Fluorouracil-based Chemotherapy Research Articles

SNPs and blood inflammatory marker featured machine learning for predicting the efficacy of fluorouracil-based chemotherapy in colorectal cancer.

Fluorouracil-based chemotherapy responses in colorectal cancer (CRC) patients vary widely, highlighting the role of pharmacogenomics in developing better predictive models. We analyzed 379 CRC patients receiving fluorouracil-based chemotherapy, collecting data on fluorouracil metabolism-related SNPs (TYMS, MTHFR, DPYD, RRM1), blood inflammatory markers, and clinical status. Six machine learning models-K-nearest neighbors, support vector machine, gradient boosting decision trees (GBDT), eXtreme Gradient Boosting (XGBoost), LightGBM, and random forest-were compared against multivariate logistic regression and a deep learning model (i.e., multilayer perceptron, MLP). Feature importance analysis highlighted seven predictors: histological grade, N and M staging, monocyte count, platelet-to-lymphocyte ratio, MTHFR rs1801131, and RRM1 rs11030918. In a five-fold cross-validation, XGBoost and GBDT exhibited superior performance, with Area Under Curve (AUC) of 0.88 ± 0.02. XGBoost excelled in identifying favorable prognosis (recall = 0.939). GBDT demonstrated balance in recognizing both categories, with a recall for favorable prognosis of 0.908 and a precision for unfavorable prognosis of 0.863. MLP had a similar AUC (0.87) with high precision for favorable prognosis (recall = 0.946). In external validation, XGBoost model achieved an accuracy of 0.79. An online prognostic tool based on XGBoost was developed, integrating metabolism-related SNPs and inflammatory markers, enhancing CRC treatment precision and supporting tailored chemotherapy.

Clinical Trial Data Review of the Combination FTD/TPI + Bevacizumab in the Treatment Landscape of Unresectable Metastatic Colorectal Cancer.

Recommended first and second line treatments for unresectable metastatic colorectal cancer (mCRC) include fluorouracil-based chemotherapy, anti-vascular endothelial growth factor (VEGF)-based therapy, and anti-epidermal growth factor receptor-targeted therapies. In third line, the SUNLIGHT trial showed that trifluridine/tipiracil + bevacizumab (FTD/TPI + BEV) provided significant survival benefits and as such is now a recommended third line regimen in patients with refractory mCRC, irrespective of RAS mutational status and previous anti-VEGF treatment. Some patients are not candidates for intensive combination chemotherapy as first-line therapy due to age, low tumor burden, performance status and/or comorbidities. Capecitabine (CAP) + BEV is recommended in these patients. In the SOLSTICE trial, FTD/TPI + BEV as a first line regimen in patients not eligible for intensive therapy was not superior to CAP + BEV in terms of progression-free survival (PFS). However, in SOLSTICE, FTD/TPI + BEV resulted in similar PFS, overall survival, and maintenance of quality of life as CAP + BEV, with a different safety profile. FTD/TPI + BEV offers a possible first line alternative in patients for whom CAP + BEV is an unsuitable treatment. This narrative review explores and summarizes the clinical trial data on FTD/TPI + BEV.

High expression of PAX8-AS1 correlates with poor prognosis and response to fluorouracil-based chemotherapy in stage II colon cancer

Decisions regarding adjuvant therapy in patients with stage II colon cancer remains controversial and challenging. We aimed to determine novel biomarkers that help to predict relapse free survival (RFS) and identify a subset of patients with stage II colon cancer who could gain survival benefits from adjuvant chemotherapy. Public microarray datasets of stage II colon cancer samples were extracted from Gene Expression Omnibus database. Global gene expression changes were then analyzed between the paired early relapse and long-term survival group to identify the differentially expressed mRNAs and lncRNAs. Based on Lasso Cox regression modeling analysis, a total of 30 mRNAs and 2 lncRNAs were finally identified. With specific formula, stage II patients in training and validation sets were divided into low and risk groups with significantly different RFS. PAX8-AS1 is the novel lncRNA which showed the highest upregulation in early relapse group. Patients with high PAX8-AS1 expression level showed notably poorer RFS in both meta GEO cohort (P = 0.04, Figure 4B) and FUSCC cohort (P < 0.001, Figure 4C). Among the stage II patients with high PAX8-AS1 level, administration of fluorouracil-based adjuvant chemotherapy provided a substantial improvement in RFS (P = 0.002, Figure 3C). Further mechanistic study unveiled that PAX8-AS1 increases the response of CRC cells to chemotherapy in vitro and in vivo by maintaining the mRNA stability of PAX8. In conclusion, PAX8-AS1 as a novel and reliable biomarker for predicting prognosis and identification of patients with stage II disease who could gain survival benefit from fluorouracil-based adjuvant chemotherapy.

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer.

More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.

Multivariate prognostic index and triplet regimen efficacy predictive index in locally advanced and metastatic gastric cancer: pooled analysis from three clinical trials using individual patient data.

To construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy. Between 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled. We collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index. Univariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted. Seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (p = 0.018). The constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.

Raltitrexed Chemotherapy Regimen Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer: A Prospective Multicenter Phase II Trial.

Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab. This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity. Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed. Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).

Leucovorin Dosing for Gastrointestinal Cancer

What Is the Issue?&#x0D; &#x0D; Since 2008, the shortage of leucovorin has had a significant impact on fluorouracil-based chemotherapy. Many institutions worldwide provided possible options to relieve the leucovorin shortage, including using treatment without leucovorin, lowering the standard leucovorin dose, or using alternative drugs.&#x0D; If lowering the body surface area-adjusted standard dose of leucovorin does not affect efficacy and safety, then implementation of a low flat-dose protocol may prevent mistakes that result during dose calculation and save pharmacy compounding time and costs.&#x0D; Decision-makers want to know if any clinical evidence supports a low flat-dose protocol for leucovorin.&#x0D; &#x0D; What Did We Do?&#x0D; &#x0D; To inform decisions about using flat-dose leucovorin in conjunction with fluorouracil-based chemotherapy, CADTH sought to identify and summarize literature comparing the clinical effectiveness of flat dosing versus weight-based leucovorin dosing. We also attempted to identify evidence-based recommendations for leucovorin dosing for colorectal or upper gastrointestinal cancer.&#x0D; A research information specialist conducted a literature search of the peer-reviewed and grey literature with a search strategy focused on leucovorin, dosing, and colorectal or gastrointestinal cancers. The search was limited to English-language documents published since 2013. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.&#x0D; &#x0D; What Did We Find?&#x0D; &#x0D; We found 1 small retrospective cohort study (58 patients) comparing low flat-dose 50 mg leucovorin with body surface area-adjusted to high dose 200 mg/m2 to 500 mg/m2 leucovorin in patients with colorectal cancer. The study found no statistically significant differences between the 2 doses in survival or complication rates.&#x0D; We found no evidence-based guidelines regarding leucovorin dosing for colorectal or upper gastrointestinal cancer. However, we found several guidelines with unclear methodology reporting leucovorin doses used in different fluorouracil-based regimens.&#x0D; &#x0D; What Does it Mean?&#x0D; &#x0D; Limited evidence from this review suggests that the standard weight-based dosing of leucovorin may be reduced to a low flat-dose. However, we require a larger and well conducted trial to confirm the findings of that study.&#x0D; Decision-makers may wish to consider that reducing the dose of leucovorin may conserve the supply, reduce pharmacy compounding time and control acquisition costs.&#x0D;

Long-Term Outcome of Rectal Cancer Patients Treated by High-Dose Radiotherapy and Concurrent Chemotherapy

To explore the therapeutic efficacy and adverse effects of high-dose radiotherapy concurrently with chemotherapy in treating patients with non-metastatic rectal cancer. Patients were enrolled if they were diagnosed with stage I-III rectal adenocarcinoma, refused surgery and received high-dose pelvic radiotherapy and concurrent chemotherapy instead. Their clinical data were retrospectively analyzed for calculating local control and survival rates. Treatment related toxicities was evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). Between April 2006 and February 2021, a total of 93 patients in our medical center were eligible for this study, with a median age of 61 (range, 21-84) years. Of those, 86 (92.5%) patients had tumors located within 5 cm of the anal verge. There were 8 (8.6%), 30 (32.3%) and 55 (59.1%) patients diagnosed with stage I, II and III, respectively. All patients received fluorouracil-based chemotherapy (single-agent fluorouracil or FOLFOX regimen). The irradiation techniques included three-dimensional conformal and intensity-modulated radiation therapy. The median total radiation dose for gross tumor volume (GTV) was 80 (range, 60-90) Gy. The 15 (16.1%) patients refusing surgery before treatment received one course of radiation (60-70 Gy/30-35 Fr). And a 2-course radiation (Course 1, 45-50 Gy/25 Fr; Course 2: 24-40 Gy/12-20 Fr) were given to the 78 (83.9%) patients who failed to achieve clinical complete remission (cCR) after neoadjuvant chemoradiotherapy but still refused surgery, with a median interval of 79 (range, 35-195) days. The median follow-up duration was 66 (range, 10-161) months. The 3- and 5-year overall survival (OS) rates for all patients were 90.5% and 72.7%, respectively. The clinical complete remission rate at the end of chemoradiotherapy was 69.9%. Colostomy was performed in the 14 patients whose rectal tumor did not attain cCR or progressed. There was no grade 4/5 severe acute toxicity. No patient suffered from intestinal perforation. Only one patient developed anal stenosis. Because of rectal bleeding, blood transfusion was performed in 7 patients, and one patient underwent an enterostomy. High-dose radiotherapy concurrent with chemotherapy brought encouraging survival outcomes, satisfactory organ preservation and acceptable short- and long-term side effects. It might be a safe and non-invasive alternative to abdominoperineal resection in rectal cancer patients refusing or unsuitable for surgery, especially for those with a low-position tumor.

Induction Fluorouracil-Based Chemotherapy and PET-Adapted Consolidation Chemoradiation with Esophagectomy for High-Risk Gastroesophageal Adenocarcinoma.

Background: Neoadjuvant chemoradiation with esophagectomy is standard management for locally advanced esophageal adenocarcinoma. Induction chemotherapy with a tailored approach to chemoradiation based on metabolic response to therapy on PET was explored as an alternative strategy in the CALGB 80803 trial. We sought to describe real-world institutional experience implementing this approach outside of a clinical trial. Methods: Patients who were treated with induction fluorouracil-leucovorin-oxaliplatin (FOLFOX) or fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) with tailored chemoradiation based on PET response and subsequent esophagectomy were identified from a prospectively maintained database. Primary outcomes were pathologic complete response (pCR) and overall survival (OS) following completion of all therapy. Results: There were 35 patients who completed induction chemotherapy, chemoradiation, and esophagectomy. Thirty-three completed restaging PET following induction chemotherapy with metabolic response seen in 76% (n = 25/33). The pCR rate was 31% (n = 11/35) and the ypN0 rate was 71% (n = 25/35). Among the patients who demonstrated metabolic response to induction FOLFOX/FLOT and subsequently continued fluorouracil-based chemoradiation, the pCR rate was 39% (n = 9/23). The rate of pathologically negative lymph nodes in this group was high (n = 19/23, 83%) with 100% R0 resection rate (n = 23/23). With the median follow-up of 43 months, the median OS was not reached for this group and was significantly longer than the OS for the remainder of the cohort (p = 0.027, p = 0.046 adjusted for clinical stage). Conclusions: Induction FOLFOX/FLOT chemotherapy with evaluation of sensitivity via metabolic response and tailored chemoradiation seems to lead to high pCR and ypN0 rates in high-risk patients with adenocarcinoma of the esophagus and GE junction. This approach in clinical practice seems to recapitulate encouraging results in clinical trials.

A Novel Gene Signature Associated with Protein Post-translational Modification to Predict Clinical Outcomes and Therapeutic Responses of Colorectal Cancer.

Accumulated evidence highlights the biological significance of diverse protein post-translational modifications (PTMs) in tumorigenicity and progression of colorectal cancer (CRC). In this study, ten PTM patterns (ubiquitination, methylation, phosphorylation, glycosylation, acetylation, SUMOylation, citrullination, neddylation, palmitoylation, and ADP-ribosylation) were analyzed for model construction. A post-translational modification index (PTMI) with a 14-gene signature was established. CRC patients with high PTMI had a worse prognosis after validating in nine independent datasets. By incorporating PTMI with clinical features, a nomogram with excellent predictive performance was constructed. Two molecular subtypes of CRC with obvious difference in survival time were identified by unsupervised clustering. Furthermore, PTMI was related to known immunoregulators and key tumor microenvironment components. Low-PTMI patients responded better to fluorouracil-based chemotherapy and immune checkpoint blockade therapy compared to high-PTMI patients, which was validated in multiple independent datasets. However, patients with high PTMI might be sensitive to bevacizumab. In short, we established a novel PTMI model by comprehensively analyzing diverse post-translational modification patterns, which can accurately predict clinical prognosis and treatment response of CRC patients.

Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial)

BackgroundBiliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients.MethodsThe NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon’s two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China.DiscussionThe NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research.Trial registrationChinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Efficacy and safety of Xian-Lian-Jie-Du optimization decoction as an adjuvant treatment for prevention of recurrence in patients with stage IIIB/IIIC colon cancer: study protocol for a multicentre, randomized controlled trial

IntroductionColon cancer remains one of the most prevalent cancers worldwide. Unfortunately, there are no recognized and effective therapeutic strategies to prevent tumor recurrence after radical resection and chemotherapy, and the disease-free survival (DFS) in patients with stage IIIB or IIIC disease remains unsatisfactory. Xian-Lian-Jie-Du optimization decoction (XLJDOD) is a Chinese herbal medicine (CHM) empirical prescription, which has been validated experimentally and clinically that could inhibit the progression of colorectal cancer and ameliorate the symptoms. The purpose of this study is to evaluate the efficacy and safety of XLJDOD in prevention of recurrence of colon cancer.MethodsThis study is a multi-center, double-blind, randomized, placebo-controlled trial conducted at 13 hospitals of China. Following the completion of surgery and adjuvant 5- fluorouracil-based chemotherapy, a total of 730 subjects with stage IIIB or IIIC colon cancer will be randomized in a 1:1 ratio to an intervention group (n = 365; XLJDOD compound granule) and a control group (n = 365; Placebo). Patients will receive 6-month treatments and be followed up with 3 monthly assessments for 2 years. The primary outcome is 2-year DFS rate and the secondary outcomes are 1, 2-year relapse rate (RR), overall survival (OS) and quality of life (QoL). Safety outcomes such as adverse events will be also assessed. A small number of subgroup analysis will be carried out to explore the heterogeneity of effects of XLJDOD.DiscussionThe outcomes from this randomized controlled trial will provide objective evidences to evaluate XLJDOD’s role as an adjuvant treatment in colon cancer.Trial registrationwww.ClinicalTrials.gov, identifier: NCT05709249. Registered on 31 Jan 2023.

Efficacy and safety of immunochemotherapy, immunotherapy, chemotherapy, and targeted therapy as first-line treatment for advanced and metastatic esophageal cancer: a systematic review and network meta-analysis

The treatment of esophageal cancer has entered a new phase with the development of immunotherapy. The current investigation purpose is to investigate and contrast the efficacy and safety of immunotherapy, immunochemotherapy, chemotherapy, and targeted therapy as first-line treatment for individuals suffering from advanced and metastatic esophageal cancer. Within the framework of this systematic review and network meta-analysis, clinical trials published or reported in English up until 01 May, 2022, were retrieved from Embase, PubMed, Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov databases, ESMO, and ASCO. The analysis incorporated randomized controlled trials (RCTs) from phase 2 to 3 that evaluated a minimum of two first-line therapeutic regimens for metastatic esophageal cancer were included in the analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary clinical outcomes included the incidence of objective response rate (ORR), and adverse events (AEs) of any grade and ≥3 grade. Relative summary data were extracted from included studies by GZ, HS, WS, and TD. For clear statistical analysis, chemotherapy was divided into two categories of fluorouracil-based chemotherapy (FbCT) and fluorouracil-free chemotherapy (FfCT). Bayesian frequentist approach was employed to conduct the network meta-analysis. The indirect intercomparison between regimens was presented with league tables (HRs and 95% CI for OS and PFS, ORs and 95% CI for ORR and AEs). A greater surface value under the cumulative ranking (SUCRA) indicates a higher potential ranking for the corresponding treatment. A further calculation of relative results about esophageal squamous cell cancer was performed in the subgroup analysis. The current protocol for the systematic review has been properly registered on PROSPERO (registration number: CRD42021241145). The final analysis comprised 17 trials that involved 9128 patients and 19 distinct treatment regimens. Within the scope of investigated immunotherapy (IO) combinations, toripalimab+FfCT (tori+FfCT) demonstrated the best OS advantages (tori+FfCT vs. FbCT, HR 0.57, 95% CI 0.38-0.85; tori+FfCT vs. FfCT, HR 0.58, 95% CI 0.43-0.78). In terms of PFS, camrelizumab+FfCT (cam+FfCT) demonstrated the best PFS advantages (FbCT vs. cam+FfCT, HR 1.79, 95% CI 1.22-2.63; FfCT vs. cam+FfCT, HR 1.79, 95% CI 1.47-2.17). Nivolumab+FbCT (nivo+FbCT vs. FfCT, OR 3.29, 95% CI 1.43-7.56) showed the best objective responses. Compared to the conventional chemotherapy regimen, the toxicity was observed to be the slightest for the tori+FfCT (FbCT vs. tori+FfCT, OR 3.07, 95% CI 1.22-7.7) and sintilimab+FfCT (FbCT vs. sin+FfCT, OR 2.93, 95% CI 1.16-7.37). The results in this study were evaluated as having a low heterogeneity since the I2 value was ≤25% in all analyses. Compared to foreign IO combinations, sin+FfCT, tori+FfCT, cam+FfCT, and tisle+FbCT are superior first-line treatment options for patients with advanced and metastatic esophageal cancer. Although foreign IO combinations, such as pembro+FbCT and nivo+FbCT obtained better objective response rates than other IO combinations, the addition of chemotherapy to IO worsens the safety profiles. Our findings could provide complementary evidence for current guideline recommendations. This work was supported by a grant from the Science and Technology Program of Guangzhou, China (202206010103); and Natural Science Foundation of Guangdong Province (2022A1515012469).

Bleeding and thrombotic events in bevacizumab-treated patients with colorectal cancer on novel oral anticoagulants and antiplatelet medications

BackgroundBevacizumab is a humanized monoclonal anti-VEGF antibody often given in combination with fluorouracil-based chemotherapy as therapy for metastatic colorectal cancer (mCRC). The bleeding and thrombotic event rates in the setting of concurrent novel oral anticoagulants with and without aspirin and bevacizumab treatment in patients with mCRC remain unclear. Methods462 patients with mCRC at Barnes-Jewish Hospital were identified between December 1, 2016 and December 1, 2021 and screened for concurrent treatment with bevacizumab and anticoagulant or antiplatelet therapy. Demographic and clinical information was extracted by electronic chart review. Results21 patients were identified who received bevacizumab and either apixaban or rivaroxaban for mCRC treatment. Aspirin was prescribed in some of these patients within three years of starting apixaban or rivaroxaban. Of the 13 patients without aspirin prescription, nine were given apixaban, and four were given rivaroxaban while on bevacizumab. Four out of nine of the patients who received apixaban had epistaxis, and only one case resulted in any treatment discontinuation. Three out of four of the patients who received rivaroxaban experienced bleeding, and one of these three patients discontinued bevacizumab. We also looked at eight patients who had received aspirin. Two out of seven patients who received apixaban/bevacizumab/aspirin experienced bleeding and discontinued a medication. The patient who received rivaroxaban/bevacizumab/aspirin experienced bleeding and discontinued bevacizumab. No patient experienced adverse thrombotic events. ConclusionsPatients with mCRC treated with bevacizumab and apixaban with no history of aspirin use within three years have a relatively low risk of bleeding that warrants treatment discontinuation.

Bleeding and thrombotic events in patients with colorectal cancer treated with bevacizumab and receiving novel oral anticoagulants and antiplatelet medications.

104 Background: Bevacizumab is a humanized monoclonal VEGF antibody given in combination with fluorouracil-based chemotherapy for metastatic colorectal cancer (mCRC). Many patients with mCRC also have cardiovascular comorbidities requiring anticoagulation or antiplatelet therapy. The bleeding and thrombotic event rates in the setting of concurrent novel oral anticoagulants (NOACs) and bevacizumab treatment in patients with mCRC remain unclear. Methods: 462 patients with mCRC at Barnes-Jewish Hospital were identified between December 1, 2016 and December 1, 2021 and screened for concurrent treatment with bevacizumab and anticoagulant or antiplatelet therapy. Demographic and clinical information was extracted by electronic chart review. Results: 21 patients were identified who received bevacizumab and either apixaban or rivaroxaban for mCRC treatment. Aspirin was prescribed in some of these patients within 3 years of starting apixaban or rivaroxaban. Of the 13 patients who had no history of aspirin prescription, 9 were given apixaban, and 4 were given rivaroxaban while on bevacizumab. 44.4% of the patients who received apixaban experienced bleeding. All these events were epistaxis, and only 25% of the cases resulted in any treatment discontinuation. 75% of the patients who received rivaroxaban experienced bleeding events, which 33.3% of the time resulted in discontinuation of either rivaroxaban or bevacizumab. We also looked at 8 patients who had received aspirin in the last three years: 7 patients were on apixaban, and one was on rivaroxaban while on concomitant aspirin and bevacizumab. 28.6% of the patients who received apixaban with bevacizumab and aspirin experienced an adverse bleeding event that resulted in some form of treatment discontinuation. Meanwhile, the patient who received rivaroxaban with bevacizumab and aspirin experienced a bleeding event that resulted in discontinuation of a medication. No patient experienced any adverse thrombotic events. Conclusions: Patients with mCRC treated with bevacizumab and apixaban with no history of prior aspirin use within three years have a relatively low risk of developing bleeding events that warrant treatment discontinuation. The addition of NOAC to bevacizumab therapy does not appear to increase the risk of adverse thrombotic events.

Expression pattern of secretory-cell-related transcriptional signatures in colon adenocarcinomas defines tumor microenvironment characteristics and correlates with clinical outcomes.

Despite the connection of secretory cells to distinct mucus-containing colon cancer histological subtypes and the interaction of secretory cells with immune cells in the pathogenesis of intestinal inflammatory diseases, whether the secretory cell signatures are associated with tumor microenvironment (TME) heterogeneity and can aid in colon cancer patient classification have not been investigated. Here, by performing the principal component analysis and consensus clustering analysis, we identified four distinct expression patterns based on secretory cell signatures which were significantly associated with different clinical behaviors, TME landscape, pathway activation, genomic mutations, and DNA methylation characteristics. Subsequently, a 'SCS score' model was constructed. The high SCS score indicated a pattern of 'secretory cell subtype 2', which was characterized by stromal infiltration and activation, and predicted poor prognosis and low sensitivity to fluorouracil-based chemotherapy and immunotherapy, but high sensitivity to PI3K catalytic subunit inhibitors. In conclusion, our study comprehensively uncovered the tumor heterogeneity related to secretory cell signature expression patterns. Moreover, the SCS score can supplement routine histopathological assessments to guide personalized therapeutic strategies in colon cancer patients.

Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy

BackgroundAT-rich interaction domain 1A (ARID1A) encodes a vital component of switch/sucrose non-fermentable chromatin-remodeling complex. Given its association with genomic instability, we conducted this study to determine whether ARID1A mutation status had an impact on therapeutic responsiveness in gastric cancer (GC), especially combinatory chemo-immunotherapy.MethodsWe retrospectively enrolled a total of 1162 patients from five independent cohorts. ZSHS Cohort and TCGA Cohort were designed to inform chemotherapeutic relevance and immunobiology of ARID1A-mutant GC based on tissue samples and sequencing data, respectively. MSKCC Cohort, mGC Cohort, and Melanoma Cohort were utilized to interrogate the predictive efficacy of ARID1A mutation to programmed cell death protein 1 (PD-1) blockade.ResultsARID1A mutation was enriched in EBV-positive, hypermutated-single nucleotide variant and microsatellite-unstable subtype GC, and was predictive of responsiveness to both fluorouracil-based chemotherapy and PD-1 blockade. Specifically, ARID1A mutation score was a highly sensitive indicator (91%) of response to pembrolizumab. Mechanistically, ARID1A mutation correlated with extensive DNA damage repair deficiency and immunogenic tumor microenvironment (TME) featured by elevated activated subsets of CD8+ T cells, CD4+ T cells, and NK cells. Type 17T helper cells were typically abundant in ARID1A-mutant GC and might be a precondition for chemosensitivity conferred by ARID1A mutation. Furthermore, ARID1A mutation indicated elevated expression of VEGFA and CLDN18, as well as over-representation of ERBB2 and FGFR2 signaling pathway.ConclusionsARID1A-mutant GC displayed immunogenic TME and might be a candidate for both monotherapy and the combination of frontline chemotherapy and PD-1 blockade.

A novel oxidative stress- and ferroptosis-related gene prognostic signature for distinguishing cold and hot tumors in colorectal cancer.

Oxidative stress and ferroptosis exhibit crosstalk in many types of human diseases, including malignant tumors. We aimed to develop an oxidative stress- and ferroptosis-related gene (OFRG) prognostic signature to predict the prognosis and therapeutic response in patients with colorectal cancer (CRC). Thirty-four insertion genes between oxidative stress-related genes and ferroptosis-related genes were identified as OFRGs. We then performed bioinformatics analysis of the expression profiles of 34 OFRGs and clinical information of patients obtained from multiple datasets. Patients with CRC were divided into three OFRG clusters, and differentially expressed genes (DEGs) between clusters were identified. OFRG clusters correlated with patient survival and immune cell infiltration. Prognosis-related DEGs in three clusters were used to calculate the risk score, and a prognostic signature was constructed according to the risk score. In this study, patients in the low-risk group had better prognosis, higher immune cell infiltration levels, and better responses to fluorouracil-based chemotherapy and immune checkpoint blockade therapy than high-risk patients; these results were successfully validated with multiple independent datasets. Thus, low-risk CRC could be defined as hot tumors and high-risk CRC could be defined as cold tumors. To further identify potential biomarkers for CRC, the expression levels of five signature genes in CRC and adjacent normal tissues were further verified via an in vitro experiment. In conclusion, we identified 34 OFRGs and constructed an OFRG-related prognostic signature, which showed excellent performance in predicting survival and therapeutic responses for patients with CRC. This could help to distinguish cold and hot tumors in CRC, and the results might be helpful for precise treatment protocols in clinical practice.

Influence of the skeletal muscle index on pharmacokinetics and toxicity of fluorouracil.

The body composition of patients has been associated with tolerability and effectiveness of anticancer therapy. This study aimed to assess the influence of the skeletal muscle index (SMI) on the pharmacokinetics and toxicity of fluorouracil. Patients treated in an oncological practice with fluorouracil-based chemotherapy and undergoing therapeutic drug monitoring were retrospectively investigated. Computed tomography images were analyzed to measure abdominal skeletal muscle areas in Hounsfield units for the psoas major muscle, back and total skeletal muscle to determine the SMI. For the latter, an automated segmentation method was used additionally. SMI measures were tested as covariates on fluorouracil clearance in a population pharmacokinetic model. Furthermore, regression analyses were performed to analyze the influence of SMI measures on the probability of clinically relevant adverse events (CTCAE grades ≥ 2). Fluorouracil plasma concentrations of 111 patients were available. Covariate analyses showed significant improvements of the model fit by all SMI measures. However, interindividual variability of fluorouracil clearance was only slightly reduced, whereas the SMI of the back muscle showed the largest reduction (-1.1 percentage points). Lower SMI values of the back muscle increased the probability for polyneuropathy and lower SMI of the psoas increased the probability for fatigue. Our results suggest that pharmacokinetics and toxicity of fluorouracil may be associated with specific SMI measures which deserve further investigation.

Circulating exosomal gastric cancer-associated long noncoding RNA1 as a noninvasive biomarker for predicting chemotherapy response and prognosis of advanced gastric cancer: A multi-cohort, multi-phase study.

SummaryBackgroundA previous validated study has identified the diagnostic value of circulating exosomal lncRNA-GC1 for detecting and monitoring gastric cancer. We aimed to further determine the predictive role of circulating exosomal lncRNA-GC1 for prognosis and chemotherapy response.MethodsWe retrospectively conducted a multi-phase analysis with four independent cohorts of 981 patients. A training cohort was used to generate the predictive model. One internal and two external cohorts were recruited as validation cohorts. Patients with stage II or III gastric cancer in the combined cohort were used to evaluate the predictive value of circulating exosomal lncRNA-GC1 for chemotherapy response.FindingsIn the training cohort, circulating exosomal lncRNA-GC1 was identified as an independent prognostic predictor for disease-free and overall survival. A prognostic risk stratification model based on circulating exosomal lncRNA-GC1 and AJCC stage revealed better predictive accuracy for disease-free and overall survival than the traditional AJCC stage system alone (C-index: DFS 0.701 vs 0.614; OS 0.720 vs 0.611, both P<0.05). And it has been further verified in the validation cohorts. In interaction analysis, for stage II and III GC, patients with low-level of circulating exosomal lncRNA-GC1 derived more survival benefit from adjuvant chemotherapy (P < 0.05); while those with high-level did not.InterpretationMeasurement of circulating exosomal lncRNA-GC1 provides clinically important prognostic information and could complement the AJCC stage to optimize decision-making for selecting patients who could benefit more from fluorouracil-based chemotherapy after surgery.FundingThe funders are listed in the Acknowledgement.