Study of Pemetrexed-based Chemotherapy for Patients with Locally Advanced or Metastatic Cancers

Purpose: This study was conducted to observe the efficacy and safety of pemetrexed based chemotherapyin treating patients with locally advanced or metastatic cancers as first-line, second-line or third-line therapy.Materials and Methods: From May 2011 to January 2015, we recruited 29 patients with advanced breast cancer,19 patients with advanced ovary cancer, 17 patients with advanced esophageal cancer,5 patients with advancedgallbladder cancer,5 patients with advanced cervical cancer and 1 patient with advanced tongue cancer inJiangsu Cancer Hospital and Research Institute.All of them were pathologically confirmed and treated withpemetrexed based chemotherapy. After two cycles of treatment,efficacy and safety can be evaluated. Results:For pemetrexed based regimens,including 76 patients with 6 kinds of advanced cancer were considered eligiblefor inclusion. Complete remission represents CR, partial remission represents PR, stable disease represents SD,progressive disease represents PD. Among 29 patients with advanced breast cancer, 4 patients chose pemetrexedbased regimens as second-line treatment,1 of them was PR,the other 3 got SD. The last 25 patients made useof this chemotherapy as third-line treatment, except one patient could not be assessed, 2 of them got PR,6 ofthem got SD,the remaining 16 of them finally were PD.19 patients with advanced ovary cancer,5 patients usedthis regimens as second-line treatment, 3 of them got PD,the remaining patients got SD, respectively. The last14 patients made use of pemetrexed based regimens as third-line treatment,. RR (CR+PR) was 28.5%. Among17 patients with advanced esophageal cancer, 2 patients made use of pemetrexed based regimens as first-linetreatment,both of them got PR.4 of them used this chemotherapy as second-line regimen, except 2 patients couldnot be assessed,the remaining 2 was PD at last. The last 11 patients was third-line users, RR (CR+PR) was 18.2%.Among 5 patients with advanced gallbladder cancer, pemetrexed based regimens was used in 1 patient as firstlinetreatment and 1 patient as second-line treatment. The curative effect was SD and PD, respectively. 3 patientsaccepted pemetrexed based regimens as third-line treatment, 2 of them got PD as results and another was SD.Among 5 patients with advanced cervical cancer, just 1 patient adopted pemetrexed based regimens as first-linetreatment, whose curative effect was PR.2 patients chose this chemotherapy regimens as second-line treatment.Both of them got PD as their consequence. The last 2 patients made use of the regimens as third-line treatment,the effect of them was PD and SD, respectively. The one who with advanced tongue cancer, pemetrexed basedregimens was used as second-line treatment, and the consequence was PD. About 71.1% patients experienced bonemarrow suppression. Among them, 5 patients reached 4 grade. Other toxicity of pemetrexed were neurotoxicity,fatigue, diarrhea, dysphagia and vomiting. No treatment related death occurred with pemetrexed-based treatment.Conclusions: Pemetrexed based chemotherapy has considerable effect in patients with advanced cancers suchas breast cancer,esophageal cancer and ovary cancer. More randomly clinical trials are needed to verify theresults.     

Immunotherapy in Gastric Cancer

Immune checkpoint inhibition is a new standard of targeted therapy in the treatment of advanced or metastatic gastric cancer (GC) and is represented in various combinations with and without chemotherapy in every therapy line within clinical trials. In advanced adenocarcinoma of GC, gastroesophageal junction cancer (GEJC) and esophageal cancer (EC), the combination of nivolumab and chemotherapy in first-line therapy improves overall survival (OS) in PD-L1 (programmed cell death protein 1)-positive patients with approval in Europe (PD-L1 CPS (combined positivity score) ≥ 5), USA and Taiwan (CHECKMATE-649) and pembrolizumab plus chemotherapy for GEJC and EC in Europe (CPS ≥ 10) and the USA (KEYNOTE-590). Furthermore, pembrolizumab plus trastuzumab and chemotherapy show clear benefits in OS and are approved as first-line treatment of Her2 (human epidermal growth factor receptor-2)-positive tumors in the USA (KEYNOTE-811). Nivolumab demonstrates superior OS regardless of PD-L1 expression in third-line therapy with approval in Japan (ATTRACTION-02) and pembrolizumab prolonged the duration of response in PD-L1 positive patients with approval in the USA in PD-L1 CPS ≥ 1 patients (KEYNOTE-059). This review reflects the rationale and current results of phase II and III clinical trials investigating various immune checkpoint inhibitors targeting PD-L1/1 and CTLA (anticytotoxic T-lymphocyte-associated antigen)-4 in combination with and without chemotherapy and Her2-targeted therapy in GC.     

Activity of Nivolumab and Utility of Neutrophil-to-Lymphocyte Ratio as a Predictive Biomarker for Advanced Non–Small-Cell Lung Cancer: A Prospective Observational Study

BackgroundThe immune checkpoint inhibitor nivolumab is entering routine oncologic practice. We investigated the safety and efficacy of nivolumab in the real world and alternative predictive factors for survival in patients with advanced non–small-cell lung cancer (NSCLC).Patients and MethodsWe performed a prospective observational study to evaluate the activity of nivolumab treatment for chemotherapy-refractory NSCLC. Patients were treated with nivolumab once every 2 weeks, and the efficacy was assessed every 8 ± 2 weeks.ResultsFifty-two patients were enrolled after nivolumab approval in Japan. These patients received a median of 4 (range, 1-43) cycles of nivolumab. Overall objective response was observed in 12 patients (23.1%). Median progression-free survival was 2.1 (95% confidence interval, 1.0-3.2) months, and 1-year overall survival rate was 59.9%. A total of 23 immune-related adverse events occurred in 20 patients, as follows: 7 cases of pneumonitis, 6 of oral mucositis, 5 of hypothyroidism, 2 of colitis, 2 of liver dysfunction, and 1 of arthritis. All patients recovered after appropriate management. A pretreatment neutrophil-to-lymphocyte ratio (NLR) of ≥ 5 was significantly associated with poor prognosis compared to NLR < 5 (hazard ratio, 4.52; 95% confidence interval, 1.84-11.14; P = .013), independently.ConclusionNivolumab showed promising activity with a manageable safety profile in clinical practice, consistent with effects of previous clinical trials. This drug could affect a specific population of patients with advanced NSCLC, and pretreatment NLR was a candidate for surrogate markers for survival benefit of patients with NSCLC treated with nivolumab.     

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric,gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.     

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

IntroductionNivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort.MethodsPatients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review.ResultsOverall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively.ConclusionsWhereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.     

Safety and efficacy of nivolumab in the treatment of cancers: A meta‐analysis of 27 prospective clinical trials

Immune checkpoint inhibition therapy has benefited people and shown powerful anti‐tumor activity during the past several years. Nivolumab, a fully human IgG4 monoclonal antibody against PD‐1, is a widely studied immune checkpoint inhibitor for the treatment of cancers. To assess the safety and efficacy of nivolumab, 27 clinical trials on nivolumab were analyzed. Results showed that the summary risks of all grade adverse effects (AEs) and grade ≥3 AEs were 0.65 and 0.12. The rate of nivolumab‐related death was 0.25%. The most common any grade AEs were fatigue (25.1%), rush (13.0%), pruritus (12.5%), diarrhea (12.1%), nausea (11.8%) and asthenia (10.4%). The most common grade ≥3 AEs were hypophosphatemia (only 2.3%) and lymphopenia (only 2.1%). The pooled objective response rate (ORR), 6‐month progression‐free survival (PFS) rate and 1‐year overall survival (OS) rate were 0.26, 0.40 and 0.52, respectively. The odds ratio of ORR between PD‐L1 positive and negative was 2.34 (95% CI 1.77–3.10, p < 0.0001). The odds ratios of ORR, 6‐month PFS rate and 1‐year OS rate between nivolumab and chemotherapeutics were 2.77 (95% CI 1.69–4.56, p < 0.0001), 1.97 (95% CI 1.02–3.81, p = 0.04) and 1.87 (95% CI 1.46–2.40, p <0.0001), respectively. In conclusion, nivolumab has durable outcomes with tolerable AEs and drug‐related deaths in cancer patients. Nivolumab monotherapy has better treatment response compared with chemotherapy, whereas chemotherapeutics have significantly higher risk of adverse effects than nivolumab.     

培美曲塞用于转移性或晚期宫颈癌患者三线及以上治疗的疗效及安全性

目的:观察培美曲塞用于转移性或晚期宫颈癌三线及以上治疗的近期疗效及安全性。方法:收集2016年1月至2016年12月在空军军医大学西京医院肿瘤科住院的转移性或晚期宫颈鳞癌患者,接受三线及以上治疗者共11例,选择培美曲塞为基础的化疗方案。每2周期进行疗效及安全性评估,主要指标包括客观缓解率（objective response rate,ORR）、疾病控制率（disease control rate,DCR）、无进展生存期（progression-free survival,PFS）和不良反应。结果:11例中10例患者为三线治疗,1例患者为四线治疗。疗效评估:部分缓解（partial remission,PR）4例（36%）,稳定（stable disease,SD）5例（45%）,病情进展（progressive disease,PD）2例（18%）。ORR为36%（4例）,DCR为82%（9例）,中位PFS 6.3个月（3.0~10.6个月）。安全性评估:3级及以上不良反应包括中性粒细胞减少（3例,27%）、血小板减少（2例,18%）、总胆红素升高（1例,9%）、间接胆红素升高（1例,9%）。结论:培美曲塞用于转移性或晚期宫颈癌三线及以上化疗具有良好的疗效和安全性。     

Third-Line Nivolumab Monotherapy in Recurrent SCLC: CheckMate 032

Introduction

For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC.

化疗间期序贯应用厄洛替尼治疗晚期非小细胞肺癌的临床观察

目的　评价化疗后序贯给予厄洛替尼在晚期非小细胞肺癌（ＮＳＣＬＣ）中的客观缓解率和毒副反应。方法　初治或复治的局部晚期或晚期ＮＳＣＬＣ患者共３９例,初治患者２５例采用ＧＣ方案化疗,复治患者１４例方案为多西他赛或培美曲塞,化疗间歇期序贯给予厄洛替尼（１５０ｍｇ／天,ｄ１５～ｄ２８）,２８天为１周期。连用６周期,直至疾病进展或毒副反应不能耐受。结果　３９例患者至随访结束时共完成化疗１３５个周期,平均化疗３４６个周期。所有患者均可进行疗效评价,其中获ＰＲ９例（初治７例）,ＳＤ２３例（初治１４例）,ＰＤ７例（初治２例）。总体客观缓解率（ＲＲ）为２３１％,其中初治ＲＲ为２８.０％（７／２５）,复治ＲＲ１４.３％（２／１４）,总体疾病控制率（ＤＣＲ）为８２.１％,初治患者为９２.０％,复治患者６４.３％。主要不良反应为皮疹和血液系统毒性。结论　化疗序贯厄洛替尼治疗ＮＳＣＬＣ近期疗效较好,毒副反应可耐受,远期疗效有待进一步观察。     

尼妥珠单抗联合化疗治疗晚期非小细胞肺癌

目的 评价尼妥珠单抗联合化疗治疗晚期非小细胞肺癌(NSCLC)的价值.方法 回顾性分析2009年1月至2010年10月采用尼妥珠单抗联合化疗的37例晚期NSCLC患者的临床资料.其中Ⅲb期12例,Ⅳ期25例.采用尼妥珠单抗联合铂类为基础的化疗方案24例,尼妥珠单抗联合非铂类药物的化疗方案13例.尼妥珠单抗联合化疗作为一线方案患者10例,二线方案23例,三线方案4例.结果 37例患者共计化疗137个周期,平均每例3.7个周期.其中完全缓解(CR)1例,部分缓解(PR)9例,稳定(SD)16例,进展(PD)11例,有效率(RR)为27.0%,临床获益率(CBR)为70.3%.主要毒副反应为骨髓抑制和胃肠道反应,仅有1例患者出了Ⅰ度座疮样皮疹.结论 尼妥珠单抗联合化疗治疗晚期NSCLC患者可提高疗效,且耐受性良好.

Abstract：

Objective To evaluate the role of nimotuzumab in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Methods The clinical data of 37 NSCLC patients who received nimotuzumab in combination with chemotherapy in Tianjin Medical University Cancer Hospital from January 2009 to October 2010 were retrospectively reviewed. Of the thirty-seven patients, 12patients were in stage Ⅲ B, 25 patients in stage Ⅳ. Twenty-four patients recived platinum-based chemotherapy in combination with nimotuzumab, 13 patients recived nonplatinum-based chemotherapy in combination with nimotuzumab. Ten patients received nimotuzumab in combination with chemotherapy as first-line regimen, 23 patients as second-line regimen, 4 patients as third-line regimen. Results Of the 37advanced NSCLC patients who received nimotuzumab in combination with chemotherapy, the total number ofchemotherapy were 137 cycles, the mean number was 3.7 cycles. One patient had complete remission (CR), 9 patients had partial remission (PR), 16 cases had stable disease (SD), and 11 patients hadprogressive disease (PD). The response rate (RR) was 27% and clinical benefit rate (CBR) was 70.3%.The main side effects were bone marrow suppression and gastrointestinal reactions. Grade I acneiform rash was found in one patient. Conclusion The regimen of nimotuzumab in combination with chemotherapy can improve the response rate and was well tolerated in patients with advanced non-small cell lung cancer.     

中性粒细胞淋巴细胞比值（NLR）与晚期非小细胞肺癌一线化疗疗效及预后的关系

目的:观察中性粒细胞淋巴细胞比值（NLR）及其动态变化与晚期非小细胞肺癌（NSCLC）患者一线化疗疗效和预后的关系。方法:回顾性分析2011年12月至2016年12月苏州大学附属常州肿瘤医院收治的102例接受一线化疗的晚期NSCLC患者的临床资料。分析患者一线化疗前和2周期后的外周血NLR与临床的相关性,通过建立患者工作特征曲线（ROC）,获得最佳界值,通过Kaplan-Meier方法进行生存分析,单因素和Cox多因素分析NLR及其动态变化与一线化疗疗效和总生存期之间的关系。结果:NLR在2周期化疗后显著下降,NLR2（2周期化疗后NLR）和NLR0（治疗前NLR）分别为（2.53±1.27）和（3.25±1.72）（P=0.000）;NLR2与一线化疗2周期和4周期的疗效显著相关（P＜0.05）,疾病进展患者高于部分缓解和疾病稳定患者（P＜0.05）;单因素分析显示OS与NLR0、NLR2、4周期后疗效显著相关（P＜0.05）,与性别、年龄、体力状况、病理类型、肿瘤分期、EGFR基因情况、2周期化疗疗效均无关（P＞0.05）;多因素分析表明,NLR0（P=0.000）、4周期后疗效（P=0.047）是OS的独立预测因素。 结论:化疗前NLR与NSCLC的预后显著相关,化疗后NLR与一线化疗疗效显著相关,NLR可能是一个预测晚期NSCLC一线化疗疗效和预后较理想的指标。     

晚期NSCLC一线化疗疾病控制与生存关系的分析

目的回顾性分析一线化疗疾病控制（DCR）与进展（PD）患者之间生存的差别,探讨DCR可否预测生存。方法本文回顾性分析本院一线含铂联合化疗86例ⅢB期/Ⅳ期非小细胞肺癌（NSCLC）患者,化疗的疗效按WHO标准分为CR,PR,SD,PD。结果一线化疗后DCR共64例（74.4%）[其中CR 0例,PR 30例（34.9%）,SD 34例（39.5%）],PD 22例（25.6%）。DCR和PD患者中位生存期（MST）有统计学意义,为14.2月和5.1月（P〈0.001）。CR＋PR和SD患者MST有统计学意义,为15.0月和11.0月（P=0.030）。COX多因素回归分析显示一线化疗疾病控制（P=0.017）,ECOG评分（P=0.046）是总生存的独立预后因素。结论本研究提示晚期NSCLC患者一线化疗疾病控制患者其生存较进展患者好,疾病控制比化疗有效似乎更能反映化疗疗效,预测生存期。     

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study

Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T‐cell activation through overexpression of the inhibitory receptor programmed death 1 (PD‐1) ligands. The PD‐1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single‐arm, open‐label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty‐four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee‐assessed overall response rate was 34.8% (90% confidence interval, 20.8–51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0–71.4). Treatment‐related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment‐related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI‐142533.)     

Haematologic Parameters in Metastatic Colorectal Cancer Patients Treated with Capecitabine Combination Therapy

Background: The standard treatment in the metastatic colorectal cancer consists of 5-FU based infusionalregimens. However, with oral fluoropyrimidines, equal tumor responses may be obtained. Capecitabine causesmacrocytosis of the cells by inhibition of DNA synthesis. In this context, a relationship was found between meancorpuscular volume (MCV) and response to therapy in breast cancer patients treated with Capecitabine, butwhether this relationship also pertains in colorectal cancer has not been established. Materials and Methods: Atotal of 102 metastatic colorectal cancer patients treated with a oxaliplatin (XELOX)±Bevacizumab combinationwere retrospectively evaluated. Patients were randomized into three groups. Hematological parameters (MCV,MPV, PCT, PLT, NLR) were recorded retrospectively, before treatment and after 3 cycles of chemotherapy.Results: After three cycles of therapy, 20 (19.6%) patients had progressive disease (PD), 41 (40.1%) hadstable disease (SD), and 41 (40.1%) demonstrated a partial response (PR). In 62 (60.7%) treatment was withcapesitabin plus XELOX therapy, and in 40 (39.2%) it was XELOX-Bevacizumab combination therapy. Therewas no difference among three groups before the treatment in terms of MCV, MPV, PCT, PLT, and NLR.MCV showed significant increase in chemotherapy response groups (PR and SD). In addition, a significantdecrease was observed for platelet count in chemotherapy response groups. While NLR decrease was seen inonly a PR group, PCT decrease was observed in all three groups. PCT and PLT values were higher in patientsreceiving Bevacizumab. Conclusions: PLT, PCT, MPV, and NLR values were decreased due to Capecitabinebasedchemotherapy, however MCV was increased. PCT and PLT values were higher in patients who receivedBevacizumab than those who did not. MCV, PLT, and NLR can be considered as important factors in predictingresponse to colorectal carcinoma treatment.     

晚期非小细胞肺癌一线化疗疗效与生存关系的分析

背景与目的第三代新药组成的方案在晚期NSCLC一线化疗中使大部分患者能够取得疾病控制(CR PR SD),我们进行了本项回顾性分析以探讨一线化疗疾病控制与疾病未控(PD)患者之间生存的差别,以及疾病控制患者有效(CR PR)和稳定(SD)患者之间生存的差别,明确与患者生存有关的预后因素。方法本项回顾性分析纳入了完成第三代新药组成的铂类或非铂类方案一线化疗的118例IIIB期(伴恶性胸水)/IV期NSCLC患者,一线化疗的疗效按RECIST标准根据影像学结果评价为CR,PR,SD,PD四种情况。结果一线化疗后CR PR SD共86例(72.9%)[其中CR2例(1.7%),PR47例(39.8%),SD37例(31.4%)],PD32例(27.1%)。CR PR SD和PD患者MST有统计学差别,为17.8月和8.4月(P=0.001)。CR PR和SD患者MST无统计学差别,为18.1月和15.5月(P=0.917),中位PFS无统计学差别,为7.1月和6.9月(P=0.622)。Cox多因素回归分析显示分期(IIIB期或IV期)、化疗线程(≤3线或≥4线)、一线化疗疾病是否控制是总生存的独立预后因素。结论本研究结果表明,晚期NSCLC患者一线化疗有效和稳定的患者其生存较进展患者好,疾病稳定患者的生存获益与有效患者无明显差别。     

Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer

PURPOSE: Selective internal radiation therapy (SIRT) with SIR-Spheres(R) is a new technique for selectively targeting high doses of radiation to tumours within the liver. The primary objectives of this randomised trial were to compare the response rate, time to progressive disease (PD), and toxicity of a regimen of systemic fluorouracil/leucovorin chemotherapy versus the same chemotherapy plus a single administration of SIR-Spheres in patients with advanced colorectal liver metastases. The trial was designed to presage a larger trial that would have survival as the primary outcome. PATIENTS AND METHODS: Twenty-one patients with previously untreated advanced colorectal liver metastases, with or without extrahepatic metastases, were randomised into the study. RESULTS: Using RECIST criteria, the response rate for 11 patients receiving the combination treatment was significantly greater than for 10 patients receiving chemotherapy alone (First Integrated Response; 10 PR, 1 SD vs. 0 PR, 6 SD, 4 PD, P < 0.001 and Best Confirmed Response; 8 PR, 3 SD vs. 0 PR, 6 SD, 4 PD P < 0.001). The time to PD was greater for patients receiving the combination treatment (18.6 months vs. 3.6 months, P < 0.0005). Median survival was significantly longer for patients receiving the combination treatment (29.4 months vs. 12.8 months, P = 0.02). One patient in the combination arm died from chemotherapy induced neutropenic sepsis after the fourth chemotherapy cycle. There were more Grade 3 and 4 toxicity events in patients receiving the combination treatment. There was no difference in quality-of-life over a 3 month period between the two treatments when rated by patients (P = 0.96) or physicians (P = 0.98). CONCLUSIONS: This small phase 2 randomised trial demonstrated that the addition of a single administration of SIR-Spheres to a regimen of systemic fluorouracil/leucovorin chemotherapy significantly increased both treatment related response, time to PD, and survival with acceptable toxicity. The combination of SIR-Spheres plus systemic chemotherapy is now the subject of ongoing trials to further define patient benefit.     

Efficacy of First-line Chemotherapy Affects the Second-Line Setting Response in Patients with Advanced Non-Small Cell Lung Cancer

Background: Chemotherapy is the mainstay of treatment for the majority of patients with advanced nonsmall cell lung cancer (NSCLC) without driver mutations and many receive therapies beyond first-line. Secondline chemotherapy has been disappointing both in terms of response rate and survival and we know relatively little about the prognostic factors. Materials and Methods: One thousand and eight patients with advanced NSCLC who received second-line chemotherapy after progression were reviewed in Shanghai PulmonaryHospital, China, from September 2005 to July 2010. We analyzed the effects of potential prognostic factors on the outcomes of second-line chemotherapy (overall response rate, ORR; progression free survival, PFS; overall survival, OS). Results: The response and progression free survival of first-line chemotherapy affects the ORR, PFS and OS of second-line chemotherapy (ORR: CR/PR 15.4%, SD 10.1%, PD2.3%, p<0.001; PFS: CR/PR 3.80 months, SD 2.77 months, PD 2.03 months, p<0.001; OS: CR/PR 11.60 months, SD 10.33 months, PD 6.57 months, p=0.578, p<0.001, p<0.001, respectively). On multivariate analysis, better response to first-line therapy (CR/PR: HR=0.751, p=0.002; SD: HR=0.781, p=0.021) and progression within 3-6 months (HR=0.626, p<0.001), together with adenocarcinoma (HR=0.815, p=0.017), without liver metastasis (HR=0.541, p=0.001), never-smoker(HR=0.772, p=0.001), and ECOG PS 0-1 (HR=0.745, p=0.021) were predictors for good OS following secondline chemotherapy. Conclusions: Patients who responded to first-line chemotherapy had a better outcome after second-line therapy for advanced NSCLC, and the efficacy of first-line chemotherapy, period of progression, histology, liver metastasis, smoking status and ECOG PS were independent prognostic factors for OS.     

Health-related quality of life results from the phase III CheckMate 067 study

BackgroundNivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067.Patients and methodsHRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated.ResultsNivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause.ConclusionThese results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.Study numberNCT01844505.     

动态、长程肿瘤标志物检测在评价晚期不可切除肺癌患者一线化疗疗效中的应用价值

目的:探讨动态、长程肿瘤标志物检测在评价晚期不可切除肺癌患者化疗疗效中的应用价值。方法:收集2014年1月至2016年1月扬州大学附属医院呼吸科收治的75例晚期肺癌患者为研究对象。以患者首次化疗之前的CEA、SF、CA125检查结果为基线标准,分别在第2、4、6周期化疗结束之后重复检测肿瘤标志物水平。随访并记录临床参数,分析在化疗周期中CEA、SF、CA125的变化及其临床意义。结果:第2周期化疗结束后,分别有10例、51例、14例患者达到PR、SD、PD疗效标准。第4周期结束后,分别有11例、44例、20例达到PR、SD、PD疗效标准。第6周期时,仅获得48例患者的随访资料,分别有7例、21例、20例患者达PR、SD、PD疗效标准。在第2周期、第4周期化疗结束后,各疗效组之间的CEA变化状态具有明显差异（P<0.05）,但各疗效组之间SF、CA125的变化状态仅在第6周期化疗结束后具有显著差异（P<0.05）。相关性分析发现,CEA变化趋势与第2周期（r=-0.296,P=0.012）、第4周期（r=-0.404,P<0.001）影像学疗效存在负相关关系。SF变化趋势（r=-0.405,P=0.023）、CA125变化趋势（r=-0.418,P=0.039）与第6周期影像学疗效存在负相关关系。在第2、4、6周期,CEA对疗效评价的曲线下面积分别为0.682、0.693、0.806,SF相应的曲线下面积分别为0.576、0.793、0.757,CA125相应的曲线下面积分别为0.653、0.610、0.679。Cox回归分析发现,仅有第2周期后影像学疗效评价、ECOG PS评分≥2分（χ2=2.596,P=0.031）是影响晚期肺癌患者PFS的独立性危险因素（P<0.05）。结论:肿瘤标志物对评价晚期不可切除肺癌患者化疗效果的效能欠佳。CEA对第2、4周期化疗效果有一定评价效能,SF、CA125仅对第6周期化疗效果有较高预判效能。     

The value of carcinoembryonic antigens in patients with advanced lung cancer: in relation to chemotherapy

The serum carcinoembryonic antigens (CEA) levels in 177 advanced lung cancer patients were studied to assess their value for the prognosis and indicating the effectiveness of chemotherapy. The relationship of pretreatment CEA levels with histology and stage of disease was also examined. Levels in excess of 5 ng/ml and 20 ng/ml were found in 55% and 32% of lung cancer patients, respectively. The elevated CEA levels were more frequently observed in patients with adenocarcinoma (65% in excess of 5 ng/ml) and extensive disease, but pretreatment CEA levels were not significantly correlated with the histology and clinical stage of disease. In 102 patients with adenocarcinoma, there was no significant difference of survival time in each patient with CEA levels less than 5 ng/ml, 5.0 less than or equal to - less than 20 ng/ml and in excess of 20 ng/ml; median survival time was 7, 7, 8 mo, respectively, and response to chemotherapy was not significant in each of these groups. Serial serum CEA measurements in patients with pretreatment levels in excess of 20 ng/ml correlated well with changes in disease status reflecting clinical response to chemotherapy. Mean percent changes of CEA levels to pretreatment levels were-77.4% in patients with partial response (PR), -55.6% in those with minor response (MR), -4.0% in patients with no change (NC) and +79.0% in patients showing progressive disease (PD). There was a significant difference in the percent changes of CEA levels between patients with an objective response (PR) and patients who had none (MR + NC) (p less than 0.02). CEA levels of all patients who had PD increased or unchanged. Serial measurements of serum CEA are useful in patients whose pretreatment levels are more than 20 ng/ml for monitoring the response to chemotherapy, and may be a useful noninvasive technique for patients with unmeasurable disease as a monitor of tumor burden in response to chemotherapy and recurrent disease.