FOLFOX Regimen Research Articles

Evaluation of Standardized Extract of Centella Asiatica on Cell Viability and Repressive Cancer Migration in Metastatic Colorectal Cancer Cells in Vitro

Centella Asiatica has been traditionally used as herbal medicine to treat various disorders, such as ulcers and psoriatic disease. ECa233 is an herbal extract of Centella Asiatica containing madecassoside (46.3 %) and asiaticoside (41.6 %) that shows a highly acceptable safety profile appropriate for drug development and use as an herbal drug for humans. 5-fluorouracil (5-FU) is a chemotherapeutic agent generally known as the first-line chemotherapy for colorectal cancer. Representative combined chemotherapy with 5-FU, namely the FOLFOX regimen (5-FU, leucovorin, oxaliplatin), has been widely used in hospitals and is typically selected as a chemotherapeutic regimen in prescriptions. However, the unresolved problems appearing in clinical situations are the refusal to accept the chemotherapy leading to drug resistance and the severe side effects after being administered intravenously to the entire body. Therefore, the discovery of a novel pure standard agent to enhance the efficacy of 5-FU and overcome this drug resistance still needs to be explored. To assess the pharmacological activity and safety profile of ECa233 is a major goal in cancer drug discovery. ECa233 was evaluated for its anti-cancer, anti-migration, anti-invasive activities and was explored regarding the safety data on normal cells. The results demonstrated that ECa233 effectively inhibited the cell viability, colony forming, and truly inactivated cell migration/invasion through repressive the MMP-9 invasive factor. Pharmacological interaction with 5-FU was synergism in cancer cells and highly safe to normal cell growth. The results suggest that ECa233 could be used as a combinative drug therapy with standard chemotherapy treatment and other medicinal drugs such as a targeted therapy to treat colorectal cancer patients.

Construction of artificial neural network model for predicting the efficacy of first-line FOLFOX chemotherapy for metastatic colorectal cancer

Objective: To explore and establish an artificial neural network (ANN) model for predicting the efficacy of first-line FOLFOX chemotherapy for metastatic colorectal cancer. Methods: A set of FOLFOX chemotherapy data from a group of patients with metastatic colorectal cancer (mCRC) (GSE104645) was downloaded from the GEO database as a training set. According to the FOLFOX protocol, the efficacy was divided into two groups: the chemo-sensitive group (including complete response and partial response) and the chemo-resistant group (including stable disease and progressive disease), including 31 cases in the sensitive group and 23 in the resistant group. Then, chip data (accessible number: GSE69657) from Fujian Medical University Union Hospital were chosen as a test set. A total of 30 patients were enrolled in the study, including 13 in the sensitive group and 17 in the resistant group. The batch effect correction was performed on the expression values of the two sets of matrices using the R 3.5.1 software Combat package. The gene expression difference of sensitive and resistant group in GSE104645 was analyzed by the GEO2R platform. P<0.05 and the absolute value of log(2)FC>0.33 (FC abbreviation of fold change) were used as the threshold value to screen the drug resistance and sensitive genes of the FOLFOX regimen. An ANN was constructed using the multi-layer perceptron (MLP) to perform the FOLFOX regimen on the GSE104645 dataset. The GSE69657 expression matrix and clinical efficacy parameters were then used for retrospective verification. Receiver operating characteristic(ROC) curves were used to evaluate the test results and predictive power. Results: A total of 2, 076 differentially expressed genes in GSE104645 were selected, of which 822 genes were up-regulated and 1, 254 genes were down-regulated in the chemo-resistance group. The down-regulated genes were sensitive genes. GO analysis of the biological processes in which the differentially expressed genes were involved, revealed that they were mainly involved in the regulation of substance metabolism. A total of 39 genes were included in the final model construction. This was a neural network model with two hidden layers. The accuracy of predicting training samples and test samples was 75.7% and 76.5%, respectively, and the area under the ROC curve was 0.875. The chip data set of our department (GSE69657) was set as the test set, and the area under the ROC curve was 0.778. Conclusions: In this study, an artificial neural network model is successfully constructed to predict the efficacy of first-line FOLFOX regimen for metastatic colorectal cancer based on the microarray, and an independent external verification is also conducted. The model has good stability and well prediction efficiency. Besides, the results of this study suggest that the gene functions related to oxaliplatin resistance are mainly enriched in the regulation process of substance metabolism.

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study.

We aim to compare the efficiency and toxicity of three different 5-fluorouracil (5-FU) administration types in 5-FU, leucovorin, and oxaliplatin (FOLFOX) combination treatment for adjuvant therapy in colorectal cancer (CRC). Five hundred and seventy patients with stage III colorectal carcinoma who received different FOLFOX regimens after curative resection were included. Patients were divided into three groups as FOLFOX-4, modified FOLFOX-6 (mFOLFOX-6), and mFOLFOX-4 for comparison of toxicity and disease-free survival (DFS) and overall survival (OS) times. Three-year DFS rates for FOLFOX-4, mFOLFOX-6, and mFOLFOX-4 groups were 65%, 72%, and 72%, respectively. Five-year OS rates for FOLFOX-4, mFOLFOX-6, and mFOLFOX-4 groups were 69%, 75%, and 67%, respectively. There was no statistically significant difference between the three treatment groups in terms of DFS and OS (p = 0.079, and p = 0.147, respectively). Among grade 1-2 adverse events (AE), thrombocytopenia, neuropathy, and stomatitis were more common in the mFOLFOX-6-treated group. The frequency of grade 1-2 nausea and vomiting were similar in mFOLFOX-6 (36.3% and 24%, respectively) and mFOLFOX-4 (32.4% and 24.7%, respectively) groups but were higher than that in the FOLFOX-4 (19.5% and 11.3%, respectively) group. Among the most common grade 3-4 AE, neutropenia (53.4%, 9%, and 13.5%, respectively) and diarrhea (10.5%, 2.2%, and 2.4, respectively) were more common in FOLFOX-4. The rate of anemia and febrile neutropenia was similar in treatment groups (p = 0.063, and p = 0.210, respectively). In the adjuvant treatment of stage III CRC patients, three different 5-FU administration types in FOLFOX combination treatment can be used with similar efficiency and manageable toxicity.

Correlation analysis of adjuvant chemotherapy duration and postoperative death in Chinese patients with colorectal cancer: a retrospective cohort study

IntroductionIt is not known whether adjuvant chemotherapy duration is non-linearly associated with postoperative mortality risk. This study was designed to examine this relationship in Chinese patients with colorectal cancer.Material and methodsThis cohort study was conducted in 1171 participants with stage III and high-risk stage II colorectal cancer, who were treated in China between July 1, 2011, and September 1, 2018. The target independent variable was adjuvant chemotherapy duration, and the dependent variable was postoperative death.ResultsAfter adjusting for confounding factors, an increase in adjuvant chemotherapy duration was negatively correlated with the risk of postoperative death (hazard ratio (HR) = 0.95, 95% confidence interval (CI): 0.900.99). However, a non-linear relationship between therapy duration and postoperative death was observed in the group with bolus and infused fluorouracil with oxaliplatin (FOLFOX). In this group, the incidence of death decreased only when chemotherapy duration was more than 14 weeks (HR = 0.78, 95% CI: 0.630.97). A stronger association between adjuvant chemotherapy duration and postoperative death was detected in the capecitabine and oxaliplatin (CAPOX) group (HR = 0.71, 95% CI: 0.55–0.94) compared with the FOLFOX group (HR = 0.96, 95% CI: 0.92–1.01).ConclusionsThe duration of adjuvant chemotherapy with the FOLFOX regimen is associated with a non-linear reduction in postoperative deaths, which is only apparent after at least 14 weeks of treatment. However, patients with colorectal cancer may receive CAPOX adjuvant treatment for a longer duration.

Predictive value of KRAS mutation and excision repair cross-complementing 1 (ERCC1) protein overexpression in patients with colorectal cancer administered FOLFOX regimen

BackgroundRecent studies have reported that KRAS mutational status is correlated with ERCC1 expression level. The purpose of this study was to determine the clinical significance of the KRAS mutation and ERCC1 overexpression status as predictive factors for resistance against oxaliplatin-based treatment. MethodsWe retrospectively analyzed clinicopathologic features, KRAS mutation status, and ERCC1 overexpression status in 386 patients with colorectal cancer (CRC) who underwent curative-intent surgery. Of these patients, 84 were administered the FOLFOX regimen as a first-line or adjuvant treatment. Disease-free survival and overall survival in groups separated by KRAS and ERCC1 statuses were analyzed. ResultsWild-type KRAS and ERCC1 overexpression were observed in 25.5% of all patients. Among the 84 patients who were treated with the FOLFOX regimen, 73 patients were evaluated for KRAS and ERCC1 status. There were no significant differences in disease-free survival or overall survival in groups separated by KRAS mutation and ERCC1 expression status. Subgroup analysis of patients with wild-type KRAS showed that overall survival in the ERCC1 overexpression group was lower than that of patients in the ERCC1 underexpression group (p = 0.029); however, no significant difference was found in the mutant KRAS patient group (p = 0.671). ConclusionsOur results suggest that CRC with wild-type KRAS and ERCC1 overexpression might be associated with oxaliplatin resistance. When considering oxaliplatin-based chemotherapy, the status of both KRAS mutation and ERCC1 overexpression should be evaluated.

Dihydropyrimidine dehydrogenase level and the redox status in patients with colorectal cancer are prognostic for adverse effects of fluoropyrimidines

Drug resistance and toxicity are the most widespread limitations in the pursuit of sufficient antitumor effectiveness and successful control of oncological diseases, including colorectal cancer (CRC). Herein the objective was to investigate some hematological side effects of the chemotherapeutic regimen FOLFOX-4, their relation to dihydropyrimidine dehydrogenase (DPD) levels and the associated alterations in CRC patients’ plasma free-radical scavenging properties and extent of oxidative molecular damage. Thirty-eight patients with histologically confirmed CRC diagnoses, assigned to chemotherapy with the FOLFOX-4 regimen, were recruited. The diagnostic methods included a complete physical examination, blood routine test and general biochemistry. The DPD levels were assayed. The patients’ plasma free-radical scavenging properties and extent of molecular oxidative damage were determined by spectrophotometry and enhanced chemiluminescence. The clinico-pathological and demographics characteristics of the patients were in agreement with the reports from retrospective cohort studies. The FOLFOX-4 regimen induced a decrease in plasma free-radical scavenging properties and increased extent of lipid peroxidation. White blood cells, granulocytes and lymphocytes decreased significantly after the first cycle of the therapy. The patients’ DPD level decreased statistically significantly in the case of severe reduction (more than 25%) of white blood cells and granulocyte counts. The obtained data are in agreement with already known facts concerning the side effects of the FOLFOX-4 regimen and associated changes in redox homeostasis. Genetic predisposition to effectively metabolize and tolerate the applied therapy, i.e. DPD levels, could modulate some aspects of the observed changes in the aforementioned parameters.

Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma.

Background:Lenvatinib is the first-line treatment for advanced hepatocellular carcinoma, but prognosis is still unsatisfactory. Recently, hepatic arterial infusion chemotherapy (HAIC), and immune checkpoint inhibitors showed promising results for advanced hepatocellular carcinoma. Considering different anti-malignancy mechanisms, combining these three treatments may improve outcomes. This study aimed to compare the efficacy and safety of lenvatinib, toripalimab, plus HAIC versus lenvatinib for advanced hepatocellular carcinoma.Methods:This was a retrospective study including patients treated with lenvatinib [8 mg (⩽60 kg) or 12 mg (>60 kg) once daily] or lenvatinib, toripalimab plus HAIC [LeToHAIC group, lenvatinib 0–1 week prior to initial HAIC, 240 mg toripalimab 0–1 day prior to every HAIC cycle, and HAIC with FOLFOX regimen (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 h, every 3 weeks)]. Progression-free survival, overall survival, objective response rate, and treatment-related adverse events were compared.Results:From February 2019 to August 2019, 157 patients were included in this study: 71 in the LeToHAIC group and 86 in the lenvatinib group. The LeToHAIC group showed longer progression-free survival (11.1 versus 5.1 months, p < 0.001), longer overall survival (not reached versus 11 months, p < 0.001), and a higher objective response rate (RECIST: 59.2% versus 9.3%, p < 0.001; modified RECIST: 67.6% versus 16.3%, p < 0.001) than the lenvatinib group. In addition, 14.1% and 21.1% of patients in the LeToHAIC group achieved complete response of all lesions and complete response of the intrahepatic target lesions per modified RECIST criteria, respectively. Grade 3/4 treatment-related adverse events that were more frequent in the LeToHAIC group than in the lenvatinib group included neutropenia (8.5% versus 1.2%), thrombocytopenia (5.6% versus 0), and nausea (5.6% versus 0).Conclusions:Lenvatinib, toripalimab, plus HAIC had acceptable toxic effects and might improve survival compared with lenvatinib alone in advanced hepatocellular carcinoma.

ВОЗМОЖНОСТИ НУТРИТИВНОЙ ПОДДЕРЖКИ ПРОБИОТИКОМ «БИОВЕСТИН» В БОРЬБЕ С ГАСТРОИНТЕСТИНАЛЬНЫМИ ОСЛОЖ-НЕНИЯМИ У ОНКОЛОГИЧЕСКИХ ПАЦИЕНТОВ В ПЕРИОД ПРОВЕДЕНИЯ ХИМИОТЕРАПИИ

The incidence of oncological pathology in Russia and throughout the world is steadily growing, and the mortality rate is not decreasing either. A large number of locally advanced and neglected cases of cancer of various location are revealed. Treatment of these forms requires polychemotherapy (PCT). The study included 52 patients with oncological pathology of various location: head and neck, stomach, large intestine, they underwent adjuvant chemotherapy according to the PF, TPF and FOLFOX regimens, which include an infusion of 5-fluorouracil for 2–5 days. The study analyzed gastrointestinal toxicity according to CTCAE, version 4.03, 2010. It was revealed that the addition of the probiotic Biovestin to meal reduces gastrointestinal toxicity by 2 times compared with the control group and reduces the risk of interruption of the PCT course by 19 % due to the development of side effects. Thus, the addition of the probiotic Biovestin has shown its effectiveness, safety and simplicity of use in the prevention of gastrointestinal disorders in cancer patients under conditions of PCT.

External validity of clinical trials with diverse trastuzumab-based chemotherapy regimens in advanced gastroesophageal adenocarcinoma: data from the AGAMENON-SEOM registry.

Background:Trastuzumab combined with cisplatin and fluoropyrimidines, either capecitabine or 5-fluorouracile (XP/FP), is the standard first-line treatment for advanced, HER2-positive, gastric cancer patients based on the ToGA trial. Despite the lack of phase III trials, many clinicians administer trastuzumab with alternative regimens. One meta-analysis suggests that substituting cisplatin for oxaliplatin might lead to greater efficacy and less toxicity.Methods:594 patients with HER2-positive gastroesophageal adenocarcinoma were recruited from the AGAMENON-SEOM registry. The objective was to evaluate the external validity of clinical trials with chemotherapy and trastuzumab.Results:The regimens used in at least 5% of the patients were XP (27%), oxaliplatin and capecitabine (CAPOX) (26%), oxaliplatin and 5-fluorouracil (FOLFOX) (14%), FP (14%), triplet with anthracycline/docetaxel (7%), and carboplatin-FU (5%). Median exposure to trastuzumab was longer with FOLFOX (11.4 months, 95% CI, 9.1–21.0) versus ToGA regimens (7.5, 6.4–8.5), p < 0.001. Patients with HER2-IHC 3+ cancers had higher response rates than those with IHC 2+/FISH+, odds-ratio 1.97 (95% CI, 1.25–3.09). The results achieved with CAPOX–trastuzumab were comparable to those attained with ToGA regimens. FOLFOX–trastuzumab was superior to ToGA schemes in terms of overall survival (OS), with a greater magnitude of effect in IHC 2+/FISH+ tumors (HR 0.47, 0.24–0.92) compared with IHC 3+ (HR 0.69, 0.49–0.96), and in diffuse (HR 0.37, 0.20–0.69) versus intestinal-type tumors (HR 0.76, 0.54–1.06).Conclusion:We have updated the external validity of clinical trials with trastuzumab in first-line treatment of gastric cancer. Our data confirm the comparable outcomes of ToGA regimens and CAPOX–trastuzumab in clinical practice and point toward a possible benefit of FOLFOX–trastuzumab, contingent on the subtypes typically less sensitive to trastuzumab, to be confirmed in clinical trials.

CHEMOTHERAPY IN RECTAL CANCER

The aim: To evaluate and analyze early and late results of treatment of patients with rectal cancer after chemotherapy. Materials and methods: The study is based on the results of observation of 779 patients with stage II, III and IV rectal cancer (RC) who were divided into groups according to the chemotherapy treatment. Results: In the course of chemotherapy treatment of RC patients, most of them received the FOLFOX regimen treatment – 87 patients (43.5%). 40 people (20%) received Mayo regimen. 36 patients (18%) underwent FOLFIRI regimen. Another 33 patients received the XELOX regimen chemotherapy (16.5%). In four cases, patients underwent Tegafur monotherapy (2%). Conclusions: The obtained data for patients with stage III RC showed that at all studied time intervals, the highest percentage of surviving patients was recorded in those who received chemotherapeutic treatment according to the FOLFOX regimen. In patients with stage II RC, the most effective was Mejo regimen – 30.7% (survived patients for the 5 year observation).

Current status of doublet combinations of platinum and fluoropyrimidines using oxaliplatin for advanced gastric cancer.

The most common treatment for advanced gastric cancer (AGC) is systemic chemotherapy. The standard treatment for advanced gastric cancer differs worldwide. In Japan, two phase III clinical trials demonstrated the non-inferiority of S-1 compared with 5-fluorouracil (5-FU) and superiority of cisplatin plus S-1 (CS), compared with S-1, with respect to overall survival (SPIRITS trial). Oxaliplatin (L-OHP) has a favorable toxicity profile compared with cisplatin; hence, a phase III clinical trial (G-SOX trial) demonstrated the progression-free survival (PFS) and overall survival in CS was 5.4 and 13.1 months and those in SOX was 5.5 and 14.1 months, respectively. Serious adverse events were more frequently seen in CS than in SOX. So, SOX is as effective as CS for advanced gastric cancer with favorable safety profile. After the publication of this G-SOX trial, the combination of oral or intravenous 5-FU and various doses of L-OHP have been reported. And FOLFOX6 regimen (FOLFOX: a combination of 1-LV and FU with L-OHP) was approved for the treatment of AGC in Japan in 2017. FOLFOX was promising for patients with severe peritoneal metastasis from AGC, because the FOLFOX regimen does not require hydration and does not include oral agents. This review summarizes the efficacy and safety of doublet combinations of platinum and fluoropyrimidines using L-OHP for advanced gastric cancer.

Bevacizumab Plus FOLFOX-4 Combined With Deep Electro-Hyperthermia as First-line Therapy in Metastatic Colon Cancer: A Pilot Study.

Bevacizumab plus FOLFOX-4 regimen represents the first-line therapy in patients affected by metastatic colorectal cancer (mCRC). Hyperthermia has been considered an effective ancillary treatment for cancer therapy through several anti-tumor mechanisms, sharing with Bevacizumab the inhibition of angiogenesis. Up to now, scientific literature offers very few clinical data on the combination of bevacizumab plus oxaliplatin-based chemotherapy with deep electro-hyperthermia (DEHY) for metastatic colon cancer (mCC) patients. Therefore, we aimed at evaluating the efficacy of this combination based on the possible interaction between the DEHY and bevacizumab anti-tumor mechanisms. We conducted a retrospective analysis on 40 patients affected by mCC treated with the combination of bevacizumab plus FOLFOX-4 (fluorouracil/folinic acid plus oxaliplatin) and DEHY (EHY2000), between January 2017 and May 2020. DEHY treatment was performed weekly, with capacitive electrodes at 80–110 W for 50 min, during and between subsequent bevacizumab administrations, on abdomen for liver or abdominal lymph nodes metastases and thorax for lung metastases. Treatment response assessment was performed according to the Response Evaluation Criteria for Solid Tumors (RECIST). The primary endpoints were disease control rate (DCR) and progression-free survival (PFS). The secondary endpoint was overall survival (OS). DCR, counted as the percentage of patients who had the best response rating [complete response (CR), partial response (PR), or stable disease (SD)], was assessed at 90 days (timepoint-1) and at 180 days (timepoint-2). DCR was 95% and 89.5% at timepoint-1 and timepoint-2, respectively. The median PFS was 12.1 months, whereas the median OS was 21.4 months. No major toxicity related to DEHY was registered; overall, this combination regimen was safe. Our results suggest that the combined treatment of DEHY with bevacizumab plus FOLFOX-4 as first-line therapy in mCC is feasible and effective with a favorable disease control, prolonging PFS of 2.7 months with respect to standard treatment without DEHY for mCC patients. Further studies will be required to prove its merit and explore its potentiality, especially if compared to conventional treatment.

Occurrence and Management of Thrombocytopenia in Metastatic Colorectal Cancer Patients Receiving Chemotherapy: Secondary Analysis of Data From Prospective Clinical Trials

IntroductionChemotherapy-induced thrombocytopenia (CIT) contributes to treatment dose delay and/or modification, often resulting in poorer survival and disease progression. We explored the incidence and clinical consequences of CIT among metastatic colorectal cancer (mCRC) patients. Materials and MethodsData from two prospective randomized phase 3 trials of mCRC patients receiving either first-line FOLFOX4 (fluorouracil, leucovorin, oxaliplatin) or second-line FOLFIRI (fluorouracil, leucovorin, irinotecan) were analyzed. Thrombocytopenia was defined by platelet count < 100 × 109/L (further categorized by grade) and by recorded adverse events (AEs). Co-occurrence of anemia (hemoglobin < 12 g/dL) and neutropenia (neutrophil count < 2 × 109/L) and clinical consequences of CIT were also evaluated. ResultsAmong 1078 mCRC patients in the FOLFOX4 study, cumulative incidence of CIT based on platelet count was 37% (grade 3, 2%; grade 4, 1%) during an average 8 months’ follow-up. Neutropenia or anemia were absent in 44% of CIT episodes; 62% of CIT AEs led to chemotherapy dose delay, change, and/or discontinuation. Among 1067 mCRC patients in the FOLFIRI study, cumulative incidence of CIT based on platelet count was 4% (grade 3, < 1%; grade 4, 0) during an average 4 months’ follow-up. Neutropenia or anemia were absent in 22% of CIT episodes; 32% of CIT AEs led to chemotherapy dose delay, change, and/or discontinuation. With both regimens, transfusions and hospitalizations after CIT AEs were rare (< 3%). ConclusionCIT was common among mCRC patients receiving the FOLFOX4 regimen. The most frequent consequence of CIT was a delay in chemotherapy, highlighting the unmet need in CIT management.

Even a partial pathological response is associated with lower relapse rates in patients with operable rectal cancer undergoing neoadjuvant chemotherapy.

Neoadjuvant chemotherapy to treat locally advanced rectal cancer is an effective therapeutic strategy for the prevention of local recurrence and distant organ metastasis after surgery. To assess the prognostic significance of histopathological tumor response in rectal cancer patients undergoing neoadjuvant chemotherapy. This study included patients with operable rectal cancer who received neoadjuvant chemotherapy using the FOLFOX regimen (5-fluorouracil, l-leucovorin, and oxaliplatin) in a hospital between February 2012 and November 2017. The main outcome measure was disease-free survival with respect to histopathological response to neoadjuvant chemotherapy in resected specimens. The median follow-up was 32 months. Of 48 patients treated with neoadjuvant FOLFOX, 24 (50%) were classified as responders, which included two patients with pathological complete response and 22 patients with partial response. The remaining 24 patients (50%) were classified as nonresponders. Responders had a significantly better 3-year disease-free survival than nonresponders (86% vs. 62%, p = .02). Patients whose surgical specimens show a pathological complete response or partial response have good oncologic outcomes.

S2832 Mucinous Signet-Cell Adenocarcinoma of the Ileum: A Diagnostic Challenge

INTRODUCTION: Malignancies of the small intestine are rare, and signet-ring cell carcinoma is one of the rarest forms of adenocarcinoma that can arise in the small bowel. We present a rare case of a patient who originally presented with abdominal pain and radiographic findings suggestive of ileal congestion and question of an infective process concerning for Crohn’s disease (CD). After an extensive work-up including multiple colonoscopies and computerized tomography scans (CT), the patient underwent an exploratory laparotomy and resection of an ileocolic mass was positive for signet ring cell adenocarcinoma. CASE DESCRIPTION/METHODS: A 68-year-old woman with a new diagnosis of Crohn’s disease presented as a transfer for recurrent severe lower-abdominal pain and weight loss. The patient had initially presented to an outside hospital. Family history was positive for CD. The initial CT scan revealed wall thickening and fat stranding of the terminal ileum with right lower quadrant mesenteric lymph nodes. An initial colonoscopy showed a normal colon with superficial, linear erosions in the distal rectum. The patient’s bloodwork was pertinent for an elevated C-reactive protein and calprotectin. Given these findings, the patient was diagnosed with CD and treated. After multiple readmissions for similar pain and a repeat CT scan showing a possible abscess or phlegmon, the patient was transferred. Upon arrival, the patient was hemodynamically stable with unchanged labs. A repeat colonoscopy was performed and a biopsy of the terminal ileum showed mild inflammatory changes and congestion. The pathological analysis confirmed the presence of SRCC. The patient underwent an esophagogastroduodenoscopy (EGD) to assess for malignancy, which was negative. An exploratory laparotomy was performed along with the resection of an ileocolic mass. Pathology confirmed mucinous adenocarcinoma with signet-ring cell differentiation. The patient was started on FOLFOX regimen. She is currently on her third cycle of chemotherapy and doing well with an aim to cure. DISCUSSION: The aforementioned case illuminated the diagnostic challenge of signet-cell adenocarcinoma of the ileum. This case report is important because it highlights the importance of considering malignancy in the differential diagnosis when newly diagnosed inflammatory bowel disease does not respond to treatment. Despite its rarity, clinicians should maintain a suspicion of SRCC in the absence of histological confirmation.Figure 1.: Tubulovillous adenoma. Cecal polyp showing finger-like projections formed by fibrovascular cores and lined by dysplastic epithelium. Invasive carcinoma is noted identified (H&E stain, 20x).Figure 2.: Invasive signet ring cell carcinoma of the colon with extracellular mucin pools. The tumor is seen invading the muscularis propria (arrow). A ruptured abscess is noted within the muscularis next to the invasive carcinoma (arrowhead) (H&E stain, 20x).Figure 3.: Invasive carcinoma showing signet ring cell morphology, at higher magnifications (H&E stain, Figure D: 400x).

S1730 Postpartum Hematochezia in 28-Year-Old Due to Primary Signet Ring Adenocarcinoma of Colon

INTRODUCTION: Colorectal cancer (CRC) is the 3rd leading cause of deaths in the United States.Out of all primary colorectal cancers, adenocarcinoma accounts for the majority of cases.Mucinous and signet ring types are less frequent.Primary signet ring cell carcinoma of the colon is < 1% of all CRC. >96% signet ring carcinoma arise from stomach and rest from other part of GI tract, urinary bladder and breast. CASE DESCRIPTION/METHODS: 29 YO F with no PMH,6 months postpartum, came in with 6 months hx of decreased appetite and 80 lbs weight loss since delivery. Reported intermittent hematochezia with constipation for past 6 months.Reported abdominal pain for few years but never seek medical advice until recently. Used NSAID for almost a year. No Fhx of colon or gastric cancers. Never had colonoscopy or EGD. She is non-smoker and drinks occasionally.CT abd pelvis showed sigmoid wall thickening with para aortic and iliac lymphadenopathy. Her labs were significant with Hb of 9.1 and CEA 384. (AFP- 3.4, CA125 -12.8, CA19-9 -22.4, CA27-29 -37 , CA 15-3 -14.7). Flexible sigmoidoscopy showed ulcerated partially obstructing mass in distal sigmoid colon with 3-4 mm lumen. Biopsy showed adenocarcinoma with signet ring features. Immunohistochemistry tumor cells with CK20+, CDX2+, CK7-, synaptophysin- and chromogranin -.EGD was unremarkable. Pt was diagnosed with M1 disease given para aortic lymphadenopathy.RAS, BRAF, MSI testing is pending.Pt was started on neoadjuvant therapy with FOLFOX regimen given high risk partial obstruction with no clinical signs of obstruction and the plan was follow it with colostomy or stent placement. DISCUSSION: Signet ring carcinoma of colon (SRCC) occurs mostly in young female < 40 YO.SRC cells show high BRAF mutation rate and more prevalent MSI compared to adenocarcinoma. Loss of E cadherin expression is associated with high grade and invasive nature of SRC.Tumor staging is the best predictor of overall prognosis. 5 yr survival rate is 0-12% and disease recurrence is higher compared to adenocarcinoma.Patients with SRCC can benefit from intensified adjuvant chemotherapy given high risk of recurrence and distant metastasis. According to a retrospective study on 22 patients with primary signet ring carcinoma,11 patients were cured with surgical resection.It was found that age, gender,FHx, the size of the tumor, presence of liver metastasis, depth of invasion, and addition of adjuvant as well as neoadjuvant therapies, had no statistically significant effect on the survival period (P > 0.05).

Fluorouracil Supplemented With Oxaliplatin or Irinotecan for Solid Tumors: Indications From Clinical Characteristics and Health Outcomes of Patients.

Fluorouracil combined with oxaliplatin (FOLFOX) and fluorouracil combined with irinotecan (FOLFIRI) are both first-line clinical chemotherapy regimens. However, clinicians' selection of FOLFIRI or FOLFOX medication regimens and their effects on patients' health outcomes are not clear. The aim of this study was to evaluate the impacts on patient characteristics of FOLFIRI or FOLFOX medication regimen selection and the effects of each regimen on patients' health outcomes in a real-world setting. Three thousand seven hundred and twenty-five patients were retrieved and 610 of them were eventually included in this study based on the inclusion and exclusion criteria. The percentages of the TNM stage, cetuximab, bevacizumab, and tumor metastases between the FOLFIRI and FOLFOX groups were different (P < 0.001). In the multivariate Cox proportional hazards model, a significantly higher non-convalescent incidence of the FOLFOX group was found as compared with the FOLFIRI group (HR = 2.211, 95% CI = 1.257–3.888, P = 0.006). In conclusion, the TNM stage, whether combined with cetuximab or bevacizumab, and whether there was tumor metastasis presented as the key factors affecting medication selection between the FOLFIRI and FOLFOX regimens. The FOLFIRI regimen exhibited better effects on patients' long-term health outcomes than did the FOLFOX regimen. This study was registered on the World Health Organization International Clinical Trials Registry Platform (ChiCTR2000029201).Trial registration: ChiCTR2000029201.

ANALYSIS OF SAFETY OF NEOADJUVANT CHEMORADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED GASTRIC CANCER (RESULTS OF A MULTICENTER RANDOMIZED TRIAL)

The purpose of the study was to immediate results of neoadjuvant chemoradiotherapy in patients with locally advanced gastric cancer were analyzed in a multicenter randomized trial. Material and Methods . The comparative analysis of neoadjuvant chemotherapy regimens, toxicity and postoperative complications was carried out. Patients of the study group received conformal radiation therapy (46 Gy in 2 Gy daily fractions) concurrently with chemotherapy with Capecitabine at a dose of 1850 mg/m 2 divided in two equal doses during the course of radiation therapy, and Oxaliplatin at a dose of 85 mg/m 2 on days 1 and 21. After an interval of 4–6 weeks and a control examination, in the absence of evident disease progression, patients were scheduled for surgery (gastrectomy or subtotal gastrectomy with D2 lymph node dissection) and 4 cycles of adjuvant chemotherapy according to the FOLFOX4 or CAPOX regimen. The treatment program for patients in the control group included surgery (gastrectomy or subtotal gastrectomy with D2 lymph node dissection) after randomization, and 6 cycles of adjuvant chemotherapy using the same regimens. The study included 70 patients with an equal distribution between groups. Results . Among the patients of the study group, grade 1 and 2 toxicity was the most common; grade 3 toxicity occurred in 9 cases; grade 4 and 5 toxicity was not observed. Among the manifestations of hematological toxicity, thrombocytopenia and leukopenia were the most common (57–60 % of patients), and grade 3 hematological toxicity was observed in 6 (17.1 %) cases. Among the manifestations of gastrointestinal toxicity, nausea, vomiting and decreased appetite prevailed; grade 3 toxicity was observed only in 3 (8.6 %) cases. The radiation component of neoadjuvant therapy was completed in 32 (91 %) patients. Both protocol-prescribed oxaliplatin infusions were performed in 34 (97 %) patients. Changes in capecitabine administration were required in 8 patients. Immediately before surgery, some patients had grade 1–2 toxicity, which did not prevent performing surgery. There were no statistically significant differences in the frequency and severity of complications in the early postoperative period between the comparison groups. Grade 1–2 postoperative complications were the most common.

Rash and neutropenia after the administration of oxaliplatin and 5-fluorouracil plus calcium folinate injection: a case report

A 56-year-old male patient was admitted due to a "rectal malignant tumor". He suffered from rash and neutropenia after multiple chemotherapy sessions including oxaliplatin, 5-fluorouracil (5- FU), and calcium folinate injection (CF) which are called FOLFOX regimen for short. The rash was treated with methylprednisolone + promethazine + calcium gluconate, and the neutropenia was treated by subcutaneous injection of the Recombinant Human Granulocyte Colony-Stimulating Factor Injection, the symptoms were relieved. Moreover, rashes and neutropenia are known common adverse reactions after intravenous administration of FOLFOX regimen. Based on the patient's symptoms and the timing of drug administration, a diagnosis of "rash and neutropenia due to the use of FOLFOX regimen" was made. Oxaliplatin and CF may also cause allergic reactions, including skin erythema and anaphylactic shock, etc. Once allergic reaction occurs, the fatality rate is higher than that of Penicillin. Therefore, sufficient attention should be paid to the patients reported in this paper who received FOLFOX regimen for multiple times and had multiple rashes and adverse reactions of neutropenia. Medical staff should closely monitored the adverse reactions and changes in vital signs of patients treated with this regimen during chemotherapy, and the chemotherapy regimen should be adjusted or terminated when necessary. The adverse reactions reported in this article deserve clinical attention.

Abstract 561: Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers

Abstract Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types including non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and gastric cancer (GC). SAR408701 is an antibody-drug conjugate (ADC) which consists of anti-CEACAM5 antibody conjugated to the maytansinoid DM4 cytotoxic agent, a highly potent tubulin inhibitor. SAR408701 was investigated in a First in Human trial (FIH) in patients with advanced solid tumors. During the early dose escalation phase, preliminary anti-tumor activity was observed with objective response reported in 3 patients with CRC and 1 patient with GC. In an interim analysis of an ongoing expansion cohort of patients with non-squamous NSCLC and with CEACAM5 expression in ≥ 50% of tumor cells, 25% overall response rate (ORR) (8/32 evaluable patients) and 37.5% (12 patients) stable disease were observed. In parallel to FIH trial, several preclinical studies were performed to support the clinical development of SAR408701 in NSCLC, CRC and GC. A single mouse trial (SMT) was carried out on a panel of 28 patent-derived xenografts (PDX) covering the top 3 indications. The SMT format employs a single mouse per PDX model and treatment arm and uses RECIST criteria as readout. Results showed an efficacy profile in the preclinical trial close to that obtained in clinic with an ORR of 10% in CRC, of 50% in lung cancers and of 37.5% in GC. The efficacy of SAR408701 is correlated with CEACAM5 expression in lung and gastric indications. To further assess the potential of SAR408701 in NSCLC, preclinical investigations have been done to determine if an ADC-DM4 could be beneficially combined with immune checkpoint inhibitors (ICIs). The capacity of DM4-treated tumor cells to immunize immune competent mice to the tumor was evaluated, indicating that DM4 can induce immunogenic cell death. This result supports the development of SAR408701 in combination with ICIs in NSCLC. The combination of SAR408701 with 4 different standard of care (SoC) therapies were tested in 2 CRC PDX models, one sensitive and one resistant to SAR408701 alone. Combinations of SAR408701 were evaluated with either FOLFOX regimen, FOLFIRI regimen, TAS-102 or cetuximab. All combinations resulted in significantly better antitumor activity than single agent arms in both resistant and sensitive PDXs without an increase in toxicity and showed a therapeutic synergy. These results suggest that SAR408701 can be advantageously combined with SoC in gastro-intestinal (GI) cancers. In summary, preclinical data show that SAR408701 displays a strong antitumor activity as a single agent in NSCLC and in combination with SOC in GI cancers, supporting further development in these indications. Furthermore, SAR408701 could be a potential good candidate to be combined with ICIs in NSCLC. Citation Format: Stephanie Decary, Olivier Lemaitre, Anne-Marie Lefebvre, Alexandra Ferrier, Marielle Chiron, Dmitri Wiederschain, Anne-Sophie Lacoste-Bourgeacq, Nathalie Le Bail, Sukhvinder Sidhu, Cecile Combeau, Mustapha Chadjaa, Celine Nicolazzi. Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 561.