Irinotecan Combination Therapy Research Articles

Therapy-related myeloid neoplasms after treatment for ovarian cancer: A retrospective single-center case series.

Therapy-related myeloid neoplasms (t-MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single-center case series has examined t-MNs in epithelial ovarian cancer (EOC). All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t-MNs. Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow-up period was 45 months (interquartile range, 27-81) months. Ten patients (1.2%) developed t-MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t-MN onset was 42 months (range, 21-94 months), with t-MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1-7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t-MN. All patients died (eight cancer-related deaths and two t-MN-related deaths). None of the patients was able to restart cancer treatment. The median survival time from t-MN onset was 4 months. Patients with EOC who developed t-MN were unable to restart cancer treatment and had a significantly worse prognosis.

The effective combination therapies with irinotecan for colorectal cancer.

Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.

FOLFIRI Chemotherapy for Patients With Metastatic Urachal Carcinoma.

Urachal carcinoma is a rare cancer, with limited evidence regarding systemic chemotherapy for metastatic urachal carcinoma. This study aimed to evaluate the efficacy and safety of a combination therapy of 5-fluorouracil and irinotecan (FOLFIRI) in patients with metastatic urachal carcinoma. Patients with metastatic urachal carcinoma treated with FOLFIRI between March 2008 and April 2023 at the Department of Medical Oncology, Tohoku University Hospital, were retrospectively analyzed using medical records. Six patients with urachal carcinoma received FOLFIRI. The histological type was adenocarcinoma in all patients. The metastatic or recurrent sites were the peritoneum, lungs, lymph nodes, and local relapse sites. Three patients received FOLFIRI as first-line chemotherapy, and the other three received FOLFIRI as second-line chemotherapy. Two patients had only non-measurable lesions as the targets of tumor response. The best response was the stable disease or non-complete response/non-progressive disease in four patients, with a disease control rate of 67%. The median progression-free survival was 7.5 months. In two patients with ascites only as the site of metastasis, the amount of ascites and serum tumor marker levels decreased after FOLFIRI was initiated. Grade 3/4 toxicities included grade 3 neutropenia in one patient and grade 3 diarrhea in one patient. FOLFIRI has modest efficacy and good tolerability for the treatment of metastatic urachal carcinoma.

NCOG-06. BEVACIZUMAB ALONE VERSUS BEVACIZUMAB PLUS IRINOTECAN IN PATIENTS WITH RECURRENT GLIOBLASTOMA: A NATIONWIDE POPULATION-BASED STUDY

Abstract INTRODUCTION There is no established treatment for recurrent glioblastoma. For the treatment of recurrent glioblastoma, the antiangiogenic antibody, bevacizumab, is used either alone or in combination with Irinotecan. This study aimed to compare the survival of patients receiving bevacizumab monotherapy (BEV) and those receiving bevacizumab plus irinotecan combination therapy (B+I) in recurrent glioblastoma (GBM), using a nationwide population-based dataset. METHODS Patients matching the ICD code C71.x were screened from the national database. From January 2008 to November 2021, 846 patients who had undergone surgery or biopsy and received concurrent chemoradiotherapy with Temozolomide were included. Of these, 450 received BEV, while 396 received B+I. The patients' demographic characteristics, inpatient stay duration, prescription frequency, and survival outcomes were compared between the two groups. RESULTS The median overall survival from initial surgery was 22.60 months (9% CI: 20.50 – 24.21) and 20.44 months (95% CI: 18.55 – 22.60) in the BEV and B+I groups, respectively (p=0.5079, log rank test). The BEV group was older and had a higher percentage of females compared to the B+I group. Younger age, female gender, and having surgery rather than biopsy were associated with better prognosis. CONCLUSION This study found no significant difference in overall survival between bevacizumab alone versus bevacizumab plus irinotecan combination therapy in patients with recurrent GBM. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy may be a suitable treatment option.

NCOG-08. BEVACIZUMAB ALONE VERSUS BEVACIZUMAB PLUS IRINOTECAN IN PATIENTS WITH RECURRENT GLIOBLASTOMA: A NATIONWIDE POPULATION-BASED STUDY

Abstract INTRODUCTION There is no established treatment for recurrent glioblastoma. For the treatment of recurrent glioblastoma, the antiangiogenic antibody, bevacizumab, is used either alone or in combination with Irinotecan. This study aimed to compare the survival of patients receiving bevacizumab monotherapy (BEV) and those receiving bevacizumab plus irinotecan combination therapy (B+I) in recurrent glioblastoma (GBM), using a nationwide population-based dataset. METHODS Patients matching the ICD code C71.x were screened from the national database. From January 2008 to November 2021, 846 patients who had undergone surgery or biopsy and received concurrent chemoradiotherapy with Temozolomide were included. Of these, 450 received BEV, while 396 received B+I. The patients' demographic characteristics, inpatient stay duration, prescription frequency, and survival outcomes were compared between the two groups. RESULTS The BEV group was older and had a higher percentage of females compared to the B+I group. The survival analysis revealed no significant difference in survival times between the two groups in the univariate and multivariate analysis. Younger age, female gender, and having surgery rather than biopsy were associated with better prognosis. CONCLUSION This study found no significant difference in overall survival between bevacizumab monotherapy and bevacizumab plus irinotecan combination therapy in patients with recurrent GBM. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy may be a suitable treatment option.

Abstract 2674: Synergistic combinations of lurbinectedin with irinotecan and ONC212 in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with a five-year survival rate below 10% according to the American Cancer Society. Novel chemotherapeutics and targeted therapies in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin is a chemotherapeutic synthetic tetrahydroisoquinoline alkaloid that inhibits active transcription by binding to guanine rich sequences in the minor groove of DNA. Lurbinectedin has been shown to reduce oncogenic transcription by stalling and degrading RNA Polymerase II while also inducing single- and double-stranded breaks to DNA, causing subsequent apoptosis. Lurbinectedin received accelerated FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. We recently described a synergistic interaction between lurbinectedin and ONC201/TIC10, a compound that induces the TRAIL pathway, in killing SCLC cell lines associated with activation of p-Chk1 and the integrated stress response. We now demonstrate lurbinectedin’s efficient killing of pancreatic tumor cells as a single agent in PANC-1, BxPC-3, and HPAF-II cell lines, with IC-50s corresponding to sub-nanomolar concentrations. We also demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells in vitro. We further demonstrate a combination of lurbinectedin and ONC212, an imipridone, the same class of compounds as ONC201, also results in synergistic killing of pancreatic tumor cells. Cell viability was measured using the CellTiterGlo assay at varying drug concentrations. We hypothesize a combination therapy of lurbinectedin and irinotecan or ONC212 can enhance immune cell killing of pancreatic tumor cells. This is being explored by co-culturing CD8+ T lymphoblast cells with pancreatic tumor cells treated with lurbinectedin, irinotecan, ONC212, and combination, along with molecular mechanisms of cell death and effects on cytokines in the tumor microenvironment. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. Citation Format: Tej Tummala, Arielle De La Cruz, Ash Uruchurtu, Nicholas R. Liguori, Abbas E. Abbas, Leiqing Zhang, Christopher G. Azzoli, Lanlan Zhou, Wafik S. El-Deiry. Synergistic combinations of lurbinectedin with irinotecan and ONC212 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2674.

Phase II Study of Ramucirumab Plus Irinotecan Combination Therapy as Second-Line Treatment in Patients with Advanced Gastric Cancer: HGCSG1603

BackgroundRamucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer.Materials and MethodsPatients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug.ResultsThirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%–41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed.ConclusionAlthough the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.

Quality of life and Q-TWiST were not adversely affected in Ewing sarcoma patients treated with combined anlotinib, irinotecan, and vincristine: (Peking University People's Hospital Ewing sarcoma trial-02, PKUPH-EWS-02).

Background:Combined treatment with anlotinib, irinotecan, as well as vincristine for advanced Ewing sarcoma (EWS) has been verified been effective in the prospective trial of Peking University People's Hospital EWS trial-02. We aimed to assess the dynamic changes in health-related quality of life (QoL) and the benefit-risk in quality-adjusted survival in current study.Methods:Twelve “pediatric” patients and 23 “adult” patients were enrolled. QoL was assessed with the EORTC QLQ-C30 for adults and PedsQL 3.0 Cancer Module for children and adolescents. The quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis was used to describe treatment results.Results:Progression-free survival was not accompanied by diminished QoL. Differences in scores on the QoL global health status and specific functioning before, during, and after treatment were not significantly different with time (P = .14 for adults and .91 for children). During treatment, there was a statistically insignificant trend towards improved QoL with reduced tumor burden (P = .14 for adults and .10 for children), but QoL significantly declined with progression of disease (P = .05 for adults and .04 for children). The most common adverse events were neutropenia (12.1%), leukopenia (16.6%), anemia (12.7%), and diarrhea (4.93%). Results across the trial analyses showed that the median time of Q-TWiST was 0.73 (interquartile range, 0–1.57) months, whereas the median time with toxicity before disease progression was 3.9 (interquartile range, 2.3, 6.1).Conclusion:QoL exhibited a trend towards improvement in accordance with high objective response in this trial with the receipt of combination therapy of anlotinib, vinsristine, and irinotecan for advanced EWS. The toxicity profile did not translate into significantly worse overall scores during treatment.

Evaluation of pharmacogenomics and hepatic nuclear imaging-related covariates by population pharmacokinetic models of irinotecan and its metabolites.

Body surface area (BSA)-based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization. Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants. Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%. The identified UGT1A3_c.31T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.

P-97 Updated results of HGCSG1603: A phase 2 trial of ramucirumab plus irinotecan combination therapy as second-line treatment for patients with advanced gastric cancer

Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. We previously reported the efficacy and safety of RAM plus irinotecan (IRI) combination therapy in the second-line treatment for advanced gastric cancer (AGC). This is an updated analysis of the HGCSG1603 trial.

Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first\u2010line treatment for metastatic colorectal cancer: Safety lead\u2010in results from the QUATTRO-II study

SummaryBackground FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

Synergic fabrication of combination therapy of Irinotecan and 5-Fluorouracil encapsulated polymeric nanoparticles for the treatment of gastric cancer therapy

A novel combination therapy for the treatment of gastric cancers has been established using two or more medications with a wide range of mode of actions. The effectiveness of this hybrid drug delivery mechanism involving irinotecan (SN-38) and 5-fluorouracil (5FU) was improved based on their potent anti-tumor capacity, which increased the anticancer property of gastric cells through stabilizing the tumor microenvironment. The encapsulation of SN-38 and 5FU anticancer drugs co-loaded in polyethylene glycol (PEG) and polylactide-co-glycolide (PLGA) nanoparticles (NPs) are incompetent owing to the inadequacy of the dual anticancer drugs SN-38 and 5FU encapsulated in polymeric biodegradable nanoparticles. Transmission microscopy (TEM) was used to examine the morphology of SN-38@NPs, 5FU@NPs, and SN-38-5FU@NPs, and the structure and size of these nanoparticles. Furthermore, the stability of these nanoparticles was assessed using dynamic light scattering (DLS). SN-38-5FU@NPs also induced in vitro apoptosis of human gastric cells, such as NCI-N87 and SGC-791. Morphological shifts and cell death were detected using various biochemical staining, such as Calcein+/PI and Hoechst staining. Additionally, the mechanistic investigation of cell death was verified using flow cytometry in Annex V-FITC. Altogether, this dual drug delivery approach indicates that SN-38-5FU@NPs might be used as a potential tool to improve the effectiveness of gastric cancer therapy.

Results of a phase II trial of ramucirumab plus irinotecan as second-line treatment for patients with advanced gastric cancer (HGCSG 1603).

217 Background: Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. The RAINBOW trial showed RAM plus paclitaxel (PTX) increased overall survival (OS) compared with PTX alone for advanced gastric cancer (AGC) in second-line treatment. WJOG 4007 trial demonstrated equivalent efficacy between irinotecan (IRI) and PTX. We conducted this trial to examine the efficacy and safety of RAM plus IRI combination therapy in the second-line treatment for AGC. Methods: This non-randomized, single arm, phase 2 trial was carried out at 22 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM 8 mg/kg and IRI 150 mg/m2 combination therapy administered every two weeks were continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint was progression-free survival (PFS) rate at six-month, the target was set as 16% with an expected threshold of 39%. A total of 35 cases are planned for registration. The secondary endpoints were OS, PFS, response rate (RR) and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011180029. Results: Between Jan 2018 and Sept 2019, 35 patients were enrolled. Median age was 70 (range, 47-80); female/male were 10/25; ECOG PS 0/1, 22/13. PFS rate at six months was 26.5% (95%C.I., 13.2-41.8%, p = 0.1353). Median PFS and OS were 4.2 (95%C.I., 2.5-5.4 months) and 9.6 months (95%C.I., 6.5-16.6 months), respectively. RR was 26% and disease control rate was 85%. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (51%), leucopenia (43%), anemia (20%), anorexia (14%), febrile neutropenia (11%), diarrhea (9%), hypertension (9%), proteinuria (9%), hypokalemia (9%), hypoalbuminemia (9%), thrombocytopenia (6%), and hyponatremia (6%). No death and new safety signals with a causal relation to study treatment were observed. Conclusions: Although the primary endpoint was not achieved statistically, the results are clinically encouraging, especially take into account that more elderly patients enrolled in this trial. The combination of RAM plus IRI has anti-cancer activity and manageable safety profile in second-line treatment for patients with AGC. Clinical trial information: jRCTs011180029.

1644P Dynamic changes in quality of life and Q-TWiST analysis for Ewing sarcoma patients following anlotinib and irinotecan: A combination of phase Ib and II trial

For advanced Ewing sarcoma (EWS) progression upon first-line chemotherapy, we investigated a novel treatment combination with anti-angiogenesis tyrosine kinase inhibitors (aaTKIs), anlotinib and classic 10-day irinotecan administration strategy in PKUPH-EWS-02. Health-related quality of life (QoL) was an exploratory endpoint in this trial. The objective of this study was to assess dynamic changes in quality of life (QoL) and determine the benefit-risk in terms of quality-adjusted survival for patients using these therapies. QoL was assessed using Questionnaire EORTC QLQ-C30 for adults and PedsQL™ 3.0 Cancer Module for children and adolescents respectively at baseline and at weeks 6, 12, 18, 24 and after progression/off-treatment. The primary QoL endpoint was the dynamic change in QoL scale. The Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to describe treatment results. Compliance with HRQoL assessments was good, ranging from 77.78% of off-treatment/progression to 100% at baseline or other periods. During treatment a tendency of improving QoL could be noticed with alleviation of tumor burden whereas after progression a deterioration of QoL would appear. The Intraclass correlation efficient, ICC of PedsQL™ 3.0 Cancer Module showed good to excellent correlation between child self- and parent proxy-reports (range, 0.636-0.908). Like adults, we did not notice any deterioration of QoL during treatment except for progression. Among the descriptive subscales, no reported significantly worse symptom was noticed. QoL had a trend for improvement in accordance with high objective response in this trial with the receipt of combination therapy of anlotinib and irinotecan for advanced Ewing sarcoma. The toxicity profile of anlotinib and irinotecan was reflected in the patients’ self-reported symptoms but did not translate into significantly worse overall scores during treatment.

Development and In Vitro Evaluation of Long Circulating Liposomes for Targeted Delivery of Gemcitabine and Irinotecan in Pancreatic Ductal Adenocarcinoma.

The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)-based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX-cholesteryl chloroformate lipopolymer conjugate (PETOX-ChC) with a carbonate linkage was prepared and characterized by 1H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze-thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2nm and a zeta potential of - 33.63 ± 1.23mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomesrespectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes.

P-77 Real-world evidence on second-line treatment of fluoropyrimidine, irinotecan, and anti-VEGF antibody for metastatic colorectal cancer

Bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL) have been the mainstay of anti-VEGF treatment for metastatic colorectal cancer (mCRC), and the combination therapy of fluoropyrimidine plus irinotecan with an anti-VEGF antibody has been now widely used for the treatment of second-line mCRC. Although data from routine clinical practice often complement those from clinical trials, real-world evidence (RWE) for these combination therapies has been limited.

A case of chemotherapy for unresectable sigmoid colon cancer with severe cardiac dysfunction

Abstract Background In the treatment of advanced cancer patients with severe cardiac dysfunction, there is a risk that the side effects of the chemotherapy may lead to a serious situation, and it is necessary to carefully judge the indications. There were only a few reported cases of chemotherapy for such patients. Here we report our experience with a patient who had continued chemotherapy for more than a year and a half for advanced sigmoid colon cancer with severe cardiac dysfunction. Case presentation A 73-year-old man came to our hospital because positive fecal occult blood was pointed out in a medical examination in March 2017. He had been diagnosed dilated cardiomyopathy at the age of sixty, and his LVEF was about 25% by the recent echocardiogram. A colonoscopy was performed in May, sigmoid colon cancer was found, and further CT examination was revealed multiple liver metastases. We determined that surgery was not a possible treatment option for him, and we decided to perform chemotherapy. In June we introduced to the patient S-1 plus oxaliplatin combination therapy. We changed to S-1 plus irinotecan combination therapy because of becoming PD from November in the same year. After that SD was maintained for a while, but it became PD by December 2018, and we changed to FTD/TPI as the third line chemotherapy from January 2019. Discussion Median survival of BSC follow-up for unresectable advanced recurrent colorectal cancer was reported to be 6 to 8 months. This case has survived more than a year and a half after starting chemotherapy, suggesting that chemotherapy should be performed as much as possible even for cancer patients with severe cardiac dysfunction. However, there are few such case reports, and it is necessary to accumulate and study more cases from now on.

HGCSG 1603: Phase II study of ramucirumab and irinotecan combination therapy as second-line treatment in patients with metastatic or advanced gastric cancer.

TPS183 Background: As second-line chemotherapy for gastric cancer, a survival benefit has been shown in several clinical trials. Irinotecan and taxanes are recommended as second-line regimen. However, therapeutic outcomes have remained unsatisfactory and more effective treatment are expected. Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody that prevents ligand binding of VEGF-A, VEGF-C, and VEGF-D and the receptor-mediated pathway activation in endothelial cells, subsequently inhibiting neovascularization. In the REGARD study, RAM monotherapy for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma improved median overall survival (mOS) compared with placebo. Moreover, in the RAINBOW study, RAM plus paclitaxel (PTX) versus placebo plus PTX, mOS showed significantly longer in RAM plus PTX group than in placebo plus PTX group. In contrast, there are no data on the efficacy of RAM and irinotecan in the second-line treatment for gastric cancer. The WJOG 4007 study demonstrated an equivalent efficacy between irinotecan and PTX. In this study, we propose to examine the efficacy of RAM plus irinotecan. Methods: This study is carried out as a multicenter, non-randomized, single arm, prospective, phase II study. The patients with metastatic or advanced gastric cancer that is refractory or intolerance to primary chemotherapy are eligible for this study. RAM and irinotecan combination therapy is administered every two weeks, which is continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint is progression-free survival rate at six months, and the secondary endpoints are OS, progression-free survival, response rate, safety, and dose intensity for each drug. A total of 35 cases areplanned for registration. This study is registered with the University Hospital Medical Information Network. Clinical trial information: UMIN000030372.

Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer.

PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n=146) and 2 (n=70); irinotecan cohorts 1 (n=228) and 2 (n=276); and combination cohort (n=230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, P<0.001; OS, 16.9 vs. 31.5 months, HR: 2.38, P=0.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45–0.91, P=0.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47–0.78, P<0.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62–1.02, P=0.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin- or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.

Cetuximab plus irinotecan versus panitumumab in patients with refractory metastatic colorectal cancer in Ontario, Canada.

The addition of irinotecan to an epidermal growth factor receptor (EGFR) antibody has previously been shown to improve tumor response rate and time to progression but not overall survival (OS) for refractory metastatic colorectal cancer (mCRC). We assessed the "real-world" effectiveness and toxicity of the combination versus monotherapy. In Ontario, Canada, universal public funding is available for either cetuximab plus irinotecan (Cmab + I) combination therapy or panitumumab (Pmab) monotherapy, only in patients with refractory nonmutated RAS mCRC. All patients diagnosed before December 2012 and treated with an EGFR antibody for mCRC were identified from the Ontario drug database and linked to the Ontario Cancer Registry and other administrative databases to ascertain baseline characteristics, health services utilization, and outcomes. Multivariable Cox and logistic models were constructed to compare the time to treatment discontinuation (TTD), OS, emergency department (ED) or hospital visits between Cmab + I and Pmab. Observable confounders were adjusted for using propensity score methods. One thousand and eighty-one patients were identified (Cmab + I: 278, Pmab: 803). Patients receiving Cmab + I were younger (mean age 61 vs 64 years) and had a longer duration of prior irinotecan treatment. The use of Cmab + I as compared to Pmab alone was associated with a prolonged TTD [median: 3.8 months vs 2.8 months] and an improved OS [median: 8.8 months vs. 5.9 months] with an adjusted HR of 0.62 [95% CI 0.53-0.73, p < 0.001]. Both treatment regimens afforded similar 14-day mortality and incidence of ED or hospital visits. The findings for patients over and below the age of 65 were similar.