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1.
Radiother Oncol ; 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32474129

RESUMO

BACKGROUND AND PURPOSE: The COVID-19 pandemic warrants operational initiatives to minimize transmission, particularly among cancer patients who are thought to be at high-risk. Within our department, a multidisciplinary tracer team prospectively monitored all patients under investigation, tracking their test status, treatment delays, clinical outcomes, employee exposures and quarantines. MATERIALS AND METHODS: Prospective cohort tested for SARS-COV-2 infection over 35 consecutive days of the early pandemic (03/19/2020-04/22/2020). RESULTS: A total of 121 Radiation Oncology patients underwent RT-PCR testing during this timeframe. Of the 7 (6%) confirmed-positive cases, 6 patients were admitted (including 4 warranting intensive care), 2 of whom died from acute respiratory distress syndrome. Radiotherapy was deferred or interrupted for 40 patients awaiting testing. As the median turnaround time for RT-PCR testing decreased from 1.5 (IQR: 1-4) to ≤1-day (P<0.001), the median treatment delay also decreased from 3.5 (IQR: 1.75-5) to 1 business day (IQR: 1-2) [P<0.001]. Each patient was an exposure risk to a median of 5 employees (IQR: 3-6.5) through prolonged close contact. During this timeframe, 39 care-team members were quarantined for a median of 3 days (IQR: 2-11), with a peak of 17 employees simultaneously quarantined. Following implementation of a "dual PPE policy," newly quarantined employees decreased from 2.9 to 0.5 per day. CONCLUSION: The severe adverse events noted among these confirmed-positive cases support the notion that cancer patients are vulnerable to COVID-19. Active tracking, rapid diagnosis, and aggressive source control can mitigate the adverse effects on treatment delays, workforce incapacitation, and ideally outcomes.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32360653

RESUMO

BACKGROUND: Clinical trials are considered the "gold-standard" in evidence-based medicine, yet few cancer patients ultimately enroll. Here we examine patients screened for thoracic radiation oncology (TRO) clinical trials to better understand enrollment trends. METHODS: A prospective database tracking screening and enrollment for patients referred for TRO consultation at our institution from 2016-2019 was evaluated. Proportional enrollment rates, patient and disease characteristics, self-reported socioeconomic factors, and reasons for ineligibility or non-enrollment across seventeen radiotherapy trials were compared. RESULTSENROLLMENT: data on 2372 patients were available for analysis. 40.0% (949) were deemed "not eligible" (NE) for any trial or unwilling to be further screened. Reasons for ineligibility included: stage (44%), histology (13%), radiotherapy not indicated (12%), patient decision (7%), and enrollment in a competing medical or surgical oncology trial (5%). THE REMAINING: 60.0% (1423) were "potentially eligible" (PE) for one or more trials. Most had non-small cell lung cancer (NSCLC) (71%) or esophageal cancer (16%), and there were significantly fewer stage IV PE (29%) vs. NE (49%) patients (P<0.0001). A total of 281/2372 (11.9%) patients enrolled. Notable reasons for non-enrollment were inclusion/exclusion criteria (58%), patient declined (14%), and physician decision (5%). The proportion of Caucasian patients was higher in the PE vs. NE group (82.5% vs 75.8%; p<0.001). Additionally, Caucasian race (87.9% vs. 81.2%; p = 0.008), English language preference (96.4% vs. 92.9%; p=0.032) and non-Hispanic/Latino ethnicity (94.0% vs. 90.1%; p=0.042) were significant in enrolled vs. non-enrolled PE patients. CONCLUSIONS: Only 12% of patients screened for radiotherapy trials ultimately enrolled and more than two-thirds had no trial available or were found ineligible. In addition, 19% of potential eligible patients did not enroll due to the patient or physician declining. Future trials may benefit from pragmatic designs with more inclusive enrollment criteria and multidisciplinary engagement of referring providers.

3.
JAMA Netw Open ; 3(4): e203277, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320035

RESUMO

Importance: Small cell lung cancer (SCLC) is an aggressive neoplasm requiring rapid access to subspecialized multidisciplinary care. For this reason, insurance coverage such as Medicaid may be associated with oncologic outcomes in this disproportionately economically vulnerable population. With Medicaid expansion under the Affordable Care Act, it is important to understand outcomes associated with Medicaid coverage among patients with SCLC. Objective: To determine the association of Medicaid coverage with survival compared with other insurance statuses. Design, Setting, and Participants: This cohort study included adult patients with limited-stage (LS) and extensive-stage (ES) SCLC in the US National Cancer Database from 2004 to 2013. Data were analyzed in January 2019. Main Outcomes and Measures: Patients were analyzed with respect to insurance status. Associations of insurance status with survival were interrogated with univariate analyses, multivariable analyses, and propensity score matching. Results: A total of 181 784 patients with SCLC (93 131 [51.2%] female; median [interquartile range] age; 67 [60-75] years for patients with LS-SCLC and 68 [60-75] years for patients with ES-SCLC) were identified, of whom 70 247 (38.6%) had LS-SCLC and 109 479 (60.2%) had ES-SCLC. On univariate analyses of patients with LS-SCLC, Medicaid coverage was not associated with a survival advantage compared with being uninsured (hazard ratio, 1.02; 95% CI, 0.96-1.08; P = .49). Likewise, on multivariable analyses of patients with ES-SCLC, compared with being uninsured, Medicaid coverage was not associated with a survival advantage (hazard ratio, 1.00; 95% CI, 0.96-1.03; P = .78). After propensity score matching, median survival was similar between the uninsured and Medicaid groups both among patients with LS-SCLC (14.4 vs 14.1 months; hazard ratio, 1.05; 95% CI, 0.98-1.12; P = .17) and those with ES-SCLC (6.3 vs 6.4 months; hazard ratio, 1.00; 95% CI, 0.96-1.04; P = .92). Conclusions and Relevance: Despite of billions of dollars in annual federal and state spending, Medicaid was not associated with improved survival in patients with SCLC compared with being uninsured in the US National Cancer Database. These findings suggest that there are substantial outcome inequalities for SCLC relevant to the policy debate on the Medicaid expansion under the Affordable Care Act.

4.
Radiother Oncol ; 147: 8-14, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32224318

RESUMO

PURPOSE: The goal of this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. METHODS AND MATERIALS: A model-based approach, based on three widely used normal tissue complication probability (NTCP) models for radiation pneumonitis (RP), was applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected ΔNTCP value was above a threshold of 5%. The endpoint chosen matched that of the original trial, the first occurrence of severe (grade ≥3) RP. RESULTS: Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for lung cancer using RP as the normal tissue endpoint. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. This result does show limitations in NTCP models which would affect the success of a model-based trial approach. No conclusion regarding the development of RP in patients randomized by the model-based approach could statistically be made. CONCLUSIONS: Uncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. The impact of these uncertainties on enrollment in model-based trials depends on the predicted difference between the two treatment arms and on the set threshold for patient stratification. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint.

5.
Radiat Oncol ; 15(1): 55, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138753

RESUMO

PURPOSE: To quantify tumor anatomic change of non-small cell lung cancer (NSCLC) patients given passive-scattering proton therapy (PSPT) and intensity-modulated radiation therapy (IMRT) through 6-7 weeks of treatment, and analyze the correlation between anatomic change and the need to adopt adaptive radiotherapy (ART). MATERIALS AND METHODS: Weekly 4D CT sets of 32 patients (8/8 IMRT with/without ART, 8/8 PSPT with/without ART) acquired during treatment, were registered to the planning CT using an in-house developed deformable registration algorithm. The anatomic change was quantified as the mean variation of the region of interest (ROI) relative to the planning CT by averaging the magnitude of deformation vectors of all voxels within the ROI contour. Mean variations of GTV and CTV were compared between subgroups classified by ART status and treatment modality using the independent t-test. Logistic regression analysis was performed to clarify the effect of anatomic change on the probability of ART adoption. RESULTS: There was no significant difference (p = 0.679) for the time-averaged mean CTV variations from the planning CT between IMRT (7.61 ± 2.80 mm) and PSPT (7.21 ± 2.67 mm) patients. However, a significant difference (p = 0.001) was observed between ART (8.93 ± 2.19 mm) and non-ART (5.90 ± 2.33 mm) patients, when treatment modality was not considered. Mean CTV variation from the planning CT in all patients increases significantly (p < 0.001), with a changing rate of 1.77 mm per week. Findings for the GTV change was similar. The logistic regression model correctly predicted 71.9% of cases in ART adoption. The correlation is stronger in the PSPT group with a pseudo R2 value of 0.782, compared to that in the IMRT group (pseudo R2 = 0.182). CONCLUSION: The magnitude of target volume variation over time could be greater than the usual treatment margin. Mean target volume variation from the planning position can be used to identify lung cancer patients that may need ART.

6.
Sci Adv ; 6(11): eaaz6162, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32195353

RESUMO

Non-small cell lung cancer (NSCLC) is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. More than half of patients with NSCLC die after developing distant metastases, so rapid, minimally invasive prognostic biomarkers are needed to reduce mortality. We used proteomics to identify proteins differentially expressed on extracellular vesicles (EVs) of nonmetastatic 393P and metastatic 344SQ NSCLC cell lines and found that tetraspanin-8 (Tspan8) was selectively enriched on 344SQ EVs. NSCLC cell lines treated with EVs overexpressing Tspan8 also exhibited increased Matrigel invasion. Elevated Tspan8 expression on serum EVs of individuals with stage III premetastatic NSCLC tumors was also associated with reduced distant metastasis-free survival, suggesting that Tspan8 levels on serum EVs may predict future metastasis. This result suggests that a minimally invasive blood test to analyze EV expression of Tspan8 may be of potential value to guide therapeutic decisions for patients with NSCLC and merits further study.

7.
Radiother Oncol ; 146: 200-204, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32220701

RESUMO

PURPOSE: To develop and test an Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model to predict radiation-induced esophagitis (RE) in non-small cell lung cancer (NSCLC) patients receiving passive-scattering proton therapy (PSPT). MATERIAL AND METHODS: We retrospectively reviewed 328 NSCLC patients receiving PSPT at our institution. Esophagitis severity was graded by physicians according to the Common Toxicity Criteria for Adverse Events version 3.0, and the primary endpoint was grade ≥2 RE within 6 months from the first treatment. LKB model parameters (n, m, and TD50) were determined using maximum likelihood estimation. Overall performance of the model was quantified by Nagelkerke's R2 and the scaled Brier score. Discriminative ability was evaluated using the area under the receiver operating curve (AUC), and calibration was assessed with the Hosmer-Lemeshow goodness-of-fit test. Bootstrap internal validation was performed to assess the model uncertainty and generalizability. RESULTS: Grade 2-3 RE was observed in 136 (41.5%) patients, and no grade 4-5 RE was reported. The optimal LKB parameters were: n = 0.24, m = 0.51, and TD50 = 44.83 Gy (relative biological effectiveness). The optimism-corrected AUC was 0.783, and the Hosmer-Lemeshow test showed significant agreement between predicted and observed morbidity. Bootstrap validation verified that the model was robust to similar future populations. CONCLUSION: Our LKB NTCP model to predict grade ≥2 RE in NSCLC patients who received PSPT showed good predictive performance and robustness to similar future populations, and a smaller volume effect than the previously observed in photon-treated populations. External validation of the model is warranted.

8.
Head Neck ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32129548

RESUMO

BACKGROUND: Metastatic head and neck cancers (HNCs) predominantly affect the lungs and have a two-year overall survival (OS) of 15% to 50%, if amenable for pulmonary metastasectomy. METHODS: Retrospective review of the two-year local control (LC), local-regional control (LRC) within the same lobe, OS, and toxicity rates in consecutive patients with metastatic pulmonary HNC who underwent stereotactic ablative radiotherapy (SABR) January 2007 to May 2018. RESULTS: Evaluated 82 patients with 107 lung lesions, most commonly squamous cell carcinoma (SCC; 64%). Median follow-up was 20 months (range: 9.0-97.6). Systemic therapy administered in 34%. LC, LRC, and OS rates were 94%, 90%, and 62%. Patients with oligometastatic disease had a higher OS than polymetastatic disease, 72% vs 44% (HR = 0.30, 95% CI: 0.14-0.64; P = .008). OS in oligometastatic non-SCC and SCC were 100% and 66% (P = .03). There were no grade ≥3 toxicities. CONCLUSIONS: Metastatic pulmonary HNCs after SABR have a two-year OS rate comparable to pulmonary metastasectomy.

9.
J Clin Oncol ; 38(14): 1569-1579, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32160096

RESUMO

PURPOSE: Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer. METHODS: This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up). RESULTS: This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial's stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. CONCLUSION: For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

10.
Clin Lung Cancer ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32089476

RESUMO

INTRODUCTION: The standard of care for stage IIIA (N2) non-small-cell lung cancer (NSCLC) includes concurrent definitive chemoradiation (dCRT) followed by durvalumab, thus challenging the role of surgery in resectable patients. We assessed locoregional disease control and survival in patients with surgically resected and unresected stage IIIA (N2) NSCLC disease. PATIENTS AND METHODS: We conducted a retrospective analysis from prospectively collected databases at MD Anderson Cancer Center. Patients undergoing neoadjuvant chemotherapy and surgery or dCRT for clinical stage IIIA (N2) disease (2004-2014) were evaluated. Primary outcomes included locoregional disease control, disease-free survival (DFS), and overall survival (OS). Kaplan-Meier outcome analyses were performed. RESULTS: Of the 159 resected patients, the majority had lobectomy (82.4%), followed by pneumonectomy (11.9%) and sublobar resection (5.7%). The 30- and 90-day mortality rates were 0.6% and 1.3%, respectively. At median follow-up of 52.8 months, recurrence was 55.3%, with 44.0% having distant and 15.1% locoregional recurrence. At 5 years, OS was 50.8% and DFS was 33.1% Median OS was 61.2 months. A total of 366 patients underwent dCRT, with intensity-modulated radiation in 64.5%, proton therapy in 26.0%, and 3-dimensional conformal radiotherapy in 9.6%. The mean dose was 68.1 Gy. At median follow-up of 20.8 months, recurrence was 53.6%, with distant and locoregional recurrence of 40.7% and 30.3%, respectively. At 5 years, OS was 29.2% and DFS was 20.5%. Median OS was 27.5 months. CONCLUSION: Stage IIIA (N2) NSCLC continues to be a heterogeneous disease, and patients with surgically resected and unresected disease represent different risk populations. Ongoing immunotherapy trials may further redefine treatment algorithms in this complex patient population.

11.
Radiother Oncol ; 145: 178-185, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32044530

RESUMO

BACKGROUND & PURPOSE: Stereotactic ablative radiation therapy (SABR) is an emerging treatment option for patients with pulmonary metastases; identifying patients who would benefit from SABR can improve outcomes. MATERIALS & METHODS: We retrospectively analyzed local failure (LF), distant failure (DF), overall survival (OS), and toxicity in 317 patients with 406 pulmonary metastases treated with SABR in January 2006-September 2017 at a tertiary cancer center. RESULTS: Median follow-up time was 23 months. Primary adrenal, colorectal, sarcoma, or pancreatic ("less responsive") tumors led to high rates of LF. LF rates for patients with less responsive vs. responsive tumors were 4.6% vs. 1.6% at 12 months and 12.8% vs. 3.9% at 24 months (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.11-0.73; Log-Rank P = 0.0087). A nomogram for 24-month local control was created using Cox multivariate factors (surgical history, planning target volume, primary disease site, lung lobe location). Treating patients with ≤3 pulmonary metastases vs. >3 pulmonary metastases was associated with improved 24-month (74.2% vs. 59.3%) and 48-month (47.7% vs. 35.1%) OS (HR 0.66, 95% CI 0.47-0.95; Log-Rank P = 0.043), and reduced 12-month (22.5% vs. 50.8%) and 24-month (31.8% vs. 61.4%) intrathoracic DF (HR 0.53, 95% CI 0.38-0.74; Log-Rank P < 0.0001). The most common toxicity was asymptomatic pneumonitis (14.8%). Six patients had grade 3 events (5 pneumonitis, 1 brachial plexus). CONCLUSIONS: SABR for pulmonary metastases was effective and well tolerated. Irradiating limited intrathoracic sites of disease led to improved OS and intrathoracic DM. Higher SABR doses or surgery could be considered for less radio-responsive primary tumors.

12.
Cell Res ; 30(2): 146-162, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31949285

RESUMO

Ferroptosis, a form of regulated cell death caused by lipid peroxidation, was recently identified as a natural tumor suppression mechanism. Here, we show that ionizing radiation (IR) induces ferroptosis in cancer cells. Mechanistically, IR induces not only reactive oxygen species (ROS) but also the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis, resulting in elevated lipid peroxidation and ferroptosis. ACSL4 ablation largely abolishes IR-induced ferroptosis and promotes radioresistance. IR also induces the expression of ferroptosis inhibitors, including SLC7A11 and GPX4, as an adaptive response. IR- or KEAP1 deficiency-induced SLC7A11 expression promotes radioresistance through inhibiting ferroptosis. Inactivating SLC7A11 or GPX4 with ferroptosis inducers (FINs) sensitizes radioresistant cancer cells and xenograft tumors to IR. Furthermore, radiotherapy induces ferroptosis in cancer patients, and increased ferroptosis correlates with better response and longer survival to radiotherapy in cancer patients. Our study reveals a previously unrecognized link between IR and ferroptosis and indicates that further exploration of the combination of radiotherapy and FINs in cancer treatment is warranted.

13.
Am J Clin Oncol ; 43(4): 231-235, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31990759

RESUMO

BACKGROUND: Metformin reduces glucose uptake in physiologic tissues and has been shown to affect non-small cell lung cancer (NSCLC) metabolism. We hypothesized that positron emission tomography (PET) scans could detect the impact of metformin on glucose uptake in NSCLC and we sought to test this hypothesis in a prospective clinical trial. MATERIALS AND METHODS: A single-blinded phase II clinical trial was performed with subjects randomized 6:1 to 3 to 4 weeks of metformin versus placebo for inoperable early-stage NSCLC. PET scans were performed at baseline, mid-treatment (after 2 wk study medication), and 6 months postradiation. The primary endpoint of the trial was tumor metabolic response to metformin by PERCIST before definitive radiation. Stereotactic body radiotherapy to 50 Gy in 4 fractions was used for peripheral tumors and 70 Gy in 10 fractions for central tumors. RESULTS: There were 14 subjects randomized to the metformin and 1 to placebo. Histologies were 60% adenocarcinoma, 33.3% squamous cell carcinoma, and 6.7% poorly differentiated carcinoma. At mid-treatment PET scan, 57% of subjects randomized to metformin met PERCIST criteria for metabolic response, of which 75% had progressive metabolic disease and 25% had partial metabolic response, whereas the placebo subject had stable metabolic disease. At 6 months, the metformin arm had 69% complete metabolic response, 23% partial metabolic response and 1 progressive metabolic disease, and the subject treated with placebo had a complete metabolic response. There were no CTCAE grade ≥3 toxicities. CONCLUSIONS: Despite low accrual, majority of subjects treated with metformin had metabolic responses by PERCIST criteria on PET imaging. Contrary to the effect of metformin on most physiologic tissues, most tumors had increased metabolic activity in response to metformin.

14.
Clin Cancer Res ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911545

RESUMO

PURPOSE: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers. EXPERIMENTAL DESIGN: We developed a pan-cancer deep machine learning model integrating tumor mutation burden, microsatellite instability, and somatic copy-number alterations to classify tumors of different types into different genomic clusters, and assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy. RESULTS: Our model grouped 8,646 tumors of 29 cancer types from The Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden. CONCLUSIONS: Our study provides a proof for principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.

15.
Int J Cancer ; 146(5): 1359-1368, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241775

RESUMO

Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , DNA Tumoral Circulante/genética , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Adulto , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Capecitabina/farmacologia , Capecitabina/uso terapêutico , DNA Tumoral Circulante/sangue , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Adulto Jovem
16.
J Thorac Oncol ; 15(1): 101-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31479748

RESUMO

INTRODUCTION: Stereotactic body radiotherapy (SBRT) results in excellent local control of stage I NSCLC. Radiobiology models predict greater tumor response when higher biologically effective doses (BED10) are given. Prior studies support a BED10 greater than or equal to 100 Gy with SBRT; however, data are limited comparing outcomes after various SBRT regimens. We therefore sought to evaluate national trends and the effect of using "low" versus "high" BED10 SBRT courses on overall survival (OS). METHODS: This retrospective study used the National Cancer Data Base to identify patients diagnosed with clinical stage I (cT1-2aN0M0) NSCLC from 2004 to 2014 treated with SBRT. Patients were categorized into LowBED (100-129 Gy) or HighBED (≥130 Gy) groups. A 1:1 matched analysis based on patient and tumor characteristics was used to compare OS by BED10 group. Tumor centrality was not assessed. RESULTS: O 25,039 patients treated with LowBED (n = 14,756; 59%) or HighBED (n = 10,283; 41%) SBRT, 20,542 were matched. Shifts in HighBED to LowBED SBRT regimen use correlated with key publications in the literature. In the matched cohort, 5-year OS rates were 26% for LowBED and 34% for HighBED groups (p = 0.039). On multivariate analysis, receipt of LowBED was associated with significantly worse survival (hazard ratio = 1.046, 95% confidence interval: 1.004-1.090, p = 0.032). CONCLUSIONS: LowBED SBRT for treating stage I NSCLC is becoming more common. However, our findings suggest SBRT regimens with BED10 greater than or equal to 130 Gy may confer an additional survival benefit. Additional studies are required to evaluate the dose-response relationship and toxicities associated with modern HighBED SBRT.

17.
Br J Radiol ; 93(1107): 20190378, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31430188

RESUMO

Radiation therapy is an essential component of treatment for locally advanced non-small cell lung cancer (NSCLC) but can be technically challenging because of the proximity of lung tumors to nearby critical organs or structures. The most effective strategy for reducing radiation-induced toxicity is to reduce unnecessary exposure of normal tissues by using advanced technology; examples from photon (X-ray) therapy have included three-dimensional conformal radiation therapy versus its predecessor, two-dimensional radiation therapy, and intensity-modulated photon radiation therapy versus its predecessor, three-dimensional conformal therapy. Using particle-beam therapy rather than photons offers the potential for further advantages because of the unique depth-dose characteristics of the particles, which can be exploited to allow still higher dose escalation to tumors with greater sparing of normal tissues, with the ultimate goal of improving local tumor control and survival while preserving quality of life by reducing treatment-related toxicity. However, the costs associated with particle therapy with protons are considerably higher than the current state of the art in photon technology, and evidence of clinical benefit from protons is increasingly being demanded to justify the higher financial burden on the healthcare system. Some such evidence is available from preclinical studies, from retrospective, single-institution clinical series, from analyses of national databases, and from single-arm prospective studies in addition to several ongoing randomized comparative trials. This review summarizes the rationale for and challenges of using proton therapy to treat thoracic cancers, reviews the current clinical experience, and suggests topics for future research.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Órgãos em Risco/efeitos da radiação , Terapia com Prótons/métodos , Lesões por Radiação/prevenção & controle , Radioterapia de Intensidade Modulada/métodos , Carcinoma Pulmonar de Células não Pequenas/patologia , Previsões , Humanos , Neoplasias Pulmonares/patologia , Tratamentos com Preservação do Órgão/métodos , Estudos Prospectivos , Terapia com Prótons/economia , Terapia com Prótons/tendências , Qualidade de Vida , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/economia , Radioterapia de Intensidade Modulada/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do Tratamento
18.
Int J Radiat Oncol Biol Phys ; 106(2): 349-357, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678224

RESUMO

PURPOSE: NCT01725165 was a phase II prospective trial in which patients with non-small cell lung cancer were randomized to local consolidative therapy (LCT) versus maintenance therapy or observation (MT/O). METHODS AND MATERIALS: Peripheral blood from patients enrolled on NCT01725165 were labeled as (1) baseline, (2) early follow-up (FU) if obtained in the first or second FU evaluation (6-18 weeks), and (3) late FU if obtained in the third to sixth FU evaluations (22-50 weeks). All patients who underwent LCT and were included in this analysis received radiation. Among 49 randomized patients, 21 patients underwent T cell CDR3 variable region sequencing using immunoSEQ, 31 patients underwent circulating tumor DNA (ctDNA) analysis using next-generation sequencing with a 1021 cancer gene panel, and cytokine concentration was assayed in 19 patients using enzyme-linked immunosorbent assay. All analyses were exploratory and not corrected for multiple testing. RESULTS: No associations were identified between baseline T cell repertoire and ctDNA metrics with patient outcomes. Among baseline cytokines, interleukin 1α was the only cytokine associated with both overall survival (hazard ratio, 0.02; 95% confidence interval, 0.1-0.5; P = .0006) and progression-free survival (hazard ratio, 0.5; 95% confidence interval, 0.2-0.9; P = .03). At early FU, LCT was associated with decreased ctDNA burden, including lower number of detected mutations (median, 2 [interquartile range {IQR}, 1-6] vs 6 [IQR, 4-18]) and decreased average variable allele frequency (VAF; median, 0.006 [IQR, 0.003-0.010] vs 0.011 [IQR, 0.007-0.014]) compared with MT/O. Among 6 patients with serial ctDNA analysis, a rise in ctDNA detected mutation burden preceded clinical progression by 6.7 months. At early FU, LCT was associated with changes in T cell clonality that suggested oligoclonal expansion specifically increased T cell clonality (median, 0.15 [IQR, 0.12-0.24] vs 0.10 [IQR, 0.05-0.13]) and frequency of top 10 clones (median, 0.14 [IQR, 0.06-0.18] vs 0.21[IQR, 0.19-0.28]). CONCLUSION: LCT was associated with decreased ctDNA burden and oligoclonal expansion at early FU timepoints. Baseline interleukin 1α was associated with improved patient outcomes.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/radioterapia , DNA Tumoral Circulante/sangue , Citocinas/sangue , Neoplasias Pulmonares/radioterapia , Alelos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , DNA Tumoral Circulante/genética , Impressões Digitais de DNA , Ensaio de Imunoadsorção Enzimática , Seguimentos , Perfilação da Expressão Gênica/métodos , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação , Intervalo Livre de Progressão , Estudos Prospectivos , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/efeitos da radiação , Fatores de Tempo , Pesquisa Médica Translacional , Conduta Expectante
19.
Int J Radiat Oncol Biol Phys ; 106(1): 100-107, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31627177

RESUMO

PURPOSE: In patients with non-small cell lung cancer (NSCLC), concurrent chemoradiation therapy (CRT) exacerbates a cluster of difficult-to-manage symptoms, especially cancer-related fatigue. Minocycline is a readily available, low-cost antibiotic with antiinflammatory properties. We conducted a phase 2 randomized, double-blinded, placebo-controlled trial to investigate the effect of minocycline in reducing CRT-symptom burden in NSCLC. METHODS AND MATERIALS: Patients with NSCLC scheduled to receive CRT provided consent and were randomized to receive either minocycline (100 mg twice daily) or a matching placebo during 6 to 7 weeks of CRT. Patient-reported fatigue and other symptoms were assessed on MD Anderson Symptom Inventory weekly from the start of CRT for 12 weeks. The primary outcome was 12-week (±2 days) area under the curve for symptom burden, which was compared between treatment groups. RESULTS: Forty of 49 enrolled patients (80%) were evaluable (19 on minocycline and 21 on placebo). There were no grade 3 + adverse events related to the study medication. Fatigue was significantly reduced in the minocycline group compared with placebo group during the 12-week trial period (area under the curve = 31.2 ± 14.2 vs 45.0 ± 20.9, P = .011), with a large effect size (Cohen's d = 0.77). Pain (Cohen's d = 0.54) and shortness of breath (Cohen's d = 0.55) were also significantly reduced in the minocycline group (all P < .05). CONCLUSIONS: Minocycline during CRT for NSCLC was feasible, had a low toxicity profile, and yielded a clinically and statistically significant positive signal in reducing symptom burden related to NSCLC and CRT. This study is a proof of concept so a larger trial in CRT patients is warranted.


Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimiorradioterapia/efeitos adversos , Fadiga/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Minociclina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Carcinoma Pulmonar de Células não Pequenas/complicações , Método Duplo-Cego , Dispneia/tratamento farmacológico , Fadiga/etiologia , Feminino , Humanos , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Estudos Prospectivos , Qualidade de Vida
20.
J Thorac Oncol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31778797

RESUMO

INTRODUCTION: Consolidation durvalumab after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC. We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without additive toxicity. METHODS: This phase II study was conducted in two parts. Part 1 (n = 10) involved administration of conventionally fractionated CRT followed by consolidation chemotherapy (atezolizumab [two cycles] and maintenance atezolizumab up to 1 y). Part 2 (n = 30) involved administration of cCRT with atezolizumab followed by the same consolidation and maintenance therapies as in part 1. Programmed cell death ligand-1 staining cutoffs (1% or 50%) using Dako 22C3 immunohistochemistry were correlated with clinical outcomes. RESULTS: The overall toxicities for part 1/2 were overall adverse events of grade 3 and above of 80%/80%; immune-related adverse events of grade 3 and above of 30%/20%; and pneumonitis of grade 2 and above of 10%/16%, respectively. In part 1, for preliminary efficacy results, with a median follow-up of 22.5 months, the median progression-free survival was 18.6 months, and the overall survival was 22.8 months. In part 2, with a median follow-up time of 15.1 months, the median progression-free survival was 13.2 months, and the overall survival was not reached. There was no difference in cancer recurrence regardless of programmed cell death ligand-1 status. CONCLUSIONS: Atezolizumab with cCRT is safe and feasible and has no added toxicities compared with historical rates.

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