Chronological Trends in Progression-Free,Overall, and Post-Progression Survival in First-Line Therapy for Advanced NSCLC

BackgroundThere is a debate about the merits of progression-free survival (PFS) versus overall survival (OS) as primary endpoints in NSCLC. It has been postulated that post-progression therapy may influence OS in both arms. To investigate this issue, we analyzed chronological trends in PFS and OS in advanced NSCLC using restricted mean survival times (RMSTs).MethodsWe digitized survival curves from first-line phase III trials published between 1998 and 2015 in 13 leading journals to compute RMSTs for PFS and OS at three truncation landmarks (5, 12, and 18 months).ResultsAmong the 161 trials identified, RMSTs could be computed for both endpoints in 102, 97, and 82 trials for the 5-, 12-, and 18-month truncation landmarks, respectively. Post-progression survival in the control arm, quantified as mean OS minus mean PFS truncated at 18 months, was on average 3.3 months between 1998 and 2003, 4.4 months between 2004 and 2009, and 5.4 months between 2010 and 2015. This increase was due to increasing RMST for OS over time, with no increase in RMST for PFS. The average within-trial difference in RMSTs between experimental and control arm was close to 0 for OS and less than 1 month for PFS.ConclusionsThere is a progressive increase in post-progression survival in NSCLC trials, likely from salvage therapy. These results question both PFS and OS as sensitive endpoints in first-line trials, but suggest that the outlook for patients is improving regardless of within-trial gains.     

Programmed Death 1 and Programmed Death Ligand 1 Inhibitors in Advanced and Recurrent Urothelial Carcinoma: Meta-analysis of Single-Agent Studies

We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1–treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies.     

DP和IP方案二线治疗氟尿嘧啶类药物化疗失败的进展期胃癌疗效比较

目的 探讨氟尿嘧啶类药物化疗失败后多西他赛联合顺铂(DP)和伊立替康联合顺铂(IP)方案二线治疗进展期胃癌的疗效.方法 回顾性分析接受氟尿嘧啶类药物基础化疗失败的进展期胃癌患者120例,按照二线治疗方案的不同,分为DP组与IP组.DP组65例,行多西他赛联合顺铂化疗,IP组55例,行伊立替康联合顺铂化疗.比较两组患者临床疗效、生活质量、不良反应、以及生存情况.结果 DP组临床有效率与控制率分别为27.69％、56.92％,与IP组的21.82％、52.73％比较,无统计学差异(P＞0.05).两组治疗后体质量与卡氏评分均较同组治疗前明显上升(P＜0.05),但两组比较,无统计学差异(P＞0.05).两组白细胞减少、血小板减少、血红蛋白减少、恶心、呕吐、乏力、肝功能损害、神经毒性发生率比较,无统计学差异(P ＞0.05);DP组腹泻、胆碱能综合征发生率分别为9.23％、0,明显低于IP组的65.45％、10.91％ (P ＜0.05),脱发、口腔黏膜炎发生率分别为100.00％、49.23％,明显高于IP组的38.18％、25.45％ (P ＜0.05).截至2016年10月31日,DP组生存5例,IP组生存4例.DP组中位肿瘤无进展生存期为4.1个月,IP组为4.5个月;DP组中位生存期为6.1个月,IP组为5.8个月,两组患者中位肿瘤无进展生存期与中位生存期比较,无统计学差异(P＞0.05).结论 对氟尿嘧啶类药物基础化疗失败后的进展期胃癌患者行多西他赛联合顺铂或伊立替康联合顺铂方案二线治疗疗效相近,能明显提升患者生活质量,且不良反应小.     

中性粒细胞与淋巴细胞比值对T3N0M0期食管鳞癌术后辅助治疗预后的预测价值

目的:评估术前中性粒细胞/淋巴细胞比值(neutrophil-to-lymphocyte ratio,NLR)与T3N0M0期食管鳞癌患者临床病理指标及预后的相关性,探索其对术后辅助治疗的预测价值。方法:回顾性分析2008~2014年行根治性手术的317例食管鳞癌患者的临床病理资料,以NLR的中位数2.14作为截点,分为高NLR组(NLR≥2.14)和低NLR组(NLR<2.14);高NLR组159例,低NLR组158例。分析NLR与临床病理、预后相关性及对术后辅助治疗的指导作用。结果:不同NLR分组患者的远期生少质量评估、肿瘤位置,以及肿瘤分期存在差异,差异有统计学意义(P<0.05)。多因素Cox回归分析的结果表明,高NLR组患者发生死亡的风险是低NLR组患者的1.43倍(HR:1.43,95%CI:1.01~2.02,P=0.041)。Kaplan-Meier分析表明,不同NLR分组患者的5年总生存率存在差异,差异有统计学意义(P=0.006),高NLR组患者的5年总生存率低于低NLR组(50%vs 70%);不同NLR分组患者的无进展生存率存在差异,差异有统计学意义(P=0.017),高NLR组患者的无进展生存率低于低NLR组(45%vs 60%)。在低NLR值组中,术后辅助治疗与单纯手术治疗患者的5年总生存率存在差异(P<0.001),术后辅助治疗患者的5年总生存率高于单纯手术治疗(75%vs 45%);术后辅助治疗与单纯手术治疗患者的无进展生存率存在差异(P<0.001),术后辅助治疗患者的无进展生存率高于单纯手术治疗(78%vs 40%)。在高NLR值组中,术后辅助治疗与单纯手术患者的5年总生存率和无进展生存率差异无统计学意义。结论:NLR与T3N0M0期食管鳞癌临床病理指标具有相关性,对术后辅助治疗也提供了指导作用。     

Prolonged Duration of Therapy Is Associated With Improved Survival in Patients Treated for Relapsed/Refractory Multiple Myeloma in Routine Clinical Care in the United States

Background

In clinical trials, an extended therapy duration has been associated with better outcomes in patients with newly diagnosed multiple myeloma (NDMM). However, data on how the therapy duration affects the outcomes for patients with relapsed/refractory multiple myeloma (RRMM) are limited. We conducted a large, retrospective study in the United States to evaluate the effect of the duration of second-line therapy on overall survival.

A Systematic Review and Meta-Analysis of the Role of Immune Checkpoint Inhibitors (ICI) as Adjuvant Treatment for Localized High-Risk Muscle-Invasive Urothelial Carcinoma (MIUC)

Nivolumab, a PD-1 ICI has been recently approved for the adjuvant treatment of high-risk MIUC patients. However, conflicting data from another randomized controlled trial (RCT) with atezolizumab makes the benefit of this treatment uncertain. We performed a systematic review and study-level meta-analysis to evaluate the benefit in terms of disease-free survival (DFS) with ICI adjuvant treatment for patients with high-risk MIUC. Considering the Preferred Reporting Items for Systematic Review statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to October 30, 2021. The statistical analysis was performed by RevMan 5.4 software in intention-to-treat (ITT) population and in predetermined subgroups. Two RCTRCT, with a total of 1518 patients, met the inclusion criteria. Systemic immunotherapy was atezolizumab for 406 patients and nivolumab for 353 patients. In the ITT population there was a nonsignificant benefit with the systemic adjuvant immunotherapy (HR:0.79, 95% CI 0.62-1.00; z = 2.00) but with high heterogeneity (I² = 65%). Regarding the subgroups, there was no benefit in PD-L1 negative (HR:0.81, 95% CI 0.70-1.00; z = 1.96, I² = 0%) and in non-neoadjuvant chemotherapy (HR:0.95, 95% CI 0.78-1.15; z = 0.56, I² = 0%). Adjuvant treatment with ICI to patients with high-risk MIUC reveals a nonsignificant impact in DFS. The lack of clinical benefit was demonstrated in all subgroups. These data reinforce the need for a careful selection of patients before offering this approach in daily practice.     

索拉非尼对中晚期肝癌介入治疗患者生存率及不良反应的影响

目的 探讨索拉非尼对中晚期肝癌介入治疗患者生存率及不良反应的影响.方法 按照随机数字表法将80例中晚期肝癌介入治疗患者均分为实验组和对照组.对照组行介入治疗,实验组在此基础上加用索拉非尼,对比2组患者临床疗效、临床症状改善情况、不良反应以及生存情况.结果 2组患者临床疗效对比,差异无统计学意义(P＞0.05).实验组患者食欲减退和肝区疼痛改善率均显著优于对照组,差异具有统计学意义(P＜0.05);实验组患者高血压、手足综合征及腹泻发生率显著高于对照组,差异具有统计学意义(P＜0.05).实验组患者6个月、12个月、24个月生存率以及中位无进展生存期均显著高于对照组,差异具有统计学意义(P＜0.05).结论 索拉非尼可延长中晚期肝癌介入治疗患者生存时间,改善临床症状,但会明显增加不良反应,临床用药需谨慎.     

Nomogram to Assess the Survival Benefit of New Salvage Agents for Metastatic Urothelial Carcinoma in the Era of Immunotherapy

Introduction

Optimal end points in phase 2 trials evaluating salvage therapy for metastatic urothelial carcinoma are necessary to identify promising drugs, particularly immunotherapeutics, where response and progression-free survival may be unreliable. We developed a nomogram using data from phase 2 trials of historical agents to estimate the 12-month overall survival (OS) for patients to which observed survival of nonrandomized data sets receiving immunotherapies could be compared.

Primary Carcinoma of the Fallopian Tube: A retrospective study of patients reported to the Danish Cancer Registry in a five-year period

Fifty-two patients with carcinoma of the fallopian tube diagnosed and treated during a 5-year period in Denmark were reviewed. The median age of the patients was 60 years. No patients had a preoperative diagnosis. History and clinical findings were similar to previously reported series. Treatment consisted of hysterectomy and bilateral salpingo-oophorectomy, often succeeded by postoperative whole pelvic irradiation. Five-year survival was 37.4%, depending on stage. In stage I+II the survival rates were similar regardless of whether postoperative radiation therapy had been given or not. Little is known about the patterns of spread. The relatively bad prognosis for stages I and II after radical surgery indicates early undetected metastases and the need for more aggressive adjunctive therapy.     

Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma

BackgroundEarly progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC.Patients and MethodsWe performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors.ResultsWe included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months.ConclusionAmong patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.