Oxaliplatin-based Chemotherapy Research Articles

A prospective randomized controlled clinical trial investigating the efficacy of low-dose olanzapine in preventing nausea and vomiting associated with oxaliplatin-based and irinotecan-based chemotherapy

ObjectiveThe aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors.MethodsPatients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions.Results1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05).ConclusionOlanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients.Clinical Trial Registration:https://www.chictr.org.cn/index.html, identifier: ChiCTR20000368269, 25/08/2020.

Prospective, Observational Study of Aflibercept Use in Combination with FOLFIRI in Patients with Metastatic Colorectal Cancer: A Real-World Effectiveness Study

Background: This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. Methods: Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. Results: A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9–9.9] and 27.0 months [95% CI, 23.9–30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). Conclusions: The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed.

First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial.

We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. ClinicalTrials.gov number, NCT03388190 (02/01/2018).

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription.

Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related mortality globally. Resistance to chemotherapy, especially during CRC treatment, leads to reduced effectiveness of drugs and poor patient outcomes. Long noncoding RNAs (lncRNAs) have been implicated in various pathophysiological processes of tumor cells, including chemotherapy resistance, yet the roles of many lncRNAs in CRC remain unclear. To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance. Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance. Various bioinformatics tools were employed to elucidate molecular mechanisms. The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction. Functional assays, including MTT, wound healing, and Transwell, were conducted to investigate the functional implications of lncRNA alterations. Interactions between lncRNAs and transcription factors were examined using RIP and luciferase reporter assays, while Western blotting was used to confirm downstream pathways. Additionally, a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance. LncRNA prion protein testis specific (PRNT) was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2 (HIPK2) expression. PRNT was demonstrated to sponge transcription factor zinc finger protein 184 (ZNF184), which in turn could regulate HIPK2 expression. Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin, with overexpression leading to decreased sensitivity and decreased expression reducing resistance. Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT. The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo. The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184. This regulatory mechanism enhances CRC progression and resistance to oxaliplatin, positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.

A β-Galactosidase-Activated Fluorogenic Reporter for the Detection of Gastric Cancer In Vivo and in Urine.

Although gastric cancer (GC) is one of the most frequent malignant tumors in the digestive tract with high morbidity and mortality, it remains a diagnostic dilemma due to its reliance on invasive biopsy or insensitive assays. Herein, we report a fluorescent gastric cancer reporter (FGCR) with activatable near-infrared fluorescence (NIRF) signals and high renal-clearance efficiency for the detection of orthotopic GC in a murine model via real-time imaging and remote urinalysis. In the presence of gastric-tumor-associated β-galactosidase (β-Gal), FGCR can be fluorescently activated for in vivo NIRF imaging. Relying on its high renal-clearance efficiency (∼95% ID), it can be rapidly excreted through kidneys to urine for the ultrasensitive detection of tumors with a diameter down to ∼2.1 mm and for assessing the prognosis of oxaliplatin-based chemotherapy. This study not only provides a new approach for noninvasive auxiliary diagnosis and prognosis of GC but also provides guidelines for the development of fluorescence probes for cancer diagnosis.

Should Cytoreductive Surgery Alone for Peritoneal Metastases of Colorectal Origin be Centralized? A National Study of 4159 Procedures.

Addition of oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery (CRS) in the treatment of peritoneal metastases of colorectal origin (CRPM) did not show any survival benefit in the PRODIGE 7 trial (P7). This study aimed to investigate whether perioperative outcomes after CRS alone for CRPM patients is mediated by hospital volume and to determine the effect of P7 on French practice for CRPM patients treated respectively with CRS alone and CRS/HIPEC. Data from CRPM patients treated with CRS alone between 2013 and 2020 in France were collected through a national medical database. The study used a cutoff value of the annual CRS-alone caseload affecting the 90-day postoperative mortality (POM) determined from our previous study to define low-volume (LV) HIPEC and high-volume (HV) HIPEC centers. Perioperative outcomes were compared between no-HIPEC, LV-HIPEC, and HV-HIPEC centers. The trend between years and HIPEC rates was analyzed using the Cochrane-Armitage test. Data from 4159 procedures were analyzed. The patients treated in no-HIPEC and LV-HIPEC centers were older compared withHV-HIPEC centers (p < 0.0001) and had a higher Elixhauser comorbidity index (p < 0.0001) and less complex surgery (p < 0.0001). Whereas the major morbidity (MM) rate did not differ between groups (p = 0.79), the 90-day POM was lower in HV-HIPEC centers than in no-HIPEC and LV-HIPEC centers (5.4% vs 15% and 13.3%; p < 0.0001), with lower failure-to-rescue (FTR) (p < 0.0001). After P7, the CRS/HIPEC rate decreased drastically in Cancer centers (p < 0.001), whereas patients treated with CRS alone are still referred to expert centers. Centralization of CRS alone should improve patient selection as well as FTR and POM. After P7, CRS/HIPEC decreased mostly in Cancer centers, without any impact on the number of CRS-alone cases referred to expert centers.

Abstract 2522: Predictive value of tumor mutational burden (TMB) in patients with metastatic microsatellite-stable (MSS) colorectal cancer (CRC) given first-line oxaliplatin-based chemotherapy and immune checkpoint blockade (ICB)

Abstract Purpose: Most CRC patients harbor primarily non-immunogenic MSS tumor. The randomized METIMMOX trial (NCT03388190) examined if 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) repeatedly. Half of study patients assigned to this experimental treatment had significantly extended progression-free survival (PFS) while the other half had shortened PFS, compared to the control-group patients given standard FLOX chemotherapy with median PFS 9.3 months. Here we explored if somatic mutations (mut) unveiled by next-generation sequencing might provide insights into responsiveness to the METIMMOX regimen. Procedures: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to the control group of FLOX (oxaliplatin, 5-fluorouracil, folinic acid) Q2W or the experimental 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. Diagnostic tumor biopsies and baseline metastasis biopsies were sequenced with the TruSight Oncology 500 assay. TMB was calculated using only coding, non-synonymous single-nucleotide variants and insertions/deletions with variant allele frequency ≥5% and sequencing depth ≥50 ×, applying the effective panel size as the megabases (Mb) denominator. Results: Sequencing data were acquired from 20 experimental-group patients with median PFS 7.9 months (minimum 2.0, maximum 41.6). Median TMB was 5.1 mut/Mb (minimum 0.8, maximum 11.8), concordant in patient-paired primary tumor and metastasis specimens. The TMB was associated with treatment outcome; the higher TMB, the better PFS with hazard ratio 0.83 (95% confidence interval (CI) 0.70-0.98; p = 0.026, Cox regression) for a PFS event with increasing TMB. TMB cut-off as low as 5.0 mut/Mb distinguished between patient groups (p = 0.007, log-rank test) with median PFS 34.9 months (95% CI 10.6-59.2; TMB&amp;gt;5, n = 10) and median PFS 4.6 months (95% CI 2.7-6.5; TMB≤5, n = 10). In the TMB&amp;gt;5 group, 8/10 were KRAS- or BRAF-mutant cases. In the TMB≤5 group, 9/10 metastasis specimens were RAS/BRAF-wildtype cases. Conclusions: TMB &amp;gt;5 mut/Mb was associated with tumor KRAS or BRAF driver mutation and remarkably long PFS in first-line treatment of patients with abdominal metastases from MSS-CRC with alternating short-course oxaliplatin-based chemotherapy and ICB. Citation Format: Anne Hansen Ree, Paula A. Bousquet, Hilde L. Nilsen, Torben Lüders, Shixiong Wang, Tina Visnovska, Diana L. Bordin, Eirik Høye, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne G. Guren, Halfdan Sorbye, Kjersti Flatmark, Sebastian Meltzer. Predictive value of tumor mutational burden (TMB) in patients with metastatic microsatellite-stable (MSS) colorectal cancer (CRC) given first-line oxaliplatin-based chemotherapy and immune checkpoint blockade (ICB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2522.

Cardiotoxicity Induced by Capecitabine and Oxaliplatin in Gastric Cancer Treatment: A Rare Case of Cardiac Arrest and Cardiogenic Shock.

Combination-based adjuvant chemotherapy utilising capecitabine and oxaliplatin is widely used in gastric cancer treatment. Rare but severe cardiac events such as prolonged QT, cardiac arrest and cardiogenic shock can result from their use. A 45-year-old female with gastric adenocarcinoma was started on capecitabine-oxaliplatin chemotherapy one week before presenting to the emergency department with weakness. Blood pressure was 78/56 mmHg, heart rate 140 bpm and oxygen saturation 85%. She became unresponsive with pulseless ventricular fibrillation; CPR was initiated with immediate intubation. She received two shocks with a return of spontaneous circulation. Laboratory tests revealed serum potassium (3.1 mmol/l), magnesium (1.1 mg/dl) and troponin (0.46 ng/ml). An EKG revealed sinus tachycardia with a prolonged QT interval (556 ms). The combined effects of capecitabine, oxaliplatin and electrolyte abnormalities likely contributed to the QT prolongation. An echocardiogram demonstrated an ejection fraction of 10%-15%. An emergent right-heart catheterisation showed right atrial pressure of 10 mmHg and pulmonary artery pressure of 30/18 mmHg; cardiac output and index were not recorded. An intra-aortic balloon pump was placed, and she was admitted to the ICU for cardiogenic shock requiring norepinephrine, vasopressin and dobutamine. A repeat echocardiogram showed a significantly improved ejection fraction of 65%, and she was discharged. Capecitabine and oxaliplatin cardiotoxicity is an exceedingly rare occurrence, with both drugs reported to cause QT prolongation. Healthcare providers must recognise the QT prolongation effects of capecitabine and oxaliplatin, leading to life-threatening cardiac arrhythmias. Recognise the QT-prolonging effects of capecitabine and oxaliplatin-based chemotherapy.Recognise that cardiogenic shock and cardiac arrest with capecitabine and oxaliplatin-based chemotherapy can occur in individuals with benign cardiac history, especially early in treatment.

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response

BackgroundThe inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies.MethodsWe optimized drug screen methods on 5–11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient’s response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness.ResultsDrug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003).ConclusionsOur study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.

Optimal duration of oxaliplatin-based adjuvant chemotherapy in patients with different risk factors for stage II-III colon cancer: a meta-analysis.

The duration of oxaliplatin-based chemotherapy in high-risk stage II, low-risk stage III, and high-risk stage III colon cancer (CC) patients is controversial. To reduce the risk of adverse events (AEs) without compromising efficacy while improving chemotherapy compliance is crucial. The authors searched Cochrane, Embase, Pubmed, and Web of Science databases for articles from inception to August 8, 2023, the main outcomes were disease-free survival, overall survival, chemotherapy completion rates, and AE frequency. Six randomized controlled trials (RCTs) involving 10332 patients were included. Disease-free survival analysis revealed that only the high-risk stage III CC patients experienced better results with the 6-month FOLFOX regimen when compared with the 3-month regimen [Hazard ratio (HR): 1.32, 95% CI: 1.15-1.51, P <0.0001). Overall survival (OS) analysis revealed that extending the use of FOLFOX and CAPEOX regimens did not provide survival benefits for stage III CC patients (HR: 1.16, 95% CI: 0.9-1.49, and HR: 0.89, 95% CI: 0.67-1.18, P =0.40). The completion rate of the 3-month oxaliplatin-based adjuvant chemotherapy regimen was significantly higher than that of the 6-month regimen [Relative risk (RR): 1.16, 95% CI: 1.06-1.27, P =0.002]. Moreover, the 3-month regimen had significantly lower AE rates than the 6-month regimen (RR: 0.62, 95% CI: 0.57-0.68, P <0.00001), with differences mainly concentrated in grade 3/4 neutropenia (RR: 0.70, 95% CI: 0.59-0.85, P =0.0002), peripheral sensory neuropathy at ≥grade 2 (RR: 0.45, 95% CI: 0.38-0.53, P <0.00001), and hand-foot syndrome at ≥grade 2 (RR: 0.36, 95% CI: 0.17-0.77, P =0.009). The 6-month FOLFOX regimen should only be recommended for high-risk stage III CC, while the 3-month regimen can be recommended for other stages. A 3-month CAPEOX regimen can be recommended for stage II-III CC.

Cilostazol improves the prognosis after hepatectomy in rats with sinusoidal obstruction syndrome.

Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS+CZ (MCT+CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48h after MCT administration. Postoperative survival rates were evaluated (n=9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. The cumulative 10-day postoperative survival rate was significantly higher in the SOS+CZ group than in the SOS group (88.9% vs 33.3%, P=0.001). Total SOS scores were significantly lower in the SOS+CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS+CZ group than in the SOS group on POD 1 (86.1±8.2% vs 63.8±9.3%, P=0.003). Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Incidence, Severity and Clinical Correlation of Oxaliplatin Induced Neuropathy in Patients with Colorectal Cancer: A Single Institutional Experience

Background: Colorectal cancer is the third most commonly diagnosed cancer worldwide, and its incidence is increasing in developing countries. Chemotherapy plays a significant role in the treatment of locally advanced and metastatic colorectal cancer. Oxaliplatin has remained the backbone of the treatment of colorectal carcinoma. The primary dose-limiting toxicity of oxaliplatin is neuropathy, which can reduce compliance during therapy and impair daily living activities. With limited data regarding the occurrence of oxaliplatin-induced peripheral neuropathy (OIPN) in the Indian population, we aimed to determine the incidence and severity of oxaliplatin-induced neurotoxicity and its clinical correlation with various clinical parameters in patients with colorectal carcinoma in a cancer care centre from North-East India. Material and Methods: A prospective observational analysis was performed on all histologically confirmed cases of colorectal adenocarcinoma who received oxaliplatin-based chemotherapy either in an adjuvant setting or first-line palliative setting at Dr. B. Borooah Cancer Institute between April 2019 to March 2020. Results: Our study evaluated 76 patients with colorectal carcinoma with a mean age of 54.07 ± 10 years. The majority (65.8%) of the patients had adenocarcinoma of the colon, and 34.2% had rectal adenocarcinoma. Twenty-three (30.3%) patients presented with metastatic disease. Oxaliplatin-based chemotherapy regimens were either CAPOX (72.4%) or FOLFOX (27.6%). Acute OIPN was observed in 59 patients (77.6%), and the most common symptom was cold-induced perioral paraesthesia. The most frequent grade for acute OIPN was grade II (30.3%). Chronic OIPN was seen in 47 (61.8%) patients, with the majority developing grade II neuropathy and was manifested mainly after 4th cycle of chemotherapy. The incidence of OIPN was higher in the patients aged ≥60 years, with a cumulative oxaliplatin dose of &gt; 1000 mg/m2 and baseline low serum magnesium or calcium level. Conclusion: Oxaliplatin is one of the essential chemotherapy drugs used in colorectal cancer with significant dose-limiting toxicity of peripheral neuropathy. Well-timed identification of neuropathic symptoms can increase treatment adherence and improve the patient’s quality of life.&#x0D;

Claudin 18.2 as a New Biomarker in Gastric Cancer—What Should We Know?

Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive. This review navigates the evolving landscape of GC biomarkers, with a specific focus on Claudin 18.2 (CLDN18.2) as an emerging and promising target. Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. As this novel therapeutic avenue unfolds, understanding the nuanced decision making regarding the selection of anti-CLDN18.2 therapies over other targeted agents in metastatic GC becomes crucial. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.

The effects of oxaliplatin-based adjuvant chemotherapy in high-risk stage II colon cancer with mismatch repair-deficient: a retrospective study

BackgroundFor high-risk stageIImismatch repair deficient (dMMR) colon cancers, the benefit of adjuvant chemotherapy remains debatable. The principal aim of this study was to evaluate the prognostic value of high-risk factors and the effect of oxaliplatin-based adjuvant chemotherapy among dMMR stageIIcolon cancers.MethodsPatients with stage II dMMR colon cancers diagnosed between June 2011 and May 2018 were enrolled in the study. Clinicopathological characteristics, treatment, and follow-up data were retrospectively collected. The high-risk group was defined as having one of the following factors: pT4 disease, fewer than twelve lymph nodes harvested (< 12 LNs), poorly differentiated histology, perineural invasion (PNI), lymphatic vascular invasion (LVI), or elevated preoperative carcinoembryonic antigen (CEA). The low-risk group did not have any risk factors above. Factors associated with disease-free survival (DFS) were included in univariate and multivariate Cox analyses.ResultsWe collected a total of 262 consecutive patients with stage II dMMR colon cancer. 179 patients (68.3%) have at least one high-risk factor. With a median follow-up of 50.1 months, the low-risk group was associated with a tended to have a better 3-year DFS than the high-risk group (96.4% vs 89.4%; P = 0.056). Both elevated preoperative CEA (HR 2.93; 95% CI 1.26–6.82; P = 0.013) and pT4 disease (HR 2.58; 95% CI 1.06–6.25; P = 0.037) were independent risk factors of recurrence. Then, the 3-year DFS was 92.6% for the surgery alone group and 88.1% for the adjuvant chemotherapy group (HR 1.64; 95% CI 0.67–4.02; P = 0.280). Furthermore, no survival benefit from oxaliplatin-based adjuvant chemotherapy was observed in the high-risk group and in the subgroups with pT4 disease or < 12 LNs.ConclusionsThese data suggests that not all high-risk factors have a similar impact on stage II dMMR colon cancers. Elevated preoperative CEA and pT4 tumor stage are associated with increased recurrence risk. However, oxaliplatin-based adjuvant chemotherapy shows no survival benefits in stage II dMMR colon cancers, either with or without high-risk factors.

An expatiate review on adjuvant chemotherapy of colorectal cancer

Colorectal cancer is the second leading cause of cancer-related death and the third most common cancer globally. For loco regional colon cancer, surgery is the sole curative option. Adjuvant chemotherapy aims to eliminate micro metastases and increase survival. It has been most convincingly proven in stage III illness, even though there is ongoing debate on the usefulness of adjuvant chemotherapy for stage II illness. For the past fifteen years, six months of adjuvant chemotherapy with an oxaliplatin-based chemotherapy has been the accepted standard of care for stage III colon cancer. It is still advised to use 6 months of adjuvant chemotherapy for individuals with stage II illness and high clinicopathological risk. Chemo radiation therapy (CRT) is frequently used as neoadjuvant or adjuvant therapy in the treatment of stage II and stage III rectal cancers because this cancer type has a higher risk of local recurrence than other cancer types.

Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer

Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.

Real-world treatment patterns and unmet need in patients with previously treated metastatic colorectal cancer that is not MSI-H or dMMR.

53 Background: Regorafenib and trifluridine/tipiracil (TAS-102) are standard of care (SoC) systemic anticancer treatments (SACT) for metastatic colorectal cancer (mCRC) patients perviously treated with fluoropyrimidine (5-FU), irinotecan, &amp; oxaliplatin-based chemotherapy. However, evidence is limited on post-chemotherapy &amp; later SACT for patients with mCRC that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This study assessed real-world patient characteristics and treatment patterns in community oncology practices among previously treated, not MSI-H/dMMR mCRC patients. Methods: This retrospective cohort study utilized The US Oncology Network (iKnowMed) electronic health record database, supplemented by chart review. The study cohort comprised adult, not MSI-H/dMMR mCRC patients treated with chemotherapy (5-FU/capecitabine, irinotecan, and oxaliplatin) who initiated subsequent SACT or received best supportive care (BSC) between 1/1/2016 &amp; 12/31/2021. Index date for SACT users was the regimen start date. For patients on BSC and no subsequent SACT/BSC, index date was last chemotherapy administration date. Patients were followed from index date through 8/31/2022, date of death or last contact date, whichever occurred first. Descriptive statistics were used to report patient and treatment characteristics. Results: The study consisted of 292 mCRC patients, with a median age of 57 (range: 49, 68) years. The predominant histology was adenocarcinoma (n = 237, 81.2%) with 1.7% other histology and rest missing, 198 (67.8%) patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and 206 (70.5%) had primary tumors located in the colon. Liver (n = 207, 70.9%) and lung (n = 78, 26.7%) were the most common metastasis sites. Diabetes (n = 33, 11.3%) and peripheral vascular disease (n = 18, 6.2%) were the most common comorbidities. Eighty-seven (29.8%) patients received at least one chemotherapy in the adjuvant/neo-adjuvant setting, while majority (70.2%) patients received chemotherapies in the metastatic setting. Overall, 203 (69.5%) received SACT post-chemotherapy, 84 (28.8%) received BSC and 5 (1.7%) did not receive SACT/BSC. Among the SACT post-chemotherapy users, 30 (14.8%) received regorafenib, 25 (12.3%) received TAS-102 and 148 (72.9%) received other SACT. Other SACT included irinotecan-based (n = 76, 37.4%), oxaliplatin-based (n = 30, 14.8%), irinotecan and oxaliplatin-based (n = 6, 3.0%) chemotherapy, and anti-EGFR (n = 15, 7.4%) or anti-VEGF (n = 8, 3.0%) targeted therapies. Conclusions: Overall, only 27.1% of previously treated mCRC patients with tumors that were not MSI-H or dMMR received SoC. The real-world variability in choice of treatments and the high percentage of patients rechallenged with chemotherapy in subsequent lines, highlights an unmet need in this population.

Enrichment of circulating helper-T (Th) and unswitched memory-B (NSwM-B) cell populations and responsiveness to immune checkpoint blockade (ICB) in microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC).

150 Background: The anti-tumor activity of ICB in MSS/pMMR-CRC is limited. However, recent studies have highlighted the possibility of inducing ICB responsiveness by oxaliplatin-based chemotherapy. The understanding of underlying mechanisms and identification of rational biomarkers are major focus areas in immuno-oncology. Methods: Patients with previously untreated, unresectable abdominal metastases from MSS/pMMR-CRC were randomly assigned to the oxaliplatin-based standard Nordic FLOX regimen (control arm) or 2 FLOX cycles followed by 2 ICB (nivolumab) cycles in a repeat sequential schedule (experimental arm). Radiologic response assessment was done every 8 weeks, and the study arms reached identical primary endpoint – median progression-free survival (PFS) 9.3 months. Experimental-arm patients at one study center had peripheral blood mononuclear cells (PBMC) prepared at study entry (V1), after the initial 2 FLOX cycles (V3), and after the succeeding 2 nivolumab cycles (V5). The PBMC were incubated with 19 cell-surface antibodies and analyzed by mass cytometry. Patients were categorized in PFS &gt;9.3 months (improved; n = 7) or PFS &lt;9.3 months (shortened; n = 6). Live cell clusters were identified by hierarchically applying automated 1D gates to the available lineage markers. After gating, all cells were assigned to soft clusters according to phenotypes. The cluster sizes were used to compute the differential abundance of immune-cell populations and a Peacock test assessed multivariate changes between the improved and shortened PFS groups. Results: Circulating CD4+ (Th) cells and CD27+IgD+ (NSwM-B) cells were concurrently enriched in the improved PFS group. After the initial 2 FLOX cycles (V3), median increase (from V1) was 2.89% (of lymphocyte count) for Th cells and 0.54% (of leukocyte count) for NSwM-B cells (p &lt; 0.001). Continued responses occurred over the succeeding 2 nivolumab cycles (until V5) with median increase of 1.19% for Th cells and 0.19% for NSwM-B cells (p &lt; 0.001). The association between the immune-cell alterations and PFS was validated by categorizing the cases in above or below the median increase in Th and NSwM-B cell populations from V1 to V5. The high-increase group achieved median PFS 15.0 months (95% CI, 10.8-19.2) compared to 4.0 months (95% CI, 1.9-22.1) for the low-increase group (log-rank; p = 0.002). Conclusions: This unsupervised analysis of high-dimensional PBMC data from a limited case number revealed that circulating Th and NSwM-B cell populations may mediate ICB responsiveness invoked by short-course oxaliplatin-based chemotherapy in patients with abdominal metastases from MSS/pMMR-CRC. Owing to weaknesses of such a post-hoc analysis, further studies are needed to confirm the generalizability of these findings. Clinical trial information: NCT003388190 .

Development of an improved risk stratification scheme for stage II and III colorectal cancers through incorporation of the digital pathology biomarker QuantCRC.

162 Background: There is a need to improve current risk stratification of stage II and III colorectal cancer (CRC) to better inform risk of recurrence and guide adjuvant chemotherapy. The purpose of this study is to examine whether integration of QuantCRC, an AI-based digital pathology biomarker utilizing hematoxylin and eosin-stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. Methods: ASCO and QuantCRC-integrated risk schemes were applied to an observational cohort of 1,068 stage II and III CRCs. The stage II integrated scheme utilizes pT3 vs. pT4 and QuantCRC-derived risk groups. The stage III integrated scheme utilizes pT1-3 vs. pT4, pN1 vs. pN2, and QuantCRC-derived risk groups. Performance metrics included log-rank test, hazard ratios and Somers’ Dxy rank correlation. Results: Integration of QuantCRC provides improved risk stratification compared to the ASCO scheme for stage II and III CRC. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared to the ASCO scheme (69.3% vs. 60.4%) without decreased 3-year RFS. The QuantCRC-integrated scheme provided larger hazard ratios (HR) for both intermediate-risk (3.04, 95%CI 1.81-5.10, P=2.8x10-5) and high-risk (4.62, 95%CI 2.02-10.61, P=0.0003) groups compared to ASCO intermediate-risk (2.09, 95%CI 1.21-3.63, P=0.008) and high-risk (3.08, 95%CI 1.57-6.01, P=0.001) groups. The QuantCRC-integrated scheme for stage III tumors identified a small group of 80/518 (15.4%) CRCs at very high risk of recurrence with HR of 4.08 (95%CI 2.68-6.23, P=6.5x10-11) compared to a HR of 2.42 (95%CI 1.72-3.38, P=3.1x10-7) for 228/518 (44.0%) high-risk CRCs in the ASCO scheme. QuantCRC-integrated risk groups remained prognostic in stage III CRCs when stratified by presence or absence of any adjuvant chemotherapy. No difference in RFS were seen in QuantCRC-integrated low-risk and intermediate-risk stage III CRCs stratified by 3 vs. 6-months of oxaliplatin-based adjuvant chemotherapy suggesting that these two groups can be treated with 3-months of adjuvant therapy. Conclusions: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance.

Real-world impact on overall survival of oxaliplatin-based adjuvant chemotherapy in older patients with colorectal cancer in Mexico.

61 Background: Colorectal cancer (CRC) is one of the most commonly diagnosed cancer both in Mexico and worldwide, with the peak incidence in patients &gt;65 years. The use of adjuvant chemotherapy (CT) improves the prognosis of high-risk CRC. The benefit from fluorouracil (FU)-based CT across all age groups is not questionable, but the use of oxaliplatin (Ox) is controversial. Methods: Original, retrospective, observational study. Included patients diagnosed with CRC adenocarcinoma treated at the Instituto Nacional de Cancerología México, between 2004 to 2022. Statistical analysis required: X2 and t-test, Kaplan Meier, Log Rank, and Cox Regression. Statistical significance differences were assessed when p was bilaterally &lt;0.05. Results: From 1,238 patients with localized CRC, 275 patients were included in analysis and divided into 2 groups: young (≤ 30 years) (n = 54), and older (≥ 70 years) (n = 221). Most patients were female for both groups (55%). Comorbidities were observed in 2% of young patients and 51% of older patients (p &lt; 0.001). Stages (S) were: II (31%; 39%), and III (59%; 47%). CT was received in 70% of young and 47% of older patients (p = 0.002). Regarding CT regimens, 56% and 21% of young and older patients respectively, had oxaliplatin (p &lt; 0.001), while 21% of young and 32% of older patients did not complete the CT (p = 0.012). Overall survival (OS) analysis was performed considering age and S. S-II median-OS was not reached (NR) for both groups, while S-III median-OS was 170 months (m) for young versus NR for older (p = 0.690). When including CT in OS analysis, patients S-II median-OS was NR for all groups (p = 0.081), while S-III median-OS was 170 m with and 19 m without CT for young versus NR with and 89 m without CT for older, respectively (p = 0.010, 95% CI 0.059-0.123). In S-III older patients, a sub-analysis was performed considering Ox: 10-year-OS was 71% versus 60% for patients treated with and without Ox respectively (p = 0.030, 95% CI 0.25-0.93). In Cox-Regression analysis for patients with clinical stage III, regimen completion (p = 0.004; HR 0.38, 95% CI 0.201-0.745) and Ox (p = 0.022; HR 0.423, 95% CI 0.203-0.881) remained as predictor factors of OS. Conclusions: There are no studies which compare the administration of CT between young and older patients or the description of these populations in Mexico. Young patients are more likely to receive CT with Ox assumingly due to the lack of comorbidities and life expectancy. The benefit of CT on OS in young patients is not in question. An increase in OS was found in older patients who received CT with Ox, but a higher percentage of treatment discontinuation secondary to toxicity. As recommended by the literature, its essential to integrate assessment in older patients to determine which patients will benefit from complete CT regimens to increase their OS, apart from their chronological age.