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1.
Baohui Han Kai Li Qiming Wang Yizhuo Zhao Li Zhang Jianhua Shi Zhehai Wang Yin Cheng Jianxing He Yuankai Shi Weiqiang Chen Xiuwen Wang Yi Luo Kejun Nan Faguang Jin Baolan Li Yinlan Chen Jianying Zhou Donglin Wang 《The lancet oncology》2017
Background
Anlotinib hydrochloride, an oral tyrosine kinase inhibitor targeting VEGFR, FGFR, PDGFR, and c-kit, showed promising efficacy in a phase 2 study. Here, we evaluated the efficacy and safety of anlotinib as third-line treatment for advanced non-small-cell lung cancer.Methods
We did a randomised, double-blind, placebo-controlled phase 3 trial (ALTER-0303) at 31 sites. Eligible patients with stage 3B/4 non-small-cell lung cancer who progressed after at least two lines of previous therapies were randomly assigned (2:1) to receive anlotinib (12 mg once a day from day 1 to 14 of a 21-day cycle) or placebo until progression or intolerable toxicity. Enrolled patients harbouring EGFR or ALK mutations must have failed in previous match-targeted therapies. The primary endpoint was overall survival. This trial is registered with ClinicalTrials, number NCT02388919.Findings
Between February, 2015, and August, 2016, we randomly assigned 437 patients. The baseline characteristics of the anlotinib group (n=294) and placebo group (n=143) were well balanced in age, gender, ECOG performance status, and gene status. With 292 overall survival events (67%), a significant improvement in overall survival was observed in the anlotinib group compared with the placebo group (hazard ratio 0·68, 95% CI 0·54–0·87 p=0·0018), according to investigator-assessed results (table).Interpretation
The ALTER-0303 trial met its primary endpoint; anlotinib significantly improved overall survival in advanced non-small-cell lung cancer with a manageable safety profile. The results strongly suggest that anlotinib should be considered as a candidate for the third-line treatment or beyond in advanced non-small-cell lung cancer.Funding
Chia-tai Tianqing Pharmaceutical Co Ltd. 相似文献2.
Zhitao Ying Xiaoyu Xiang Yuqin Song Ning Ding Yufu Lin Wen Zheng Xiaopei Wang Ningjing Lin Meifeng Tu Yan Xie Chen Zhang Weiping Liu Lijuan Deng Yanling Liu Yunqiang Yue Xueyun Yu Hanzhi Liu Panpan Duan Jun Zhu 《The lancet oncology》2017
Background
Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have poor outcomes with the available strategies. Based on the promising results seen in patients treated with anti-CD19 CAR T-cell therapy in relapsed or refractory B-cell non-Hodgkin lymphoma, we initiated a phase 1 study to evaluate the safety and efficacy in patients. Autologous T cells were genetically modified to express a chimeric antigen receptor consisting of an anti-CD19-scFv domain with CD3ζ and 4–1BB signalling domains.Methods
We did this phase 1 study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma in Peking University Cancer Hospital, Beijing, China. Patients received a CAR T-cell infusion after a conditioning regimen of cyclophosphamide (250 mg/m2) and fludarabine (25 mg/m2) daily for 3 days. Three CAR T cell doses were tested: 5?×?104 CAR T cells/kg, 1?×?105 CAR T cells/kg, and 1?×?106 CAR T cells/kg. Primary endpoints included safety and pharmacokinetics of CAR T cells. Secondary endpoints include complete response, overall response, and duration of response per International Working Group Criteria. This trial is registered at ClinicalTrials, number NCT02842138.Findings
As of March 2017, 14 patients were enrolled and ten patients, with a median age of 37 years (range 24–68) underwent response evaluation. Of the ten evaluable patients, four were women, six were men, three had follicular lymphoma, and seven had diffuse large B-cell lymphoma. The median number of previous therapies was 2·5 (range 2–7). The first group of three patients (two with follicular lymphoma and one with diffuse large B-cell lymphoma) received 5?×?104 CAR T cells/kg. Two patients with follicular lymphoma achieved partial remission on day 28, and one of these patients achieved complete remission 3 months later. The second group of three patients (one with follicular lymphoma and two with diffuse large B-cell lymphoma) received 1?×?105 CAR T cells/kg. The patient with follicular lymphoma achieved partial remission on day 28. The last group of four patients (all were diagnosed with diffuse large B-cell lymphoma) received 1?×?106 CAR T cells/kg. Three patients (75%) achieved partial remission on day 28. One patient attained progressive disease on day 28, and died 10 days later due to disease progression. A significant CAR T-cell expansion was detected in this case. On day 26, 26·8% of the patient's peripheral blood mononuclear cells were CAR T cells. PD1 expression was significant in her expanded CAR T cells. 78·3% of CD8-positive CAR T cells and 71·4% of CD4-positive CAR T cells expressed PD1 on day 26, as compared with 22% and 42% on day 13, respectively in the same patient. Increased PD1-expressing CAR T cells were also found in other patients' peripheral blood. No serious adverse event was observed in any patient. Two patients had mild fever (grade 1–2). In-vivo expansion of CAR T cells was detected in all patients between day 14–28. All responding patients were still in remission at the last follow-up (range 2·5–9·0 months).Interpretation
This study demonstrated early promising activity of anti-CD19 CAR T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The toxicities of cytokine release syndrome were mild and manageable. Our study also provided the first clinical evidence that expanded CAR T cells could express PD1. Blocking PD1 pathway might enhance the effector function of CAR T cells and improve the clinical outcomes of CAR T-cell therapy.Funding
Marino Biotechnology Co, Ltd. 相似文献3.
Yirui Zhai Honglian Ma Zhouguang Hui Lujun Zhao Dongming Li Jun Liang Xiaozhen Wang Liming Xu Bo Chen Yu Tang Runye Wu Yujin Xu Ming Chen Luhua Wang 《The lancet oncology》2017
Background
Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small lung cancer, with frequently unsatisfactory results. We aimed to evaluate the efficacy and safety of the addition of continuous intravenous infusion of recombinant human endostatin (Endostar) to concurrent chemoradiotherapy.Methods
We did this prospective, phase 2 study (HELPER) in patients with inoperable stage III non-small-cell lung cancer (defined by the American Joint Committee on Cancer 7th edn staging system) with an E performance score of 0–2; diagnoses were made on the basis of pathology or cytology results. All enrolled patients received thoracic radiation at doses of 60–66 Gy and continuous intravenous infusions of Endostar (7·5 mg/m2 per 24h, 120 h continuously, 120 h per cycle; from day ?5 to day ?1, days 10–13, days 24–28, and days 38–42). Additionally, patients received two cycles of etoposide (50 mg/m2; days 1–5 and days 29–33) plus cisplatin (50 mg/m2; day 1, 8, 29, and 36). The primary endpoint was progression-free survival and the secondary endpoints were objective response, overall survival, local recurrence-free survival, and toxicities.Findings
From November, 2012, to June, 2015, 73 patients were enrolled and 67 patients were evaluable. 56 patients were male and 11 patients were female. The median age was 59 years (range 31–69). Most patients (44, 66%) had squamous cell carcinoma. 27 patients (40%) had stage IIIa disease, and 40 (60%) had stage IIIb disease. Severe adverse events were observed in two patients (one had massive haemoptysis and one had pneumonia). The most common adverse event was leucopenia (96%; 45% were grade 3–4). The complete response was 12% and partial response was 64%. The median follow-up time was 37·1 months (range 20·1–52·1). The median overall survival was 34·7 months (21·9–47·4), progression-free survival was 13·3 months (5·5–21·0), and local recurrence-free survival was 27·1 months. Progression-free survival was 51% at 1 year, 35% at 2 years, and 28% at 3 years, overall survival was 82% at 1 year, 60% at 2 years, and 48% at 3 years, and local recurrence-free survival was 73% at 1 year, 55% at 2 years, and 50% at 3 years.Interpretation
For patients with unresectable stage III non-small-cell lung cancer, continuous intravenous human recombinant endostatin in combination with concurrent chemoradiotherapy is an effective treatment with tolerable toxicities. A phase 3 study is warranted.Funding
None. 相似文献4.
Ruinuo Jia Tanyou Shan Fuyou Zhou Anping Zheng Lixin Wan Zhiqiao Xu Guobao Zheng Xiaoyong Luo Yingjuan Zheng Yanhui Cui Guifang Zhang Dan Zhou Jiachun Sun Guoqiang Kong Xiaozhi Yuan Ruina Yang Jing Ren Wei Wang Shegan Gao 《The lancet oncology》2017
Background
Chemoradiotherapy with fluorouracil and cisplatin (PF) has shown greater clinical efficacy for local advanced oesophageal cancer but with high rate of acute toxicities. We designed the CRTCOESC study to evaluate the effect and safety of capecitabine with or without oxaliplatin versus PF with chemoradiotherapy in Chinese patients with oesophageal cancer.Methods
We this randomised, open-label, multicentre trial in nine cancer centres in Henan province, China, in Chinese patients with biopsy-proven squamous oesophageal cancer (T2-4N0-2M0). We randomly assigned patients (1:1:1) to receive single capecitabine, capecitabine plus oxaliplatin, or PF, and every patient received daily radiation of 50 Gy in 2 Gy dose per fraction. Patients were stratified by different regimens cycles. Both grade 3–5 acute toxicities and 2-year overall survival were the primary endpoint, with a planned accrual of 249 patients to detect a decrease in grade 3–5 acute toxicities from 40% to 20%. Interim analysis of acute toxicities and overall response was planned for the first 120 patients. This study is registered with ClinicalTrials, number NCT02025036.Findings
Between October, 2014, and December, 2016, we accrued 128 patients, of whom 118 were eligible. 86 patients finished at least 16 weeks' follow-up and were included in the interim report (n=24 capecitabine group, n=37 capecitabine plus oxaliplatin group, and n=25 PF group). Pretreatment characters (age, gender, weight, performance status, clinical stage, lymphonodus status, and pathology grade) did not differ between the groups. Incidence of grade 3–5 acute toxicities was 25% in the capecitabine group, 32% in the capecitabine plus oxaliplatin group, and 64% in the PF group (p=0·03); the incidence was significantly lower in the capectitabine groups than the PF group (capectitabine vs PF p=0·041; capecitabine plus oxaliplatin vs PF p=0·022) and did not differ between capectitabine and capecitabine plus oxaliplatin (p=0·738). 56 patients had finished 1-year follow-up (n=12 capecitabine group, n=26 capecitabine plus oxaliplatin group, and n=18 PF group). The 1-year overall survival was 75% in the capecitabine group, 92% in the capecitabine plus oxaliplatin group, and 76% in the PF group (p=0·166). Nine patients died in total: three patients in the capecitabine group, two patients in the capecitabine plus oxaliplatin group, and four patients in the PF group.Interpretation
Compared with PF, chemoradiotherapy with single capecitabine with or without oxaliplatin showed lower incidence of acute toxicities and similar 1-year overall survival.Funding
National Natural Science Foundation of China. 相似文献5.
Background
Sublobar resection is a potential alternative to lobectomy for elderly patients with early-stage non-small-cell lung cancer, with better short term outcomes and similar oncological outcomes. We aimed to compare sublobar resection and lobectomy in patients with clinical stage T1N0M0 non-small-cell lung cancer aged 70 years or older.Methods
We did this prospective, open label, randomised, controlled, multicentre, non-inferiority, phase 3 trial (STEPS; registered with the Chinese Thoracic Oncology Group, number CTON1504) comparing sublobar resection and lobectomy for treatment of elderly patients with early-stage non-small-cell lung cancer. Patients were aged 70 years or older, with preoperative thoracic CT showing suspected peripheral non-small-cell lung cancer, clinical stage IA, consolidation to maximum tumour diameter ratio of 0·5 or higher, and were eligible for sublobar resection with sufficient margin. Intraoperative eligibility criteria included histologically confirmed invasive non-small-cell lung cancer, pathological exclusion of suspected lymph node involvement, and feasibility of sublobar resection in terms of surgical margin requirement. Patients gave informed consent, completed 4-year mortality index and comprehensive geriatric assessment if necessary, and had both forced expiratory volume in 1 s and diffusing capacity of the lungs for carbon monoxide of 50% or more in pulmonary function tests. Patients were excluded if they had a previous history of thoracic surgery and malignant tumour history within the past 5 years. We expect a total of 339 patients to be randomly assigned to the two treatment groups and participants will be followed-up every 6 months for 3 years. The primary outcome is 3-year disease-free survival (with a non-inferiority margin of 15%). The study will develop in accordance to the Declaration of Helsinki. Ethical Committee approval (Peking University Institutional Review Board) was obtained on Oct 30, 2014, before registration (reference number IRB00001052-13053). This trial is registered with ClinicalTrials, number NCT02360761.Findings
As of Jan 29, 2016, 66 patients have been registered to the study; the accrual is slower than anticipated. One patient receiving sublobar resection died of a surgical complication.Interpretation
To our knowledge, the present study is the only prospective, multicentre, randomised, controlled trial to compare sublobar resection and lobectomy for elderly patients (≥70 years) with early-stage non-small-cell lung cancer.Funding
Medtronic Inc. 相似文献6.
Xin Wang Yongyang Yu Xiangbing Deng Wenjian Meng Hong Zhu Dan Jiang Hua Zhuang Bing Wu Zhiping Li Meng Qiu Hongfeng Gou Feng Bi Feng Xu Ziqiang Wang Zongguang Zhou 《The lancet oncology》2017
Background
Standard neoadjuvant concurrent chemoradiotherapy does not improve overall survival in stage II–III rectal cancer and total neoadjuvant treatment might be a better treatment option for patients with high risk factors. We aimed to evaluate the safety and efficacy of total neoadjuvant treatment (CAPOX [oxaliplatin and capecitabine] and intensity-modulated radiation therapy [IMRT] with volumetric-modulated arc therapy [VMAT]) in patients with rectal cancer with high risk factors.Methods
We did this phase 2 trial in patients who were diagnosed with stage II–III rectal cancer. We recruited patients with at least one high risk factors: cT4b, cN2, extramural venous invasion positive, involved mesorectal fascia positive, or lateral lymph nodes positive. Three cycles of induction CAPOX were followed by pelvic IMRT with VMAT and two cycles of concurrent CAPOX. Three cycles of consolidation CAPOX were delivered after radiotherapy. Primary endpoints were pathological complete response and R0 resection. This study is registered with the Chinese Clinical Trial Registry, number ChiCTR-OIN-17012284.Findings
From June, 2015, to April, 2017, 47 patients were evaluable. One patient (2%) who had acute intestinal obstruction after the first cycle of chemotherapy underwent emergency total mesorectal excision. A total of 29 patients (62%) completed eight cycles of chemotherapy and 46 patients (98%) completed the planned radiotherapy. 17 patients (36%) achieved a pathological complete response or clinical complete response, in which 12 patients (71%) completed eight cycles of chemotherapy. Five patients (11%) refused the operation and selected a watch and wait strategy. R0 resection for patients who underwent total mesorectal excision was 100%. The mean operation time was 207 min (median 195 min, range 120–370 min) and the mean estimated blood loss was 89 mL (median 50 mL, range 10–500 mL). The most common grade 3 or worse adverse events associated with the neoadjuvant administration were leucopenia (10%), diarrhoea (5%), radiation dermatitis (5%), and thrombocytopenia (2%). The most common grade 3 or worse surgery-related complications were pelvic abscesses, anastomotic leakage, and haemorrhage, which were observed in one patient, respectively.Interpretation
Total neoadjuvant treatment is effective and safe for patients with local advanced rectal cancer with high risk factors. Long-term efficacies of total neoadjuvant treatment need to be evaluated.Funding
Project of Health and Family Planning Commission of Sichuan Province. 相似文献7.
Jie Shen Zheng-Yun Zou Li-Feng Wang Jing Yan Wei-Wei Kong Fan-Yan Meng Fang-Jun Chen Juan Du Jie Shao Qiu-Ping Xu Ru-Tian Li Jia Wei Xiao-Ping Qian Bao-Rui Liu 《The lancet oncology》2017
Background
We aimed to investigate a new treatment method for the treatment of advanced hepatocellular carcinoma. The method was a cellular immune therapy based on personalised peptide vaccination (PPV-DC-CTL) combined with radiotherapy.Methods
We did a phase 1 study in which patients with advanced hepatocellular carcinoma who were not eligible for surgery, as confirmed by multidisciplinary consultation, were treated with precise radiotherapy combined with PPV-DC-CTL in the Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Nanjing, China. To personalise the vaccine, the peptide candidate library, including mutated peptides and highly expressed peptides, was established according to the gene mutation and expression spectra of hepatocellular carcinoma and previous studies about PPV. Peptides for vaccination of every patient were selected from the peptide candidate library, with the consideration of the pre-existing immunity of the host before vaccination. The assay of peptide-specific IFN-γ production was used to define pre-existing immunity. Side-effects were measured with a haemogram. This study is registered with the Chinese Clinical Trial Registry, number ChiCTR-OIC-16010025.Findings
A total of nine patients with advanced hepatocellular carcinoma were admitted. Four patients had multiple liver metastases (liver lesions more than three pieces), one patient had liver metastasis and portal vein tumour thrombosis, one patient had lung and bone metastases, two patients had liver and lung metastases, and one patient had liver metastasis and peritoneal metastasis. Following radiotherapy and 1–3 cycles of PPV-DC-CTL treatment, AFP concentrations were significantly reduced in six patients compared with baseline concentrations, and imaging assessment of the lesions showed a partial response in three of the patients and stable disease in the other three patients. An objective response was achieved in 33% and disease control in 66%. This regimen was found to be safe and well tolerated because none of the patients developed liver or kidney side-effects. Only one patient developed grade 2 bone marrow suppression, and the other patients had no significant side-effects.Interpretation
Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced hepatocellular carcinoma, which is well tolerated, safe, feasible, and effective.Funding
National Natural Science Foundation of China, Jiangsu Provincial Medical Youth Talent, and the Key Medical Science and Technology Development Project of Nanjing. 相似文献8.
Xieqiao Yan Xinan Sheng Bixia Tang Zhihong Chi Chuanliang Cui Lu Si Li Li Mao Bin Lian Siming Li Li Zhou Xuan Wang Xue Bai Yan Kong Jie Dai Jun Guo 《The lancet oncology》2017
Background
CM082 (X-82) is an oral multikinase inhibitor that targets VEGFR, PDGFR, and CSF1R. We aimed to investigate the safety profile of CM082 in combination with everolimus for treatment of metastatic renal cell carcinoma.Methods
We did a phase 1 study in Chinese patients aged 18–75 years, with histologically or cytologically confirmed diagnosis of clear cell renal cell carcinoma, which had progressed on at least one VEGFR tyrosine kinase inhibitor therapy in Peking University Cancer Hospital, Beijing, China. 3+3 dose escalation was done from 100 mg to 200 mg to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of oral CM082 daily in combination with oral everolimus 5 mg daily. We further assessed the safety and efficacy of this combination regimen in an expansion cohort.Findings
Between Sept 11, 2015, and July 12, 2016, we enrolled 22 patients with clear cell renal cell carcinoma. At the cutoff date (Aug 16, 2017), 15 patients had completed treatment, four patients had discontinued treatment, and three patients were still on treatment. 21 patients (95%) had received at least one VEGFR tyrosine kinase inhibitor therapy. DLT was observed in one (17%) of six patients: grade 4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, and was chosen as the optimal biological dose regimen. CM082 was well tolerated by most patients at a daily dose of 200 mg or less; grade 3–4 adverse events and adverse reactions were reported in 14 (64%) patients. The most common grade 3–4 adverse event (10%) and adverse reaction (14%) were hypertension. 20 patients (91%) were evaluable for tumour response per Response Evaluation Criteria In Solid Tumors version 1.1. Promising antitumour activity of CM082 and everolimus 5 mg in patients with metastatic renal cell carcinoma has been shown. No complete remission was seen. Partial response was observed in six (30%) of 20 patients, and stable disease was achieved in 14 (70%) of 20 patients. The objective response was achieved in 30% and disease control in 100%. At CM082 200 mg plus everolimus 5 mg, five (36%) of 14 patients had partial response and nine (64%) of 14 patients had stable disease with 100% disease control. The median progression-free survival was 7·9 months (95% CI 4·5–17·0).Interpretation
CM082 in combination with everolimus 5 mg was well tolerated in patients with advanced renal cell carcinoma who received at least one previous VEGFR tyrosine kinase inhibitor. MTD was not reached at up to CM082 200 mg plus everolimus 5 mg. This dose regimen was chosen as the recommended phase 2 dose for Chinese patients with renal cell carcinoma.Funding
AnewPharma. 相似文献9.
Ruihua Xu Fenghua Wang Qi Li Jianhua Shi Lin Shen Qingyuan Zhang Xianglin Yuan Yi Jiang Nong Xu Ye Chen Xichun Hu Xiaoyan Lin Shujun Yang Chao Ren 《The lancet oncology》2017
Background
Patients with unresectable or recurrent nasopharyngeal cancer who have disease progression after standard therapy have few treatment options and represent an important, unmet medical need. Nasopharyngeal cancer is closely associated with Epstein-Barr virus (EBV) infection and has been reported to have high concentrations of PD-L1 expression and tumour-infiltrating lymphocytes, which indicate a potential implication of PD-1 blockade in the treatment of nasopharyngeal cancer. JS001, a humanised recombinant IgG4 antibody against PD-1, selectively blocks the interactions of PD-1, with its ligands PD-L1 and PD-L2, and promotes antigen-specific T-cell activation. Results of a phase 1 study of JS001 treatment in Chinese patients with heavily pretreated solid tumours have shown an acceptable safety profile in doses up to 10 mg/kg once every 2 weeks until progressive disease, intolerance, withdrawal of consent, or investigator decision. Here we report the safety and efficacy of JS001 in a phase 1b/2 clinical study.Methods
We did this open-label, phase 1b/2, clinical study in Chinese patients with refractory or metastatic nasopharyngeal cancer received JS001 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity. All patients with measurable disease were assessed for clinical response every 8 weeks according to the immune-related Response Evaluation Criteria In Solid Tumors (iRECIST) criteria. Tumour PD-L1 expression, plasma EBV DNA concentration, and additional potential predictive biomarkers were monitored for correlation with clinical response. This study is registered with ClinicalTrials, number NCT02915432.Findings
Between Dec 29, 2016, and June 19, 2017, we enrolled 48 patients with nasopharyngeal cancer. Of 23 evaluable patients, the median age was 46 years (range 33–70), 81% were male, and EBV serology tested positive in 92%. Adverse events occurred in 46 (96%) of 48 patients, which were mostly grade 1 or 2. Grade 3 and worse adverse events occurred in 17 patients (35%), including abnormal liver function (n=6, 13%), dysphagia (n=2, 4%), and pulmonary infection (n=2, 4%). Rapid and deep clinical responses were observed. Seven patients (15%) had partial responses while ten patients (21%) achieved stable disease, with the proportion of patients who achieved an objective response of 30% and a disease control of 73%. The responses seemed unrelated to PD-L1 expression status on tumour biopsy.Interpretation
JS001 treatment has shown good clinical activity in heavily pretreated patients with nasopharyngeal cancer and a manageable safety profile. We plan to enrol 54 patients with nasopharyngeal cancer to further monitor the safety and efficacy of JS001 treatment.Funding
Shanghai Science and Technology Innovation Fund. 相似文献10.
K. Lehmann D. Eshmuminov P. Bauerfeind C. Gubler P. Veit-Haibach A. Weber H. Abdul-Rahman M. Fischer C. Reiner P.M. Schneider 《European journal of surgical oncology》2017,43(1):196-202
Introduction
The accuracy of preoperative lymph-node staging in patients with adenocarcinoma of the esophagogastric junction (AEG) or gastric cancer (GC) is low. The aim of this study was to assess the accuracy of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT) for lymph-node staging in patients with AEG or GC, with or without neoadjuvant treatment.Patients and methods
221 consecutive patients with GC (n = 88) or AEG (n = 133) were evaluated. Initial staging included endoscopic ultrasound (EUS), multidetector spiral CT (MDCT) and PET-CT. PET-CT was performed for restaging in patients after neoadjuvant treatment (n = 94). Systematic lymphadenectomy was routinely performed with histopathological assessment of individual mediastinal and abdominal lymph-node stations. Preoperative staging from EUS, MDCT, and PET-CT was correlated with histopathological results.Results
PET-CT showed a high specificity (91%) and positive predictive value (89%) for the preoperative detection of lymph-node metastases. In comparison, EUS was more sensitive (73% versus 50%, P < 0.01) but less specific (60%, P < 0.01). In patients with intestinal/mixed-type tumors, PET-CT improved the detection of extra-regional lymph-node metastases (P = 0.01) and distant metastases (P = 0.01) compared to CT alone. In contrast, lymph-node assessment by PET/CT after neoadjuvant treatment (32%, P < 0.01) and in diffuse-type cancers (24%, P < 0.01) is futile because of low sensitivities.Conclusion
PET-CT does not improve the overall accuracy of N staging, but does improve specificity compared to EUS and MDCT in AEG and GC. We do not recommend routine PET-CT for the initial staging in patients with diffuse-type cancer or for restaging of lymph nodes after neoadjuvant treatment. 相似文献11.
Natasha B. Leighl Naiyer A. Rizvi Lopes Gilberto de Lima Wichit Arpornwirat Charles M. Rudin Alberto A. Chiappori Myung-Ju Ahn Laura Q.M. Chow Lyudmila Bazhenova Arunee Dechaphunkul Patrapim Sunpaweravong Keith Eaton Jihong Chen Sonja Medley Srinivasu Poondru Margaret Singh Joyce Steinberg Rosalyn A. Juergens Shirish M. Gadgeel 《Clinical lung cancer》2017,18(1):34-42.e2
Introduction
First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non–small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes.Patients and Methods
We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non–small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival.Results
After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results.Conclusion
Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer. 相似文献12.
Tetsuhiko Asao Yutaka Fujiwara Kota Itahashi Shinsuke Kitahara Yasushi Goto Hidehito Horinouchi Shintaro Kanda Hiroshi Nokihara Noboru Yamamoto Kazuhisa Takahashi Yuichiro Ohe 《Clinical lung cancer》2017,18(4):e251-e258
Background
Second-generation anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib and ceritinib, have recently been approved for treatment of ALK-rearranged non–small-cell lung cancer (NSCLC). An optimal strategy for using 2 or more ALK inhibitors has not been established. We sought to investigate the clinical impact of sequential use of ALK inhibitors on these tumors in clinical practice.Patients and Methods
Patients with ALK-rearranged NSCLC treated from May 2010 to January 2016 at the National Cancer Center Hospital were identified, and their outcomes were evaluated retrospectively.Results
Fifty-nine patients with ALK-rearranged NSCLC had been treated and 37 cases were assessable. Twenty-six received crizotinib, 21 received alectinib, and 13 (35.1%) received crizotinib followed by alectinib. Response rates and median progression-free survival (PFS) on crizotinib and alectinib (after crizotinib failure) were 53.8% (95% confidence interval [CI], 26.7%-80.9%) and 38.4% (95% CI, 12.0%-64.9%), and 10.7 (95% CI, 5.3-14.7) months and 16.6 (95% CI, 2.9-not calculable), respectively. The median PFS of patients on sequential therapy was 35.2 months (95% CI, 12.7 months-not calculable). The 5-year survival rate of ALK-rearranged patients who received 2 sequential ALK inhibitors from diagnosis was 77.8% (95% CI, 36.5%-94.0%).Conclusion
The combined PFS and 5-year survival rates in patients who received sequential ALK inhibitors were encouraging. Making full use of multiple ALK inhibitors might be important to prolonging survival in patients with ALK-rearranged NSCLC. 相似文献13.
Background
Immune-related adverse events (irAEs) are commonly encountered, when using programmed death-1/programmed death-ligand-1 (anti-PD-1/PD-L1) therapy and are often managed with corticosteroids. The effect of irAEs, particularly when steroids are required, on patient survival is not well established.Methods
In this retrospective analysis, data for 157 patients with various tumor types treated with anti-PD-1/PD-L1 therapy were obtained. Kaplan–Meier and Cox regression analyses were used to assess the effect of irAEs and corticosteroids on progression-free survival (PFS).Results
A total of 45 irAEs were recorded for 157 patients. Twenty-one patients received systemic corticosteroids. Patients who developed irAEs, as well as those who received systemic corticosteroids, had improved PFS by Kaplan–Meier estimate. Multivariate Cox regression showed that irAEs were associated with improved PFS (hazard ratio of 0.33, P <0.001) which persisted even with use of systemic corticosteroids (hazard ratio of 0.38, P?=?0.03).Conclusions
irAEs are associated with improved PFS in patients receiving anti-PD-1/PD-L1 therapy. This association does not appear to be altered by the use of systemic corticosteroids. 相似文献14.
Yaxiong Zhang Zhonghan Zhang Xiaodan Huang Shiyang Kang Gang Chen Manli Wu Siyu Miao Yan Huang Hongyun Zhao Li Zhang 《Clinical lung cancer》2017,18(5):e333-e340
Background
Five major first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, icotinib, afatinib, and dacomitinib, are currently optional for patients with advanced non–small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, there was no head-to-head-based network meta-analysis among all the TKIs in EGFR-mutated populations.Methods
Eligible literature was searched from an electronic database. Data of objective response rate, disease control rate, progression-free survival, and overall survival were extracted from enrolled studies. Multiple treatment comparisons based on Bayesian network integrated the efficacy of all included treatments.Results
Six phase III randomized trials involving 1055 EGFR-mutated patients with advanced NSCLC were enrolled. Multiple treatment comparisons showed that 5 different EGFR-TKIs shared equivalent therapeutic efficacy in terms of all outcome measures. Rank probabilities indicated that dacomitinib and afatinib had potentially better efficacy compared with erlotinib, gefitinib, and icotinib in the EGFR-mutated patients. When compared with other agents, potential survival benefits (progression-free and overall survival) were observed in dacomitinib, whereas afatinib showed a better rank probability in overall response rate and disease control rate.Conclusion
Our study indicated a preferable therapeutic efficacy in the second-generation TKIs (dacomitinib and afatinib) when compared with the first-generation TKIs (erlotinib, gefitinib, and icotinib). 相似文献15.
Catherine Guilbault Aurelie Garant Sergio Faria Scott Owen Linda Ofiara Marie Duclos Vera Hirsh Neil Kopek 《Clinical lung cancer》2017,18(5):565-571
Background
Standard treatment for unresectable stage III non–small-cell lung cancer (NSCLC) is concurrent chemo-radiation (CRT). A regimen of induction carboplatin and gemcitabine followed by CRT was developed at the McGill University Health Centre to prevent delays in treatment initiation. We report the long-term outcomes with this regimen based on a pooled analysis of both protocol patients from a phase II study and nonprotocol patients.Methods and Materials
Outcomes and toxicity data were retrieved for 142 patients with stage III NSCLC: 43 patients treated on protocol between January 2003 and November 2004, and 101 patients treated off-protocol between December 2004 and August 2013. Patients received 2 cycles of carboplatin with an area under the curve of 5 intravenously (IV) on day 1 and gemcitabine 1000 mg/m2 IV on days 1 and 8 every 3 weeks, followed on day 50 by CRT, 60 Gy/30 over 6 weeks, concomitantly with 2 cycles of paclitaxel 50 mg/m2 IV and gemcitabine 100 mg/m2 IV on days 1 and 8 every 3 weeks.Results
The median overall survival was 23.2 months. With a median follow-up of 23.8 months, the 3-, 4-, and 5-year overall survival was 38%, 30%, and 26%, respectively. The median and 5-year progression-free survival rates were 12.5 months and 25%, respectively. Rates of grade ≥ 3 hematologic, esophageal, and respiratory toxicity were 20%, 10%, and 10%, respectively. Forty-eight patients received further lines of chemotherapy.Conclusion
The present analysis affirms the favorable toxicity profile of this novel induction chemotherapy, without apparent compromise in clinical outcomes, when compared with regimens using immediate concurrent CRT. 相似文献16.
Corey J. Langer Luis G. Paz-Ares Antoinette J. Wozniak Cesare Gridelli Filippo de Marinis Jean-Louis Pujol Belen San Antonio Jian Chen Jingyi Liu Ana B. Oton Carla Visseren-Grul Giorgio V. Scagliotti 《Clinical lung cancer》2017,18(5):489-496
Background
In a phase III study, maintenance pemetrexed showed superior survival over placebo (PARAMOUNT) for patients with advanced non-squamous non-small cell lung cancer (NSCLC) who completed 4 cycles of pemetrexed plus cisplatin (PC) induction therapy, with low incidence of treatment-emergent adverse events (TEAEs) generally associated with pemetrexed. Prior analyses did not account for toxicities carried over from induction; thus, the current analysis was developed to understand toxicities that may be attributed to pemetrexed maintenance versus PC induction, and how treatment duration affects toxicity.Patients and Methods
Selected clinically relevant TEAEs were explored in 2 analyses: assessing induction versus maintenance treatment in PARAMOUNT, and comparing PC from PARAMOUNT with toxicity data from a previous phase III study that established the role of PC in front-line therapy of non-squamous NSCLC (JMDB trial).Results
In PARAMOUNT, the incidence of most drug-related TEAEs was higher during induction than maintenance, for both the pemetrexed and placebo randomized populations. The majority of TEAEs during maintenance, except renal events, were carried over from induction with no change in severity from the end of induction; the incidence of TEAEs associated with pemetrexed maintenance was low. The cross-trial analysis showed that 6 cycles of PC in JMDB compared with 4 cycles in PARAMOUNT increased grade 1/2 fatigue (34.1% vs. 25.0%), anemia (24.0% vs. 13.5%), and renal events (11.8% vs. 3.6%).Conclusions
Safety data presented here support the favorable risk benefit of 4 cycles of PC followed by maintenance pemetrexed in patients with advanced non-squamous NSCLC. 相似文献17.
Edward B. Garon Martin Reck Luis Paz-Ares Santiago Ponce Jesus Corral Jaime Oscar Juan Ernest Nadal Pablo Lee Rita Dalal Jingyi Liu Shuang He Joseph Treat Kazuhiko Nakagawa 《Clinical lung cancer》2017,18(1):96-99
Introduction
We present the treatment rationale and study design for the RELAY study (NCT02411448 ). This phase Ib/III study will assess safety, tolerability, and efficacy of the combination of ramucirumab with erlotinib in previously untreated stage IV non–small-cell lung cancer patients with an activating epidermal growth factor receptor (EGFR) mutation.Patients and Methods
The study is being conducted in approximately 120 sites in North America, Europe, and Asia and is currently open for enrollment. In part A (phase Ib), approximately 12 patients will receive ramucirumab (10 mg/kg) every 2 weeks with erlotinib (150 mg) every day. Dose-limiting toxicity will be assessed during 2 cycles (4 weeks) of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every 2 weeks with erlotinib daily until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary end point is progression-free survival, on the basis of investigator assessment. Secondary end points include overall survival, objective response rate, disease control rate, duration of response, safety, and quality of life.Conclusion
Erlotinib with ramucirumab combination was chosen because the addition of an antiangiogenic agent, such as ramucirumab, would further improve the efficacy of erlotinib, which is a standard of care in the first-line treatment of patients with activating EGFR mutations. 相似文献18.
David R. Spigel Alexander Luft Henrik Depenbrock Rodryg Ramlau Mazen Khalil Joo-Hang Kim Carlos Mayo Grace Yi Chao Coleman Obasaju Ronald Natale 《Clinical lung cancer》2017,18(5):480-488
Background
The combination of necitumumab with gemcitabine-cisplatin significantly improved overall survival (OS) in patients with stage IV squamous non–small-cell lung cancer (NSCLC), in the phase III SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) trial. Paclitaxel-carboplatin was selected as an alternative standard of care in the current phase II study.Patients and Methods
Patients were randomized (stratified according to Eastern Cooperative Oncology Group performance status and sex) 2:1 to ≤ six 3-week cycles (Q3W) of paclitaxel and carboplatin with or without necitumumab. Chemotherapy was paclitaxel 200 mg/m2 on day 1 Q3W and carboplatin area under the curve 6 on day 1 Q3W. Necitumumab 800 mg, on days 1 and 8, was continued until disease progression or intolerable toxicity occurred. The primary end point was objective response rate (ORR) on the basis of Response Evaluation Criteria In Solid Tumors version 1.1.Results
One hundred sixty-seven patients were randomized to the necitumumab-containing arm (n = 110) or the chemotherapy-only arm (n = 57). The combination of necitumumab with chemotherapy resulted in an ORR of 48.9% versus 40.0%. Median progression-free survival and OS were 5.4 versus 5.6 months (hazard ratio [HR], 1.0) and 13.2 versus 11.2 months (HR, 0.83; P = .379) in each treatment arm, respectively. Disease control rate was 87.2% versus 84.0%. Grade ≥ 3 adverse events typically associated with epidermal growth factor receptor (EGFR) monoclonal antibodies showing a > 2% increase were hypomagnesemia (5.7% vs. 0) and rash (2.8% vs. 0). Any Grade thromboembolic events occurred in < 4% of patients in either arm.Conclusion
The results of our study support previously reported results that the combination of necitumumab with chemotherapy improves survival in patients with advanced squamous NSCLC and shows a safety profile consistent with that of EGFR monoclonal antibodies. 相似文献19.
L.M. van Veenendaal M.F. Madu M.E.T. Tesselaar C. Verhoef D.J. Grünhagen A.C.J. van Akkooi 《European journal of surgical oncology》2017,43(11):2157-2162
Background
Merkel cell carcinoma (MCC) is a rare and potentially aggressive neuroendocrine tumor of the skin, with a propensity for locoregional metastases. In two expert referral centers, isolated limb perfusion (ILP) is used to obtain locoregional control in selected locoregionally advanced MCC patients. This study describes our experience.Method
Patients who underwent ILP for MCC were analyzed. ILP was performed with melphalan and tumor necrosis factor (TNF) combination therapy. Depending on the institution, either a normothermic or a hyperthermic temperature regimen was used. Baseline characteristics, toxicity data, locoregional progression-free survival (LPFS) and overall survival (OS) were assessed.Results
Four males and 6 females with a median age of 78 years (IQR 61–84 years) were included. Four patients underwent ILP for upper extremity disease and 6 for lower extremity disease. All patients received combination therapy with Melphalan and TNF, one patient with the addition of interferon-gamma. No signs of systemic toxicity were present post-ILP. Severe locoregional toxicity (compartment syndrome) occurred in 1 patient and 1 elderly patient with extensive atherosclerosis had to undergo transfemoral amputation due to critical ischemia. Eight patients could be included for response evaluation. The overall response rate (ORR) was 87.5% with a complete response (CR) rate of 62.5%. Two long-term responses of 53 months and 71 months were observed. Median LPFS was 5 months and median OS was 54 months.Conclusion
ILP shows a high CR rate that can be durable. Therefore, ILP should be considered an effective treatment modality for locally advanced MCC. 相似文献20.
Bryan J. Schneider Gregory P. Kalemkerian Shirish M. Gadgeel Manuel Valdivieso Deborah M. Hackstock Wei Chen Lance K. Heilbrun John C. Ruckdeschel Antoinette J. Wozniak 《Clinical lung cancer》2017,18(3):299-302
