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1.
Oncologist ; 28(6): 551-e454, 2023 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-37053467

RESUMO

BACKGROUND: Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. METHODS: Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. RESULTS: Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. CONCLUSION: No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Docetaxel , Neoplasias Pulmonares/patologia , Fator A de Crescimento do Endotélio Vascular , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ramucirumab
2.
Cancer ; 128(10): 2025-2035, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35195274

RESUMO

BACKGROUND: Cancer cachexia is a syndrome characterized by anorexia and decreased body weight. This study evaluated the efficacy and safety of anamorelin, an orally active, selective ghrelin receptor agonist, in patients with cancer cachexia and a low body mass index (BMI). METHODS: This multicenter, open-label, single-arm study enrolled Japanese patients with non-small cell lung cancer or gastrointestinal cancer with cancer cachexia (BMI < 20 kg/m2 , involuntary weight loss > 2% in the last 6 months, and anorexia). Patients were administered 100 mg of anamorelin once daily for up to 24 weeks. The primary end point was a composite clinical response (CCR) at 9 weeks, which was defined as an increase in body weight of ≥5% from the baseline, an increase of ≥2 points in the score of the 5-item Anorexia Symptom Scale of the Functional Assessment of Anorexia/Cachexia Therapy, and being alive. RESULTS: One hundred two patients were eligible and enrolled. The means and standard deviations for age and BMI were 71.0 ± 8.2 years and 17.47 ± 1.48 kg/m2 , respectively. The CCR rate at 9 weeks was 25.9% (95% confidence interval [CI], 18.3%-35.3%), which met the primary end point with a lower 95% CI exceeding the prespecified minimum of 8%. Improvements in body weight and anorexia were durable and were accompanied by improvements in patients' global impression of change for appetite/eating-related symptoms and overall condition. Adverse drug reactions occurred in 37 of 101 treated patients (36.6%), with the most common being glycosylated hemoglobin increases, constipation, and peripheral edema. CONCLUSIONS: Anamorelin improved body weight and anorexia-related symptoms in patients with cancer cachexia and a low BMI with durable efficacy and favorable safety and tolerability. LAY SUMMARY: Anamorelin is a drug that stimulates appetite and promotes weight gain. This clinical trial was aimed at determining its efficacy and safety in Japanese cancer patients with a low body mass index and cachexia, a syndrome associated with anorexia and weight loss. Anamorelin was found to improve body weight and anorexia-related symptoms in these patients, and these effects were durable for up to 24 weeks. Moreover, anamorelin was generally well tolerated. These findings suggest that anamorelin is a valuable treatment option for patients with cancer cachexia and a low body mass index.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anorexia/tratamento farmacológico , Anorexia/etiologia , Índice de Massa Corporal , Peso Corporal , Caquexia/tratamento farmacológico , Caquexia/etiologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Grelina/análogos & derivados , Humanos , Hidrazinas , Neoplasias Pulmonares/tratamento farmacológico , Oligopeptídeos
3.
Oncologist ; 27(11): 903-e834, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36181763

RESUMO

BACKGROUND: Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. CONCLUSION: Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos/efeitos adversos , Compostos de Anilina/efeitos adversos , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Mutação
4.
Blood Purif ; 51(10): 866-874, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35152211

RESUMO

INTRODUCTION: The bioimpedance spectroscopy (BIS) method is used in individual patients requiring body fluid volume measurement. In a hemodialysis facility, however, regular screening of body fluid volumes is also necessary. Such screening, by kinetic modeling, may become possible by calculating distribution volumes of urea and uric acid from regular blood test results. OBJECTIVE: The aim is to compare uric acid distribution volumes with BIS-extracellular volume, urea distribution volume with BIS-total body water, and difference between urea and uric acid distribution volumes with BIS-intracellular volume. METHODS: We reanalyzed stored blood test data of 53 hemodialysis patients obtained together with BIS data of the same patients in our previous study. RESULTS: Significant correlations were found between urea distribution volume and total body water predicted by the BIS method, between uric acid distribution volume and extracellular volume predicted by the BIS method, and between the difference of uric acid distribution volume from urea distribution volume and intracellular volume predicted by the BIS method. In Bland-Altman analysis, comparison of each pair showed no systematic error. The mean difference between each pair was minimal. CONCLUSION: Fluid volumes in different body compartments can be estimated by kinetic modeling as well as by the BIS method.


Assuntos
Água Corporal , Ácido Úrico , Composição Corporal , Impedância Elétrica , Humanos , Diálise Renal , Análise Espectral/métodos , Ureia
5.
Oncologist ; 25(3): 208-e417, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32162814

RESUMO

LESSONS LEARNED: The biweekly GEM plus CBDCA dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC. The biweekly GEM plus CBDCA regimen could be considered an alternative to the 3-week regimen in NSCLC. BACKGROUND: The gemcitabine (GEM)-carboplatin (CBDCA) combination is widely used for non-small cell lung cancer (NSCLC) and has some efficacy in elderly patients; however, a high incidence of thrombocytopenia is observed, and the optimal dosage and administration schedules are unknown. This multicenter phase II trial evaluated the efficacy and tolerability of GEM-CBDCA for elderly patients with chemotherapy-naive NSCLC. METHODS: Patients with chemotherapy-naive performance status 0-1 and with stage IIIB/IV NSCLC were administered chemotherapy biweekly (GEM 1,000 mg/m2 with CBDCA area under the blood concentration-time curve (AUC) 3 on days 1 and 15 every 4 weeks). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-eight patients were enrolled. Median age was 76 years (range, 70-83); 35 patients were men (73%), and 27 patients had adenocarcinoma (56%). The ORR was 29.2% (95% confidence interval [CI], 17.0-44.1). The median PFS, median OS, and 1-year survival was 5.9 months (95% CI, 4.1-6.6), 13.3 months (95% CI, 8.3-23.5), and 58%, respectively. Grade ≥3 hematological toxicities included neutropenia (29.2%), thrombocytopenia (4.2%), and anemia (20.8%). The incidence of grade ≥3 nonhematological toxicities was <5%. CONCLUSION: This GEM-CBDCA combination administered biweekly showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Resultado do Tratamento , Gencitabina
6.
Oncologist ; 25(8): e1146-e1157, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385918

RESUMO

LESSONS LEARNED: The usefulness of maintenance gemcitabine (GEM) after biweekly carboplatin + GEM in elderly patients with non-small cell lung cancer could not be proved. Superior overall survival was obtained in the group that did not receive maintenance therapy. BACKGROUND: The primary objective of this randomized phase II study was to assess progression-free survival (PFS) in elderly patients with advanced non-small cell lung cancer (NSCLC) treated with gemcitabine (GEM) maintenance therapy versus best supportive care following first-line GEM plus carboplatin (CBDCA). METHODS: Elderly chemotherapy-naive patients with stage IIIB or IV NSCLC were randomly assigned 1:1 to the control arm or the study arm. All patients received biweekly combination therapy with GEM and CBDCA (1,000 mg/m2 GEM and CBDCA at an area under the curve [AUC] of 3 on days 1 and 15, every 4 weeks). In the study arm, patients with objective response or stable disease following three or four cycles of initial chemotherapy received maintenance GEM. RESULTS: Eighty-four patients were enrolled. The objective response rates (ORRs) were 17.5% in the control arm and 14.0% in the study arm. The most common toxicity was neutropenia (control arm: 47.5% and study arm: 69.8%). The median progression-free survivals were 4.99 months (control arm) and 4.44 months (study arm), and the median overall survivals (OSs) were 21.7 months (control arm) and 8.2 months (study arm). CONCLUSION: Our data do not support maintenance GEM after biweekly CBDCA+GEM in elderly patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Resultado do Tratamento , Gencitabina
7.
Oncologist ; 24(11): 1420-e1010, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31332099

RESUMO

LESSONS LEARNED: This clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3-weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non-small cell lung cancer (NSCLC).The weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3-weekly regimen in Japanese patients with NSCLC. BACKGROUND: Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non-small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients. METHODS: Chemonaive patients with IIIB/IV NSCLC and a performance status of 0-1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks). RESULTS: A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression-free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W). CONCLUSION: The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3-weekly regimen in NSCLC treatment.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida
8.
Oncologist ; 24(8): 1033-e617, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31040252

RESUMO

LESSONS LEARNED: In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer. BACKGROUND: Although monotherapy with cytotoxic agents, including docetaxel and pemetrexed, is recommended for patients with previously treated advanced non-small cell lung cancer (NSCLC), its outcomes are unsatisfactory. S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC. METHODS: Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. Primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed. CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Ácido Oxônico/administração & dosagem , Paclitaxel/administração & dosagem , Tegafur/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Anemia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/etiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/efeitos adversos , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Tegafur/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia
9.
Oncologist ; 24(4): 459-e131, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30578309

RESUMO

LESSONS LEARNED: Coadministration of S-1 and paclitaxel in elderly patients with advanced non-small cell lung cancer showed favorable efficacy.Coadministration of S-1 and paclitaxel in elderly patients with advanced non-small lung cancer showed tolerable toxicity. BACKGROUND: Although monotherapy with cytotoxic agents including docetaxel or vinorelbine are recommended for elderly patients with advanced non-small cell lung cancer (NSCLC), the outcome is not satisfactory. We evaluated the efficacy and safety of S-1 and paclitaxel (PTX) as a first-line cotreatment in elderly patients with advanced NSCLC. METHODS: Oral S-1 was administered on days 1-14 every 3 weeks at 80, 100, and 120 mg per day for patients with body surface area < 1.25 m2, 1.25-1.5 m2, and > 1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. The primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Seventeen patients were enrolled with response and disease control rates of 47.1% and 88.2%, respectively. Median PFS and OS were 5.6 and 35.0 months, respectively. Hematological grade 3 or 4 toxicities included leukopenia (55.8%), neutropenia (52.9%), febrile neutropenia (11.8%), and anemia (11.8%). Nonhematological grade 3 toxicities included stomatitis (23.5%), diarrhea (5.9%), and interstitial lung disease (5.9%), and grade 5 toxicities included interstitial lung disease (5.9%). CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Ácido Oxônico/administração & dosagem , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida , Tegafur/administração & dosagem
10.
Oncologist ; 24(5): 593-e170, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30651400

RESUMO

LESSONS LEARNED: Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients.In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population.Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. BACKGROUND: Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. RESULTS: A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%-72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1-82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. CONCLUSION: Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/farmacologia , Idoso , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Progressão da Doença , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade
11.
Invest New Drugs ; 37(2): 291-296, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30121935

RESUMO

This phase I study was aimed at determining the maximum tolerated dose (MTD) and recommended dose (RD) for oral S-1 plus paclitaxel combination therapy in elderly patients with non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients (age, >70 years) with stage III/IV NSCLC were treated with paclitaxel intravenously at four dose levels (DLs), 60, 70, 80, and 90 mg/m2, on day 1 and 8, and with S-1 (80 mg/m2) orally on days 1-14 every 3 weeks. MTD was defined as the dose at which two of the initial three patients experienced dose-limiting toxicities (DLTs). Three patients were added when the initial three patients experienced DLTs. The dose administered in three of the six patients with DLTs met the definition of MTD. The RD was defined as a dose 1 DL below the MTD. Fifteen patients including six on DL 1 and three each on DLs 2, 3, and 4 were enrolled. One patient experienced a DLT (febrile neutropenia) at DL 1. The remaining DLTs were noted at DL 4 (in one patient each): febrile neutropenia, grade (G) 3 skin rash, G3 diarrhea, G3 stomatitis, and G3 international normalized ratio (INR) elevation. The MTD of paclitaxel was 90 mg/m2. The RD for both S-1 and paclitaxel was 80 mg/m2 (DL 3). The response rate was 45.5% (8 of 15 patients achieved a partial response). In conclusion, the RD of both S-1 and paclitaxel was 80 mg/m2 in the combination therapy for chemotherapy-naïve patients with advanced NSCLC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Ácido Oxônico/administração & dosagem , Paclitaxel/administração & dosagem , Prognóstico , Tegafur/administração & dosagem , Distribuição Tecidual
12.
Cancer ; 124(3): 606-616, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29205286

RESUMO

BACKGROUND: Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO-7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia. METHODS: This double-blind clinical trial (ONO-7643-04) enrolled 174 patients with unresectable stage III/IV non-small cell lung cancer (NSCLC) and cachexia in Japan. Patients were randomized to daily oral anamorelin (100 mg) or a placebo for 12 weeks. The primary endpoint was the change from the baseline LBM (measured with dual-energy x-ray absorptiometry) over 12 weeks. The secondary endpoints were changes in appetite, body weight, quality of life, handgrip strength (HGS), and 6-minute walk test (6MWT) results. RESULTS: The least squares mean change (plus or minus the standard error) in LBM from the baseline over 12 weeks was 1.38 ± 0.18 and -0.17 ± 0.17 kg in the anamorelin and placebo groups, respectively (P < .0001). Changes from the baseline in LBM, body weight, and anorexia symptoms showed significant differences between the 2 treatment groups at all time points. Anamorelin increased prealbumin at weeks 3 and 9. No changes in HGS or 6MWT were detected between the groups. Twelve weeks' treatment with anamorelin was safe and well tolerated in NSCLC patients. CONCLUSIONS: Anamorelin significantly increased LBM and improved anorexia symptoms and the nutritional state, but not motor function, in Japanese patients with advanced NSCLC. Because no effective treatment for cancer cachexia is currently available, anamorelin can be a beneficial treatment option. Cancer 2018;124:606-16. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.


Assuntos
Caquexia/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hidrazinas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Idoso , Composição Corporal/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Método Duplo-Cego , Feminino , Humanos , Hidrazinas/efeitos adversos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos
13.
Invest New Drugs ; 36(5): 903-910, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29846848

RESUMO

Background A global multicenter study demonstrated superiority of carboplatin + nab-paclitaxel (PTX) therapy compared to carboplatin + PTX in terms of response rate (RR) and non-inferiority in terms of progression free survival (PFS) and overall survival (OS) in untreated patients with stage IIIB/IV non-small cell lung cancer; no clinical findings have so far been reported on maintenance therapies with nab-PTX. The aim of this study was to determine the efficacy and safety of maintenance therapy with nab-PTX following carboplatin + nab-PTX combination therapy. Methods Carboplatin (AUC 6) was administered on Day 1; and nab-PTX 100 mg/m2 on Days 1, 8, and 15, and dosing was repeated in 4 courses of 4 weeks each. In patients with clinical response was observed at the end of the 4th course, nab-PTX maintenance therapy was repeated. Results Out of 39 patients included in the efficacy analysis, 19 (48.7%) patients completed the induction therapy and 15 (38.5%) were transitioned to maintenance therapy. The median PFS in the maintenance phase was 6.5 (90%CI 1.4-11.4) months. The median OS in 15 patients was 12.6 (95%CI: 7.4-not reached). Grade ≥ 3 toxicities observed in more than 5% of patients were neutropenia (55.0%), anemia (15.0%), and febrile neutropenia (5.0%), with no increase during the maintenance phase. Conclusions Although statistically significance was not demonstrated presumably due to a limited transition rate from induction to maintenance phase, nab-PTX was suggested to be a useful treatment option following the induction therapy with nab-PTX in patients with advanced NSCLC.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Albuminas/efeitos adversos , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos
14.
BMC Cancer ; 18(1): 1241, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30537950

RESUMO

BACKGROUND: The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples. METHODS: Seventy-eight advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after resistance to initial EGFR-TKI treatment were enrolled at 5 institutions in Japan. We validated the association between the emergence of the T790M mutation and their clinical profiles. RESULTS: Thirty-nine patients tested positive for T790M and 39 tested negative in the re-biopsy samples. The objective response rate to initial EGFR-TKIs was higher in patients with the T790M mutation than in those without the mutation (89.7% versus 51.2%, p < 0.001). Moreover, there was a significant difference in the maximal tumor shrinkage rate relative to baseline in T790M-positive tumors compared with T790M-negative tumors (42.7% versus 24.0%, p = 0.001). Multivariate analysis demonstrated that the maximum tumor shrinkage rate was a significant predictive factor for the detection of the T790M mutation (p = 0.023, odds ratio 1.03, 95% confidence interval 1.00-1.05). CONCLUSIONS: Our retrospective observations suggested that the maximum tumor shrinkage rate with initial EGFR-TKI treatment might be one of the promising predictive biomarkers for emerging refractory tumors with the EGFR-T790M mutation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Cancer Sci ; 108(1): 116-123, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27783867

RESUMO

Malignant mesothelioma (MM) incidence is increasing drastically worldwide as an occupational disease resulting from asbestos exposure. However, no curative treatment for MM of advanced stage is available. Thus, new therapeutic approaches for MM are required. Because malignant pleural mesothelioma (MPM) cells spread along the pleural surface in most patients, MPM can be targeted using intrapleural therapeutic approaches. In this study, we investigated the effectiveness of the intrapleural instillation of a replication-competent adenovirus as an oncolytic agent against MPM. We constructed a vascular endothelial growth factor promoter-based conditionally replicative adenovirus (VEGF-CRAd) that replicates exclusively in VEGF-expressing cells. All of the MM cell lines that we tested expressed VEGF mRNA, and VEGF-CRAd selectively replicated in these MM cells and exerted a direct concentration-dependent oncolytic effect in vitro. Furthermore, our in vivo studies showed that pre-infection of MM cells with VEGF-CRAd potently suppressed MPM tumor formation in nude mice, and that intrapleural instillation of VEGF-CRAd prolonged the survival time of tumor-bearing mice. Our results indicate that VEGF-CRAd exerts an oncolytic effect on MM cells and that intrapleural instillation of VEGF-CRAd is safe and might represent a promising therapeutic strategy for MPM.


Assuntos
Adenoviridae/crescimento & desenvolvimento , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Mesotelioma/patologia , Mesotelioma/terapia , Terapia Viral Oncolítica , Neoplasias Pleurais/terapia , Regiões Promotoras Genéticas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Replicação Viral/genética , Adenoviridae/genética , Animais , Morte Celular , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/virologia , Mesotelioma/virologia , Mesotelioma Maligno , Camundongos , Camundongos Nus , Neoplasias Pleurais/patologia , Neoplasias Pleurais/virologia , Transgenes/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Infect Chemother ; 19(2): 202-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23053498

RESUMO

Febrile neutropenia frequently develops after chemotherapy, and the prompt administration of antimicrobial agents is required for treatment. In the present study, we searched for predictive factors for the failure of the initial antimicrobial agents used for febrile neutropenia (FN) in patients with lung cancer. Sixty FN patients treated in our ward from June 2005 to May 2011 were retrospectively analyzed. The definition of FN and the response to antimicrobial agents were determined by the Japanese guidelines. We divided the FN patients into two groups by their response to the initial antimicrobial agents. Next, the characteristics of the two groups were compared. The Multinational Association of Supportive Care in Cancer (MASCC) score did not differ between the two groups. The non-responder group demonstrated significant elevation of serum C-reactive protein (CRP) level. A multivariate analysis demonstrated that a CRP level higher than 10 mg/dl is an independent risk factor for the failure of initial antimicrobial agents for FN with lung cancer (OR 11.0, 95 % CI 1.635-74.5). When the CRP score was added to the MASCC score, the scoring system could more precisely predict the failure of initial antimicrobial agents in patients with lung cancer who developed febrile neutropenia.


Assuntos
Antibacterianos/uso terapêutico , Proteína C-Reativa/metabolismo , Neutropenia Febril Induzida por Quimioterapia/sangue , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Neoplasias Pulmonares/sangue , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Falha de Tratamento
18.
Transl Lung Cancer Res ; 12(8): 1802-1806, 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37691860

RESUMO

Background: The combination of erlotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) antibody, is one of the most effective treatments for patients with non-small cell lung cancer (NSCLC) and EGFR mutation. However, little is known about the safety and efficacy of this combination treatment for patients with brain metastases. Methods: This single arm, prospective, open-label, multicenter, phase II study will recruit 32 NSCLC patients with EGFR mutation (except for T790M mutation) and brain metastases (asymptomatic or mild symptoms). Patients will be treated with erlotinib at a dose of 150 mg/body once daily and ramucirumab at a dose of 10 mg/kg once every 2 weeks. The primary endpoint is intracranial overall response rate (iORR) and the secondary endpoints are intracranial disease control rate, intracranial progression-free survival (iPFS), extracranial ORR, extracranial PFS, ORR, overall PFS, overall survival (OS), and safety. The planned number of enrollments was calculated based on a one-sample binomial test (normal approximation) with a two-sided α level of 5% and 80% power, assuming that the expected iORR is 65% and the iORR threshold is 40%. Discussion: A prospective study to confirm the safety and efficacy of the combined erlotinib plus ramucirumab treatment for NSCLC patients with EGFR mutation and brain metastases is ongoing. Trial Registration: Japan Registry of Clinical Trials, jRCTs051220059.

19.
Proteomes ; 11(1)2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36810562

RESUMO

EGFR mutations are strong predictive markers for EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with non-small-cell lung cancer (NSCLC). Although NSCLC patients with sensitizing EGFR mutations have better prognoses, some patients exhibit worse prognoses. We hypothesized that various activities of kinases could be potential predictive biomarkers for EGFR-TKI treatment among NSCLC patients with sensitizing EGFR mutations. In 18 patients with stage IV NSCLC, EGFR mutations were detected and comprehensive kinase activity profiling was performed using the peptide array PamStation12 for 100 tyrosine kinases. Prognoses were observed prospectively after the administration of EGFR-TKIs. Finally, the kinase profiles were analyzed in combination with the prognoses of the patients. Comprehensive kinase activity analysis identified specific kinase features, consisting of 102 peptides and 35 kinases, in NSCLC patients with sensitizing EGFR mutations. Network analysis revealed seven highly phosphorylated kinases: CTNNB1, CRK, EGFR, ERBB2, PIK3R1, PLCG1, and PTPN11. Pathway analysis and Reactome analysis revealed that the PI3K-AKT and RAF/ MAPK pathways were significantly enriched in the poor prognosis group, being consistent with the outcome of the network analysis. Patients with poor prognoses exhibited high activation of EGFR, PIK3R1, and ERBB2. Comprehensive kinase activity profiles may provide predictive biomarker candidates for screening patients with advanced NSCLC harboring sensitizing EGFR mutations.

20.
Front Physiol ; 14: 1133037, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36891139

RESUMO

During hemodialysis (HD), blood pressure (BP) changes are frequently observed. However, the mechanism of BP changes during HD has not been fully clarified. The cardio-ankle vascular index (CAVI) reflects the arterial stiffness of the arterial tree from the origin of the aorta to the ankle independent from BP during measurement. Additionally, CAVI reflects functional stiffness in addition to structural stiffness. We aimed to clarify the role of CAVI in regulating the BP system during HD. We included 10 patients undergoing 4-hour HD (total 57 HD sessions). Changes in the CAVI and various hemodynamic parameters were evaluated during each session. During HD, BP decreased and CAVI significantly increased (CAVI, median [interquartile range]; 9.1 [8.4-9.8] [0 min] to 9.6 [9.2-10.2] [240 min], p < 0.05). Changes in CAVI from 0 min to 240 min were significantly correlated with water removal rate (WRR) (r = -0.42, p = 0.002). Changes in CAVI at each measurement point were negatively correlated with ΔBP (Δsystolic BPeach MP, r = -0.23, p < 0.0001; Δdiastolic BPeach MP, r = -0.12, p = 0.029). Whereas one patient exhibited a simultaneous decrease in BP and CAVI during the initial 60 min of HD. Arterial stiffness monitored with CAVI generally increased during HD. CAVI elevation is associated with decreased WWR and BP. An increase in CAVI during HD may reflect the contraction of smooth muscle cells and play an important role in BP maintenance. Hence, measuring CAVI during HD may distinguish the cause of BP changes.

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