低位直肠癌术后肠道连续性的建立方式和功能评定

吻合器的广泛应用使低位直肠癌手术的保肛率增加,但常规的结肠断端和直肠的端-端吻合术常常给一些患者带来排便过频等症状。应用结肠J型储袋术后可以形成结肠的逆蠕动从而减少了术后排便的次数而不会造成新的直肠排便困难。J型储袋术的另一个优点是吻合并发症的低发生率。比起端-端吻合术,血运更好的吻合技术端-侧吻合术更受到青睐。结肠储袋术在常规开腹手术和肠镜直肠癌的手术中安全并且可以有效提高肠道功能。     

FDA Approval Summary: Crizotinib for the Treatment of Metastatic Non‐Small Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangements

On August 26, 2011, crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non‐small cell lung cancer (NSCLC) that is ALK‐positive as detected by a test approved by the U.S. Food and Drug Administration (FDA). Approval was based on two single‐arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks. On November 20, 2013, crizotinib received regular approval based on confirmation of clinical benefit in study A8081007, a randomized trial in 347 patients with ALK‐positive advanced NSCLC who had previously received one platinum‐containing regimen. Patients were assigned (1:1) to receive crizotinib 250 mg orally twice daily or standard of care (docetaxel or pemetrexed). The primary endpoint was progression‐free survival (PFS) determined by independent radiology review; secondary endpoints were ORR and overall survival (OS). PFS was significantly longer in the crizotinib arm, with median PFS of 7.7 and 3.0 months in the crizotinib and chemotherapy arms, respectively, and a 46% absolute increase in ORR but no difference in OS between treatment arms at the interim analysis. The most common adverse drug reactions (>25%) in crizotinib‐treated patients were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. The most serious toxicities of crizotinib were hepatotoxicity, interstitial lung disease or pneumonitis, and QT‐interval prolongation. Crizotinib's rapid clinical development program (6 years from identification of ALK rearrangements in a subset of NSCLC to full FDA approval) is a model of efficient drug development in this new era of molecularly targeted oncology therapy.     

EML4-ALK阳性表达非小细胞肺癌患者的临床特征及治疗现状

棘皮动物微管相关类蛋白4（EML4）与间变性淋巴瘤激酶（ALK）融合基因首次被发现存在于部分非小细胞肺癌中。该融合基因是由2号染色体上2区1带和2区3带易位形成,可以诱导肿瘤生成,而ALK 抑制剂能够拮抗其促肿瘤生成活性。本文旨在介绍EML4-ALK基因阳性表达肺癌患者的临床特征及该基因在肺癌诊断、治疗中的意义。     

克唑替尼治疗 ALK 融合基因阳性的晚期非小细胞肺癌患者的疗效分析

目的：探讨克唑替尼治疗中国 ALK 融合基因阳性的非小细胞肺癌（NSCLC）患者的疗效和安全性。方法14名患者接受至少4周的克唑替尼（250 mg,q12h）治疗,以评价治疗后的近期疗效、生活质量、不良反应。结果12例患者口服克唑替尼治疗后,11例（91.67%）获得部分缓解,1例（8.33%）获得疾病稳定,客观缓解率为91.67%;在生活质量评估中,患者的疲乏、气短、睡眠等均得到改善;不良反应主要为消化道症状,其次是谷丙转氨酶升高（64.29%）,视觉障碍（57.14%）,大部分为1～2级。结论克唑替尼作为 ALK 融合基因阳性的 NSCLC 患者的靶向治疗,具有良好的疗效及安全性,不良反应轻微。     

Pharmacologic study (JP28927) of alectinib in Japanese patients with ALK+ non‐small‐cell lung cancer with or without prior crizotinib therapy

We report pharmacokinetics, efficacy and safety data for a new 150‐mg alectinib capsule in ALK+ non‐small‐cell lung cancer in a multicenter, open‐label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor‐naïve and ‐pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40‐mg and 150‐mg capsules) until investigator‐determined lack of clinical benefit. Co‐primary endpoints were: bioequivalence of alectinib 20/40 mg vs 150 mg; food effect with 150 mg; and safety. Thirty‐five patients were enrolled; median treatment duration was 13.1 months (range 1.1?15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC_last ± standard deviation 3230 ± 914 h·ng/mL vs 3710 ± 1040 h·ng/mL, respectively, for 150‐mg vs 20/40‐mg capsules. Food effect with 150 mg alectinib was negligible. Treatment‐related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment‐related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1?2.1). For the full analysis set (n = 35) and crizotinib‐failure subpopulations (n = 23), the overall response rate was 70.0% (95% CI 50.6?85.3) and 65.0% (95% CI 40.8?84.6), and median progression‐free survival was 13.9 months (95% CI 11.1?not reached) and 12.9 months (95% CI 3.9?not reached), respectively. The 150‐mg capsule had a similar exposure profile to 20/40‐mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.     

Detection of Nonreciprocal/Reciprocal ALK Translocation as Poor Predictive Marker in Patients With First-Line Crizotinib-Treated ALK-Rearranged NSCLC

IntroductionDuring nonreciprocal/reciprocal translocation process, 5′-anaplastic lymphoma kinase (ALK) sometimes gets retained in the genome and is detectable by next-generation sequencing; however, no study has investigated its clinical significance. Our study aimed to assess the impact of harboring 5′-ALK on the efficacy of crizotinib.MethodsA total of 150 patients with next-generation sequencing–identified ALK-rearranged NSCLC from March 2014 to July 2018 at the Hunan Cancer Hospital were enrolled in this study. The efficacy of crizotinib as first-line therapy was evaluated in 112 patients according to the retention of 5′-ALK.ResultsAmong the 150 patients with NSCLC, nonreciprocal/reciprocal translocation was detected in 18.7% (28 of 150), and 3′-ALK fusion alone was detected in 81.3% (122 of 150). Among the 112 patients who received first-line crizotinib, 89 had 3′-ALK fusion alone (79 echinoderm microtubule associated protein-like 4 [EML4]-ALK and 10 non–EML4-ALK), and 23 had nonreciprocal/reciprocal ALK translocation. Among the patients with nonreciprocal/reciprocal ALK translocation, three patients harbored dual concurrent 3′-ALK fusions. Patients with nonreciprocal/reciprocal ALK translocation had higher incidence of brain metastasis at baseline than those with 3′-ALK fusion alone (39.1% versus 13.4%, p = 0.028). Crizotinib-treated patients with nonreciprocal/reciprocal ALK translocation had significantly shorter median progression-free survival (PFS) compared with patients carrying 3′-ALK fusion alone (6.1 m versus 12.0 m, p = 0.001) or with EML4-ALK fusion alone (6.1 m versus 12.6 m, p = 0.001). Multivariate analysis revealed that harboring nonreciprocal/reciprocal ALK translocation was an independent predictor of worse PFS for crizotinib-treated ALK-rearranged NSCLC (p = 0.0046).ConclusionsPresence of nonreciprocal/reciprocal ALK translocation was predictive for worse PFS and greater likelihood of baseline brain metastases in patients with ALK-rearranged NSCLC who received first-line crizotinib.     

ALK‐positive non–small cell lung cancer: Mechanisms of resistance and emerging treatment options

Targeted therapy has emerged as an effective treatment option for certain molecular subsets of advanced stage non–small cell lung cancer (NSCLC). The discovery of the echinoderm microtubule‐associated protein like 4–anaplastic lymphoma kinase (EML4‐ALK) translocation as an oncogenic driver has led to the development of novel therapies with activity in vitro and in the clinic. The first‐in‐class tyrosine kinase inhibitor crizotinib is effective against ALK‐positive NSCLC and is currently used as first‐line or salvage therapy in the setting of advanced disease. However, resistance inevitably develops through a variety of mechanisms, including point mutations affecting the fusion protein, activation of bypass signaling pathways, copy number gain of ALK, and other means. Increased understanding of these pathways is essential for tailoring treatment choices to improve outcomes and minimize toxicities. Potent second‐generation ALK inhibitors currently in trials are producing encouraging results in ALK‐positive NSCLC, even in patients with acquired resistance to crizotinib. The success in identifying the ALK translocations and rapidly developing targeted drugs to exploit it paves the way for a better understanding of NSCLC biology and the quest to provide effective, personalized treatment for lung cancer patients. Cancer 2014;120:2392–2402. © 2014 American Cancer Society.     

Fluorescence In Situ Hybridization,Immunohistochemistry, and Next‐Generation Sequencing for Detection of EML4‐ALK Rearrangement in Lung Cancer

Background.

The U.S. Food and Drug Administration-approved method for detecting EML4-ALK rearrangement is fluorescence in situ hybridization (FISH); however, data supporting the use of immunohistochemistry (IHC) for that purpose are accumulating. Previous studies that compared FISH and IHC considered FISH the gold standard, but none compared data with the results of next-generation sequencing (NGS) analysis.

Materials and Methods.

We studied FISH and IHC (D5F3 antibody) systematically for EML4-ALK rearrangement in 51 lung adenocarcinoma patients, followed by NGS in case of discordance.

Results.

Of 51 patients, 4 were positive with FISH (7.8%), and 8 were positive with IHC (15.7%). Three were positive with both. NGS confirmed that four of the five patients who were positive with IHC and negative with FISH were positive for ALK. Two were treated by crizotinib, with progression-free survival of 18 and 6 months. Considering NGS as the most accurate test, the sensitivity and specificity were 42.9% and 97.7%, respectively, for FISH and 100% and 97.7%, respectively, for IHC.

Conclusion.

The FISH-based method of detecting EML4-ALK rearrangement in lung cancer may miss a significant number of patients who could benefit from targeted ALK therapy. Screening for EML4-ALK rearrangement by IHC should be strongly considered, and NGS is recommended in borderline cases. Two patients who were negative with FISH and positive with IHC were treated with crizotinib and responded to therapy.     

Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non‐small cell lung cancer

Limited treatment options are available for stage IIIB/IV non‐small cell lung cancer (NSCLC). Nivolumab, a programmed cell death‐1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site‐assessed ORR, overall survival (OS), progression‐free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC‐assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site‐assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4–25.4), 2.7 (range 1.2–5.5) and 4.2 (95% CI 1.4–7.1) months, respectively. The IRC‐assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment‐related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ?discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy. Clinical trial registration number: JapicCTI‐132072     

KEYNOTE‐025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1–positive advanced non–small‐cell lung cancer

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD‐1), has been shown to improve overall survival (OS) in patients with previously treated advanced non–small‐cell lung cancer (NSCLC) with programmed death ligand 1 (PD‐L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE‐025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD‐L1 TPS ≥1% and had received ≥1 platinum‐doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD‐L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD‐L1 TPS ≥50%. Thirty‐eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41‐78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3‐5 treatment‐related adverse events (AE); 9 patients (24%) experienced immune‐mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD‐L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6‐61). Among evaluable patients with PD‐L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10‐38). Median (95% CI) progression‐free survival and OS were 3.9 (2.0‐6.2) months and 19.2 (8.0‐26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD‐L1–expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE‐010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.)     

Final safety and efficacy of erlotinib in the phase 4 POLARSTAR surveillance study of 10 708 Japanese patients with non‐small‐cell lung cancer

Interstitial lung disease (ILD) occurrence and risk factors were investigated in the Japanese non‐small‐cell lung cancer, post‐marketing, large‐scale surveillance study, POLARSTAR. All patients with unresectable, recurrent/advanced non‐small‐cell lung cancer who were treated with erlotinib in Japan between December 2007 and October 2009 were enrolled. Primary endpoints were patterns of ILD and risk factors for onset of ILD and ILD‐related death. Overall survival, progression‐free survival, and occurrence of adverse drug reactions were secondary endpoints. Interstitial lung disease was confirmed in 429 (4.3%) patients. Concurrent/previous ILD (hazard ratio, 3.19), emphysema or chronic obstructive pulmonary disease (hazard ratio, 1.86), lung infection (hazard ratio, 1.55), smoking history (hazard ratio, 2.23), and period from initial cancer diagnosis to the start of treatment (<360 days; hazard ratio, 0.58) were identified as significant risk factors for developing ILD by Cox multivariate analysis. Logistic regression analysis identified Eastern Cooperative Oncology Group performance status 2–4 (odds ratio, 2.45 [95% confidence interval, 1.41–4.27]; P = 0.0016), ≤50% remaining normal lung area (odds ratio, 3.12 [1.48–6.58]; P = 0.0029), and concomitant honeycombing with interstitial pneumonia (odds ratio, 6.67 [1.35–32.94]; P = 0.02) as poor prognostic factors for ILD death. Median overall survival was 277 days; median progression‐free survival was 67 days. These data confirm the well‐characterized safety profile of erlotinib. Interstitial lung disease is still an adverse drug reaction of interest in this population, and these results, including ILD risk factors, give helpful information for treatment selection and monitoring. Erlotinib efficacy was additionally confirmed in this population. (POLARSTAR trial ML21590.)     

Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non‐small‐cell lung cancer patients with EGFR mutations

This study was designed to examine the prediction of pretreatment circulating bilirubin and cholesterol for overall survival in 459 advanced non‐small‐cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Circulating total bilirubin, direct bilirubin (DB), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) levels were measured at baseline. The mean age (standard deviation) of all study patients was 58.7 (10.5) years, and 42.9% of them was males. Ever smokers accounted for 27.0% and lung adenocarcinoma for 90.4%. The median follow‐up time and survival time were 29.5 and 34.9 months, respectively. Patients with higher DB had a 1.68‐fold increased risk of death compared with patients with lower DB (hazard ratio [HR] = 1.68, 95% confidence interval [CI]: 1.22–2.30, p = 0.001), while patients with higher TC were at a 63% reduced risk of death compared with patients with lower TC (HR = 0.37, 95% CI: 0.20–0.67, p = 0.001). As for HDL‐C, patients with higher levels had the risk of death reduced by 46% (HR = 0.54, 95% CI: 0.29–1.00, p = 0.049) compared with patients with lower levels. After the Bonferroni correction, only DB and TC were significantly associated with NSCLC survival. Our findings demonstrate for the first time that pretreatment DB was identified as a significant risk factor, yet TC as a protective factor, for overall survival in NSCLC patients with EGFR mutations.     

Smoke exposure,histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer

Aberrant methylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers. There are major smoke exposure, histology, geography and gender-related changes in non-small cell lung cancer (NSCLC). We investigated smoking-related, histologic, geographic and gender differences in the methylation profiles of resected NSCLCs. We examined 514 cases of NSCLC and 84 corresponding nonmalignant lung tissues from 4 countries (USA, Australia, Japan and Taiwan) for the methylation status of 7 genes known to be frequently methylated in lung cancers [p16, RASSF1A (RAS association domain family 1), APC, RARbeta, CDH13, MGMT and GSTP1]. Multivariate analyses were used for data analysis. Adenocarcinoma was the major histologic type in women and never smokers; analyses that involved smoke exposure and gender were limited to this histology. Our major findings are a) methylation status of any single gene was largely independent of methylation status of other genes; b) the rates of methylation of p16 and APC and the mean Methylation Index (MI), a reflection of the overall methylation status, were significantly higher in ever smokers than in never smokers; c) the mean MI of tumors arising in former smokers was significantly lower than the mean of current smokers; d) the methylation rates of APC, CDH13 and RARbeta were significantly higher in adenocarcinomas than in squamous cell carcinomas; e) methylation rates of MGMT and GSTP1 were significantly higher in the USA and Australian cases than in those from Japan and Taiwan; and (f) no significant gender-related differences in methylation patterns were noted. Our findings demonstrate important smoke exposure, histologic type and geography-related differences in the methylation profiles of NSCLC tumors.