The association between systemic immune-inflammation index and cardiotoxicity related to 5-Fluorouracil in colorectal cancer.

BACKGROUND AND AIMS: The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. METHODS: The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted. RESULTS: Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 109/L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). CONCLUSION: Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.

Two cases of metastatic colorectal cancer with prolonged liver injury following capecitabine combination chemotherapy.

We present two cases of metastatic colorectal cancer where a liver injury developed while receiving capecitabine. In both cases, the patients were switched from oral capecitabine to a continuous intravenous 5-fluorouracil infusion and were able to continue treatment without a relapse of hepatotoxicity.

In vitro cytoprotective and in vivo anti-oral mucositis effects of melatonin and its derivatives.

According to our preliminary study, melatonin and its N-amide derivatives (N-(2-(1-4-bromobenzoyl-5-methoxy-1H-indol-3-yl)ethyl)acetamide (BBM) and 4-bromo-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide (EBM)) inhibited the marker of acute inflammation in tests in vitro and in vivo. The anti-inflammatory agent is intended for the prevention and treatment of chemotherapy-induced toxicity. In this study aimed to evaluate the effect of melatonin and its derivatives on mechanisms related to chemotherapy-induced oral mucositis by in vitro ROS and 5-FU-induced human keratinocyte cells as well as in vivo oral mucositis model. In in vitro H2O2-induced HaCaT cells, BBM had the highest level of protection (34.57%) at a concentration 50 µM, followed by EBM (26.41%), and melatonin (7.9%). BBM also protected cells against 5-FU-induced to 37.69-27.25% at 12.5-100 µM while EBM was 36.93-29.33% and melatonin was 22.5-11.39%. In in vivo 5-FU-induced oral mucositis in mice, melatonin, BBM, and EBM gel formulations protected tissue damage from 5-FU similar to the standard compound, benzydamine. Moreover, the weight of mice and food consumption recovered more quickly in the BBM group. These findings suggested that it was possible to develop BBM and EBM as new therapeutic agents for the treatment of oral mucositis.

Association of oxaliplatin-containing adjuvant duration with post-treatment fall-related injury and fracture in patients with stage III colon cancer: a population-based retrospective cohort study.

PURPOSE: Oxaliplatin-containing adjuvant chemotherapy yields a significant survival benefit in stage III colon cancer and is the standard of care. Simultaneously, it causes dose-dependent peripheral neuropathy that may increase the risk of fall-related injury (FRI) such as fracture and laceration. Because these events carry significant morbidity and the global burden of colon cancer is on the rise, we examined the association between treatment with a full versus shortened course of adjuvant chemotherapy and post-treatment FRI and fracture. METHODS: In this overlap propensity score weighted, retrospective cohort study, we included patients aged ≥ 18 years with resected stage III colon cancer diagnosed 2007-2019 and treated with oxaliplatin-containing adjuvant chemotherapy (oxaliplatin plus a fluoropyrimidine; capecitabine [CAPOX] or 5-fluorouracil and leucovorin [FOLFOX]). Propensity score methods facilitate the separation of design from analysis and comparison of baseline characteristics across the weighted groups. Treatment groups were defined as 50% (4 cycles CAPOX/6 cycles FOLFOX) and > 85% (7-8 cycles CAPOX/11-12 cycles FOLFOX) of a maximal course of adjuvant chemotherapy to approximate the treatment durations received in the IDEA collaboration. The main outcomes were time to any FRI and time to fracture. We determined the subdistribution hazard ratios (sHR) estimating the association between FRI/fracture and treatment group, accounting for the competing risk of death. RESULTS: We included 3,461 patients; 473 (13.7%) received 50% and 2,988 (86.3%) received > 85% of a maximal course of adjuvant therapy. For post-treatment FRI, median follow-up was 4.6 years and total follow-up was 17,968 person-years. There were 508 FRI, 301 fractures, and 692 deaths. Treatment with > 85% of a maximal course of therapy conferred a sHR of 0.84 (95% CI 0.62-1.13) for post-treatment FRI and a sHR of 0.72 (95% CI 0.49-1.06) for post-treatment fracture. CONCLUSION: For patients with stage III colon cancer undergoing treatment with oxaliplatin-containing adjuvant chemotherapy, any potential neuropathy associated with longer durations of treatment was not found to result in greater rates of FRI and fracture. Within the limits of this retrospective study, our findings suggest concern about FRI, while mechanistically plausible, ought not to determine treatment duration.

Dasabuvir alleviates 5-fluorouracil-induced intestinal injury through anti-senescence and anti-inflammatory.

5-Fluorouracil (5-Fu) is a basic drug that is used to treat colorectal cancer. Patients who receive 5-Fu chemotherapy often experience side effects that affect the digestive system, such as intestinal injury and diarrhoea, which significantly affect patient compliance with anticancer treatment and quality of life. Therefore, identifying approaches to treat or prevent these side effects is urgent. Dasabuvir (DSV) is a hepatitis C virus inhibitor, but its impact on 5-Fu-induced intestinal injury remains unknown. Our study investigated the effects of DSV on 5-Fu-induced intestinal injury in HUVECs, HIECs and male BALB/c mice. We found that 5-Fu caused intestinal damage by inducing senescence, increasing inflammatory factor expression, and generating oxidative stress. Compared with 5-Fu treatment alone, DSV inhibited senescence by reducing senescence-ß-galactosidase (SA-ß-gal) activity, the senescence-associated secretory phenotype (SASP, including IL-1, IL-6, and TNF-α) and senescence marker expression levels (p16, p21, and p53). Moreover, the anti-senescence effect of DSV was achieved by inhibiting the mTOR signaling pathway. DSV increased antioxidant enzyme levels and alleviated intestinal tissue injury in mice. In addition, DSV suppressed the 5-Fu-induced increase the diarrhoea scores and ameliorated the weight loss, food intake and water intake of the mice. Overall, this study indicated that DSV could be used to treat chemotherapy-induced intestinal damage.

A propensity score-matched comparison of neoadjuvant chemoradiotherapy with cisplatin-5FU and carboplatin-paclitaxel in locally advanced esophageal squamous cell carcinoma: A Turkish oncology group study.

BACKGROUND: Neoadjuvant treatment is the standard treatment in locally advanced ESCC. However, the optimal chemotherapy regimen is not known. METHOD: This is a retrospective observational cohort study conducted with propensity score matching. Patients with resectable ESCC from 13 tertiary centers from Türkiye were screened between January 2011 and December 2021. We compared the efficacy and safety of neoadjuvant chemoradiotherapy with the CF and the CROSS regimens in patients with ESCC. RESULTS: Three hundred and sixty-two patients were screened. Patients who received induction chemotherapy (n = 72) and CROSS-ineligible (n = 31) were excluded. Two hundred and fifty nine patients received neoadjuvant chemoradiotherapy. After propensity score matching (n = 97 in both groups), the mPFS was 18.4 months (95% CI, 9.3-27.4) and 25.7 months (95% CI, 15.6-35.7; p = 0.974), and the mOS was 35.2 months (95% CI, 18.9-51.5) and 39.6 months (95% CI 20.1-59.2; p = 0.534), in the CF and the CROSS groups, respectively. There was no difference between subgroups regarding PFS and OS. Compared with the CF group, the CROSS group had a higher incidence of neutropenia (34.0% vs. 62.9%, p < 0.001) and anemia (54.6% vs. 75.3%, p = 0.003) in all grades. On the other hand, there was no significant difference in grade 3-4 anemia, grade 3-4 neutropenia, and febrile neutropenia between groups. There were more dose reductions and dose delays in the CROSS group than in the CF group (11.3% vs. 3.1%, p = 0.026 and 34.0% vs. 17.5%, p = 0.009, respectively). The resection rate was 52.6% in the CF-RT and 35.1% in the CROSS groups (p = 0.014). CONCLUSION: Favorable PFS and pCR rates and a comparable OS were obtained with the CROSS regimen over the CF regimen as neoadjuvant chemoradiotherapy in patients with ESCC.

Strategies for DPYD testing prior to fluoropyrimidine chemotherapy in the US.

PURPOSE: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. METHODS: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. RESULTS: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. CONCLUSION: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.

Comparison of the second-line treatment efficacy in advanced gastric cancer patients previously treated with taxane-based triplet chemotherapy: a Turkish Oncology Group Study.

OBJECTIVE: This study aimed to assess the efficacy and safety of FOLFIRI and paclitaxel in patients with advanced gastric cancer (AGC) who were previously treated with first-line modified docetaxel, cisplatin, 5-fluorouracil (mDCF), or 5-fluorouracil, oxaliplatin, docetaxel (FLOT). METHODS: Patients who received a triplet regimen in the first line setting and were treated with FOLFIRI or paclitaxel in the second-line treatment were included. RESULTS: The study included 198 patients, with 115 receiving FOLFIRI and 83 receiving paclitaxel. The median age was 58 (range = 24-69). The median progression-free survival (mPFS) was 5.2 [95% confidence interval (CI) = 4.4-5.5] months in the FOLFIRI arm, and 4.1 (95% CI = 3.3-4.6) months in the paclitaxel arm (p = .007). The median overall survival (mOS) was 9.4 (95% CI = 7.4-10.5) months in the FOLFIRI arm and 7.2 (95% CI = 5.6-8.3) months in the paclitaxel arm (p = .008). Grade 3-4 neuropathy was higher in patients receiving paclitaxel compared to those receiving FOLFIRI (p = .04). Grade 3-4 diarrhea was 8% in the FOLFIRI arm and 2.4% in the paclitaxel arm (p = .02). CONCLUSION: Beyond progression with docetaxel-based triplet chemotherapy, FOLFIRI may be preferred as a second-line treatment over paclitaxel due to its longer mPFS and mOS.

Nanoliposomal irinotecan and fluorouracil plus leucovorin versus fluorouracil plus leucovorin in patients with cholangiocarcinoma and gallbladder carcinoma previously treated with gemcitabine-based therapies (AIO NALIRICC): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: There is an unmet need for effective therapies in pretreated advanced biliary tract cancer. We aimed to evaluate the efficacy of nanoliposomal irinotecan and fluorouracil plus leucovorin compared with fluorouracil plus leucovorin as second-line treatment for biliary tract cancer. METHODS: NALIRICC was a multicentre, open-label, randomised, phase 2 trial done in 17 German centres for patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, metastatic biliary tract cancer, and progression on gemcitabine-based therapy. Patients were randomly assigned (1:1) to receive intravenous infusions of nanoliposomal irinotecan (70 mg/m2), fluorouracil (2400 mg/m2), and leucovorin (400 mg/m2) every 2 weeks (nanoliposomal irinotecan group) or fluorouracil (2400 mg/m2) plus leucovorin (400 mg/m2) every 2 weeks (control group). Randomisation was by permutated block randomisation in block sizes of four, stratified by primary tumour site. Investigator-assessed progression-free survival was the primary endpoint, which was evaluated in all randomly assigned patients. Secondary efficacy outcomes were overall survival, objective response rate, and quality of life. Safety was assessed in all randomly assigned patients who received at least one dose of the study treatment. Enrolment for this trial has been completed, and it is registered with ClinicalTrials.gov, NCT03043547. FINDING: Between Dec 4, 2017, and Aug 2, 2021, 49 patients were randomly assigned to the nanoliposomal irinotecan group and 51 patients to the control group. Median age was 65 years (IQR 59-71); 45 (45%) of 100 patients were female. Median progression-free survival was 2·6 months (95% CI 1·7-3·6) in the nanoliposomal irinotecan group and 2·3 months (1·6-3·4) in the control group (hazard ratio [HR] 0·87 [0·56-1·35]). Median overall survival was 6·9 months (95% CI 5·3-10·6) in the nanoliposomal irinotecan group and 8·2 months (5·4-11·9) in the control group (HR 1·08 [0·68-1·72]). The objective response rate was 14% (95% CI 6-27; seven patients) in the nanoliposomal irinotecan group and 4% (1-14; two patients) in the control group. The most common grade 3 or worse adverse events in the nanoliposomal irinotecan group were neutropenia (eight [17%] of 48 vs none in the control group), diarrhoea (seven [15%] vs one [2%]), and nausea (four [8%] vs none). In the control group, the most common grade 3 or worse adverse events were cholangitis (four [8%] patients vs none in the nanoliposomal irinotecan group) and bile duct stenosis (four [8%] vs three [6%]). Treatment-related serious adverse events occurred in 16 (33%) patients in the nanoliposomal irinotecan group (grade 2-3 diarrhoea in five patients; one case each of abdominal infection, acute kidney injury, pancytopenia, increased blood bilirubin, colitis, dehydration, dyspnoea, infectious enterocolitis, ileus, oral mucositis, and nausea). One (2%) treatment-related serious adverse event occurred in the control group (worsening of general condition). Median duration until deterioration of global health status, characterised by the time from randomisation to the initial observation of a score decline exceeding 10 points, was 4·0 months (95% CI 2·2-not reached) in the nanoliposomal irinotecan group and 3·7 months (2·7-not reached) in the control group. INTERPRETATION: The addition of nanoliposomal irinotecan to fluorouracil plus leucovorin did not improve progression-free survival or overall survival and was associated with higher toxicity compared with fluorouracil plus leucovorin. Further research is necessary to define the role of irinotecan-based combinations in second-line treatment of biliary tract cancer. FUNDING: Servier and AIO-Studien.

[A Case of Consciousness Disorder Due to Hyperammonemia Induced by Modified FOLFOX6 for Multiple Liver Metastasis from Rectal Cancer].

A 74-year-old man underwent laparoscopic-assisted high anterior resection with D3 lymph node dissection for rectal cancer, which was simultaneously accompanied by multiple liver metastases. The patient received mFOLFOX6 therapy for liver metastases 1 month after the surgery. Anorexia, nausea, and vomiting appeared on the second day of treatment. On the third day of treatment, impaired consciousness(JCS Ⅱ-20)and flapping tremors appeared. Blood tests revealed hyperammonemia, and the patient was diagnosed with impaired consciousness due to hyperammonemia, which was inferred to be caused by 5-fluorouracil(5-FU). Intravenous infusion and branched-chain amino acids were administered, and the patient recovered. The underlying disease of renal dysfunction, constipation, and dehydration due to chemotherapy might have induced the hyperammonemia. It is important to note that hyperammonemia can lead to a disturbance of consciousness during chemotherapy including 5-FU.

Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase (DPYD) Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

PURPOSE: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. METHODS: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. RESULTS: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence. CONCLUSION: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.

Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D.

BACKGROUND: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. RESULTS: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. CONCLUSION: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. GOV IDENTIFIER: ClinicalTrials.gov; NCT03374254.

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Olaparib with or without bevacizumab versus bevacizumab plus a fluoropyrimidine as maintenance therapy in advanced colorectal cancer: The randomized phase 3 LYNK-003 study.

BACKGROUND: The randomized, open-label, phase III LYNK-003 study assessed the efficacy of first-line maintenance olaparib, alone or in combination with bevacizumab, versus bevacizumab plus a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer (mCRC). We present results of the prespecified interim futility analysis. METHODS: Eligible participants were ≥18 years of age with unresectable or mCRC that had not progressed after induction with first-line bevacizumab plus 5-fluorouracil plus oxaliplatin plus leucovorin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX). Participants were randomly assigned 1:1:1 to olaparib plus bevacizumab, olaparib alone, or bevacizumab plus a fluoropyrimidine (5-fluorouracil or capecitabine). The primary end point was progression-free survival (PFS) per RECIST v1.1 by central review. RESULTS: Between August 2020 and May 2022, 309 participants were assigned to olaparib plus bevacizumab (n = 104), olaparib (n = 107), or bevacizumab plus fluoropyrimidine (n = 98). At interim analysis, with a median follow-up of 7.6 months (range 0.1-19.7 months), the median PFS was 3.7 months (95% CI 2.8-5.3) with olaparib plus bevacizumab (HR 1.52; 95% CI 1.02-2.27; P = 0.982) and 3.5 months (95% CI 2.0-3.7) with olaparib (HR 2.11; 95% CI 1.39-3.18; P = 0.999) versus 5.6 months (95% CI 3.8-5.9) with bevacizumab plus fluoropyrimidine. Treatment-related adverse events occurred in 64 (62%), 52 (50%), and 57 (59%) participants, respectively. There were no treatment-related deaths. CONCLUSION: The LYNK-003 study was stopped prematurely as criteria for futility were met. Maintenance olaparib with or without bevacizumab did not demonstrate clinical efficacy compared with bevacizumab plus a fluoropyrimidine. GOV REGISTRATION: NCT04456699.

Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.

Background: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Materials and methods: Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). Results: A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7-30.1) and the median PFS was 11.9 months (95% CI, 6.7-17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Conclusion: Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.

Exploring microRNA patterns as biomarkers of FOLFOX chemotherapy-induced peripheral neuropathy in patients with colorectal cancer.

FOLFOX is a combination of chemotherapeutic agents (5-fluorouracil, leucovorin, and oxaliplatin) and is used to treat advanced colorectal cancer (CRC) but induces various side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most critical side effects that compromise the quality of life of patients with CRC undergoing FOLFOX chemotherapy. This study aimed to evaluate circulating miRNA, cortisol and catecholamine as potential biomarkers that can predict FOLFOX-CIPN symptoms. High-throughput microRNA (miRNA) sequencing was performed on the RNA circulating in the plasma of eight patients with CRC who underwent FOLFOX chemotherapy. miRNA expression profiles were evaluated according to two groups: those who underwent ≤3 cycles and those who underwent ≥6 cycles of FOLFOX chemotherapy. The identified miRNAs were validated in 27 patients with CRC who underwent FOLFOX chemotherapy using quantitative reverse transcription polymerase chain reaction. Target genes were predicted using bioinformatics and functional analyses. Cortisol and catecholamine concentrations in peripheral plasma were measured using an enzyme-linked immunosorbent assay. miR-3184-5p was differentially expressed when miRNA expression was compared between the groups that underwent ≤3 and ≥6 cycles of FOLFOX chemotherapy. Cortisol levels were significantly higher in the group that underwent ≥6 cycles of FOLFOX chemotherapy than in the group that underwent ≤3 cycles. This study suggests that miR-3184-5p may be a potential marker for predicting CIPN.

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma.

BACKGROUND: The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated. AIM: To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC. METHODS: We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen. RESULTS: The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs). CONCLUSION: The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.

A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

5-Fluorouracil Induced Hypertriglyceridemia During the Colorectal Cancer Treatment in a Patient With Multifactorial Chylomicronemia Syndrome: A Case Report.

PURPOSE: The case of a 47-year-old female patient who underwent sigmoidectomy for metastatic colorectal cancer is reported. Treatment with capecitabine and 5-fluorouracil induced severe hypertriglyceridemia repeatedly. METHODS: Based on laboratory tests and clinical evaluations, treatment was suggested by specialists. FINDINGS: After treatment with capecitabine, the patient's triglycerides increased from 19.7 mmol/L to 42 mmol/L. It was proposed that the patient had multifactorial chylomicronemia syndrome triggered by secondary factors. Statins, fenofibrate, ezetimib, and metformin were added to the therapy. After metastases appeared, FOLFIRI (leucovorin calcium [folinic acid], 5-fluorouracil, and irinotecan hydrochloride) chemotherapy and biological treatment (cetuximab) followed and triglycerides increased to 55.3 mmol/L. IMPLICATIONS: Monitoring triglyceride levels before and during therapy is suggested.