RESUMEN
OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. RESULTS: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5-59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2-5.4) and 10.4 months (95% CI, 8.1-14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). CONCLUSIONS: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.
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Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Anorexia/inducido químicamente , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Neutropenia Febril Inducida por Quimioterapia/etiología , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Hiponatremia/inducido químicamente , Irinotecán , Masculino , Persona de Mediana Edad , Criterios de Evaluación de Respuesta en Tumores Sólidos , Retratamiento , Tasa de Supervivencia , Trombocitopenia/inducido químicamenteRESUMEN
Background The efficacy and safety of bevacizumab in elderly patients with non-small cell lung cancer remain controversial. This study focused on both selecting fit elderly patients and overcoming interpatient variability with respect to pharmacodynamics. Methods Elderly (age: ≥70 years) patients with advanced non-squamous non-small cell lung cancer were enrolled. Patients with uncontrolled congestive heart failure and uncontrolled diabetes were excluded. The treatment regimen comprised carboplatin at an area under the curve of 5 mg/ml/min on day 1, paclitaxel at 90 mg/m2 on days 1 and 8, and bevacizumab at 15 mg/kg on day 1 every 21 days for up to 4 cycles, followed by maintenance bevacizumab. Dose reduction due to side effects was performed, with a wide range of doses of paclitaxel from 23 mg/m2/week to 60 mg/m2/week. Results Of the 36 patients entered, 38.9% required a dose reduction or cancellation of paclitaxel administration on day 8, and 75% patients were able to complete 4 cycles of triplet therapy. The response rate, primary endpoint, was 69.4% (95% confidence interval [CI]: 51.9-83.7). The median progression free survival and overall survival were 8.4 months and 29.2 months, respectively. The most common adverse events included neutropenia, hypertension, anemia, and infection. Although Grade ≥ 3 adverse events were observed in 24 patients (66.7%), there were no deaths due to toxicity. Conclusion Carboplatin plus weekly paclitaxel with bevacizumab is a feasible, effective first-line regimen for elderly non-small cell lung cancer patients. (UMIN00006622).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Resultado del TratamientoRESUMEN
Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8(+) T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4(+)CD25(+) Foxp3(+) Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4(+) T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8(+) T cells were responsible for this augmentation. Using Rag2(-/-) mice or depletion of recipient CD8(+) T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4(+) T cells enhanced the proliferation of CD8(+) T cells and the priming of tumor-specific CD8(+) T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.
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Citotoxinas/farmacología , Fibrosarcoma/terapia , Depleción Linfocítica , Linfopenia/terapia , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Cisplatino/farmacología , Ciclofosfamida/farmacología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Resistencia a Medicamentos/inmunología , Etopósido/farmacología , Femenino , Fibrosarcoma/inducido químicamente , Fibrosarcoma/inmunología , Fibrosarcoma/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Linfopenia/inducido químicamente , Linfopenia/inmunología , Linfopenia/patología , Metilcolantreno , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Paclitaxel/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patología , Células Tumorales Cultivadas , Vidarabina/análogos & derivados , Vidarabina/farmacología , Irradiación Corporal Total , GemcitabinaRESUMEN
BACKGROUND: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI. METHODS: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25% from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or ≥ 1.5 times the baseline level. RESULTS: Eighty of the 84 patients (95.2%) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4%). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95% confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95% CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI. CONCLUSIONS: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use.
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Lesión Renal Aguda/patología , Cisplatino/efectos adversos , Insuficiencia Renal Crónica/patología , Neoplasias Torácicas/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Adulto , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Cisplatino/administración & dosificación , Creatinina/sangre , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/tratamiento farmacológico , Factores de Riesgo , Neoplasias Torácicas/complicaciones , Neoplasias Torácicas/patologíaRESUMEN
PURPOSE: In a comparative phase 3 study involving 1114 Japanese patients receiving highly emetogenic chemotherapy (HEC), palonosetron (PALO) was found to be superior to granisetron (GRA) for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in the delayed phase. This post hoc analysis of the phase 3 study evaluated the efficacy of PALO for the control of nausea. METHODS: The proportion of patients without nausea was assessed at 24-h intervals during the acute phase (0-24 h), delayed phase (24-120 h), and overall (0-120 h). No nausea rates were also evaluated by sex, type of chemotherapy (cisplatin or doxorubicin/epirubicin plus cyclophosphamide [AC/EC]), and age (<55 vs. ≥55 years). Nausea severity was categorized using a 4-point Likert scale (0 = no nausea to 3 = severe nausea). RESULTS: The proportion of patients without nausea was significantly higher in the PALO arm than in the GRA arm in the delayed phase (37.8 % vs. 27.2 %; p = 0.002) and overall (31.9 % vs. 25.0 %; p = 0.0117). When analyzed by stratification factors, the proportion of patients without nausea was significantly higher in the PALO arm in the delayed phase and overall in patients who were female, younger, or treated with cisplatin and in the delayed phase in patients who were older or treated with doxorubicin or epirubicin plus cyclophosphamide (all p < 0.05). CONCLUSIONS: PALO was more effective than GRA in prophylaxis of HEC-induced nausea in the delayed phase and overall. In addition, PALO was more effective than GRA in young and female patients, who are at high risk of CINV, both in the delayed phase and overall.
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Antieméticos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/uso terapéutico , Granisetrón/uso terapéutico , Isoquinolinas/uso terapéutico , Náusea/inducido químicamente , Náusea/tratamiento farmacológico , Quinuclidinas/uso terapéutico , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , PalonosetrónRESUMEN
OBJECTIVE: Epidermal growth factor receptor tyrosine kinase inhibitors are effective as first-line therapy for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations. However, it is unknown whether second-line platinum-based chemotherapy after epidermal growth factor receptor tyrosine kinase inhibitor therapy could lead to better outcomes. We evaluated the efficacy of second-line platinum-based chemotherapy after gefitinib for advanced non-small cell lung cancers harboring epidermal growth factor receptor mutations (the NEJ002 study). METHODS: Seventy-one non-small cell lung cancers, treated with gefitinib as first-line therapy and then receiving platinum-based chemotherapy as second-line therapy were evaluated in NEJ002. Patients were evaluated for antitumor response to second-line chemotherapy by computed tomography according to the criteria of the Response Evaluation Criteria in Solid Tumors group (version 1.0). RESULTS: Of the 71 patients receiving platinum-based chemotherapy after first-line gefitinib, a partial response was documented in 25.4% (18/71), stable disease in 43.7% (31/71) and progression of disease in 21.1% (15/71). The objective response and disease control rates were 25.4% (18/71) and 69% (49/71), respectively. There was no significant difference between first- and second-line chemotherapy in objective response and disease control rates for advanced non-small cell lung cancer harboring activating epidermal growth factor receptor mutations. In the analysis of epidermal growth factor receptor mutation types, the objective responses of deletions in exon 19 and a point mutation in exon 21 (L858R) were 27.3% (9/33) and 28.1% (9/32), respectively, but these differences between objective response rates were not significant. CONCLUSIONS: The efficacy of second-line platinum-based chemotherapy followed at progression by gefitinib was similar to first-line platinum-based chemotherapy, and epidermal growth factor receptor mutation types did not influence the efficacy of second-line platinum-based chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Eliminación de Secuencia , Adulto , Anciano , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Esquema de Medicación , Exones , Femenino , Gefitinib , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Quinazolinas/administración & dosificación , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Cytotoxic lymphodepletion therapies augment antitumor immune responses. The generation and therapeutic efficacy of antitumor effector T cells (T(E)s) are enhanced during recovery from lymphopenia. Although the effects of lymphodepletion on naive T cells (T(N)s) and T(E)s have been studied extensively, the influence of lymphodepletion on suppressor cells remains poorly understood. In this study, we demonstrate a significant increase of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in sublethally irradiated lymphopenic mice. These radio-resistant Tregs inhibited the induction of T(E)s in tumor-draining lymph-nodes (TDLNs) during recovery from lymphopenia. The transfer of T(N)s into lymphopenic tumor-bearing mice resulted in some antitumor effects; however, Treg depletion after whole-body irradiation and reconstitution strongly inhibited tumor progression. Further analyses revealed that tumor-specific T cells were primed from the transferred T(N)s, whereas the Tregs originated from irradiated recipient cells. As in irradiated lymphopenic mice, a high percentage of Tregs was observed in cyclophosphamide-treated lymphopenic mice. The inhibition of Tregs in cyclophosphamide-treated mice significantly reduced tumor growth. These results indicate that the Tregs that survive cytotoxic therapies suppress antitumor immunity during recovery from lymphopenia and suggest that approaches to deplete radio and chemo-resistant Tregs can enhance cancer immunotherapies.
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Linfocitos T CD4-Positivos/inmunología , Depleción Linfocítica , Linfopenia/inmunología , Linfopenia/terapia , Traumatismos Experimentales por Radiación/prevención & control , Linfocitos T Reguladores/inmunología , Animales , Antineoplásicos Alquilantes/uso terapéutico , Proliferación Celular , Terapia Combinada , Ciclofosfamida/uso terapéutico , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Linfopenia/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Traumatismos Experimentales por Radiación/inmunología , Traumatismos Experimentales por Radiación/patología , Irradiación Corporal TotalRESUMEN
A 65-year-old woman with left chest pain, back pain, and palpitation that had persisted for 2 months was referred to our hospital. Computed tomography of her chest showed an anterior mediastinal tumor with mediastinal lymphadenopathy, left pleural effusion, and pericardial effusion. Endobronchial ultrasound-guided transbronchial needle aspiration of the subcarinal lymphadenopathy was performed. The pathological findings and other examinations such as bone scintigraphy suggested advanced thymic cancer (stage IV b according to the Masaoka classification of thymic epithelial tumors). The patient was treated with combination chemotherapy of carboplatin(area under the curve [AUC]=6, 656 mg/body, day 1) and weekly paclitaxel (70 mg/m², 100 mg/body, days 1, 8, and 15). After 4 cycles of chemotherapy, a partial response was achieved and the pericardial effusion disappeared. The patient did not experience any severe toxicity, except for grade 1 nausea, grade 2 anemia, and grade 2 alopecia. Weekly paclitaxel combined with carboplatin appears to be a useful regimen with minimal toxicity for advanced thymic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Timo/tratamiento farmacológico , Anciano , Carboplatino/administración & dosificación , Femenino , Humanos , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Neoplasias del Timo/patología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. METHODS: We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. RESULTS: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes erbB-1 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Anciano , Antineoplásicos/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/secundario , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Paclitaxel/administración & dosificación , Análisis de SupervivenciaRESUMEN
Accumulating evidence suggests that most solid malignancies consist of heterogeneous tumor cells and that a relatively small subpopulation, which shares biological features with stem cells, survives through potentially lethal stresses such as chemotherapy and radiation treatment. Since the survival of this subpopulation of cancer stem cells (CSC) plays a critical role in recurrence, it must be eradicated in order to cure cancer. We previously reported that vaccination with CD133(+) murine melanoma cells exhibiting biological CSC features induced CSC-specific effector T cells. These were capable of eradicating CD133(+) tumor cells in vivo, thereby curing the parental tumor. In the current study, we indicated that DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked (DDX3X) is an immunogenic protein preferentially expressed in CD133(+) tumor cells. Vaccination with DDX3X primed specific T cells, resulting in protective and therapeutic antitumor immunity. The DDX3X-primed CD4(+) T cells produced CD133(+) tumor-specific IFNγ and IL-17 and mediated potent antitumor therapeutic efficacy. DDX3X is expressed in various human cancer cells, including lung, colon, and breast cancer cells. These results suggest that anti-DDX3X immunotherapy is a promising treatment option in efforts to eradicate CSC in the clinical setting.
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ARN Helicasas DEAD-box/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias/inmunología , Células Madre Neoplásicas/inmunología , Antígeno AC133 , Animales , Antígenos CD/inmunología , ARN Helicasas DEAD-box/metabolismo , Femenino , Glicoproteínas/inmunología , Humanos , Inmunoterapia , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapia , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Péptidos/inmunologíaRESUMEN
Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.
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Anticuerpos Monoclonales , Neoplasias , Receptores del Factor de Necrosis Tumoral/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Interferón gamma/genética , Interferón gamma/inmunología , Activación de Linfocitos , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones SCID , Trasplante de Neoplasias , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/genética , Tasa de Supervivencia , Ligando Inductor de Apoptosis Relacionado con TNF , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron. METHODS: Chemotherapy-naïve lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2-3 and the oral administration of 8 mg of dexamethasone on days 2-4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0-120 h). RESULTS: The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0%, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7%, respectively. The most common adverse event was grade 1 or 2 constipation. CONCLUSIONS: Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC.
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Cisplatino/efectos adversos , Dexametasona/administración & dosificación , Isoquinolinas/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Morfolinas/administración & dosificación , Náusea/tratamiento farmacológico , Quinuclidinas/administración & dosificación , Vómitos/tratamiento farmacológico , Adulto , Anciano , Antieméticos/administración & dosificación , Antieméticos/efectos adversos , Antineoplásicos/efectos adversos , Aprepitant , Dexametasona/efectos adversos , Quimioterapia Combinada , Femenino , Humanos , Isoquinolinas/efectos adversos , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Náusea/inducido químicamente , Náusea/prevención & control , Palonosetrón , Estudios Prospectivos , Quinuclidinas/efectos adversos , Antagonistas del Receptor de Serotonina 5-HT3/administración & dosificación , Antagonistas del Receptor de Serotonina 5-HT3/efectos adversos , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/efectos adversos , Resultado del Tratamiento , Vómitos/inducido químicamente , Vómitos/prevención & controlRESUMEN
BACKGROUND: For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, first-line gefitinib produced a longer progression-free survival interval than first-line carboplatin plus paclitaxel but did not show any survival advantage in the North East Japan 002 study. This report describes the quality of life (QoL) analysis of that study. METHODS: Chemotherapy-naïve patients with sensitive EGFR-mutated, advanced NSCLC were randomized to receive gefitinib or chemotherapy (carboplatin and paclitaxel). Patient QoL was assessed weekly using the Care Notebook, and the primary endpoint of the QoL analysis was time to deterioration from baseline on each of the physical, mental, and life well-being QoL scales. Kaplan-Meier probability curves and log-rank tests were employed to clarify differences. RESULTS: QoL data from 148 patients (72 in the gefitinib arm and 76 in the carboplatin plus paclitaxel arm) were analyzed. Time to defined deterioration in physical and life well-being significantly favored gefitinib over chemotherapy (hazard ratio [HR] of time to deterioration, 0.34; 95% confidence interval [CI], 0.23-0.50; p < .0001 and HR, 0.43; 95% CI, 0.28-0.65; p < .0001, respectively). CONCLUSION: QoL was maintained much longer in patients treated with gefitinib than in patients treated with standard chemotherapy, indicating that gefitinib should be considered as the standard first-line therapy for advanced EGFR-mutated NSCLC in spite of no survival advantage.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Calidad de Vida , Quinazolinas/uso terapéutico , Adulto , Anciano , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Supervivencia sin Enfermedad , Determinación de Punto Final , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Paclitaxel/uso terapéutico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The blockade of immune suppression against antitumor responses is a particularly attractive strategy when combined with agents that promote tumor-specific CTLs. In this study, we have attempted to further improve the CTL induction and potent antitumor efficacy of a combination mAb-based therapy (termed "trimAb therapy") that comprises tumor cell death-inducing anti-death receptor 5 mAb and immune activating anti-CD40 and anti-CD137 mAbs. Among trimAb-treated tumors, the infiltration of CD4(+) Foxp3(+) cells was greater in progressing tumors compared with stable tumors. Blockade of CTLA-4 (CD152)-mediated signals by an antagonistic mAb substantially increased the tumor rejection rate of trimAb therapy, although the immune responses of draining lymph node cells were not augmented. Interestingly, by comparison, additional treatment with agonistic anti-glucocorticoid-induced TNF receptor mAb, antagonistic anti-programmed death-1 (CD279) mAb, or agonistic anti-OX40 (CD134) mAb significantly augmented immune responses of draining lymph node cells, but did not augment the therapeutic effect of trimAb. CD4 T cell depletion reduced the antitumor effect of anti-CTLA-4 mAb treatment alone, but did not reduce the tumor rejection rate of trimAb in conjunction with anti-CTLA-4 mAb. Thus, the blockade of the CTLA-4-mediated inhibitory signal in tumor infiltrating CTL may be the most effective strategy to augment the effect of immune therapies that generate tumor-specific CTL.
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Anticuerpos Bloqueadores/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/terapia , Animales , Anticuerpos Bloqueadores/fisiología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/fisiología , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos de Superficie/inmunología , Proteínas Reguladoras de la Apoptosis/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Antígeno CTLA-4 , Citotoxicidad Inmunológica , Proteína Relacionada con TNFR Inducida por Glucocorticoide , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Activación de Linfocitos/inmunología , Depleción Linfocítica , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Receptor de Muerte Celular Programada 1 , Transporte de Proteínas/inmunología , Receptores de Factor de Crecimiento Nervioso/inmunología , Receptores OX40/inmunología , Receptores del Factor de Necrosis Tumoral/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patologíaRESUMEN
PURPOSE: Prevention of chemotherapy-induced nausea and vomiting (CINV) is of great importance for the completion of multiple cycles of cancer chemotherapy. Palonosetron is a second-generation 5-HT(3) receptor antagonist with proven efficacy for both acute and delayed CINV. This study was designed to assess the safety and efficacy of 0.75 mg palonosetron in repeated cycles of highly emetogenic chemotherapy or anthracycline-cyclophosphamide combination (AC/EC). METHODS: We gave 0.75 mg palonosetron to 538 patients 30 min prior to ≥ 50 mg/m(2) cisplatin or AC/EC on day 1. Prophylactic dexamethasone was administered on days 1-3. The primary endpoint was the incidence rate of adverse events (AEs). The secondary endpoint was complete response rate (CR, defined as no emesis and no rescue medication) throughout the study period. RESULTS: Treatment-related AEs were seen in 44% (237 of 538 patients). Serious AEs were seen in 4% (23 of 538 patients), all considered unrelated or unlikely to be related to palonosetron. Only one patient discontinued the study due to a treatment-related AE. No trend toward worsening of AEs was observed in subsequent cycles of chemotherapy. Complete response rates were maintained throughout repeated cycles. CONCLUSION: The extraordinary safety profile and maintenance of efficacy of 0.75 mg palonosetron combined with dexamethasone were demonstrated throughout repeated chemotherapy cycles.
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Antieméticos/uso terapéutico , Isoquinolinas/uso terapéutico , Náusea/prevención & control , Quinuclidinas/uso terapéutico , Vómitos/prevención & control , Anciano , Antieméticos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/efectos adversos , Dexametasona/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Isoquinolinas/efectos adversos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/tratamiento farmacológico , Palonosetrón , Quinuclidinas/efectos adversos , Antagonistas del Receptor de Serotonina 5-HT3/efectos adversos , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
Background: This multicenter, open-label, single-arm phase II study [Niigata Lung Cancer Treatment Group (NLCTG) 1302] was conducted to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) monotherapy for previously treated patients with advanced non-small cell lung cancer (NSCLC). We also investigated chemotherapy-induced peripheral neuropathy (CIPN) to evaluate the quality of life (QOL). Methods: Sixty-five patients with advanced NSCLC from 14 participating institutions who had previously undergone one or two cytotoxic chemotherapy regimens were enrolled in this study. The patients received 100 mg/m2 nab-paclitaxel intravenously on days 1, 8, and 15, every 4 weeks. The primary endpoint was overall objective response rate. CIPN symptoms were prospectively assessed using the Patient Neurotoxicity Questionnaire (PNQ) and Common Terminology Criteria for Adverse Events (CTCAE). Results: The overall response rate (ORR) was 18.5% [95% confidence interval (CI): 10.9-29.6%], and the median progression-free survival (PFS) was 3.4 (95% CI: 2.5-4.3) months. Median overall survival (OS) was 8.6 (95% CI: 7.1-10.2) months. The most common non-hematologic grade ≥3 adverse events were infection (7.7%) and hyponatremia (4.6%). Neutropenia was the most common grade 3 or 4 adverse event (30.8%), and febrile neutropenia developed in 6.2% patients. The PNQ and CTCAE scores for motor peripheral neuropathy were low (kappa =0.10). Conclusions: The primary endpoint was achieved. Nab-paclitaxel was well tolerated and showed anti-tumor activity in patients with previously treated NSCLC. This study demonstrates a low degree of concordance in CIPN grading between physicians and patients. Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000012343).
RESUMEN
Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2-16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.
RESUMEN
Accumulating evidence suggests that cancer cells possess a small subpopulation that survives during potentially lethal stresses, including chemotherapy, radiation treatment, and molecular-targeting therapy. CD133 is a putative marker that distinguishes a minor subpopulation from normal differentiated tumor cells in many cancers. Although it is necessary to eradicate all cancer cells to obtain a cure, effective treatment to eliminate the CD133(+) treatment-tolerant cells has not been elucidated. In this study, we demonstrated that a CD133(+) subpopulation in murine melanoma is immunogenic and that effector T cells specific for the CD133(+) melanoma cells mediated potent antitumor reactivity, curing the mice of the parental melanoma. CD133(+) melanoma antigens preferentially induced type 17 T helper (Th17) cells and Th1 cells but not Th2 cells. CD133(+) melanoma cell-specific CD4(+) T-cell treatment eradicated not only CD133(+) tumor cells but also CD133(-) tumor cells while inducing long-lasting accumulation of lymphocytes and dendritic cells with upregulated MHC class II in tumor tissues. Further, the treatment prevented regulatory T-cell induction. These results indicate that T-cell immunotherapy is a promising treatment option to eradicate CD133(+) drug-tolerant cells to obtain a cure for cancer.
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Antígenos CD/inmunología , Glicoproteínas/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Péptidos/inmunología , Linfocitos T/inmunología , Células TH1/inmunología , Células Th17/inmunología , Antígeno AC133 , Animales , Antígenos CD/farmacología , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/patología , Femenino , Glicoproteínas/farmacología , Inmunoterapia Activa/métodos , Inmunoterapia Adoptiva/métodos , Complejo Mayor de Histocompatibilidad , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Péptidos/farmacología , Linfocitos T/patología , Células TH1/patología , Células Th17/patologíaRESUMEN
BACKGROUND: Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2(nd) EGFR-TKI administration. METHODS: We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment. RESULTS: Three patients (27%) were treated with gefitinib as the 2(nd) EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2(nd) EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2(nd) EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2(nd) EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy. CONCLUSIONS: Our results indicate that a 2(nd) EGFR-TKI treatment can be an effective treatment option for gefitinib responders.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Anciano , Diarrea/inducido químicamente , Clorhidrato de Erlotinib , Exantema/inducido químicamente , Femenino , Gefitinib , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/efectos adversos , Retratamiento , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Afatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity. METHODS: This single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with EGFR mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire. RESULTS: Forty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1-91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively. CONCLUSIONS: Prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).