Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

内囊预警综合征的临床特征和预后

目的 分析内囊预警综合征（capsular warning syndrome，CWS）的临床特点、影像学特征及治疗预后，
以提高对此病的认识。
方法 回顾性分析战略支援部队特色医学中心神经内科2013年1月-2018年12月收住院治疗的CWS的
临床资料、影像学特征及治疗预后情况。
结果 共12例患者，男性8例（66.67%），中位年龄为60岁。高脂血症9例（75.0%），高血压8例
（66.67%），糖尿病4例（33.33%），肿瘤病史3例（25.0%）。纯运动性卒中4例（33.33%），运动伴有构
音障碍者4例（33.33%），运动及感觉性障碍3例（25.00%），纯感觉障碍1例（8.33%）。影像学示豆纹
动脉供血区新发脑梗死6例（50%）。所有患者给予口服双联抗血小板治疗，其中3例症状复发患者又
给予静脉溶栓和静脉抗血小板治疗。3个月随访，所有患者均未再出现症状发作，10例mRS评分为0
分，2例mRS评分分别为4分及3分。
结论 CWS主要表现为运动障碍，发作刻板，常见原因为动脉粥样硬化性。在本组病例中发现双重
抗血小板治疗有效，静脉溶栓效果不肯定。     

Diffusion-weighted MRI and PET/CT reproducibility in epithelial ovarian cancers during neoadjuvant chemotherapy

PurposeTo investigate the reproducibility of diffusion-weighted (DW) MRI and ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG)-Positron emission tomography/CT (PET/CT) in monitoring response to neoadjuvant chemotherapy in epithelial ovarian cancer.Materials and methodsTen women (median age, 67 years; range: 41.8–77.3 years) with stage IIIC-IV epithelial ovarian cancers were included in this prospective trial (NCT02792959) between 2014 and 2016. All underwent initial laparoscopic staging, four cycles of carboplatine-paclitaxel-based chemotherapy and interval debulking surgery. PET/CT and DW-MRI were performed at baseline (C0), after one cycle (C1) and before surgery (C4). Two nuclear physicians and two radiologists assessed five anatomic sites for the presence of ≥ 1 lesion. Target lesions in each site were defined and their apparent diffusion coefficient (ADC), maximal standardized uptake value (SUV-max), SUV-mean, SUL-peak, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were monitored (i.e., 10 patients × 5 sites × 3 time-points). Their relative early and late changes were calculated. Intra/inter-observer reproducibilities of qualitative and quantitative analysis were estimated with Kappa and intra-class correlation coefficients (ICCs).ResultsFor both modalities, inter- and intra-observer agreement percentages were excellent for initial staging but declined later for DW-MRI, leading to lower Kappa values for inter- and intra-observer variability (0.949 and 1 at C0, vs. 0.633 and 0.643 at C4, respectively) while Kappa values remained > 0.8 for PET/CT. Inter- and intra-observer ICCs were > 0.75 for SUV-max, SUL-peak, SUV-mean and their change regardless the time-point. ADC showed lower ICCs (range: 0.013–0.811). ANOVA found significant influences of the evaluation time, the measurement used (ADC, SUV-max, SUV-mean, SUV-max, SUL-peak, MTV or TLG) and their interaction on ICC values (P = 0.0023, P< 0.0001 and P =0.0028, respectively).ConclusionWhile both modalities demonstrated high reproducibility at baseline, only SUV-max, SUL-peak, SUV-mean and their changes maintained high reproducibility during chemotherapy.     

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

Abbreviations

CIs

confidence intervals

ctDNA

circulating tumor DNA

ddPCR

droplet digital PCR

EGFR

epidermal growth factor receptor

MFs

mutant fractions

NGS

next‐generation sequencing

NSCLC

non‐small cell lung cancer

ORR

overall response rate

OS

overall survival

PD

progressive disease

PFS

progression‐free survival

PR

partial response

SD

stable disease

TKI

tyrosine kinase inhibitor

     

Significant reduction of postoperative pain and opioid analgesics requirement with an Enhanced Recovery After Thoracic Surgery protocol

ObjectiveTo evaluate differences in postoperative pain control and opioids requirement in thoracic surgical patients following implementation of an Enhanced Recovery after Thoracic Surgery protocol with a comprehensive postoperative pain management strategy.Material and MethodsA retrospective analysis of a prospectively maintained database of patients undergoing pulmonary resections by robotic thoracoscopy or thoracotomy from January 1, 2017, to January 31, 2019, was conducted. Multimodal pain management strategy (opioid-sparing analgesics, infiltration of liposomal bupivacaine to intercostal spaces and surgical sites, and elimination of thoracic epidural analgesia use in thoracotomy patients) was implemented as part of Enhanced Recovery after Thoracic Surgery on February 1, 2018. Outcome metrics including patient-reported pain levels, in-hospital and postdischarge opioids use, postoperative complications, and length of stay were compared before and after protocol implementation.ResultsIn total, 310 robotic thoracoscopy and 62 thoracotomy patients met the inclusion criteria. This pain management strategy was associated with significant reduction of postoperative pain in both groups with an overall reduction of postoperative opioids requirement. Median in-hospital opioids use (morphine milligram equivalent per day) was reduced from 30 to 18.36 (P = .009) for the robotic thoracoscopy group and slightly increased from 15.48 to 21.0 (P = .27) in the thoracotomy group. More importantly, median postdischarge opioids prescribed (total morphine milligram equivalent) was significantly reduced from 480.0 to 150.0 (P < .001) and 887.5 to 150.0 (P < .001) for the thoracoscopy and thoracotomy groups, respectively. Similar short-term perioperative outcomes were observed in both groups before and following protocol implementation.ConclusionsImplementation of Enhanced Recovery after Thoracic Surgery allows safe elimination of epidural use, better pain control, and less postoperative opioids use, especially a drastic reduction of postdischarge opioid need, without adversely affecting outcomes.     

腹腔镜低位直肠癌根治术中应用盆腔腹膜关闭技术的疗效研究

目的:探讨盆腔腹膜关闭技术在腹腔镜低位直肠癌根治术应用的疗效。方法:回顾性分析2012年1月至2016年5月我院54例腹腔镜低位直肠癌根治术中行盆底腹膜关闭患者和57例未行盆底腹膜关闭患者的临床资料。结果:盆腔腹膜关闭组与盆腔腹膜未关闭组在手术时间、术中出血量、肛门排气时间、术后进食时间以及盆腔引流管拔除时间等方面差异均无统计学意义(P>0.05)。盆腔腹膜关闭组中8例患者发生短期并发症;6例患者发生中期并发症;14例患者发生远期并发症,均为肠梗阻。盆腔腹膜未关闭组中31例患者发生短期并发症,28例患者发生中期并发症,36例患者发生远期并发症。所有患者均治疗好转。Coxs回归模型分析提示,盆腔腹膜是否关闭是腹腔镜低位直肠癌根治术患者术后生存的独立指标。结论:腹腔镜Miles术中行盆底腹膜关闭安全可行,具有临床实用价值。     

基于CT图像的评分模型预测食管鳞癌喉返神经旁淋巴结转移风险

目的:基于原发肿瘤及淋巴结CT特征建立评分模型预测食管鳞癌患者喉返神经旁淋巴结(RLN-LN)转移风险。方法:回顾性收集2014年1月至2019年12月于北京大学肿瘤医院行食管癌根治术并清扫RLN-LN的92例食管鳞癌患者。根据术后淋巴结病理结果分为RLN-LN转移组(n=37)和非转移组(n=55)。评估术前CT图像,记录食管癌患者年龄、性别、分化程度、肿瘤位置、肿瘤大小(肿瘤长度、肿瘤厚度、厚度/长度)、RLN-LN大小(淋巴结短径、长径、短径/多平面重建(MPR)最长径]。采用多元logistic回归筛选独立预测因子并建立评分模型,采用ROC曲线评估评分模型及独立预测因子诊断RLN-LN转移的效能,采用Z检验比较曲线下面积(AUC)的差异。应用Hosmer-Lemeshow检验和校准曲线评估模型拟合度。结果:肿瘤位置、肿瘤长度、RLN-LN短径、短径/MPR最长径是RLN-LN转移的独立预测因子,其诊断RLN-LN转移的AUC分别为0.586、0.705、0.831、0.777。基于以上4个CT特征建立评分模型,评分模型诊断RLN-LN转移的AUC为0.903(95%CI 0.846~0.959),优于各单一CT特征(Z=5.812,P<0.001;Z=2.161,P=0.030;Z=2.929,P=0.003;Z=4.052,P<0.001)。拟合优度Hosmer-Lemeshow检验结果显示P=0.555,校准曲线提示评分模型预测RLN-LN转移风险与实际转移风险之间具有良好的一致性。结论:基于CT图像的评分模型有助于食管鳞癌RLN-LN转移状态危险分层。