Oxaliplatin-based Chemotherapy Research Articles

Prognostic factors of survival and recurrence after liver transplantation for unresectable colorectal liver metastases: Results from the TransMet trial.

3561 Background: Liver transplantation (LT) has recently proved to improve the survival of selected patients with unresectable colorectal liver metastases (uCRLM) compared to chemotherapy (C) alone. However, recurrence rates remain high, stressing the need for a better patient selection. This exploratory study aimed to identify prognostic factors associated with recurrence and death in patients undergoing LT as part of the TransMet trial. Methods: Data from 36 patients of the LT+C arm (per protocol population) were analyzed including age, gender, TNM and RAS status of the primary tumor, characteristics of metastases at diagnosis and at LT, chemotherapy regimen, tumor response (RECIST), and timeframe from primary resection to LT. Associations with recurrence and death were explored. Variables with > 5 observations per group and p-values ≤ 0.10 in univariable analysis were included in multivariable models. Results: Among the 36 transplanted patients, 27 experienced recurrence and 9 died after 50-month follow-up. Recurrence: At univariable analysis two factors were associated to a higher risk: serum CEA levels > 5 ng/ml at time of LT (11/11 vs 11/18, p 0.01) and oxaliplatin-based first line chemotherapy (14/16 vs 13/20, p 0.04). Two other factors showed a trend toward statistical significance: Female sex (14/15 vs 13/21, p 0.10) and > 20 metastases at diagnosis (11/17 vs 16/19, p 0.09). At multivariable analysis, CEA levels at LT > 5 ng/ml (HR: 2.91; 95% CI: 1.0–8.2; p 0.04) emerged as an independent predictor of recurrence. Female sex (HR: 2.2; 95% CI: 0.8–5.3; p 0.08) and oxaliplatin-based first line chemotherapy (HR: 2.0; 95% CI: 0.8–4.8; p 0.13) were also associated with around 2-fold higher risk of recurrence, although not reaching statistical significance. Death : At univariable analysis,two factorswere significantly associated with a higher risk: female sex (7/15 vs 2/21 for male, p 0.03) and > 24 cycles of chemotherapy before LT (8/19 vs 1/15, p 0.05). Two other factors showed a trend toward higher mortality: no response to 1 st line chemotherapy (6/14 vs 3/22, p 0.06) and stable disease (vs partial response) before LT (8/22 vs 1/14, p 0.08). At multivariable analysis, female sex emerged as independent predictor of death (HR 5.1; 95% CI: 1.0-25.0; p = 0.04). More than 24 cycles of chemotherapy (HR 7.1; 95% CI: 0.9 – 51.0; p 0.07) and stable disease (vs partial response) at LT, showed an approximately 7-fold increase in the risk of mortality, although not reaching statistical significance. Conclusions: Within the limits of a reduced sample size, these results suggest that LT should be envisaged early in the history of potential candidates to LT to reduce the number of cycles of chemotherapy. Both morphological and biological tumor response, initially and at time of LT, are essential. The notable influence of female sex on post-LT outcome needs to be further explored. Clinical trial information: NCT02597348 .

Metastatic site pattern as predictor of outcome of first-line alternating oxaliplatin-based chemotherapy and nivolumab for patients with microsatellite-stable (MSS) colorectal cancer (CRC).

3533 Background: The randomized METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy (FLOX) alternating with nivolumab for previously untreated, unresectable abdominal metastases (mets) from MSS CRC. A subgroup of patients assigned to this experimental (exp) treatment had remarkably extended progression-free survival (PFS) compared to the control group patients given standard FLOX chemotherapy with median PFS 9.3 months. We explored if the extent of involved organs might be decisive for responsiveness to the METIMMOX regimen. Methods: Patients with measurable infradiaphragmatic (liver, peritoneal, nodal) mets were randomly assigned to the control group of FLOX (oxaliplatin, 5-fluorouracil, folinic acid) Q2W or the exp group of alternating 2 cycles each of FLOX Q2W and nivolumab Q2W, with prespecified break periods. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. For this post hoc analysis, at baseline, the principal metastatic site was defined by the 2 largest mets (main lesions) of the dominant infradiaphragmatic organ and the global metastatic pattern by the main and subsidiary lesions of all involved organs. Patients without adverse events leading to treatment discontinuation, thus with conclusive end of treatment (EoT) tumor data, were categorized into discrete outcome groups. Results: Of 36 exp group patients reaching the first radiologic reassessment, enabling formal evaluation, 31 proceeded to EoT tumor data. Of these, 6 patients (3 of 25 with liver main lesions, 3 of 4 with lymph node main lesions) had complete response (CR), including 3 of 3 BRAF -V600E cases. The remaining 3 CR cases had tumor mutational burden (TMB) 9.4-11.8. Of all 25 patients with liver mets, 13 (52%) had objective response and 5 (20%) stable disease. All 16 patients with objective response had improved PFS (median 15.5 months, 95% CI 12.4-18.5; p < 0.001, log-rank test). None of main or subsidiary lesions in peritoneum or lungs responded to the treatment. The 3 outcome groups comprised 7 patients with PFS 19.8-41.6 months (longer than twice the median), 8 with PFS 9.9-16.4 months (above median), and 16 with PFS 1.9-9.2 months (below median). At baseline, the best outcome group cases would have been predicted by the combination of right-sided primary, small main lesions (sum of diameters 42 mm or less), and all mets confined to the liver and/or lymph nodes; the mid group cases by left-sided or rectal primary along with peritoneal or lung subsidiary lesions; and the poor outcome cases by extended organ mets. Conclusions: Alternating short-course oxaliplatin-based chemotherapy and nivolumab was particularly efficient in treating unresectable liver or lymph node mets from right-sided MSS CRC with intermediate TMB or the BRAF driver mutation, but inefficient at peritoneal and lung mets. Clinical trial information: NCT03388190 .

OrigAMI-3: A randomized, phase 3 study of amivantamab plus FOLFIRI vs cetuximab or bevacizumab plus FOLFIRI in participants with recurrent, unresectable, or metastatic RAS/BRAF wild-type colorectal cancer.

TPS3638 Background: Among patients with metastatic colorectal cancer (mCRC), approximately 50% are wild-type for KRAS , NRAS , and BRAF ( RAS/BRAF WT) without actionable genomic alterations. Standard first-line therapy for RAS/ B RAF WT mCRC is 5-FU-based doublet chemotherapy (FOLFOX or FOLFIRI) plus anti-EGFR or anti-VEGF therapy. The choice of second-line treatment is dependent on first-line treatment (eg, oxaliplatin-based chemotherapy in the first-line necessitates irinotecan-based in the second-line, and vice versa). Known resistance mechanisms to anti-EGFR therapy are MET alterations, with MET amplification occurring in 5%-23% of EGFR-resistant mCRC and increasing in prevalence over subsequent lines of therapy. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity and is FDA-approved for 4 indications in EGFR -mutated advanced non-small cell lung cancer. In the phase 1b/2 OrigAMI-1 study (NCT05379595), amivantamab plus FOLFIRI demonstrated promising antitumor activity, independent of line of therapy, in participants (pts) with RAS / BRAF WT mCRC without prior anti-EGFR exposure (Pietrantonio ESMO 2024). The objective of this phase 3 randomized study is to assess the efficacy of amivantamab plus FOLFIRI vs cetuximab or bevacizumab plus FOLFIRI, as second-line therapy for pts with recurrent RAS / BRAF WT mCRC. Methods: The global OrigAMI-3 study (NCT06750094) is planned to open in 230 sites in 25 countries. Eligible pts will be WT for KRAS , NRAS , and BRAF , have recurrent unresectable or mCRC, and must have had disease progression on one prior line of systemic therapy for metastatic disease (prior regimen must be fluoropyrimidine-based and oxaliplatin-based therapy). Pts with treated, stable, and asymptomatic brain metastases are allowed. Key exclusion criteria include known dMMR/MSI-H status without prior immunotherapy, HER2-positive or amplified tumor, and prior exposure to irinotecan or agents targeting EGFR or MET. Approximately 700 pts will be randomly assigned 1:1 to receive subcutaneous amivantamab (co-formulated with recombinant human hyaluronidase [rHuPH20]) plus FOLFIRI vs intravenous cetuximab or bevacizumab (investigator’s choice, per local guidelines) plus FOLFIRI. Randomization will be stratified by choice of cetuximab or bevacizumab, primary tumor location (left vs right-sided), duration of first-line therapy (< 6 months or ≥6 months), and prior anti-VEGF therapy (yes or no). The dual primary endpoints will be progression-free survival by blinded independent central review and overall survival. Secondary endpoints include objective response rate, duration of response, and patient-reported outcomes. Safety assessments will include monitoring adverse events and laboratory abnormalities. Clinical trial information: NCT06750094 .

Exploring early kinetic profiles of CEA, ctDNA and cfDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer

Exploring early kinetic profiles of CEA, ctDNA and cfDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer

Trends in the treatment of stage IIB/C and IIIA colorectal cancer: A National Cancer Database (NCDB) analysis.

e15658 Background: The standard treatment for early-stage colon cancer (CC) involves upfront surgical resection of the primary tumor and regional lymph nodes, followed by adjuvant chemotherapy (CT) in selected patients. The benefit of adjuvant CT in stage II CC is controversial, with decisions guided by clinicopathologic risk factors. For stage III CC, fluoropyrimidine (FP)-based CT with or without oxaliplatin is recommended, with regimen duration (3 vs. 6 months) tailored to clinicopathologic features. Although stage IIIA generally has a better prognosis than IIC, trials supporting oxaliplatin-based CT included both stages. This study aimed to compare outcomes of stage IIIA patients treated with surgery alone or with adjuvant CT and assess the impact of nodal dissection extent and age. Differences between stages IIB/C and IIIA were also explored. Methods: Using the National Cancer Database (NCDB), we identified adults aged ≥18 with stage IIB, IIC, and IIIA colon adenocarcinoma diagnosed between 2010-2020 who underwent surgery. Baseline characteristics were compared using Fisher’s exact and Mann-Whitney U tests. Kaplan-Meier analysis estimated 3- and 5-year survival, with log-rank tests for comparisons. Cox proportional hazards models assessed overall survival and prognostic factors. Results: The study included 5870 stage IIB, 3046 stage IIC, and 5195 stage IIIA CC patients, with median diagnosis ages of 71, 69, and 66, respectively. Adjuvant CT was given to 37%, 46.6%, and 74% of stage IIB, IIC, and IIIA patients, respectively. Among pts with stage IIB, 802 (37%) patients received FP only and 1291 (60%) patients received FP and oxaliplatin. Among patients with stage IIC, 415 (29%) patients received FP monotherapy and 964 (68%) pts received FP and oxaliplatin. Among patients with stage IIIA, 780 (20%) patients received FP single agent and 2918 (76%) pts received FP combination with oxaliplatin. Stage IIIA showed superior 3-year overall survival (3yOS) compared to IIB and IIC (85.6%, 71%, and 72.4%, p < 0.001). Oxaliplatin addition improved 3yOS in stage IIIA (92.9% vs. 84.3%, p < 0.001) but not in stages IIB (p = 0.8) or IIC (p = 0.6). In stage IIIA, T1N2A patients did not benefit from adjuvant CT (3yOS: 87.4% vs. 75%, p = 0.3) on univariate analysis and multivariate analysis (HR: 1.21, 95% CI 0.5 – 2.9, p = 0.4), while T1-2N1 patients showed improved 3yOS (96.7% vs. 73.5%, p < 0.001). Lymphadenectomy extent impacted survival; CT improved outcomes across < 12, 12-20, and > 20 lymph nodes examined (p < 0.001). Adjuvant CT benefits were consistent across age groups ( < 70: 3yOS of 93.2% vs. 77.6%, p < 0.001; ≥70: 3yOS of 85% vs. 63.3%, p < 0.001). Conclusions: Adjuvant CT benefits stages IIB, IIC, and IIIA, but oxaliplatin adds survival benefits only in stage IIIA. Notably, T1N2A patients did not benefit from adjuvant CT, highlighting the need to to rediscuss pathological staging in CC given different impact of T and N stages in prognosis.

Geriatric 8 score as a prognostic factor of the efficacy and safety of oxaliplatin-based chemotherapy in elderly patients with metastatic colorectal cancer

ObjectiveOxaliplatin (L-OHP) is effective in the treatment of metastatic colorectal cancer (mCRC). However, given concerns about the possible impact of L-OHP-based chemotherapy regimens in the face of physical functional decline, the question of whether they should be actively recommended for elderly patients remains unclear. This study evaluated the relationship between the Geriatric 8 (G8) score, which assesses overall function in the elderly, and the efficacy and safety of L-OHP-based chemotherapy regimens.MethodsThis retrospective study included mCRC patients aged ≥ 70 years who received L-OHP as first-line therapy between January 2017 and December 2022. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was incidence of adverse events (Grade ≥ 2). Patients were classified into high (≥ 14 points) and low (< 14 points) G8 score groups for comparison.ResultsA total of 55 patients were included. Median PFS was significantly longer in the high G8 score group compared to the low G8 score group (12.4 vs. 6.0 months, P = 0.034). No significant difference in OS was observed (27.9 vs. 29.8 months, P = 0.833). The overall incidence of adverse events was comparable, but nausea incidence tended to be higher in the low G8 score group (0% vs. 25.5%, P = 0.096).ConclusionThe G8 score may serve as a useful prognostic factor in elderly mCRC patients receiving L-OHP. Those with lower G8 scores may be at higher risk of L-OHP-induced nausea.

Predictive factors for efficacy of oxaliplatin-based chemotherapy in advanced well-differentiated neuroendocrine tumors: an observational cohort study and meta-analysis.

Oxaliplatin-based chemotherapy (OX-CT) has shown promising antitumor activity in advanced well-differentiated neuroendocrine tumors (WD-NETs). However, no meta-analysis has been conducted to explore the factors associated with ORR and PFS of OX-CT, and data are still limited in Chinese cohort. We performed a retrospective cohort study with advanced WD-NETs who received OX-CT. We also conducted a systematic review and performed a meta-analysis to explore factors associated with ORR and PFS. A total of 27 patients were included, with 21 receiving OX-CT as first line. Furthermore, 18 were of pancreas origin, and the median Ki-67 was 30%. The ORR and DCR were 29.6% and 81.5%, respectively. The median PFS was 9.3 months (95%CI: 4.6-14.0), and OS was not reached. A Ki-67 value >10% predicted higher ORR (36.4% vs. 0.0%, p = 0.28) and better PFS (10.0 vs. 2.1 months, p = 0.06). Patients with hepatic tumor burden ≤25% had a similar ORR (33.3% vs. 22.2%, p = 0.68), but with a trend of longer PFS (10.2 vs. 4.7 months, p = 0.21) than those >25%. Both ORR and PFS were independent of MGMT status. A total of 962 patients were included in the systemic review. The pooled ORR (28.2%, p = 0.84) and DCR (82.9%, p = 0.85) were comparable with this cohort. No difference was observed between GEMOX and FOLFOX/CAPOX in both ORR (23.9% vs. 29.6%, p = 0.19) and PFS (10.5 vs. 11.8 months, p = 0.69). Enhanced ORR was seen in pNETs than epNETs (36.8% vs. 16.7%, p < 0.001) and also in G3 NETs than G1-2 NETs (45.5% vs. 24.7%, p < 0.001). The pooled median PFS and OS were 10.8 months (95%CI: 8.8-12.8) and 30.4 months (95%CI: 24.8-35.9). Oxaliplatin-based chemotherapy could be a good option for advanced WD-NETs with high Ki-67 index and pancreatic origin.

Radiomic-based models are able to predict the pathologic response to different neoadjuvant chemotherapy regimens in patients with gastric and gastroesophageal cancer: a cohort study

BackgroundThere is a clinical need to identify early predictors for response to neoadjuvant chemotherapy (NAC) in patients with gastric and gastroesophageal junction cancer (GC and GEJC). Radiomics involves extracting quantitative features from medical images. This study aimed to apply radiomics to build prediction models for the response to NAC.MethodsAll consecutive patients with non-metastatic GC and GEJC undergoing NAC and surgical resection in an Italian high-volume referral center between 2005 and 2021 were considered eligible. In patients selected, the CT scans performed upon staging were reviewed to segment the tumor and extract radiomic features using MODDICOM. The primary endpoint was to develop and validate radiomic-based predictive models to identify major responders (MR: tumor regression grade TRG 1–2) and non-responders (NR: TRG 4–5) to NAC. Following an initial feature selection, radiomic and combined radiomic-clinicopathologic prediction models were built for the MR or NR status based on logistic regressions. Internal validation was performed for each model. Radiomic models (in the entire case series and according to NAC regimens) were evaluated using the receiver operating characteristic area under the curve (AUC), sensitivity, and negative predictive value (NPV).ResultsThe study included 77 patients undergoing NAC and subsequent tumor resection. The MR prediction model after all types of NAC (AUC of 0.876, CI 95% 0.786 − 0.966, sensitivity 83%, and NPV 96%) was based on a statistical feature. The models predicting NR among patients undergoing epirubicin with cisplatin and fluorouracil (ECF), epirubicin with oxaliplatin and capecitabin (EOX), or fluorouracil with oxaliplatin and docetaxel (FLOT) (AUC 0.760, CI 95% 0.639–0.882), oxaliplatin-based chemotherapy (AUC 0.810, CI 95% 0.692–0.928), and FLOT (AUC 0.907, CI 95% 0.818 − 0.995) were based on statistical, morphological and textural features.ConclusionsThe developed radiomic models resulted promising in predicting the response to different neoadjuvant chemotherapy strategies. Once further implemented on larger datasets, they could be valuable and cost-effective instruments to target multimodal treatment in patients with GC.

NEIL3 Deficiency Enhances HCC Cell Sensitivity to Oxaliplatin by Inhibiting the Fanconi Anaemia Pathway.

Despite some achievements in oxaliplatin-based chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC), the abnormal activation of DNA damage repair pathways in HCC cells remains a major problem, limiting the efficacy of oxaliplatin-based chemotherapy. In a previous study, we found that endonuclease VIII-like protein 3 (NEIL3) is expressed in a high proportion of patients with HCC and associated with an unfavourable prognosis. However, the role of NEIL3 in chemoresistance is still unclear. The aim of this study was to evaluate whether and how NEIL3 regulates oxaliplatin anti-tumour efficacy. Gene expression after oxaliplatin treatment in HCC cell lines was assessed by real-time quantitative PCR, western blot analysis and bioinformatics analysis. The effect of NEIL3 on regulating oxaliplatin efficacy was assessed using cell counting kit-8 assays, colony formation assays, flow cytometry and an in vivo nude mice study. Mechanistic insights into the sensitivity to oxaliplatin mediated by the inhibition of NEIL3 were obtained through immunofluorescence and RNA sequencing analyses. Our findings demonstrated that NEIL3 expression was markedly downregulated after oxaliplatin administration. NEIL3 knockdown impaired cell viability and colony formation and increased apoptosis in HCC cells exposed to oxaliplatin. In addition, NEIL3 inhibition reduced tumour progression and enhanced oxaliplatin efficacy in xenograft nude mice models. Furthermore, knocking down NEIL3 significantly increased the oxaliplatin-mediated inhibition of the Fanconi anaemia pathway. Our results revealed that NEIL3 may be a promising therapeutic target for improving oxaliplatin efficacy in the treatment of HCC.

A Case Study on Complete Pathological Response in Advanced Rectal Cancer Patient with Oxaliplatin-based Chemotherapy without Cumulative Neurotoxicity.

The pathological response in rectal cancer treatment provides insight into the molecular mechanisms, including genetic alterations and signaling pathways that influence tumor behavior and resistance to treatment. This report describes a 34-year-old Iraqi male diagnosed with stage III rectal cancer who achieved a complete pathological response following treatment with oxaliplatin-based chemotherapy. Notably, this outcome was achieved without the administration of chemoradiotherapy or the occurrence of neurotoxicity despite the efficacious cumulative‑dose administration (1700mg/m2) of oxaliplatin. Genomic analysis revealed the presence of a heterozygous (Ile/Val) genotype in the GSTP1 gene, which may have contributed to the observed treatment response. Genetic biomarkers play a crucial role in refining treatment strategies by enabling a more precise selection of patients who may safely forgo radiotherapy, thereby minimizing its associated toxicities. Additionally, molecular profiling can help predict susceptibility to oxaliplatin-induced neurotoxicity, facilitating dose adjustments or alternative therapeutic approaches to enhance treatment tolerance and long-term quality of life. Our findings highlight the importance of molecular profiling in optimizing treatment strategies while minimizing toxicity, especially in situations where radiological assessments suggest residual disease or produce unclear results.

Efficacy and safety of oxaliplatin-based chemotherapy as first-line treatment in elderly patients with metastatic colorectal cancer: a meta-analysis.

The global burden of colorectal cancer (CRC) continues to rise, with elderly populations disproportionately affected. Despite oxaliplatin's established role in first-line metastatic CRC (mCRC) therapy, its clinical utility in older adults remains debated due to concerns over efficacy, toxicity, and survival outcomes. This meta-analysis evaluates the therapeutic benefits and risks of oxaliplatin-based regimens in elderly patients with mCRC, with emphasis on tumor response, survival endpoints, and treatment-related toxicities. We systematically reviewed PubMed, Web of Science, Cochrane Library, and Chinese databases (CNKI, Wan Fang) through November 2024 for randomized controlled trials (RCTs) comparing oxaliplatin-based chemotherapy to non-oxaliplatin regimens in patients aged ≥65 with mCRC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), complete response (CR), partial response (PR), disease control rate (DCR), and grade 3-4 adverse events. Data were pooled using random- or fixed-effects models in STATA 14.0 based on heterogeneity (I² statistic). Subgroup analyses explored heterogeneity sources, including chemotherapy combinations (e.g., bevacizumab, panitumumab). Seven RCTs (1,839 patients) met inclusion criteria. Oxaliplatin significantly improved tumor response rates versus control regimens: ORR (OR 2.18, 95% CI 1.75-2.72; P<0.001), CR (OR 2.57, 1.11-5.97; P=0.028), and PR (OR 1.69, 1.28-2.22; P<0.001). No significant survival benefit was observed for OS (HR 0.97, 0.86-1.08; P=0.58) or PFS (HR 0.90, 0.79-1.01; P=0.07), though trends favored oxaliplatin. Grade 3-4 neutropenia (RR 1.84, 1.32-2.57), diarrhea (RR 2.01, 1.45-2.78), and sensory neuropathy (RR 3.12, 1.98-4.91) were more frequent with oxaliplatin. Subgroup analysis attributed DCR heterogeneity (I²=66%) to regimen differences, with reduced variability in bevacizumab/pantiumumab-combined subgroups. This analysis demonstrates oxaliplatin's capacity to enhance tumor response in elderly mCRC patients, potentially alleviating symptoms and improving quality of life. However, the absence of significant survival gains underscores the complex interplay between tumor biology and therapeutic resistance. Mechanistically, chemotherapy-driven clonal selection may favor residual resistant subpopulations, as evidenced by liquid biopsy studies linking tumor evolution to disease progression. While toxicity profiles were manageable, the elevated risk of neurotoxicity and myelosuppression necessitates vigilant monitoring in this vulnerable cohort. Oxaliplatin-based first-line therapy provides clinically meaningful tumor response improvements in elderly mCRC patients, though survival advantages remain elusive. Treatment decisions should balance response benefits against toxicity risks, prioritizing individualized strategies informed by geriatric assessments and molecular profiling. Future trials must integrate biomarker-driven approaches (e.g., ctDNA monitoring, RAS/RAF stratification) to optimize therapeutic precision in aging populations.

Histone lactylation drives liver cancer metastasis by facilitating NSF1-mediated ferroptosis resistance after microwave ablation.

Histone lactylation drives liver cancer metastasis by facilitating NSF1-mediated ferroptosis resistance after microwave ablation.

Development of a Comprehensive Decision Support Tool for Chemotherapy-Cycle Prescribing: Initial Usability Study.

Chemotherapy cycle prescription is generally carried out through a multistep manual process that is prone to human error. Clinical decision support tools can provide patient-specific assessments that support clinical decisions, improve prescribing practices, and reduce medication errors. We hypothesized that a knowledge-based, patient-derived, evidence-directed decision support tool consisting of multiple modules focusing on the core duties preceding chemotherapy-cycle prescription could result in a more cost-effective and error-free approach and streamline the workflow. A 1-arm, multicenter, prospective clinical trial ("Follow-up of Cancer Patients Receiving Chemotherapy or Targeted Therapy by Electronic Patient Reported Outcomes-tool" [ECHO] 7/2019-1/2021; NCT04081558) was initiated to investigate the tool. The most important inclusion criteria were the presence of colorectal cancer (CRC) treated with oxaliplatin-based chemotherapy, age ≥18 years, Eastern Cooperative Oncology Group [ECOG] performance score of 0 to 2, and internet access. A decision support tool that included digital symptom monitoring, a laboratory value interface, and treatment schedule integration for semiautomated chemotherapy cycle prescribing was integrated into the care pathway. Performance was assessed by the percentage of chemotherapy cycles with sent and completed symptom questionnaires, while perceptions of health care professionals (HCPs) on the feasibility of the approach were collected through a 1-time semistructured interview. The ECHO trial included 43 patients with CRC treated with doublet or triplet chemotherapy in an adjuvant or metastatic setting. Altogether, 843 electronic patient-reported outcome (ePRO) symptom questionnaires were completed. Of the 15 recorded symptoms, fatigue (n=446, 52.9%) and peripheral neuropathy (n=429, 50.9%) were reported most often, while 137 grade 3 to 4 symptoms were recorded, of which diarrhea (n=5, 4%) and peripheral neuropathy (n=4, 3%) were the most common. During the study, 339 chemotherapy cycles were prescribed, and for the 77% (n=262) of new chemotherapy cycles, ePRO questionnaire data were available within preset limits (completed within 3 days prior to chemotherapy scheduling) while 65% of the cycles (n=221) had symptom questionnaire grading at ≤1%, and 67% of the cycles (n=228) had laboratory values in a preset range. The recommendations by the tool for a new chemotherapy cycle were tier 1 (green; meaning "go") in 145 (42.8%) of the cycles, tier 2 (yellow; "evaluate") in 83 (25%), and tier 3 (red; "hold") in 111 (32.7%). HCPs (n=3) were interviewed with a questionnaire (comprising 8 questions), revealing that they most valued the improved workflow, faster patient evaluation, and direct messaging option. In this study, we investigated the feasibility of a decision support system for chemotherapy-cycle pre-evaluation and prescription that was developed for the prospective ECHO trial. The study showed that the functionalities of the investigated tool were feasible and that an automated approach to chemotherapy-cycle prescription was possible for nearly half of the cycles.

The Dynamic Changes of Circulating Myeloid-Derived Suppressor Cells (MDSCs) Subsets in Colorectal Cancer Patients Undergoing Oxaliplatin-Based Chemotherapy

PurposeIncreased level of circulating myeloid-derived suppressor cells (MDSCs) in colorectal cancer (CRC) patients has been associated with higher tumor stage and poorer survival due to poorer response to therapeutic agents. However, studies reported inconsistent results on how chemotherapeutic agents affecting the depletion of two major types of MDSCs, polymophonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC). The present study aims to learn deeper on the dynamic changes of circulating MDSCs, especially in response to oxaliplatin-based treatment in CRC patients.MethodsThis was a prospective study that recruited 30 treatment-naive patients with varying stages of CRC who were scheduled to receive oxaliplatin-based chemotherapy. Blood sampling was conducted prior to and at several time points during and after chemotherapy. Multicolor flow cytometry assay was used to analyse the proportion of HLA-DR– and CD33+ with CD15+ (PMN-MDSCs) or CD14+ (M-MDSCs) cells within peripheral blood mononuclear cells (PBMCs). Other essential tumor biomarkers such as carcinoembryonic antigen (CEA) and tumor-infiltrating lymphocytes (TILs) were also assessed. As a control, 14 healthy subjects were recruited in this study.ResultsIndonesian treatment-naive CRC patients exhibited significantly higher circulating PMN-MDSCs compared to healthy subjects (p = 0.003), while M-MDSCs levels showed no significant difference between the groups (p = 0.890). Following chemotherapy, the MDSCs level demonstrated dynamic changes. Interestingly, a subgroup of CRC patients with decreased in both PMN- and M-MDSCs levels on D-14 of chemotherapy consistently showed a significant reduction in MDSCs levels during and after therapy completion compared to baseline (p = 0.0078).ConclusionsCirculating MDSCs level, particularly PMN-MDSCs, in CRC patients, was significantly higher compared to healthy subjects. Changes in both circulating PMN- and M-MDSCs levels at D-14 chemotherapy might have prognostic value in oxaliplatin-based chemotherapy.

Neoadjuvant oxaliplatin-based chemotherapy vs. primary surgery for locally advanced colon cancer : Results of the randomized OPTICAL study

Neoadjuvant oxaliplatin-based chemotherapy vs. primary surgery for locally advanced colon cancer : Results of the randomized OPTICAL study

A Post Hoc Analysis of Older Patients with Metastatic Colorectal Cancer Receiving Oxaliplatin-Based Chemotherapy Plus Bevacizumab: The Randomized Obelics Study.

Phase II trials and subgroup analyses of clinical studies suggest that bevacizumab plus an oxaliplatin-based chemotherapy doublet is effective and tolerable in fit older patients with metastatic colorectal cancer (mCRC). To evaluate the influence of age on the incidence of side effects and efficacy of this combination in patients with mCRC randomized in the prospective phase III OBELICS study. In total, 230 patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 out of 1 were retrieved on the basis of age (190 < 70 years and 40 ≥ 70 years). They received bevacizumab 5 mg/kg administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm) and oxaliplatin 85 mg/m2 on day 1, plus capecitabine 1000 mg/m2 twice a day (bid) orally on days 1-10 or levofolinic acid, 200 mg/m2, bolus 5-fluorouracil (5-FU) 400 mg/m2, and a 46-h intravenous infusion of 5-FU 2400 mg/m2, every 14 days; oxaliplatin was discontinued after 12 cycles. The primary end point was the overall response rate (ORR). Efficacy and toxicity analyses are reported in aggregate form because there were no statistically significant differences between the two arms. Patient characteristics are well balanced between older and younger patients. No difference in ORR was observed between the two groups (50% for the older patients versus 57.9% for the younger ones; p = 0.36). The median PFS was 10.8 (95% confidence interval [CI], 9.9-12.2) and 11.3 (95% CI 8.3-13.0) months, respectively, for subjects younger than 70 years and those aged ≥ 70 years, with an adjusted hazard ratio (HR) of 1.16 (95% CI 0.80-1.68; p = 0.43). The median OS was 26.2 (95% CI 23.3-32.7) for the former and 23.2 (95% CI 17.3-35.3) months for the latter, respectively, with an adjusted HR of 1.60 (95% CI 1.08-2.37; p = 0.027). Considering all forms of toxicity, the most severe ones were not statistically different between the two groups (65% for the older patients and 60.6% for the younger ones, p = 0.61). Bevacizumab plus an oxaliplatin-based chemotherapy doublet were effective in older patients randomized in the OBELICS trial, and the adverse event profile was not dissimilar from that of younger patients; no new safety concerns were identified. This post hoc analysis confirms that fit older patients with mCRC should be considered for treatment with this regimen.

Impact of tumor and node stages on the efficacy of adjuvant oxaliplatin-based chemotherapy in stage III colon cancer patients: anACCENT pooled analysis.

Standard adjuvant treatment of stage III colon cancer (CC) is fluoropyrimidine with oxaliplatin. Recently, stage III was subdivided into low-risk (T1-3, N1) and high-risk (T4 and/or N2), with the benefit of adding oxaliplatin varying across these substages. In this study, we aimed to assess the impact of oxaliplatin on survival outcomes in subdividing stage III CC patients based on T and N staging. A total of 4942 stage III CC patients were pooled from the three randomized pivotal trials of oxaliplatin. Kaplan-Meier curves, Cox models stratified by study, and interaction tests were used to assess the oxaliplatin effect across subgroups based on T and N stages. The primary endpoint was overall survival (OS). The prevalence of tumor stages was T1-2 12.4%, T3 74.4%, and T4 13.1%; nodal stages were N1 64.7% and N2 35.3%. A significant OS benefit from oxaliplatin was seen only in T3 (5-year OS= 77.2% versus 73.0%, P < 0.001): T3N1 (hazard ratio 0.72, 95% confidence interval 0.62-0.85, P < 0.001) and T3N2 (hazard ratio 0.81, 95% confidence interval 0.69-0.95, P= 0.010). No benefit was observed for T1-2 (5-year OS= 87.8% versus 88.7%, P= 0.644) or T4 patients (5-year OS= 62.6% versus 60.2%, P= 0.648). Subgroup analysis revealed a significant interaction between T stage and the effect of oxaliplatin treatment on OS, whereas no such interaction was observed for N stage. Our analysis revealed that oxaliplatin-based chemotherapy offers a significant survival benefit in stage III CC patients with T3 tumors. In contrast, no survival benefit was observed for T1-2 or T4 patients. These results suggested that T stage plays a more crucial role than N stage in predicting treatment benefit, highlighting the need for tailored treatment strategies based on tumor characteristics.

TROP2 expression in small bowel adenocarcinoma: A potential target for novel therapeutic strategies.

799 Background: Small bowel adenocarcinoma (SBA) is a rare cancer with limited chemotherapy options. To explore TROP2 as a potential therapeutic target for SBA and develop new treatment strategies, we examined TROP2 protein expression in SBA and analyzed associated clinicopathological features and prognosis, including PD-L1 expression levels in the same tumor samples from our previous studies. Methods: We retrospectively reviewed patients diagnosed with SBA who underwent adjuvant or palliative chemotherapy between July 2010 and July 2023 at our hospital. Immunohistochemistry staining of TROP2 (clone: SP295) was performed for pathological samples. The intensity of TROP2 membranous staining in tumor cells was classified as 0 (absent), 1 (weak to moderate), or 2 (strong). TROP2 positivity was defined as intensity 1 with ≥ 50% expression or intensity 2 with ≥ 10% expression. We also assessed overall survival (OS) in patients receiving palliative chemotherapy to examine the association between prognosis and TROP2, excluding microsatellite instability-high (MSI-H) patients treated with immunotherapy. Results: Pathological samples and clinical data were available for 51 patients. The median age was 63 years (range: 23–82), and 76% were male. Most patients (94%) had a performance status (PS) of 0–1. The primary lesion was in the duodenum in 49% of patients and in the jejunum or ileum in 51%. Surgery and adjuvant chemotherapy resulted in no recurrence in 12% of patients, while 88% received oxaliplatin-based palliative chemotherapy for unresectable SBA. Among those with unresectable SBA, 8% (4/51) had MSI-H and were treated with immunotherapy. TROP2 positivity was 84.3% (43/51). There were no differences in age, sex, or primary lesion between the TROP2-positive and TROP2-negative groups. In this cohort, the median CPS was 3 (range, 0–60). CPS was lower in TROP2-positive samples compared to negative samples (median CPS 7.9% vs. 23.4%, p = 0.030). However, all MSI-H cases were found to be TROP2-positive. Among patients receiving palliative chemotherapy, excluding those with MSI-H treated with immunotherapy, OS did not differ significantly between TROP2-positive and TROP2-negative patients (17.0 months vs. 9.2 months, HR 0.70, p = 0.480). Even after adjusting for age and PS, TROP2 expression was not identified as a prognostic factor. Conclusions: Our study highlighted that TROP2 is frequently expressed in SBA, suggesting it could be an effective therapeutic target for new treatment strategies. Further investigation is needed to confirm its potential.

Liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab as second-line therapy in metastatic colorectal cancer (IRIS): A multi-center, single-arm, prospective, phase II study.

195 Background: In patients with advanced colorectal cancer (CRC), the recommended second-line treatment following first-line therapy with oxaliplatin-based regimens is irinotecan-based therapy. Liposomal irinotecan, a novel formulation of traditional irinotecan, has demonstrated potential to enhance efficacy while minimizing toxicity. This study aims to investigate the efficacy and safety of liposomal irinotecan in combination with 5-FU/LV and bevacizumab as a second-line treatment option for metastatic CRC. Methods: This is a multi-center, single-arm, prospective, phase II study. Patients with metastatic CRC who received oxaliplatin-based chemotherapy as first-line treatment were enrolled to receive liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab regimen until disease progression and/or unacceptable toxicity. The primary endpoint is objective response rate (ORR), secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 50 patients were enrolled from Jan 2024 to Jul 2024 across 6 sites in China. The median age was 56.5 years (range: 30.0-76.0), with 58.0% male and 36.0% ECOG 0. Among the patients, 38.0% had left-sided colon cancer, 24.0% had right-sided colon cancer, and 38.0% had rectal cancer. As of Sept 14, 2024, 39 patients had at least one tumor assessment and 19 patients were still on treatment. ORR and DCR were 20.5% (8/39, 95% CI: 9.3%-36.5%) and 84.6% (33/39, 95% CI: 69.5%-94.1%), respectively. Eleven patients had disease progression and 5 patients died, and the median PFS and OS were not reached. The relative dose intensity of liposomal irinotecan and 5-fluorouracil were 92.8% (range: 23.6%-109.6%) and 89.5% (range: 13.3%-116.8%), respectively. During treatment, 43 (86.0%) patients had at least one adverse event (AE) and 24 (48.0%) had grade 3-4 AE. Most common (≥ 10%) grade 3-4 AEs were neutropenia (20.0%), leukocytopenia (16.0%) and diarrhea (10.0%). No unexpected toxicities observed in this study. Conclusions: These preliminary results reveled that liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab after oxaliplatin-based treatment for metastatic CRC was well tolerated with encouraging clinical activity, which warrants further follow up. Clinical trial information: NCT06184698 .

Computational Evaluation of Improved HIPEC Drug Delivery Kinetics via Bevacizumab-Induced Vascular Normalization.

Background: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) using the original 30 min protocol has shown limited benefits in patients with peritoneal metastasis of colorectal cancer (PMCRC), likely due to the short duration, which limits drug penetration into tumor nodules. Bevacizumab, an antiangiogenic antibody that modifies the tumor microenvironment, may improve drug delivery during HIPEC. This in silico study evaluates the availability of oxaliplatin within tumor nodules when HIPEC is performed after bevacizumab treatment. Methods: Using a computational fluid dynamics (CFD) model of HIPEC, the temperature and oxaliplatin distribution within the rat abdomen were calculated, followed by a model of drug transport within tumor nodules located at various sites in the peritoneum. The vascular normalization effect of the bevacizumab treatment was incorporated by adjusting the biophysical parameters of the tumor nodules. The effective penetration depth values, including the thermal enhancement ratio of cytotoxicity, were then compared between HIPEC alone and HIPEC combined with the bevacizumab treatment. Results: After bevacizumab treatments at doses of 0.5 mg/kg and 5 mg/kg, the oxaliplatin availability increased by up to 20% and 45% when HIPEC was performed during the vascular normalization phase, with the penetration depth increasing by 1.5-fold and 2.3-fold, respectively. Tumors with lower collagen densities and larger vascular pore sizes showed higher oxaliplatin enhancement after the combined treatment. Bevacizumab also enabled a reduction in the oxaliplatin dose (up to half at 5 mg/kg bevacizumab) while maintaining effective drug levels in the tumor nodules, potentially reducing systemic toxicity. Conclusions: These findings suggest that administering oxaliplatin-based HIPEC during bevacizumab-induced vascular normalization could significantly improve drug penetration and enhance treatment efficacy.