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1.
Int J Clin Oncol ; 28(1): 79-88, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36414827

RESUMEN

BACKGROUND: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. METHODS: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation. RESULTS: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively. CONCLUSIONS: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Gefitinib/uso terapéutico , Clorhidrato de Erlotinib/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/efectos adversos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Receptores ErbB/genética , Estimación de Kaplan-Meier , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Mutación , Supervivencia sin Enfermedad
2.
Oncologist ; 26(1): 19-e52, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32918791

RESUMEN

LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Quimioradioterapia , Cisplatino/uso terapéutico , Terapia Combinada , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Paclitaxel/uso terapéutico
3.
Curr Treat Options Oncol ; 22(8): 71, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34110522

RESUMEN

OPINION STATEMENT: Lung cancer is the most common form of cancer in humans and the leading cause of cancer-related death worldwide. Traditionally, lung cancer has been diagnosed as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). However, recent developments in molecular pathology have revolutionized the diagnosis and treatment of the disease, thus improving patient prognosis and increasing the number of survivors. In advanced NSCLC cases, molecularly targeted drugs for patients with positive driver gene mutation/rearrangement, and immune checkpoint inhibitors for those with a positive biomarker, have changed the standard of care. SCLC is a highly malignant entity. In addition to the chemotherapy and radiotherapy, immune checkpoint inhibitors have recently provided some hope for extended-stage SCLC. Smoking cessation is related to decreased morbidity. However, early metastasis remains a significant challenge. Recently, cancer therapy-related cardiovascular disease (CTRCD) has emerged as diverse pathophysiology, including fulminant myocarditis, fatal arrhythmia, pericarditis, hypertension, and thrombosis, that emerged with modern lung cancer therapies. Cardio-oncology is a new interdisciplinary collaboration to develop methodologies to manage cardiovascular risk factors and CTRCDs with the common goal of minimizing unnecessary interruption of cancer treatment and maximizing outcomes of lung cancer survivors.


Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Enfermedades Cardiovasculares/etiología , Neoplasias Pulmonares/terapia , Antineoplásicos/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida/efectos adversos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores
4.
Lancet Oncol ; 21(6): 843-850, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32502444

RESUMEN

BACKGROUND: Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma. METHODS: This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777. FINDINGS: Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events. INTERPRETATION: The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma. FUNDING: Center for Clinical Trials, Japan Medical Association.


Asunto(s)
Antineoplásicos/administración & dosificación , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/administración & dosificación , Timoma/tratamiento farmacológico , Neoplasias del Timo/tratamiento farmacológico , Anciano , Antineoplásicos/efectos adversos , Progresión de la Enfermedad , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Timoma/enzimología , Timoma/mortalidad , Timoma/secundario , Neoplasias del Timo/enzimología , Neoplasias del Timo/mortalidad , Neoplasias del Timo/patología , Factores de Tiempo
5.
Jpn J Clin Oncol ; 48(4): 367-375, 2018 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-29474558

RESUMEN

BACKGROUND: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. METHODS: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days). RESULTS: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient. CONCLUSIONS: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC. CLINICALTRIALS.GOV IDENTIFIER: NCT01828112.


Asunto(s)
Pueblo Asiatico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Reordenamiento Génico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , Sulfonas/uso terapéutico , Adulto , Anciano , Quinasa de Linfoma Anaplásico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Crizotinib , Supervivencia sin Enfermedad , Docetaxel , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pemetrexed/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/efectos adversos , Piridinas/efectos adversos , Pirimidinas/efectos adversos , Sulfonas/efectos adversos , Taxoides/uso terapéutico , Resultado del Tratamiento
6.
Invest New Drugs ; 33(2): 380-8, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25502863

RESUMEN

Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5%) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4%) and pyrexia (23.5%). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).


Asunto(s)
Anticuerpos Monoclonales/farmacología , Proteínas Ligadas a GPI/biosíntesis , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Japón , Masculino , Dosis Máxima Tolerada , Mesotelina , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico
7.
Invest New Drugs ; 33(5): 1058-67, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26259955

RESUMEN

BACKGROUND: Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. METHODS: In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)). RESULTS: In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). CONCLUSIONS: Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.).


Asunto(s)
Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Pueblo Asiatico , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Japón , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Piridonas/administración & dosificación , Piridonas/efectos adversos , Piridonas/farmacocinética , Pirimidinonas/administración & dosificación , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , Gemcitabina
8.
Invest New Drugs ; 32(5): 946-54, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24875132

RESUMEN

BACKGROUND: AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer. METHODS: Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m(2) (on days 1, 8 and 15 of a 28-day cycle). RESULTS: Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade ≥3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively. CONCLUSION: Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-3/antagonistas & inhibidores , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Pueblo Asiatico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/sangre , Quinazolinas/farmacocinética
9.
Medicine (Baltimore) ; 103(27): e38734, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38968528

RESUMEN

Cancer is a common health problem worldwide. Early cancer education for adolescents and young adults (AYAs) is important for the prevention or early detection of cancer. In this questionnaire-based cross-sectional study, we examined the cancer awareness among parents of AYAs. Japanese adults with junior or senior high school children were included in this study. The cancer awareness measure (CAM) was used to assess cancer awareness, and the survey was conducted in December 2021. Warning signs, barriers to seeking help, and risk factors were surveyed using an online anonymous questionnaire. In addition, personal information, the presence of other cancer survivors, attendance at cancer seminars, conversations with children about cancer, interest in cancer education for children, and previous cancer screening were surveyed. A t-test or Spearman correlation coefficient was used to compare the total CAM scores for the individual factors. The relationship between cancer-screening behavior and individual factors was analyzed using the χ2 test. In addition, multiple regression analysis or logistic regression analysis was used to identify the factors influencing cancer awareness or cancer-screening behavior. Responses were obtained from the 612 participants. The mean CAM score was 3.7 for cancer warning signs, 4.3 for barriers to seeking help, and 6.5 for risk factors. Cancer warning signs were associated with gender and the presence of a spouse, family member, or friend who had experienced cancer. Barriers to seeking help were associated with age, gender, and education, while risk factors were associated with gender, education, and conversations about cancer with children. Moreover, these scores were associated with each cancer screening behavior. Cancer awareness among Japanese adults with AYAs was influenced by gender, academic background, occupation, the presence of cancer survivors around them, and whether they had conversations about cancer with their children, as well as their cancer screening behavior.


Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Neoplasias , Padres , Humanos , Estudios Transversales , Masculino , Femenino , Neoplasias/psicología , Neoplasias/epidemiología , Adolescente , Adulto Joven , Adulto , Padres/psicología , Encuestas y Cuestionarios , Detección Precoz del Cáncer/psicología , Factores de Riesgo , Persona de Mediana Edad , Japón/epidemiología
10.
Arch Public Health ; 82(1): 71, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38745251

RESUMEN

BACKGROUND: The early detection and prevention of many cancers is possible. Therefore, public awareness about cancer risk factors and warning signs must be increased to ensure early diagnosis. Although Japan has implemented mandatory cancer education in junior high and high schools, few studies have evaluated teachers' cancer awareness. This study aimed to determine Japanese junior high and high school teachers' awareness of cancer and related factors. METHODS: This cross-sectional study obtained data through an online questionnaire survey using questions from the Cancer Awareness Measure (CAM) developed by Cancer Research UK. Thirty items were selected from three CAM modules: cancer risk factors, cancer warning signs, and barriers to seeking help. Descriptive statistics were used for socio-demografic data and CAM module questions. The χ2 test was performed on the relationship between cancer awareness and socio-demographic data. Multiple logistic regression analysis was used to identify factors influencing cancer awareness. RESULTS: Respondents included 316 junior high school and 463 high school teachers (541 men; 238 women; average age = 48.2 years; average teaching experience = 23.5 years). An average of 5.41 out of 11 cancer risk factors were recognized. More than 70% of teachers recognized smoking, exposure to another person's cigarette smoke, and having a close relative with cancer as risk factors. On average, 4.52 out of 9 cancer warning signs were recognized. More than 50% of teachers recognized the warning signs of unexplained lump or swelling, unexplained weight loss, and unexplained bleeding. Barriers to seeking help had a low average score of 4.51 out of 20. However, the most commonly recognized "barriers to seeking help" were "too busy to make time," "difficult to make an appointment," "worried about what the doctor might find," and "too scared." Moreover, the common factors that affected awareness of cancer risk factors and cancer warning signs were gender and cancer experience of relatives. Factors that affected awareness of "barriers to seeking help" were "participation in cancer-related workshops," age, gender, and cancer experience of relatives. CONCLUSIONS: Cancer awareness education should consider interventions that can improve knowledge of the symptoms and signs related to cancer without increasing the awareness of barriers to seeking help.

11.
Lung Cancer ; 191: 107557, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38626709

RESUMEN

OBJECTIVES: The main objective of this report was to detail the long-term follow-up data from the REMORA study, which investigated the safety and efficacy of lenvatinib in patients with thymic carcinoma. In addition, an exploratory analysis of the association between relative dose intensity (RDI) and the efficacy of lenvatinib is presented. MATERIALS AND METHODS: The single-arm, open-label, phase 2 REMORA study was conducted at eight Japanese institutions. Forty-two patients received oral lenvatinib 24 mg once daily in 4-week cycles until the occurrence of intolerable adverse events or disease progression. The REMORA long-term follow-up data were evaluated, including overall survival (OS). RDI was calculated by dividing the actual dose administered to the patient by the standard recommended dose. This trial is registered on JMACCT (JMA-IIA00285) and on UMIN-CTR (UMIN000026777). RESULTS: The updated median OS was 28.3 months (95 % confidence interval [CI]: 17.1-34.0 months), and the OS rate at 36 months was 35.7 % (95 % CI: 21.7 %-49.9 %). When grouped by RDI of lenvatinib, the median OS was 38.5 months (95 % CI: 31.2-not estimable) in patients with ≥ 75 % RDI and 17.3 months (95 % CI: 13.4-26.2 months) in patients with < 75 % RDI (hazard ratio 0.46 [95 % CI: 0.22-0.98]; P = 0.0406) at 8 weeks. Patients who maintained their lenvatinib dose over 8 weeks had a higher objective response rate than patients whose doses were reduced (75.0 % vs 29.4 %; P = 0.0379). No new safety concerns or treatment-related deaths were reported, and lenvatinib had a tolerable safety profile. CONCLUSION: This follow-up report updated OS in patients with metastatic or recurrent thymic carcinoma. A higher RDI of lenvatinib at 8 weeks could be associated with improved outcomes.


Asunto(s)
Recurrencia Local de Neoplasia , Compuestos de Fenilurea , Quinolinas , Timoma , Humanos , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Quinolinas/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Timoma/tratamiento farmacológico , Timoma/mortalidad , Timoma/patología , Adulto , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/patología , Neoplasias del Timo/mortalidad , Metástasis de la Neoplasia , Anciano de 80 o más Años , Resultado del Tratamiento
12.
JTO Clin Res Rep ; 5(2): 100631, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38322711

RESUMEN

Osimertinib administration has been approved as an adjuvant treatment after complete surgical resection in patients with EGFR-mutated NSCLC. This article presents the first report of life-threatening postoperative osimertinib-induced interstitial lung disease. An 83-year-old male patient underwent right upper lobectomy (pathologic stage IIA) and osimertinib (80 mg/d) was initiated on postoperative day 75. On day 44 of osimertinib administration, chest computed tomography revealed diffuse ground-glass opacities; accordingly, osimertinib-induced interstitial lung disease was diagnosed. Steroid pulse therapy was initiated using a high-flow nasal cannula to treat dyspnea and hypoxemia, rapidly improving the respiratory status and imaging findings; moreover, the patient's clinical course was excellent. This case report suggests that the postoperative occurrence of severe osimertinib-induced interstitial lung disease is a crucial factor that must be considered in patient decision-making regarding perioperative treatment.

13.
Cancer Sci ; 104(4): 481-5, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23331490

RESUMEN

Erythropoiesis-stimulating agents (ESA) reduce the need for transfusions and improve the quality of life in patients receiving chemotherapy, but several clinical trials have suggested that ESA might have a negative impact on survival. To evaluate the efficacy and safety of ESA, epoetin beta and darbepoetin alfa, including their impact on overall survival and thromboembolic events, we conducted an individual data-based meta-analysis of three randomized, placebo-controlled trials studying Japanese patients with chemotherapy-induced anemia. All trials were conducted in compliance with Good Clinical Practice. A total of 511 patients with solid tumor or lymphoma (epoetin beta or darbepoetin alfa, n = 273; placebo, n = 238) were included. The ESA significantly reduced the risk of transfusion (relative risk, 0.47; 95% confidence interval, 0.29-0.76). No significant effect of the ESA on overall survival was observed (unadjusted hazard ratio, 1.00; 95% confidence interval, 0.75-1.34). A prespecified subgroup analysis showed no strong interaction between the baseline hemoglobin concentration and the effect of ESA on overall survival. Among the ESA-treated patients, the highest hemoglobin achieved during the treatment period in each patient had no impact on mortality. No increase in thromboembolic events was observed in the ESA-treated patients (0.7% vs 1.7% placebo). The ESA reduced the risk of transfusion without a negative impact on the survival of patients with chemotherapy-induced anemia.


Asunto(s)
Anemia/tratamiento farmacológico , Antineoplásicos/efectos adversos , Eritropoyetina/análogos & derivados , Hematínicos/uso terapéutico , Anemia/inducido químicamente , Anemia/mortalidad , Pueblo Asiatico , Darbepoetina alfa , Eritropoyetina/administración & dosificación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación
14.
Cancer Sci ; 104(1): 98-104, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23020774

RESUMEN

OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 mg once weekly and our biomarker analysis suggested that this anti-angiogenesis vaccine is biologically active.


Asunto(s)
Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/terapia , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores de Tumor , Vacunas contra el Cáncer/administración & dosificación , Antígeno HLA-A24/inmunología , Humanos , Activación de Linfocitos , Persona de Mediana Edad , Neoplasias/metabolismo , Neovascularización Patológica/terapia , Linfocitos T Citotóxicos/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/efectos adversos , Vacunas de Subunidad/uso terapéutico
15.
Invest New Drugs ; 31(1): 108-14, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22415795

RESUMEN

BACKGROUND: Saracatinib (AZD0530) is a selective, oral Src inhibitor that has demonstrated antitumour activity in preclinical studies. METHODS: This open-label, dose-escalation, phase I study evaluated the safety and tolerability of saracatinib in Japanese patients with advanced solid tumours (clinicaltrials.gov NCT00704366). Patients received continuous once-daily oral dosing with saracatinib starting 7 days after a single dose in ascending dose cohorts until dose-limiting toxicity (DLT) or disease progression. Pharmacokinetics and efficacy were also evaluated. RESULTS: A total of 12 patients received saracatinib at doses of 50 (n = 3), 125 (n = 6), and 175 mg (n = 3). Median durations of exposure were 65, 44, and 16 days in the 50, 125, and 175 mg cohorts, respectively. The most common adverse events were diarrhoea (67 %), nausea (67 %), decreased appetite (58 %), lymphopenia (50 %) and pyrexia (50 %). The most common grade ≥3 adverse events were leukopenia, lymphopenia, neutropenia, and haemoglobin decreased (all 17 %). DLTs occurred in two patients, both in the 175 mg cohort: grade 3 aspartate aminotransferase increased with grade 3 gamma-glutamyltransferase increased (n = 1); and grade 3 hypoxia (n = 1). Following a single dose, saracatinib median t(max) across the doses was 2-4 h, and thereafter plasma concentrations declined in a biphasic manner, with mean terminal half-life of approximately 45 h. Geometric mean saracatinib exposures were 0.8-2.1 times greater than those reported in Caucasian patients. The best response was stable disease (50 mg, n = 2; 125 mg, n = 1). CONCLUSIONS: Saracatinib was tolerated in Japanese patients with advanced solid tumours at doses up to 125 mg.


Asunto(s)
Benzodioxoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Familia-src Quinasas/antagonistas & inhibidores , Adulto , Anciano , Pueblo Asiatico , Benzodioxoles/efectos adversos , Benzodioxoles/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética
16.
J Adolesc Young Adult Oncol ; 12(1): 9-33, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-35180351

RESUMEN

The purpose of this review was to establish what cancer education programs have been carried out aimed at adolescents and young adults (AYAs) and what outcomes they achieved. The databases used were MEDLINE, CINAHL, and Web of Science, and the search period was set as 2011-2020. The extracted literature was evaluated for quality using the Joanna Briggs Institute's critical appraisal tools. The subjects of the analysis were 29 studies: 10 randomized controlled trials and 19 quasi-experimental designs. Regarding the varieties of cancers found in the data, in descending order, 10 documents looked at cervical cancer, 9 looked at cancer in general, and 4 looked at breast cancer. Most studies focused on AYAs exclusively, with just three studies involving their parents simultaneously. Many studies used lecture-based intervention, with information technology-based interventions using websites and cell phones. Topics included in the program were cancer epidemiology, cancer risk factors, cancer warning signs and symptoms, prevention methods, and screening methods. After the intervention, all studies showed statistically significant improvements in at least one outcome measure, which included knowledge and awareness of cancer, health beliefs, and intent to take preventive action, demonstrating a basis for educational intervention. Educating AYAs about cancer at a time when their ways of life are becoming more concrete can be expected to have a positive impact on cancer preventing behaviors in adulthood, increase their parents' awareness of cancer, and have a positive impact on behavior around screening.


Asunto(s)
Neoplasias de la Mama , Neoplasias del Cuello Uterino , Femenino , Humanos , Adolescente , Adulto Joven , Padres , Evaluación de Resultado en la Atención de Salud , Factores de Riesgo
17.
Oncol Lett ; 26(6): 520, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37927418

RESUMEN

Gefitinib is a key drug used in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. Gefitinib therapy is superior to conventional chemotherapy for the progression-free survival rate of patients with EGFR mutations. However, 10-26% of patients develop grade 3 or higher hepatotoxicity during gefitinib treatment; therefore, the development of preclinical tests for hepatotoxicity prior to clinical use is desirable. The present study evaluated the use of induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iPSC-heps), as a platform for preclinical test development. Patient-derived iPSCs were generated by reprogramming peripheral blood mononuclear cells obtained from two groups of gefitinib-treated patients with severe hepatotoxicity [toxicity group (T group)] or mild hepatotoxicity [no clinical toxicity group (N group)]. To examine the hepatotoxicity, the iPSCs from both T and N groups were differentiated into hepatocytes to obtain iPSC-heps. Differentiation was confirmed by measuring the expression levels of hepatocyte markers, such as albumin or α-fetoprotein, via western blotting and quantitative PCR analyses. Cytotoxicity in iPSCs and iPSC-heps after gefitinib treatment was evaluated using a lactate dehydrogenase release assay. The gefitinib-induced cytotoxicity in iPSCs from the T group was significantly higher than that from the N group, whereas there were no significant differences between the groups of iPSC-heps. These results suggested that using iPSCs in preclinical assessment may be a good indicator for the prediction of gefitinib-induced cytotoxicity in clinical use.

18.
J Thorac Oncol ; 18(10): 1334-1350, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37364849

RESUMEN

INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Quimioradioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Estadificación de Neoplasias , Microambiente Tumoral
19.
Biochem Biophys Res Commun ; 407(1): 219-24, 2011 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-21377448

RESUMEN

Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC(50) of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Terapia Recuperativa/métodos , Anciano , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Femenino , Amplificación de Genes , Humanos , Lapatinib , Persona de Mediana Edad , Receptor ErbB-2/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Insuficiencia del Tratamiento
20.
Anticancer Res ; 41(10): 5137-5145, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34593465

RESUMEN

BACKGROUND: For epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), administration of EGFR tyrosine kinase inhibitors (TKIs) is mandatory to prolong survival. To date, a comparison of second- and third-generation EGFR-TKIs has not been reported as far as we are aware. PATIENTS AND METHODS: We retrospectively investigated the survival time of patients diagnosed with EGFR-mutated advanced or recurrent NSCLC who had received afatinib, a second-generation EGFR-TKI, or osimertinib, a third-generation EGFR-TKI, as the first-line treatment. RESULTS: Among the 49 patients included in the study, 15 received afatinib and 34 received osimertinib. No significant differences in overall survival were observed between the two groups [afatinib vs. osimertinib=36 vs. 33 months (hazard ratio=2.917, 95% confidence interval=0.780-10.905; p=0.112)]. T790M mutation was detected in three of the patients in the afatinib group, and all three subsequently received osimertinib. The median overall survival of these three patients and of the 12 without the mutation were 63 and 36 months, respectively. CONCLUSION: There was no apparent difference in the effect on survival between second- and third-generation EGFR-TKIs, whereas the sequential administration of second- followed by third-generation EGFR-TKIs appeared to confer a better long-term prognosis.


Asunto(s)
Acrilamidas/uso terapéutico , Afatinib/uso terapéutico , Compuestos de Anilina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
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