免疫检查点抑制剂联合同步放化疗在周围型非小细胞肺癌老年患者中的应用价值分析

目的 探究免疫检查点抑制剂联合同步放化疗在治疗周围型非小细胞肺癌老年患者中的应用价值.方法 将98例周围型非小细胞肺癌患者按不同的治疗方法分为同步放化疗组与联合治疗组,每组49例.同步放化疗组进行同步放化疗,联合治疗组在同步放化疗组基础上进行免疫检查点抑制剂治疗.比较两组患者治疗前后的T淋巴细胞亚群水平、脂肪酸合成酶(FAS)、肿瘤型M2丙酮酸激酶(TuM2-PK)、血管内皮生长因子(VEGF)、细胞角质蛋白19片段抗原21-1(CYFRA21-1)、癌胚抗原(CEA)、糖类抗原125(CA125),观察两组患者的临床疗效及不良反应发生情况.结果 治疗后,联合治疗组患者CD4+、CD3+水平均明显高于同步放化疗组(P﹤0.01),CD8+水平明显低于同步放化疗组(P﹤0.01),联合治疗组患者FAS、TuM2-PK、VEGF、CYFRA21-1、CEA、CA125水平均明显低于同步放化疗组(P﹤0.01).联合治疗组患者总有效率高于同步放化疗组,不良反应总发生率低于同步放化疗组,差异均有统计学意义(P﹤0.05).结论 在周围型非小细胞肺癌老年患者中应用同步放化疗联合免疫检查点抑制剂,使患者病情进展得到有效控制,明显改善其免疫功能,抑制患者肿瘤生长及转移,并改善其预后.     

Immune checkpoint inhibitors retain effectiveness in older patients with cutaneous metastatic melanoma

IntroductionImmune checkpoint inhibitors (ICIs) have dramatically changed the treatment landscape for advanced melanoma, but their use in older patients remains understudied. An age-related decline in immune function is of concern when treating older patients because host immune factors can influence clinical outcomes with immunotherapy. Therefore, we aimed to evaluate the effectiveness of ICIs in patients 65 years and older.MethodsUsing the SEER-Medicare data, we evaluated survival by first systemic treatment type in a retrospective cohort study of patients aged 65 years and older who were diagnosed with stage IV cutaneous melanoma between 2012 and 2015. Cox proportional hazards regression was used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals.ResultsA total of 541 patients were included in this study. Median survival differed significantly between groups (p < 0.0001) and was longest in patients treated with PD-1 inhibitors (34.0 months), followed by CTLA-4 inhibitors (16.8 months), targeted therapy (9.7 months), chemotherapy (7.1 months), and no systemic therapy (3.6 months). The ICI survival benefit persisted after adjusting for age, sex, comorbidities, M stage, the presence of brain metastases, and evaluation at an NCI-designated cancer center. Hazard ratios comparing ICIs to no systemic therapy were 0.35 (95% CI: 0.24–0.52) for PD-1 inhibitors and 0.48 (95% CI: 0.37–0.63) for CTLA-4 inhibitors. We did not observe a difference in ICI effectiveness by age group (65–74 vs ≥75).ConclusionsIn a nationally representative cohort of patients with advanced melanoma, ICI therapy delivered in a real world setting significantly improved survival in patients aged 65 years and older.     

Treatment-related toxicity and outcomes in older versus younger patients with esophageal cancer treated with neoadjuvant chemoradiation

BackgroundNeoadjuvant chemoradiation (nCRT) followed by esophagectomy is the standard treatment for locally advanced esophageal cancer. Older patients are often felt to be poor candidates for nCRT. Limited data is available to guide the use of nCRT in this population.MethodsA retrospective review of patients treated at a tertiary cancer center between 2002 and 2014 was conducted grouping patients by age (≥ 65 or < 65) for evaluation of differences in toxicity and outcomes. Evaluation of pre-treatment platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) was also performed. Univariate (UVA) and multivariate analyses (MVA) determined associations between age, toxicities and outcomes. The Kaplan-Meier method (KM) assessed overall survival (OS) and relapse free survival (RFS).Results125 patients were identified for this study (67 aging <65, and 58 ≥ 65). In the UVA, advanced age was only associated with increased hematologic toxicity (p = .04). After adjusting for covariates in the MVA, there were no significant differences in toxicity between older and younger patients. There were also no differences between overall survival and relapse free survival between age groups. Increased pre-treatment NLR was strongly correlated with advanced age (p = .01), increased hospitalizations (p = .04), and decreased RFS (p = .002).ConclusionsOlder patients who underwent nCRT followed by esophagectomy had similar toxicities and outcomes as younger patients suggesting that nCRT before esophagectomy is safe in select older adults with esophageal cancer. PLR and NLR may serve as prognostic markers of aging, toxicity, and outcomes. Further research is warranted to optimize the therapy of older patients with this disease.     

Geriatric assessment and treatment outcomes in older adults with cancer receiving immune checkpoint inhibitors

ObjectivesImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, but outcomes in older adults are not well defined. We evaluated the associations of geriatric assessment (GA) domains with treatment-related outcomes in older adults with solid tumors receiving ICIs.MethodsWe performed a single-center, retrospective study of patients age ≥65 years diagnosed with solid tumors who received ICIs and were evaluated with a GA from January 2011 to April 2017. Using Wilcoxon rank sum test, we examined the associations of GA domains and treatment-related outcomes, including the number of ICI cycles received, best response, immune-related adverse events (irAEs), and hospitalizations during ICI treatment.ResultsWe identified 28 patients (median age at ICI treatment = 78 years, range 66–93); 60% had Eastern Cooperative Oncology Group (ECOG) Performance Status of ≥2; 39% had lung cancer; 89% had stage IV cancer; and 50% received pembrolizumab. Seventy-five percent had at least one GA domain impairment. Patients with any instrumental activities of daily living (IADL) impairment received fewer cycles of ICI (median: 2.0 vs. 7.0 cycles, p = 0.02). In this small sample, neither age nor GA domain measures were associated with best response, irAEs, or hospitalization during ICI treatment.ConclusionsOlder adults treated with ICIs had a high prevalence of impairments in GA domains, and IADL impairments were associated with shorter duration of ICI treatment. Future prospective studies are needed to evaluate the role of the GA further in this vulnerable patient population in the immunotherapy era.     

Immune checkpoint inhibitor use in antisynthetase syndrome

We report on the unique case of a patient with antisynthetase syndrome and metastatic non–small cell lung cancer undergoing therapy with the PD‐1 checkpoint inhibitor, nivolumab. Despite adequate autoimmune disease control over a period of 12 months, the patient rapidly experienced a flare of interstitial lung disease following initial nivolumab administration, which ultimately proved fatal. The use of immune checkpoint inhibitors in patients with autoimmune disease is becoming more commonplace, however this is the first reported case of the use of these agents in a patient with antisynthetase syndrome. Additionally, the patient's initial clinical presentation with antisynthetase syndrome and simultaneous primary lung cancer, a rare association of which there are few case reports, makes this case interesting and unusual.     

Neurotoxicities associated with immune checkpoint inhibitor therapy

Journal of Neuro-Oncology - Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal...     

Checkpoint inhibitor immunotherapy toxicity and overall survival among older adults with advanced cancer

ObjectivesDespite growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response, the relationship between immune-related adverse events (irAEs) and overall survival (OS) among older adults [age ≥ 70 years (y)] remains unknown. The study goal was to determine differences in OS based on age and ≥ grade 3 (G3) irAEs.Materials and MethodsThis was a retrospective cohort study of 673 patients with advanced cancer. Patients who received ≥1 dose of IO at our institution from 2011 to 2018 were eligible. The primary outcome was OS from the start of first line of IO treatment, compared between four patient groups stratified by age and ≥ G3 irAEs with adjustment for patient characteristics using a Cox proportional hazards model.Results and ConclusionAmong all 673 patients, 35.4% were ≥ 70y, 39.8% had melanoma, and 45.6% received single-agent nivolumab. Incidence and types of ≥G3 irAEs did not differ by age. Median OS was significantly longer for all patients with ≥G3 irAEs (unadjusted 21.7 vs. 11.9 months, P = 0.007). There was no difference in OS among patients ≥70y with ≥G3 irAEs (HR 0.94, 95% CI 0.61–1.47, P = 0.79) in the multivariable analysis. Patients <70y with ≥G3 irAEs had significantly increased OS (HR 0.33, 95% CI 0.21–0.52, P < 0.001). Younger patients, but not older adults, with high-grade irAEs experience strong survival benefit. This difference may be due to the toll of irAEs themselves or the effects of treatments for irAEs, such as corticosteroids. Factors impacting OS of older adults after irAEs must be determined and optimized.     

An overview of the toxicities of checkpoint inhibitors in older patients with cancer

Checkpoint inhibitors offer an exciting new option for treatment of a wide variety of cancers. By binding to surface receptors or their associated ligands on T cells, this class of drugs enhances immune activation and response to cancer cells. In available studies, the drugs are well tolerated, although toxicity involving skin, gastrointestinal tract, liver, lungs, and endocrine organs has been observed. Unfortunately, few studies to date have included patients older than 70?years of age. Since aging has been linked to changes in immune function, there are theoretical concerns that this patient population might experience a different profile of adverse events. This article reviews the tolerability of checkpoint inhibitors in older patients with cancer in clinical practice.     

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

Sarcomas are a heterogenous group of mesenchymal cancers comprising over 100 subtypes. Current chemotherapy for all but a very few subtypes has limited efficacy, resulting in 5-year relative survival rates of 16% for metastatic patients. While sarcomas have often been regarded as an “immune cold” tumor category, recent biomarker studies have confirmed a great deal of immune heterogeneity across sarcoma subtypes. Reports from the first generation of clinical trials treating sarcomas with immunotherapy demonstrate a few positive responses, supporting efforts to stratify patients to optimize response rates. This review summarizes recent advances in knowledge around immune biomarker expression in sarcomas, the potential use of new technologies to complement these study results, and clinical trials particularly of immune checkpoint inhibitor therapy in sarcomas.Each of the immune biomarkers assessed was reviewed for subtype-specific expression patterns and correlation with prognosis. Overall, there is extensive heterogeneity of immune biomarker presence across sarcoma subtypes, and no consensus on the prognostic effect of these biomarkers. New technologies such as multiplex immunohistochemistry and high plex in situ profiling may offer more insights into the sarcoma microenvironment. To date, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits. Combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma and alveolar soft-part sarcoma. Better understanding of the sarcoma immune status through biomarkers may help decipher the reasons behind differential responses to immunotherapy.     

肿瘤免疫检查点治疗中的疾病暴发性进展及其应对策略

[摘要] 以PD-1/PD-L1 等免疫检查点为靶点,应用单克隆抗体加以阻断,从而达到激活免疫系统杀灭肿瘤的目的,是当今肿瘤生物治疗的重要手段。在部分肿瘤患者,免疫检查点抑制剂（ICIs）治疗可完全治愈或者有效抑制肿瘤,显著延长生存期;但是在部分肿瘤患者,ICIs 治疗导致病情加重,出现暴发性进展（HPD）的现象,即免疫检查点治疗后肿瘤发生反常的加速生长,首次评效时肿瘤生长速率（TGR）比治疗前增加大于50%（△TGR>50%）。本文重点讨论ICIs 治疗中HPD的相关问题,如HPD的发现过程、潜在的病理生理机制,以及未来如何应对这一挑战。     

Efficacy and safety of immune checkpoint inhibitor immunotherapy in elderly cancer patients

Purpose

There is limited evidence on the efficacy and safety of anti-programmed cell death protein 1 (PD-1)-/anti-programmed death-ligand 1 (PD-L1)-based immunotherapy in the elderly, particularly those aged over 75 years.

Methods/patients

The clinical response and toxicity profile of anti-PD-1-/anti-PD-L1-based immunotherapy in patients aged over 75 years were assessed in this retrospective observational study conducted in the Medical Oncology Service of a tertiary level hospital. The associations among clinical responses, adverse events, and geriatric syndromes were evaluated.

Results

In total, 20 patients aged between 75 and 94 years were evaluated. Pembrolizumab and nivolumab were the most commonly used drugs. A clinical benefit (stable disease, partial response or complete response) was documented in 13 patients (65%). This proportion was 80% in patients aged between 75 and 79 years, and 50% in those aged over 79 years (p?=?0.236). The adverse events were similar to those reported in younger patients. At least one clinical adverse event (cAE) and one laboratory adverse event (lAE) was reported in 75% and 55% of patients, respectively. Polypharmacy was observed for all patients and multi-morbidity in 95%. Patients without gait disorders showed more responses to immunotherapy. The number of lAEs was significantly associated with the number of commonly prescribed drugs (slope?=?0.218, p?=?0.010), the Eastern Cooperative Oncology Group score, and the number of cAEs.

Conclusions

The elderly can obtain benefits from anti-PD-1-/anti-PD-L1-based immunotherapy. The toxicity profile was similar to that reported in younger counterparts.

     

Improved outcomes associated with higher surgery rates for older patients with early stage nonsmall cell lung cancer

BACKGROUND:

Although surgery offers the greatest chance of a cure for patients with early stage nonsmall cell lung cancer (NSCLC), older and sicker patients often fail to undergo resection. The benefits of surgery in older patients and patients with multiple comorbidities are uncertain.

METHODS:

The authors identified a national cohort of 17,638 Medicare beneficiaries aged ≥66 years living in Surveillance, Epidemiology, and End Results (SEER) areas who were diagnosed with stage I or II NSCLC during 2001 to 2005. Areas with high and low rates of curative surgery for early stage lung cancer were compared to estimate the effectiveness of surgery in older and sicker patients. Logistic regression models were used to assess mortality according to the quintile of area‐level surgery rates, adjusting for potential confounders.

RESULTS:

Less than 63% of patients underwent surgery in low‐surgery areas, whereas >79% underwent surgery in high‐surgery areas. High‐surgery areas operated on more patients of advanced age and patients with chronic obstructive pulmonary disease than low‐surgery areas. The adjusted all‐cause 1 year mortality was 18% in high‐surgery areas versus 22.8% in low‐surgery areas (adjusted odds ratio [OR], 0.89; 95% confidence interval [CI], 0.86‐0.93) for each 10% increase in the surgery rate).The 1‐year lung‐cancer‐specific mortality similarly was lower in high‐surgery areas (12%) versus low‐surgery areas (16.9%; adjusted OR, 0.86; 95% CI, 0.82‐0.91) for each 10% increase in the surgery rate.

CONCLUSIONS:

Higher rates of surgery for stage I/II NSCLC were associated with improved survival, even when older patients and sicker patients underwent resection. The authors concluded that more work is needed to identify and reduce barriers to surgery for early stage NSCLC. Cancer 2012;. © 2011 American Cancer Society.     

The association between social support and chemotherapy-related toxicity in older patients with cancer

ObjectivesThe goal of this study was to evaluate the relationship between social support (SS) and grade 3–5 chemotherapy-related toxicities among older adults with cancer.MethodsThis is a secondary analysis of a prospective longitudinal study of patients aged 65+ with solid cancer which led to the development of a predictive model for grade 3–5 chemotherapy-related toxicity (the Cancer and Aging Research Group [CARG] Chemotherapy Toxicity Risk Score). SS was measured by a modified version of Medical-Outcome Study-Social Support Survey and grade 3–5 hematological and non-hematological toxicities were captured and graded using CTCAE version 3.0. Patients were categorized into those with poor (SS score ≤ 75) and good SS (score of 76–100). Multivariate polychotomous logistic regression was used to examine the associations between SS and chemotherapy-related toxicity with adjustment for the CARG Toxicity Risk Score.ResultsCompared to patients with good SS, those with poor SS were less likely to have grade 3–5 toxicity, especially for non-hematological toxicity (adjusted OR = 0.52, p = .02). Patients who did not have someone to take them to the doctor “most” or “all of the time” were less likely to have grade 3–5 non-hematological toxicity compared to patients who had someone to take them to the doctor most or all of the time (adjusted OR = 0.32, p = .02).ConclusionOur study showed that patients with poor SS, especially those with less availability of someone to take them to doctors were less likely to have a documented grade 3–5 non-hematological toxicity.