Combination Of Oxaliplatin Research Articles

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment.

The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (DLD1, SW620, HCT116, LS174T). Our results confirmed the synergy between folinic acid and 5-fluorouracil and additivity, or even antagonism, between the other drugs of the combination. The drug combination administered at clinical doses resulted in significantly higher antagonistic interactions compared to the low-dose optimized drug combination (ODC). We found that the concomitant administration of the optimized drug combination (ODC) was comparatively active to sequential administration. However, the administration of oxaliplatin or the active metabolite of irinotecan seemed to sensitize the cells to the combination of folinic acid and 5-fluorouracil. ODCs were similarly active in non-cancerous cells as compared to the clinically used doses, indicating a lack of reduction of side effects. Interestingly, ODCs were inactive in CRC cells chronically pretreated with FOLFOXIRI, suggesting the occurrence of resistance. We were unable to improve FOLFOXIRI in terms of efficacy or specificity. Improvement of CRC treatment should come from the optimization of targeted drugs and immunotherapy strategies.

Ursolic acid potentiated oxaliplatin to induce apoptosis in colorectal cancer RKO cells.

Ursolic acid (UA) is found in multiple anticancer herbs and has shown anticancer effects in colorectal cancer (CRC) cells. The present study aimed to observe the effects of a combination of UA and oxaliplatin (Oxa), a frequently used chemotherapeutic drug in CRC, on human CRC RKO cells. The results showed that UA and Oxa synergistically inhibited the proliferation of RKO cells. A combination of UA and Oxa induced apoptosis in RKO cells and increased the activities of caspase-3, caspase-8, and caspase-9. Z-VAD-FMK, a caspase inhibitor, significantly antagonized UA- and Oxa-activated caspase-3, caspase-8, and caspase-9 and induced apoptosis. In addition, UA and Oxa downregulated the expression of X-linked inhibitor of apoptosis (XIAP) and Survivin in RKO cells. These observations suggested that a combination of UA and Oxa elicited synergistically anticancer effects in RKO cells and provided new evidence for potential application of UA and Oxa for CRC treatment.

Ipilimumab or FOLFOX with Nivolumab and Trastuzumab in previously untreated HER2-positive locally advanced or metastatic EsophagoGastric Adenocarcinoma - the randomized phase 2 INTEGA trial (AIO STO 0217)

BackgroundEsophagogastric adenocarcinoma (EGA) currently represents a main cause of cancer related death. Despite an intensified treatment for locally advanced or metastatic EGA with a doublet chemotherapy consisting of a platinum compound and a fluoropyrimidine in combination with trastuzumab for HER2-positive disease or in selected cases with docetaxel, survival remains poor. Recently, immune-oncology based strategies relevantly improved the treatment of different solid tumors and showed some promise in late or later stage trials in EGA. Notably, the combination of immunotherapy with trastuzumab to enhance anti-tumor immunity through activation of innate and adaptive immunity was beneficial in preclinical studies or clinical studies in breast cancer.MethodsThe INTEGA study is an open-label, randomized, multicenter, exploratory phase II trial designed to assess clinical performance, safety and tolerability of ipilimumab or 5-FU/folinic acid and oxaliplatin (FOLFOX) in combination with nivolumab and trastuzumab in patients with previously untreated HER2-positive, locally advanced or metastatic EGA. The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in terms of overall survival. Secondary objectives are safety and tolerability, efficacy in terms of progression-free survival and objective response rate and blood-based signatures (e.g. immune response or suppression of anti-HER2 resistance) that may correlate with treatment response.DiscussionRecent evidence from the phase II NCT02954536 study (oxaliplatin, capecitabine, trastuzumab and pembrolizumab) suggests the clinical feasibility of combining chemotherapy, trastuzumab and checkpoint inhibition in EGA. However, evidence for a chemotherapy-free regimen is also mounting in HER2-positive disease (NCT02689284) i.e. margetuximab and Pembrolizumab. Both studies excelled with high overall response rates and manageable toxicities. The INTEGA study aims to comparatively assess these results and select a promising new 1st line regimen which then needs to be confirmed in a randomized phase III trial. Further, the translational part of the study might help to better stratify patients and tailor treatment of either arm.Trial registrationNCT03409848 24.01.2018.

FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers

Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers. To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX. Starting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. ClinicalTrials.gov Identifier: NCT01928290.

Immunotherapy combining NK and T cell activation with IL-15 super agonist (N-803), off-the-shelf high-affinity CD16 NK (haNK) or PDL1 targeted haNK and checkpoint inhibitor in relapsed/refractory advanced pancreatic cancer.

e15015 Background: Pancreatic cancer is the third leading cause of cancer-related deaths in the US. Patients who relapse after first/second-line chemotherapy have a 2 month median survival. In this relapsed population, there is no approved therapy. Effective response requires a coordinated approach that orchestrates both the innate and adaptive immune system. We hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with clinical benefit. We describe a first-in-human novel combination immunotherapy protocol of chemoradiation, cytokine-induced NK and T cell activation, checkpoint inhibition, and off-the-shelf allogeneic high-affinity NK cell infusion (haNK). We report the first complete response (CR) to an NK-based immunotherapy combination in pancreatic cancer. Methods: QUILT-3.039/3.060/3.070/3.080 enrolled a total of 12 patients (8M/4F), median age 57.5 (35-74), ECOG 0-2) with advanced pancreatic with progressive disease after prior chemotherapy. There were differences in the dose and schedule of agents used across the various protocols. Common elements were: 1. Reduced dose metronomic chemotherapy (combinations of aldoxorubicin, gemcitabine, abraxane, oxaliplatin, 5FU, and cyclophosphamide) 2. SBRT, 3. Avelumab, 4. N803 (IgG1 Fc-engineered IL-15-fusion protein), 5. Allogeneic haNK cells. This experience led to a SPIND substituting allogeneic haNK cells with allogeneic haNK cells targeted against PDL-1. All treatment was in an outpatient setting. A median of 6 cycles of haNK cells (2-15) were delivered for a cumulative median dose of 29.0 x 109 cells per patient (8.0-56.0 x 109). Results: In 12 patients across 4 studies, a median of 6 (2,15) cycles of treatment were delivered, resulting in median PFS of 6.6 mo (3.3-12.4), OS 8.1 mo (5.0-27.0). 11/12 (92%) patients experienced stable disease (SD) for > 8 weeks. 11/12 (92%) also experience at least 1 grade 3 AE: neutropenia (92%), anemia (50%), febrile neutropenia (17%), diarrhea (8%), hyperglycemia (25%), hyponatremia (17%), and elevated alkaline phosphatase (8%). The SPIND patient (79 yo M, ECOG 1) received 7 cycles and achieved a CR by PET with 5 months follow-up to date. No grade 4 AEs were seen. No severe immune related AE’s were seen. Conclusions: Orchestrated immunomodulatory outpatient combination treatment is feasible and results in clinical benefit and CR in selected patients with acceptable toxicity.

Phase II, open-label, randomized study of first-line zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in Claudin 18.2–positive metastatic pancreatic cancer (mPC).

TPS4667 Background: Combinations of folinic acid, fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX) along with GN are standard first-line treatment options for mPC. Despite treatment advances, mPC has a poor prognosis with a 5-year survival rate of < 5%, emphasizing an urgent need for new targeted therapeutics. Claudin 18.2 (CLDN18.2) is a tight junction protein restricted to normal gastric mucosa cells; however, in the context of malignant transformation, CLDN18.2 is frequently expressed in carcinomas derived from organs that do not normally express it, such as pancreatic adenocarcinoma (50-70% express CLDN18.2). Zolbetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2, designed to mediate cancer cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Methods: This phase 2 study (NCT03816163) with a safety lead-in phase will assess safety and antitumor activity of zolbetuximab plus GN in patients (pts) with histologically confirmed mPC with high CLDN18.2 expression (≥75% of tumor cells demonstrate moderate-to-strong IHC staining). The safety lead-in will assess safety/tolerability of zolbetuximab (n = 3 at 1,000 mg/m2 on Cycle 1 Day 1 then 600 mg/m2 Q2W then expand/de-escalate using a 3+3 design) plus GN and confirm the recommended phase 2 dose (RP2D). Dose-limiting toxicities (DLTs), defined as a specified toxicity that occurs during the DLT assessment period and is related to zolbetuximab, will be assessed after Cycle 1 (28 days). After determining the RP2D, approximately 129 pts will be randomly assigned 2:1 to receive either zolbetuximab RP2D Q2W on Days 1 and 15 plus GN on Days 1, 8, and 15 of each cycle ( Arm 1), or GN alone on Days 1, 8, and 15 of each cycle ( Arm 2). Randomization will be stratified by ECOG performance status (0 or 1) and liver metastasis (yes or no). Imaging (CT/MRI) will be performed at baseline and every 8 weeks until investigator-assessed disease progression (per RECIST v1.1 criteria) or the start of other systemic anticancer treatment, whichever comes earlier. Primary objectives are to confirm RP2D (safety lead-in), to assess antitumor activity measured by overall survival (randomization phase), and to establish the safety/tolerability profile of zolbetuximab plus GN across the study. Key secondary endpoints in the randomization phase are progression-free survival and objective response rate. As of January 2020, this study is recruiting pts at 74 centers. Clinical trial information: NCT03816163 .

A new prognostic model for high-grade appendiceal mucinous neoplasms with peritoneal carcinomatosis.

e16718 Background: Peritoneal carcinomatosis of appendiceal origin (PCAO) is a rare malignancy accounting for less than 1% of all cancers. High-grade appendiceal mucinous neoplasms (HAMN) have a poor prognosis and are often treated with cytoreductive surgery (CRS), with hyperthermic intraperitoneal chemotherapy (HIPEC) followed by adjuvant systemic chemotherapy (ASC). Peritoneal cancer index (PCI) and completeness of cytoreduction score (CCR) are useful prognostic tools in patients with PCAO undergoing CRS/HIPEC. However, neither PCI nor CCR take response to ASC into account. Therefore, we propose an enhanced prognostic scoring system (tumor response index, TRI) that incorporates response to ASC as assessed at the completion of treatment. Methods: We retrospectively reviewed the charts of patients with PCAO who received care at the Van Elslander Cancer Center between January 2011 until December 2018. All patients with HAMN who underwent CRS/HIPEC followed by ASC were included. TRI was assessed by comparing the patients' performance status, tumor markers and imaging at the completion of ASC to those prior to the initiation of ASC. A competing risk model, Kaplan-Meier analysis and multivariate Cox regression analysis were used to estimate correlations between TRI and clinical outcomes (PFS and OS). TRI was also compared to PCI and CCR using the Akaike’s Information Criteria (AIC). Results: A total of 84 charts were reviewed. Patients were divided into groups based on their TRI score. The median age was 57 years with 55% females and 85% Caucasians. Approximately 20% of patients had signet-ring features. The most common ASC regimen used was a combination of 5-fluorouracil, oxaliplatin (FOLFOX) and bevacizumab (65%). The table depicts the median PFS and OS of each TRI group. Lower TRI was associated with significantly better PFS and OS. For all outcomes, AIC was substantially reduced by adding TRI to PCI and CCR, suggesting that TRI is a better predictor of PFS and OS. Conclusions: This study proposes TRI as an effective prognostic tool in patients with PCAO and HAMN after CRS/HIPEC/ASC. [Table: see text]

Neutropenia in colorectal cancer treated with oxaliplatin-based hyperthermic intraperitoneal chemotherapy: An observational cohort study.

BACKGROUNDThe implications of neutropenia after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) treatment have never been investigated.AIMTo evaluate the occurrence of neutropenia and its effect on the risk of increased Clavien-Dindo morbidity as well as its effect on overall or disease-free survival.METHODSAll patients with colorectal peritoneal metastases (1996-2015) completing cytoreductive surgery and oxaliplatin-based HIPEC treatment from a bi-institutional database (Uppsala and Sydney) were included in the study. Clavien-Dindo grade 3-4 morbidity differences between the neutropenia group vs non-neutropenia group were calculated and Kaplan-Meier curves with log rank test were rendered. Univariate and multivariable Cox regression models for disease-free survival were implemented.RESULTSTwo hundred and forty-six patients were identified – 32 postoperative any-grade neutropenia patients and 214 non-neutropenia patients. The neutropenia group had more combination oxaliplatin + irinotecan treatment than the non-neutropenia group (66% vs 13%, P = 0.0001). The neutropenia group was not associated with increased Clavien-Dindo grade 3-4 morbidity. Median overall survival was 53 mo vs 37 mo for the neutropenia and non-neutropenia group, P = 0.07. Median disease-free survival was 16 mo vs 11 mo, respectively, P = 0.02. Neutropenia was an independent prognostic factor for disease-free survival with hazard ratio: 0.58, 95% confidence interval: 0.36-0.95, P = 0.03.CONCLUSION13% of patients developed neutropenia which was not associated with increased Clavien-Dindo grade 3-4 morbidity. Neutropenia was an independent positive prognostic factor for disease-free survival and was associated with more intense HIPEC treatment. This is in direct contrast to the current paradigm of decreasing the treatment intensity.

MON-908 Carcinoid Causing Catastrophic Calcemia

Intro: Carcinoid tumors are rare, slow growing, indolent neuroendocrine tumors typically originating from enterochromaffin in the gastrointestinal tract and bronchopulmonary tree1. While often found to be secreting serotonin, many different secretory products have been described2. We present the case of a patient with refractory hypercalcemia due to a carcinoid tumor producing parathyroid hormone related peptide (PTHrP). Case: A 65-year-old male was found to have hypercalcemia of 14.7 mg/dL after presenting for nausea and vomiting. He was treated with Zolendronic acid and intravenous (IV) fluids as initial work-up revealed an appropriately suppressed parathyroid hormone level, no monoclonal spike, and a PTHrP that was dramatically elevated. He refused further work-up initially but was admitted two months later for persistent severe hypercalcemia. Computed tomography imaging showed innumerable liver lesions. Histologic analysis of the largest liver lesion was consistent with carcinoid tumor. For the next two years, he was managed outpatient with Pamidronate, Denosumab, and Sandostatin, along with two liver embolizations. Control of serum calcium levels became more difficult and he had multiple hospitalizations for symptomatic hypercalcemia until chemotherapy, Sunitinib, was initiated. Calcium levels normalized for one year after starting Sunitinib prior to onset of suspected medication-induced pancreatitis. He was switched to Everolimus but did not respond to that and was readmitted mere weeks later for symptomatic hypercalcemia and a combination of Folinic acid, Fluorouracil, and Oxaliplatin (Folfox) was started. He continued to get frequent bisphosphonates and IV fluids along with Folfox but several months later he stopped responding to all medical options. His calcium level climbed to 19.9mg/dL and he underwent a technically complicated surgical procedure in which significant tumor burden was removed from his liver. Since surgery, the patient has remained normocalcemic without additional medical therapy. Discussion: Carcinoid tumors are uncommon with reported incidence of 40 per one million people2. PTHrP is most commonly produced by squamous cell lung cancer, renal cell cancer, gynecologic cancers, and lymphoma3. Carcinoid tumors producing PTHrP with resultant hypercalcemia is rare with a few cases reported in literature4. Our patient had a complex treatment course including IV fluids, anti-resorptive agents, somatostatin analogs, liver embolization, chemotherapeutic agents, and eventual surgical debulking. Surgical intervention is not commonly required for carcinoid tumors5. This patient had a rare tumor, producing an uncommon hormone, and required extensive treatment. This case shows the importance of a multidisciplinary approach in patients with hypercalcemia secondary to carcinoid tumors but refractory to traditional therapy.

MIR600HG suppresses metastasis and enhances oxaliplatin chemosensitivity by targeting ALDH1A3 in colorectal cancer.

Background: Metastasis and chemoresistance indicate a poor prognosis in colorectal cancer (CRC) patients. However, the mechanisms that lead to the development of chemoresistance and metastasis in CRC remain unclear.Materials and methods: We combined clinical and experimental studies to determine the role of MIR600HG in CRC metastasis and chemoresistance. The statistical analysis was performed using GraphPad Prism software, version 8.0.Results: We detected down-regulated expression of long non-coding RNA (lncRNA) MIR600HG in CRC specimens and cell lines compared with normal controls, and the expression level of MIR600HG was inversely correlated with the overall survival of CRC patients. The inhibition of MIR600HG stimulated CRC cell metastasis and chemoresistance. In addition, our data showed that the inhibition of MIR600HG stimulated CRC stemness, while the overexpression of MIR600HG suppressed stemness. Importantly, our animal experiments showed that MIR600HG inhibited tumour formation and that the combination of MIR600HG inhibition and oxaliplatin (Oxa) treatment significantly inhibited tumour growth compared with that with either intervention alone. Furthermore, we demonstrated that MIR600HG exerts its anticancer role by targeting ALDH1A3 in CRC.Conclusions: Our data suggest that MIR600HG functions as a tumour suppressor and that the overexpression of MIR600HG inhibits tumour invasion and enhances chemosensitivity, providing a new strategy for CRC treatment.

Dose and Sequence Dependent Synergism from the Combination of Oxaliplatin with Emetine and Patulin Against Colorectal Cancer.

Colorectal cancer is the third most commonly diagnosed cancer in the world, causing many deaths every year. Combined chemotherapy has opened a new horizon in treating colorectal cancer. The objective of the present study is to investigate the activity of oxaliplatin in combination with emetine and patulin against colorectal cancer models. IC50 values of oxaliplatin, emetine and patulin were determined against human colorectal cancer cell lines (HT-29 and Caco-2) using MTT reduction assay. Synergistic, antagonistic and additive effects from the selected binary combinations were determined as a factor of sequence of administration and added concentrations. Proteomics was carried out to identify the proteins which were accountable for combined drug action applying to the selected drug combination. Oxaliplatin in combination with patulin produced synergism against human colorectal cancer models depending on dose and sequence of drug administration. Bolus administration of oxaliplatin with patulin proved to be the best in terms of synergistic outcome. Altered expressions of nine proteins (ACTG, PROF1, PPIA, PDIA3, COF1, GSTP1, ALDOA, TBA1C and TBB5) were considered for combined drug actions of oxaliplatin with patulin. Bolus administration of oxaliplatin with patulin has the potential to be used in the treatment of colorectal cancer, and would warrant further evaluation using suitable animal model.

β-Sitosterol Reverses Multidrug Resistance via BCRP Suppression by Inhibiting the p53-MDM2 Interaction in Colorectal Cancer.

Phytosterols are widely present in vegetable oils, nuts, cereal products, fruits, and berries. Phytosterol-induced treatment sensitivity has recently shed light on alleviating multidrug resistance in cancer therapy. Here, we demonstrated that β-sitosterol, the most common dietary phytosterol, recovers oxaliplatin (OXA) sensitivity in drug-resistant colorectal cancer (CRC) cells by inhibiting breast cancer resistance protein (BCRP) expression. We further showed evidence that β-sitosterol could activate p53 by disrupting the p53-MDM2 interaction, leading to an increase in p53 translocation to the nucleus and silencing the nuclear factor-κB (NF-κB) pathway, which is necessary for BCRP expression. Finally, we suggested that the combination of OXA and β-sitosterol has a synergistic tumor suppression effect in vivo using a xenograft mouse model. These results revealed that β-sitosterol is able to mediate the p53/NF-κB/BCRP signaling axis to regulate the response of CRC to chemotherapy. The combined application of β-sitosterol and OXA can be a potential way to improve CRC treatment.

Novel treatment of refractory / recurrent pulmonary hepatoblastoma.

There is no consensus about how to manage pulmonary metastasis in patients with hepatoblastoma. We reviewed a treatment with a combination of oxaliplatin, vincristine, and topotecan (OVT) paired with radiofrequency ablation (RFA) of 12 patients with multiple refractory / recurrent pulmonary hepatoblastoma. The medical records from patients with ≤21years of age presenting with multiple deposits (≥2) of refractory / recurrent pulmonary hepatoblastoma were reviewed. The following data were extracted from each patient: age, gender, histological subtyping, cycles of OVT, tumor size, biomarkers, chemotherapy regimen and dosage, RFA details, treatment response, follow up, and patient outcomes. The primary outcome measure was the complete response (CR) of pulmonary diseases, and secondary outcomes were event-free survival rate and overall survival rate. Of 12 assessable patients, three (25%) (95% CI, 46.3-104) patients achieved PR (partial resopnse) after they finished OVT. After RFA, five (41.7%) (95% CI, 8.95-74.4) patients achieved CR (complete response). The 2 year event-free survival rate was 33% (95% CI, 20.5-64.6). The 2 year overall survival for the study group was 41.7% (95% CI, 8.9-74.4). All toxicity events were handled satisfactorily and no toxic related deaths were observed. Our review report shows that OVT combined with RFA can be a successful treatment modality for previously heavily treated refractory / recurrent pulmonary metastatic lesions from hepatoblastoma.

Perioperative docetaxel, oxaliplatin, and capecitabine (DOX) in resectable adenocarcinomas of lower esophagus, esophagogastric junction, and stomach.

349 Background: In a real-world scenario, Fluorouracil-based triplet combination chemotherapies have limited feasibility with regards to toxicity, need for central venous access, and hospitalization. The primary objective of this study was to assess pathological tumor regression to Capecitabine-based triplet regimes, with the additional possible benefit of overcoming the aforementioned barriers. Methods: This Single-Arm, Prospective study investigated the primary outcome of histopathologic regression to perioperative Docetaxel, Oxaliplatin, and Capecitabine (DOX) combination regime in histologically confirmed resectable Esophageal, Esophagogastric Junction, and Gastric Adenocarcinomas. Three preoperative and 3 postoperative cycles of Docetaxel 60mg/m2 plus Oxaliplatin 100mg/m2 on Day 1, with Capecitabine 500mg/m2 twice daily from Day 1 to Day 21 were administered, with cycles repeating every 21 days. Histopathologic regression was assessed by Modified Ryan’s Schema on surgical specimen. The study had an 80% power (two-sided significance of 0.05) to detect a 20% pathological complete response. Secondary endpoints were Overall Survival, Progression-Free Survival, and Toxicity analysis. Results: Between June 2017 to May 2019, 28 patients (median age 54.5 years [Range 33 – 82]; Male 78.6%; ECOG PS 1/2 = 42.9%/57.1%) were enrolled in the study of which 92.9% completed preoperative chemotherapy. Of the 20 patients operated upon, 100% were R0 resections. Pathological complete response was observed in 20% (4/20). Ninety percent of the operated patients completed the postoperative treatment. The most common grade ≥3 toxicities were Palmar-Plantar Erythrodysesthesia (10.7%), Fatigue (10.7%), and Diarrhoea (7.1%). Conclusions: Perioperative DOX met its primary endpoint of 20% pathologic complete regression with a favourable toxicity profile and was feasible to administer in resectable Esophageal, Esophagogastric Junction, and Gastric Adenocarcinomas. This regimen deserves further evaluation in larger phase III trials.

Conversion surgery for advancedgastric cancer with peritoneal metastasis.

450 Background: Patients with peritoneal metastasis have significantly poor prognosis. We have performed pretherapeutic staging laparoscopy (SL) to diagnose peritoneal metastasis for patients with large type 3, type 4 or serosa-invasive gastric cancer. When peritoneal metastasis disappears by chemotherapy for patients with positive peritoneal cytology (CY1) or peritoneal dissemination (P1), we perform the conversion surgery (CS). Methods: We retrospectively analyzed clinical outcomes of 134 patients with advanced gastric cancer who underwent SL between 2005 from 2016. We examined safety and usefulness of CS for patients with CY1 or P1. Results: CY0P0, CY1P0 and P1 were found in 67, 28 and 39 patients, respectively. The median survival time (MST) of patients with CY0P0, CY1P0 and P1 were 39, 21 and 11 months (CY0P0 vs CY1P0; p = 0.029, CY0P0 vs P1; p<0.001, CY1P0 vs P1; p<0.001). In patients with CY1P0, 20 of 26 patients who received chemotherapy underwent the second look SL, and 14 patients (54%) underwent CS (R0) as peritoneal cytology turned negative. These regimens of chemotherapy were S-1/CDDP (n = 9), Docetaxel/CDDP/S-1 (n = 2), SOX (n = 2) and S-1/Docetaxel (n = 1) and the median number of treatment courses was5courses. The MSTs of patients with or without CS were 40 months and 11 months (p<0.001). Then, there was no difference in overall survival between patients with CS and patients with CY0P0 at the first SL (p = 0.866). All patients with P1received chemotherapy, and 11 of these patients underwent the second look SL. As peritoneal metastasis of 7 patients (18%) disappeared by chemotherapy, they underwent CS (R0). The MSTs of patients with or without CS were 31 months and 9 months (p = 0.026). Regarding complications after CS, surgical-site infection and interstitial pneumonia each occurred in one patient (grade II), and intestinal obstruction (grade IIIa) occurred in one patient. There was no mortality. Conclusions: This study suggests that CS is probably safe and may contribute to improve the survival rate of patients with peritoneal metastasis. Moreover, we developed the NSOX regimen, comprised of a combination nab-paclitaxel, S-1 and oxaliplatin, and have performed a phase I/II trial using the NSOX regimen (UMIN000030909).

S-1 Plus Leucovorin and Oxaliplatin in Combination with Lentinan as First-line Therapy in Patients with Metastatic Gastric Cancer

Background: Metastatic gastric cancer has a poor prognosis, despite recent therapeutic improvements. The phase 3 SOLAR study confirmed better efficacy of S-1, oxaliplatin, and leucovorin (SOL) than S-1 plus cisplatin in advanced gastric cancer. Lentinan, (1, 3)-glucan purified from Shiitake mushrooms, has been reported to improve the overall survival of cancer patients receiving chemotherapy. We conducted a preliminary study of SOL combined with lentinan during these 4 years. Methods: The clinical study was approved by the ethics committee of Nagoya Memorial Hospital in 2016. After explaining the protocol of this study, patients with recurrent or unresectable gastric cancer were enrolled, if they had the intention to participate. Medical records were retrospectively reviewed to determine the objective response rate (ORR), disease control rate, overall survival, and adverse effects. Results: Twelve patients (age: 59-81 years; sex: 9 men, 3 women) with metastatic gastric cancer (liver: 3, lung: 2, peritoneal: 12, ascites: 9) were treated with SOL in combination with lentinan as the first-line regimen. The cycles ranged from 4 to 15. The ORR and disease control rates were 58.3% (complete response [CR], 1; partial response, 6) and 91.7%, respectively. One patient with CR survived for > 23 months after the initiation of chemotherapy. Concerning adverse events, peripheral neuropathy was the most common event observed in all patients. However, there were no severe side effects, such as febrile neutropenia and diarrhea. Conclusions: SOL combined with lentinan can be a promising option for the treatment of far advanced metastatic gastric cancer.

STAT3 inhibitory stattic enhances immunogenic cell death induced by chemotherapy in cancer cells.

Induction of immunogenic cell death (ICD) is considered a promising strategy for cancer immunotherapy. Stattic is an inhibitor of STAT3, which is found constitutively active in many cancers and plays a major role in cancer progression. In the present study, we proposed to evaluate whether stattic can enhance the effects of chemotherapy in the induction of ICD in cancer cells harboring hyperactive STAT3. The growth inhibitory effects of stattic and chemo agents including doxorubicin (DOX) and oxaliplatin (OXP) were evaluated using MTT assay in B16F10 and CT26 cell lines. Flow cytometry was applied to study cell apoptosis and calreticulin (CRT) surface exposure. The levels of high mobility group box1 (HGMB1), heat shock protein70 (HSP70) and interleukin-12 (IL-12) were measured using ELISA. Treatment of B16F10 and CT26 cells with stattic in combination with DOX resulted in synergistic antitumor effects with combination index being 0.82 and 0.87, respectively. Interestingly, we found a higher level of ICD markers including CRT expression as well as HMGB1 and HSP70 secretion in the cells received combination therapy of stattic and DOX as compared with monotherapies. Moreover, exposure of dendritic cells (DCs) to conditioned media (CM) from cancer cells treated with stattic and/or DOX resulted in secretion of IL-12, which is an indicator of DCs maturation and induction of Th1 response. OXP and stattic monotherapy induced ICD in CT26 cells and stimulated IL-12 secretion by DCs; however, we did not observe a significant increase in the level of ICD in CT26 cells and IL-12 secretion by DCs when CT26 cells were treated with stattic and OXP combination as compared with monotherapy groups. These findings indicate that STAT3 inhibitory stattic can increase ICD induced by DOX. Graphical abstract.

Capecitabine, Oxaliplatin, Irinotecan, and Bevacizumab Combination Followed by Pazopanib Plus Capecitabine Maintenance for High-Grade Gastrointestinal Neuroendocrine Carcinomas

Gastrointestinal neuroendocrine carcinoma (NEC) is a lethal, uncommon, and understudied neoplasm. We present the efficacy and safety of first-line capecitabine (CP), oxaliplatin, irinotecan, and bevacizumab (CAPOXIRI-BEV) combination followed by pazopanib plus CP maintenance therapy in patients with advanced high-grade poorly differentiated gastrointestinal NEC. This was a two-stage phase II study conducted at multiple institutions. Patients were consecutively enrolled and had advanced NEC of the colon or small bowel. Patients received irinotecan 125 mg/m, oxaliplatin 80 mg/m on day 1, CP 1000 mg/m twice daily on days 1 to 14, plus bevacizumab 8 mg/kg on day 1 for six 21-day cycles. Maintenance therapy was given to those who responded (complete response/partial response) or had stable disease after 6 cycles with CAPOXIRI-BEV with pazopanib 800 mg daily plus CP 1600 mg/m daily on days 1 to 14 every 3 weeks until disease progression or unacceptable toxicity. Patients who progressed on CAPOXIRI-BEV received standard etoposide-carboplatin. The primary endpoint was overall response rate. Twenty-two patients were enrolled of whom 19 were evaluable. The median age was 60 years. The overall response rate (3 complete response/6 partial response) was 47.4% (95% confidence interval: 29.5-76.1), the overall disease control rate was 78.9% (95% confidence interval: 62.6-99.6), and, at median 30 (11 to 41 mo) months' follow-up, 5 patients (26.3%) were still alive. Median progression-free survival was 13 months, and the 1-year progression-free survival rate was 52.6%. The median overall survival was 29 months. The median overall survival of the 9 patients who responded versus those with stable disease/progressive disease was 30.5 versus 14 months, respectively. The median duration of response was 16 months. Predictable toxicity was observed. First-line CAPOXIRI-BEV followed by pazopanib plus CP maintenance therapy for advanced NEC demonstrates promising efficacy and predictable toxicity. Further investigation is warranted.

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

BackgroundCombining anti-cancer therapies with orthogonal modes of action, such as direct cytotoxicity and immunostimulatory, hold promise for expanding clinical benefit to patients with metastatic disease. For instance, a chemotherapy agent Oxaliplatin (OXP) in combination with Interleukin-12 (IL-12) can eliminate pre-existing liver metastatic colorectal cancer and protect from relapse in a murine model. However, the underlying dynamics associated with the targeted biology and the combinatorial space consisting of possible dosage and timing of each therapy present challenges for optimizing treatment regimens. To address some of these challenges, we developed a predictive simulation platform for optimizing dose and timing of the combination therapy involving Mifepristone-induced IL-12 and chemotherapy agent OXP.MethodsA multi-scale mathematical model comprised of impulsive ordinary differential equations was developed to describe the interaction between the immune system and tumor cells in response to the combined IL-12 and OXP therapy. An ensemble of model parameters were calibrated to published experimental data using a genetic algorithm and used to represent three different phenotypes: responders, partial-responders, and non-responders.ResultsThe multi-scale model captures tumor growth patterns of the three phenotypic responses observed in mice in response to the combination therapy against a tumor re-challenge and was used to explore the impacts of changing the dose and timing of the mixed immune-chemotherapy on tumor growth subjected to a tumor re-challenge in mice. An increased ratio of CD8 + T effectors to regulatory T cells during and after treatment was key to improve tumor control in the responder cohort. Sensitivity analysis indicates that combined OXP and IL-12 therapy worked more efficiently in responders by increased priming of T cells, enhanced CD8 + T cell-mediated killing, and functional inhibition of regulatory T cells. In a virtual cohort that mimics non-responders and partial-responders, simulations show that an increased dose of OXP alone would improve the response. In addition, enhanced IL-12 expression alone or an increased number of treatment cycles of the mixed immune-chemotherapy can barely improve tumor control for non-responders and partial responders.ConclusionsOverall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dose and timing in combined cancer treatment strategies.

Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers.

Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers.