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2.
Lancet Digit Health ; 3(9): e565-e576, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34332931

RESUMO

BACKGROUND: Current risk stratification for patients with malignant pleural mesothelioma based on disease stage and histology is inadequate. For some individuals with early-stage epithelioid tumours, a good prognosis by current guidelines can progress rapidly; for others with advanced sarcomatoid cancers, a poor prognosis can progress slowly. Therefore, we aimed to develop and validate a machine-learning tool-known as OncoCast-MPM-that could create a model for patient prognosis. METHODS: We did a retrospective study looking at malignant pleural mesothelioma tumours using next-generation sequencing from the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). We collected clinical, pathological, and routine next-generation sequencing data from consecutive patients with malignant pleural mesothelioma treated at the Memorial Sloan Kettering Cancer Center (New York, NY, USA), as well as the MSK-IMPACT data. Together, these data comprised the MSK-IMPACT cohort. Using OncoCast-MPM, an open-source, web-accessible, machine-learning risk-prediction model, we integrated available data to create risk scores that stratified patients into low-risk and high-risk groups. Risk stratification of the MSK-IMPACT cohort was then validated using publicly available malignant pleural mesothelioma data from The Cancer Genome Atlas (ie, the TCGA cohort). FINDINGS: Between Feb 15, 2014, and Jan 28, 2019, we collected MSK-IMPACT data from the tumour tissue of 194 patients in the MSK-IMPACT cohort. The median overall survival was higher in the low-risk group than in the high-risk group as determined by OncoCast-MPM (30·8 months [95% CI 22·7-36·2] vs 13·9 months [10·7-18·0]; hazard ratio [HR] 3·0 [95% CI 2·0-4·5]; p<0·0001). No single factor or gene alteration drove risk differentiation. OncoCast-MPM was validated against the TCGA cohort, which consisted of 74 patients. The median overall survival was higher in the low-risk group than in the high-risk group (23·6 months [95% CI 15·1-28·4] vs 13·6 months [9·8-17·9]; HR 2·3 [95% CI 1·3-3·8]; p=0·0019). Although stage-based risk stratification was unable to differentiate survival among risk groups at 3 years in the MSK-IMPACT cohort (31% for early-stage disease vs 30% for advanced-stage disease; p=0·90), the OncoCast-MPM-derived 3-year survival was significantly higher in the low-risk group than in the high-risk group (40% vs 7%; p=0·0052). INTERPRETATION: OncoCast-MPM generated accurate, individual patient-level risk assessment scores. After prospective validation with the TCGA cohort, OncoCast-MPM might offer new opportunities for enhanced risk stratification of patients with malignant pleural mesothelioma in clinical trials and drug development. FUNDING: US National Institutes of Health/National Cancer Institute.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares/diagnóstico , Aprendizado de Máquina , Mesotelioma Maligno/diagnóstico , Neoplasias Pleurais/diagnóstico , Idoso , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/mortalidade , Masculino , Mesotelioma Maligno/classificação , Mesotelioma Maligno/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , New York/epidemiologia , Neoplasias Pleurais/classificação , Neoplasias Pleurais/mortalidade , Prognóstico , Estudos Retrospectivos , Risco , Fatores de Risco , Análise de Sobrevida
3.
Nat Commun ; 12(1): 4669, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344873

RESUMO

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.


Assuntos
Sistema Nervoso Central/metabolismo , Chaperonas Moleculares/metabolismo , Mapeamento de Interação de Proteínas/instrumentação , Proteoma/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Sondas Moleculares/farmacologia , Sondas Moleculares/uso terapêutico , Tomografia por Emissão de Pósitrons
4.
Med Dosim ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34426041

RESUMO

Deep inspiration breath hold (DIBH) has dosimetric advantages for lung cancer patients treated with external beam therapy, but is difficult for many patients to perform. Proton therapy permits sparing of the downstream organs at risk (OAR). We compared conventionally fractionated proton (p) and photon(x) plans on both free breathing (FB) and DIBH planning CTs to determine the effect of DIBH with proton therapy. We evaluated 24 plans from 6 lung cancer patients treated with photon DIBH on a prospective protocol. All patients were re-planned using pencil beam scanning (PBS) proton therapy. New plans were generated for FB datasets with both modalities. All plans were renormalized to 60 Gy. We evaluated dosimetric parameters for heart, lung and esophagus. We also compared FBp to DIBHx parameters to quantify how FBp plans compare to DIBHx plans. Significant differences were found for lung metrics V20 and mean lung dose between FB and DIBH plans regardless of treatment modality. Furthermore, lung metrics for FBp were comparable or superior to DIBHx, suggesting that FB protons may be a viable alternative for those patients that cannot perform DIBH with IMRT. The heart dose metrics were significantly different for the 5 out of 6 patients where the PTV overlapped the heart as DIBH moved heart out of the high dose volume. Heart dose metrics were further reduced by proton therapy. DIBH offers similar relative advantages for lung sparing for PBS as it does for IMRT but the magnitude of the DIBH related gains in OAR sparing were smaller for PBS than IMRT. FBp plans offer similar or better lung and heart sparing compared to DIBHx plans. For IMRT patients who have difficulty performing DIBH, FB protons may offer an alternative.

5.
Cancers (Basel) ; 13(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34359634

RESUMO

In this study, we investigated the prognostic factors for radiation-induced dyspnea after hypo-fractionated radiation therapy (RT) in 106 patients treated with Stereotactic Body RT for Non-Small-Cell Lung Cancer (NSCLC). The median prescription dose was 50 Gy (range: 40-54 Gy), delivered in a median of four fractions (range: 3-12). Dyspnea within six months after SBRT was scored according to CTCAE v.4.0. Biologically Effective Dose (α/ß = 3 Gy) volume histograms for lungs and heart were extracted. Dosimetric parameters along with patient-specific and treatment-related factors were analyzed, multivariable logistic regression method with Leave-One-Out (LOO) internal validation applied. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC) and calibration plot parameters. Fifty-seven patients (53.8%) out of 106 developed dyspnea of any grade after SBRT (25/57 grade ≥ 2 cases). A three-variable predictive model including patient comorbidity (COPD), heart volume and the relative lungs volume receiving more than 15 Gy was selected. The model displays an encouraging performance given by a training ROC-AUC = 0.71 [95%CI 0.61-0.80] and a LOO-ROC-AUC = 0.64 [95%CI 0.53-0.74]. Further modeling efforts are needed for dyspnea prediction in hypo-fractionated treatments in order to identify patients at high risk for developing lung toxicity more accurately.

6.
Lung Cancer ; 159: 66-73, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34311346

RESUMO

OBJECTIVES: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. MATERIALS AND METHODS: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. RESULTS: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%-99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%-74%) were concordant with plasma ctDNA. ctDNA matched patients to ALK-directed therapy with subsequent clinical response, including four patients matched on the basis of ctDNA results alone due to inadequate or delayed tissue testing. Serial ctDNA analysis detected MET amplification (n = 2) and ALK G1202R mutation (n = 2) as mechanisms of acquired resistance to ALK-directed therapy. CONCLUSION: Our findings support a complementary role for ctDNA in detection of ALK fusions and other alterations at diagnosis and therapeutic resistance settings.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Arildialquilfosfatase , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutação , Estudos Prospectivos , Receptores Proteína Tirosina Quinases/genética
8.
J Thorac Oncol ; 16(8): 1392-1402, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33992811

RESUMO

INTRODUCTION: KEAP1-NFE2L2-mutant NSCLCs are chemoradiation resistant and at high risk for local-regional failure (LRF) after concurrent chemoradiation (cCRT). To elucidate the impact of durvalumab on local-regional control, we evaluated LRF in patients with NSCLC treated with cCRT with and without durvalumab. METHODS: Patients with stage III NSCLC treated with cCRT or cCRT and durvalumab who underwent tumor genomic profiling were evaluated. The incidence of LRF and outcomes of patients with and without KEAP1-NFE2L2-mutant tumors were evaluated. RESULTS: We analyzed 120 consecutive patients (cCRT alone, n = 54; cCRT and durvalumab, n = 66). Patients treated with cCRT alone had significantly more LRF events compared with those treated with cCRT and durvalumab, with 12-month LRF incidence of 39% (95% confidence interval [CI]: 24%-54%) and 18% (95% CI: 8%-28%), respectively (p = 0.002). Among patients treated with cCRT alone and cCRT and durvalumab, 20 patients (37%) and 18 patients (27%), respectively, had KEAP1-NFE2L2-mutant tumors. In patients treated with cCRT alone, those with KEAP1-NFE2L2-mutant tumors had worse local-regional control (p = 0.015), and on multivariate analysis, KEAP1-NFE2L2 mutation predicted for LRF (hazard ratio = 3.9, 95% CI: 1.6-9.8, p = 0.003). Nevertheless, patients with and without KEAP1-NFE2L2-mutant tumors had similar LRF outcomes (p = 0.541) when treated with cCRT and durvalumab, and mutational status did not predict for LRF (p = 0.545). Among those with KEAP1-NFE2L2-mutant tumors, cCRT and durvalumab significantly reduced the incidence of LRF compared with cCRT alone: 12-month LRF incidence of 62% (95% CI: 40%-84%) versus 25% (95% CI: 4%-46%), respectively (p = 0.021). CONCLUSIONS: Durvalumab after cCRT significantly improves local-regional control and reduces LRF in chemoradiation-resistant KEAP1-NFE2L2-mutant NSCLC tumors.


Assuntos
Neoplasias Pulmonares , Anticorpos Monoclonais/uso terapêutico , Quimiorradioterapia , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Fator 2 Relacionado a NF-E2/metabolismo
9.
Nat Rev Clin Oncol ; 18(9): 547-557, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33911215

RESUMO

The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapias em Estudo/tendências , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Terapia Combinada , Humanos , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante , Estadiamento de Neoplasias , Terapias em Estudo/métodos
10.
Med Phys ; 48(7): 3702-3713, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33905558

RESUMO

PURPOSE: Despite the widespread availability of in-treatment room cone beam computed tomography (CBCT) imaging, due to the lack of reliable segmentation methods, CBCT is only used for gross set up corrections in lung radiotherapies. Accurate and reliable auto-segmentation tools could potentiate volumetric response assessment and geometry-guided adaptive radiation therapies. Therefore, we developed a new deep learning CBCT lung tumor segmentation method. METHODS: The key idea of our approach called cross-modality educed distillation (CMEDL) is to use magnetic resonance imaging (MRI) to guide a CBCT segmentation network training to extract more informative features during training. We accomplish this by training an end-to-end network comprised of unpaired domain adaptation (UDA) and cross-domain segmentation distillation networks (SDNs) using unpaired CBCT and MRI datasets. UDA approach uses CBCT and MRI that are not aligned and may arise from different sets of patients. The UDA network synthesizes pseudo MRI from CBCT images. The SDN consists of teacher MRI and student CBCT segmentation networks. Feature distillation regularizes the student network to extract CBCT features that match the statistical distribution of MRI features extracted by the teacher network and obtain better differentiation of tumor from background. The UDA network was implemented with a cycleGAN improved with contextual losses separately on Unet and dense fully convolutional segmentation networks (DenseFCN). Performance comparisons were done against CBCT only using 2D and 3D networks. We also compared against an alternative framework that used UDA with MR segmentation network, whereby segmentation was done on the synthesized pseudo MRI representation. All networks were trained with 216 weekly CBCTs and 82 T2-weighted turbo spin echo MRI acquired from different patient cohorts. Validation was done on 20 weekly CBCTs from patients not used in training. Independent testing was done on 38 weekly CBCTs from patients not used in training or validation. Segmentation accuracy was measured using surface Dice similarity coefficient (SDSC) and Hausdroff distance at 95th percentile (HD95) metrics. RESULTS: The CMEDL approach significantly improved (p < 0.001) the accuracy of both Unet (SDSC of 0.83 ± 0.08; HD95 of 7.69 ± 7.86 mm) and DenseFCN (SDSC of 0.75 ± 0.13; HD95 of 11.42 ± 9.87 mm) over CBCT only 2DUnet (SDSC of 0.69 ± 0.11; HD95 of 21.70 ± 16.34 mm), 3D Unet (SDSC of 0.72 ± 0.20; HD95 15.01 ± 12.98 mm), and DenseFCN (SDSC of 0.66 ± 0.15; HD95 of 22.15 ± 17.19 mm) networks. The alternate framework using UDA with the MRI network was also more accurate than the CBCT only methods but less accurate the CMEDL approach. CONCLUSIONS: Our results demonstrate feasibility of the introduced CMEDL approach to produce reasonably accurate lung cancer segmentation from CBCT images. Further validation on larger datasets is necessary for clinical translation.


Assuntos
Aprendizado Profundo , Neoplasias Pulmonares , Tomografia Computadorizada de Feixe Cônico , Destilação , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Imageamento por Ressonância Magnética
11.
Ann Thorac Surg ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33844992

RESUMO

BACKGROUND: To explore the performance of a computed tomography based radiomics model in the preoperative prediction of resectability status and TNM staging in thymic epithelial tumors (TETs). METHODS: We reviewed the last preoperative computed tomography scan of patients with TETs prior to resection and pathology evaluation at our institution between February 2008 and June 2019. 101 quantitative features were extracted and a radiomics model was trained using elastic net penalized logistic regressions for each aim. In the set-aside testing sets, discriminating performance of each model was assessed with area under receiver operating characteristic curve (AUC). RESULTS: Our final population consisted of 243 patients with: 153 (87%) thymomas, 23 (9%) thymic carcinomas, and 9 (4%) thymic carcinoids. Incomplete resections (R1 or R2) occurred in 38 (16%) patients, and 67 (28%) patients had more advanced stage tumors (stage III or IV). In the set-aside testing sets, the radiomics model achieved good performance in preoperatively predicting incomplete resections (AUC 0.80) and advanced stage tumors (AUC 0.70). CONCLUSIONS: Our computed tomography radiomics model achieved good performance to predict resectability status and staging in TETs, suggesting a potential value for the evaluation of radiomic features in the preoperative prediction of surgical outcomes in thymic malignancies.

13.
Int J Radiat Oncol Biol Phys ; 110(3): 883-892, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33453309

RESUMO

PURPOSE: Acute esophagitis (AE) is a common dose-limiting toxicity in radiation therapy of locally advanced non-small cell lung cancer (LA-NSCLC). We developed an early AE prediction model from weekly accumulated esophagus dose and its associated local volumetric change. METHODS AND MATERIALS: Fifty-one patients with LA-NSCLC underwent treatment with intensity modulated radiation therapy to 60 Gy in 2-Gy fractions with concurrent chemotherapy and weekly cone beam computed tomography (CBCT). Twenty-eight patients (55%) developed grade ≥2 AE (≥AE2) at a median of 4 weeks after the start of radiation therapy. For early ≥AE2 prediction, the esophagus on CBCT of the first 2 weeks was deformably registered to the planning computed tomography images, and weekly esophagus dose was accumulated. Week 1-to-week 2 (w1→w2) esophagus volume changes including maximum esophagus expansion (MEex%) and volumes with ≥x% local expansions (VEx%; x = 5, 10, 15) were calculated from the Jacobian map of deformation vector field gradients. Logistic regression model with 5-fold cross-validation was built using combinations of the accumulated mean esophagus doses (MED) and the esophagus change parameters with the lowest P value in univariate analysis. The model was validated on an additional 18 and 11 patients with weekly CBCT and magnetic resonance imaging (MRI), respectively, and compared with models using only planned mean dose (MEDPlan). Performance was assessed using area under the curve (AUC) and Hosmer-Lemeshow test (PHL). RESULTS: Univariately, w1→w2 VE10% (P = .004), VE5% (P = .01) and MEex% (P = .02) significantly predicted ≥AE2. A model combining MEDW2 and w1→w2 VE10% had the best performance (AUC = 0.80; PHL = 0.43), whereas the MEDPlan model had a lower accuracy (AUC = 0.67; PHL = 0.26). The combined model also showed high accuracy in the CBCT (AUC = 0.78) and MRI validations (AUC = 0.75). CONCLUSIONS: A CBCT-based, cross-validated, and internally validated model on MRI with a combination of accumulated esophagus dose and local volume change from the first 2 weeks of chemotherapy significantly improved AE prediction compared with conventional models using only the planned dose. This model could inform plan adaptation early to lower the risk of esophagitis.


Assuntos
Esofagite/diagnóstico , Esofagite/etiologia , Radioterapia de Intensidade Modulada/efeitos adversos , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Feminino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
14.
J Thorac Oncol ; 16(5): 860-867, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33476803

RESUMO

INTRODUCTION: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized. METHODS: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan-Meier method. RESULTS: Overall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2-64.9), updated OS (HR = 0.71; 95% CI: 0.57-0.88) and PFS (HR = 0.55; 95% CI: 0.44-0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively. CONCLUSION: These updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia , Humanos , Neoplasias Pulmonares/tratamento farmacológico
15.
J Appl Clin Med Phys ; 22(2): 42-48, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33492763

RESUMO

Based on an analysis of published literature, our department recently lowered the preferred mean esophagus dose (MED) constraint for conventionally fractionated (2 Gy/fraction in approximately 30 fractions) treatment of locally advanced non-small cell lung cancer (LA-NSCLC) with the goal of reducing the incidence of symptomatic acute esophagitis (AE). The goal of the change was to encourage treatment planners to achieve a MED close to 21 Gy while still permitting MED to go up to the previous guideline of 34 Gy in difficult cases. We compared all our suitable LA-NSCLC patients treated with plans from one year before through one year after the constraint change. The primary endpoint for this study was achievability of the new constraint by the planners; the secondary endpoint was reduction in symptomatic AE. Planners were able to achieve the new constraint in statistically significantly more cases during the year following its explicit implementation than in the year before (P = 0.0025). Furthermore, 38% of patients treated after the new constraint developed symptomatic AE during their treatment as opposed to 48% of the patients treated before. This is a clinically desirable endpoint although the observed difference was not statistically significant. A subsequent power calculation suggests that this is due to the relatively small number of patients in the study.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radioterapia Conformacional , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Esôfago , Humanos , Neoplasias Pulmonares/radioterapia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
16.
Clin Cancer Res ; 27(8): 2200-2208, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33504552

RESUMO

PURPOSE: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models. PATIENTS AND METHODS: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. RESULTS: We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9-26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0-27.0]. The median progression-free survival was 1.8 (95% CI, 1.7-1.9) months, median overall survival was 11.4 (95% CI, 10.1-17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. CONCLUSIONS: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

17.
Pract Radiat Oncol ; 11(1): e52-e62, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33068790

RESUMO

PURPOSE: Radiation pneumonitis (RP) is a common and potentially life-threatening toxicity from lung cancer radiation therapy. Data sets reporting RP rates after postoperative radiation therapy (PORT) have historically been small and with predominantly outdated field designs and radiation techniques. We examined a large cohort of patients in this context to assess the incidence and causes of RP in the modern era. METHODS AND MATERIALS: We reviewed 285 patients with non-small cell lung cancer treated with PORT at our institution from May 2004 to January 2017. Complete dosimetric data and clinical records were reviewed and analyzed with grade 2 or higher RP as the endpoint (RP2+) (Common Terminology Criteria for Adverse Events v4.0). Patients were a median of 67 years old (range, 28-87), and most had pathologic stage III non-small cell lung cancer (91%) and received trimodality therapy (90%). Systematic dosimetric analyses using Dx increments of 5% and Vx increments of 2 Gy were performed to robustly evaluate dosimetric variables. Lung V5 was also evaluated. RESULTS: The incidence of RP2+ after PORT was 12.6%. Dosimetric factors most associated with RP2+ were total lungV4 (hazard ratio [HR] 1.04, P < .001) and heart V16 (HR 1.03, P = .001). On univariate analysis, the clinical factors of age (HR 1.05, P = .006) and carboplatin chemotherapy (HR 2.32, P = .012) were correlated with RP2+. On step-up multivariate analysis, only bivariate models remained significant, including lungV5 (HR 1.037, P < .001) and age (HR 1.052, P = .011). CONCLUSIONS: The incidence of RP after PORT is consistent with the literature. Factors correlated with RP include lung and heart doses, age, and carboplatin chemotherapy. These data also suggest that elderly patients may be more susceptible to lower doses of radiation to the lung. Based on these data, dose constraints to limit the risk of RP2+ to <5% in the setting of PORT include lungV5 ≤65% in patients <65 years old and lungV5 ≤36% in patients 65 years or older.

18.
J Natl Cancer Inst ; 113(3): 266-273, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32726432

RESUMO

BACKGROUND: Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. METHODS: We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided. RESULTS: Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors. CONCLUSIONS: We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.

19.
Int J Radiat Oncol Biol Phys ; 110(1): 172-187, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496880

RESUMO

PURPOSE: Stereotactic body radiation therapy (SBRT) has become the standard of care for inoperable early-stage non-small cell lung cancer and is often used for recurrent lung cancer and pulmonary metastases. Radiation-induced lung toxicity (RILT), including radiation pneumonitis and pulmonary fibrosis, is a major concern for which it is important to understand dosimetric and clinical predictors. METHODS AND MATERIALS: This study was undertaken through the American Association of Physicists in Medicine's Working Group on Biological Effects of Stereotactic Body Radiotherapy. Data from studies of lung SBRT published through the summer of 2016 that provided detailed information about RILT were analyzed. RESULTS: Ninety-seven studies were ultimately considered. Definitions of the risk organ and complication endpoints as well as dose-volume information presented varied among studies. The risk of RILT, including radiation pneumonitis and pulmonary fibrosis, was reported to be associated with the size and location of the tumor. Patients with interstitial lung disease appear to be especially susceptible to severe RILT. A variety of dosimetric parameters were reported to be associated with RILT. There was no apparent threshold "tolerance dose-volume" level. However, most studies noted safe treatment with a rate of symptomatic RILT of <10% to 15% after lung SBRT with a mean lung dose (MLD) of the combined lungs ≤8 Gy in 3 to 5 fractions and the percent of total lung volume receiving more than 20 Gy (V20) <10% to 15%. CONCLUSIONS: To allow more rigorous analysis of this complication, future studies should standardize reporting by including standardized endpoint and volume definitions and providing dose-volume information for all patients, with and without RILT.

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