Oxaliplatin Regimen Research Articles

A case report: interstitial pneumonia following treatment of gastric cancer with sintilimab in combination with S-1

BackgroundInterstitial pneumonia is a group of pathologies affecting the pulmonary interstitium, characterized by interstitial fibrosis and extensive alveolar consolidation. This disease can extend to the surrounding blood vessels and pulmonary interstitium, sometimes affecting the entire lung, resulting in functional limitations, including restrictive ventilatory defect, impaired gas exchange, and hypoxemia. Severe interstitial pneumonia can lead to death. Antitumor drugs can induce interstitial pneumonia. Sintilimab is an immune checkpoint inhibitor, a recombinant fully human immunoglobulin G-type programmed death protein-1 monoclonal antibody inhibitor. S-1 is a compound preparation consisting of gimeracil, oteracil potassium, and ftorafur. There have been cases of interstitial pneumonia caused by treatment with sintilimab or S-1 in clinical settings, but no cases of interstitial pneumonia caused by treatment with a combination of sintilimab and S-1 have been reported.Case reportA patient diagnosed with gastric cancer underwent nine courses of treatment using a chemotherapy regimen of combined oxaliplatin S-1., Due to severe bone marrow suppression and gastrointestinal adverse reactions, the treatment was switched to sintilimab in combination with S-1therapy., This change resulted in the development of interstitial pneumonia, as revealed by non-contrast chest Computed Tomography scans. Following a review of blood test results and a multidisciplinary consultation, we suspect that the interstitial pneumonia may have been caused either by Sintilimab alone or by the combined effects of sintilimab and S-1. The treatment was discontinued, and after receiving adequate glucocorticoid therapy, the pulmonary lesions showed slight improvement.ConclusionThis case provides a clinical reference, indicating that prior touse of sintilimab in combination with S-1 antitumor regimen, a comprehensive baseline assessment should be conducted, including blood routine examination, enzyme tests, and pulmonary imaging examination, with close monitoring of the patient’s pulmonary condition. If drug-induced lung injury is suspected, the medication should be discontinued immediately, and appropriate treatment should be initiated promptly.

The Current Status of Adjuvant Chemotherapy for Colorectal Cancer in Japan: A Paradigm Shift from Oral Fluoropyridine Single Therapy to the Oxaliplatin Regimen

The effectiveness of oxaliplatin (L-OHP) has been reported overseas; however, in Japan, the prognosis of colorectal cancer (CRC) patients is reported to be good, and there has been a long debate about the applicability of L-OHP combination therapy in Japan. In recent years, the results of the ACHIEVE trial have become clear, and the standard consensus in Japan establishes L-OHP combination therapy for a duration of 3 months as the adjuvant treatment for CRC.

Effects of tumor treating fields (TTFields) with FOLFIRINOX on BRCA WT pancreatic cancer cells.

753 Background: Pancreatic cancer remains one of the most aggressive malignancies, frequently diagnosed at the locally advanced or metastatic stage. In the advanced setting, first-line chemotherapy options include gemcitabine with nab-paclitaxel or FOLFIRINOX, a combination regimen of fluorouracil, oxaliplatin, irinotecan and leucovorin. The FOLFIRINOX regimen is however associated with greater toxicity and is hence used only in patients with good performance status. BRCA-mutated tumors seem to be more sensitive to FOLFIRINOX due to the DNA-damaging, platinum-based component of this treatment regimen. Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes crucial for cancer cell viability that have shown efficacy in preclinical pancreatic cancer models; and, in various cancer types, have been shown to reduce expression of proteins from the BRCA-dependent DNA repair pathway. The current study examined the potential use of TTFields for sensitization of BRCA wild-type pancreatic cancer cells to treatment with FOLFIRINOX. Methods: Human pancreatic BRCA wild-type cancer cells BxPC3 and AsPC1 were treated with TTFields (150 kHz; 0.7 and 1 V/cm RMS, respectively), using the inovitro device. FOLFIRINOX was administered to the cells at increasing concentrations, with or without co-treatment with TTFields. After 72h of treatment, cell count, colony formation, and apoptosis were measured. For mechanistical insight, gene and protein expression were evaluated following 24, 48, or 72h of TTFields treatment. Results: TTFields application to the pancreatic cells together with FOLFIRINOX elevated the cytotoxic, clonogenic and apoptotic effects induced by FOLFIRINOX or TTFields alone. RNA sequencing data revealed that TTFields downregulated DNA damage repair, DNA replication, and cell cycle related processes. Specifically, real-time PCR and Western blot analysis demonstrated reduced expression of several central players in the BRCA DNA damage repair pathway. Conclusions: TTFields application together with FOLFIRINOX in pancreatic cancer cells lacking background BRCA mutations exhibits potential improvement relative to FOLFIRINOX alone, that may be rationalized based on downregulation of key DNA repair pathways. Future studies should explore the possibility of reducing FOLFIRINOX treatment dose, potentially alleviating FOLFIRINOX-related toxicity.

Alternating Oxaliplatin and Irinotecan Chemotherapy Combined With Capecitabine and Bevacizumab for Microsatellite-stable Stage IV Metastatic Colon Cancer With a BRAF V600E Mutation: Two Case Reports Indicating Survival Improvement over Standard Therapy.

Colorectal cancer (CRC) has the third-highest incidence among human cancers. Advancements in chemotherapy and targeted therapy have improved the treatment outcomes for patients with CRC. However, the management of patients with unresectable metastatic CRC (mCRC) continues to be a significant challenge for clinicians worldwide, particularly for those with microsatellite stability (MSS) and the BRAF V600E mutation, as they are associated with the poorest prognosis. The present study describes two patients with unresectable MSS, BRAF V600E-mutated stage IV metastatic CRC using a biweekly alternating regimen of irinotecan and oxaliplatin combined with capecitabine and bevacizumab. Case 1 stabilized after alternating treatment, whereas Case 2 progressed after alternating treatment, with progression-free survival (PFS) of 20+ and 24.5 months, respectively. Circulating levels of carcinoemryonic antigen (CEA) dropped to near normal in both cases. A partial response (PR) was determined for both cases. The two cases suggest that an alternating chemotherapy regimen of oxaliplatin and irinotecan, combined with capecitabine and bevacizumab is effective in the treatment of MSS, BRAF V600E-mutated stage IV metastatic CRC. The progression-free survival was significantly prolonged (both exceeding 20 months) compared to the first-line standard chemotherapy regimen for this disease. With a good balance between toxicity and efficacy, this alternating chemotherapy regimen can be considered as a potential first-line option for microsatellite-stable metastatic colon cancer.

Efficacy and safety of S-1 plus oxaliplatin combined with apatinib and camrelizumab as neoadjuvant therapy for patients with locally advanced gastric or gastroesophageal junction adenocarcinoma: a protocol for a single-arm phase II trial.

Gastric cancer, as the fifth most diagnosed malignancy and the fourth leading cause of cancer-related death globally, remains a significant health concern. The potential effect of the programmed death-1 (PD-1) inhibitor, when used alongside chemotherapy and antiangiogenic agents in neoadjuvant therapy for gastric cancer, has yet to be explored in the published literature. This study aims to evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen when combined with apatinib and camrelizumab (SOXAC) as neoadjuvant therapy for patients with locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. A single-arm, open-label, single-center phase II clinical trial has been designed to evaluate the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients diagnosed with locally advanced gastric or GEJ adenocarcinoma (cT2-3N + M0 or T4NxM0). Eligible patients are to receive 2 cycles of SOXAC and 1 cycle of SOX regimen with camrelizumab (SOXC) as neoadjuvant therapy prior to radical surgery, and 3 cycles of SOXC as postoperative adjuvant therapy. The primary endpoint is major pathological remission (MPR), while secondary endpoints include pathological complete response (pCR) rate, R0 resection rate, objective response rate (ORR), operation-related outcomes, and safety. The SOX regimen remains a leading choice for neoadjuvant chemotherapy in Eastern countries. Recent studies suggest that combining chemotherapy, targeted agents, and immune checkpoint inhibitors can enhance the antitumor immune response. This phase II clinical trial seeks to assess the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients with locally advanced resectable gastric or GEJ adenocarcinoma, while also exploring the correlation between biomarkers and efficacy.Trial Registration Chinese Clinical Trial Registry (ChiCTR): ChiCTR2200062285 ( https://www.chictr.org.cn/ ).

OGC O05 - Utilising patient derived organoids to predict the response to treatment in gastric cancer

Abstract Background Gastric adenocarcinoma remains a significant global health burden. For advanced disease, treatment remains multi-modal with neoadjuvant chemotherapy followed by resectional surgery. Although the FLOT4-AIO trial has established the regimen of 5-fluorauracil, Leucovorin, Oxaliplatin and Docetaxel (FLOT) as the gold standard, some patients demonstrate a poor or no response to treatment, resulting in adverse oncological outcomes. Currently there are no accurate biomarkers to assess or predict the treatment response to neoadjuvant therapy. This study aims to explore the potential of patient-derived organoids as a predictive model to assess the treatment response to neoadjuvant chemotherapy in gastric adenocarcinoma. Method Patient derived organoids are a novel, 3 dimensional in-vitro model which recapitulates the different cells that constitute the tissue of origin. From June 2023 to June 2024, 25 patients with a confirmed diagnosis of gastric adenocarcinoma, were recruited for tissue acquisition for organoid generation. Endoscopic biopsies of cancer tissue taken during OGD and staging laparoscopy were used to generate organoids from each patient. Organoids were subsequently expanded to a sufficient volume to allow cytotoxicity assays in response to different doses of the FLOT regimen. The organoid cytotoxicity response was compared to the patients radiological and pathological response following treatment. Results Organoids were successfully generated from 76% of recruited patients (n=19). Of these, 4 patients and were excluded due to being unfit for neoadjuvant chemotherapy, whilst 2 were excluded due to the confirmation of metastatic disease, precluding neoadjuvant treatment. Finally a single patient was excluded due to mortality during neoadjuvant treatment. Of the remaining organoids, 5 were subjected to FLOT treatment within 2 weeks of tissue acquisition. Organoids demonstrated unique dose response profiles following with statistically significant differences in the IC50 values (p =0.048). The organoid responses corresponded to the clinical responses demonstrated by the patient they were derived from. Conclusion In conclusion, this study underscores the potential of patient-derived cancer organoids as a predictive model for assessing the response to neoadjuvant chemotherapy in gastric adenocarcinoma. The generation of organoids from a significant proportion of patients and the subsequent drug response testing within 2 weeks of tissue acquisition suggests this novel method has the potential to become a valuable tool for predicting patient-specific responses and guiding personalised treatment plans. As such, further research is warranted to further assess the validity of this model, refine the existing techniques and explore its potential integration into clinical practice.

Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer.

Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer have poor outcomes. Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not yet been reported. To evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer. Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: One group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate, disease control rate, and adverse events (AEs). Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, whereas it was 7.3 months in the trastuzumab group (P = 0.046); this difference was significant. The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months (P = 0. 33), and the objective response rate was 50% vs 42% (P = 0.63), respectively; these differences were not significant. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. In the first-line treatment of HER2-positive advanced gastric cancer, inetetamab and trastuzumab showed comparable efficacy. The inetetamab group showed superior PFS, and both groups had good safety.

Digital subtraction angiography-guided pancreatic arterial infusion of GEMOX chemotherapy in advanced pancreatic adenocarcinoma: a phase II, open-label, randomized controlled trial comparing with intravenous chemotherapy

BackgroundAdvanced pancreatic adenocarcinoma lacks effective treatment options, and systemic gemcitabine-based chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. New therapeutic options with better drug availability are warranted. This study aims to evaluate the safety and efficacy of digital subtraction angiography (DSA)-guided pancreatic arterial infusion (PAI) versus intravenous chemotherapy (IVC) using the gemcitabine and oxaliplatin (GEMOX) regimen in unresectable locally advanced or metastatic pancreatic cancer (PC) patients.Materials and methodsThis study prospectively enrolled 51 eligible treatment-naive patients with unresectable PC to receive GEMOX treatment via PAI or IVC (1:1 ratio randomization) from December 2015 to December 2019. Cycles were repeated monthly, and each process consisted of two treatments administered bi-weekly. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, 6-month survival, tumor-site subgroup survival, and incidences of adverse events were compared.ResultsThe median OS of the PAI and IVC groups were 9.93 months and 10.07 months, respectively (p = 0.3049). The median PFS of the PAI and IVC groups were 5.07 months and 4.23 months (p = 0.1088). No significant differences were found in the ORR (11.54% vs. 4%, p = 0.6312), DCR (53.85% vs. 44%, p = 0.482), and 1-year OS rate (44% vs. 20.92%, p = 0.27) in PAI and IVC groups. The 6-month OS rate was significantly higher in the PAI group (100%) than in the IVC group (83.67%) (p = 0.0173). The median OS of patients in PAI group with pancreatic head and neck tumors were significantly higher than those of body and tail tumors (12.867 months vs. 9 months, p = 0.0214). The incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group (p < 0.05).ConclusionGEMOX PAI therapy presented a higher 6-month OS rate and fewer adverse events than IVC in advanced pancreatic adenocarcinoma patients. Those with pancreatic head and neck tumors may yield a superior treatment outcome from PAI treatment.Trial registration numberNCT02635971.Date of registration21/12/2015.

Prolonged administration of the granisetron transdermal delivery system reduces capecitabine plus oxaliplatin regimen induced nausea and vomiting

ObjectiveTo evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy.DesignOpen-label, prospective, multi-center phase II trial.SettingThree institutions.ParticipantsFifty-four patients scheduled to receive CapeOX chemotherapy.InterventionsParticipants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone.Main outcome measuresThe primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life.ResultsThe complete control rate for delayed CINV over the entire period (25–480 h) was 72.7% (95% CI 0.57–0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69–0.95). No serious adverse events related to the antiemetic regimen were reported.ConclusionProlonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX.Trial RegistrationClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy

The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy. To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival. This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024. In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery. The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy. A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13). In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups. isrctn.org Identifier: ISRCTN59757862.

Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.

4036 Background: The phase 3 SPOTLIGHT study showed statistically significant improvements in progression-free survival (PFS) and overall survival (OS) with 1L zolbetuximab + modified folinic acid, 5-FU, and oxaliplatin regimen (mFOLFOX6) vs placebo (PBO) + mFOLFOX6 in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma at prespecified interim and later updated analyses. We present the prespecified final OS analysis. Methods: Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, D15, D29) for four 42-day cycles or to PBO + mFOLFOX6; pts without PD continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator’s discretion, until PD or discontinuation criteria were met. The primary endpoint was PFS per RECIST v1.1 by IRC. OS was a key secondary endpoint; additional secondary endpoints were objective response rate (ORR) and safety. Ad hoc analyses examined PFS and OS in per-protocol set population (PPS; pts adherent to protocol) and time to progression (TTP) by best overall response (BOR). Results: At data cutoff (September 8, 2023), 565 pts were assigned to zolbetuximab arm (n = 283) or PBO arm (n = 282). In zolbetuximab vs PBO arms, median follow-up was 18.04 vs 17.91 mo for PFS and 33.28 vs 31.38 mo for OS, respectively. Efficacy results are summarized in Table. Median PFS and OS were significantly longer in zolbetuximab vs PBO arms. Separation of PFS and OS curves occurred earlier in the PPS population analysis (excluded majority of early withdrawals) compared with the ITT population. ORR was similar between treatment arms in ITT and pts with measurable lesions – despite this, TTP for patients with BOR of CR/PR was numerically longer in zolbetuximab vs PBO arms. Safety and tolerability were maintained with no new findings. Conclusions: Zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a new standard of care option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma. Clinical trial information: NCT03504397 . [Table: see text]

Real-world efficacy and safety of capecitabine with oxaliplatin in patients with advanced adenocarcinoma of the ampulla of Vater

BackgroundAdenocarcinoma of the ampulla of Vater (AoV) is one of the rare periampullary cancers, and due to its anatomical location, it is categorized into various histologic subtypes. Its rarity and diversity pose challenges in treatment decision-making for patients with advanced AoV carcinoma. This study investigated the efficacy and safety of the combined regimen of capecitabine and oxaliplatin (CAPOX) in a real-world clinical setting.MethodsThis investigation encompassed patients with advanced AoV carcinoma who underwent CAPOX treatment. Histologic phenotypes were identified through a combination of histopathological analysis and protein expression markers, including MUC1, CDX2, CK20, and MUC2. The correlation between histopathological determinants and survival outcomes was explored, in addition to an evaluation of the safety profile of CAPOX therapy.ResultsFrom January 2010 to June 2023, 42 patients received CAPOX. Of these, 14 patients (33.3%) had not received any prior palliative chemotherapy, while 28 patients (66.7%) had undergone one prior line of chemotherapy. At a median follow up of 9.0 months, the median progression-free survival (PFS) was 4.38 months (95% CI, 2.78–5.69) and the median overall survival (OS) was 9.57 months (95% CI 7.56–11.6). The objective response and disease control rates were 38.1% and 61.9%, respectively. Patients who received CAPOX as a second-line treatment had poorer PFS (HR = 2.62; 95% CI, 1.49–4.90, p = 0.003) and OS (HR = 2.82, 95% CI, 1.47–5.38, p = 0.001) compared to those who received CAPOX as a first-line chemotherapy. There were no statistically significant differences in PFS (p = 0.185) and OS (p = 0.097) between groups based on histologic subtypes. Neutropenia (14.3%) emerged as the predominant grade 3–4 toxicity. Notably, treatment cessation occurred in select instances owing to grade 3 fatigue (9.5%) and peripheral neuropathy (9.5%).ConclusionsThis study confirmed the therapeutic efficacy and safety of CAPOX in a real-world setting, consistent with prior phase II trial results. While CAPOX proved feasible for advanced AoV carcinoma regardless of histologic subtype, its reduced effectiveness in second-line settings necessitates further research to determine its optimal palliative use.

A unique case of unresectable metastatic gastric squamous cell carcinoma treated with combined nivolumab and capecitabine/oxaliplatin complicated by immunotherapy induced pure red cell aplasia

Gastric Squamous Cell Carcinoma is an extremely rare type of gastric cancer, with an incidence of 0.04-0.07% among all gastric cancers [1]. The treatment for this malignancy has focused on surgical resection with adjuvant chemotherapy. Treatment for unresectable metastatic disease has varied, with most regimens taken from management of traditional gastric adenocarcinoma and other GI malignancies with varied success. Here, we will explore a case of a patient diagnosed with metastatic gastric squamous cell carcinoma treated with combination nivolumab and capecitabine with oxaliplatin regimen having a complicated course involving medication induced pure red cell aplasia.

A modified triplet combination of docetaxel, oxaliplatin, and fluorouracil for gastric cancer (GC) with peritoneal carcinomatosis (PC) and inoperable malignant bowel obstruction (MBO): A multi-center, non-randomized, three-cohort, phase II trial (Zhen Jing).

TPS426 Background: For GC, PC is ranked as the most common in relapse and the second common in metastasis. MBO is a frequent and preterminal complication of PC, which has been reported to have a poor overall survival (OS) of only 3 months without effective treatment. Medical therapy of gastroenteric drainage and symptomatic drugs is the cornerstone management for MBO, just alleviating symptoms. Interventional therapy and surgery are effective but indicated in limited patients (pts) with strict selection. Chemotherapy is the mainstay treatment for metastatic GC but its role in MBO is poorly defined. Only a few retrospective studies are available, showing conflicting results on obstruction clearance (OC) and OS. Methods: We are conducting the Zhen Jing trial in five Chinese centers to investigate the tolerability and efficacy of a dose-sense regimen of docetaxel, oxaliplatin and fluorouracil in MBO from GC. Cohort A is for pts in first-line setting. Cohort B is for second-line setting. Cohort C is for pts who have failed to two or more regimens. Eligible pts will receive the same experimental regimen every 28 days: docetaxel 25 mg/m2 on days 1, 8, 15; oxaliplatin 85 mg/m2 on days 1, 15; fluorouracil 1200 mg/m2 24-hour infusion on days 1, 8, 15. A Simon's two-stage optimal design is applied (table below). The primary endpoint is 60-day OC rate. Secondary endpoints are 30-day OC rate, time to OC, OC duration, safety, overall survival and quality of life. Till July 2023, a total of 34 pts has been enrolled (16 in cohort A, 9 in cohort B, 9 in cohort C). Inclusion Criteria: 18-75 years old; Eastern Cooperative Oncology Group performance status ≤ 3; adenocarcinoma of stomach or gastroesophageal junction; peritoneal carcinomatosis established by imaging data or pathological evidence; MBO below the Treitz ligament based on clinical grounds or radiological findings; inappropriate for operation judged independently by two surgeons; written informed consent. Exclusion Criteria: Treated by a combination regimen containing all the study drugs; allergy to any of the study drugs; HER-2 gene overexpression; high microsatellite instability or mismatch repair deficiency; strangulated obstruction; active gastrointestinal bleeding; uncontrolled active infection; unstable heart diseases; severe lung diseases; central nervous system diseases; concomitant cerebral or meningeal metastasis; surgery or stent are required. Clinical trial information: NCT04840264 . [Table: see text]

Comprehensive treatment focusing on transarterial chemoembolization for postoperative liver metastasis in gastric cancer patients.

To investigate the clinical efficacy of comprehensive treatment focusing on transarterial chemoembolization (TACE) for postoperative liver metastasis in patients with gastric cancer and analyze the factors influencing prognosis. A retrospective study was conducted on 116 patients who developed liver metastasis after gastric cancer surgery and were admitted to Gansu Provincial Cancer Hospital between January 2018 and February 2020. The observation group, consisting of 62 patients, received TACE with fluorouracil (FU) + irinotecan (CPT-11) + oxaliplatin (OXA) and moderate lipiodol embolization. The control group, consisting of 54 patients, received systemic S-1 and Oxaliplatin regimen (SOX) alone. The clinical efficacy and incidence of adverse reactions were compared between the two groups. Liver function indicators, tumor markers, and immunoglobulin changes were analyzed in both groups. The 2-year survival rate of patients was analyzed using the Kaplan-Meier (K-M) curve. Lasso-Cox regression was used to identify independent prognostic factors affecting the 2-year survival rate. A Nomogram model was constructed to predict outcomes. The overall clinical efficacy (P = 0.001) and objective response rate (ORR) (P = 0.001) were significantly lower in the control group compared to the observation group. No significant differences were found in ALT and AST changes between the two groups (P > 0.05). Post-treatment, CEA and CA19-9 levels were significantly lower, and IgG and IgM levels were significantly higher in the observation group (P < 0.001). There was no significant difference in the incidence of adverse reactions (P > 0.05). Lasso-Cox regression identified treatment plan, pathological differentiation, degree of liver metastasis, and pre-treatment CEA as independent prognostic factors for 2-year survival. Based on these, a Nomogram model was constructed. In the training group, the model had AUC values over 0.8 for 1- and 2-year survival rates, and in the validation group, the AUC was 0.765 and 0.687, respectively, indicating good predictive performance. Compared to the conventional SOX regimen, comprehensive treatment focusing on TACE embolization for postoperative liver metastasis in gastric cancer is more effective and can improve survival rates.

Prognostic value of the TP53 mutation in patients with pancreatic ductal adenocarcinoma receiving FOLFIRINOX

Background: KRAS, TP53, CDKN2A, and SMAD4 have been the main driver mutations in pancreatic ductal adenocarcinoma (PDAC). Studies on the clinical significance and treatment response to 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) regimen in terms of the presence of these mutations remain inconclusive. Objectives: This study aimed to compare the survival outcome and response to FOLFIRINOX chemotherapy based on the presence of four driver mutation genes. Design: A multi-center retrospective study conducted at two tertiary medical centers. Methods: This study analyzed PDAC patients who were treated with FOLFIRINOX chemotherapy as the initial treatment. Tumor specimens were analyzed by a targeted next-generation sequencing platform at two tertiary referral hospitals from January 2016 to March 2022. Patients’ demographics, survival outcomes, and chemotherapeutic response were investigated and compared according to the presence of driver mutations. Results: The analysis included 100 patients. KRAS mutation was identified in 92 (92.0%) patients, followed by TP53, CDKN2A, and SMAD4 in 63 (63.0%), 18 (18.0%), and 17 (17.0%) patients, respectively. The TP53 wild-type group demonstrated longer overall survival (OS) than the TP53 mutated group (median OS: 29 vs 19 months, p = 0.03), and TP53 served as a prognostic factor for survival (hazard ratio = 1.74, 95% confidence interval: 1.00–3.00, p = 0.048). The difference in OS according to TP53 mutation was intensified in localized pancreatic adenocarcinoma (37 vs 19 months, p = 0.01). The TP53 wild-type group demonstrated a higher objective response rate to FOLFIRINOX chemotherapy than the TP53 mutation group in localized pancreatic adenocarcinoma (50.0% vs 17.6%, p = 0.024). Conclusion: PDAC patients with wild-type TP53 demonstrated longer OS than those with TP53 mutation, and this trend was intensified in patients with localized disease. This result may be due to an impaired response to FOLFIRINOX chemotherapy in patients with TP53 mutation.

Combinatorial Implications of Nrf2 Inhibitors with FN3K Inhibitor: In vitro Breast Cancer Study.

Platinum derivatives are chemotherapeutic agents preferred for the treatment of cancers including breast cancer. Oxaliplatin is an anticancer drug that is in phase II studies to treat metastatic breast cancer. However, its usage is constrained by chemoresistance and dose-related side effects. The objective of this study is to examine the combinatorial efficacy of brusatol, an Nrf2 blocker, with oxaliplatin (a proven FN3K blocker in our study) in mitigating breast cancer growth in vitro. We performed cytotoxicity assays, combination index (CI) analysis, colony formation assays, apoptosis assays, and Western blotting. Results of our study described the chemosensitizing efficacy of brusatol in combination with lowdose oxaliplatin against breast cancer through synergistic effects in both BT-474 and T47D cells. A significant mitigation in the migration rate of these cancer cells was observed with the combination regimen, which is equivalent to the IC-50 dose of oxaliplatin (125 μM). Furthermore, ROS-mediated and apoptotic modes of cell death were observed with a combinatorial regimen. Colony formation of breast cancer cell lines was mitigated with a combinatorial regimen of bursatol and oxaliplatin than the individual treatment regimen. FN3K expression downregulated with oxaliplatin in T47D cells. The mitigation of FN3K protein expression with a combination regimen was not observed but the Nrf2 downstream antioxidant signaling proteins were significantly downregulated with a combination regimen similar to individual drug regimens. Our study concluded the combination efficacy of phytochemicals like brusatol in combination with low-dose oxaliplatin (FN3K blocker), which could enhance the chemosensitizing effect in breast cancer and minimize the overall dose requirement of oxaliplatin.

Comparison of different second line treatments for metastatic pancreatic cancer: a systematic review and network meta-analysis

BackgroundIn metastatic pancreatic ductal adenocarcinoma (mPDAC), first line treatment options usually include combination regimens of folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX or mFOLFIRINOX) or gemcitabine based regimens such as in combination with albumin-bound paclitaxel (GEM + nab-PTX). After progression, multiple regimens including NALIRI + 5-FU and folinic acid, FOLFIRINOX, 5-FU-based oxaliplatin doublets (OFF, FOLFOX, or XELOX), or 5-FU-based monotherapy (FL, capecitabine, or S-1) are considered appropriate by major guidelines. This network meta-analysis (NMA) aimed to compare the efficacy of different treatment strategies tested as second-line regimens for patients with mPDAC after first-line gemcitabine-based systemic treatment.MethodsRandomized phase II and III clinical trials (RCTs) were included if they were published or presented in English. Trials of interest compared two active systemic treatments as second-line regimens until disease progression or unacceptable toxicity. We performed a Bayesian NMA with published hazard ratios (HRs) and 95%confidence intervals (CIs) to evaluate the comparative effectiveness of different second-line therapies for mPDAC. The main outcomes of interest were overall survival (OS) and progression free survival (PFS), secondary endpoints were grade 3–4 toxicities. We calculated the relative ranking of agents for each outcome as their surface under the cumulative ranking (SUCRA). A higher SUCRA score meant a higher ranking for efficacy outcomes.ResultsA NMA of 9 treatments was performed for OS (n = 2521 patients enrolled). Compared with 5-FU + folinic acid both irinotecan or NALIRI + fluoropyrimidines had a trend to better OS (HR = 0.76, 95%CI 0.21–2.75 and HR = 0.74, 95%CI 0.31–1.85). Fluoropyrimidines + folinic acid + oxaliplatin were no better than the combination without oxaliplatin. The analysis of treatment ranking showed that the combination of NALIRI + 5-FU + folinic acid was most likely to yield the highest OS results (SUCRA = 0.7). Furthermore, the NMA results indicated that with the highest SUCRA score (SUCRA = 0.91), NALIRI + 5-FU + folinic acid may be the optimal choice for improved PFS amongst all regimens studied.ConclusionsAccording to the NMA results, NALIRI + 5-FU, and folinic acid may represent the best second-line treatment for improved survival outcomes in mPDAC. Further evidence from prospective trials is needed to determine the best treatment option for this group of patients.

Clinical utility of an international multidisciplinary virtual tumor board for fibrolamellar carcinoma.

e18624 Background: Fibrolamellar carcinoma (FLC) is a rare liver cancer with approximately 1500 new cases per year, worldwide. The lack of expertise locally often incurs significant travel for patients (pts). Virtual consults have improved access to expertise but identifying the best experts for an ultra-rare condition is difficult for pts and families and multidisciplinary tumor boards of experts offer better clinical guidance. Foundations and advocacy groups play a vital role in navigation and support for pts with rare cancers. Methods: Pts with FLC and their local treating oncologists were engaged by the FibroFighters Foundation and offered a multidisciplinary virtual tumor board (VTB) review. Each VTB included the local treating oncologist, a patient advocate, a molecular pharmacologist, and international experts in the clinical management of FLC including at least one medical oncologist, one radiation oncologist, one interventional radiologist, and one surgical oncologist. Each VTB reviewed the pts’ clinical history and relevant imaging and discussed surgical, radiological, and systemic approaches. Pts consented to the observational research protocol XCELSIOR ( NCT03793088 ) to enable longitudinal clinical summaries to be prepared and for outcomes to be annotated. Results: Between August 4th 2022 and February 9th, 2023, the VTB held a total of 71 discussions for 59 unique pts (12 discussed more than once): 12 new diagnoses, 28 relapses, 14 treatment failures, and 5 ongoing care. Median age at diagnosis of pts was 18 years (range 6-44 years). Pts were seen at 44 institutions/practices across 22 states and 4 countries (USA, Australia, Switzerland, and the Netherlands). A total of 36 unique treatment regimens were discussed, with 21 unique consensus top-ranked options delivered to treating oncologists. The most common consensus options included regimens of gemcitabine, lenvatinib, and nivolumab (13), interventional radiology (IR, 11), surgical resection (6), and a regimen of gemcitabine, oxaliplatin, and lenvatinib (6). The primary team implemented the VTB recommendations 60 times out of 71 (85%): change in systemic therapy (33), IR (11), continue current regimen (11), surgery (6), radiation oncology (2). Conclusions: This is the first demonstration of a patient-focused international multidisciplinary VTB for FLC. The high rate of recommendation adoption by local treating oncologists suggests this is a valuable service to improve patient care. Outcomes are being collected prospectively in a master observational research protocol to better define clinical utility.

Prostate-specific antigen reduction after capecitabine plus oxaliplatin chemotherapy: A case report

Prostate cancer (PC) is currently the most common malignant tumor of the genitourinary system in men. Radical prostatectomy (RP) is recommended for the treatment of patients with localized PC. Adjuvant hormonal therapy (AHT) can be administered postoperatively in patients with high-risk or locally advanced PC. Chemotherapy is a vital remedy for castration-resistant prostate cancer (CRPC), and may also benefit patients with PC who have not progressed to CRPC. A 68-year-old male was admitted to our hospital because of urinary irritation and dysuria with increased prostate-specific antigen (PSA) levels. After detailed examination, he was diagnosed with PC and treated with laparoscopic RP on August 3, 2020. AHT using androgen deprivation therapy (ADT) was performed postoperatively because of the positive surgical margin, extracapsular extension, and neural invasion but lasted only 6 mo. Unfortunately, he was diagnosed with rectal cancer about half a year after self-cessation of AHT, and was then treated with laparoscopic radical rectal resection and adjuvant chemotherapy using the capecitabine plus oxaliplatin (CapeOx) regimen. During the entire treatment process, the patient's PSA level first declined significantly after treatment of PC with laparoscopic RP and ADT, then rebounded because of self-cessation of ADT, and finally decreased again after CapeOx chemotherapy. CapeOx chemotherapy can reduce PSA levels in patients with high-risk locally advanced PC, indicating that CapeOx may be an alternative chemotherapy regimen for PC.