Elderly Patients With Advanced NSCLC: A Multicenter Prospective Single Arm Phase 2 Trial: DRAGON Study (WJOG9416L)

IntroductionDocetaxel plus ramucirumab could be a promising treatment for chemo-naive elderly patients with NSCLC, but high incidence of febrile neutropenia (FN) is a critical concern. We thus adopted a routine primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) to reduce FN and maximize the efficacy of docetaxel plus ramucirumab in elderly patients. MethodsThis is a single arm phase 2 trial for chemo-naive elderly patients (aged ≥75 y) with advanced NSCLC. Docetaxel (60 mg/m2, d 1) plus ramucirumab (10 mg/kg, d 1) with PEG-G-CSF (3.6 mg, d 2) was administered every 3 weeks until progression. The primary end point was overall response rate (ORR) (expected ORR: 35%). ResultsBetween February 2018 and January 2021, 54 patients were enrolled. Median age was 78 (range: 75–86). A total of 21 (38.9%) partial response, 22 (40.7%) stable disease, nine (16.7%) progressive disease, and two (3.7%) not assessable were confirmed, resulting in ORR of 38.9% (90% confidence interval [CI]: 27.7%–51.0%) and disease control rate of 79.6%. Median progression-free survival and overall survival were 5.2 (95% CI: 4.2–6.9) and 12.7 (95% CI: 10.2–18.9) months, respectively. There were one (1.9%) FN, two (3.7%) bleeding grade greater than or equal to 3, and one (1.9%) treatment-related death (pneumonitis). Pneumonitis occurred in five patients (9.3%). Main adverse events grade greater than or equal to 3 were observed: four (7%) thrombocytopenia; three (5.6%) neutropenia; six (11.1%) hyposodium; five (9.3%) infection; five (9.3%) hypertension; four (7.4%) anorexia; and three (5.6%) oral mucositis. ConclusionsDocetaxel plus ramucirumab with PEG-G-CSF revealed efficacy and safety for chemo-naive elderly patients with NSCLC. Primary prophylactic PEG-G-CSF highly prevented FN.

Plasticity of circulating tumor cells in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with low five-year survival rates. Recently described molecular phenotypes of SCLC exhibit differential vulnerabilities heralding potential for stratified treatment. Whilst tumor biopsy in SCLC is challenging, circulating tumor cells in the liquid biopsy are prevalent and can be repeatedly sampled accommodating the dynamic plasticity of SCLC phenotypes. The aim of this study was to characterize the heterogeneity of rare circulating cells with confirmed tumor origin and to explore a liquid biopsy approach for future clinical trials of targeted therapies. This study applied the 3rd generation of a previously validated direct imaging platform to 14 chemo-naive SCLC patients and 10 non-cancerous normal donor (ND) samples. Phenotypic heterogeneity of circulating rare cells in SCLC was observed and a patient-level classification model was established to stratify SCLC patients from non-cancerous donors. Eight rare cell groups, with combinations of epithelial, endothelial, and mesenchymal biomarker expression patterns, were phenotypically characterized. The single-cell genomic analysis confirmed the cancer cell plasticity in every rare cell group harboring clonal genomic alterations. This study shows rare cell heterogeneity and confirms cellular plasticity in SCLC providing a valuable resource for better opportunities to discover novel therapeutic targets in SCLC.

Effectiveness of NEPA, an oral fixed-dose combination of netupitant and palonosetron in the prevention of chemotherapy induce nausea (CIN): A post-hoc analysis.

e24140 Background: Despite widespread use of antiemetics, chemotherapy-induced nausea is still reported by upto 70% of adult patients receiving moderately emetogenic chemotherapy(MEC) or highly emetogenic chemotherapy (HEC) agents. Control of nausea remains an important, unmet need among cancer patients. The current evidence suggests that, overall, no significant nausea is reported by upto 75% of the patients with the aprepitant based regimens. Here, we present a post-hoc analysis of an observational study on NEPA (NEtupitant 300mg and PAlonosetron 0.50 mg) in preventing nausea in patients receiving HEC/MEC in a real-world setting in India. Methods: An open-label, single-arm, prospective study among chemonaive patients was conducted across six centers from April 2019 to December 2021 after approval from each institutional ethics committee (CTRI/2020/02/023586). A post-hoc analysis was carried out to assess the effectiveness of NEPA in preventing CIN in patients. The parameters assessed included severity of nausea using a visual analogue scale (VAS) [No significant nausea (includes no/mild nausea) &lt; 2.5cm on VAS scale, moderate nausea 2.5cm to 7.5cm, Severe nausea 7.5cm to 10cm], complete control (no nausea and complete response) and safety. Results: Of the 354 patients, 289 (81.64%) received the HEC regimen, and the remaining 65 (18.36%) received the MEC regimen. Anthracycline-Cyclophosphamide (36.16%) and FOLFOX (6.21%) were the most common HEC and MEC regimens, respectively. In the overall, acute, and delayed phases, no significant nausea was reported in 89.83%., 93.22% and 92.65% of the patients, respectively. Moderate and severe nausea was reported in 5.65%, and 1.13% of patients in the acute phase, 5.65%, and 1.69% in the delayed phase, and 8.19%, and 1.98% in the overall phase respectively. Among, those on HEC and MEC regimen, no significant nausea was reported in 93.42 % and 89.23 % respectively during the overall phase (Table 1). Complete control was achieved in 77.40% of patients in the overall phase, 82.77% in the acute phase, and 85.03% in the delayed phase. Adverse events were reported in 10 (3.4%) patients, with leg pain being the most common 3(0.8%). Conclusions: NEPA was found to be effective and well tolerated in preventing nausea in patients receiving HEC/MEC regimens, with almost 90% of patients reporting no significant nausea in real world Indian setting. Clinical trial information: CTRI/2020/02/023586 .[Table: see text]

Patient resilience and distress level prior to chemotherapy based on time estimation.

e24184 Background: Our prospective and multicentric study aimed to determine if the effects of breast cancer patients' resilience on their distress levels are mediated by the assessment of time before initiating neo/adjuvant chemotherapy. Methods: In 104 chemo-naive breast cancer patients, time estimation was evaluated by comparing each subject's prospective estimate of how rapidly one minute passed to the actual time. The Distress Thermometer of the National Comprehensive Cancer Network was used. The range of the scale is from 0 (no distress) to 10 (extreme distress). The Connor-Davidson Resilience Questionnaire (CD-RISC), a self-reported 10-item unidimensional scale, was utilized to measure resilience. Respondents rate statements on a 5-point Likert scale ranging from 0 (not true at all) to 4 (true nearly all the time). A higher score reflects greater resilience. Based on their RISC scores, patients were divided into three groups: low (up to the 33rd percentile), intermediate (between the 33rd and the 66th percentile), and high (over the 66th percentile). Patients' time estimations were similarly divided. Cronbach's α was 0.87 for all 10 items. Results: The mean age of the patients was 53.1±12.4 years. RISC scores correlated positively with time estimation (rho = 0.31, p = 0.002) and negatively with distress levels (rho = -0.445, p &lt; 0.001). A significant negative correlation was observed between time estimation and distress levels (rho = -0.394, p &lt; 0.001). Correspondence analysis revealed a significant association across the three matching groups of RISC score and time estimation (χ2 = 9.8, p = 0.044). The Jonckheere-Terpstra test revealed that patient estimates of time varied significantly between the three groups (p = 0.013). Using Hayes simple regression, we discovered that RISC scores were a significantly positive predictor of time estimation (b = 0.844, s.e. = 0.261, p &lt; 0.0001). Both RISC score (b = -0.136, s.e. = 0.031, p &lt; 0.0001) and time estimation (b = -0.041, s.e. = 0.011, p = 0.0005) were significant negative predictors for higher distress levels in the second regression. Conclusions: Via time estimation, patients' resilience influences distress levels prior to treatment initiation.

Taxanes Versus Androgen Receptor Therapy as Second-Line Treatment for Castrate-Resistant Metastatic Prostate Cancer After First-Line Androgen Receptor Therapy.

The optimal therapeutic sequence for metastatic castrate-resistance prostate cancer (mCRPC) is still debated. This study aimed to compare activity of taxanes (TAX) versus that of androgen-receptor therapy (ART) in men with mCRPC treated with first-line ART. This retrospective study included all consecutive chemo-naive mCRPC patients who have received first-line ART treatment. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with second-line ART or TAX. Overall, 175 patients treated with first-line enzalutamide (ENZA, n=75) or abiraterone (ABI, n=100) were evaluated. Among them, 69 (39%) and 30 (17%) patients received second-line TAX and ART, respectively, while 76 (43%) patients did not receive further treatment. From the start of first-line therapy, the median PFS and OS were 13 months (95% CI: 11-15) and 34 months (95% CI: 29-39), respectively, without any significant difference between ENZA and ABI. From the start of second-line therapy, the median PFS and OS were 6 months (95% CI: 5-7) and 18 months (95% CI: 14-21), respectively. Compared with ART, docetaxel was associated with significantly higher prostate-specific antigen (PSA, ≥ 50%) (29% vs. 0%, P < .001) and radiological responses (21% vs. 0%, P < .001). PFS was longer in TAX than in ART (6.7 months vs. 4 months, HR: 0.63, 95% CI: 0.41-0.96, P=.034), but there was no significant difference in OS (19 months vs. 12 months, P=.1). After propensity score adjustment, PFS (P=.2) and OS (P=.1) were similar between second-line TAX and ART. In the second-line setting, TAX provides higher PSA and radiological responses than does ART for mCRPC patients who received first-line ART, but the PFS and OS are similar. This study provides new elements to help deciding the best treatment sequence.

Yield of Staging Laparoscopy for Pancreatic Cancer in the Modern Era: Analysis of More than 1,000 Consecutive Patients.

Accurate staging prior to resection of pancreatic ductal adenocarcinoma (PDAC) is imperative to avoid unnecessary operative morbidity and oncologic futility in patients with occult intra-abdominal distant metastases. We aimed to determine the diagnostic yield of staging laparoscopy (SL) and to identify factors associated with increased risk of positive laparoscopy (PL) in the modern era. Patients with radiographically localized PDAC who underwent SL from 2017 to 2021 were retrospectively reviewed. The yield of SL was defined as the proportion of patients with PL, including gross metastases and/or positive peritoneal cytology. Factors associated with PL were assessed using univariate analysis and multivariable logistic regression. Of 1,004 patients who underwent SL, 180 (18%) had PL due to gross metastases (n = 140) and/or positive cytology (n = 96). Patients who had neoadjuvant chemotherapy prior to laparoscopy had lower rates of PL (14% vs 22%, p = 0.002). When the analysis was restricted to chemo-naive patients who had concurrent peritoneal lavage performed, 95 of 419 patients (23%) had PL. In multivariable analysis, PL was associated with younger (<60) age, indeterminate extrapancreatic lesions on preoperative imaging, body/tail tumor location, larger tumor size, and elevated serum CA 19-9 (all p < 0.05). Among patients with no indeterminate extrapancreatic lesions on preoperative imaging, the rate of PL ranged from 1.6% in patients with no risk factors to 42% in young patients with large body/tail tumors and elevated serum CA 19-9. The rate of PL in patients with PDAC remains high in the modern era. SL with peritoneal lavage should be considered for the majority of patients prior to resection, specifically those with high-risk features, and ideally prior to neoadjuvant chemotherapy.

Abstract 5370: New oncology target identification and validation platform combining artificial intelligence and preclinical pharmacology

Abstract Despite major advances in cancer therapy in the last decades, treatment resistance can develop over time. Precision medicine allows for the successful implementation of targeted therapies and stratification of patients, but treatment resistance remains a major obstacle in patient management. The identification and validation of new targets associated with cancer resistance remains a major challenge. The great diversity of molecular mechanisms involved in treatment resistance phenomena, whether intrinsic (de novo or primary) or acquired (secondary), constitutes a real therapeutic challenge for patient care. A better understanding of resistance mechanisms would allow to explore new therapeutic strategies to circumvent these phenomena in different types of cancer. The OncoSNIPE® project was developed in this context as part of a multicenter and collaborative clinical study (NCT04548960) in more than 800 chemo-naive adult patients. The objective of this project was to identify early and/or late markers of treatment resistance in three different pathologies for which resistance problems are encountered: triple negative breast cancer (TNBC) or luminal B, locally advanced or metastatic non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). The program included traditional clinical and whole exome sequencing (WES) monitoring of patient biopsies (Exom-seq and RNA-seq) at diagnosis and relapse, monitoring of blood markers (RNA-seq and Proteomics – Cytokine) at diagnosis, and the evaluation of best therapeutic responses and relapse. The program used bioinformatics, artificial intelligence, statistical learning and semantic enrichment approaches to discover the diversity of mechanisms involved in these resistances and to identify new therapeutic targets, through hetero-modal data including clinical, genomic, transcriptomic, immunological and radiomic dimensions. Subsequently, a specific flowchart for target validation was applied to the resulting list, considering the target's developmental potential, its essentiality, prior knowledge (database mining) and home-made score of the link between the target and the disease. Finally, new targets were prioritized using weighting parameter and heuristic approximation based on the Crank algorithm. Experimental work on multiple targets began in the laboratory, initially in vitro, using 2D and 3D cell culture (including cells from patient-derived xenografts) and molecular interference. A wide variety of intrinsic or acquired molecular mechanisms involved in treatment resistance are being evaluated as candidates for diagnostic and therapeutic development. Citation Format: Sebastien Vachenc, Nicolas Ancellin, Didier Grillot, Kenji Shoji, Joanna Giemza, Nathalie Jeanray, Leila Outemzabet, Salvatore Raieli, Lamine Toure, Olivier Duchamp, Fabrice Viviani, Philippe Genne, Jan Hoflack, Stéphane Gerart. New oncology target identification and validation platform combining artificial intelligence and preclinical pharmacology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5370.

Cardiac wasting in head and neck cancer and in cardiac autopsies from different cancer types: A study in a chemo-naïve setting.

Cardiac wasting is a detrimental consequence of cancer that has been traditionally ignored and often misinterpreted as an iatrogenic effect. We conducted a retrospective study on 42 chemo-naive patients affected by locally advanced head and neck cancer (HNC). Based on unintentional weight loss, patients were divided into cachectic and non-cachectic. Left ventricular mass (LVM), LV wall thickness (LVWT), interventricular septal (IVS) thickness, left ventricular internal diameter diastolic (LVIDd), left ventricular internal diameter systolic (LVIDs), internal ventricular septum diastolic (IVSd), left ventricular posterior wall thickness diastolic (LVPWd) and LV ejection fraction (LVEF) were analysed by echocardiography. In parallel, we retrospectively analysed 28 cardiac autoptic specimens of patients who either died of cancer before chemotherapy or with a diagnosis of cancer at autopsy. Presence or absence of myocardial fibrosis at microscopic observation was used for sample stratification. Conventional histology was performed. Cachectic and non-cachectic patients had a significantly different value of LVWT and IVS thickness and LVPWd. LVWT was 9.08±1.57 versus 10.35±1.41mm (P=0.011) in cachectic and non-cachectic patients, IVS was 10.00mm (8.50-11.00) versus 11.00mm (10.00-12.00) (P=0.035), and LVPWd was 9.0 (8.5-10.0) and 10.00mm (9.5-11.0) (P=0.019) in cachectic and non-cachectic patients. LVM adjusted for body surface area or height squared did not differ between the two populations. Similarly, LVEF did not show any significant decline. At multivariate logistic regression analysis for some independent predictors of weight loss, only LVWT maintained significant difference between cachectic and non-cachectic patients (P=0.035, OR=0.240; P=0.019). The secondary analysis on autoptic specimens showed no significant change in heart weight, whereas LVWT declined from 9.50 (7.25-11.00) to 7.50mm (6.00-9.00) in cardiac specimens with myocardial fibrosis (P=0.043). These data were confirmed in multivariate logistic regression analysis (P=0.041, OR=0.502). Histopathological analysis confirmed severe atrophy of cardiomyocytes, fibrosis and oedema as compared with controls. Subtle changes in heart structure and function occur early in HNC patients. These can be detected with routine echocardiography and may help to select appropriate cancer treatment regimens for these patients. Histopathological analysis provided conclusive evidence that atrophy of cardiomyocytes, oedema and fibrosis occur during cancer progression and may precede the onset of overt cardiac pathology. To our knowledge, this is the first clinical study that establishes a direct relationship between tumour progression and cardiac remodelling in HNCs and the first pathological study conducted on human cardiac autopsies from selected chemo-naïve cancer patients.

A randomized Phase II Study of Irinotecan Plus Cisplatin with or without Simvastatin in ever Smokers with Extended Disease Small Cell Lung Cancer.

This study evaluated whether an addition of simvastatin to chemotherapy improves survival in ever-smokers with extensive disease (ED)-small cell lung cancer (SCLC). This is an open-label randomized phase II study conducted in National Cancer Center (Goyang, Korea). Chemonaive patients with ED-SCLC, smoking history (≥100 cigarettes lifetime), and Eastern Cooperative Oncology Group performance status of ≤ 2 were eligible. Patients were randomized to receive irinotecan plus cisplatin alone or with simvastatin (40 mg once daily orally) for a maximum of six cycles. Primary endpoint was the the 1-year survival rate. Between September 16, 2011, and September 9, 2021, 125 patients were randomly assigned to the simvastatin (n=62) or control (n=63) groups. The median smoking pack-year was 40 years. There was no significant difference in the 1-year survival rate between the simvastatin and control groups (53.2% vs. 58.7%, p=0.535). The median progression-free survival and overall survival between the simvastatin arm vs. the control groups were 6.3 months vs. 6.4 months (p=0.686), and 14.4 months vs. 15.2 months, respectively (p=0.749). The incidence of grade 3-4 adverse events was 62.9% in the simvastatin group and 61.9 % in the control groups. In the exploratory analysis of lipid profiles, patients with hypertriglyceridemia had significantly higher 1-year survival rates than those with normal triglyceride levels (80.0% vs. 52.7%, p=0.046). Addition of simvastatin to chemotherapy provided no survival benefit in ever-smokers with ED-SCLC. Hypertriglyceridemia may be associated with better prognosis in these patient population.

Randomized phase II study of TX followed by XELOX versus the reverse sequence for chemo-naive patients with metastatic gastric cancer.

Docetaxel, platinum and fluorouracil are the three most important drugs in the treatment of MGC. This study was to compare clinical outcomes ofthe docetaxel capecitabine combinationand the oxaliplatin capecitabine combination as first-line therapy in MGC patients. In this phase II trial, MGC patients were randomly assigned and treated with either TX (capecitabine 1000 mg/m2/twice daily/1-14 days and docetaxel 60/75 mg/m2 on the 1st day) (because of toxicity, the dose of docetaxel was reduced to 60 mg/m2) or XELOX (capecitabine the same dose with TX and oxaliplatin 130 mg/m2 on the 1st day) as first-line therapy. After progression, patients were crossover to the other group as second-line treatment. Total 134 MGC patients were randomized (69 in TX, 65 in XELOX). There was no significant difference between the PFS of the two groups (TX vs XELOX, 4.6 months vs 5.1 months, p=0.359), and the SFS (9.3 months vs 7.5 months, p=0.705), OS (13.1 months vs 9.6 months, p=0.261), and ORR (46.4% vs 46.2%) were also similar. Among patients with ascites, the TX group had significantly longer PFS and OS than the XELOX group. A total of 85 patients (48 in TX, 37 in XELOX) received second-line treatment, with overall survival of second-line chemotherapy (OS2) of 8.0m and 5.3m (p=0.046), respectively. Grade 3 to 4 treatment-related adverse events of first line treatment occurred more in TX group than that in XELOX group(60.6% vs 55.4%). TX regimen is an alternative choice of first-line treatment for MGC patients. We still need to explore the large number of cohort to confirm this results.

P-257 In vitro drug screening of patient-derived 3D tumoroids replicates resistance to FOLFOX, FOLFIRI, and FOLFOXIRI in clinically resistant patients with metastatic colorectal cancer

International guidelines present three different chemotherapy regimens for first- and subsequent-line treatment of unresectable metastatic colorectal cancer (mCRC). The main doublet therapies used in first-line treatment is FOLFIRI (5-FU + irinotecan) and FOLFOX (5-FU + oxaliplatin). The two combination treatments offer a similar response rate of 34-55%. The treatments are therefore used indistinctly in the clinic. Evidence is however starting to appear showing that there are differences between the individual patients as to which of the combination treatments that are superior. One approach to increase effectiveness of chemotherapy treatment is to use a patient-derived 3D tumoroid test (such as IndiTreat ® ) to identify the most efficacious treatment and also the ones to which the patient is resistant. The tumoroids closely recapitulate a patient’s tumor. The objective of the present study was to evaluate if IndiTreat ® could distinguish between patients that are clinically drug resistant (CDR) from patients that are chemonaive to the regimens FOLFOX and FOLFIRI plus the triple combination FOLFOXIRI (5-FU + oxaliplatin + irinotecan). We included 8 chemonaive patients and 19 patients from the ongoing clinical trial, (ClinicalTrials.gov, NCT03251612). The latter were tested and treated in accordance with IndiTreat ® test results. To be enrolled in the trial, patients had to have progressive unresectable mCRC and be exposed to available standard therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents if RAS/RAF wild-type. This group was defined as CDR patients. For CDR patients, ultrasound - or CT-guided biopsies were sampled from liver metastases. A 16-gauge needle was used (SuperCore TM , Argon Medical Devices, Athens, TX, USA). The biopsies were mechanically dissociated into tissue fragments and embedded in Matrigel (Corning Life Sciences, Merck, Germany). Screening of samples from CDR patients and chemonaive patients were done according to a modified version of a procedure previously described. The tumoroids were exposed to the drug treatments for seven days. Tumoroids growth was measured by taking brightfield images with a Cytation 1 (Biotek) imaging system and quantified using 2cureX’s artificial intelligence algorithm IndiNet TM. For all three treatment regimens, the IndiTreat ® test showed that the growth inhibition of tumoroids from CDR patients was significantly less compared to chemonaive patients. The clustering for the CDR patients showed that the IndiTreat ® test identified 81%-94% of the patients as having a low growth inhibition (FOLFIRI 94%, FOLFOX 81% and FOLFOXIRI 82%). Conversely, for chemonaive patients, the IndiTreat ® test identified 88%-100% of the patients presented high growth inhibition (FOLFIRI 88%, FOLFOX 100% and FOLFOXIRI 100%). - The IndiTreat ® test is with a high degree of precision able to identify patients that are clinically resistant to the regimens of FOLFOX, FOLFIRI and FOLFOXIRI. - The present study was performed retrospectively in first- and third-line patients. To investigate the general applicability of the IndiTreat ® test, we plan to perform a prospective study in first-line treatment of mCRC with resistance as the primary endpoint. - Ultimately, the IndiTreat ® technology will assist in the identification of the most efficacious chemotherapy treatment in first-line unresectable mCRC patients.

Effectiveness of NEPA, an oral fixed-dose combination of NEtupitant and PAlonosetron in the prevention of chemotherapy-induced nausea-vomiting in patient receiving highly emetogenic chemotherapy regimens.

e24090 Background: Patients receiving Highly Emetogenic chemotherapy (HEC) are &gt; 90% risk of nausea-vomiting due to the drug's emetogenic potential and patient-related factors such as young age, female gender, low/no alcohol, H/O morning sickness and use of alternative medications. The current study was designed to assess the effectiveness of NEPA in patients receiving HEC in a real-world setting in India. Methods: An open-label, single-arm, prospective study among chemonaive patients was conducted across six centers from April 2019 to December 2021 after approval from each institutional ethics committee (CTRI/2020/02/023586). Complete response and treatment-emergent adverse events were the primary endpoints. Secondary endpoints included completion protection, complete control and severity of nausea. Results: HEC regimens were prescribed in 289 of the 360 patients enrolled in the study. Most common HEC regimen was Anthracycline-Cyclophosphamide (44.2%) followed by Paclitaxel-Carboplatin (17.9%). Average age of study population was 52.8±9.8 yrs. with male: female ratio of 1:2.1. Hypertension (17.6%) and diabetes (12.4%) were common comorbidities. Complete response in acute, delayed and overall phases were 94.4%, 94.8%, and 92.7% respectively. In overall phase, complete protection and complete control was 86.8% and 77.5% respectively. Mild, moderate and severe nausea were reported in 11.7%, 7.6%, and 2.4%, patients respectively. Adverse events were seen in 10(3.4%) patients, with leg pain being the most common 3(0.8%). One serious adverse event, unrelated to the study drug was reported. Conclusions: NEPA was effective and well tolerated in patients on a HEC regimen in the acute, delayed and overall phases with a completed response rate of &gt; 90%. Clinical trial information: CTRI/2020/02/023586. [Table: see text]