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Journal of Gastrointestinal Oncology Aug 2020There is still no general consensus on the optimal chemotherapeutic agent selection for transcatheter arterial chemoembolization (TACE) in unresectable hepatocellular...
BACKGROUND
There is still no general consensus on the optimal chemotherapeutic agent selection for transcatheter arterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). The present study aimed to compare the efficacy and safety of TACE with raltitrexed plus liposomal doxorubicin (R + PGLD) tegafur plus pirarubicin (T + P) in patients with unresectable HCC.
METHODS
A total of 148 patients with unresectable HCC treated with TACE between January 2012 and December 2016 were retrospectively analyzed. Of them, 74 patients were in the R + PGLD group and 74 patients were in the T + P group (1:1). The treatment response of the tumor, overall survival (OS) time, and adverse effects were compared between the two groups.
RESULTS
There were no significant differences in patient characteristics or embolization effect (lipiodol deposition) between the two groups (P>0.05). R + PGLD treatment had a better clinical efficacy than T + P treatment (OR: 64.9% 45.9%, P=0.031; DC: 89.2% 74.3%, P=0.032). Portal vein invasion, hepatic vein invasion, tumor size and BCLC stage were associated with OR or DC after TACE using R + PGLD treatment. Survival analysis revealed that patients who received TACE with R + PGLD had a better prognosis than those treated with T + P. Moreover, some complications in the R + PGLD group, including vomiting, myelosuppression and cardiotoxicity, were significantly lower than those in the T + P group (P<0.05).
CONCLUSIONS
TACE with raltitrexed and liposomal doxorubicin could reduce the incidence of adverse reactions and significantly improve the OS of patients with unresectable HCC.
PubMed: 32953158
DOI: 10.21037/jgo-20-59 -
British Journal of Clinical Pharmacology Mar 2021Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m every 3 weeks. However, every 2 weeks administration at 2 mg/m demonstrated a favourable toxicity profile.
METHOD
We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m ) and every 3 weeks TOMOX (RTX 3 mg/m ).
RESULTS
A three-compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48-10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates-based dose was calculated, leading to less variability in AUC than observed with the actual BSA-based or fixed doses.
CONCLUSION
These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.
Topics: Cross-Over Studies; Fluorouracil; Humans; Liver; Quinazolines; Thiophenes
PubMed: 32789966
DOI: 10.1111/bcp.14519 -
Cancer Medicine Sep 2020This study aimed to compare the efficacy and toxicity of raltitrexed (Saiweijian ) plus cisplatin (SP regimen) and 5-fluorouracil plus cisplatin (FP regimen) as... (Randomized Controlled Trial)
Randomized Controlled Trial
Raltitrexed versus 5-fluorouracil with cisplatin and concurrent radiotherapy for locally advanced nasopharyngeal carcinoma: An open labeled, randomized, controlled, and multicenter clinical trial.
BACKGROUND
This study aimed to compare the efficacy and toxicity of raltitrexed (Saiweijian ) plus cisplatin (SP regimen) and 5-fluorouracil plus cisplatin (FP regimen) as concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC).
METHODS
Eligible patients (N = 135) were allocated randomly in a ratio of 1:1 to receive CCRT with either SP or FP. At least 2 cycles of chemotherapy was administrated during radiotherapy. Progression free survival (PFS) was primary endpoint. Secondary endpoints included overall survival (OS), loco-regional relapse free survival (LRRFS), distant metastasis free survival (DMFS) and toxicity.
RESULTS
In this study, 68 patients received SP as CCRT, and 67 received FP. Objective responses were noted in 97.1% of the patients in the SP group and in 97.0% of the patients in the FP group (P = 1.00). At the end of a median 36 months follow-up period, the estimated 3-year PFS rates were 70.1% for SP and 66.6% for FP, respectively. The 3-year LRRFS, DMFS and OS rates were 88.9%, 74.7% and 84.0%, respectively, for the SP group, and 92.3%, 71.0% and 73.7%, respectively, for the FP group. Overall, there was no difference between treatment groups with regard to response or survival. The most frequent acute toxicities monitored in both groups were bone marrow suppression, gastrointestinal side effects and oral mucositis (OM). The overall incidence of grade 3-4 OM in the FP group (47.8%) was higher than in the SP group (11.8%). However, the incidence of other adverse effects observed in both groups was similar (P > .05).
CONCLUSIONS
These data indicate that SP and FP therapies have similar efficacy in treating LA-NPC. The SP regimen showed a tolerable safety profile along with a lower frequency of severe OM and therefore, an improved life quality. In conclusion, SP was a well tolerated, effective, regimen for LA-NPC treatment.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chemoradiotherapy; Chi-Square Distribution; Cisplatin; Female; Fluorouracil; Humans; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Progression-Free Survival; Quinazolines; Stomatitis; Thiophenes; Young Adult
PubMed: 32657029
DOI: 10.1002/cam4.3260 -
International Journal of Molecular... Jun 2020There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical...
There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs.
Topics: Antimetabolites, Antineoplastic; Apoptosis; Cell Proliferation; Drug Resistance, Neoplasm; Drug Therapy, Combination; Enzyme Inhibitors; Female; Fluorouracil; Humans; Liposomes; Ovarian Neoplasms; Peptide Fragments; Polyethylene Glycols; Quinazolines; Thiophenes; Thymidylate Synthase; Tumor Cells, Cultured
PubMed: 32585842
DOI: 10.3390/ijms21124452 -
Cancer Science Jul 2020MYCN gene amplification is consistently associated with poor prognosis in patients with neuroblastoma, a pediatric tumor arising from the sympathetic nervous system....
MYCN gene amplification is consistently associated with poor prognosis in patients with neuroblastoma, a pediatric tumor arising from the sympathetic nervous system. Conventional anticancer drugs, such as alkylating agents and platinum compounds, have been used for the treatment of high-risk patients with MYCN-amplified neuroblastoma, whereas molecule-targeting drugs have not yet been approved. Therefore, the development of a safe and effective therapeutic approach is highly desired. Although thymidylate synthase inhibitors are widely used for colorectal and gastric cancers, their usefulness in neuroblastoma has not been well studied. Here, we investigated the efficacies of approved antifolates, methotrexate, pemetrexed, and raltitrexed (RTX), on MYCN-amplified and nonamplified neuroblastoma cell lines. Cell growth-inhibitory assay revealed that RTX showed a superior inhibitory activity against MYCN-amplified cell lines. We found no significant differences in the protein expression levels of the antifolate transporter or thymidylate synthase, a primary target of RTX, among the cell lines. Because thymidine supplementation could rescue the RTX-induced cell growth suppression, the effect of RTX was mainly due to the reduction in dTTP synthesis. Interestingly, RTX treatments induced single-stranded DNA damage response in MYCN-amplified cells to a greater extent than in the nonamplified cells. We propose that the high DNA replication stress and elevated levels of DNA damage, which are a result of deregulated expression of MYCN target genes, could be the cause of increased sensitivity to RTX.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Damage; Dose-Response Relationship, Drug; Gene Amplification; Humans; Metabolic Networks and Pathways; N-Myc Proto-Oncogene Protein; Neuroblastoma; Quinazolines; Thiophenes; Thymidylate Synthase
PubMed: 32415892
DOI: 10.1111/cas.14485 -
Journal of Cancer Research and Clinical... May 2020Hepatic artery infusion (HAI) and drug selection by liquid biopsy precision oncotherapy are under investigation for the multidisciplinary treatment of unresectable... (Observational Study)
Observational Study
Real-life multidisciplinary treatment for unresectable colorectal cancer liver metastases including hepatic artery infusion with chemo-filtration and liquid biopsy precision oncotherapy: observational cohort study.
BACKGROUND
Hepatic artery infusion (HAI) and drug selection by liquid biopsy precision oncotherapy are under investigation for the multidisciplinary treatment of unresectable colorectal liver metastases (CRCLM) in progression after systemic therapy. Here, we compare the safety and efficacy of third-line HAI followed by target therapy with drug regimes selected by liquid biopsy precision oncotherapy to third-line systemic therapy with drug regimes selected partly by tissue biopsy precision oncotherapy, in a retrospective real-life study of 106 unresectable CRCLM patients.
METHODS
Drug regimens for HAI/target therapy were selected by assessing the sensitivity of purified circulating tumor cell (CTCs) to 5-fluorouracil, carboplatin, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, raltitrexed, and melphalan in-vitro and by real-time qRT-PCR gene expression assays, and for the Systemic therapy cohort were selected by age, comorbidity, performance status, and absence of RAS mutations. Therapeutic responses, adverse events, and quality of life were evaluated by RECIST 1.1, CTCAE 4.03, and ECOG criteria, respectively, and chemo-filtration performed following HAI to reduce systemic toxic effects.
RESULTS
HAI/target therapy with drugs selected by liquid biopsy precision oncotherapy (44 patients), resulted in 2.27% CRs, 38.63% PRs, 56.81% SD,s and 2.27% PDs; ECOG 2 to 1 improvement, but no infusion-related technical or vascular complications, or deaths. Systemic therapy (62 patients) resulted in 1.6% CRs, 17.74% PRs, 37.09% SDs, and 45.16% PDs; more grade 1-2 adverse events and 4.84% ECOG 1 to 2 worsening. The median 5 month PFS in the HAI/target therapy cohort was significantly longer than 3 months in the systemic cohort (P < 0.007) and the median 14 month survival in the HAI/target therapy cohort was longer than 8.5 months in the systemic therapy cohort but not statistically significant. Multivariate analysis identified ECOG grade 2 as the most unfavourable survival prognostic factor in both cohorts.
CONCLUSIONS
HAI plus chemo-filtration followed by target therapy, with drug regimens selected by liquid biopsy precision oncotherapy, is a safe and efficacious alternative therapeutic strategy for unresectable CRCLM in progression after two lines of systemic therapy and should be considered for a multicentre prospective phase III study, to fully confirm this potential.
Topics: Aged; Antineoplastic Agents; Cohort Studies; Colorectal Neoplasms; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liquid Biopsy; Liver Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Precision Medicine; Progression-Free Survival; Quality of Life
PubMed: 32088781
DOI: 10.1007/s00432-020-03156-3 -
Experimental Biology and Medicine... Mar 2020Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic...
UNLABELLED
Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs the lifespan of patients with peritoneal carcinomatosis of colorectal origin (CRC-PC), while the drugs used for HIPEC are limited. We investigated the application of recombinant mutant human tumor necrosis factor-α (rmhTNF) combined with raltitrexed in the HIPEC treatment in a mice model with CRC-PC. , we detected the cytotoxicity and apoptosis of human colorectal cancer cells by 3–(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Western blot, and TdT-mediated dUTP Nick End Labeling (TUNEL) assay. , we established xenograft models of CRC-PC and assessed the antitumor effect by imaging, peritoneal cancer index scoring, and TUNEL assay. The results showed that the combination of rmhTNF and raltitrexed under hyperthermia with a temperature of 42°C inhibited the growth of colorectal cancer cells significantly , and after HIPEC treatments with rmhTNF and raltitrexed, peritoneal tumor growth was prohibited . Our findings about the efficacy of rmhTNF and raltitrexed used for HIPEC to treat CRC-PC will provide experimental data and basis for their potential clinical application.
IMPACT STATEMENT
Colorectal peritoneal carcinomatosis exhibits poor prognosis and presents a treatment challenge. At present, the main treatment is surgery, supplemented by hyperthermic intraperitoneal chemotherapy (HIPEC), but the drugs used for HIPEC are limited. Our study found that the combination of recombinant mutant human TNF-α (rmhTNF) and raltitrexed (RTX) under hyperthermia with a temperature of 42°C had antitumor effect both and . The findings will provide experimental data and basis for the potential clinical application of rmhTNF and RTX, which might offer patients a new choice of therapeutic drugs.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma; Colorectal Neoplasms; HCT116 Cells; Humans; Injections, Intraperitoneal; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Peritoneal Neoplasms; Quinazolines; Recombinant Proteins; Thiophenes; Tumor Necrosis Factor-alpha
PubMed: 32041417
DOI: 10.1177/1535370220905047 -
Pharmaceutics Feb 2020Multifunctional nanoparticles (NPs) that enable the imaging of drug delivery and facilitate cancer cell uptake are potentially powerful tools in tailoring oncologic...
Multifunctional nanoparticles (NPs) that enable the imaging of drug delivery and facilitate cancer cell uptake are potentially powerful tools in tailoring oncologic treatments. Here we report the development of a layer-by-layer (LbL) formulation of folic acid (FA) and folate antimetabolites that have been well-established for enhanced tumor uptake and as potent chemotherapeutics, respectively. To investigate the uptake of LbL coated NPs, we deposited raltitrexed (RTX) or combined RTX-FA on fluorescent polystyrene NPs. The performance of these NP formulations was evaluated with CT26 murine colorectal cancer (CRC) cells in vitro and in vivo to examine both uptake and cytotoxicity against CRC. Fluorescence microscopy and flow cytometry indicated an increased accumulation of the coated NP formulations versus bare NPs. Ex vivo near-infrared (NIR) fluorescence imaging of major organs suggested the majority of NPs accumulated in the liver, which is typical of a majority of NP formulations. Imaging of the CRC tumors alone showed a higher average fluorescence from NPs accumulated in animals treated with the coated NPs, with the majority of RTX NP-treated animals showing the consistently-highest mean tumoral accumulation. Overall, these results contribute to the development of LbL formulations in CRC theranostic applications.
PubMed: 32033317
DOI: 10.3390/pharmaceutics12020133 -
Medicine Jan 2020The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable,... (Clinical Trial)
Clinical Trial
BACKGROUND
The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC).
METHODS
Eligible patients were adults with newly diagnosed untreated, unresectable esophageal cancer in stages I to IV with lymph node metastases or cervical esophageal cancer. Patients received nedaplatin 25 mg/m per day on day 1-3, raltitrexed 3 mg/m on days 1 repeated every 21 days for 2 cycles, and combined concurrent radiotherapy (2 Gy/fraction, total dose of 60 Gy).
RESULT
Thirty patients were included with squamous cell carcinoma. The median follow-up duration was 24 months. The overall response rate was 90%. The 1-year and 2-year overall survival rates for all patients were 70.4% and 55.7% with a median survival time of 30 months, and the median progression free survival was 20 month. The major toxicities were leukopenia and thrombopenia, with grade 3 to 4 leukopenia and thrombopenia were 50% and 30% of patients.
CONCLUSION
Concurrent chemoradiotherapy with raltitrexed and nedaplatin agents frequently caused myelosuppression but was highly active and suggested to be a promising treatment option for locally advanced ESCC.
Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Dose-Response Relationship, Radiation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Humans; Longitudinal Studies; Male; Middle Aged; Organoplatinum Compounds; Quinazolines; Retrospective Studies; Thiophenes; Treatment Outcome
PubMed: 31977864
DOI: 10.1097/MD.0000000000018732 -
Anti-cancer Drugs Apr 2020Our retrospective study assessed the efficacy and safety of irinotecan plus raltitrexed in esophageal squamous cell cancer (ESCC) patients who were previously treated...
Our retrospective study assessed the efficacy and safety of irinotecan plus raltitrexed in esophageal squamous cell cancer (ESCC) patients who were previously treated with multiple systemic therapies. Between January 2016 and December 2018, records of 38 ESCC patients who underwent irinotecan plus raltitrexed chemotherapy after at least one line of chemotherapy were reviewed. Efficacy assessment was performed every two cycles according to the RECIST version 1.1. A total of 95 cycles of chemotherapy were administered, and the median course was 3 (range 2-6). There was no treatment-related death. Nine patients had partial response, 21 had stable disease and eight had progressive disease. The overall objective response rate was 23.68% (9/38) and the disease control rate was78.94% (30/38). After a median follow-up of 18.5 months, the median progression-free survival and overall survival were 105 and 221 days, respectively. There were five patients (13.15%) with grade 3/4 leukopenia, three patients (7.89%) with grade 3/4 neutropenia and one patient (2.63%) with grade 3/4 diarrhea. The combination of irinotecan plus raltitrexed was effective for pretreated ESCC patients. Further studies are needed to determine the optimal dose of the two drugs.
Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Follow-Up Studies; Humans; Irinotecan; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Quinazolines; Retrospective Studies; Salvage Therapy; Survival Rate; Thiophenes
PubMed: 31917701
DOI: 10.1097/CAD.0000000000000891