PD-1/PD-L1抑制剂治疗非小细胞肺癌脑转移患者疗效的Meta分析

目的 对PD-1/PD-L1抑制剂对比化疗治疗非小细胞肺癌(non-small cell lung cancer, NSCLC)脑转移患者的疗效进行Meta分析。方法 计算机检索Pubmed、Embase、Sciencedirect、Cochrane、X-mol、中国知网、万方等数据库的文献,由2名研究者筛选文献、提取资料并对纳入研究进行偏倚风险评估,采用RevMan 5.3软件对NSCLC脑转移患者的整体生存期(overall survival, OS)、无进展生存期(progress free survival, PFS)进行Meta分析。结果 共纳入7篇随机对照试验(randomized controlled trial,RCT),包括451例NSCLC脑转移患者。Meta分析结果显示:与化疗相比,PD-1/PD-L1抑制剂能够显著提高患者的OS[HR=0.71,95%CI(0.56,0.92),P=0.008]和PFS[HR=0.53,95%CI(0.41,0.69),P<0.01];单纯化疗作为对照组,PD-1/PD-L1抑制剂联合化疗组OS[HR=0.41,95%CI(0.24,0.70),P=0.001]、PFS[HR=0.44,95%CI(0.30,0.63),P<0.01]比单药组OS[HR=0.83,95%CI(0.63,1.11),P=0.21]、PFS[HR=0.64,95%CI(0.45,0.91),P=0.01]能够更显著地降低患者的死亡风险和疾病进展风险。结论 PD-1/PD-L1抑制剂单药治疗或联合化疗对于NSCLC脑转移患者对比化疗疗效更好,其中联合化疗组优于单用组,是NSCLC脑转移患者治疗的一个优选方案。     

Pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Immune checkpoint inhibitors targeting programmed death protein 1 (PD-1) receptor and its ligand, PD-L1, have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer.

Areas covered: Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1. In the phase I KEYNOTE-001 trial, the overall response rate (ORR) was 19.4%, the median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 12.0 months for 495 unselected NSCLC patients. Strong PD-L1 expression (≥ 50%) was associated with higher ORR, longer PFS, and longer OS. The phase II/III randomized KEYNOTE-010 trial demonstrated that pembrolizumab improved OS versus docetaxel in patients with previously treated NSCLC.

Expert opinion: Pembrolizumab, demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1, thereby suggests a new treatment paradigm. However, many issues remain to be explored, including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors. Along with the identification of predictive biomarkers, further understanding of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies.     

MEDI 4736 (durvalumab) in non-small cell lung cancer

Introduction: Immune checkpoint inhibitors (ICI) are now a therapeutic option for advanced non-small cell lung cancer (NSCLC) patients. ICI, such as the PD-1 inhibitors nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab, have already been marketed for the treatment of pretreated patients with advanced NSCLC. Other notable PD-L1 inhibitors under development include avelumab and durvalumab.

Areas covered: This article reviews literature on durvalumab development, from the preclinical data to the results of phase III clinical trials, whether published or presented at international scientific conferences. Ongoing clinical trials were also reviewed.

Expert opinion: Early phase trials of durvalumab monotherapy (and in combination) have demonstrated activity in advanced NSCLC patients and it has demonstrated a good safety profile. The authors believe that durvalumab will likely play an important role in future treatment strategies for NSCLC. The PACIFIC trial assessing durvalumab after standard chemoradiotherapy for locally advanced NSCLC has already met its primary endpoint and the potential of durvalumab will be reinforced if phase III randomized studies of first-line (MYSTIC trial) and second or subsequent (ARCTIC trial) lines of therapy demonstrate superiority over the current standard of care.     

Pembrolizumab for the first-line treatment of non-small cell lung cancer

Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field.

Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and ?189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created.

Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.     

PD-L1和PD-1在非小细胞肺癌中的表达及其临床意义

目的:探讨PD-L1和PD-1在非小细胞肺癌(NSCLC)中的表达及其与患者临床病理参数、预后的相关性。方法:收集47例NSCLC标本,运用免疫组化方法检测NSCLC中PD-L1和PD-1的表达,分析其与患者各项临床指标及预后的关系。结果:PD-L1在癌细胞及癌间质淋巴细胞和巨噬细胞的表达阳性率分别为48.93%(23/47)和61.70%(29/47),两者表达水平与肿瘤临床分期及淋巴结转移呈正相关(P<0.05),与患者预后呈负相关(P<0.05)。PD-1蛋白主要定位在癌间质淋巴细胞,PD-1+淋巴细胞数量与PD-L1蛋白在癌细胞及癌间质的表达均呈正相关(P<0.05)。结论:PD-L1与NSCLC分期、淋巴结转移、PD-1阳性淋巴细胞及预后密切相关。     

Immunotherapy of non-small cell lung cancer: report from an international experts panel meeting of the Italian association of thoracic oncology

ABSTRACT

Introduction: The potential long term survival gain, related to immune adaptability and memory, the potential activity across multiple tumour types through targeting the immune system, and the opportunity for combinations offered by the unique mechanism of actions and safety profile of these new agents, all support the role of immunotherapy in the cancer treatment pathway or paradigm.

Areas covered: The authors discuss the recent advances in the understanding of immunology and antitumor immune responses that have led to the development of new immunotherapies, including monoclonal antibodies that inhibit immune checkpoint pathways, such as Programmed Death-1 (PD-1) and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4). Currently, two PD-1 inhibitors are available in clinical practice for treatment of advanced non-small cell lung cancer (NSCLC): nivolumab and pembrolizumab.

Expert opinion: Ongoing research will dictate future strategies, including the potential incorporation of immunotherapy in stage dependent treatment settings (early stage locally advanced disease and first line therapy for metastatic disease). Immunotherapy combinations are promising avenues, and careful selection of patients, doses of each agent and information supporting strategies (i.e. concomitant or sequential) is still needed.     

PD-1 checkpoint blockade alone or combined PD-1 and CTLA-4 blockade as immunotherapy for lung cancer?

Introduction: Signaling through T-cell surface, an immune checkpoint protein such as PD-1 or CTLA-4 helps dampen or terminate unwanted immune responses. Blocking a single immune checkpoint or multiple checkpoints simultaneously can generate anti-tumor activity against a variety of cancers including lung cancer.

Area covered: This review highlights the results of recent clinical studies of single or combination checkpoint inhibitor immunotherapy in non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The authors discuss pembrolizumab and pembrolizumab plus ipilimumab, durvalumab and durvalumab plus tremelimumab, nivolumab and nivolumab plus ipilimumab for NSCLC as well as nivolumab and nivolumab plus ipilimumab for SCLC.

Expert opinion: Available data suggest that, in both metastatic NSCLC and SCLC, combined PD-1 and CTLA-4 blockade may produce a higher tumor response rate than PD-1 blockade alone. Nevertheless, combination therapy is associated with an increased toxicity. Several larger-scale studies are currently ongoing. For checkpoint inhibitor immunotherapy in SCLC and NSCLC, combination therapy is associated with a higher incidence of toxicities than single therapy; however, it appears to help increase tumor response rate. The increased response rate, if confirmed in larger scale studies, will likely make combination therapy another useful therapeutic approach for lung cancer.     

The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

ABSTRACT

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC.

Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development.

Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC.     

Immunomodulators targeting the PD-1/PD-L1 protein-protein interaction: From antibodies to small molecules

Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.     

Prospects and progress of atezolizumab in non-small cell lung cancer

Introduction: Immunotherapy has recently come to the forefront of oncology treatment as a potential means of combating cancer by restoring the body’s adaptive cancer-immunity cycle. Atezolizumab is a monoclonal antibody agent that specifically targets programmed death ligand 1 (PD-L1), a key molecule in the cancer-immunity pathway, to block binding to its receptors PD-1 and B7.1.

Areas covered: This review covers the role of atezolizumab in the treatment of non-small-cell lung cancer (NSCLC). Several studies have reported promising efficacy in this indication. The phase II FIR and BIRCH studies evaluated atezolizumab monotherapy across different lines of therapy in NSCLC selected by PD-L1 expression status. The randomized POPLAR and OAK trials of atezolizumab versus docetaxel in previously treated NSCLC reported improved efficacy in the atezolizumab arm. Several ongoing studies yet to report data are also described and treatment-related adverse events are discussed.

Expert opinion: Clinical trials have shown that atezolizumab has a favorable risk-benefit ratio compared with standard chemotherapy in second-line treatment of non-oncogene-driven advanced NSCLC. Promising response rates and survival over 2 years has been reported in the first-line setting; however, more research is needed in this setting and in evaluating combinatorial strategies to treat NSCLC.     

Recent advances in immunotherapy for the treatment of prostate cancer

Introduction: Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development.

Areas covered: An autologous antigen presenting cell vaccine loaded with prostate acid phosphatase conjugated with GM-CSF, sipuleucel-T confers a survival advantage in men with metastatic castration-resistant prostate cancer (CRPC) and is now FDA approved based on the IMPACT trial. A poxvirus-based vaccine, PROSTVAC-VF TRICOM targeting prostate-specific antigen (PSA), has demonstrated improved survival in a randomized Phase II trial of patients with metastatic CRPC. Novel T lymphocyte checkpoint inhibitors of cytotoxic T lymphocyte antigen 4 and programmed death-1 are also emerging. Recognition of improved survival without an earlier clinical signal of activity by conventional criteria has led to new guidelines to evaluate immunotherapeutic agents. The clinical benefit of combining vaccines with chemotherapy, radiotherapy and other immunotherapeutic and biologic agents is being evaluated in the context of disappointing results of combination GVAX vaccine and docetaxel chemotherapy.

Expert opinion: To build on the success of early phase trials, efforts must be made to optimize vaccine approaches and patient selection.     

Ramucirumab for the treatment of advanced or metastatic non-small cell lung cancer

ABSTRACT

Introduction: On 12 December 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy.

Areas covered: This review discusses the best treatment strategy for ramucirumab, a vascular endothelial growth factor receptor-2 inhibitor for patients with advanced NSCLC.

Expert opinion: The addition of ramucirumab to docetaxel in the treatment of patients with metastatic NSCLC who have progressed on or after platinum-based chemotherapy confers a 1.4-month improvement in overall survival, with an acceptable toxicity profile. The potential impact of the approval of the programmed death receptor-1 (PD-1)-blocking antibody nivolumab or pembrolizumab on the use of ramucirumab plus docetaxel in advanced NSCLC patient population is uncertain in clinical practice. In order to improve overall outcomes for patients with advanced NSCLC, both ramucirumab plus docetaxel and the PD-1-blocking antibody should be used in any treatment line.     

Meta-analysis of the Efficacy and Tolerability of Immune Checkpoint Inhibitors Combined With Chemotherapy in First-line Treatment of Small Cell Lung Cancer

PurposeThe present study was conducted to evaluate the efficacy and tolerability of using an immune checkpoint inhibitor (ICI; programmed cell death protein 1/ligand 1 [PD-1/PD-L1] inhibitor or cytotoxic T-lymphocyte antigen [CTLA]-4 inhibitor) combined with chemotherapy in the first-line treatment of small cell lung cancer.MethodsPotential articles and studies were identified using Web of Science, Cochrane Library, and ClinicalTrials.gov. The end points included overall survival, progression-free survival, objective response rate, and adverse events. Significant heterogeneity was represented by a P value (P_h) of <0.05 or an I² value of ≥50%, and the random-effects model was applied for pooled analysis. Otherwise, the fixed-effects model was used. Subgroup analysis was performed based on the type of ICI. Potential publication bias was evaluated via funnel plot and the Egger test.FindingsFive eligible articles were included. Both overall survival (hazard ratio [HR] = 0.83; 95% CI, 0.75–0.91; P < 0.001) and progression-free survival (HR = 0.80; 95% CI, 0.73–0.86; P < 0.001) were significantly prolonged by joint ICI + chemotherapy treatment. Additionally, the rates of tolerable grade ≥3 adverse events were similar between the ICI combination regimens and conventional chemotherapy (relative risk = 1.05; 95% CI, 0.98–1.12; P = 0.17). Subanalysis demonstrated that patient survival and objective response rate were more efficiently improved with a combination of anti–PD-1/PD-L1, but not anti–CTLA-4, + chemotherapy.ImplicationsBased on data from the available literature, clinical efficacy (as measured by patient survival and objective response rate) was improved with a combination of anti–PD-1/PD-L1 + chemotherapy as first-line treatment compared with chemotherapy alone in patients with small cell lung cancer.     

PD-1/PD-L1 antagonists in gastric cancer: Current studies and perspectives

Immune checkpoints release suppressive signals for T cells, which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors. At present, programmed death receptor 1 (PD-1)/programmed death ligand-1 (PD-L1) has become the most promising therapeutic target. PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers, such as melanoma and non-small-cell lung cancer. Moreover, PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer, and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool. Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer. Furthermore, there are many molecules involved in the regulation of PD-1/PD-L1 expression, and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer. In this review, the efficacy, safety, and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.     

Pembrolizumab for the treatment of cervical cancer

Introduction: The prognosis of patients with recurrent and/or metastatic cervical cancer remains poor, with a 5-year survival rate of 17%. Most of cervical cancers are associated with the human papillomavirus (HPV) infection that leads to viral antigens production, supporting the development of immunotherapy in cervical cancer.

Areas covered: Here we report the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of cervical cancer.

Expert opinion: Single agent pembrolizumab has limited efficacy in the recurrent and/or metastatic setting in an unselected patient population. However, durable responses in PD-L1-expressing cervical cancer patients led the U.S. Food and Drug Administration to grant accelerated approval of pembrolizumab in this patient population. Outside this patient population, further development involves combinations with other treatment options including chemotherapy, radiotherapy and other immunotherapeutic agents. The identification of biomarkers of efficacy beyond PD-L1 expression will be essential in order to identify patients who will most likely benefit from pembrolizumab.     

Immune checkpoint inhibition for the treatment of mesothelioma

Introduction: Combination chemotherapy is currently standard care for advanced mesothelioma. Checkpoint blockade is a promising new treatment.

Areas covered: This review covers clinical use and biomarkers of checkpoint blockade. Medline search used keywords ‘mesothelioma’ combined with ‘checkpoint blockade’ OR ‘PD-L1? OR ‘PD1? OR ‘anti-CTLA4?; the search terms AND ‘clinical trial’ or AND ‘biomarker*’ were added. Handsearching covered abstracts from relevant meetings from 2016 to 2018 and reference lists. Data informed a narrative review.

Expert Opinion: Single agent anti-CTLA4 blockade is inactive in mesothelioma. Single agent PD-1 blockade as second or subsequent treatment gives 20–29% partial responses; no randomized comparisons against placebo or chemotherapy are available. Biomarkers of response have been difficult to identify. There is no consensus as to whether tumor PD-L1 expression predicts outcomes. Combination checkpoint inhibitors (CTLA4 and PD1 blockade) provide a small incremental increase in response rates and progression-free survival. Chemoimmunotherapy is the next frontier.     

临床、病理、MRI特征及IVIM参数联合模型预测宫颈癌程序性细胞死亡蛋白1及其配体(PD-1/PD-L1)表达

目的 基于SHAP法观察以临床、病理、MRI特征及体素内不相干运动（IVIM）成像定量参数联合模型预测宫颈癌细胞程序性死亡蛋白1（PD-1）及其配体（PD-L1）表达的价值。方法 采集63例治疗前初诊宫颈癌盆腔MRI，并对病理标本行PD-1/PD-L1免疫组织化学染色；比较PD-1表达阳性与阴性组、PD-L1表达阳性与阴性组临床、病理、MRI表现及IVIM参数（真实弥散系数D、灌注相关弥散系数D^*及灌注分数f）的差异，并以logistic回归分析筛选宫颈癌PD-1及PD-L1表达阳性的独立影响因素，建立预测宫颈癌PD-1及PD-L1表达阳性联合模型；以受试者工作特征（ROC）曲线评估模型诊断效能，以SHAP法解释其中各变量的贡献价值。结果 PD-1阳性组与阴性组、PD-L1阳性组与阴性组之间肿瘤病理分级、宫旁浸润、淋巴结转移及D值差异均有统计学意义（P均<0.05）。FIGO分期、肿瘤病理分级、宫旁浸润、淋巴结转移和D值均为宫颈癌PD-1/PD-L1表达阳性的独立影响因素（P均<0.05）；以之建立的联合模型的曲线下面积分别为0.85及0.89。根据SHAP值，联合模型中FIGO分期和肿瘤病理分级的贡献最大。结论 以宫颈癌临床、病理、MRI特征及IVIM参数D值构建的联合模型可有效预测其PD-1/PD-L1表达。     

Prognostic and therapeutic molecular markers in the clinical management of esophageal cancer

ABSTRACT

Introduction: Esophageal cancer is a deadly disease with high mortality. Treatment with chemotherapy, radiation, and surgery continues to leave many patients with disease progression and recurrence. Novel treatments are needed for this patient population. The development of molecular markers are important for identifying therapeutic targets, as well as prognosis.

Areas covered: This review evaluates three molecular markers in esophageal cancer: HER2, PD-L1, and MSI. The fundamentals of these markers, diagnosis, and rates of occurrence in esophageal cancer are explored. The prognostic potential of these markers is based on existing literature as well as application in clinical trials. Key trial findings pertaining to the therapeutic targets for HER2 and PD-1 as well as the role of MSI are discussed.

Expert commentary: Molecular markers are changing the practice for esophageal cancer. Therapeutic targeting for HER2 and PD-L1 have shown positive results in recent clinical trials. Trials evaluating immunotherapy as first-line agents are currently underway.     

一线和二线免疫治疗对非小细胞肺癌患者外周血免疫抑制细胞的影响

目的:探讨一线和二线免疫治疗对非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床疗效及外周血免疫抑制细胞的影响.方法:选择2018年1月至2019年10月复旦大学附属中山医院收治的NSCLC患者27例,其中接受PD-1抑制剂一线免疫治疗者7例(一线组)、二线免疫治疗20例(二线组),...     

The role of checkpoint inhibitors immunotherapy in advanced non-small cell lung cancer in the elderly

Introduction: Immune checkpoint inhibition is a novel treatment modality that has brought a new hope to patients with advanced NSCLC. Several molecules targeting cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 receptor/programmed death ligand-1 (PD1/PD-L1) pathways are under evaluation in NSCLC and three of them are currently approved: nivolumab and atezolizumab for advanced NSCLC after prior chemotherapy and pembrolizumab for advanced NSCLC expressing PD-L1 ≥ 1% after at least one prior chemotherapy regimen and > 50% as a first-line response.

Areas covered: To date, the efficacy and toxicity of immune checkpoint inhibitors in the elderly is unclear because available studies involved mainly a low number of elderly patients. In this paper, the authors discuss the frailty of the elderly patient and the challenges of choosing the best therapeutic strategy, focusing on the role of immune checkpoint inhibitors.

Expert opinion: There are several outstanding goals that need to be met for the proper and safe use of immunotherapeutic drugs. In terms of the elderly, it is true that age-tailored clinical trials are needed to confirm the real impact of immunotherapy and harmonize the standard of care in this specific demographic.