scholarly journals Prognostic Value of Baseline Medications Plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer: A Retrospective Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Toshiki Ogiwara ◽  
Hitoshi Kawazoe ◽  
Saeka Egami ◽  
Hironobu Hashimoto ◽  
Yoshimasa Saito ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Advanced Nsclc ◽  
Prognostic Score ◽  
Small Cell ◽  
Survival Outcomes ◽  
Cox Proportional Hazard Model ◽  
Proportional Hazard ◽  
Proportional Hazard Model ◽  
Small Cell Lung ◽  
Cox Proportional Hazard

BackgroundNivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting.MethodsWe conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression β coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes.ResultsIn total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1–2), and poor (scores 3–6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07–2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed.ConclusionsThe findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.

scholarly journals SMOKING STATUS AFFECTING SURVIVAL OF ADENOCARCINOMA LUNG CANCER PATIENTS IN KUALA LUMPUR, MALAYSIA

2017 ◽  
Vol 10 (9) ◽  
pp. 312
Author(s):  
Nida Sajid Ali Bangash ◽  
Natasha Hashim ◽  
Nahlah Elkudssiah Ismail
Keyword(s):  
Lung Cancer ◽  
Prognostic Significance ◽  
Hazard Model ◽  
Rank Test ◽  
Cox Proportional Hazard Model ◽  
Proportional Hazard ◽  
Kuala Lumpur ◽  
Proportional Hazard Model ◽  
Cox Proportional Hazard ◽  
Survival Difference

  Objective: Adenocarcinoma (AC) of the lung is now the most common histologic type of non-small cell lung cancer (NSCLC) worldwide since the past 20 years. This study was conducted to investigate survival difference among smoker and non-smoker lung AC patients.Methods: A retrospective observational study was conducted for 81 advanced NSCLC adult Malaysian patients in Radiotherapy and Oncology Clinic at Hospital Kuala Lumpur, Malaysia. A total of adult 30 Malaysian smokers and 51 non-smokers with lung AC were included. Ex-smokers were not included in the study. Demographic and clinical data were collected and described. For survival analysis, Kaplan–Meier test and log-rank test were used to calculate overall survival (OS) and analyse the difference in the survival curve. Cox proportional hazard model was used to identify prognostic significance of smoking status.Results: Non-smokers showed a significant association with female gender and Stage IV NSCLC. The median OS was higher for non-smokers (493 days) as compared to smokers (230 days). The Cox proportional hazard model showed higher hazard ratio for smokers.Conclusion: Non-smoking is an independent positive prognostic factor in lung AC.

EPID-02. COUNTY MEDIAN FAMILY INCOME AS PROGNOSTIC FACTOR IN NON-SMALL-CELL LUNG CANCER WITH BRAIN METASTASES AT PRESENTATION: A POPULATION-BASED STUDY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi86-vi86
Author(s):  
Ignacio Jusue-Torres ◽  
Alicia Hulbert ◽  
Jehad Zakaria ◽  
Kathy S Albain ◽  
Courtney Hentz ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Household Income ◽  
Population Based ◽  
Small Cell ◽  
Proportional Hazard ◽  
Small Cell Lung ◽  
Population Based Study ◽  
The Third ◽  
Cox Proportional Hazard

Abstract INTRODUCTION The purpose of this study was to characterize the impact of household income disparities in the survival of patients with non-small cell lung cancer (NSCLC) presenting with brain metastasis on a population-based level. METHODS This is a population-based cohort study using the SEER database from 2010-2016 including 15,808 NSCLC patients presenting with brain metastasis. Two-tailed log-rank test was used to compare overall survival between groups and association with survival was quantified using hazard ratios (HR) with 95 % confidence intervals (CI) assessed with univariate and multivariate Cox proportional hazard models. RESULTS Patients living in low-income counties had a median survival of 4 months when compared to 5 months for patients living in high-income counties respectively (p< 0.0001). Patients living in first and second bottom quartiles had a median survival of 4 months and 5 months and 6 months for the third and fourth top quartiles, respectively (p< 0.0001). The 1-, 2- and 5-year survival rates for living in the lower household income quartile were 21, 10 and 3% respectively, for the second quartile 24, 10 and 3%; for the third quartile 28, 14 and 4% and for the top fourth quartile 31, 17 and 4% respectively. Multivariate cox proportional hazard analysis adjusted for age, gender, race, hispanic ethnicity, marital status, insurance status, percentage of high school education in the patient’s county, histology, presence of lung metastasis, bone metastasis, liver metastasis, radiation received, surgery performed, and chemotherapy received showed that living in higher quartile household income county is associated with decrease mortality risk (p < 0.0001) HR 0.87 95% CI (0.82-92). CONCLUSION This population-based study suggests that living in higher median household income counties is associated with increased survival time and reduced risk of mortality for patients with NSCLC who have brain metastases present at diagnosis, independent of other factors.

scholarly journals Association of extended dosing intervals or delays in pembrolizumab-based regimens with survival outcomes in advanced non-small cell lung cancer

2020 ◽  
Author(s):  
Kartik Sehgal ◽  
Anushi Bulumulle ◽  
Heather Brody ◽  
Ritu R. Gill ◽  
Shravanti Macherla ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Significant Proportion ◽  
Small Cell ◽  
Survival Outcomes ◽  
Routine Practice ◽  
Small Cell Lung ◽  
Nsclc Patients

AbstractBackgroundBesides modeling/simulation-based analysis, no post-approval studies have evaluated optimal administration frequency of pembrolizumab in non-small cell lung cancer (NSCLC).Patients and MethodsWe performed a multicenter retrospective cohort study to evaluate association between survival outcomes and treatment extensions/delays of pembrolizumab-based regimens in advanced NSCLC patients. Those who had received at least four cycles in routine practice were divided into two groups: non-standard (Non-Std: ≥2 cycles at intervals >3weeks ±3days) and standard (Std: all cycles every 3weeks or 1 cycle >3weeks ±3days).ResultsAmong 150 patients, 92 (61%) were eligible for the study (Non-Std:27, Std:65). Reasons for patients with extensions/delays in the Non-Std group included: immune-related adverse events (irAEs,33%), non-irAE-related medical issues (26%), and patient-physician preference (41%). Non-Std group was more likely to have higher PD-L1 tumor proportion score, higher number of treatment cycles and pembrolizumab monotherapy. Univariate and 6-month landmark analyses showed longer median overall survival (OS) and progression-free survival (PFS) in Non-Std group compared to the Std group. After multivariable adjustment for confounding factors, there was no significant difference in OS [HR 1.1 (95%C.I.: 0.3–4.7), p=0.874] or PFS [HR 2.7 (95%C.I.: 0.8–8.8), p=0.094] between the two groups.ConclusionOur study shows that a significant proportion of advanced NSCLC patients receive pembrolizumab-based regimens with extended intervals or delays in routine clinical practice and with similar outcomes to those receiving treatment at label-specified 3-week intervals. Given the durability of benefit seen and the potential for cost reduction and decreased infusion frequency in these patients, this requires validation in prospective trials.MicroAbstractThe most cost-effective administration frequency of pembrolizumab in advanced non-small cell lung cancer (NSCLC) is unknown. We found that a significant proportion of these patients receive pembrolizumab-based regimens with extended intervals or delays in routine practice, with similar outcomes to those on label-specified 3-week interval treatments. Prospective evaluation of alternative dosing strategies is warranted to develop a more fiscally viable and patient-centered model.

scholarly journals The Independent Prognostic Effect of Marital Status On Non-Small Cell Lung Cancer Patients: A Population-Based Study

2021 ◽  
Author(s):  
Dechang Zhao ◽  
Rusi Zhang ◽  
Longjun Yang ◽  
Yongbin Lin ◽  
Yingsheng Wen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Marital Status ◽  
Median Survival ◽  
Population Based ◽  
Small Cell ◽  
Proportional Hazard ◽  
Small Cell Lung ◽  
Prognostic Effect ◽  
Cox Proportional Hazard ◽  
Nsclc Patients

Abstract Background Previous studies had demonstrated that marital status was an independent prognostic factor in multiple cancers. However, the impact of marital status on non-small cell lung cancer (NSCLC) patients was still highly controversial. In our research, we aimed to clarify the exact prognostic effect of marital status on NSCLC patients with a population-based database. Method : All NSCLC patients diagnosed between 2010–2016 were selected from the surveillance, epidemiology and end results (SEER) database. To control the confounding effect of related clinicopathological characteristics, propensity score matching (PSM) was conducted between married and unmarried groups. In addition, independent prognostic clinicopathological factors were evaluated via Cox proportional hazard regression. The survival curves of overall survival (OS) and cancer specific survival (CSS) were plotted and compared with Kaplan-Meier method and log-rank test. Results In total, 58424 NSCLC patients were enrolled according to the selection criteria. After PSM, 20148 patients were selected into each group for further analysis. The married group consistently demonstrated significantly better OS and CSS compared to unmarried group (OS median survival (95% CI): 25 (24–26) vs. 22 (21–23) months, P < 0.001; CSS median survival (95% CI): 31(30–32) vs. 27(26–28) months, P < 0.001). Moreover, single patients were associated with the worst OS (median survival (95% CI): 20 (19–22) months) and CSS (median survival (95%CI): 24(23–25) months) among unmarried subgroups. Besides, unmarried patients had a significantly worse prognosis compared to married patients in both univariate and multivariate Cox proportional hazard regressions. Furthermore, married group was associated with better survival in most subgroups. Conclusion This study demonstrated that unmarried NSCLC patients were associated with significantly worse OS and CSS compared to married NSCLC patients. Therefore, unmarried patients need not only closer surveillance, but also more social and family support, which may improve patients’ adherence and compliance, and eventually improve the survival.

Metabolomics Profiling in Prediction of Immunotherapy Efficacy in Advanced Non-small Cell Lung Cancer

2021 ◽  
Author(s):  
Ying LI ◽  
Zhi-hua ZHANG ◽  
Xu-shuo LI ◽  
Ying YANG ◽  
Rui-Xue QI
Keyword(s):  
Lung Cancer ◽  
Logistic Regression ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Survival Outcomes ◽  
Small Cell Lung ◽  
Clinical Predictors ◽  
First Line

Abstract Objective: To explore potential metabolomics biomarker in predicting the efficacy and the survival outcomes after the first-line programmed death-1 (PD-1) immunotherapy in the patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 46 consecutive eligible patients were assigned to receive first-line PD-1 immunotherapy. Serum samples were prospectively collected before initial treatment to perform metabolomics profiling analyses under the application of gas chromatography mass spectrometry (GC-MS). The metabolomics signatures were extracted by using a binary least absolute shrinkage and selection operator (LASSO) logistic regression and calculated as a metabolomics score by liner fit for each patients. The metabolomics score was further combined with the clinical predictors to build a metabolomics nomogram for predicting the immunotherapy efficacy in advanced NSCLC patients. The ROC curves were used to evaluate the predicting performance of the metabolomics score, the clinical predictors and the metabolomics nomogram.Results: Seven metabolites including Urea, Tyrosine, L-threonine, Xylitol, Thymol, Linoleic acid and DL-isoleucine were identified associated with the immunotherapy response. Age was identified as the clinical predictor by the logistic regression. The receiver operating characteristic curve (AUC) was 0.96 (95% CI: 0.92-1.00) for metabolomics score, 0.72 (95% CI: 0.53-0.91) for the clinical predictor and 0.97 (95% CI: 0.93-1.00) for the metabolomics nomogram in differentiating progressive disease (PD) groups from disease control (DC) groups. The median progression-free survival (PFS) after immunotherapy in patients with low risk was significantly longer than those with high risk in the metabolomics nomogram (11.8 vs.2.8 months, P < .001). Conclusion: This study developed an effective and convenient discriminant metabolomics nomogram that can predict the efficacy and the survival outcomes of PD-1 immunotherapy in advanced NSCLC.

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

1998 ◽  
Vol 16 (5) ◽  
pp. 1948-1953 ◽  
Author(s):  
J Zalcberg ◽  
M Millward ◽  
J Bishop ◽  
M McKeage ◽  
A Zimet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

scholarly journals A Study of Factors Affecting the Length of Hospital Stay of COVID-19 Patients by Cox-Proportional Hazard Model in a South Indian Tertiary Care Hospital

2021 ◽  
Vol 12 ◽  
pp. 215013272110002
Author(s):  
Gayathri Thiruvengadam ◽  
Marappa Lakshmi ◽  
Ravanan Ramanujam
Keyword(s):  
Hospital Stay ◽  
Tertiary Care ◽  
Length Of Hospital Stay ◽  
Hazard Model ◽  
Cox Proportional Hazard Model ◽  
Care Hospital ◽  
Proportional Hazard ◽  
Proportional Hazard Model ◽  
Cox Proportional Hazard ◽  
South Indian

Background: The objective of the study was to identify the factors that alter the length of hospital stay of COVID-19 patients so we have an estimate of the duration of hospitalization of patients. To achieve this, we used a time to event analysis to arrive at factors that could alter the length of hospital stay, aiding in planning additional beds for any future rise in cases. Methods: Information about COVID-19 patients was collected between June and August 2020. The response variable was the time from admission to discharge of patients. Cox proportional hazard model was used to identify the factors that were associated with the length of hospital stay. Results: A total of 730 COVID-19 patients were included, of which 675 (92.5%) recovered and 55 (7.5%) were considered to be right-censored, that is, the patient died or was discharged against medical advice. The median length of hospital stay of COVID-19 patients who were hospitalized was found to be 7 days by the Kaplan Meier curve. The covariates that prolonged the length of hospital stay were found to be abnormalities in oxygen saturation (HR = 0.446, P < .001), neutrophil-lymphocyte ratio (HR = 0.742, P = .003), levels of D-dimer (HR = 0.60, P = .002), lactate dehydrogenase (HR = 0.717, P = .002), and ferritin (HR = 0.763, P = .037). Also, patients who had more than 2 chronic diseases had a significantly longer length of stay (HR = 0.586, P = .008) compared to those with no comorbidities. Conclusion: Factors that are associated with prolonged length of hospital stay of patients need to be considered in planning bed strength on a contingency basis.

scholarly journals POS1329 A COHORT STUDY ON THE RISK OF DEVELOPING OBSTRUCTIVE SLEEP APNEA, TEMPOROMANDIBULAR JOINT DISORDERS AND CRANIOFACIAL DEFORMITIES IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 947.1-947
Author(s):  
K. S. K. MA ◽  
L. T. Wang
Keyword(s):  
Obstructive Sleep Apnea ◽  
Cohort Study ◽  
Juvenile Idiopathic Arthritis ◽  
Cox Proportional Hazard Model ◽  
Proportional Hazard ◽  
Proportional Hazard Model ◽  
Cox Proportional Hazard ◽  
Obstructive Sleep ◽  
Subgroup Analyses ◽  
Underlying Mechanisms

Background:Juvenile Idiopathic Arthritis (JIA), an autoimmune disease, has been proposed to be comorbid with obstructive sleep apnea (OSA).Objectives:We aimed at identifying the relationship between JIA and OSA.Methods:We performed a cohort study including JIA and OSA patients from 1999 to 2013. A total of 2791 patients diagnosed with OSA after JIA onset were recruited, which 11,164 eligible individuals without JIA history were selected as matched-controls. A Cox proportional hazard model was developed to estimate the risk of OSA in JIA patients. A cumulative probability model was adopted to assess the time-dependent effect of JIA on OSA development, implying the casual link of the association. To identify whether JIA patients have higher risks for developing temporomandibular joint (TMJ) disorders, craniofacial anomalies and deformities than non-JIA individuals, subgroup analyses was conducted. Finally, Ingenuity Systems Pathway Analysis (IPA) was conducted to identify underlying mechanisms of the above disease correlation among peripheral blood mononuclear cells (PBMCs) from rheumatic factor (RF)-positive and RF-negative JIA patients, and subcutaneous fat tissues from OSA patients, using p-value visualization for RNA-seq analyses.Results:The Cox proportional hazard model showed that JIA patients were more likely to have OSA than non-JIA individuals (adjusted hazard ratio =1.949, 95% CI =1.264–3.005). The incidence of developing OSA was particularly high among patients who developed JIA aged 18-30 years old (aHR= 2.034, 95% CI=1.305-3.169) and males (aHR=1.82, 95% CI=1.121-2.954). The risk of developing OSA increased within 0-36 months (aHR = 2.216, 95% CI = 1.001 – 4.907) and over 60 months (aHR = 2.558, 95% CI = 1.346 – 4.860) of follow-up duration after JIA onset. Subgroup analyses showed that JIA patients were more likely to have TMJ disorders (relative risk = 2.047, 95% CI = 1.446-2.898) and to receive treatment for craniofacial deformities (RR = 1.722, 95% CI = 1.38-2.148) than non-JIA controls. IPA analyses suggested that the underlying mechanisms involved activation of antigen presentation pathway followed by antigen presentation to CD4+ and CD8+ T lymphocytes, as well as B cell development.Conclusion:Our findings identified high risks of developing OSA, TMJ disorders, and craniofacial deformities following JIA onset, which the underlying mechanisms may involve both cellular and humoral immunity.Disclosure of Interests:None declared

440 Activity and safety of camrelizumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced non-small-cell lung cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A466-A466
Author(s):  
Guo Gui Sun ◽  
Jing Hao Jia ◽  
Peng Gao ◽  
Xue Min Yao ◽  
Ming Da Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Large Sample Size ◽  
Small Cell Lung ◽  
Previously Treated ◽  
Line Chemotherapy

BackgroundEffective options are limited for patients with non–small-cell lung cancer (NSCLC) whose disease progresses after first-line chemotherapy. Camrelizumab is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC. We assessed the activity and safety of camrelizumab for patients with previously treated, advanced NSCLC patients with negative oncogenic drivers.MethodsPatients who progressed during or following platinum-based doublet chemotherapy were enrolled. All patients received camrelizumab(200 mg)every 3 weeks or in combination with chemotherapy until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included disease control rate (DCR), progression-free survival (PFS) and safety.ResultsBetween Aug 5, 2019, and Jun 19, 2020, we enrolled 29 patients, 25 patients were available evaluated, ORR and DCR was 36% (9/25) and 92% (23/25), respectively. 25 of 29 patients were still receiving the treatment, the median PFS was not yet achieved. Compared with those without reactive cutaneous capillary endothelial proliferation (RCCEP), patients with RCCEP had higher ORR (60% vs. 28.6%). Treatment-related adverse events (AEs) occurred in 69.0% of patients (all Grade), and the most common were RCCEP (37.9%), pneumonitis (6.9%), and chest congestion (6.9%). Treatment-related grade 3 to 4 adverse events occurred in 10.3% of patients.ConclusionsIn patients with previously treated advanced NSCLC, camrelizumab demonstrated improved ORR and DCR, compared with historical data of the 2nd line chemotherapy, with a manageable safety profile. While patients with RCCEP derived greater benefit from camrelizumab. Further studies are needed in large sample size trials.

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