Oxaliplatin-based Chemotherapy Regimens Research Articles

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.

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;

Adjuvant oxaliplatin-based chemotherapy comparing observation alone after radical resection of metachronous metastases of colorectal cancer: interim analysis

Introduction. Despite the registered standard treatment option for patients who underwent radical resection for metachronous metastases of colorectal cancer (CRC), the feasibility of adjuvant chemotherapy (ACT) for all patients seems controversial. Due to studies demonstrating improved disease-free survival rates with postoperative chemotherapy vs observation, it would seem that there is reasonable expectation of improved overall survival (OS) rates, which, however, were not statistically different between groups. This article presents the interim results of our own study.Aim. To analyse the efficacy of ACT vs dynamic observation in patients who underwent surgery for metachronous metastases of colorectal cancer.Materials and methods. It was a prospective-retrospective, non-randomized, non-inferiority study. A total of 120 patients were recruited between June 2008 and September 2022. The ACT group included 71 patients. All patients received only oxaliplatin-based chemotherapy regimens; the dynamic observation group included 49 patients.Results. The interim analysis showed that the median disease-free survival (mDFS) in the ACT group (n = 71) was 20.9 months (13.7–28.3) vs 24.4 months in the dynamic observation group (n = 49) (11.1–37.7), HR: 0.76 (95% CI: 0.45–1.29), p = 0.29. Two-year disease-free survival (DFS) rates were 46.6% in the post-surgery chemotherapy (CT) group (n = 50) and 55.5% in the experimental group (n = 31), HR: 0.69 (95% CI: 0.39–1.2), p = 0.21.Conclusion. ACT has not improved the long-term treatment outcomes in patients who underwent radical resection for metachronous metastases of CRC.

Prognostic Impact of Primary Tumor Sidedness in Stage III Colorectal Cancer: Real-World Evidence from a Brazilian Cohort

BackgroundPrimary tumor sidedness (PTS) is an independent prognostic factor in patients with metastatic colorectal cancer (CRC), with a worse prognosis for right-sided tumors. There are limited data on the prognostic impact of PTS in stage III CRC. The main objective of this study was to analyze the prognostic impact of PTS in stage III CRC. Patients and MethodsA retrospective and uni-institutional cohort study was performed in an oncology reference center. Patients with stage III CRC treated with a 5-fluorouracil and oxaliplatin-based chemotherapy regimen (mFLOX regimen) from October 2007 to February 2013 were included. The primary outcome was the probability of overall survival (OS) at 5 years stratified by PTS. Secondary outcomes were the probability of disease-free survival (DFS) at 5 years and an analysis of the prognostic impact of clinical and molecular biomarkers. Kaplan‒Meier curves were used, and Cox models were used to evaluate prognostic factors associated with OS and DFS. ResultsOverall, 265 patients were evaluated. Transverse colon tumors, multicentric tumors, and undetermined primary subsites were excluded, resulting in 234 patients classified according to PTS: 95 with right sidedness (40.6%) and 139 with left sidedness (59.4%). The median follow-up time was 66 months [interquartile range (IQR): 39-81]. The 5-year OS probabilities for right-sided and left-sided tumors were 67% (95% CI: 58%-77%) and 82% (75%-89%), respectively [hazard ratio (HR): 2.02, 95% CI: 1.18-3.46; P = .010]. The 5-year probabilities of DFS for right-sided and left-sided tumors were 58% (49%-69%) and 65% (58%-74%), respectively (HR: 1.29, 0.84-1.97; P = 0.248). ConclusionThese data suggest that there may be a worse prognosis (inferior OS at 5 years) for resected right-sided stage III CRC patients treated in the real world. However, these data need to be confirmed by prospective studies with a larger number of participants.

Predictive Model of Oxaliplatin-induced Liver Injury Based on Artificial Neural Network and Logistic Regression.

Identifying potential high-risk groups of oxaliplatin-induced liver injury (OILI) is valuable, but tools are lacking. So artificial neural network (ANN) and logistic regression (LR) models will be developed to predict the risk of OILI. The medical information of patients treated with oxaliplatin between May and November 2016 at 10 hospitals was collected prospectively. We used the updated Roussel Uclaf causality assessment method (RUCAM) to identify cases of OILI and summarized the patient and medication characteristics. Furthermore, the ANN and LR models for predicting the risk of OILI were developed and evaluated. The incidence of OILI was 3.65%. The median RUCAM score with interquartile range was 6 (4, 9). The ANN model performed similarly to the LR model in sensitivity, specificity, and accuracy. In discrimination, the area under the curve of the ANN model was larger (0.920>0.833, p=0.019). In calibration, the ANN model was slightly improved. The important predictors of both models overlapped partially, including age, chemotherapy regimens and cycles, single and total dose of OXA, glucocorticoid drugs, and antihistamine drugs. When the discriminative and calibration ability was given priority, the ANN model outperformed the LR model in predicting the risk of OILI. Other chemotherapy drugs in oxaliplatin-based chemotherapy regimens could have different degrees of impact on OILI. We suspected that OILI may be idiosyncratic, and chemotherapy dose factors may be weakly correlated. Decision making on prophylactic medications needs to be carefully considered, and the actual preventive effect needed to be supported by more evidence.

Stage III deficient mismatch repair colon patients get greater benefit from earlier starting oxaliplatin-based chemotherapy regimen

We evaluate the prognostic value of chemotherapy and other prognostic factors on overall survival among colon patients with deficient mismatch repair (dMMR), and determine the optimum time to start chemotherapy after surgery. Data of 306 colon cancer patients with dMMR who received radical surgery were collected from three Chinese centers between August 2012 and January 2018. Overall survival (OS) was assessed with the Kaplan–Meier method and log-rank. Cox regression analysis were used to assess influencing prognosis factors. The median follow-up time for all patients was 45.0 months (range, 1.0–100). There was a nonsignificant OS benefit from chemotherapy for patients with stage I and stage II disease, including high-risk stage II disease (log-rank p: 0.386, 0.779, 0.921), and a significant OS benefit for patients with stage III and stage IV disease for receiving post-operation chemotherapy (log-rank p = 0.002, 0.019). Stage III patients benefitted from chemotherapy regimens that contained oxaliplatin (log-rank p = 0.004), and Starting chemotherapy with oxaliplatin treatment earlier resulted in better outcomes (95% CI 0.013–0.857; p = 0.035). Chemotherapy regimens containing oxaliplatin can prolong the survival time of stage III and IV dMMR colon cancer patients. This beneficial manifestation was more pronounced after starting chemotherapy treatment early post operation. High risk stage II dMMR colon patients including T4N0M0 cannot benefit from chemotherapy.

Prognostic impact of primary tumor sidedness in stage III colorectal cancer.

e15622 Background: Primary tumor sidedness (PTS) has been shown to be an independent prognostic factor for patients with metastatic colorectal cancer (CRC), with worse prognosis for right-sided tumors. There are limited data regarding the prognostic impact of PTS in stage III CRC. Objective: The main objective of this study was to analyze the prognostic impact of PTS in stage III CRC. Methods: A retrospective and uni-institutional cohort study was performed in a reference center in São Paulo-SP, Brazil. All consecutive patients with stage III CRC and treated with a 5-fluorouracil and oxaliplatin-based chemotherapy regimen (mFLOX regimen) from October 2007 to February 2013 were included. The primary outcome was probability of overall survival (OS) at 5 years stratified by PTS. Secondary outcomes were probability of disease-free survival (DFS) at 5 years stratified by PTS, and analysis of the prognostic impact of clinical and molecular biomarkers. The time-to-event variables were reported by the Kaplan Meier estimation method and prognostic factors associated with OS and DFS were assessed by Cox models. Results: 265 patients were included. Transverse colon tumors, multicentric tumors and undetermined primary subsite were later excluded, totaling 234 patients who were classified according to PTS: 95 on the right side (40.6%) and 139 on the left side (59.4%). Median age was 58 and 59 years for right- and left-sided tumors, respectively. For both groups, approximately 67% had stage IIIB. The median follow-up time was 66 months (range: 0-149). The 5-year OS probabilities for right-sided and left-sided tumors were 67% (95% CI: 58%-77%) and 82% (75%-89%), respectively. [Hazard ratio [HR]=2.02, 95% CI: 1.18–3.46; p=0.010). The 5-year probability of DFS for right-sided and left-sided tumors were 58% (49%-69%) and 65% (58%-74%), respectively. [HR=1.29, 0.84-1.97; p=0.248). Of the 234 patients, 61 patients (26%) had tissue samples available for DNA sequencing by NGS and immunohistochemical analysis. Of these, 12 patients (19.7%) had a RAS mutation, no patient had a BRAF mutation (V600E) and 6 patients (9.8%) had DNA repair enzyme deficiency (dMMR). No statistically significant difference was identified in the probability of OS and DFS at 5 years when comparing patients with right-sided and left-sided tumors when stratified by RAS mutation status and MMR status. Among patients with right-sided tumors, age &gt;70 years (HR=4.11, 1.67-10.1; p=0.002), pN2 (HR=2.52, 1.23-5.17; p=0.012) and high-risk stage III according to the IDEA trial (HR=2.95, 1.35-6.44; p=0.002) were predictors of worse OS at 5 years. Among patients with left-sided tumors, poorly differentiated histology (HR=3.93, 1.44-10.7; p=0.007) and angiolymphatic invasion (HR=5.23, 1.54-17.8; p=0.008) were predictors of worse OS in 5 years. Conclusions: Data indicate a worse prognosis (inferior OS at 5 years) for resected right-sided stage III CRC treated with adjuvant mFLOX regimen.

Supercritical fluid extract of Angelica sinensis promotes the anti-colorectal cancer effect of oxaliplatin

Oxaliplatin-based chemotherapy regimens are recommended for patients with advanced colorectal cancer (CRC). However, oxaliplatin (OXA) can cause toxic side effects at the recommended dosage. Therefore, it is necessary to find new drug candidates that can synergize with OXA and thereby lower the OXA dose while still maintaining its efficacy. Angelica sinensis is a common drug in traditional Chinese medicine and has demonstrated a significant anti-CRC effect in modern pharmacological studies. The active ingredients in Angelica sinensis can be effectively extracted by a supercritical fluid extract. In this study, the supercritical fluid extract of Angelica sinensis (A-SFE) was obtained by a stable extraction process and was chemically characterized by GC/MS. The anti-cancer effect of A-SFE when applied individually was explored in vitro through MTT, scratch, and Transwell assay. The effect of A-SFE on CRC cells under the influence of tumor-associated macrophages (TAMs) was explored by a co-culture model. The results showed that A-SFE could inhibit the viability, metastasis, and invasion of HCT116 cells, especially under the influence of TAMs. When 20-100μg/ml of A-SFE and 8-64μg/ml of OXA were used in combination in HCT116 cells, synergistic or additive effects were shown in different concentration combinations. The CT26 syngeneic mouse model was used to explore the anti-CRC effect of OXA combined with A-SFE in vivo. The tumor volume, expression levels of Ki67, MMP9, and CD206 in the OXA + A-SFE group were less than those in the OXA group. In conclusion, A-SFE has the potential to become an adjuvant drug for OXA in the treatment of CRC, which provides new strategies for anti-colorectal cancer research.

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis

The basic platelet counts of schistosomiasis patients are low. If it does not meet the requirements for chemotherapy, the patient's treatment will not be carried out, which directly affects their prognosis. Therefore the impact of treatment on platelet counts is critically important. The effects of bevacizumab plus oxaliplatin-based chemotherapy and bevacizumab plus irinotecan-based chemotherapy regimens on platelets are different but have not been determined. In order to find a more suitable plan for metastatic colorectal cancer (mCRC) patients with a history of schistosomiasis, we conducted a retrospective analysis of mCRC patients and evaluated the impact of bevacizumab on their platelets. The medical records of all mCRC patients with a history of schistosomiasis who received oxaliplatin-based chemotherapy or irinotecan-based chemotherapy as first-line treatment for no less than 4 cycles, with or without bevacizumab from September 1, 2017, to June 30, 2019, in Kunshan Hospital were reviewed. Six-month cumulative incidence rates of splenomegaly and thrombocytopenia of chemotherapy with and without bevacizumab groups, oxaliplatin-based chemotherapy with and without bevacizumab groups, irinotecan-based chemotherapy with and without bevacizumab groups were compared from the first cycle until the completion of chemotherapy using Kaplan-Meier analysis and Log-rank test. Evaluable splenic enlargement and thrombocytopenia results were obtained from 153 mCRC patients. The 6-month cumulative incidence rates of splenomegaly (23.3% vs. 55%; P=0.01) and that of thrombocytopenia (43.8% vs. 57.5%; P=0.40) were lower in the bevacizumab group than the non-bevacizumab group, however there were no statistical differences for the rates of thrombocytopenia. For patients treated with oxaliplatin, the rates of splenomegaly (19.5% vs. 66.7%; P=0.01) and thrombocytopenia (31.7% vs. 77.2%; P=0.02) were lower in the bevacizumab-treated cohort than that in the non-bevacizumab cohort. When stratified for irinotecan, there were no statistical differences in the frequency of splenomegaly between the two groups. However, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the non-bevacizumab cohort (59.4% vs. 8.7%; P=0.01). The bevacizumab plus oxaliplatin-based chemotherapy regimen is safer for mCRC patients with a history of schistosomiasis, especially for patients with a lower platelet count.

Diagnostic efficacy of deep learning-based prediction of origin for patients with cancers of unknown primary.

e13560 Background: Despite of routine medical history inquiry, laboratory analysis, histopathological analyses, endoscopy and imaging methods, 3-5% of metastatic cancers are diagnosed with unknown primary (CUP). It poses a considerable challenge as modern therapeutic options for patients with CUP are mainly limited to empirical chemotherapy (paclitaxel, carboplatin, etc.), leading to an overall poor prognosis. In current clinical trials (CUPISCO trial, PACET-CUP trial) targeting CUP for precision therapy, genomic data suggest that only 31% of CUP patients could be matched for at least one targeted or immune agent. The determination of primary tumor origin and genetic mutations could probably provide more therapeutic choices and help to significantly improve the outcome in CUP patients. Methods: To identify the primary lesion of CUP, we built a weighted ensemble model by Automated machine learning, including 13 models ( XGBoost, RandomForestGini, ExtraTreesGini, etc.), using genetic and clinical datasets containing 22,018 patients of 28 tumor types, enrolled between 2016-2021. Our genetic and clinical datasets contained 10 features including age, tumor site, gene alteration, TMB, etc. Among them, 813 sites related to tumor were covered by gene alteration. The 5-fold Cross-Validation method was used to estimate the accuracy of our diagnosis models. Results: The models were evaluated using top-k differential diagnosis accuracy, which measured how frequently the top-k predictions capture any of the primary diagnoses in the reference standard. Our diagnostic model was then performed on 8 CUP patients. All of them were successfully confirmed their diagnosis of primary origin tumor. Among these patients, 2/8 CUP patients have begun relevant systemic therapy based on the confirmed diagnosis: 1 patient with diagnosis of esophageal squamous cell carcinoma receiving the immune combination TP Regimen (Albumin paclitaxel plus cisplatin) and achieved a 9-month PFS; another patient diagnosed as colorectal cancer achieved a 2-month PFS after treatment with Oxaliplatin-based chemotherapy regimen. Preliminary results of our study demonstrated the efficiency of this Artificial Intelligence model for the diagnosis in CUP patients. Conclusions: We developed a diagnostic model on CUP using deep learning based on genomic and clinical data and preliminarily applied in clinic. Genetic characterization of CUP patients contributes to the selection of targeted therapies under unclear diagnosis, whereas our diagnosis model could equally adjust more proper precision treatment for CUP patients. In CUP patients, the combined strategy of deep learning-predicted diagnosis and genetic mutations-based therapy could help to maximize the clinical benefit in a clinical setting and optimize the clinical development of innovative therapies.

S-Adenosylmethionine Supplementation May Reduce Cancer-Related Fatigue: A Prospective Evaluation Using the FACIT-F Questionnaire in Colon Cancer Patients Undergoing Oxaliplatin-Based Chemotherapy Regimens

Background: Fatigue is a common distressing symptom for patients living with chronic or acute diseases, including liver disorders and cancer (Cancer-Related Fatigue, CRF). Its etiology is multifactorial, and some hypotheses regarding the pathogenesis are summarized, with possible shared mechanisms both in cancer and in chronic liver diseases. A deal of work has investigated the role of a multifunctional molecule in improving symptoms and outcomes in different liver dysfunctions and associated symptoms, including chronic fatigue: S-adenosylmethionine (SAM; AdoMet). The aim of this work is actually to consider its role also in oncologic settings. Patients and Methods: Between January 2006 and December 2009, at the University Campus Bio-Medico of Rome, 145 patients affected by colorectal cancer in adjuvant (n = 91) or metastatic (n = 54; n = 40 with liver metastases) setting and treated with oxaliplatin-based regimen (FOLFOX for adjuvant and bevacizumab + XELOX for metastatic ones), 76 of which with the supplementation of S-adenosylmethionine (AdoMet; 400 mg b.i.d.) (57% of adjuvant patients and 44% of metastatic ones) and 69 without AdoMet supplementation, were evaluated for fatigue prevalence using the Functional Assessment of Chronic Illnesses Therapy-Fatigue (FACIT-F) questionnaire, at 3 and 6 months after the beginning of oncologic treatment. Notably, the number of patients with liver metastases was well balanced between the group of patients treated with AdoMet and those who were not. Results: Among patients receiving oxaliplatin-based chemotherapy, both in adjuvant and in metastatic settings, after just 3 months from the beginning of chemotherapy, mean scores from questionnaire domains like FACIT-F subscale (7.9 vs. 3.1, p = 0.006), FACIT physical (6.25 vs. 3.32, p = 0.020), FACIT emotional (4.65 vs. 2.19, p = 0.045), and FACIT-F total score (16.5 vs. 8.27, p = 0.021) were higher in those receiving supplementation of AdoMet, resulting in reduced fatigue; a significant difference was maintained even after 6 months of treatment. Discussion and Conclusions: Mechanisms and strategies for managing CRF are not fully understood. This work aimed at investigating the possible role of S-adenosylmethionine supplementation in improving fatigue scores in a specific setting of cancer patients, using a FACIT-F questionnaire, a well-validated quality of life instrument widely used for the assessment of CRF in clinical trials.

Preventive Efficacy and Safety of Yiqi-Wenjing-Fang Granules on Oxaliplatin-Induced Peripheral Neuropathy: A Protocol for a Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

Background. Oxaliplatin-induced peripheral neuropathy (OIPN) is one of the most common side effects of oxaliplatin, which can cause reduction and cessation of oxaliplatin-based chemotherapy and significantly affect patients' quality of life. However, no drug has got recognition to prevent or treat OIPN. Yiqi-Wenjing-Fang (YWF) is a joint name of Chinese medicine prescriptions with similar effects of tonifying qi and warming meridians, represented by Huangqi Guizhi Wuwu decoction (HGWD) and Danggui Sini decoction (DSD), both from “Treatise on Cold Pathogenic and Miscellaneous Diseases.” YWF granules, including HGWD granules and DSD granules, have been, respectively, demonstrated to be effective in preventing OIPN in previous small-sample observations. The purpose of this study is to enlarge the sample size for further evaluation of the preventive efficacy and safety of YWF granules on OIPN. Methods and Analysis. This study is a randomized, double-blind, placebo-controlled, and multicenter clinical trial. 360 postoperative patients with stage IIa-IIIc colorectal cancer will be randomly assigned into placebo-control group, intervention group I, and intervention group II, taking the mimetic granules of YWF as placebo, HGWD granules and DSD granules, respectively. All subjects will receive oxaliplatin-based chemotherapy regimen at the same time. EORTC QLQ-CIPN20 will be used to assess the degree of OIPN as the primary outcome measure. The grades of OIPN, quality of life, chemotherapeutic efficacy, and the number of completed chemotherapy cycles are selected as the secondary outcome measures. Discussion. Based on the condition of no recognized effective drugs in preventing OIPN, evidence-based medical study will be conducted for seeking a breakthrough in the field of Chinese herb medicine. This protocol could provide reliable and systemic research basis about the efficacy of YWF granules and the differentiation of two classical prescriptions of YWF on preventing OIPN objectively. Trial Registration. This study was registered at ClinicalTrials.gov on 26 December 2020 (ID: https://clinicaltrials.gov/ct2/show/NCT04690283).

Prognostic Value of Tumor Regression Grading in Patients Treated With Neoadjuvant Chemotherapy Plus Surgery for Gastric Cancer.

ObjectiveTo validate the prognostic value of tumor regression grading (TRG) and to explore the associated factors of TRG for advanced gastric cancer (AGC) with neoadjuvant chemotherapy (NACT) plus surgery.MethodsTwo hundred forty-nine AGC patients treated with NACT followed by gastrectomy at the Mayo Clinic, USA and the Fujian Medical University Union Hospital, China between January 2000 and December 2016 were enrolled in this study. Cox regression was used to identify covariates associated with overall survival (OS) and recurrence-free survival (RFS). Logistic regression was used to reveal factors predicting tumor regression grading.ResultsFor patients with TRG 0-1, the 3- and 5-year OS rates were 85.2% and 74.5%, respectively, when compared to 56.1% and 44.1% in patients with TRG 2 and 28.2% and 23.0% in patients with TRG 3, respectively (p<0.001). TRGs were independent risk factors for OS. Similar findings were observed in RFS. Multivariable analysis revealed that an oxaliplatin-based regimen (p=0.017) was an independent predictor of TRG. The oxaliplatin-based regimen was superior to the nonoxaliplatin-based regimen for OS (38.4 months vs 19.5 months, respectively; p=0.01). Subgroup analyses by histological subtype indicated that the oxaliplatin-based regimen improved the OS in nonsignet ring cell carcinoma compared to the nonoxaliplatin-based regimen (53.7 months vs 19.5 months, respectively; p=0.011). However, similar findings were not observed in RFS.ConclusionTRG was an independent factor of AGC treated with neoadjuvant chemotherapy plus surgery. Oxaliplatin-based neoadjuvant chemotherapy regimens improve tumor response and may have an overall survival benefit for patients with nonsignet ring cell carcinoma.

Duloxetine (DL) in treatment of oxaliplatin-induced peripheral neuropathy (PN).

195 Background: Oxaliplatin is commonly used to treat many GI cancers, especially colorectal (CRC), pancreatic (PC), and gastric (GC); however, peripheral neuropathy (PN) is the dose-limiting toxicity. Duloxetine (DL) is a second-generation selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of depression, anxiety, PN-associated with diabetes or ongoing pain due to medical conditions such as fibromyalgia. In this retrospective study, we evaluated the role of DL in reduction of oxaliplatin-induced neuropathy. Methods: Patients with GI cancers receiving oxaliplatin-based chemotherapy regimens from Nov 2016 to Nov 2019 were included. Patients with pre-existing PN from other etiologies such as diabetes, alcoholism, autoimmune disease, infections, hereditary, etc. were excluded. Neurological evaluations were performed serially before initiating DL and every 4 weeks thereafter according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. DL was given at 30 mg by mouth (PO) once daily and if tolerated after 3 days, was escalated to 60 mg once daily. Response was calculated to include number of patients with stable PN, improved PN, or no benefit. Adverse toxicities were graded. Results: 53 patients with median age of 53 years (range: 38 – 72) received DL for oxaliplatin-induced PN during treatment of GI cancers (CRC: 40%, PC:30%, GC: 10%, others: 10%). Improvement in PN from higher to lower grades was witnessed at 2 weeks in only 4 patients. At 4 week of DL, 3/53 (6%) patients improved from G3 PN to G2, 6/53 (11%) from G3 to G1, and 28/53 (52.8%) from G2 to G1, 14/53 (26%) and 2/53 (4%) had stable G3 and G2 PN respectively. At 8 week of DL, 10/53 (19%) of patients improved from G3 to G2, 3/53 (6%) from G2 to G1, 23/53 (43%) from G1 to G0, while 11/53 (21%), 2/53 (4%) and 4/53 (8%) remained stable at G1, G2 and G3 respectively. Overall DL resulted in a response rate of 89% and stable PN in 11%. 5 patients had to stop DL due to G3 drowsiness, insomnia, dry mouth and headache. Overall, DL was well-tolerated with majority of toxicities in G1-2 grade: dizziness (15%), drowsiness (11%), sexual side effects (11%), dry mouth (11%), insomnia (8%), headache (8%). In addition to PN, DL helped in improving depression in 50% of these patients and decreased the pain score in an additional 23%. Conclusions: DL resulted in a clinically significant improvement in PN-induced by oxaliplatin with manageable toxicity profile. Additionally, DL also improved depression and pain score. DL may be considered as an option in ameliorating PN in these patients, however, caution must be taken about DL and other drugs interaction. Our study warrants a prospective randomized trial to study the effectiveness of DL in treating oxaliplatin-induced PN. Moreover, cost effectiveness of DL in concurrently improving PN, depression and pain needs to be studied as well.

Oral Chinese Patent Medicine Combined With Oxaliplatin-Based Chemotherapy Regimen for the Treatment of Colorectal Cancer: A Network Meta-Analysis.

Objective:To access the comparative effectiveness and safety of different oral Chinese patent medicine (OCPM) versus oxaliplatin-based chemotherapy regimen (C) alone for colorectal cancer (CRC) through network meta-analysis (NMA).Methods:Several electronic databases were searched for randomized controlled trials (RCTs) concentrated on the use of OCPM to treat CRC with C from the inception of the databases to January 10, 2021. We performed frequentist NMA and indirect comparison to compare study outcomes from the included RCTs. The risk of bias of each study was assessed using the Cochrane risk of bias tool. Confidence in evidence was assessed using Confidence in Network Meta-Analysis (CINeMA).Results:A total of 31 RCTs with 1985 participants comparing 10 OCPM, namely, Antike (ATK), Shenyi (SY), Huachansu (HCS), Boerning (BEN), Xiaoaiping (XAP), Jinlong (JL), Compound matrine (CC), Pingxiao (PX), Xihuang pill (XHW), Kangaiping (KAP) were identified. The methodological quality of included RCTs was not very high. The results of the NMA showed that the comparisons were all indirect. Among diverse OCPM, ATK + C had the highest objective response rate (ORR) with a P-score of .63 with risk ratio (RR) of 1.37 (95% CI 1.12-1.66); with a RR of 1.96 (1.26-3.05), SY + C had the highest performance status with a P-score of .73; KAP + C had the lowest nausea and vomiting with a P-score of .91 and with a RR of 0.29 (0.10-0.79); and JL + C had lowest leukopenia with a P-score of .95 with a RR of 0.47 (0.31-0.72). The results of pairwise comparison suggested no difference in outcomes among 10 kinds of OCPM + C. The comparison-adjusted funnel plots suggested that there might not be small-study effects for outcomes. According to the CINeMa approach, the confidence rating of this NMA ranged from “very low” to “low” for various comparisons.Conclusion:Based on the NMA, ATK + C, SY + C, KAP + C and JL + C were associated with more preferable and options for CRC patients when referring to ORR, performance status, nausea and vomiting, and leukopenia, respectively. However, owing to the limitations of this research, the above conclusions require further verification by more high-quality RCTs.PROSPERO registration:CRD42020160658.

Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results

BackgroundAlthough occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Materials and methodsTreatment consisted of nab-paclitaxel (125/100 mg/m2) plus GEM (1000/800 mg/m2) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m2], 5-FU bolus [400/300/200 mg/m2], 5-FU infusion [2400/2000/1600 mg/m2]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan. ResultsEleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m2, GEM 1000 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2 and 5-FU infusion 2400 mg/m2. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%. ConclusionsThe regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.

Impact of Anatomic Extent of Nodal Metastasis on Adjuvant Chemotherapy Outcomes in Stage III Colon Cancer.

An oxaliplatin-based chemotherapy regimen improves the survival outcomes of patients with stage III colon cancer. However, its complications are well-known. The purpose of this study was to distinguish between the survival outcomes of patients who underwent curative resection for stage III colon cancer with oxaliplatin chemotherapy and those who underwent such resection without oxaliplatin chemotherapy. This was a retrospective analytical study based on prospectively collected data. This study used data on patients who underwent surgery at our hospital between January 2010 and December 2014. A cohort of 254 consecutive patients who underwent curative resection for stage III colon cancer was included in this study. The patients were divided into 2 groups: patients with isolated pericolic lymph node metastasis (n = 175) and those with extrapericolic lymph node metastasis (n = 79). Clinicopathologic features and 3-year survival outcomes were analyzed with and without oxaliplatin therapy in the pericolic lymph node group. The pericolic lymph node group showed significantly improved overall survival compared with the extrapericolic lymph node group at a median follow-up of 48.5 months (95.8% vs 77.8%; p < 0.001). In contrast, there was no significant difference in overall survival (99.0% vs 92.0%; p = 0.137) and disease-free survival (89.1% vs 88.2%; p = 0.460) between the oxaliplatin and nonoxaliplatin subgroups of the pericolic lymph node group. Multivariate analysis showed that the administration of oxaliplatin chemotherapy to the pericolic lymph node group did not lead to a significant difference in the overall survival (p = 0.594). The study was limited by its retrospective design and single institutional data analysis. This study suggests that the anatomic extent of metastatic lymph nodes could affect patient prognosis, and the effect of oxaliplatin-based adjuvant chemotherapy may not be prominent in stage III colon cancer with isolated pericolic lymph node metastasis.

620P - Bevacizumab plus trifluridine/tipiracil in elderly patients with previously untreated metastatic colorectal cancer (KSCC 1602): A single-arm, phase II study

BackgroundElderly patients often cannot tolerate the usual combination of two cytotoxic agents. Recently, bevacizumab plus trifluridine/tipiracil (FTD/TPI) was shown to be a good candidate regimen for vulnerable patients. We aimed to assess the efficacy and safety of bevacizumab plus FTD/TPI in elderly patients with metastatic colorectal cancer. MethodsPatients aged 70 years or older, with previously untreated unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. The treatment consisted of FTD/TPI (35mg/m2, twice daily on Days 1–5 and Days 8–12) with bevacizumab (5mg/kg intravenously on Day 1 and 15), administrated every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). Based on a previous report, we estimated the expected PFS as 9 months and the lower limit of interest as 5 months. As this research was designed to have a statistical power of 80% and one-sided type I error of 0.10, we calculated that 32 patients were required and planned enrolling 35 patients. The secondary endpoints were response rate (ORR), overall survival (OS), and adverse events (AEs). ResultsBetween 2017 January and 2018 March, 39 patients (17 male; 22 female), with a median age of 77.5 years (range: 70–88), ECOG performance status 0 (79.5%) or 1 (20.5%), and RAS WT/MT/Unknown 23.1/41.0/35.9% were enrolled. The median PFS was 8.0 months (80% CI 6.7–11.2), and the median OS was not reached. The best response was 40.5% (15/37; 95% CI: 24.8–57.9), and the disease control rate was 86.5% (32/37; 95% CI: 71.2–95.5). The most frequently occurring grade 3 or 4 AEs were neutropenia (71.8%), leucopenia (48.7%), hypertension (20.5%), anemia (17.9%), anorexia (12.8%), febrile neutropenia (10.3%), and fatigue (10.3%). No treatment-related deaths occurred. ConclusionsIn this Phase 2 KSCC 1602 trial of bevacizumab plus FTD/TPI, the primary endpoint of PFS was achieved. This combination therapy showed favorable survival outcomes with an acceptable safety profile for elderly patients with previously untreated metastatic colorectal cancer. Clinical trial identificationUMIN000025241. Legal entity responsible for the studyKyushu Study group of Clinical Cancer. FundingTaho Pharmaceutical. DisclosureA. Makiyama: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lily Pharmaceutical; Speaker Bureau / Expert testimony: Chugai Pharmaceutical; Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Takeda Pharmaceutical. M. Kotaka: Honoraria (self): Yakult Honsya; Honoraria (self): Chugai pharmaceutical. H. Baba: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Chugai pharmaceutical. M. Mori: Research grant / Funding (institution): Taiho Pharmaceutical Co, Ltd. All other authors have declared no conflicts of interest.

Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies

BackgroundMicrosatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. Patients and methodsPatients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. ResultsAmong 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19–85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69–0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58–1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73–2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67–4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. ConclusionsIn stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. Trial identification numbersNCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.

Prognostic importance of primary tumor location in RAS mutant metastatic colorectal cancer

Objective: The prognostic value of tumor location in patients with metastatic colorectal cancer (mCRC) was reported by recent analyses in RAS wild-type patients. However, there is no enough specific data regarding prognostic value of primary tumor location in RAS mutated mCRC patients. We aimed to find if there is any relation between tumor prognosis and primary tumor location in patients with RAS mutated mCRC. Method: This retrospective study included 57 patients with mCRC who were diagnosed and treated in our hospital between January 2011 and December 2017. Characteristics features of the patients were obtained from our institution patient medical records. Patients were included to the present study if KRAS or NRAS mutation was detected in tumor tissues. Results: Twenty-nine (50.9%) of patients were female and the median age of all patients was 52 (18-80) years. Forty (70.2%) of 57 patients were defined as left side (LS) and 17 (29.8%) of patients were located in the right side (RS). As first line systemic treatment, twenty-five (43.9%) patients had received oxaliplatin-based chemotherapy while 32 (56.1%) patients had received irinotecan-based chemotherapy. Tumor sidedness did not affect on PFS (mPFS, 10.9 months for LS vs 8.1 months for RS, p=0.400) and OS (mOS, 20.9 months for LS vs 20.8 months for RS, p=0.930).The patients who had oxaliplatin based chemotherapy regimens showed better OS rate than irinotecan based regimens (28.7months vs16.3 months, p=0.017, respectively). Conclusion: Our study results support the thought that claims the sidedness of primary CRC in metastatic setting does not have effect on PFS and OS in patients with RAS mutant mCRC. However, our findings also underline the necessity of studies with larger patient populations and subgroup analyzes to evaluate potential prognostic and molecular features to determine the standart approach to this specific subgroup of the disease.