Oxaliplatin-based Chemotherapy Research Articles

Maintenance therapy with Fluoropyrimidine and cetuximab or bevacizumab after first line FOLFOX-chemotherapy in metastatic colorectal cancer according to RAS or BRAFV600E mutation status.

Fluoropyrimidine (FP) with oxaliplatin-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (mCRC); however, oxaliplatin-induced neuropathy critically affects the quality of life of patients. Maintenance strategies with FP plus bevacizumab have been well-established; nonetheless, the real-world outcomes of maintenance therapy with FP and cetuximab are unclear. We investigated the clinical outcomes of patients who underwent maintenance therapy with cetuximab. We retrospectively identified and analyzed patients with mCRC who were treated between 2012 and 2021 with first-line oxaliplatin-based induction chemotherapy (IC) plus biologic agents (either cetuximab or bevacizumab), and underwent maintenance therapy (IC regimen without oxaliplatin) after IC. In total, 19 patients who were treated with mFOLFOX6 (FP/leucovorin/oxaliplatin) with cetuximab, and 26 patients who were treated with mFOLFOX6 with bevacizumab were included. In the cetuximab group, all patients were KRAS-, NRAS-, and BRAF-wild type, whereas most patients in the bevacizumab group harbored KRAS or BRAFV600E or NRAS mutants. During the maintenance treatment, seven patients (four [21%] in the cetuximab group and three [11%] in the bevacizumab group) achieved partial response after achieving nadir during induction chemotherapy. The disease control rates of maintenance therapy were 79% and 74% in the cetuximab and bevacizumab groups, respectively. The median progression-free survival of maintenance therapy and overall survival was 5.98months and 32.4months in the cetuximab group, and 4.83months and 25.6months in the bevacizumab group, respectively. Maintenance therapy with FP plus biologic agents (either bevacizumab or cetuximab) is a feasible strategy for appropriate mCRC patients according to their RAS/BRAF status. Further large-scale randomized studies are needed to validate the efficacy of anti-epidermal growth factor receptor-based maintenance therapy.

Effect of short-course radiotherapy followed by oxaliplatin-based consolidation chemotherapy on organ preservation in locally advanced rectal cancer.

We analyzed the effectiveness, safety, and mid-term oncological outcomes of short-course radiotherapy (SCRT) and oxaliplatin-based consolidation chemotherapy in patients with locally advanced rectal cancer (LARC). We retrospectively evaluated 64 patients with LARC who underwent SCRT and tegafox (tegafur-uracil/leucovorin plus oxaliplatin) or mFOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) consolidation chemotherapy before surgery between January 2015 and December 2020. Tumor response, patient compliance, toxicity, surgical outcomes, overall survival (OS), and disease-free survival (DFS) were analyzed. Sixty-four patients with a mean age of 58.67years (44 males) were included; 48 (75%) had tumors within 5cm of the anal verge. Additionally, 93.8% of the patients underwent at least 2months of chemotherapy, and three required dose reduction. Grade III toxicity occurred in 2 patients, and 10 had a clinical complete response and opted for non-operative management. One patient experienced tumor progression and underwent further treatment without surgery. Among the 53 patients who underwent surgery, 51 (96.2%) had sphincter preservation, 3 had Clavien-Dindo grade III complications, and no mortality occurred. The complete response rate for the entire cohort was 23.4%. Moreover, 47 patients (74.6%) had a neoadjuvant rectal score of < 16 after treatment. After a median follow-up time of 32.01months, 6 (9.3%) had local recurrence, and 17 (26.6%) had distant metastasis. The 3-year OS, DFS and stoma-free rates were 89.5%, 65.5%, and 78.1% respectively. SCRT followed by oxaliplatin-based consolidation chemotherapy is safe and effective for tumor downstaging in LARC, further improving the sphincter preservation rate.

PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.

Abstract 2134: Microsatellite instability status and high risk features in decision making for adjuvant chemotherapy in stage 2 colon cancer

Abstract Background: The impact of adjuvant chemotherapy for patients with stage II colon cancer has been addressed in several clinical trials. NCCN guideline recommends that patients with stage II disease that is MSS/pMMR and at high risk for systemic recurrence can be considered adjuvant chemotherapy. However, research on whether these high-risk features or status of microsatellite instability (MSI) are predictive markers for adjuvant chemotherapy (ACT) is insufficient. Materials and Methods: We assessed the efficacy of ACT and possible interaction with MSI status and high-risk features for recurrence in patients with resected stage II colon diagnosed at 16 tertiary referral hospitals between January 2010 and December 2017. Results: According to MSI status, 394 patients (21.8%) had MSI-high tumors and 1416 (78.2%) had MSI-low or microsatellite stable (MSS) tumors. There were 881 patients (48.7%) with one or more high-risk feature for recurrence. Among 161 patients with MSI-high and high-risk features, the 5-year disease-free survival (DFS) and overall survival (OS) of patients who received no ACT, 5-FU chemotherapy, and oxaliplatin-based chemotherapy were 65.5% and 72.3%, 89.4% and 97.9%, and 88.2% 92.0%, respectively (DFS and OS: 5-FU vs. Oxaliplatin, p=0.972 and p=0.233, Oxaliplatin vs. no chemotherapy, p=0.016 and p=0.032, 5-FU vs. no chemotherapy, p=0.025 and p=0.003, respectively). Among 720 patients with MSI-low or MSS and high-risk features, the 5-year DFS and OS of patients who received no ACT, 5-FU, and oxaliplatin-based were 77.1% and 87.2%, 90.4% and 95.6%, and 86.9% 93.5%, respectively (DFS and OS: 5-FU vs. Oxaliplatin, p=0.580 and p=0.492, Oxaliplatin vs. no chemotherapy, p=0.037 and p=0.077, 5-FU vs. no chemotherapy, p=0.009 and p=0.012, respectively). In patients without risk factors, there was no benefit from ACT regardless of MSI status. Conclusions: 5-FU chemotherapy can be recommended in patients with one or more high-risk features for recurrence regardless of MSI status in stage II colon cancer. Keyword: Colonic Neoplasms, Adjuvant Chemotherapy, Microsatellite Instability, Risk Factors Citation Format: Sung Uk Bae, Woon Kyung Jeong, Seong Kyu Baek. Microsatellite instability status and high risk features in decision making for adjuvant chemotherapy in stage 2 colon cancer [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 2134.

Abstract 3279: Systemic immune response invoked by short-course oxaliplatin-based chemotherapy (FLOX) for efficacy of sequential immune checkpoint blockade (ICB; nivolumab) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC)

Abstract Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX study (NCT03388190) explored an unconventional concept, that patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivolumab). Among study patients who were assigned this highly experimental treatment, 15% obtained long-lasting complete response and more than a half met an early occurring radiologic signal of ICB responsiveness predicting significantly extended progression-free survival (PFS) compared to study control arm patients given standard FLOX chemotherapy [PMID: 36229579]. The aim of the present study was to verify if systemic tumor-defeating immunity had been invoked by the short-course FLOX treatment in the responding patients. The fms-related tyrosine kinase-3 ligand (Flt3L) is a circulating factor that reflects the direct cytotoxic effects of chemotherapy and also activates dendritic cells that present the shed tumor antigens to tumor-targeting T-cells. Procedures: Study patients were randomly assigned to the control arm of FLOX (oxaliplatin 85 mg/m2 on day 1 and bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg on days 1 and 2) Q2W or the experimental arm of repeat sequential cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. Patients were categorized into those with target lesion (TL) reduction of ≥10% or &amp;lt;10% at the first post-baseline assessment (8 weeks) [PMID: 36229579]. Serum Flt3L was measured at baseline and following the initial 2 FLOX cycles (at 4 weeks) using a Luminex assay. Results: For all subjects, median Flt3L was 103.8 pg/ml (range 24.6-306.1) at baseline and 162.4 pg/ml (range 53.3-503.8) at 4 weeks. For the experimental arm patients (n = 34), the higher 4-week Flt3L level, the deeper overall radiologic response (rho = -0.39, p = 0.022, Spearman correlation). The 4-week Flt3L level was higher in patients who obtained ≥10% TL reduction (n = 18; median 233.5 pg/ml, range 94.9-466.7) than in those who did not meet this 8-week predictive signal of extended PFS (n = 16; median 161.9 pg/ml, range 53.3-374.8; p = 0.022, Mann-Whitney U test). Selecting a 160 pg/ml cut-off, patients with 4-week Flt3L values above (n = 21) obtained longer PFS (median of 13.6 months, 95% CI 7.6-19.7) than those with serum values below (n = 13; median PFS of 5.9 months, 95% CI 2.4-9.3; p = 0.046, log-rank test). Conclusions: High circulating Flt3L after initial short-course FLOX chemotherapy, as a proxy of invoked tumor-defeating immunity, was associated with an early radiologic signal of ICB responsiveness and improved PFS in patients with MSS-mCRC. Citation Format: Sebastian Meltzer, Kjersti Flatmark, Anniken J. Fuglestad, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne G. Guren, Halfdan Sorbye, Anne Negård, Anne Hansen Ree. Systemic immune response invoked by short-course oxaliplatin-based chemotherapy (FLOX) for efficacy of sequential immune checkpoint blockade (ICB; nivolumab) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [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 3279.

Autotaxin is a novel surrogate marker for oxaliplatin-related sinusoidal obstruction syndrome in patients with colorectal liver metastasis.

Chemotherapy for colorectal liver metastasis has improved dramatically over the past few decades. However, sinusoidal obstruction syndrome induced by oxaliplatin leads to increased severe morbidity after hepatectomy for colorectal liver metastasis. Autotaxin is a novel liver fibrosis marker known to be taken up and metabolized by sinusoidal endothelial cells. This study aimed to evaluate whether Autotaxin levels could be a novel surrogate marker of sinusoidal obstruction syndrome for colorectal liver metastasis. We retrospectively evaluated 73 consecutive patients who underwent hepatectomy for colorectal liver metastasis. We assessed the relationship between their preoperative Autotaxin levels and sinusoidal obstruction syndrome. Median Autotaxin level was 0.750 mg/L. Preoperative oxaliplatin-based chemotherapy for colorectal liver metastasis was administered to 51 patients, and sinusoidal obstruction syndrome was histologically observed in 45 patients. Patients who received the oxaliplatin based chemotherapy had significantly higher Autotaxin levels than those who did not (P = 0.038). Furthermore, Autotaxin levels were higher in patients with sinusoidal obstruction syndrome than in those without (P = 0.011). Univariate and multivariate analyses revealed that Autotaxin level can be an independent predictive factor for sinusoidal obstruction syndrome preoperatively (P = 0.001). Autotaxin level is a non-invasive and promising surrogate marker for predicting sinusoidal obstruction syndrome before surgical resection for colorectal liver metastasis. This article is protected by copyright. All rights reserved.

Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon cancer from the PRODIGE 34-FFCD randomized trial.

Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients. The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled. The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2. No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.

A randomized controlled trial of hand/foot-cooling by hilotherapy to prevent oxaliplatin-related peripheral neuropathy in patients with malignancies of the digestive system

Both acute and chronic symptoms of oxaliplatin-induced peripheral neuropathy (OIPN) affect patients' treatment dose and duration as well as quality-of-life. Hand/foot-cooling has been shown to reduce taxane-induced peripheral neuropathy but there is unclear evidence in the setting of oxaliplatin. In a monocentric, open-label phase II trial, patients with malignancies of the digestive system receiving oxaliplatin-based chemotherapy were randomly assigned to receive either continuous cooling of hands and feet using hilotherapy at 11°C during oxaliplatin infusion compared with usual care (no cooling). The primary endpoint was grade ≥2 neuropathy-free rate in 12 weeks after initiation of chemotherapy. Secondary endpoints included OIPN-related treatment alterations, acute OIPN symptoms and perceived comfort of the intervention. The intention-to-treat population included 39 patients in the hilotherapy group and 38 in the control group. The grade ≥2 neuropathy-free rate at 12 weeks was 100% in the experimental group versus 80.5% in the control group (P= 0.006). This effect was persistent at 24 weeks (66.0% versus 49.2%, respectively) (P= 0.039). Next, treatment alterations-free rate at week 12 was 93.5% in the hilotherapy group compared with 83.3% in the control group (P= 0.131). Patients in the hilotherapy group experienced significantly less acute OIPN symptoms of numbness or tingling [odds ratio (OR) 0.05, 95% confidence interval (CI) 0.02-0.11, P < 0.0001], pain (OR 0.06, 95% CI 0.02-0.15, P < 0.0001) and/or cold sensitivity (OR 0.02, 95% CI 0.01-0.05, P < 0.0001) in fingers or toes as well as less pharyngeal cold sensitivity (OR 0.14, 95% CI 0.05-0.42, P= 0.0005). The majority of patients in the hilotherapy group rated the intervention as neutral, rather comfortable or very comfortable. In this first study on hand/foot-cooling in oxaliplatin alone, hilotherapy significantly reduced the incidence of grade ≥2 OIPN at 12 and 24 weeks. Hilotherapy also reduced acute OIPN symptoms and was generally well tolerated.

Cancerous inhibitor of protein phosphatase 2A enhances chemoresistance of gastric cancer cells to oxaliplatin.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a newly discovered oncogene. It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer (GC) cells. CIP2A is functionally related to chemoresistance in various types of tumors according to recent studies. The underlying mechanism, however, is unknown. Further, the primary treatment regimen for GC is oxaliplatin-based chemotherapy. Nonetheless, it often fails due to chemoresistance of GC cells to oxaliplatin. The goal of this study was to examine CIP2A expression and its association with oxaliplatin resistance in human GC cells. Immunohistochemistry was used to examine CIP2A expression in GC tissues and adjacent normal tissues. CIP2A expression in GC cell lines was reduced using small interfering RNA. After confirming the silencing efficiency, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium and flow cytometry assays were used to evaluate cell proliferation and apoptosis caused by oxaliplatin treatment. Further, the key genes and protein changes were verified using real-time quantitative reverse transcription PCR and Western blotting, respectively, before and after intervention. For bioinformatics analysis, we used the R software and Bioconductor project. For statistical analysis, we used GraphPad Prism 6.0 and the Statistical Package for the Social Sciences software version 20.0 (IBM, Armonk, United States). A high level of CIP2A expression was associated with tumor size, T stage, lymph node metastasis, Tumor Node Metastasis stage, and a poor prognosis. Further, CIP2A expression was higher in GC cells than in normal human gastric epithelial cells. Using small interfering RNA against CIP2A, we discovered that CIP2A knockdown inhibited cell proliferation and significantly increased GC cell sensitivity to oxaliplatin. Moreover, CIP2A knockdown enhanced oxaliplatin-induced apoptosis in GC cells. Hence, high CIP2A levels in GC may be a factor in chemoresistance to oxaliplatin. In human GC cells, CIP2A regulated protein kinase B phosphorylation, and chemical inhibition of the protein kinase B signaling pathway was significantly associated with increased sensitivity to oxaliplatin. Therefore, the protein kinase B signaling pathway was correlated with CIP2A-enhanced chemoresistance of human GC cells to oxaliplatin. CIP2A expression could be a novel therapeutic strategy for chemoresistance in GC.

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

Palliative systemic therapy and oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy in patients with unresectable colorectal peritoneal metastases in a phase II trial (CRC-PIPAC-II)

Palliative systemic therapy and oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy in patients with unresectable colorectal peritoneal metastases in a phase II trial (CRC-PIPAC-II)

LEANOX: Lean body mass normalization of oxaliplatin-based chemotherapy for patients with stage III colon cancer treated in adjuvant setting: Impact on oxaliplatin-induced sensitive neurotoxicity—A multicenter phase II randomized trial.

92 Background: Adjuvant chemotherapy is the current worldwide standard of care for stage III colorectal cancer (CRC) but it leads to significant neurotoxicity. We have shown in 2 cohorts of CRC patients treated with Oxaliplatin (Ox) that Ox-due neuropathy occurred in patients receiving an excess of 3.09 mg Ox/ kg Lean Body Mass (LBM). The aim of this trial was to determine whether the Ox dose adaptation based on the LBM index can reduce neurotoxicity, in patients treated for a stage III CRC. Methods: LEANOX is a randomized phase II multicentre study in patients eligible for an Ox regimen as adjuvant chemotherapy for CRC. Patients without sarcopenia (LBM index &lt;3.09mg/kg, group 1) received a dosage of Ox according to Body Surface Area (BSA) (85 mg/m²).Patients with sarcopenia (LBM index ≥3.09mg/kg) were randomized in 2 groups, group 2: dosage of Ox according to BSA (similar to group 1) and group 3: a dosage of Ox according to LBM (3.09 mg Ox/ kg LBM). Randomization (1:1) was stratified by center, age and weight loss. The primary endpoint was the percentage of patients without grade ≥2 neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy. The study required 108 randomized patients (bilateral α=0.05, 80% power) to compare the primary endpoint between groups 2 and 3 with P2=55% and P3=80%. Secondary endpoints included time to onset of grade≥2 chronic cumulative neurotoxicity, duration of the chronic cumulative neurotoxicity, cumulative Ox doses that can be delivered without reaching the dose-limiting chronic neurotoxicity, tolerance, disease free survival, overall survival and quality of life. Results: A total of 160 patients were included in 18 french centers: 33 in group 1, 64 in group 2 and 63 in group 3. Median age was 63 years, 52.5 % male, 89.3 % OMS 0 and tumoral stage was T3 (57.5%), T4 (33.8%), N1 (60.6%) and N2 (38.1%). Grade 3-4 AE events occurred in 58.0% in group 2 and 59.7% in group 3. The percentage of patients without experiencing grade ≥ 2 of neurotoxicity during the first 6 cycles of adjuvant Ox-based chemotherapy was 43.9% in group 2 vs 67.2% in group 3 (p=0.01). Conclusions: We wish to avoid severe adverse reactions to Ox regimen by personalization of cancer chemotherapy. Clinical trial information: NCT03255434 .

Second-line bevacizumab plus FOLFOX in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-based chemotherapy.

157 Background: There is a rarity of evidence for retreatment with oxaliplatin for metastatic colorectal cancer (mCRC), especially in combination with bevacizumab. This is a retrospective study of second line bevacizumab (Bev) plus FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-containing chemotherapy. Methods: Patients with age older than 18 and histologically confirmed metastatic colorectal cancer treated with second line bevacizumab plus FOLFOX in a single institute between 2015 and 2020 were enrolled. History of previous adjuvant chemotherapy regimens in patients with metachronous metastatic colorectal cancer was analyzed. Progression-free survival (PFS) and overall survival (OS) of the second line treatment were calculated using Kaplan-Meier method and compared between patients pretreated with adjuvant oxaliplatin (ReOx) and oxaliplatin-naive patients (control) with the log rank test. Results: A total of 72 patients were included. 23 patients (ReOx) were pretreated with adjuvant oxaliplatin and 49 patients (control) were oxaliplatin-naive before the second line treatment. There was a tendency of younger age in the ReOx group, but not statistically significant. Liver metastasis was significantly more frequent in the control group. The median PFS and OS in the ReOx group and the control group were 4.3 months (95% confidence interval [CI], 3.67–21.50) versus 5.5 months (95% CI, 4.23–8.20, hazard ratio [HR] = 0.84), and 10.5 months (95% CI, 5.40–30.37) versus 9.4 months (95% CI, 6.00–14.9, HR = 1.01) respectively. There was no significant difference of PFS ( p= 0.523) and OS ( p= 0.9745) between two groups. Conclusions: This study suggests a potential survival benefit of bevacizumab plus FOLFOX for mCRC patients previously treated with adjuvant oxaliplatin-containing treatment comparable to oxaliplatin-naive patients. [Table: see text]

Identification and external validation of clinical-molecular features to predict benefit from oxaliplatin reintroduction/rechallenge in patients with refractory metastatic colorectal cancer (mCRC).

153 Background: Oxaliplatin is a backbone cytotoxic treatment for mCRC patients, particularly in the front-line setting. In the refractory disease, current treatment options are scarce and with limited efficacy. Several retrospective studies have explored the efficacy of oxaliplatin reintroduction/rechallenge (OxRe) in this scenario. However, more evidence is still needed to determine which patients do benefit from this treatment strategy. Methods: The discovery cohort includes all patients treated with oxaliplatin in a third- or fourth-line setting at VHIO between 2015 and 2021 (N = 102). Results were externally validated in a real-world cohort of patients treated at community oncology practices from Oncoclínicas Group in Brazil (N = 157). We analyzed the impact of clinical-molecular features in uni- and multivariable prognostic models in terms of median progression free survival (mPFS) (discovery cohort) and median time to treatment discontinuation (mTTD) (validation cohort). For both cohorts separately, data was extracted from EHRs in structured formats (demographics, tumor characteristics, pharmacy records) and combined with elements from unstructured sources (physician notes on progression and survival status) using technology-based abstraction techniques. Results: In the discovery cohort, 102 out of 735 mCRC patients (13,9%) were eligible. Median oxaliplatin-free interval (from Oxl stop to OxRe) was 17 months (CI95% 13.0-23.2). In OxRe setting, mPFS was 4.0 months (CI95% 3.29-5.03). In PFS multivariate analysis, determinants of favorable outcome were left tumor location (p = 0.01), oxaliplatin-free interval (p = 0.03), administration of Bev in refractory setting (p = 0.001), and not receiving Bev in first-line treatment (p = 0.008). Overall, 27% of all patients had a mPFS &gt; 6 months with OxRe. In the validation cohort, out of 4,317 patients with mCRC, 157 (4%) were treated with OxRe. Median oxaliplatin-free interval was 15 months. Median time to treatment discontinuation (mTTD) of the OxRe was 3.4 months (CI95% 2.8-4.2). In multivariable model, the only independent prognostic factor was addition of Bev to OxRe (p = 0.036). Interestingly, 31% of all patients had mTTD &gt; 6 months, largely enriched (65%) in patients with first Bev exposure at the time of OxRe. Conclusions: This study suggests that in refractory mCRC patients re-exposed to oxaliplatin-based chemotherapy, the addition of Bev is associated with improved outcomes. One-third of the patients are long-term responders (PFS/TTD &gt; 6 months), reinforcing the value of this strategy in selected populations and the relevance of anti-angiogenic agents in refractory mCRC.

Association of High LAT1 Expression with Poor Prognosis and Recurrence in Colorectal Cancer Patients Treated with Oxaliplatin-Based Adjuvant Chemotherapy

The mammalian target of rapamycin (mTOR) is often activated in several cancers. We focused on two mTOR regulatory mechanisms: oxaliplatin-induced mTOR signaling and L-type amino acid transporter 1 (LAT1)-induced mTOR activation. High LAT1 expression in several cancers is associated with mTOR activation and resistance to chemotherapy. However, the significance of LAT1 has not yet been elucidated in colorectal cancer (CRC) patients treated with post-operative adjuvant chemotherapy. Immunohistochemistry was conducted to examine the significance of membrane LAT1 expression in 98 CRC patients who received adjuvant chemotherapy, including oxaliplatin. In vitro analysis was performed using CRC cell lines to determine the effects of LAT1 suppression on proliferation, oxaliplatin sensitivity, and mTOR signaling. LAT1 expression was associated with cancer aggressiveness and poor prognosis in 98 CRC patients treated with adjuvant chemotherapy. We found that positive LAT1 expression correlated with shorter survival in 43 patients treated with the capecitabine-plus-oxaliplatin (CAPOX) regimen. LAT1 suppression in CRC cells inhibited the proliferation potency and oxaliplatin-induced activation of mTOR signaling, and improved oxaliplatin sensitivity. LAT1 evaluation before adjuvant treatment may therefore be a sensitive marker for oxaliplatin-based regimens. Moreover, LAT1 may be a promising target for patients with refractory CRC.

PROPERTY: study protocol for a randomized, double-blind, multicenter placebo-controlled trial assessing neurotoxicity in patients with metastatic gastrointestinal cancer taking PHYCOCARE® during oxaliplatin-based chemotherapy

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of antineoplastic agents, ranging in prevalence from 19% to over 85%. Clinically, CIPN is a predominantly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. The high prevalence of CIPN among cancer patients makes it a major problem for both patients and survivors, as well as for their health care providers, especially because there is currently no single effective method of preventing CIPN; moreover, the options for treating this syndrome are very limited.Phycocyanin, a biliprotein pigment and an important constituent of the blue-green algae Spirulina platensis, has been reported to possess significant antioxidant and radical-scavenging properties, offering protection against oxidative stress, which is one of the hypothetic mechanisms, between others, of CIPN occurrence.MethodsOur hypothesis is that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastrointestinal cancers. Our trial will be a randomized double-blind placebo-controlled study with 110 randomized patients suffering from metastatic gastrointestinal adenocarcinoma including esogastric, colorectal, and pancreatic cancers. Patients are being followed up in the gastroenterology or oncology departments of seven French hospitals.DiscussionDue to the neuropathy, patients need to avoid injury by paying careful attention to home safety; patients’ physicians often prescribe over-the-counter pain medications. If validated, our hypothesis should help to limit neurotoxicity without the need to discontinue chemotherapy.Trial registrationClinicalTrials.gov NCT05025826. First published on August 27, 2021.

Long Non-Coding RNA BCAR4 Promotes Oxaliplatin Resistance in Colorectal Cancer by Modulating miR-484-3p/RAB5C Expression

Background: Oxaliplatin-based chemotherapy resistance is a major cause of recurrence in patients with colorectal cancer (CRC). Increasing evidence indicates that lncRNA BCAR4 is involved in the occurrence and development of various cancers. However, the effect of BCAR4 on CRC chemotherapy resistance remains unclear. Methods: Real-time quantitative PCR and Western blotting were used to detect the expression levels of gene and protein, respectively. The role of BCAR4 in drug resistance was evaluated by cell viability and apoptosis experiments. Luciferase reporter assay and Western blot analysis confirmed the relationship between BCAR4, miR-483-3p, and RAB5C. Results: Luciferase reporter assay and Western blotting analysis confirmed the relationship among BCAR4, miR-483-3p, and RAB5C. The results showed that the expression levels of BCAR4 and RAB5C were increased in CRC tumor tissue. The expression levels of BCAR4 were increased in patients with chemotherapy resistance. Functional analysis showed that knockdown of BCAR4 reduced the expression levels of proteins related to stemness, decreased the activity of cells, and promoted apoptosis of CRC cells, while overexpression of RAB5C reversed these effects. Moreover, the results showed that BCAR4 promoted oxaliplatin resistance by inhibiting cell apoptosis. Mechanistically, BCAR4 sponged miR-483-3p and promoted the expression of RAB5C. Knockdown of BCAR4 reduced tumor size and enhanced cell sensitivity to oxaliplatin in vivo. Conclusion: The results suggested that BCAR4/miR-483-3p/RAB5C axis has the potential to be explored as a novel therapeutic target for CRC treatment.

Enhanced De Novo Lipid Synthesis Mediated by FASN Induces Chemoresistance in Colorectal Cancer.

Oxaliplatin is one of the most widely used chemotherapy drugs for colorectal cancer (CRC). Resistance to oxaliplatin threatens the prognosis of CRC. Since previous studies have aroused interest in fatty acid metabolism in cancer, in this study, we determined whether fatty acid biosynthesis and the related regulating mechanism contribute to oxaliplatin resistance in CRC. The effect of the fatty acid synthase (FASN) and its inhibitor Orlistat was characterized in Gene Expression Omnibus (GEO) databases, oxaliplatin-resistant cell lines, and xenografts. MRNA-seq and analysis identified related pathway changes after the application of Orlistat, which was verified by Western blotting. By leveraging the GEO databases, FASN and closely related gene signatures were identified as being correlated with the response to oxaliplatin-based chemotherapy and poor prognosis. Additionally, FASN-upregulated expression promoted oxaliplatin resistance in CRC cell lines. We then applied Orlistat, a typical FASN inhibitor, in cell culture and xenograft models of oxaliplatin-resistant CRC, which attenuated the resistance to oxaliplatin. Additionally, the combination of the FASN inhibitor and oxaliplatin significantly increased cell cycle arrest and facilitated apoptosis, partly due to the diminished phosphorylation of the MAPK/ERK and PI3K/AKT pathways. In vivo studies showed that inhibiting fatty acid biosynthesis with Orlistat restrained the growth of xenograft tumors and increased the responsiveness to oxaliplatin. Our study revealed that FASN enhanced resistance to oxaliplatin in CRC. The inhibition of FASN could rescue the response to oxaliplatin by regulating MAPK/ERK and PI3K/AKT pathways.

Survival Analysis and Prognostic Factors for Metastatic Colorectal Cancer Patients Treated with Chemotherapy

Background: Currently, there are limited data on prognostic factors in metastatic colorectal cancer (mCRC) patients treated with chemotherapy. Prognostic factors in colorectal cancer remain varied in each situation when considering their use in different contexts. Objective: To analyze the independent prognostic factors of mCRC in patients receiving chemotherapy. Materials and Methods: Data from 156 mCRC patients completely treated by first-line chemotherapy were collected between 2013 and 2018. A retrospective observational cohort study was conducted to evaluate the survival analysis and prognostic factors. A univariate and multivariate Cox’s proportional-hazards model were used to explore and identify the independent prognostic factors for overall survival. An analysis of the restricted mean survival time (RMST) method was used to estimate the event-free time from zero to 24 months. Results: Median overall survival was 18.3 months (96% CI 15.31 to 20.95). The multivariate Cox’s proportional-hazards model revealed two rognostic factors for decreased survival, poor Eastern Cooperative Oncology Group (ECOG) performance status greater than or equal to 2 (HR 2.05, 95% CI 1.08 to 3.86; p=0.027) and hypoalbuminemia lower than 3.5 g/dL (HR 3.47, 95% CI 2.10 to 5.75, p&lt;0.001). Analysis of the RMST method was used to estimate the event-free time from zero to 24 months in the group receiving first-line oxaliplatin-based chemotherapy, secondline oxaliplatin-based chemotherapy, and second-line irinotecan-based chemotherapy. It was found that only the group receiving second-line oxaliplatin-based chemotherapy had significantly longer survival time than the comparison groups, with an adjusted mean of survival time of 21.12 months (different mean 5.99, 95% CI 3.99 to 8.00, p&lt;0.001). Conclusion: Poor ECOG performance status greater than or equal to 2, and hypoalbuminemia lower than 3.5 g/dL can be used as prognostic factors in mCRC patients receiving chemotherapy. Keywords: Survival; Prognostic factors; Metastatic colorectal cancer; Chemotherapy

Emerging roles of non-coding RNAs in colorectal cancer oxaliplatin resistance and liquid biopsy potential.

Colorectal cancer (CRC) is one of the most common malignancies of the digestive tract, with the annual incidence and mortality increasing consistently. Oxaliplatin-based chemotherapy is a preferred therapeutic regimen for patients with advanced CRC. However, most patients will inevitably develop resistance to oxaliplatin. Many studies have reported that non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs, and circular RNAs, are extensively involved in cancer progression. Moreover, emerging evidence has revealed that ncRNAs mediate chemoresistance to oxaliplatin by transcriptional and post-transcriptional regulation, and by epigenetic modification. In this review, we summarize the mechanisms by which ncRNAs regulate the initiation and development of CRC chemoresistance to oxaliplatin. Furthermore, we investigate the clinical application of ncRNAs as promising biomarkers for liquid CRC biopsy. This review provides new insights into overcoming oxaliplatin resistance in CRC by targeting ncRNAs.