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INTRODUCTION: Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy. PATIENTS AND METHODS: We focused on patients who received 12 cycles of FOLFIRINOX (arm A, Nâ =â 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, Nâ =â 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated. RESULTS: Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant. CONCLUSION: Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337).
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Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Irinotecán , Leucovorina , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Masculino , Femenino , Persona de Mediana Edad , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Pronóstico , Calidad de Vida , Oxaliplatino/uso terapéutico , Oxaliplatino/administración & dosificación , Adulto , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. METHODS: This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8-12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). RESULTS: As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0-74.0) and disease control rate of 94.4% (95% CI, 72.7-99.9). CONCLUSIONS: First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04228601.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Anciano , Adenocarcinoma/tratamiento farmacológico , Adulto , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Dosis Máxima Tolerada , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the safety, tolerability, and preliminary efficacy of multiple doses of pegylated irinotecan (JK1201I) as a second-line monotherapy for treating small-cell lung cancer (SCLC) patients. METHODS: According to the "3 + 3" dose-escalation principle, patients received intravenous JK1201I at 180 or 220 mg/m2 once every 3 weeks for four cycles. Progression-free survival (PFS), overall survival (OS), median progression-free survival (mPFS), and median overall survival (mOS) were evaluated. The Kaplan-Meier method was used to analyze PFS and overall OS. Brookmeyer and Crowley's method was used for mPFS and mOS. RESULTS: This study included 29 patients with stage III-IV SCLC (stage IIIa, n = 1; stage IIIb, n = 1; and stage IV, n = 27). Of these, 26 patients were enrolled in the 180 mg/m2 dose group, and 3 patients were enrolled in the 220 mg/m2 dose group. No dose-limiting toxicity (DLT) was noted during the first 28 days of treatment. Grade 3 or higher adverse events were recorded in the 180 mg/m2 group, including diarrhea (11.5%, 3/26), neutropenia (7.7%, 2/26), and leukopenia (7.7%, 2/26). In the 220 mg/m2 group, one patient (33.3%, 1/3) experienced neutropenia or leukopenia. In the 180 mg/m2 group, 38.5% (10/26) of patients achieved an objective response rate (ORR), with a disease control rate (DCR) of 73.1% (19/26). The mPFS and mOS were 3.4 and 12.1 months, respectively. In the 220 mg/m2 group, one patient had stable disease, and one had progressive disease (PD). The ORR, DCR, mPFS, and mOS were 0% (0/3) and 33.3% (1/3), 2.7 months and 2.7 months, respectively. CONCLUSION: JK1201I exhibits promising efficacy and relatively low toxicities as a second-line monotherapy for SCLC, warranting further large-scale clinical studies to evaluate its efficacy in greater detail.
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Irinotecán , Neoplasias Pulmonares , Polietilenglicoles , Carcinoma Pulmonar de Células Pequeñas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Anciano , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Polietilenglicoles/efectos adversos , Adulto , Resultado del Tratamiento , Estadificación de Neoplasias , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. METHODS: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. RESULTS: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. CONCLUSIONS: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Irinotecán , Quinazolinas , Tiofenos , Humanos , Persona de Mediana Edad , Quinazolinas/uso terapéutico , Quinazolinas/efectos adversos , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Anciano , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Tiofenos/uso terapéutico , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Estudios Prospectivos , Adulto , Supervivencia sin Progresión , Adulto JovenRESUMEN
BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic neoplasm. Recently, molecular analysis revealed that PACC shows a high frequency of the BRCA1/2 mutation and is likely to be considered a cancer associated with hereditary breast and ovarian cancer (HBOC). Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors. However, no case reports exist of germline BRCA1-mutated synchronous and metachronous PACC. CASE: A 58-year-old man was diagnosed with synchronous and metachronous PACC at the age of 56 and underwent two surgeries. Ten months after the second surgery, the patient developed multiple liver metastases. Gemcitabine plus nab-paclitaxel therapy was administered as first-line chemotherapy. After seven cycles, computed tomography examination revealed progressive disease (PD). Therefore, modified FOLFIRINOX (mFFX) was administered as second- line chemotherapy. After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP) identified a BRCA1 pathogenic variant that was confirmed to be germline origin. Accordingly, we treated the patient with olaparib; however, he was diagnosed with PD after 4 months. He subsequently died 5 years and 9 months after the initial surgery, and 3 years and 10 months after chemotherapy. Based on the genetic data of the patients, his family members received genetic counseling followed by cascade testing. Consequently, the same gBRCA1 pathogenic variant was detected in the son and his surveillance for HBOC-related cancers was initiated. CONCLUSION: We diagnosed a 58-year-old man with a synchronous and metachronous PACC with germline BRCA1 pathogenic variant. Considering that PACC is likely to have BRCA1/2 mutations responsible for HBOC, we need to be aware of the possible presence of multifocal and/or metachronous tumors in patients with PACC. Additionally, patients with PACC should undergo genetic examinations, which would be beneficial in determining treatment strategies and health care for blood relatives.
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Protocolos de Quimioterapia Combinada Antineoplásica , Proteína BRCA1 , Carcinoma de Células Acinares , Mutación de Línea Germinal , Neoplasias Pancreáticas , Humanos , Persona de Mediana Edad , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteína BRCA1/genética , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/terapia , Oxaliplatino/administración & dosificación , Leucovorina/administración & dosificación , Irinotecán/administración & dosificación , Paclitaxel/administración & dosificación , Fluorouracilo/administración & dosificaciónRESUMEN
PURPOSE: The objective of this study was to determine the recommended Phase 2 dose (RP2D) of pevonedistat, a first in class inhibitor of NEDD8 activating enzyme, in combination with irinotecan (IRN) and temozolomide (TMZ) in children with cancer. METHODS: This Phase 1 study used a rolling 6 design to evaluate escalating doses of pevonedistat in combination with standard doses of IRN and TMZ in pediatric patients with recurrent/refractory solid or CNS tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50 mg/m2) and TMZ (orally, 100 mg/m2), on days 8-12 of a 28-day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN/TMZ on days 1-5 of a 21-day cycle. RESULTS: Thirty patients enrolled; all were eligible and evaluable for toxicity. Six patients each enrolled on pevonedistat dose levels (DL) 1 (15 mg/m2), 2 (20 mg/m2), 3 (25 mg/m2) and 4 (35 mg/m2) as well as an expanded pharmacokinetic (PK) cohort at DL4. The maximum tolerated dose (MTD) was not exceeded. 2/12 (17 %) patients treated at the RP2D (35 mg/m2) experienced a cycle 1 dose limiting toxicity (DLT). IRN is unlikely to affect the pharmacokinetics of pevonedistat. Two patients had a partial response and 6 patients had prolonged stable disease (> 6 cycles). CONCLUSIONS: Pevonedistat in combination with IRN/TMZ is well tolerated in children with solid or CNS tumors. The RP2D of pevonedistat is 35 mg/m2 on days 1, 3, 5 in combination with IRN/TMZ.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ciclopentanos , Neoplasias , Pirimidinas , Humanos , Femenino , Masculino , Niño , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adolescente , Neoplasias/tratamiento farmacológico , Preescolar , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/efectos adversos , Ciclopentanos/administración & dosificación , Ciclopentanos/uso terapéutico , Ciclopentanos/farmacología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Temozolomida/administración & dosificación , Dosis Máxima Tolerada , Resistencia a Antineoplásicos/efectos de los fármacos , Adulto Joven , Proteína NEDD8RESUMEN
BACKGROUND/AIM: Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer. CASE REPORT: A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica , Liasas de Carbono-Azufre , Metionina , Neoplasias Pancreáticas , Humanos , Femenino , Liasas de Carbono-Azufre/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/sangre , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metionina/administración & dosificación , Estadificación de Neoplasias , Biomarcadores de Tumor/sangre , Fluorouracilo/administración & dosificación , Antígeno CA-19-9/sangre , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Administración OralRESUMEN
Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash (n = 1), neutropenia (n = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab , Neoplasias Colorrectales , Irinotecán , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Cetuximab/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Adulto , Repeticiones de Microsatélite/genética , Proteínas ras/genética , Metástasis de la Neoplasia , Receptores ErbB/genéticaRESUMEN
Introduction: In recent years, the development of drug-eluting embolization beads that can be imaged has become a hot research topic in regard to meeting clinical needs. In our previous study, we successfully developed nano-assembled microspheres (NAMs) for multimodal imaging purposes. NAMs can not only be visualized under CT/MR/Raman imaging but can also load clinically required doses of doxorubicin. It is important to systematically compare the pharmacokinetics of NAMs with those of commercially available DC Beads and CalliSpheres to evaluate the clinical application potential of NAMs. Methods: In our study, we compared NAMs with two types of drug-eluting beads (DEBs) in terms of irinotecan, drug-loading capacity, release profiles, microsphere diameter variation, and morphological characteristics. Results: Our results indicate that NAMs had an irinotecan loading capacity similar to those of DC Beads and CalliSpheres but exhibited better sustained release in vitro. Conclusion: NAMs have great potential for application in transcatheter arterial chemoembolization for the treatment of colorectal cancer liver metastases.
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Irinotecán , Microesferas , Imagen Multimodal , Irinotecán/administración & dosificación , Irinotecán/farmacología , Humanos , Imagen Multimodal/métodos , Portadores de Fármacos/química , Liberación de Fármacos , Quimioembolización Terapéutica/métodos , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/farmacologíaRESUMEN
BACKGROUND: Early tumor shrinkage (ETS) is a prognostic predictor for patients treated with chemotherapy in colorectal cancer, although scarce studies evaluated its potential in locally advanced pancreatic cancer (LAPC). In this exploratory analysis of JCOG1407, a randomized phase II study comparing modified 5-fluorouracil, levofolinate, irinotecan, and oxaliplatin (mFOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP), we evaluated whether ETS can predict prognosis of patients with LAPC. METHODS: Of the 126 patients enrolled in JCOG1407, 112 with measurable lesions were included in this study. ETS was defined as a ≥20 % reduction in tumor diameter compared with baseline at the initial imaging assessment 6-10 weeks after initiating chemotherapy. Patients were divided into the ETS (achieved ETS) and non-ETS (failed to achieve ETS) groups based on their ETS status. The impact of ETS on overall survival (OS) was compared using multivariable Cox regression analysis. RESULTS: Fourteen of 55 (25.5 %) and 24 of 57 (42.1 %) patients in the mFOLFIRINOX and GnP arms, respectively, achieved ETS. In the overall population, mFOLFIRINOX arm, and GnP arm, the median OS in the ETS and non-ETS groups was 27.1 and 20.4, 29.8 and 20.6, and 24.1 and 20.4, months, respectively. The adjusted hazard ratios of OS for the ETS group in the overall population, mFOLFIRINOX arm, and GnP arm were 0.451 (95 % confidence interval [CI]: 0.270-0.754), 0.371 (95 % CI: 0.149-0.926), and 0.508 (95 % CI: 0.255-1.004), respectively. CONCLUSIONS: ETS may be a prognostic predictor in chemotherapy-naïve patients with LAPC treated with mFOLFIRINOX or GnP.
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Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Fluorouracilo , Gemcitabina , Irinotecán , Leucovorina , Oxaliplatino , Paclitaxel , Neoplasias Pancreáticas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Oxaliplatino/uso terapéutico , Oxaliplatino/administración & dosificación , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Anciano , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Albúminas/administración & dosificación , Albúminas/uso terapéutico , Pronóstico , Adulto , Resultado del TratamientoRESUMEN
Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7 days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 120 mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150 mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 150 mg/m2).
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Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Combinación de Medicamentos , Gemcitabina , Irinotecán , Oxaliplatino , Ácido Oxónico , Paclitaxel , Neoplasias Pancreáticas , Tegafur , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Masculino , Persona de Mediana Edad , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Albúminas/administración & dosificación , Albúminas/uso terapéutico , Albúminas/efectos adversos , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Oxaliplatino/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Tegafur/administración & dosificación , Tegafur/efectos adversos , Tegafur/uso terapéutico , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Ácido Oxónico/uso terapéutico , AdultoRESUMEN
PURPOSE: In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy. PATIENTS AND METHODS: The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11. RESULTS: The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed. CONCLUSION: The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Irinotecán , Leucovorina , Oxaliplatino , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Femenino , Persona de Mediana Edad , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Anciano , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Adulto , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Supervivencia sin Progresión , Estudios CruzadosRESUMEN
INTRODUCTION: This multicenter phase I/IIa study aimed to determine the recommended phase II dose (RP2D) and evaluate the safety and preliminary efficacy of liposomal irinotecan (nal-IRI), oxaliplatin, and S-1 (NASOX) as first-line treatment for advanced pancreatic adenocarcinoma. METHODS: Patients with locally advanced or metastatic pancreatic adenocarcinoma without prior systemic treatment for advanced disease, aged ≥ 19 years, with measurable disease, and Eastern Cooperative Oncology Group performance status of 0-1 were eligible. The primary endpoints were to determine the dose-limiting toxicity (DLT) in the phase I cohort and overall response rate (ORR) in the phase IIa cohort. The intention-to-treat (ITT) analysis included patients who received the RP2D. RESULTS: In phase I, seven patients were screened, and six were assessed for DLT. None experienced DLT during the first cycle. The RP2D was determined as nal-IRI 50 mg/m2 and oxaliplatin 60 mg/m2 on day 1, S-1 40 mg/m2 twice daily on days 1-7 every 14 days. For the ITT (N = 41; 7, and 34 from phases I and IIa, respectively), the most common grade 3-4 treatment-emergent adverse events were neutropenia (31.7 %), enterocolitis (9.8 %), anorexia (7.3 %), and diarrhea (2.4 %). The ORR was 58.5 % (1 complete, and 23 partial responses). Two underwent conversion surgery; both achieved R0 resection. With median follow-up of 17.5 months, median progression-free survival was 6.5 months (95 % confidence interval [CI], 5.0-8.1) and median overall survival was 11.4 months (95 % CI, 9.8-15.5). CONCLUSION: NASOX exhibited a manageable safety profile and encouraging efficacy outcomes consistent with NALIRIFOX, showing potential to replace infusional 5-fluorouracil with oral S-1 in the triplet regimen.
Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Combinación de Medicamentos , Irinotecán , Oxaliplatino , Ácido Oxónico , Neoplasias Pancreáticas , Tegafur , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Masculino , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Oxaliplatino/efectos adversos , Femenino , Persona de Mediana Edad , Ácido Oxónico/administración & dosificación , Ácido Oxónico/uso terapéutico , Ácido Oxónico/efectos adversos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Tegafur/administración & dosificación , Tegafur/uso terapéutico , Tegafur/efectos adversos , Liposomas , Adulto , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: The standard of care for the treatment of locally advanced rectal cancer (LARC) results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free survival (DFS) and metastasis-free survival (MFS) with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival (OS) is reported here. PATIENTS AND METHODS: The study design, participants, and primary endpoint DFS have been reported for this multicenter, randomized, open-label, phase III trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on magnetic resonance imaging, and staged cT3/T4. Key secondary endpoints included OS, MFS, and local and metastatic recurrence rate. RESULTS: With a median follow-up of 82.2 months, the 7-year DFS was 67.6% [95% confidence interval (CI) 60.7% to 73.9%] and 62.5% (95% CI 55.6% to 68.6%) [restricted mean survival time (RMST) difference 5.73 months, 95% CI 0.05-11.41 months, P = 0.048] in the neoadjuvant chemotherapy and the standard-of-care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0% to 84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8% to 77.8%) in the standard-of-care group (RMST difference 6.1 months, 95% CI 0.93-11.37 months, P = 0.021). The 7-year OS was 81.9% (95% CI 75.8% to 86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7% to 81.2%) in the standard-of-care group (RMST difference 4.37 months, 95% CI 0.35-8.38 months, P = 0.033). The safety profile remained unchanged since the previous analysis. CONCLUSIONS: Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in LARC patients, and should be considered as one of the best options of care for these patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Neoplasias del Recto/mortalidad , Terapia Neoadyuvante/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Fluorouracilo/administración & dosificación , Supervivencia sin Enfermedad , Quimioradioterapia/métodos , Adenocarcinoma/terapia , Adenocarcinoma/patología , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Quimioterapia Adyuvante/métodos , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéuticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Irinotecán , Quinazolinas , Sistema de Registros , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Estudios Prospectivos , Masculino , Femenino , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Persona de Mediana Edad , Anciano , Metástasis de la Neoplasia , Adulto , TiofenosRESUMEN
PURPOSE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. CONCLUSION: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Combinación de Medicamentos , Irinotecán , Pirrolidinas , Timina , Trifluridina , Uracilo , Humanos , Timina/administración & dosificación , Trifluridina/administración & dosificación , Trifluridina/uso terapéutico , Trifluridina/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Persona de Mediana Edad , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/uso terapéutico , Anciano , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Uracilo/análogos & derivados , Uracilo/administración & dosificación , Uracilo/uso terapéutico , Uracilo/efectos adversos , Adulto , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. METHODS: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . DISCUSSION: Building on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).
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Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Neoplasias del Recto/mortalidad , Neoplasias del Recto/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Neoadyuvante/métodos , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Masculino , Femenino , Supervivencia sin Enfermedad , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Capecitabina/administración & dosificación , Capecitabina/uso terapéutico , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Persona de Mediana Edad , Resultado del Tratamiento , Calidad de Vida , Estadificación de Neoplasias , Compuestos OrganoplatinosRESUMEN
OBJECTIVE: Colorectal cancer, one of the most frequently diagnosed cancers worldwide, has a high mortality rate. Thus, our research aims to examine the preventive effects of diosmin (DIO) alone and in conjunction with the anti-cancer drug irinotecan (camptothecin-11, CPT-11), on 1,2-dimethylhydrazine (DMH)-induced colon cancer (CC) in male Wistar rats. MATERIALS AND METHODS: Fifty adult male Wistar rats were categorized into five groups. Group I (Normal) received saline 0.9 orally % as a vehicle once a week for 14 weeks. Group II (DMH) received DMH (20 mg/kg/week) orally dissolved in 0.9% saline for 14 weeks and 1% carboxymethylcellulose (CMC) every other day for the final 10 weeks. Group III (DMH+DIO) received DMH orally for 14 weeks and DIO (10 mg/kg, suspended in 1% CMC) every other day for the final 10 weeks. Group IV (DMH+CPT-11) received DMH orally for 14 weeks and intraperitoneal injection of CPT-11 (3 mg/kg) twice a week for the final 10 weeks. Group V (DMH+DIO+CPT-11) orally received DMH for 14 weeks and both DIO and CPT-11. RESULTS: All treated groups showed a significant reduction (p<0.05) in their elevated serum malondialdehyde levels and significant amelioration (p<0.05) of their lowered activities of colon glutathione-S-transferase (GST) and glutathione reductase (GR) as well as serum glutathione level (GSH). In addition, simultaneous treatment with DIO and CPT-11 led to a significant decrease (p<0.05) in the elevated serum levels of carcinoembryonic antigen (CEA) in rats administered with DMH, as well as a reduction in the colon expression levels of the inflammatory mediator (NF-κB), cell proliferator protein (Ki-67), and proapoptotic protein (p53). CONCLUSIONS: These findings suggest DIO, CPT-11, and their combination have anticarcinogenic effects against DMH-induced CC by suppressing oxidative stress, simulating the antioxidant defense system, attenuating the inflammatory effects, and reducing cell proliferation.
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1,2-Dimetilhidrazina , Neoplasias del Colon , Diosmina , Irinotecán , Ratas Wistar , Animales , Masculino , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Neoplasias del Colon/metabolismo , Ratas , Diosmina/farmacología , Diosmina/administración & dosificación , Irinotecán/farmacología , Irinotecán/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacología , Estrés Oxidativo/efectos de los fármacosRESUMEN
This study aimed to compare second-line treatment outcomes for patients with unresectable pancreatic cancer previously treated with gemcitabine plus nab-paclitaxel (GnP) therapy. We conducted an integrated analysis of two retrospective studies included 318 patients receiving nanoliposomal irinotecan + 5-fluorouracil/folinic acid (NFF) (n = 102), S-1 (n = 57), or FOLFIRINOX (n = 14) as second-line treatment. Median overall survival (OS) in the NFF group was 9.08 months, significantly better than S-1 (4.90 months, P = 0.002). FOLFIRINOX had a median OS of 4.77 months, not statistically different from NFF. Subgroup analyses of OS indicated NFF was generally superior, however, a statistical interaction was observed between the treatment regimen in serum Alb < 3.5 g/dL (P = 0.042) and serum CRP ≥ 0.3 mg/dL (P = 0.006). Median progression-free survival (PFS) was 2.93 months for NFF, significantly better than S-1 (2.53 months, P = 0.024), while FOLFIRINOX had a comparable PFS (3.04 months, P = 0.948). Multivariate analysis identified the serum CRP, serum CA19-9, duration of first-line GnP therapy, and use (yes/no) of S-1 for second-line treatment as independent predictors for OS. This study concludes that second-line NFF therapy demonstrated a more favorable OS compared to S-1 therapy, however, it is still important to consider the patient background characteristics while selecting the most appropriate treatment.
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Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Combinación de Medicamentos , Fluorouracilo , Gemcitabina , Irinotecán , Leucovorina , Oxaliplatino , Paclitaxel , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Anciano , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Albúminas/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Estudios Retrospectivos , Ácido Oxónico/administración & dosificación , Ácido Oxónico/uso terapéutico , Tegafur/administración & dosificación , Tegafur/uso terapéutico , Adulto , Liposomas , Resultado del Tratamiento , Anciano de 80 o más AñosRESUMEN
Colorectal cancer represents a worldwide spread type of cancer and it is regarded as one of the leading death causes, along with lung, breast, and prostate cancers. Since conventional surgical resection and chemotherapy proved limited efficiency, the use of alternative drug delivery systems that ensure the controlled release of cytostatic agents possess immense potential for treatment. In this regard, the present study aimed to develop and evaluate the efficiency of a series of irinotecan-loaded magnetite-silica core-shell systems. The magnetite particles were obtained through a solvothermal treatment, while the silica shell was obtained through the Stöber method directly onto the surface of magnetite particles. Subsequently, the core-shell systems were physico-chemically and morpho-structurally evaluated trough X-ray diffraction (XRD) and (high-resolution) transmission electron microscopy ((HR-)TEM) equipped with a High Annular Angular Dark Field Detector (HAADF) for elemental mapping. After the irinotecan loading, the drug delivery systems were evaluated through Fourier-transform infrared spectroscopy (FT-IR), thermogravimetry and differential scanning calorimetry (TG-DSC), and UV-Vis spectrophotometry. Additionally, the Brunauer-Emmett-Teller (BET) method was employed for determining the surface area and pore volume of the systems. The biological functionality of the core-shells was investigated through the MTT assay performed on both normal and cancer cells. The results of the study confirmed the formation of highly crystalline magnetite particles comprising the core and mesoporous silica layers of sizes varying between 2 and 7 nm as the shell. Additionally, the drug loading and release was dependent on the type of the silica synthesis procedure, since the lack of hexadecyltrimethylammonium bromide (CTAB) resulted in higher drug loading but lower cumulative release. Moreover, the nanostructured systems demonstrated a targeted efficiency towards HT-29 colorectal adenocarcinoma cells, as in the case of normal L929 fibroblast cells, the cell viability was higher than for the pristine drug. In this manner, this study provides the means and procedures for developing drug delivery systems with applicability in the treatment of cancer.