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BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Humanos , Compuestos de Anilina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , 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 , Mutación , Pemetrexed/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
INTRODUCTION: Biomarkers for predicting the outcome of ipilimumab plus nivolumab (Nivo-Ipi) treatment in cancer patients have not been identified. Herein, we investigated the prognostic significance of inflammatory and nutritional markers in patients with advanced non-small cell lung cancer (NSCLC) receiving Nivo-Ipi. METHODS: Our study retrospectively analyzed 101 patients with advanced NSCLC who received Nivo-Ipi at a single institution. Inflammatory and nutritional indices were correlated with patient outcomes and included the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). RESULTS: The NLR significantly correlated with the PLR, SII, PNI, ALI, and GPS. Regarding therapeutic efficacy, the NLR, SII, and PNI predicted a partial response, and all indices predicted progressive disease. In subgroup analyses, the SII, PNI, and ALI predicted the outcome of patients with adenocarcinoma, whereas only the PNI predicted the outcome of patients with non-adenocarcinoma. The PNI and SII were the most useful indices in patients with a programmed death ligand-1 expression level of <1% and ≥1%, respectively. CONCLUSION: The NLR, PLR, SII, PNI, ALI, and GPS were significantly associated with the outcome of Nivo-Ipi treatment in patients with NSCLC. The PNI was the most suitable marker regardless of histological type. The SII and PNI were the most promising markers for patients with and without PD-L1 expression, respectively.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Nivolumab , Ipilimumab/uso terapéutico , Estudios Retrospectivos , Recuento de Linfocitos , Pronóstico , Inflamación/tratamiento farmacológico , Neutrófilos/patologíaRESUMEN
INTRODUCTION: Established biomarkers for predicting chemoradiotherapy efficacy for limited-disease small cell lung cancer (LD-SCLC) are lacking. The inflammation-based Glasgow Prognostic Score (GPS), comprising serum C-reactive protein (CRP) and albumin levels, can predict survival in advanced cancer. This study investigated whether metabolic and inflammatory markers, including the GPS, can predict the efficacy of chemoradiotherapy in patients with LD-SCLC. METHODS: We retrospectively analyzed 124 patients who underwent chemoradiotherapy for LD-SCLC at two institutions between April 2007 and June 2021, and assessed the prognostic significance of various metabolic and inflammatory markers. The GPS was calculated using the CRP and albumin concentrations, and categorized as follows: 0, CRP<1.0 mg/dL and albumin≥3.5 mg/dL; 1, elevated CRP or decreased albumin; and 2, CRP≥1.0 mg/dL and albumin<3.5 mg/dL. Differences in progression-free survival (PFS) and overall survival (OS) were examined using Kaplan-Meier curves and Cox proportional-hazard models. RESULTS: The overall response rate was 95.1% (95% confidence interval [CI]: 89.6-97.9%). The median PFS and OS from chemoradiotherapy initiation were 12.6 (95% CI: 9.9-15.4) and 29.0 (95% CI: 24.8-45.5) months, respectively. The GPS demonstrated independent predictive ability for the effectiveness of chemoradiotherapy, wherein favorable scores (GPS 0-1) were significantly correlated with superior PFS and OS compared to unfavorable scores (GPS 2: PFS: 14.8 vs. 6.7 months, p=0.0001; OS: 35.4 vs. 11.0 months, p<0.0001). CONCLUSION: This preliminary examination revealed that the GPS was significantly associated with PFS and OS in patients undergoing chemoradiotherapy for LD-SCLC, indicating its potential utility in assessing the therapeutic outcomes in LD-SCLC.
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OBJECTIVE: Cancer is a well-known risk factor for venous thromboembolism. The D-dimer level is used to predict venous thromboembolism; however, reports on an appropriate D-dimer cut-off value in Japanese patients with advanced lung cancer are lacking. Therefore, this study aimed to calculate the D-dimer cut-off value for venous thromboembolism at the time of lung cancer diagnosis. METHODS: The Rising-venous thromboembolism/NEJ037 study was a multicenter, prospective observational study. Patients with lung cancer who were contraindicated for radical resection or radiation were enrolled and followed up for 2 years. In the present study (jRCT no. 061180025), a receiver operating characteristic curve for D-dimer levels was created using the dataset of the Rising-venous thromboembolism/NEJ037 study. RESULTS: The Rising-venous thromboembolism/NEJ037 study included a total of 1008 patients, of whom 976, whose D-dimer levels had been measured at the time of cancer diagnosis, were included in the present study. At the time of lung cancer diagnosis, 62 (6.3%) and 914 (93.7%) patients presented with and without venous thromboembolism, respectively. The D-dimer values ranged from 0.1 to 180.1 µg/ml and from 0.1 to 257.2 µg/ml in patients with and without venous thromboembolism, respectively. The receiver operating characteristic curve was discriminative with a cut-off value of 3.3 µg/ml and an area under the curve of 0.794 (sensitivity, 0.742; specificity, 0.782; 95% confidence interval, 0.725-0.863). CONCLUSIONS: This is the first study to calculate the D-dimer cut-off value in Japanese patients with advanced lung cancer. Patients with D-dimer levels ≥3.3 µg/ml at the time of initial diagnosis may have coexisting venous thromboembolism.
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BACKGROUND: The relationship between antinuclear antibody (ANA) and the efficacy of programmed death-1 (PD-1) blockade remains controversial. Here, we investigated the prognostic significance of ANA titer in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab monotherapy as the first-line treatment, compared with that of platinum-based chemotherapy with PD-1 blockade. METHODS: Our clinical data based on the ANA titer (1:80) were retrospectively reviewed for patients with advanced NSCLC, who were treated with first-line pembrolizumab monotherapy and platinum-based chemotherapy with PD-1 blockade. Immunohistochemical staining for tumor-infiltrating lymphocytes such as CD4, CD8 and Foxp3 was performed. RESULTS: Among 106 patients treated with pembrolizumab, 19 (17.9%) tested high for ANA. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high ANA than in those with low ANA, and high ANA was identified as an independent prognostic predictor, particularly in the subgroup with programmed death ligand-1 (PD-L1) ≥ 50%. However, no statistically significant difference in PFS and OS based on the ANA titer was observed in 59 patients treated with combinational chemotherapy and immunotherapy. High numbers of intratumoral Foxp3 and stromal CD8 were significantly associated with low ANA. CONCLUSIONS: Assessment of preexisting ANA titers was useful to prognose PD-1 blockade as a first-line setting, particularly for the PD-L1 ≥ 50% subgroup, but not in the case of combined immunotherapy and chemotherapy.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/metabolismo , Anticuerpos Antinucleares/uso terapéutico , Pronóstico , Estudios Retrospectivos , Receptor de Muerte Celular Programada 1 , Relevancia Clínica , Factores de Transcripción Forkhead/uso terapéuticoRESUMEN
Most multigene mutation tests require tissue specimens. However, cytological specimens are easily obtained in the clinical practice and provide high-quality DNA and RNA. We aimed to establish a test that utilizes cytological specimens and performed a multi-institutional study to investigate the performance of MINtS, a test based on next-generation sequencing. A standard procedure for specimen isolation was defined. The specimens were considered suitable for the test if >100 ng DNA and >50 ng RNA could be extracted from them. In total, 500 specimens from 19 institutions were investigated. MINtS detected druggable mutations in 63% (136 of 222) of adenocarcinomas. Discordant results between MINtS and the companion diagnostics were observed in 14 of 310 specimens for the EGFR gene, and 6 of 339 specimens for the ALK fusion genes. Confirmation by other companion diagnostics for the EGFR mutations or the clinical response to an ALK inhibitor all supported the results obtained by MINtS. MINtS along with the isolation procedure presented in the current study will be a platform to establish multigene mutation tests that utilize cytological specimens. UMIN000040415.
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Neoplasias Pulmonares , Humanos , Citología , Neoplasias Pulmonares/patología , Mutación , Proteínas Tirosina Quinasas Receptoras/genética , ARNRESUMEN
One-day or two-day intervals are generally inserted into scheduled conditioning regimens for allogeneic hematopoietic cell transplantation, primarily due to various social circumstances, such as unexpected natural adversities, abrupt deterioration of patient health, and delays in graft source arrival. We compared the clinical outcomes of patients with interrupted conditioning with those with ordinarily scheduled conditioning. We analyzed 83 patients (children and adolescents) with oncologic disease who underwent myeloablative conditioning with total body irradiation. Overall and event-free survival were similar between the groups ( P =0.955, P =0.908, respectively). Non-relapse mortality and relapse rates were similar between the groups ( P =0.923, P =0.946, respectively). The engraftment rate was not affected by interruption ( P =1.000). In contrast, the incidence of chronic graft-versus-host disease (GVHD) was higher in the interrupted group compared with the scheduled group, although there was no statistical significance (42% vs. 19%, P =0.063). Conditioning interruption was identified to be an independent risk factor for chronic GVHD by multivariate analysis (odds ratio: 3.72; 95% CI: 1.04 to 13.3; P =0.043). In conclusion, apart from the incidence of chronic GVHD, clinical outcomes were not affected by one-day or two-day intervals during conditioning.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Niño , Adolescente , Humanos , Enfermedad Injerto contra Huésped/etiología , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Factores de Riesgo , Acondicionamiento Pretrasplante/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Management of cancer-associated venous thromboembolism (VTE) is essential in cancer treatment selection and prognosis. However, currently, no method exists for assessing VTE risk associated with advanced lung cancer. Therefore, we assessed VTE risk, including driver gene mutation, in advanced lung cancer and performed a Khorana score validation. METHODS: The Rising-VTE/NEJ037 study was a multicenter prospective observational study that included patients with advanced lung cancer. In the Rising-VTE/NEJ037 study, the Khorana score was calculated for enrolled patients with available data on all Khorana score components. The modified Khorana score was based on the body mass index of ≥ 25 kg/m2, according to the Japanese obesity standard. A multivariate logistic regression analysis, including patient background characteristics, was performed to evaluate the presence of VTE 2 years after the lung cancer diagnosis. RESULTS: This study included 1008 patients with lung cancer, of whom 100 (9.9%) developed VTE. From the receiver operating characteristic curve analysis, VTE risk could not be determined because both the Khorana score (0.518) and modified Khorana score (0.516) showed very low areas under the curve. The risk factors for VTE in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2 and diastolic blood pressure. CONCLUSION: The Khorana score, which is widely used in cancer-VTE risk assessment, was less useful for Japanese patients with advanced lung cancer. Prothrombin fragment 1 + 2, a serum marker involved in coagulation, was more suitable for risk identification. CLINICAL TRIAL INFORMATION: jRCTs061180025.
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Neoplasias Pulmonares , Tromboembolia Venosa , Humanos , Femenino , Tromboembolia Venosa/genética , Estudios Prospectivos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/genética , Factores de Riesgo , Pronóstico , Medición de Riesgo , Estudios RetrospectivosAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirimidinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Receptores ErbB/genéticaRESUMEN
BACKGROUND: Small-cell lung cancer (SCLC) accounts for 12-15% of lung cancers and has a limited prognosis, with approximately one-third of SCLC patients having a poor performance status (PS). Patients with extensive-stage (ES) SCLC and a poor PS have a poor prognosis. For this population, overall survival from carboplatin and etoposide treatment is 7-8 months, and treatment development is an unmet medical need. Recently, the combination of an anti-PD-L1 (a ligand for programmed cell death 1) antibody and platinum-based chemotherapy has become the standard of care for ES-SCLC patients with a good PS (PS 0-1). We hypothesized that the combination of the anti-PD-L1 antibody durvalumab with carboplatin and etoposide would be feasible and effective for such patients. METHODS: We initiated a multicenter phase II study of durvalumab combined with carboplatin and etoposide in previously untreated ES-SCLC patients with a poor PS (PS 2-3). Eligible patients will receive durvalumab plus carboplatin and etoposide every 3 to 4 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. The dosages of carboplatin and etoposide for the second and subsequent cycles will be adaptively determined based on the adverse events of the first cycle. A total of 56 patients (43 patients with a PS of 2 and 13 patients with a PS of 3) will be enrolled in this study, with a 24-month enrollment period and a 12-month follow-up. The primary endpoint is the tolerability of carboplatin and etoposide plus durvalumab in previously untreated ES-SCLC patients with a poor PS. The secondary endpoints are the 1-year survival rate, objective response rate, progression-free survival, overall survival, ratio of PS improvement, and safety. DISCUSSION: The results of this study are intended to establish the safety and efficacy of carboplatin and etoposide plus durvalumab in patients with ES-SCLC and a poor PS. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT), jRCTs031200319. Registered 21 January 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs031200319.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carboplatino , Etopósido , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. METHODS: The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. RESULTS: This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18-24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments. CONCLUSIONS: The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Leucocitos Mononucleares/metabolismo , Nivolumab/farmacología , Nivolumab/uso terapéutico , Linfocitos T Reguladores/metabolismo , Antígeno B7-H1/metabolismoRESUMEN
BACKGROUND: Nedaplatin and nab-paclitaxel are each efficacious in the treatment of squamous cell lung cancer. PATIENTS AND METHODS: Eligibility criteria were: no prior chemotherapy, advanced squamous cell lung cancer; performance status 0-1, age > 20 years but < 75 years, and adequate hematologic, hepatic and renal function. Patients received escalating doses of nab-paclitaxel under a fixed dose of nedaplatin (100 mg/m2, day 1) every 3 weeks in phase I. The initial nab-paclitaxel dose was 100 mg/m2 on days 1 and 8 (level 1), and the next dose was 100 mg/m2 on days 1, 8, and 15 (level 2). In phase II, patients received the recommended doses. The primary endpoint was tumor response rate. RESULTS: In phase I, three patients at level 1 experienced no dose-limiting toxicities (DLTs) and two patients at level 2 experienced DLTs. Level 1 was thus determined as the recommended dose. Twenty-three patients were enrolled in phase II. The 3 patients in level 1 and 23 patients in phase II were included together for analyses. Three of these 26 patients were excluded from response analysis due to pneumonia and patient refusal. Response rate was 91.3% (95% confidence interval, 72.0-98.9%). Toxicities observed during all cycles were tolerable. CONCLUSIONS: The recommended dose for this combination was nedaplatin at 100 mg/m2 on day 1 and nab-paclitaxel at 100 mg/m2 on days 1 and 8 every 3 weeks. The combination of nedaplatin and nab-paclitaxel appears safe and efficacious in patients with untreated advanced squamous cell lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Adulto Joven , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Paclitaxel/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/etiología , Células Epiteliales/patologíaRESUMEN
OBJECTIVES: Only a few prospective studies have been conducted to examine the efficacy and safety of systemic chemotherapy for patients with pulmonary sarcomatoid carcinomas (PSCs). There is, thus, a crucial need to develop novel treatment strategies for this rare tumor. PATIENTS AND METHODS: Chemotherapy-naïve patients with histologically confirmed PSCs were assigned to receive either carboplatin/paclitaxel alone (CP) or with bevacizumab (CPB) followed by bevacizumab maintenance. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. RESULTS: This study was closed before accumulating the expected number of cases due to slow patient accrual. Eventually, 16 patients were enrolled. The ORR was 25.0% and disease control rate was 56.3%. CPB was administered in all four patients with an objective response [partial response (PR)]; among the four PR cases, two patients had pleomorphic carcinoma, and two had carcinosarcoma. Median PFS and median survival time (MST) in all the enrolled patients were 2.6 months and 8.8 months, respectively. Median PFS was 1.2 months in the CP group and 4.2 months in the CPB group. In addition, MST was 7.9 months in the CP group and 11.2 months in the CPB group. Hematological and non-hematological adverse events were common and reversible, although ileus (grade 4) and nasal bleeding (grade 3) occurred in one case each in the CPB group. CONCLUSIONS: CPB might be effective as first-line treatment for PSCs. Further study is warranted to clarify the role of cytotoxic chemotherapy for this rare and aggressive tumor. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000008707).
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Carcinoma , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carboplatino/efectos adversos , Carcinoma/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Paclitaxel/efectos adversos , Estudios ProspectivosRESUMEN
BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Childhood cancer survivors are at an increased risk of impaired renal function. The aim of the present study was to assess the frequency of and risk factors for long-term renal dysfunction in patients with solid tumors using the estimated glomerular filtration rate (eGFR). METHODS: We retrospectively evaluated eGFR in 52 patients with solid tumors (25 females, 27 males) who received chemotherapy and were regularly followed up in our institute. Decreased eGFR was defined as <90 ml/min/1.73 m2 . Cases under treatment and of death were excluded. RESULTS: Median age at the diagnosis of the primary disease was 2.4 years (range, 0.0-23.9 years) and the median follow-up period was 98.4 months (range, 14.4-231.6 months). The mean cumulative incidence of decreased eGFR was 24.7 ± 2.2%. Multivariate analysis showed that decreased eGFR correlated with an older age at diagnosis (≥2.3 years) (hazard ratio 7.330, p = 0.018). CONCLUSION: Although previous studies have indicated that the risk of long-term nephrotoxicity is higher in patients treated at a younger age, the present study showed that patients treated at an older age were at an increased risk of decreased eGFR.
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Neoplasias , Insuficiencia Renal , Masculino , Femenino , Humanos , Niño , Estudios Retrospectivos , Tasa de Filtración Glomerular , Neoplasias/complicaciones , Factores de Riesgo , Riñón/fisiologíaRESUMEN
BACKGROUND: Lymphocyte reconstitution after hematopoietic stem cell transplantation (HSCT) is important for the prevention of infections, as well as for the reduction of recurrence, by its graft versus tumor effect. However, these lymphocytes may also play a role in the development of graft-versus-host disease (GVHD). Few studies have investigated the association between lymphocyte reconstitution and clinical outcomes after HSCT. METHODS: This issue was investigated by retrospectively analyzing pediatric patients who received their first allogeneic-HSCT using a newly developed parameter, the LD-index, which evaluates both the intensity and duration of lymphopenia. A total of 101 patients underwent allo-HSCT from April 2007 to August 2019 in our hospital. Excluding patients who died before lymphocyte recovery or underwent multiple HSCT, 78 patients were analyzed for associations between the LD-index with various factors relating to HSCT. RESULTS: A significantly high association was observed between a low LD-index and the incidence of chronic GVHD (P = 0.0019). Analysis of predictive factors for chronic GVHD was carried out using univariate analysis. Lower LD-index, donor source and duration of lymphopenia were found to be significant factors associated with chronic GVHD. Multivariate analysis, however, only identified an association between a lower LD-index and an increased incidence of chronic GVHD (P = 0.00081). CONCLUSIONS: Early reconstitution of lymphocytes after allo-HSCT is associated with a higher incidence of chronic GVHD.
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Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Linfopenia , Humanos , Niño , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Linfocitos , Linfopenia/complicacionesRESUMEN
OBJECTIVE: Monitoring quality of life (QoL) in patients with cancer can provide insight into functional, psychological and social consequences associated with illness and its treatment. The primary objective of this study is to examine the influence of cultural factors on the communication between the patient and the health care provider and the perceived QoL in women with breast cancer in Japan and the Netherlands. METHODS: In Japanese and Dutch women with early breast cancer, the number, content and frequency of QoL-related issues discussed at the medical encounter were studied. Patients completed questionnaires regarding QoL and evaluation of communication with the CareNoteBook. RESULTS: The total number, frequency and content of QoL-related issues discussed differed between the two countries. Japanese women (n = 134) were significantly more reticent in discussing QoL-issues than the Dutch women (n = 70) (p < .001). Furthermore, Dutch patients perceived the CareNoteBook methodology significantly more positively than the Japanese patients (p < .001). Both groups supported the regular assessment via a CareNoteBook methodology. CONCLUSIONS: Japanese women are more reluctant in expressing their problems with the illness, its treatment and patient-physician communication than Dutch women.
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Neoplasias de la Mama , Calidad de Vida , Neoplasias de la Mama/psicología , Neoplasias de la Mama/terapia , Femenino , Humanos , Japón , Relaciones Médico-Paciente , Calidad de Vida/psicología , Encuestas y CuestionariosRESUMEN
BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), the impact of first-line treatment on overall survival (OS) may be influenced by subsequent therapies. Thus, using patient-level data, we assessed the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS among patients with high-programmed death-ligand 1 (PD-L1) expression undergoing first-line pembrolizumab monotherapy for NSCLC. METHODS: We reviewed data from 133 patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC at 6 Japanese centers between February 2017 and December 2018. The correlations of PFS and PPS with OS were evaluated at the patient level. RESULTS: Linear regression analyses and Spearman's rank correlation coefficient revealed that PPS was strongly correlated with OS (r = 0.76, p < 0.05, R2 = 0.65), while PFS was only moderately correlated with OS (r = 0.71, p < 0.05, and R2 = 0.4). Furthermore, PPS was significantly associated with performance status at the end of pembrolizumab monotherapy, as well as the use of platinum-based combination chemotherapy after pembrolizumab monotherapy (both p < 0.05). CONCLUSIONS: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, PPS was more strongly correlated with OS, relative to the relationship between PFS and OS. Therefore, subsequent treatment appears to significantly influence OS in patients with disease progression following first-line pembrolizumab monotherapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/farmacología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). METHODS: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. RESULTS: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. CONCLUSION: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. TRIAL REGISTRATION: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).
Asunto(s)
Afatinib/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Afatinib/administración & dosificación , Afatinib/efectos adversos , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Relación Dosis-Respuesta a Droga , Receptores ErbB/antagonistas & inhibidores , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/epidemiología , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Enfermedades de la Piel/inducido químicamenteRESUMEN
BACKGROUND: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are more likely to have chemotherapy-related complications than children. In addition, several reports have shown that infections account for most of the therapy-related mortality during cancer treatment in AYAs. Thus, we hypothesized that chemotherapy-induced myelosuppression is more severe in AYAs than in children, and the state of neutropenia was compared between children and AYAs using the D-index, a numerical value calculated from the duration and depth of neutropenia. PROCEDURE: This study retrospectively analyzed 95 patients newly diagnosed with ALL at our institution between 2007 and 2019. Of these, 81 were children (<15 years old) and 14 were AYAs (≥15 years old). The D-index and duration of neutropenia during induction chemotherapy for ALL were compared between children and AYAs. RESULTS: The median D-index of children was significantly higher than that of AYAs (8187 vs 6446, respectively, P = .017). Moreover, the median duration of neutropenia was also significantly longer in children than in AYAs (24.0 days vs 11.5 days, respectively, P = .007). CONCLUSION: Contrary to our expectations, myelosuppressive toxicity during induction chemotherapy for ALL was more severe in children than in AYAs.