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1.
Yang Qu Katsura Emoto Takashi Eguchi Rania G. Aly Hua Zheng Jamie E. Chaft Kay See Tan David R. Jones Mark G. Kris Prasad S. Adusumilli William D. Travis 《Journal of thoracic oncology》2019,14(3):482-493
Introduction
Major pathologic response after neoadjuvant chemotherapy (NAC) for NSCLC has been defined as 10% or less residual viable tumor without distinguishing between histologic types. We sought to investigate whether the optimal cutoff percentage of residual viable tumor for predicting survival differs between lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC).Methods
Tumor slides from 272 patients treated with NAC and surgery for clinical stage II-III NSCLC (ADC, n = 192; SCC, n = 80) were reviewed. The optimal cutoff percentage of viable tumor for predicting lung cancer–specific cumulative incidence of death (LC-CID) was determined using maximally selected rank statistics. LC-CID was analyzed using a competing-risks approach. Overall survival was evaluated using Kaplan-Meier methods and Cox proportional hazard analysis.Results
Patients with SCC had a better response to NAC (median percentage of viable tumor: SCC versus ADC, 40% versus 60%; p = 0.027). Major pathologic response (≤10% viable tumor) was observed in 26% of SCC cases versus 12% of ADC cases (p = 0.004). The optimal cutoff percentage of viable tumor for LC-CID was 10% for SCC and 65% for ADC. On multivariable analysis, viable tumor 10% or less was an independent factor for better LC-CID (p = 0.035) in patients with SCC; in patients with ADC, viable tumor 65% or less was a factor for better LC-CID (p = 0.033) and overall survival (p = 0.050).Conclusions
In response to NAC, the optimal cutoff percentage of viable tumor for predicting survival differs between ADC and SCC. Our findings have implications for the pathologic assessment of resected specimens, especially in upcoming clinical trials design. 相似文献2.
Sara Gagno Mario Rosario D’Andrea Mauro Mansutti Chiara Zanusso Fabio Puglisi Eva Dreussi Marcella Montico Paola Biason Erika Cecchin Donatella Iacono Stefania Russo Marika Cinausero Silvana Saracchini Giampietro Gasparini Donata Sartori Mario Bari Elena Collovà Rosa Meo Giuseppe Toffoli 《Clinical breast cancer》2019,19(2):137-145.e4
Introduction
Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.Patients and Methods
Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility.Results
Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor–4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively.Conclusion
In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management. 相似文献3.
Vanesa Ortega Antonio Antón Isabel Garau Noemia Afonso Lourdes Calvo Yolanda Fernández María Martínez-García Esperanza Blanco Pilar Zamora Mirta García José Juan Illarramendi César Augusto Rodríguez Sánchez Miguel Sampayo Elena Aguirre José Manuel Pérez-García Javier Cortés Antonio Llombart-Cussac 《Clinical breast cancer》2019,19(2):105-112
Background
Eribulin has efficacy in patients with progression after ≥ 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors.Patients and Methods
Eribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received ≥ 1 dose of eribulin.Results
The median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia.Conclusion
Eribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC. 相似文献4.
I. Alex Bowman Alisha Bent Tri Le Alana Christie Zabi Wardak Yull Arriaga Kevin Courtney Hans Hammers Samuel Barnett Bruce Mickey Toral Patel Tony Whitworth Strahinja Stojadinovic Raquibul Hannan Lucien Nedzi Robert Timmerman James Brugarolas 《Clinical genitourinary cancer》2019,17(2):e263-e272
Background
Brain metastases (BM) occur frequently in patients with metastatic kidney cancer and are a significant source of morbidity and mortality. Although historically associated with a poor prognosis, survival outcomes for patients in the modern era are incompletely characterized. In particular, outcomes after adjusting for systemic therapy administration and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors are not well-known.Patients and Methods
A retrospective database of patients with metastatic renal cell carcinoma (RCC) treated at University of Texas Southwestern Medical Center between 2006 and 2015 was created. Data relevant to their diagnosis, treatment course, and outcomes were systematically collected. Survival was analyzed by the Kaplan-Meier method. Patients with BM were compared with patients without BM after adjusting for the timing of BM diagnosis, either prior to or during first-line systemic therapy. The impact of stratification according to IMDC risk group was assessed.Results
A total of 56 (28.4%) of 268 patients with metastatic RCC were diagnosed with BM prior to or during first-line systemic therapy. Median overall survival (OS) for systemic therapy-naive patients with BM compared with matched patients without BM was 19.5 versus 28.7 months (P = .0117). When analyzed according to IMDC risk group, the median OS for patients with BM was similar for favorable- and intermediate-risk patients (not reached vs. not reached; and 29.0 vs. 36.7 months; P = .5254), and inferior for poor-risk patients (3.5 vs. 9.4 months; P = .0462). For patients developing BM while on first-line systemic therapy, survival from the time of progression did not significantly differ by presence or absence of BM (11.8 vs. 17.8 months; P = .6658).Conclusions
Survival rates for patients with BM are significantly better than historical reports. After adjusting for systemic therapy, the survival rates of patients with BM in favorable- and intermediate-risk groups were remarkably better than expected and not statistically different from patients without BM, though this represents a single institution experience, and numbers are modest. 相似文献5.
Megan Greally Joanne F. Chou Daniela Molena Valerie W. Rusch Manjit S. Bains Bernard J. Park Abraham J. Wu Karyn A. Goodman David P. Kelsen Yelena Y. Janjigian David H. Ilson Geoffrey Y. Ku 《Journal of thoracic oncology》2019,14(3):540-546
Introduction
Preoperative or definitive chemoradiation is an accepted treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The MUNICON study showed that positron-emission tomography (PET) response following induction chemotherapy was predictive of outcomes in patients with gastroesophageal junction adenocarcinoma. We evaluated the predictive value of PET following induction chemotherapy in ESCC patients and assessed the impact of changing chemotherapy during radiation in PET nonresponders.Methods
We retrospectively reviewed all patients with locally advanced ESCC who received induction chemotherapy and chemoradiation; all patients had a PET before and after induction chemotherapy. Survival was calculated from date of repeat PET using Kaplan-Meier analysis and compared between groups using the log-rank test.Results
Of 111 patients, 70 (63%) were PET responders (defined as a 35% or more decrease in maximum standard uptake value) to induction chemotherapy. PET responders received the same chemotherapy during radiation. Of 41 PET nonresponders, 16 continued with the same chemotherapy and 25 were changed to alternative chemotherapy with radiation. Median progression-free survival (70.1 months versus 7.1 months, p < 0.01) and overall survival (84.8 months versus 17.2 months, p < 0.01) were improved for PET responders versus nonresponders. Median progression-free survival and overall survival for PET nonresponders who changed chemotherapy versus those who did not were 6.4 months versus 8.3 months (p = 0.556) and 14.1 versus 17.2 months (p = 0.81), respectively.Conclusions
PET after induction chemotherapy highly predicts for outcomes in ESCC patients who receive chemoradiation. However, our results suggest that PET nonresponders do not benefit from changing chemotherapy during radiation. Future trials should use PET nonresponse after induction chemotherapy to identify poor prognosis patients for novel therapies. 相似文献6.
Daichi Fujimoto Hiroshige Yoshioka Yuki Kataoka Takeshi Morimoto Tae Hata Young Hak Kim Keisuke Tomii Tadashi Ishida Masataka Hirabayashi Satoshi Hara Manabu Ishitoko Yasushi Fukuda Moon Hee Hwang Naoki Sakai Motonari Fukui Hitoshi Nakaji Mitsunori Morita Tadashi Mio Toyohiro Hirai 《Journal of thoracic oncology》2019,14(3):468-474
Introduction
Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression.Methods
We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors–defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors–defined second progressive disease or death.Results
Among the 542 patients included, 20% and 53% showed a typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (n = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the patients who showed pseudoprogression than the PFS of the patients with a typical response (p < 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than did patients showing typical progression (p = 0.001).Conclusions
Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed a typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression. 相似文献7.
Jessica J. Lin Ginger Y. Jiang Nencyben Joshipura Jennifer Ackil Subba R. Digumarthy Sandra P. Rincon Beow Y. Yeap Justin F. Gainor Alice T. Shaw 《Journal of thoracic oncology》2019,14(4):683-690
Background
Central nervous system (CNS) metastases represent a significant source of morbidity and mortality for patients with ALK tyrosine kinase gene (ALK)-positive NSCLC. Alectinib has demonstrated robust CNS activity in both crizotinib-naive and crizotinib-resistant settings. However, the CNS efficacy of alectinib has not been established in patients with untreated symptomatic, large CNS metastases.Methods
In this retrospective study, patients were eligible if they had advanced ALK-positive NSCLC with large (defined as ≥1 cm) or symptomatic CNS metastases and received alectinib. Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1.Results
Of the 19 patients, 15 (79%) had measurable CNS disease at baseline and were evaluable for response. The CNS objective response rate in these patients was 73.3% (95% confidence interval [CI]: 44.9%–92.2%), the CNS disease control rate was 100.0% (95% CI: 78.2%–100.0%), and the median CNS duration of response was 19.3 months (95% CI: 14.3 months–not evaluable). In 18 evaluable patients with measurable and/or nonmeasurable baseline CNS disease, the CNS objective response rate was 72.2% (95% CI: 46.5%–90.3%), the CNS disease control rate was 100.0% (95% CI: 81.5%–100.0%), and the median CNS duration of response was 17.1 months (95% CI: 14.3 months–not evaluable). All eight patients with symptoms attributable to CNS metastases had clinical improvement upon starting alectinib therapy. Six patients (32%) eventually required salvage brain radiotherapy.Conclusions
Alectinib demonstrated meaningful CNS efficacy in patients with ALK-positive NSCLC with untreated symptomatic or large brain metastases. 相似文献8.
Morgan R.L. Lichtenstein Ryan D. Nipp Alona Muzikansky Kelly Goodwin Danyon Anderson Richard A. Newcomb Justin F. Gainor 《Journal of thoracic oncology》2019,14(3):547-552
Introduction
Immunotherapy has revolutionized the treatment of NSCLC, but little is known about the activity of programmed cell death 1 and programmed death ligand 1 blockade across age groups.Methods
We retrospectively evaluated patients with NSCLC who initiated programmed cell death 1 and programmed death ligand 1 inhibitors from January 2013 through July 2017. Medical records and radiographic imaging were reviewed to determine progression-free survival (PFS) and overall survival (OS). We also compared immunotherapy-related toxicities, steroid use, and hospitalizations by age.Results
Of the 245 patients, 26.1% were younger than 60 years, 31.4% were age 60 to 69 years, 31.0% were age 70 to 79 years, and 11.4% were age 80 years or older. The median PFS times by age group were as follows: younger than 60 years, 1.81 months; age 60 to 69 years, 2.53 months; age 70 to 79 years, 3.75 months; and age 80 years or older, 1.64 months (log-rank p value = 0.055). The median OS times by age group were as follows: younger than 60 years, 13.01 months; age 60 to 69 years, 14.56 months; age 70 to 79 years, 12.92 months; and age 80 years or older, 3.62 months (log-rank p value = 0.011). Rates of immunotherapy-related toxicities, steroid use, and hospitalizations did not differ by age.Conclusions
Although the OS and PFS benefits of immunotherapy differ by age, the rates of toxicity are similar regardless of age. 相似文献9.
Ibiayi Dagogo-Jack Hayley Robinson Mari Mino-Kenudson Anna F. Farago Vashine Kamesan A. John Iafrate Alice T. Shaw Jochen K. Lennerz 《Journal of thoracic oncology》2019,14(5):835-843
Introduction
Lung cancer patients with tumors harboring actionable alterations can achieve very durable responses to first-line targeted therapy. However, identifying targetable alterations using next-generation sequencing (NGS) is a complex and time-intensive process. As actionable genetic alterations are enriched in lung cancers arising in patients with limited smoking history, we designed a workflow to expedite NGS testing for this group.Methods
We developed a protocol to allow for next-day extraction of nucleic acids from frozen tissue. Specimens were designated as high priority during sequencing. We determined the interval between biopsy and NGS results to evaluate whether the workflow reduced the pre-analytical period and in-laboratory turnaround time and allowed for rapid initiation of genotype-matched therapy.Results
Between January 2017 and May 2018, 21 patients participated in the expedited sequencing program. The median interval between biopsy and NGS results was 10.7 days. Six patients received results within 1 week of biopsy. Performing molecular analysis on frozen tissue and prioritizing sequencing and analysis of these specimens reduced the pre-analytical period from 3.5 to 1.3 days (p < 0.0001) and shortened in-laboratory turnaround time by 3 days (11.8 versus 8.4 business days, p < 0.0001). Ninety-three percent of patients with an actionable molecular alteration received first-line targeted therapy. The median time-to-initiation of treatment was 19.7 days from biopsy.Conclusions
Sequencing and analyzing nucleic acids from frozen tissue is a practical strategy for shortening the time to matched therapy. The significant advantage of upfront treatment with targeted therapies in subsets of lung cancer patients provides rationale for developing workflows that accelerate comprehensive molecular analysis. 相似文献10.
Bernardo Cacho-Díaz Héctor Spínola-Maroño Nancy Reynoso Alberto González-Aguilar Alejandro Mohar-Betancourt 《Clinical breast cancer》2019,19(2):e394-e398
Introduction
Breast cancer (BC) is the most common cancer in women, and the incidence of brain metastasis (BM) from BC ranges from 20% to 30%, with a median survival of 10 to 15 months. Previous reports have shown that the presence of obesity or diabetes negatively impacts survival. The present study investigates the association between obesity or diabetes mellitus (DM) and overall survival of patients with BC with BM.Materials and Methods
A database from 2 referral centers for the period of July 2014 to February 2018 was analyzed. The inclusion criteria were as follows: patients who had a confirmed diagnosis of BC with BM were followed and treated at these centers. Demographic data, body weight and height, clinical and oncologic history, functional status, prognostic scales, and prognoses were examined.Results
A total of 228 patients were included. The median age at BM was 50 years; the median survival after diagnosis was 12.1 months; 108 patients had a body mass index (BMI) ≥ 25, and 40 (17%) patients had DM. The association between survival and the presence of BMI > 25 exhibited a P value of 0.3.Discussion
We found no association between overweight, obesity, or DM and survival in patients with BC with BM. The role of obesity in cancer is a robust research topic, as there are many questions to be answered.Conclusion
Obesity as a prognostic indicator should be further studied, because we found no association between overall survival and either patients with BM from BC with a BMI > 25 or those with normal weight. 相似文献11.
12.
Maxime Vanmechelen Diether Lambrechts Thomas Van Brussel Annelies Verbiest Gabrielle Couchy Patrick Schöffski Herlinde Dumez Philip R. Debruyne Evelyne Lerut Jean-Pascal Machiels Vincent Richard Maarten Albersen Vincent Verschaeve Stéphane Oudard Arnaud Méjean Pascal Wolter Jessica Zucman-Rossi Benoit Beuselinck 《Clinical genitourinary cancer》2019,17(2):e235-e246
Background
There are no validated markers that predict response or resistance in patients with metastatic clear-cell renal cell carcinoma (mccRCC) treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors such as sunitinib and pazopanib. Recently, single nucleotide polymorphism (SNP) rs2981582 in Fibroblast Growth Factor Receptor 2 (FGFR2) was found to be associated with clinical outcome in patients with mccRCC treated with pazopanib and sunitinib. We aimed to validate these findings in patients treated with sunitinib.Materials and Methods
Germline DNA was collected in patients with mccRCC starting first-line systemic therapy with sunitinib. SNP rs2981582 in FGFR2 C>T was genotyped. Association of the genotype with response rate, tumor shrinkage, median progression-free survival (mPFS), and median overall survival (mOS) was studied.Results
We collected clinical data from 154 patients with available germline DNA. Baseline prognostic markers were well-balanced between both subgroups. Patients with the TT genotype had a poorer outcome compared with patients with the CT/CC genotype. The median shrinkage of selected tumor target lesions during treatment with sunitinib was ?16% versus ?31% (P = .002), mPFS was 8 versus 15 months (P = .0007), and mOS was 22 versus 33 months (P = .04), respectively. On multivariate analysis, rs2981582 remained an independent predictor of PFS (hazard ratio, 2.858; 95% confidence interval, 1.659-4.923; P < .0001) and OS (hazard ratio, 1.795; 95% confidence interval, 1.003-3.212; P = .049).Conclusion
Polymorphism rs2981582 in FGFR2 is correlated to PFS and OS in patients with mccRCC treated with sunitinib. Prospective validation of the impact of this SNP is warranted. 相似文献13.
Alp Tuna Beksac Mesude Bicak Ishan Paranjpe David J. Paulucci John P. Sfakianos Ketan K. Badani 《Clinical genitourinary cancer》2019,17(2):e314-e322
Background
Chromophobe renal cell carcinoma (chRCC) is known as an indolent tumor; however, mortality still occurs. We sought to determine the clinicopathologic and genomic factors associated with aggressive chRCC.Patients and Methods
Two different datasets were used to identify patients with clinical stage III and IV chRCC. Eighteen patients from The Cancer Genome Atlas (TCGA) database and 1693 patients from the American College of Surgeons National Cancer Database (NCDB) were used for analysis. From the TCGA, RNA-Seq expression analysis of 18,745 genes was conducted between the recurrent (n = 5; 27.8%) and nonrecurrent patients (n = 13; 72.2%). Biological significance was identified via pathway enrichment and gene function analyses. From the NCDB, Cox proportion hazards regression models were used to identify variables associated with overall survival (OS) at a median follow-up of 41.4 months.Results
Between the 2 groups, 2182 genes were differentially expressed. The most commonly overexpressed pathways were neuroactive ligand-receptor interactions and cytokine-cytokine receptor interactions. The most activated gene functions were cellular, metabolic, and multicellular organismal processes. In the NCDB, multivariable analysis, age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03-1.05; P < .001), TNM stage IV versus III (HR, 3.86; 95% CI, 2.98-5.00; P < .001), and positive surgical margin (HR, 1.68; 95% CI, 1.45-1.96; P < .001) were associated with worse OS at a median follow-up of 41.4 months. Five-year OS was significantly lower for stage IV patients compared with stage III patients (80.0% vs. 29.9%; P < .001).Conclusions
Patients with recurrent chRCC demonstrated a differential gene expression of specific biochemical pathways. Clinical parameters associated with worse OS included age, stage, and positive surgical margin. 相似文献14.
Amandine Gouverneur Juliette Coutureau Jérémy Jové Magali Rouyer Angela Grelaud Sophie Duc Stéphane Gérard Denis Smith Alain Ravaud Cécile Droz Marie-Agnès Bernard Régis Lassalle Annie Forrier-Réglat Pernelle Noize 《Clinical colorectal cancer》2019,18(1):e150-e162
Background
Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Their real-life evaluation is insufficient, especially in elderly and frail patients. The aim was to describe use, safety, and effectiveness of targeted therapies in first-line mCRC treatment according to age.Patients and Methods
Two field cohorts of patients initiating bevacizumab or cetuximab for first-line mCRC were pooled. Patients characteristics, use, and safety were compared between younger and elderly patients (<75 vs. ≥75 years). Two-year overall survival (OS) and progression-free survival (PFS) were estimated in both age groups using the Kaplan–Meier method adjusted on factors associated with death or progression identified with Cox multivariate modeling.Results
Eight hundred patients (n = 411, 51.4% bevacizumab) were included: 498 (62.3%) male, median age 64 years, 118 (14.8%) Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥2. Elderly patients (n = 126, 15.8%) were more often treated with 5-fluorouracil alone than younger. Severe adverse events were equivalent across age groups. ECOG-PS ≥1, abnormal hemoglobin, and abnormal alkaline phosphatases were associated with a higher risk of death; OS adjusted on these factors was similar between elderly and younger patients. ECOG-PS ≥1, lung metastases, abnormal hemoglobin, and abnormal creatinine clearance were associated with a higher risk of progression or death; PFS adjusted on these factors was similar across groups.Conclusion
Despite treatment adaptations, elderly patients could benefit from targeted therapies as younger without safety warning. 相似文献15.
Song-Tao Xu Jun-Jie Xi Wen-Zhao Zhong Wei-Min Mao Lin Wu Yi Shen Yong-Yu Liu Chun Chen Ying Cheng Lin Xu Jun Wang Ke Fei Xiao-Fei Li Jian Li Cheng Huang Zhi-Dong Liu Shun Xu Ke-Neng Chen Yi-Long Wu 《Journal of thoracic oncology》2019,14(3):503-512
Introduction
Adjuvant gefitinib therapy prolonged disease-free survival in patients with resected early-stage EGFR-mutation positive NSCLC in the ADJUVANT study (CTONG 1104). However, treatment failure patterns after gefitinib therapy are less well characterized.Methods
Overall, 222 stage N1–N2, EGFR-mutant NSCLC patients received gefitinib or vinorelbine plus cisplatin (VP) treatment. Tumor recurrences or metastases occurring during follow-up were defined as treatment failure; sites and data of first treatment failure were recorded. A post hoc analysis of treatment failure patterns which was estimated by Kaplan-Meier and hazard rate curves in modified intention-to-treat patients was conducted.Results
There were 114 recurrences and 10 deaths before recurrence across 124 progression events. Spatial distribution analysis showed that the first metastasis site was most frequently the central nervous system in the gefitinib group (29 of 106 [27.4%]), extracranial metastases were most frequent in the VP group (32 of 87 [36.8%]). Temporal distribution analysis showed lower tumor recurrence with gefitinib than with VP 0 to 21 months post-surgery. However, recurrence with gefitinib showed a constant rate of increase 12 months post-surgery. The first peak of extracranial metastasis appeared during 9 to 15 months with VP and 24 to 30 months with gefitinib. The highest peak for central nervous system metastases post-surgery occurred after 12 to 18 months with VP and 24 to 36 months with gefitinib.Conclusions
Adjuvant gefitinib showed advantages over VP chemotherapy in treatment failure patterns especially in extracranial metastasis. Adjuvant tyrosine kinas inhibitors may be considered as a treatment option in resected stage N1–N2 EGFR-mutant NSCLC but longer duration should be explored. 相似文献16.
Jean-Louis Pujol Laurent Greillier Clarisse Audigier-Valette Denis Moro-Sibilot Lionel Uwer José Hureaux Florian Guisier Delphine Carmier Jeannick Madelaine Josiane Otto Valérie Gounant Patrick Merle Pierre Mourlanette Olivier Molinier Aldo Renault Audrey Rabeau Martine Antoine Marc G. Denis Pierre-Jean Souquet 《Journal of thoracic oncology》2019,14(5):903-913
Introduction
This randomized phase II trial aimed at evaluating the engineered programmed cell death ligand 1 (PD-L1) antibody atezolizumab in SCLC progressing after first-line platinum–etoposide chemotherapy.Methods
Patients were randomized 2:1 to atezolizumab (1200 mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to 6 cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O’Brien-Fleming stopping rules was used. The null hypothesis was rejected if more than 12 of 45 patients were responders.Results
Overall, 73 patients were randomized (atezolizumab n = 49; chemotherapy n = 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% confidence interval [CI]: 0.0–6.8), whereas 8 others had stable disease (20.9% disease control rate; 95% CI: 8.8–33.1). Among eligible chemotherapy patients (n = 20), 10% achieved an objective response (65% disease control rate). Median progression-free survival was 1.4 months (95% CI: 1.2–1.5) with atezolizumab and 4.3 months (95% CI: 1.5–5.9) with chemotherapy. Overall survival did not significantly differ between groups. Median overall survival was 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively (adjusted hazard ratioatezolizumab : 0.84, 95% CI: 0.45–1.58; p = 0.60). Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone).Conclusions
Atezolizumab monotherapy in relapsed SCLC failed to show significant efficacy. No unexpected safety concerns were observed. 相似文献17.
Paola Morelato Assunção Tamires Prates Lana Márcia Torresan Delamain Gislaine Oliveira Duarte Roberto Zulli Irene Lorand-Metze Carmino Antonio de Souza Erich Vinicius de Paula Katia Borgia Barbosa Pagnano 《Clinical Lymphoma, Myeloma & Leukemia》2019,19(3):162-166
Background
Cardiovascular events (CVEs) have been observed in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors.Patients and Methods
We retrospectively evaluated the incidence of CVEs on 233 consecutive patients with chronic myeloid leukemia, of which 116 were treated with imatinib, 75 with dasatinib, and 42 with nilotinib. The median follow-up was 2047, 1712, and 1773 days, respectively.Results
The cumulative incidence of CVEs was 4.29%. Three events occurred during dasatinib treatment, 6 during nilotinib treatment, and none during imatinib treatment (P ≤ .001). Arterial occlusive events occurred in 2 (2.6%) of 75 patients treated with dasatinib and in 6 (14.2%) of 42 patients treated with nilotinib (P ≤ .001). Furthermore, all of them occurred in patients with high-risk (n = 2) and very high-risk (n = 6) cardiovascular risk, contributing to 4.3% of mortality.Conclusion
CVEs were more frequent in patients treated with second-generation tyrosine kinase inhibitors. Arterial occlusive events were more frequent in patients treated with nilotinib, with high and very high cardiovascular risk. 相似文献18.
Chao Zhang Shao-lei Li Qiang Nie Song Dong Yang Shao Xue-ning Yang Yi-long Wu Yue Yang Wen-zhao Zhong 《Journal of thoracic oncology》2019,14(4):726-731
Background
Locally advanced NSCLC is one of the most heterogeneous conditions, with multidimensional treatments involved. Neoadjuvant therapy had been commonly considered an optimal management strategy for patients with operable locally advanced. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy has remained poorly explored in locally advanced disease.Methods
We have described 11 ALK receptor tyrosine kinase gene (ALK)-positive patients with pathologically confirmed N2 NSCLC who were treated with neoadjuvant crizotinib. All the patients were treatment naive and received crizotinib at a starting dose of 250 mg twice daily. Patient 3 was provided with dynamic monitoring before and after neoadjuvant therapy through next-generation sequencing of plasma and tissue. In case 4, next-generation sequencing of preoperative tissue was performed.Results
Of the 11 patients, 10 had a partial response and one was stable disease after neoadjuvant crizotinib, with one suffering from grade 4 hepatic damage. Of the 11 patients, 10 (91.0%) received an R0 resection and 2 patients achieved a pathological complete response to neoadjuvant crizotinib. Six patients had disease recurrence, with five of them receiving crizotinib as first-line treatment and achieving a long duration of response. Dynamic monitoring of both plasma and tissue simultaneously indicated a decrease in sensitive ALK signaling in patient 3 and a partial response (approximately 50% of partial response), and no ALK-dependent resistance variants were captured.Conclusion
Neoadjuvant crizotinib may be feasible and well tolerated in locally advanced disease for complete resection. Crizotinib therapy before surgery may provide thorough elimination of circulating molecular residual disease and not influence the reuse of first-line crizotinib, but ongoing prospective trials are warranted to prove its efficacy in the neoadjuvant setting. 相似文献19.
Kurtis D. Davies Aprille Lomboy Carolyn A. Lawrence Michael Yourshaw Gregary T. Bocsi D. Ross Camidge Dara L. Aisner 《Journal of thoracic oncology》2019,14(4):737-741
Introduction
Genomic variants that lead to MET proto-oncogenem receptor tyrosine kinase (MET) exon 14 skipping represent a potential targetable molecular abnormality in NSCLC. Consequently, reliable molecular diagnostic approaches that detect these variants are vital for patient care.Methods
We screened tumor samples from patients with NSCLC for MET exon 14 skipping by using two distinct approaches: a DNA-based next-generation sequencing assay that uses an amplicon-mediated target enrichment and an RNA-based next-generation sequencing assay that uses anchored multiplex polymerase chain reaction for target enrichment.Results
The DNA-based approach detected MET exon 14 skipping variants in 11 of 856 NSCLC samples (1.3%). The RNA-based approach detected MET exon 14 skipping in 17 of 404 samples (4.2%), which was a statistically significant increase compared with the DNA-based assay. Among 286 samples tested by both assays, RNA-based testing detected 10 positives, six of which were not detected by the DNA-based assay. Examination of primer binding sites in the DNA-based assay in comparison with published MET exon 14 skipping variants revealed genomic deletion involving primer binding sequences as the likely cause of false negatives. Two samples positive via the DNA-based approach were uninformative via the RNA-based approach due to poor-quality RNA.Conclusions
By circumventing an inherent limitation of DNA-based amplicon-mediated testing, RNA-based analysis detected a higher proportion of MET exon 14 skipping cases. However, RNA-based analysis was highly reliant on RNA quality, which can be suboptimal in some clinical samples. 相似文献20.
Rafiye Ciftciler Haluk Demiroglu Yahya Buyukasık Elifcan Aladag Salih Aksu Ibrahim C. Haznedaroglu Nilgun Sayınalp Osman Ozcebe Umit Yavuz Malkan Hakan Goker 《Clinical Lymphoma, Myeloma & Leukemia》2019,19(3):177-182