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1.
Front Oncol ; 10: 587849, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33244458

RESUMO

Background: Erlotinib-based combination therapy leads to increased efficacy but also toxicity for EGFR-mutated NSCLC. Reducing the dose of erlotinib could improve treatment tolerability, but few evidences are available regarding its efficacy at reduced dose. This randomized phase-2 study intends to compare the efficacy and tolerability between lower dose erlotinib (100 mg/d) and standard dose gefitinib (250 mg/d) in EGFR-mutated NSCLC. Methods: Patients with EGFR-mutated advanced NSCLC were randomized at 1:1 ratio to receive erlotinib 100 mg/d or gefitinib 250 mg/d until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). Results: Between April 2013 and September 2018, 171 patients were randomized to receive erlotinib (n = 85) and gefitinib (n = 86); 74 in the erlotinib group and 83 in the gefitinib group were include in analysis. DCR with erlotinib and gefitinib were 91% [95% CI 81.7-95.3] and 93% [85.1-96.6], respectively (P = 0.613). Response rate was 62% [50.8-72.4] in the erlotinib group and 53% [42.4-63.4] in the gefitinib group (P = 0.247). No significant difference was observed between erlotinib and gefitinib in median progression-free survival [10.1 vs. 11.3 months, HR = 1.295 [0.893-1.879], P = 0.171] and median overall survival [26.6 vs. 28.7 months, HR = 0.999 [0.637-1.569], P = 0.998]. Subgroup analyses by line of treatment, EGFR subtypes and status of central nervous system (CNS) metastasis found similar results. More toxicity [any-grade, 80 [96%] vs. 66 [89]; grade 3-4, 11 [13%] vs. 4 [5%]] and toxicity-related discontinuation [10 [12%] vs. 3 [4%]] occurred with gefitinib compared with erlotinib. But no significant difference was observed. Conclusion: Lower dose erlotinib (100 mg/d) achieved comparable efficacy compared with standard dose gefitinib (250 mg/d) in EGFR-mutated NSCLC. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT01955421.

2.
Cancer Manag Res ; 12: 10353-10360, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116890

RESUMO

Purpose: The purpose of this study was to evaluate the anti-tumor activity and safety of anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with gemcitabine plus platinum (GP) as a first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). Patients and Methods: This retrospective study analyzed RM-NPC patients at Sun Yat-sen University Cancer Center who received anti-EGFR antibody plus GP as a first-line treatment between July 2007 and November 2018. Survival analyses were performed using the Kaplan-Meier method with Log rank test. Cox proportional hazards model was used for the multivariate analysis. Results: A total of 84 patients were enrolled. The median progression-free survival (PFS) was 10.3 months (95% CI, 6.9-13.6 months), and the median overall survival (OS) was 42.8 months (95% CI, 24.6-60.9 months). The objective response rate and disease control rate were 67.9% and 92.9%, respectively. The multivariate analysis identified a higher baseline EBV DNA level as a risk factor for both PFS (P=0.025) and OS (P=0.013). Additionally, age≥44 years (P =0.003), non-cisplatin (P= 0.009), and poor KPS (≤80) (P =0.034) were other risk factors for OS. The most common adverse events were leukopenia (n=73, 86.9%). The most common grade 3-4 AEs were leukopenia (n=30, 35.7%) and thrombocytopenia (n=22, 26.2%). Conclusion: Anti-EGFR monoclonal antibody plus GP achieved promising antitumor activity with a tolerable toxicity profile in RM-NPC as a first-line treatment. Randomized clinical trials are warranted to compare the efficacy of GP with or without anti-EGFR antibody in these patients.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32989605

RESUMO

BACKGROUND: Previous researches have indicated physical activity (PA) may be associated with lower risk of lung cancer. However, causal relationship between PA and risk of lung cancer is not clear. We aimed to inspect the causal effect of PA on lung cancer. METHODS: We analyzed summary data of accelerator-measured PA and lung cancer from the genome-wide association study (GWAS) using two-sample Mendelian randomization (MR) method. We obtained summary data of accelerator-measured PA from UK Biobank, data of lung cancer patients from Consortium and International Lung Cancer Consortium (ILCCO) to investigate possible causal effect of PA on lung cancer. RESULTS: According to result of MR using inverse variance weighted method (IVW), we found that genetically predicted higher PA level did not causally decrease risk of lung cancer (OR 0.95, 95% CI 0.88-1.03, p = 0.238). Results of MR-Egger and weighted median method were consistent with IVW method. CONCLUSION: Our mendelian randomization study showed that genetically higher PA is not causally associated with risk of lung cancer. More researches are needed to investigate relationship between PA and lung cancer.

4.
Transl Lung Cancer Res ; 9(3): 471-483, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32676311

RESUMO

Background: Osimertinib is a potent third-generation EGFR tyrosine kinase inhibitor (TKI) with robust activity in advanced EGFR-mutant non-small cell lung cancer (NSCLC), including those with T790M resistance mutation. However, a broad interpatient variability was observed. This study aimed to evaluate whether EGFR-mutant genotypes affect the clinical outcomes and resistance mechanisms in T790M-positive NSCLC patients receiving osimertinib therapy. Methods: All NSCLC patients treated with osimertinib in our institute were screened. We included those with known EGFR-mutant genotypes and T790M positivity. Clinical outcomes including objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS), were evaluated and compared between different EGFR genotypes. Patients with next-generation sequencing testing or tumor rebiopsy after osimertinib treatment were analyzed for resistance mechanisms. Results: ORR, CBR, PFS, and OS were all non-significantly different among patients harboring EGFR exon 19 deletion (19Del, n=136), L858R (n=93), and uncommon mutations (n=6). However, a subset of tumors with deletion starting at E746 (ΔE746, n=98), but not non-ΔE746 tumors (n=38), had better clinical outcomes than L858R tumors (n=93). Frequencies of T790M loss and C797S acquisition after osimertinib treatment were similar between 19Del (n=56) and L858R tumors (n=33). However, compared with L858R tumors (n=33), those with 19Del ΔE746 subtype (n=40) had a higher whereas non-ΔE746 subtype (n=16) had a similar frequency of acquired C797S mutation. Combined analysis of our cohort and public cohort confirmed these findings. Conclusions: Our findings indicate that the EGFR 19Del subtypes affect the clinical outcomes and resistance mechanisms to osimertinib in T790M-positive patients. Identifying patients with relatively worse treatment outcomes may be informative for establishing new therapies for these patients.

5.
Support Care Cancer ; 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728801

RESUMO

INTRODUCTION: Patient-reported outcomes (PROs) have been widely accepted in western countries. However, limited attention has been given to PROs in China due to a lack of research on the agreement between doctors' and patients' reports of adverse events. This study aims to reveal the perception gap of chemotherapy-induced adverse events between doctors and cancer patients in China. METHODS: An observational study was administered at Sun Yat-Sen University Cancer Center (SYSUCC). Totally, 200 adult cancer patients undergoing chemotherapy participated. Patient reports were collected by nurses via telephone. Doctor reports were collected by nurses based on their medical records. The agreement between doctors and patients was analyzed by Cohen's κ. RESULTS: Agreement between doctors and patients varied among different symptoms: 0.26 for nausea/vomiting, 0.49 for constipation, 0.63 for diarrhea, 0.65 for general pain, and 0.76 for rash. Doctors' underreporting rates were 70% for nausea/vomiting, 50% for diarrhea, 38% for rash, 33% for constipation, and 29% for general pain. CONCLUSIONS: The perception gap of chemotherapy-induced adverse events between doctors and patients exists in China, especially regarding subjective symptoms. Introduction of PROs in both clinical trials and routine clinical practice should be considered in China.

6.
Clin Transl Med ; 10(1): 107-115, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32508007

RESUMO

BACKGROUND: Nivolumab plus ipilimumab (N-I) or pembrolizumab (PEM) is associated with survival improvement as chemotherapy-free, first-line treatment for patients with advanced non-small cell lung carcinoma (NSCLC) and positive programmed cell death ligand 1 (PD-L1). However, no direct comparison data exist between these two regimens to inform clinical decisions. Therefore, we performed indirect comparison for N-I versus PEM using frequentist methods. RESULTS: Three randomized trials (KEYNOTE-024, KEYNOTE-042, and CheckMate 227) involving 2372 patients were included. For patients with tumor PD-L1 level of ≥1%, pooled meta-analyses showed that both N-I and PEM improved overall survival (OS) relative to chemotherapy (N-I: hazard ratio [HR] 0.82, 95% CI 0.69-0.97; PEM: HR 0.81, 95% CI 0.71-0.93); whereas only N-I significantly improved progression-free survival (PFS) (N-I: HR 0.79, 95% CI 0.65-0.96; PEM: HR 1.07, 95% CI 0.94-1.21). Neither N-I nor PEM was associated with improved objective response rate (ORR) compared with chemotherapy (N-I: relative risk [RR] 1.20, 95% CI 0.98-1.46; PEM: RR 1.03, 95% CI 0.86-1.23). Indirect comparisons showed that N-I was associated with longer PFS than PEM (HR 0.77, 95% CI 0.62-0.95). However, N-I was not superior to PEM in terms of OS (HR 0.98, 95% CI 0.77-1.24) and ORR (RR 1.17, 95% CI 0.89-1.52). N-I showed a less favorable toxicity profile relative to PEM (all grade adverse events: RR 1.28, 95% CI 1.17-1.40). CONCLUSIONS: N-I and PEM provide comparable OS benefit for PD-L1-positive NSCLC. N-I further improves PFS relative to PEM but at meaningful cost of toxicities.

8.
Clin Transl Med ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32508029

RESUMO

BACKGROUND: Dual blockade of both EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced antitumor efficacy versus EGFR-TKIs alone. Apatinib is an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI). This pilot study aims to evaluate the tolerability, pharmacokinetic profile, and antitumor activity of apatinib plus gefitinib as a therapy for EGFR-mutant advanced NSCLC. METHODS: Advanced non-squamous NSCLC participants harbored with the EGFR 19 deletion or the 21 L858R point mutation were included. There were two cohorts: Cohort A: apatinib 500 mg + gefitinib 250 mg. Cohort B: apatinib 250 mg + gefitinib 250 mg. The primary endpoint was safety profile. Other endpoints consisted of PK analysis, objective response rate (ORR), and progression-free survival (PFS). Exploratory analysis was conducted using next-generation sequencing of plasma circulating-tumor DNA. RESULTS: Between July 2016 and April 2017, 13 of NSCLC patients were recruited. Six patients were pooled in Cohort A, while seven patients were in Cohort B. Adverse events (AEs) were tolerable (mostly grade 1-2) and the treatment-related AEs were similar in both cohorts: rash (100% vs 71.4%), diarrhea (66.7% vs 71.4%), hypertension (66.7% vs 71.4%), proteinuria (66.7% vs 42.9%), and hand-foot skin reaction (33.3% vs 28.6%). The area under plasma concentration-time curve for the steady state of apatinib was 2864.73 ± 2605.54 ng mL-1  h-1 in Cohort A and 2445.09 ± 1550.89 ng mL-1  h-1 in Cohort B. Of the 11 patients evaluable for efficacy, Cohort A achieved an ORR of 80.0% and reached a median PFS of 19.2 months, while it was 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a prolonged PFS tendency (20.99 months v 13.21 months, P = .0624). The EGFR-T790M mutation remained the dominant resistance mechanism. CONCLUSION: Apatinib (500 mg) plus gefitinib (250 mg) showed a tolerable safety profile and encouraging antitumor activity for advanced EGFR-mutant NSCLC in the first-line setting. Phase III trials of apatinib (500 mg) plus gefitinib (250 mg) are warranted. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02824458, date of registration June 23, 2016.

9.
Oncologist ; 25(8): 650-e1145, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32134163

RESUMO

LESSONS LEARNED: Results of the KEYNOTE-032 study showed that the safety and pharmacokinetic profiles of pembrolizumab in Chinese patients were comparable with those observed in international studies, and antitumor activity was encouraging. These data support further evaluation of pembrolizumab to improve clinical outcomes in Chinese patients with advanced non-small cell lung cancer. BACKGROUND: The KEYNOTE-032 study evaluated pembrolizumab pharmacokinetics and clinical outcomes in Chinese patients with locally advanced and/or metastatic non-small cell lung cancer (NSCLC) and prior treatment failure and/or ineligibility for standard therapy. METHODS: Patients were randomized 1:1:1 to pembrolizumab 2 mg/kg, 10 mg/kg, or 200 mg every 3 weeks (up to 35 cycles). Safety and pharmacokinetics were primary endpoints; antitumor activity was a secondary endpoint. RESULTS: A total of 42 of 44 randomized patients received pembrolizumab treatment (2 mg/kg, n = 14; 10 mg/kg, n = 13; 200 mg, n = 15). Treatment-related adverse events (AEs) occurred in 29 of 42 (69%) patients (grade 3-4, 4/42 [10%]); 5 (12%) had immune-mediated AEs and infusion reactions. Pembrolizumab single dose half-life following 2 mg/kg, 10 mg/kg, and 200 mg was 15.1, 15.8, and 12.3 days, respectively. Serum exposure at the doses studied (range, 2-10 mg/kg) was approximately linear; steady-state area under the curve0-21 days (95% confidence interval [CI]) was 730.9 (627.4-851.6), 2,819.2 (2,009.4-3,955.4), and 931.0 (724.4-1,196.6) µg•day/mL, respectively. After 7.9 (range, 0.7-13.1) months median follow-up overall, objective response rate was 14.3% (95% CI, 5.4%-28.5%); median progression-free survival was 2.1 (95% CI, 2.1-4.2) months, and median overall survival was not reached (95% CI, 6.6 months-not reached). CONCLUSION: Pembrolizumab had manageable toxicity, linear serum exposure, and encouraging antitumor activity in Chinese patients with advanced NSCLC.

10.
Clin Transl Med ; 9(1): 17, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32067121

RESUMO

BACKGROUND: Despite the impressive anti-tumor activity of osimertinib in epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) patients, 30-40% of patients still show limited response. There is therefore a need to identify biomarkers that accurately predict the response to osimertinib therapy. In this study, 54 patients with targeted next-generation sequencing of circulating tumor DNA before osimertinib treatment and known T790M positivity were included. We investigated the predictive value of baseline circulating tumor DNA-derived biomarkers on osimertinib therapy. RESULTS: Baseline maximum somatic allele frequency (MSAF) level was not associated with objective response rate (ORR) (P = 0.886) and progression-free survival (PFS) (P = 0.370) of osimertinib treatment. T790M relative mutation purity (RMP, defined here as the ratio of T790M AF to MSAF) quartiles were found to be significantly associated with ORR (P for trend = 0.002) and PFS (P for trend = 0.006), and a cut off value of 0.24 identified two distinct prognostic groups [Hazard ratio (HR) = 0.36 for low T790M RMP, 95% confidence interval (CI) 0.18-0.72, P = 0.004). Additionally, although T790M relative mutation abundance (RMA, defined as T790M AF/EGFR driver AF) quartiles were not significantly associated with ORR (P for trend = 0.063), a cut off value of 0.30 also identified two distinct prognostic groups (HR = 0.43 for low T790M RMA, 95% CI 0.22-0.85, P = 0.015). However, in multivariate analysis, grouping of T790M RMP showed a better predictive value (HR = 0.46, 95% CI 0.20-1.05, P = 0.066) than T790M RMA (HR = 0.71, 95% CI 0.31-1.61, P = 0.409). Moreover, T790M RMP as continuous covariate was independently predictive of PFS (HR = 0.15, 95% CI 0.03-0.79, P =0.025), while T790M RMA was not (HR = 1.14, 95% CI 0.49-2.66, P =0.766). An external validation cohort further confirmed the T790M RMP was significantly associated with PFS of osimertinib therapy. CONCLUSIONS: This study established the independent predictive role of T790M RMP in NSCLC patients receiving osimertinib treatment.

11.
ESMO Open ; 5(1)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32054633

RESUMO

BACKGROUND: Patients with a history of prior cancer are frequently excluded from cancer trials. Previous studies indicated that prior cancer does not adversely impact clinical outcomes for patients with lung cancer older than 65 years. However, it remains unknown whether these results are applicable to patients with lung cancer aged younger than 65 years old. The study aimed to investigate the impact of prior cancer history on younger patients with lung cancer. METHODS: We identified younger patients with lung cancer (<65 years) diagnosed between 2004 and 2009 in the Surveillance, Epidemiology, and End Results database. Propensity score matching was performed to balance differences in baseline characteristics between groups. Kaplan-Meier method and the Cox proportional hazards model were used to evaluate the impact of prior cancer on overall survival (OS). RESULTS: Among 103 370 eligible patients with lung cancer, 15.18% had a history of prior cancer. Lung and bronchus (25.83%), breast (14.13%), prostate (8.85%) and cervix uteri (4.74%) were the most common prior cancer types. Of prior cancers, 61.56% are localised and regional stages. More than 67.98% of prior cancers were diagnosed within 5 years of the index lung cancer diagnosis. The median times of diagnosis for prior cancers were 38 months. Patients with prior cancer had the same/non-inferior OS as that of patients without a prior cancer diagnosis (propensity score-adjusted HR=1.01, 95% CI=0.99 to 1.04, p=0.324). Subgroup analyses stratified by timing of prior cancer displayed almost the same tendency (p>0.05). Interestingly, early-stage patients with a history of prior cancer had adverse survival curves (p<0.05). Advanced-stage patients with prior cancer had non-inferior survival (p>0.05). CONCLUSIONS: A prior cancer diagnosis has a heterogeneous effect on the survival of patients with lung cancer aged <65 years across different stages, but further prospective studies are still warranted.

12.
Cancer Med ; 9(5): 1721-1732, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31955525

RESUMO

BACKGROUND: Platinum-based chemotherapy is the standard of care as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC); however, the prognosis of patients with RM-NPC remains poor. The aim of this study was to evaluate the role of anti-epidermal growth factor receptor (anti-EGFR) antibody plus chemotherapy for RM-NPC. METHODS: RM-NPC patients who received first-line chemotherapy plus an anti-EGFR antibody were recruited from Sun Yat-Sen University Cancer Center between July 2007 and November 2017. Survival analyses were performed using the Kaplan-Meier method with a log-rank test. A Cox proportional hazards model was used for the multivariate analyses. RESULTS: A total of 203 patients were enrolled in the present study. The median follow-up time was 34.3 months (interquartile range: 19.7-66.5 months). The median progression-free survival (PFS) was 8.9 months (95% CI: 7.7-10.0 months) and the median overall survival (OS) was 29.1 months (95% CI: 23.5-34.6 months). The 1-, 3-, and 5-year PFS and OS rates were 35.5% and 79.6%, 15.2% and 42.5%, and 11.6% and 23.6%, respectively. The objective response rate (ORR) was 67.5% and the disease control rate (DCR) was 91.1%. The multivariate analysis identified the following prognostic factors for PFS: anti-EGFR agent (P = .010), recurrence/metastasis sequence (P = .016), KPS (P = .017), and combined chemotherapy regimen (P = .015). Independent risk factors for OS included age >43 years (P = .002), Karnofsky performance score ≤80 (P < .001), and higher level of baseline Epstein-Barr virus (EBV) DNA (P = .008). Leukopenia was the most common adverse event (AE) in this cohort (any grade, 84.2%; grades 3-4, 43.4%). CONCLUSIONS: Anti-EGFR antibody plus chemotherapy achieved promising antitumor activity with a tolerable toxicity profile in RM-NPC. Thus, randomized clinical trials are warranted to compare the efficacy of chemotherapy with or without anti-EGFR antibody in these patients.

13.
J Immunother Cancer ; 7(1): 322, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753012

RESUMO

BACKGROUND: Hepatitis B virus (HBV) reactivation is a serious complication in patients with cancers and HBV infection undergoing immunosuppressant treatment or chemotherapy. However, the safety of anti-programmed cell death (PD) -1 and anti-programmed cell death-ligand 1 (PD-L1) therapy in these patients is unknown because they were excluded from clinical trials of immunotherapy. METHODS: This retrospective cohort study involved consecutive hepatitis B surface antigen (HBsAg) -positive cancer patients who were referred to Sun Yat-sen University Cancer Center and received an anti-PD-1/PD-L1 antibody between January 1, 2015 and July 31, 2018. The primary end point was the rate of the occurrence of HBV reactivation. RESULTS: In total, 114 eligible patients were included, among whom 90 (79%) were male, and the median (range) age was 46 (16-76) years. Six patients (5.3%) developed HBV reactivation, occurring at a median of 18 weeks (range, 3-35 weeks) from the commencement of immunotherapy. Among these patients, all of them had undetectable baseline HBV DNA; one had prophylactic antiviral therapy while five did not; four were positive for Hepatitis B e antigen while the other two were negative. At reactivation, the median HBV DNA level was 3.89 × 104 IU/mL (range, 1.80 × 103-6.00 × 107 IU/mL); five had HBV-related hepatitis and one exhibited increasing HBV DNA level without alanine transaminase elevation. No HBV-related fatal events occurred. The lack of antiviral prophylaxis was the only significant risk factor for HBV reactivation (odds ratio, 17.50 [95% CI, 1.95-157.07], P = .004). CONCLUSIONS: HBV reactivation occurs in a subset of HBsAg-positive cancer patients undergoing anti-PD-1 or anti-PD-L1 immunotherapy. Regular monitoring of HBV DNA and antiviral prophylaxis are advised to prevent this potentially fatal complication.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Vírus da Hepatite B/fisiologia , Hepatite B/complicações , Hepatite B/virologia , Neoplasias/complicações , Ativação Viral/efeitos dos fármacos , Ativação Viral/imunologia , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Feminino , Hepatite B/diagnóstico , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
14.
Ann Transl Med ; 7(18): 439, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31700875

RESUMO

Background: With the improvement of survival for non-small cell lung cancer (NSCLC), research focused on second primary malignancy (SPM) in NSCLC survivors is becoming urgent. This study aimed to estimate the risk of SPM in NSCLC patients. Methods: We retrospectively analysed NSCLC patients diagnosed between 2004 and 2010 in SEER database. We firstly evaluated the crude and cumulative incidence of SPM. SPM incidence in NSCLC survivors compared to that in the reference population was calculated as standardized incidence ratio (SIR). A competing risk nomogram was also built, to predict the incidence of SPM. Results: The crude and 10-year cumulative incidences of SPM were 4.04% and 5.05%, respectively, while the SIR was 1.62. The nomogram was well calibrated and had good discriminative ability, with c-index of 0.80. It showed a significantly wide interval of SPM cumulative incidence between the first and tenth-decile according to the risk model (1.04% vs. 16.70%, P<0.05). The decision curve analysis indicated that the clinical net benefit of risk model was larger than that in other scenarios (all-screening or no-screening) in a range of threshold probabilities (1% to 20%). Conclusions: Our study firstly performed a systematic estimation of the incidence of SPM in NSCLC, which implied the necessity of a risk predicting model. We developed the first competing risk nomogram to predict the risk of SPM, which performed well in the evaluation and might be helpful for individualized SPM screening.

15.
Cancer Commun (Lond) ; 39(1): 69, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699150

RESUMO

BACKGROUND: Gefitinib, as the first epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC), has been proved to significantly improve the progression-free survival (PFS) in the first-line setting but suffers from resistance 7-10 months after treatment initiation. Apatinib (YN968D1), a potent vascular endothelial growth factor receptor (VEGFR) 2-TKI, specifically binds to VEGFR2 and leads to anti-angiogenetic and anti-neoplastic effect. Concurrent inhibition of VEGFR and EGFR pathways represents a rational approach to improve treatment responses and delay the onset of treatment resistance in EGFR-mutant NSCLC. This ACTIVE study aims to assess the combination of apatinib and gefitinib as a new treatment approach for EGFR-mutant NSCLC as a first-line setting. METHODS: This multicenter, randomized, double-blind, placebo-controlled phase III study (NCT02824458) has been designed to assess the efficacy and safety of apatinib or placebo combined with gefitinib as a first-line treatment for patients with EGFR-mutant advanced NSCLC. A total of 310 patients with EGFR-mutation (19del or 21L858R), pathological stage IIIB to IV non-squamous NSCLC were to be enrolled. The primary endpoint is investigator assessment of PFS, and the secondary endpoints include independent radiological central (IRC)-confirmed PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to progressive disease (TTPD), duration of response (DoR), quality of life (QoL) and safety. The patients are randomized in a 1:1 ratio to receive gefitinib (250 mg, p.o. q.d.) plus apatinib (500 mg, p.o. q.d.) or gefitinib plus placebo, given until disease progression or intolerable adverse events. Exploratory biomarker analysis will be performed. This study is being conducted across China and comprises of 30 participating centers. Enrollment commenced in August 2017 and finished in December 2018, most of the patients are in the follow-up period. ANTICIPATED OUTCOMES AND SIGNIFICANCE: The present study will be the first to evaluate the efficacy and safety profile of the combination of apatinib plus gefitinib as a first-line therapy for patients with EGFR-positive advanced non-squamous NSCLC. Importantly, this trial will provide comprehensive evidence on the treatment of EGFR-TKIs combined with antiangiogenic therapy. Trial registration Clinicaltrials.gov NCT02824458. Registered 23 June 2016.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Estudos Multicêntricos como Assunto , Mutação , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Lung Cancer ; 137: 100-107, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31568886

RESUMO

OBJECTIVES: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of primary lung cancer. Due to the lack of prospective studies, the optimal first-line chemotherapy regimens and survival outcomes remain unclear. MATERIALS AND METHODS: This real-world, retrospective study enrolled consecutive patients with unresectable pulmonary LELC. The survival outcomes, prognosis, and comparative efficacy of different chemotherapy regimens were investigated. RESULTS: In total, 127 patients were included in the analyses. The first-line chemotherapy regimens included gemcitabine plus platinum (GP, n = 19 [15.0%]), taxanes plus platinum (TP, n = 70 [55.1%]) and pemetrexed plus platinum (AP, n = 38 [30.0%]). 25 (19.7%) patients underwent palliative thoracic radiotherapy. 60 (47.2%) patients had detectable baseline Epstein-Barr virus (EBV) DNA. For the entire cohort, objective response was obtained in 41 patients (32.3%). Median progression-free survival (PFS) and overall survival (OS) were 7.7 months (95% CI, 6.6-8.8) and 36.7 months (95% CI, 30.9-42.5), respectively. Among the three chemotherapy regimens, GP achieved the highest response rate (GP, 63.2% vs. TP, 30.0% vs. AP, 21.1%; p = 0.005). Median PFS in the GP group (8.8 months) was also significantly longer than that in the TP group (7.9 months) and AP group (6.4 months) (p = 0.031). In the multivariate model, cycles of first-line chemotherapy (p < 0.001), palliative thoracic radiotherapy (p < 0.001), and chemotherapy regimens (p = 0.031) remained independent prognostic factors for PFS; while cycles of first-line chemotherapy (p = 0.002), baseline EBV DNA (p = 0.033) and palliative thoracic radiotherapy (p = 0.041) were significantly associated with OS. CONCLUSION: Gemcitabine-based chemotherapy and palliative thoracic radiotherapy are active in pulmonary LELC. These data provide added evidence for the similarity between pulmonary LELC and nasopharyngeal carcinoma in endemic area. Randomized controlled studies are needed to further define the standard-of-care for patients with advanced pulmonary LELC.


Assuntos
Adenocarcinoma de Pulmão/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Quimiorradioterapia/mortalidade , Neoplasias Pulmonares/mortalidade , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/radioterapia , Adenocarcinoma de Pulmão/secundário , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Platina/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem
17.
Ann Transl Med ; 7(14): 299, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31475169

RESUMO

Background: Prior cancer is a common exclusion criterion in nasopharyngeal carcinoma (NPC) trials. However, whether a prior cancer diagnosis affects trial outcomes is still unknown. We aimed to determine the impact of prior cancer on survival in NPC patients. Methods: We identified patients diagnosed with NPC between 2004 and 2009 in the Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by chi-squared test and t-test as appropriate. Propensity score-adjusted Kaplan-Meier methods and Cox proportional hazard models were used to evaluate the impact of prior cancer on overall survival (OS). Results: Among 3,131 eligible NPC patients, 349 (11.15%) patients had a history of prior cancer. The Kaplan-Meier curves did not show a statistically significantly different OS (P=0.19). Subgroup analyses stratified by timing of prior cancer and AJCC TNM stage of index cancer displayed the same tendency: prior cancer did not adversely affect OS compared to patients without prior cancer (P>0.05). Furthermore, in propensity score-adjusted COX models analysis, patients with prior cancer had the same/non-inferior OS [hazard ratio (HR) =1.12; 95% confidence interval, 0.88 to 1.42]. Conclusions: Among patients with NPC, prior cancer does not convey an adverse effect on clinical outcomes, regardless of the timing of prior cancer and AJCC TNM stage of index cancer. Broader inclusion trial criteria could be adopted in NPC patients with a history of prior cancer. However, further studies are still needed to confirm this conclusion.

19.
Nat Commun ; 10(1): 3108, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311932

RESUMO

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare and distinct subtype of primary lung cancer characterized by Epstein-Barr virus (EBV) infection. Herein, we reported the mutational landscape of pulmonary LELC using whole-exome sequencing, targeted deep sequencing and single-nucleotide polymorphism arrays. We identify a low degree of somatic mutation but widespread existence of copy number variations. We reveal predominant signature 2 mutations and frequent loss of type I interferon genes that are involved in the host-virus counteraction. Integrated analysis shows enrichment of genetic lesions affecting several critical pathways, including NF-κB, JAK/STAT, and cell cycle. Notably, multi-dimensional comparison unveils that pulmonary LELC resemble NPC but are clearly different from other lung cancers, natural killer/T-cell lymphoma or EBV-related gastric cancer in terms of genetic features. In all, our study illustrates a distinct genomic landscape of pulmonary LELC and provides a road map to facilitate genome-guided personalized treatment.


Assuntos
Carcinoma/genética , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/isolamento & purificação , Neoplasias Pulmonares/genética , Adulto , Idoso , Carcinoma/terapia , Carcinoma/virologia , Análise Mutacional de DNA , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Genômica , Humanos , Pulmão/patologia , Pulmão/virologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/virologia , Masculino , Pessoa de Meia-Idade , Medicina de Precisão/métodos
20.
Int J Epidemiol ; 48(3): 743-750, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31219597

RESUMO

BACKGROUND: We aimed to investigate whether more years spent in education are causally associated with a lower risk of lung cancer, through a two-sample Mendelian randomization study. METHODS: The main analysis used publicly available genetic summary data from two large consortia [International Lung Cancer Consortium (ILCCO) and Social Science Genetic Association Consortium (SSGAC)]. Genetic variants used as instrumental variables for years of education were derived from SSGAC. Finally, genetic data from three additional consortia (TAG, GLGC, GIANT) were analysed to investigate whether education could causally alter common lung cancer risk factors. The exposure was the genetic predisposition to higher levels of education, measured by 73 single nucleotide polymorphisms from SSGAC. The primary outcome was the risk of lung cancer (11 348 events in ILCCO). Secondary outcomes based on different histological subtypes were also examined. Analyses were performed using the package TwoSampleMR in R. RESULTS: Genetic predisposition towards 3.6 years of additional education was associated with a 52% lower risk of lung cancer (odds ratio 0.48, 95% confidence interval 0.34 to 0.66; P = 1.02 × 10 - 5). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely. The Mendelian randomization assumptions did not seem to be violated. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index and a favourable blood lipid profile. CONCLUSIONS: Our study indicated that low education is a causal risk factor in the development of lung cancer. Further work is needed to elucidate the potential mechanisms.


Assuntos
Adenocarcinoma de Pulmão/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Fumar Cigarros/epidemiologia , Escolaridade , Neoplasias Pulmonares/epidemiologia , Índice de Massa Corporal , Colesterol/sangue , Predisposição Genética para Doença , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Tempo , Triglicerídeos/sangue
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