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1.
J Immunother Cancer ; 11(12)2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-38040420

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival (OS). We hypothesized that adding programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy would be well tolerated and increase TILs among patients with localized PDAC. METHODS: Patients were randomized 2:1 to Arm A (receiving pembrolizumab plus chemoradiotherapy (capecitabine and external beam radiation)) or Arm B (receiving chemoradiotherapy alone) before anticipated pancreatectomy. Primary endpoints were (1) incidence and severity of adverse events during neoadjuvant therapy and (2) density of TILs in resected tumor specimens. TIL density was assessed using multiplexed immunofluorescence histologic examination. RESULTS: Thirty-seven patients were randomized to Arms A (n=24) and B (n=13). Grade ≥3 adverse events related to neoadjuvant treatment were experienced by 9 (38%) and 4 (31%) patients in Arms A and B, respectively, with one patient experiencing dose-limiting toxicity in Arm A. Seventeen (71%) and 7 (54%) patients in Arms A and B, respectively, underwent pancreatectomy. Median CD8+ T-cell densities in Arms A and B were 67.4 (IQR: 39.2-141.8) and 37.9 (IQR: 22.9-173.4) cells/mm2, respectively. Arms showed no noticeable differences in density of CD8+Ki67+, CD4+, or CD4+FOXP3+ regulatory T cells; M1-like and M2-like macrophages; or granulocytes. Median OS durations were 27.8 (95% CI: 17.1 to NR) and 24.3 (95% CI: 12.6 to NR) months for Arms A and B, respectively. CONCLUSIONS: Adding pembrolizumab to neoadjuvant chemoradiotherapy was safe. However, no convincing effect on CD8+ TILs was observed.


Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Terapia Neoadyuvante , Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Microambiente Tumoral
2.
J Natl Cancer Inst ; 115(8): 994-997, 2023 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-37202363

RESUMEN

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. The most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging because of paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies.


Asunto(s)
Perfilación de la Expresión Génica , Neoplasias Primarias Desconocidas , Humanos , Estudios de Factibilidad , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Neoplasias Primarias Desconocidas/genética , Estudios Prospectivos
3.
J Immunother Cancer ; 10(5)2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35618285

RESUMEN

BACKGROUND: Cancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with CUP. METHODS: The study was designed as a phase 2 basket trial for independent rare tumor cohorts including CUP. Adult patients with CUP who had progressed on previous systemic therapy, performance status 0/1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) were eligible. Patients received pembrolizumab (200 mg) intravenously every 21 days. Twenty-nine patients were enrolled and treated between August 2016 and June 2020. The primary endpoint was non-progression rate (NPR) at 27 weeks (NPR-27) per immune-related RECIST. Key prespecified secondary endpoints were confirmed objective response rate (ORR), safety, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Pretreatment biopsies were examined for biomarkers of response (programmed cell death ligand-1 (PD-L1) expression and tumor infiltrating lymphocytes (TILs)). RESULTS: Among 25 (of 29 enrolled) eligible and evaluable patients, 14 (56%) had poorly differentiated carcinoma. Patients received a median of two lines of therapy prior to enrollment. Median follow-up was 27.3 months. NPR-27 was observed in seven patients (28.0% (95% CI: 12.1 to 49.4)). ORR was 20.0% (95% CI: 6.8 to 40.7) with five patients achieving immune-related partial response with median DoR of 14.7 months (95% CI: 9.8 to 19.6). Median PFS and OS were 4.1 (95% CI: 3.1 to 5.1) and 11.3 (95% CI: 5.5 to 17.1) months, respectively. Treatment-related adverse events of any and grade ≥3 were seen in 19 (76%) and 4 (16%) patients, respectively. One (4%) patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Neither PD-L1 nor TILs were associated with NPR-27. Both positive PD-L1 staining (44.4% vs 6.3%; p=0.040) and intense TIL infiltration (44.4% vs 6.3%; p=0.040) were associated with response. CONCLUSION: Pembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile. TRIAL REGISTRATION NUMBER: NCT02721732.


Asunto(s)
Antígeno B7-H1 , Neoplasias Primarias Desconocidas , Adulto , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Humanos , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Supervivencia sin Progresión
4.
BMC Cancer ; 22(1): 14, 2022 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-34980020

RESUMEN

BACKGROUND: Personalized and effective treatments for pancreatic ductal adenocarcinoma (PDAC) continue to remain elusive. Novel clinical trial designs that enable continual and rapid evaluation of novel therapeutics are needed. Here, we describe a platform clinical trial to address this unmet need. METHODS: This is a phase II study using a Bayesian platform design to evaluate multiple experimental arms against a control arm in patients with PDAC. We first separate patients into three clinical stage groups of localized PDAC (resectable, borderline resectable, and locally advanced disease), and further divide each stage group based on treatment history (treatment naïve or previously treated). The clinical stage and treatment history therefore define 6 different cohorts, and each cohort has one control arm but may have one or more experimental arms running simultaneously. Within each cohort, adaptive randomization rules are applied and patients will be randomized to either an experimental arm or the control arm accordingly. The experimental arm(s) of each cohort are only compared to the applicable cohort specific control arm. Experimental arms may be added independently to one or more cohorts during the study. Multiple correlative studies for tissue, blood, and imaging are also incorporated. DISCUSSION: To date, PDAC has been treated as a single disease, despite knowledge that there is substantial heterogeneity in disease presentation and biology. It is recognized that the current approach of single arm phase II trials and traditional phase III randomized studies are not well-suited for more personalized treatment strategies in PDAC. The PIONEER Panc platform clinical trial is designed to overcome these challenges and help advance our treatment strategies for this deadly disease. TRIAL REGISTRATION: This study is approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center, IRB-approved protocol 2020-0075. The PIONEER trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04481204 .


Asunto(s)
Protocolos Antineoplásicos , Carcinoma Ductal Pancreático/terapia , Ensayos Clínicos Fase II como Asunto/métodos , Neoplasias Pancreáticas/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Adulto , Teorema de Bayes , Femenino , Humanos , Masculino , Terapia Neoadyuvante/métodos , Resultado del Tratamiento
5.
J Gastrointest Oncol ; 12(5): 2268-2274, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34790391

RESUMEN

BACKGROUND: Objective responses to first-line systemic chemotherapy in metastatic pancreatic cancer patients are seen in less than one third of cases. Unfortunately, a significant amount will have disease progression (PD) on their first restaging imaging. With patients' short life expectancy, it is crucial for clinicians to be prudent when deciding whom and when to treat. Our study aimed to evaluate outcomes of patients that progressed on their first restaging imaging on 1st line therapy. METHODS: We retrospectively analyzed patients diagnosed between 2010-2017 whose first restaging imaging demonstrated PD. The primary outcome was overall survival (OS) from metastatic diagnosis date to death. Patients who were lost to follow-up were excluded. RESULTS: Out of 262 total patients reviewed, 98 patients (37%) were included. Sixty-five (66%) received 2nd line therapy, and 33 (34%) did not. Reasons patients did not pursue 2nd line therapy were performance status (PS) decline, organ dysfunction, or patient choice for alternative therapy. Median ages for patients who did and did not receive 2nd line therapy were 61 and 67, respectively (P<0.001). More patients had a poor PS at the time of initial diagnosis in the non-2nd line therapy group (7.5% vs. 31.0%, P=0.021). Median OS for those receiving 2nd line therapy was 9 months (95% CI: 7-11 months) compared to 4 months (95% CI: 3-5 months) for those not receiving 2nd-line therapy (P<0.001). CONCLUSIONS: Although likely biased due to better performance status and younger age, our patients who progressed rapidly on 1st line therapy showed an OS benefit if they received 2nd line therapy. These results suggest that patients maintaining a good PS after immediate progression on 1st line therapy should be offered 2nd line therapy.

6.
Cancer Med ; 10(15): 5041-5050, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34250759

RESUMEN

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression-free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34-0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34-0.68, p = <0.0001). In multivariate analysis, the impact of ATB remained significant for PFS (HR 0.59, p = 0.005) and borderline statistically significant for OS (HR 0.69, p = 0.06). When we analyzed by chemotherapy regimen, we found that patients who received gemcitabine-based chemotherapy as first-line therapy (n = 118) had significantly prolonged OS (HR 0.4, p 0.0013) and PFS (HR 0.55, p 0.02) if they received antibiotics, while those receiving 5FU-based chemotherapy (n = 98) had only prolonged PFS (HR 0.54, p = 0.03). Antibiotics-associated modulation of the microbiome is associated with better outcomes in patients with metastatic PDAC.


Asunto(s)
Antibacterianos/uso terapéutico , Antineoplásicos/uso terapéutico , Infecciones Bacterianas , Carcinoma Ductal Pancreático/terapia , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias Pancreáticas/terapia , Supervivencia sin Progresión , Adulto , Anciano , Anciano de 80 o más Años , Infecciones Bacterianas/tratamiento farmacológico , Carcinoma Ductal Pancreático/microbiología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/secundario , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Métodos Epidemiológicos , Femenino , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Pancreáticas/microbiología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Gemcitabina
7.
Cancer Discov ; 11(11): 2738-2747, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34261675

RESUMEN

Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum-pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1-64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35-80) and 85% (95% CI, 60-95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial-mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease. SIGNIFICANCE: Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial-mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659.


Asunto(s)
Antígeno B7-H1 , Mesotelioma , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/metabolismo , Bevacizumab/uso terapéutico , Biomarcadores de Tumor , Humanos , Mesotelioma/tratamiento farmacológico , Mesotelioma/genética , Mesotelioma/patología , Factor A de Crecimiento Endotelial Vascular/uso terapéutico
8.
Clin Cancer Res ; 27(12): 3414-3421, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33858857

RESUMEN

PURPOSE: Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors. EXPERIMENTAL DESIGN: We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012-2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302). RESULTS: Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68-0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts. CONCLUSIONS: Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.


Asunto(s)
Neoplasias Pulmonares , Neoplasias Primarias Desconocidas , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/diagnóstico , Nomogramas , Pronóstico
9.
Br J Cancer ; 124(12): 1970-1977, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33785875

RESUMEN

BACKGROUND: Limited accessibility of the tumour precludes longitudinal characterisation for therapy guidance in pancreatic ductal adenocarcinoma (PDAC). METHODS: We utilised dielectrophoresis-field flow fractionation (DEP-FFF) to isolate circulating tumour cells (CTCs) in 272 blood draws from 74 PDAC patients (41 localised, 33 metastatic) to non-invasively monitor disease progression. RESULTS: Analysis using multiplex imaging flow cytometry revealed four distinct sub-populations of CTCs: epithelial (E-CTC), mesenchymal (M-CTC), partial epithelial-mesenchymal transition (pEMT-CTC) and stem cell-like (SC-CTC). Overall, CTC detection rate was 76.8% (209/272 draws) and total CTC counts did not correlate with any clinicopathological variables. However, the proportion of pEMT-CTCs (prop-pEMT) was correlated with advanced disease, worse progression-free and overall survival in all patients, and earlier recurrence after resection. CONCLUSION: Our results underscore the importance of immunophenotyping and quantifying specific CTC sub-populations in PDAC.


Asunto(s)
Carcinoma Ductal Pancreático/patología , Transición Epitelial-Mesenquimal/fisiología , Células Neoplásicas Circulantes/patología , Neoplasias Pancreáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/sangre , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/diagnóstico , Células Cultivadas , Progresión de la Enfermedad , Monitoreo de Drogas/métodos , Femenino , Humanos , Inmunofenotipificación , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Células Neoplásicas Circulantes/clasificación , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/diagnóstico , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico
10.
Oncologist ; 26(4): e650-e657, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33524217

RESUMEN

BACKGROUND: Cancer of unknown primary (CUP) presenting as bone-predominant (BCUP) or lymph node-only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the "one-treatment-fits-all" approach. MATERIALS AND METHODS: We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non-BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan-Meier method was used to estimate overall survival and compared using log-rank test. RESULTS: In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor-risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor-risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil-to-lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS. CONCLUSION: BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor-risk Culine group and high neutrophil-to-lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long-term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site-directed therapy. IMPLICATIONS FOR PRACTICE: Cancer of unknown primary (CUP) rarely presents as bone-predominant (BCUP) or lymph node-only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor-risk group and neutrophil-to-lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided.


Asunto(s)
Neoplasias Primarias Desconocidas , Humanos , Estimación de Kaplan-Meier , Ganglios Linfáticos , Neoplasias Primarias Desconocidas/terapia , Paclitaxel , Pronóstico
11.
Ann Surg ; 273(4): 806-813, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31274655

RESUMEN

OBJECTIVE: We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint. BACKGROUND: We previously demonstrated that a pMR to preoperative therapy, defined as detection of <5% viable cancer cells in the surgical specimen on histopathological analysis, is an important prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Pretreatment and posttreatment computed tomography scans of consecutive patients who received preoperative chemotherapy and/or (chemo)radiation before pancreatectomy for PDAC between January 2010 and December 2018 were rereviewed. Response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, other radiographic changes in tumor size and anatomic extent, and posttreatment CA 19-9 levels were compared between patients who did and did not have a pMR on final histopathologic analysis of their surgical specimens. RESULTS: A total of 290 patients with localized PDAC underwent pancreatectomy between 2010 and 2018 after receiving preoperative chemotherapy (n = 36; 12%), (chemo)radiation (n = 87; 30%), or both (n = 167; 58%). Among them, 28 (10%) experienced pMR, including 9 (3.1%) who experienced pathologic complete response. On multivariable logistic regression, low posttreatment CA 19-9 level, RECIST partial response, and reduction in tumor volume were confirmed to be independently associated with pMR (P < 0.01). CONCLUSIONS: We identified serologic and radiographic indicators of pMR that could help inform the delivery of preoperative therapy to patients with PDAC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Estadificación de Neoplasias , Pancreatectomía , Neoplasias Pancreáticas/terapia , Cuidados Preoperatorios/métodos , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Neoplasias Pancreáticas/diagnóstico , Valor Predictivo de las Pruebas , Estudios Retrospectivos
12.
Cancers (Basel) ; 12(12)2020 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-33291471

RESUMEN

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta; q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-naïve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.

13.
Oncologist ; 25(11): e1807-e1811, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32893931

RESUMEN

BACKGROUND: Although recent advances in immunotherapy have transformed the treatment landscape for many anatomically defined cancers, these therapies are currently not approved for patients diagnosed with cancer of unknown primary (CUP). Molecular cancer classification using gene expression profiling (GEP) assays has the potential to identify tumor type and putative primary cancers and thereby may allow consideration of immune checkpoint inhibitor (ICI) therapy options for a subset of patients with CUP. Herein, we evaluated and characterized the ability of a 92-gene assay (CancerTYPE ID) to provide a molecular diagnosis and identify putative tumor types that are known to be sensitive to ICI therapies in patients with CUP or uncertain diagnosis. FINDINGS: A total of 24,426 cases from a large-scale research database of 92-gene assay clinical cases were classified, of which 9,350 (38%) were predicted to have an ICI-eligible tumor type. All ICIs with approved indications as of March 2020 were included in the analysis. Non-small cell lung cancer (NSCLC) was the most frequent molecular diagnosis and accounted for 33% of the ICI-eligible tumor types identified and 13% of the overall reportable results. In addition to NSCLC, the assay also frequently identified urothelial carcinomas, gastric cancer, and head and neck squamous cell carcinoma. The distributions of identified tumor types with indications for ICI therapy were similar across age and gender. CONCLUSIONS: Results suggest that molecular profiling with the 92-gene assay identifies a subset of ICI-eligible putative primary cancers in patients with CUP. We propose a treatment strategy based on available tests, including clinicopathologic features, GEP, and ICI biomarkers of response.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Primarias Desconocidas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Perfilación de la Expresión Génica , Humanos , Inmunoterapia , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Neoplasias Primarias Desconocidas/genética
14.
JAMA Surg ; 155(9): 832-839, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32667641

RESUMEN

Importance: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown. Objective: To evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival. Design, Setting, and Participants: This case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months. Exposures: Administration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy. Main Outcomes and Measures: Resection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy. Results: In total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA-including low rates of local tumor downstaging-did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07). Conclusions and Relevance: In this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.


Asunto(s)
Albúminas/uso terapéutico , Antineoplásicos/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antígeno CA-19-9/sangre , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/mortalidad , Estudios de Cohortes , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/uso terapéutico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Radiografía , Tasa de Supervivencia , Resultado del Tratamiento , Gemcitabina
15.
Cancer Med ; 9(15): 5406-5415, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32519420

RESUMEN

BACKGROUND: Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. METHODS: Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments. RESULTS: From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m2 at fixed-dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. CONCLUSION: Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Albúminas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapéutico , Anciano , Albúminas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Femenino , Humanos , Masculino , Paclitaxel/farmacología , Estudios Retrospectivos , Gemcitabina
16.
Ann Surg Oncol ; 27(10): 3939-3947, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32266574

RESUMEN

BACKGROUND: The incidence and magnitude of indicators of radiographic response of pancreatic cancer to systemic chemotherapy and (chemo)radiation administered prior to anticipated pancreatectomy are unclear. METHODS: Sequential computed tomography scans of 226 patients with localized pancreatic cancer who received chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) or gemcitabine and nanoparticle albumin-bound paclitaxel (GA) with or without (chemo)radiation and who subsequently underwent surgery with curative intent from January 2010 to December 2018 at The University of Texas MD Anderson Cancer Center and Verona University Hospital were re-reviewed and compared. RESULTS: Overall, 141 patients (62%) received FOLFIRINOX, 70 (31%) received GA, and 15 (7%) received both; 164 patients (73%) received preoperative (chemo)radiation following chemotherapy and prior to surgery; and 151 (67%), 70 (31%), and 5 (2%) patients had Response Evaluation Criteria in Solid Tumors (RECIST) stable disease, partial response, and progressive disease, respectively. The tumors of 29% of patients with borderline resectable or locally advanced cancer were downstaged after preoperative therapy. Radiographic downstaging was more common with chemotherapy than with (chemo)radiation (24% vs. 6%; p = 0.04), and the median tumor volume loss after chemotherapy was significantly greater than that after (chemo)radiation (28% vs. 17%; p < 0.01). CONCLUSIONS: Less than one-third of patients treated with FOLFIRINOX or GA with or without (chemo)radiation experienced either RECIST partial response or radiographic downstaging prior to surgery. The incidence of tumor downstaging was higher and the magnitude of tumor volume loss was greater following chemotherapy than after (chemo)radiation.


Asunto(s)
Neoplasias Pancreáticas , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Pancreatectomía , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/terapia , Resultado del Tratamiento
17.
J Immunother Cancer ; 8(1)2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32188704

RESUMEN

BACKGROUND: Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers. METHODS: In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR). RESULTS: A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug. CONCLUSIONS: The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma supports further evaluation of pembrolizumab in this patient population. TRIAL REGISTRATION NUMBER: NCT02721732.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Enfermedades Raras/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Pronóstico , Enfermedades Raras/patología , Tasa de Supervivencia , Adulto Joven
18.
Pancreatology ; 20(3): 501-504, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31932214

RESUMEN

BACKGROUND: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. METHODS: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). RESULTS: 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0-5.7) with a median OS of 11.6 months (95% CI: 6.14-15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0-12.8) and 12.2 months (95% CI: 4.8-30.8), respectively. CONCLUSIONS: In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Estimación de Kaplan-Meier , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Oxaliplatino/uso terapéutico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
19.
Ann Surg ; 271(6): 996-1002, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31895709

RESUMEN

OBJECTIVE: We sought to determine whether postoperative chemotherapy after preoperative therapy and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) prolongs survival. BACKGROUND: Data to support administering postoperative chemotherapy to patients who received preoperative therapy are lacking. METHODS: All patients with PDAC who underwent pancreatectomy after preoperative therapy between 2010 and July 2017 at The University of Texas MD Anderson Cancer Center were identified. To control for selection bias, patients who received postoperative therapy and patients who did not were matched by propensity scores based on factors associated with the use of postoperative chemotherapy. RESULTS: Among 245 patients treated with a median of 4 cycles of preoperative treatment and pancreatectomy, 155 (63%) initiated postoperative chemotherapy and 90 (37%) did not. Patients who received postoperative therapy had a higher median cancer antigen 19-9 level before surgery, larger median tumor diameter, higher rate of extrapancreatic invasion, and lower rate of pathologic major response. The propensity-matched cohort comprised 122 patients: 61 who received postoperative chemotherapy and 61 who did not. The median overall survival (OS) and recurrence free survival (RFS) for patients who received postoperative therapy were 42 and 17 months, respectively, versus 32 and 12 months for patients who did not (OS: P = 0.06; RFS: P = 0.04). Postoperative therapy was marginally associated with a longer OS (hazard ratio 0.55, 95% confidence interval 0.29-1.01; P = 0.05) and significantly associated with a longer RFS (hazard ratio 0.55, 95% confidence interval 0.29-0.96; P = 0.04). CONCLUSIONS: Despite being administered more frequently to patients with poor prognostic factors, postoperative chemotherapy after preoperative therapy and pancreatectomy for PDAC was of clinical benefit.


Asunto(s)
Adenocarcinoma/terapia , Antineoplásicos/uso terapéutico , Estadificación de Neoplasias , Pancreatectomía/métodos , Neoplasias Pancreáticas/terapia , Cuidados Posoperatorios/métodos , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Periodo Preoperatorio , Pronóstico , Estudios Retrospectivos , Texas/epidemiología
20.
Clin Cancer Res ; 26(6): 1385-1394, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31871297

RESUMEN

PURPOSE: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer. EXPERIMENTAL DESIGN: Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records. RESULTS: Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival. CONCLUSIONS: We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Terapia Molecular Dirigida/métodos , Neoplasias Pancreáticas/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Estudios de Cohortes , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pronóstico , Análisis de Secuencia de ADN/métodos , Tasa de Supervivencia
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