The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients

The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C–IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node–positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.     

纳武利尤单抗联合替莫唑胺同步放疗治疗 老年晚期小细胞肺癌脑转移的疗效

目的 分析纳武利尤单抗联合替莫唑胺（temozolomide,TMZ）同步放疗治疗老年晚期小细胞肺癌（small cell lung cancer,SCLC）脑转移的疗效。方法 选择2017年1月至2020年12月于九江市第一人民医院治疗的72例老年晚期SCLC脑转移患者,根据随机数字表法将其分为两组,每组各36例。对照组患者采用TMZ同步放疗治疗,观察组患者采用纳武利尤单抗联合TMZ同步放疗。比较两组患者的临床疗效、血清肿瘤标志物水平、总生存（overall survival,OS）时间、无进展生存（progress free survival,PFS）时间、生存质量及不良反应。结果 观察组患者的疾病控制率显著高于对照组（P<0.05）;治疗后,观察组患者的血清胃泌素释放肽前体（progastrin releasing peptide,ProGRP）、神经元特异性烯醇化酶（neuron specific enolase,NSE）水平均显著低于对照组（P<0.05）,OS、PFS时间均显著长于对照组（P<0.05）,生存质量显著优于对照组（P<0.05）。两组患者的肝功能损害、消化道反应、血小板减少、白细胞减少、骨髓抑制发生率比较,差异均无统计学意义（P>0.05）。结论 老年晚期SCLC脑转移患者采用纳武利尤单抗联合TMZ同步放疗可缩小颅内病灶,降低ProGRP、NSE水平,延长患者生存期,提高患者生活质量,且安全可靠。     

Immune checkpoint inhibitors in acute myeloid leukemia

Understanding the immune biology of AML and designing rational approaches to target or harness the immune environment to improve outcomes is an area of intense research in AML. There are two primary immune checkpoint harnessing modalities under clinical evaluation in AML: T-cell (such as PD1 inhibitors nivolumab and pembrolizumab) and macrophage (such as the anti-CD47 antibody magrolimab) These work synergistically with hypomethylating agents. Patients who do not achieve complete or partial responses based on IWG criteria often achieve durable stable disease or hematologic improvement, which may provide meaningful benefit for patients, even in the absence of traditional response unlike cytotoxic therapies. Patients should ideally be prospectively selected for CPI based therapies based on pre-treatment biomarkers, as there are definite populations that are more likely to respond. Immune toxicities are often mistaken for infection or other adverse event; however, if identified and treated early and aggressively with steroids, immune toxicity outcomes can be improved. Therefore, in the formative stage of development ideally only centers with experience in immune therapies should perform CPI studies in AML.     

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma

BackgroundThe anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy.Patients and methodsA multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed.ResultsIn total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively.ConclusionsIpilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.     

Adrenal insufficiency following nivolumab therapy in patients with recurrent or metastatic head and neck cancer

Nivolumab, an anti-programmed cell death-1 monoclonal antibody, is currently used to treat many types of advanced cancers including recurrent and metastatic head and neck cancer. However, there are increasing reports concerning immune-related adverse events related to nivolumab therapy. Here, we report three patients who presented with adrenal insufficiency following nivolumab therapy. Two were diagnosed as having isolated adrenocorticotropic hormone (ACTH) deficiency and one was diagnosed as having primary adrenal insufficiency. All three patients complained of progressive fatigue and appetite loss, so we measured their blood cortisol and ACTH levels and diagnosed them as having adrenal deficiency. Treatment with nivolumab was discontinued for all three patients, and replacement therapy using hydrocortisone was successful after a few days in all cases. Two patients subsequently resumed nivolumab therapy because their general condition had improved. Complaints of fatigue and appetite loss during cancer treatment are common and tend to be regarded as unimportant. Although adrenal insufficiency due to nivolumab is relatively rare, complaints of these symptoms could lead to the detection of adrenal insufficiency at an early stage. The present report highlights the importance of the early recognition of adrenal insufficiency.     

Pituitary-adrenal dysfunction caused by nivolumab for head and neck cancer

Nivolumab exerts antitumor effects by inhibiting binding of PD-L1 to PD-1, and offers proven effectiveness in various disease areas, including cancers of the head and neck. The mechanisms of action lead nivolumab to induce immune-related adverse events (irAE). We report a case of pituitary-adrenal dysfunction to isolated adrenocorticotropic hormone (ACTH) deficiency as an irAE of nivolumab in a patient treated for head and neck cancer. This is the first report of an irAE of nivolumab in the field of head and neck squamous cell cancer. The patient was a man in his 50s with cancer of the tongue and hypopharynx that recurred after chemoradiotherapy, surgery and chemotherapy. After starting nivolumab, irAEs developed after 8 courses. The case was managed from the early stages in collaboration with the endocrinology department. Pituitary-adrenal hypofunction due to isolated ACTH deficiency was diagnosed on the basis of endocrine tests. The patient responded to hydrocortisone replacement therapy and has been able to continue treatment with nivolumab while continuing oral hydrocortisone. Although irAEs involving pituitary gland disorders are rare, these events can become life-threatening when severe. Early diagnosis and treatment are essential and require regular blood sampling and collaboration with specialists from an early stage.     

纳武利尤单抗联合GP化疗方案在非小细胞肺癌治疗中的应用

目的探讨纳武利尤单抗联合GP化疗方案在非小细胞肺癌(NSCLC)治疗中的应用效果。方法回顾性分析81例NSCLC患者临床资料,将其中接受单纯GP化疗方案的40例NSCLC患者设为对照组,将接受纳武利尤单抗联合GP化疗方案的41例NSCLC患者设为观察组。对比2组近期临床疗效、肿瘤标志物[糖类抗原125(CA-125)、癌胚抗原(CEA)]、1年生存率及不良反应。结果观察组临床控制率高于对照组,差异有统计学意义(P<0.05)。治疗后,2组CA-125、CEA水平均下降,但观察组低于对照组,差异有统计学意义(P<0.05)。观察组1年生存率高于对照组,差异有统计学意义(P<0.05)。2组不良反应对比,差异无统计学意义(P>0.05)。结论纳武利尤单抗联合GP化疗方案用于NSCLC患者治疗中可提升临床疗效,降低肿瘤标志物水平,延长患者生存期,且安全性较高。