RESUMO
OBJECTIVE: Carbohydrate antigen 19-9 (CA19-9) is a prognostic marker for patients with pancreatic cancer (PC), but its value as a treatment biomarker is unclear. SUMMARY BACKGROUND DATA: Although CA19-9 is an established prognostic marker for patients with PC, it is unclear how CA19-9 monitoring should be used to guide multimodality treatment and what level of change in CA19-9 constitutes a meaningful treatment response. METHODS: CA19-9 measurements at diagnosis (pretx), after completion of all planned neoadjuvant therapy (preop), and after surgery (postop) were analyzed in patients with localized PC who had an elevated CA19-9 (≥35âU/dL) at diagnosis. Patients were classified by: 1) quartiles of pretx CA19-9 (Q1-4); 2) proportional changes in CA19-9 (ΔCA19-9) after the completion of neoadjuvant therapy; 3) normalization (CA19-9 <35âU/dL) of preop CA19-9; and 4) normalization of postop CA19-9. RESULTS: Among 131 patients, the median overall survival (OS) was 30 months; 68 months for the 33 patients in Q1 of pretx CA19-9 (<80âU/dL) compared with 25 months for the 98 patients in Q2-4 (P = 0.03). For the 98 patients in Q2-4, preop CA19-9 declined (from pretx) in 86 (88%), but there was no association between the magnitude of ΔCA19-9 and OS (P = 0.77). Median OS of the 98 patients who did (n = 29) or did not (n = 69) normalize their preop CA19-9 were 46 and 23 months, respectively (P = 0.02). Of the 69 patients with an elevated preop CA19-9, 32 (46%) normalized their postop CA19-9. Failure to normalize preop or postop CA19-9 was associated with a 2.77-fold and 4.03-fold increased risk of death, respectively (P < 0.003) as compared with patients with normal preop CA19-9. CONCLUSIONS: Following neoadjuvant therapy, normalization of CA19-9, rather than the magnitude of change, is the strongest prognostic marker for long-term survival.
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Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Antígeno CA-19-9/metabolismo , Terapia Neoadjuvante , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC). METHODS: Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted. RESULTS: Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC. CONCLUSION: Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway.
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Mutação em Linhagem Germinativa , Neoplasias Pancreáticas , Predisposição Genética para Doença , Testes Genéticos , Células Germinativas , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genéticaRESUMO
OBJECTIVES: One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery. METHODS: In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery. RESULTS: The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC. CONCLUSIONS: We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Terapia Neoadjuvante , Neoplasias Pancreáticas/terapia , Medicina de Precisão , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Humanos , Biópsia Guiada por Imagem , Masculino , Ohio , Pancreatectomia , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Radioterapia Adjuvante , Resultado do Tratamento , Ultrassonografia de Intervenção , WisconsinRESUMO
PURPOSE: To describe venous thromboembolism (VTE) rates in patients with pancreatic cancer (PC) during neoadjuvant therapy. METHODS: Factors associated with VTE were evaluated using multivariable logistic regression modeling in patients with resectable and BLR PC treated with neoadjuvant therapy between 2009 and 2014. RESULTS: Prevalent VTEs were detected in 13 (5%) of the 260 patients. Incident VTEs were detected in 26 patients (10%); 9 (8%) of the 109 resectable and 17 (11%) of the 151 BLR patients (P = 0.53). Of the 26 incident events, 9 (35%) were PEs, 9 (35%) were extremity DVTs, and 8 (31%) involved the SMV/PV. VTEs were catheter-related in 7 (27%) of the 26 patients. Rh(D) antigen positivity was associated with a decreased risk of incident VTE (OR:0.32, 95%CI:0.11-0.85, P = 0.02). Completion of neoadjuvant therapy to include surgery occurred in 176 (75%) of the 234 patients without incident VTE as compared to 14 (54%) of the 26 patients with incident VTE (P = 0.02). The median survival for all 260 patients was 24.3 months: 17.0 months versus 24.6 months for patients who did and did not develop incident VTE during neoadjuvant therapy (P = 0.11). CONCLUSIONS: Patients with localized PC who receive neoadjuvant therapy are at significant risk of VTE and thromboprophylaxis may be warranted. J. Surg. Oncol. 2016;114:581-586. © 2016 Wiley Periodicals, Inc.
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Terapia Neoadjuvante , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/prevenção & controle , Idoso , Antineoplásicos/uso terapêutico , Quimiorradioterapia Adjuvante , Estudos de Coortes , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Seleção de Pacientes , Prevalência , Fatores de Risco , Tromboembolia Venosa/diagnósticoRESUMO
BACKGROUND: The prognostic value of CA19-9 in patients with pancreatic cancer (PC) treated with neoadjuvant therapy has not been well described. METHODS: Pre-treatment CA19-9 levels (with concomitant normal bilirubin level) in patients with localized PC were categorized as normal (≤35), low (36-200), moderate (201-1000), or high (>1000). Post-treatment CA19-9 was measured after neoadjuvant therapy, prior to surgery. RESULTS: Pre-treatment CA19-9 levels were evaluable in 235 patients, levels were normal in 60 (25%) patients, low in 78 (33%) patients, moderate in 69 (29%) and high in 28 (12%). After neoadjuvant therapy, post-treatment CA19-9 normalized (≤ 35) in 40 (51%) of the patients in the low group, 14 (21%) of the moderate and 5 (19%) of the high group (P < 0.001). Of the 235 patients, 168 (71%) completed all intended therapy including a pancreatectomy; 44 (73%), 62 (79%), 46 (67%) and 16 (57%) of the normal, low, moderate and high groups (P = 0.10). Among these 168 patients, the median overall survival was 38.4, 43.6, 44.7, 27.2 and 26.4 months for normal, low, moderate and high CA19-9 groups (log rank P = 0.72). Among resected patients, an elevated pre-treatment CA19-9 was of little prognostic value; instead, it was the CA19-9 response to neoadjuvant therapy that was prognostic [hazard ratio (HR): 1.80, P = 0.02]. CONCLUSIONS: Among patients who completed neoadjuvant therapy and surgery, pre-treatment CA19-9 obtained at the time of diagnosis was not predictive of overall survival, but normalization of post-treatment CA19-9 in response to neoadjuvant therapy was highly prognostic.
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Adenocarcinoma/terapia , Antígenos Glicosídicos Associados a Tumores/sangue , Estadiamento de Neoplasias , Neoplasias Pancreáticas/terapia , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico , Idoso , Biomarcadores Tumorais/sangue , Biópsia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
OBJECTIVES: Laparoscopy is recommended to detect radiographically occult metastases in patients with pancreatic cancer before curative resection. This study was conducted to test the hypothesis that diagnostic laparoscopy (DL) is cost-effective in patients undergoing curative resection with or without neoadjuvant therapy (NAT). METHODS: Decision tree modelling compared routine DL with exploratory laparotomy (ExLap) at the time of curative resection in resectable cancer treated with surgery first, (SF) and borderline resectable cancer treated with NAT. Costs (US$) from the payer's perspective, quality-adjusted life months (QALMs) and incremental cost-effectiveness ratios (ICERs) were calculated. Base case estimates and multi-way sensitivity analyses were performed. Willingness to pay (WtP) was US$4166/QALM (or US$50,000/quality-adjusted life year). RESULTS: Base case costs were US$34,921 for ExLap and US$33,442 for DL in SF patients, and US$39,633 for ExLap and US$39,713 for DL in NAT patients. Routine DL is the dominant (preferred) strategy in both treatment types: it allows for cost reductions of US$10,695/QALM in SF and US$4158/QALM in NAT patients. CONCLUSIONS: The present analysis supports the cost-effectiveness of routine DL before curative resection in pancreatic cancer patients treated with either SF or NAT.
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Laparoscopia/economia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Árvores de Decisões , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/economia , Anos de Vida Ajustados por Qualidade de Vida , Estados UnidosRESUMO
BACKGROUND: Borderline resectable pancreatic cancer is best treated by multimodality therapy. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) tripled the response rate and significantly increased median survival for patients with advanced pancreatic cancer and shows promise for neoadjuvant use. Toxicity concerns prompted a careful analysis of our initial FOLFIRINOX experience. METHODS: All patients diagnosed with borderline resectable, biopsy-proven pancreatic adenocarcinoma treated with neoadjuvant FOLFIRINOX between July 2010 and December 2012 were reviewed. Primary outcome was surgical resectability. Secondary outcomes were treatment-related toxicities and survival. RESULTS: FOLFIRINOX followed by gemcitabine- or capecitabine-based chemoradiation was initiated in 18 patients. The most common grade 3 or 4 toxicities during chemotherapy were gastrointestinal, including nausea/emesis (n = 5), weight loss (n = 3) and diarrhea (n = 2), and hematologic (n = 2; neutropenia); five patients (36%) required a total of six admissions. Neoadjuvant therapy was completed in 15 of 18 patients (83%), and 12 (67%) underwent pancreatectomy (10 Whipple, 2 total pancreatectomy) including portal vein resection/reconstruction in 10 (83%). Disease progression precluded surgery in 6 of the 18 patients (33%). All 12 resected patients had negative (R0) margins. Only 2 of 12 (17%) were node positive (median node count: 26.5 [range: 15-39]). There were no in-hospital or 30-day mortalities and no clinical pancreatic leaks or reoperations. Of the 12 patients who completed all intended therapy, 7 (58.3%) are alive, including 5 who have no evidence of disease (median months from diagnosis: 22 months [range: 18-35 months). The six patients who did not complete all planned therapy are deceased (months from diagnosis: 6.9-17.5 months). CONCLUSION: FOLFIRINOX followed by chemoradiation as neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma is safe, and our initial experience suggests favorable resection rates compared with previous reports in this high-risk patient population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Resultado do Tratamento , GencitabinaRESUMO
OBJECTIVES: This study was conducted to determine if routine staging chest computed tomography (CT) or positron emission tomography (PET) scanning alters the clinical management of patients with newly diagnosed pancreatic adenocarcinoma. METHODS: All new pancreas cancers seen in medical oncology, radiation oncology and surgery from 1 June 2008 to 20 June 2010 were retrospectively reviewed. Patients with metastatic disease on chest CT or PET, that had been unsuspected on initial imaging, were identified. RESULTS: Pancreatic adenocarcinoma was present in 247 consecutive patients. Abdominal CT demonstrated metastases in 108 (44%) and localized disease in 139 (56%) patients. Chest CT and PET were not performed in 15 (11%) of these 139 patients. In the remaining 124 patients, CT imaging suggested resectable disease in 46, borderline resectable disease in 52 and locally advanced disease in 26 patients. Chest CT demonstrated an unsuspected lymphoma in one patient with borderline resectable disease and PET identified extrapancreatic disease in two patients with locally advanced disease. Chest CT and PET added no information in 121 (98%) of the 124 patients. CONCLUSIONS: The addition of chest CT and PET to high-quality abdominal CT is of little clinical utility; additional sites of metastasis are rarely found. As the quality of abdominal imaging declines, the yield from other imaging modalities will increase. Dedicated pancreas-specific abdominal CT remains the cornerstone of initial staging in suspected or biopsy-proven pancreatic cancer.
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Adenocarcinoma/diagnóstico , Futilidade Médica , Estadiamento de Neoplasias/métodos , Neoplasias Pancreáticas/diagnóstico , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Procedimentos Desnecessários , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/secundário , Humanos , Imagem Multimodal , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
PURPOSE: To assess safety and efficacy of folinic acid, 5-fluorouracil, gemcitabine (FFG) and folinic acid, fluorouracil, oxaliplatin (FOLFOX4) regimens with added bevacizumab as first-line treatment in patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Patients with Stage III unresectable or Stage IV adenocarcinoma of the colon or rectum were randomly assigned to either FFG weekly for 6 weeks of an 8-week cycle or FOLFOX4 every 2 weeks. After FDA approval, bevacizumab 5 mg/kg was added every 2 weeks. Treatment continued until disease progression. Planned enrollment was 190 patients. Primary endpoint was overall response rate (ORR); secondary endpoints included evaluation of adverse events, time to progression (TTP), and overall survival (OS). Disease Control Rate (DCR; % of patients with complete or partial responses or stable disease) was a post hoc analysis. RESULTS: The trial was stopped prematurely due to low enrollment. Of 84 enrolled patients (42 to each arm), 36 patients (18 in each arm) received bevacizumab. ORR was greater (P = .002) for FOLFOX4 (17/42; 40.5%) than for FFG (4/42; 9.5%); however, TTP, OS, and DCR results were not statistically different comparing FOLFOX4 and FFG. Peripheral neuropathy was more frequent (P = <.001) with FOLFOX4 (18/42; 42.9%) than with FFG (1/42; 2.4%). CONCLUSIONS: FFG and FOLFOX4 were generally well tolerated. Based on ORR, FOLFOX4 was superior to FFG. However, differences in TTP and OS comparing regimens were inconclusive. General use of gemcitabine as a biomodulator of 5-fluorouracil in CRC cannot be recommended at this time and the regimen remains investigational.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Adenocarcinoma/secundário , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Progressão da Doença , Esquema de Medicação , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosAssuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Fluoruracila/administração & dosagem , Leucovorina/administração & dosagem , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Neoplasias Pancreáticas/terapia , Camptotecina/administração & dosagem , Feminino , Humanos , Irinotecano , Masculino , OxaliplatinaRESUMO
BACKGROUND: More than 70% of patients with localized pancreatic cancer treated with upfront surgery develop disease recurrence. Herein we describe the radiographic patterns and timing of disease recurrence after neoadjuvant therapy and surgery in patients with pancreatic cancer. METHODS: Radiographic patterns of first disease recurrence were examined in patients with localized pancreatic cancer who completed neoadjuvant therapy and surgery. Disease recurrence was classified as local (pancreas, resection bed, or peripancreatic vasculature); regional (peritoneum or abdominal wall); or distant (liver, lung, bone). Progression-free survival was calculated from the date of diagnosis to the date of recurrence. RESULTS: Of 306 consecutive patients who completed neoadjuvant therapy and surgery, 149 (49%) had resectable pancreatic cancer and 157 (51%) had borderline resectable disease. Neoadjuvant therapy consisted of chemoradiation (32%), chemotherapy (14%), or both therapies (54%). Overall, primary therapy (including preoperative and postoperative therapy) consisted of chemoradiation alone in 29 (9%), chemotherapy alone in 14 (5%), and both therapies in 263 (86%) patients. At a median follow-up of 27 months, 186 (61%) of the 306 patients had recurrent pancreatic cancer. Sites of first recurrence were local-only in 29 (9%), regional-only in 19 (6%), distant-only in 87 (28%), and multisite in 51 (17%). The overall median progression-free survival for all patients was 24 months. Neoadjuvant chemoradiation reduced the odds of local-only recurrence (odds ratio: 0.21; 95% confidence interval: 0.06-0.77; P = .02). CONCLUSION: After neoadjuvant therapy and surgery, 9% of patients were found to have local-only recurrence. Treatment sequencing that incorporates neoadjuvant chemoradiation may improve local disease control.
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Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/epidemiologia , Pâncreas/diagnóstico por imagem , Pancreatectomia , Neoplasias Pancreáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Quimiorradioterapia/estatística & dados numéricos , Quimiorradioterapia Adjuvante/métodos , Quimiorradioterapia Adjuvante/estatística & dados numéricos , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/estatística & dados numéricos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/prevenção & controle , Oxaliplatina/uso terapêutico , Pâncreas/cirurgia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Intervalo Livre de Progressão , Radiografia/estatística & dados numéricos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Background: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy. Methods: Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUVdx) and 3.5 after neoadjuvant therapy (preoperative; SUVpreop). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal ( ≤ 35 U/mL) or elevated. Results: Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUVdx was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUVpreop was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUVdx and 22 months for the 98 patients with a high SUVdx (p = 0.03). Median OS for patients with low SUVdx/normal preop CA19-9, high SUVdx/normal preop CA19-9, low SUVdx/elevated preop CA19-9, and high SUVdx/elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively (p < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery (p < 0.001). Conclusion: Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC.
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INTRODUCTION: Tumor profiling can improve the selection of oncologic therapies in patients with pancreatic cancer (PC). The impact of neoadjuvant therapy on tumor testing is unknown. METHODS: Molecular profiling using commercially available 53-, 315-, or 472-gene next generation sequencing (NGS) panels was performed on surgical specimens following neoadjuvant therapy. All specimens with 472-gene sequencing also had immunohistochemical (IHC) testing. Treatment recommendations were based on somatic variants and IHC staining. RESULTS: NGS was performed on 74 patient specimens: 42 (57%) with a 472-gene panel, 28 (38%) with a 315-gene panel, 3 (4%) had 472- and 315-gene panels, and 1 (1%) patient had 53- and 472-gene panels (78 total tests). Likely pathogenic/pathogenic variants were identified in 73 (94%) of the 78 tests. Of the 73 samples with variants identified, 13 (18%) variants were associated with an actionable treatment: ATM (n = 10), BRCA1 (n = 1), PIK3CA (n = 1), and BRCA2 (n = 1). No patient had more than one actionable variant. Based on NGS results, the most commonly recommended therapy was a platinum agent (n = 12/78, 15%). Of the 46 specimens that underwent IHC analysis, overlapping chemotherapeutic treatment recommendations were identified in 40 (87%) specimens. CONCLUSION: Using current multigene NGS panels, actionable variants were identified in 13 (18%) of 74 surgical specimens and primarily involved genes of the DNA repair pathway. Anecdotal reproducibility of test concordance was low.
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Proteína BRCA1/genética , Proteína BRCA2/genética , DNA de Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pancreáticas/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Reprodutibilidade dos Testes , Neoplasias PancreáticasRESUMO
Introduction/Background: Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood. Methods: Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1-3), N2 (≥4). Results: Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses (n = 21 for NR, 48%) as compared to patients who received chemoradiation alone (n = 25 for NR, 24%) or patients who received both therapies (n = 33 for NR, 17%) (Table 1; p = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively (p = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15-2.54; p = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02-2.01; p = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64-3.93; p < 0.001) were associated with increased risk of death. Conclusions: Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.
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BACKGROUND: When pancreatic neoplasms occlude or encase the superior mesenteric-portal-splenic vein confluence with abutment of the posterior lateral wall of the superior mesenteric artery, a mesocaval shunt with or without a distal splenorenal shunt allows for safe dissection of the porta hepatis and separation of the pancreatic tumor from the superior mesenteric artery. Herein we report long-term results of the largest known series of portosystemic shunts performed at the time of pancreatectomy. METHODS: All patients who underwent pancreatic resection with a mesocaval shunt or distal splenorenal shunt were identified from our prospective database. Demographics, perioperative treatment, and outcomes were reviewed. RESULTS: A total of 34 patients underwent mesocaval shunt or distal splenorenal shunt, including 25 at the time of pancreatoduodenectomy, 6 during total pancreatectomy, and 3 after prior pancreatectomy. There were 15 mesocaval shunts, 16 distal splenorenal shunts, 2 combined mesocaval/distal splenorenal shunts, and 1 distal splenoadrenal vein shunt. The mesocaval group included 11 temporary and 6 permanent (3 delayed) shunts. Median operative time was 9 hours (range 6.5-13), median estimated blood loss was 950 mL (range 200-5,000), and median duration of hospital stay was 11 days (range 7-35). Four patients experienced complications that required intervention (Clavien-Dindo grade ≥III), but there were no 90-day mortalities. For patients with adenocarcinoma, median overall survival was 31 months at a median follow-up of 19 months. All but 1 shunt (distal splenorenal) were patent at last follow-up. CONCLUSION: Mesenteric venous shunting facilitates a safe and complete tumor resection in patients who require a complex pancreatectomy, many of whom would otherwise be deemed inoperable.
Assuntos
Pancreatectomia , Derivação Portossistêmica Cirúrgica , Derivação Esplenorrenal Cirúrgica , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Ligadura , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Veias Renais/cirurgia , Veia Esplênica/cirurgia , Adulto JovemRESUMO
BACKGROUND: It is difficult to successfully deliver multimodality therapy to patients with operable pancreatic cancer. Data on the natural history of such efforts are necessary for physicians to guide shared decision-making with patients and families. We report the survival of consecutive patients with borderline resectable pancreatic cancer who received neoadjuvant therapy before surgery. METHODS: Data regarding demographics, neoadjuvant therapy, surgery, pathology, and survival duration were abstracted on consecutive patients with borderline resectable pancreatic cancer diagnosed between 2009 and 2017 and not treated on available clinical trials. Borderline resectable pancreatic cancer was defined based on ≥1 of the following: local tumor anatomy, pretreatment serum carbohydrate antigen 19-9 >2,000 U/mL, and the presence of radiographic lesions indeterminate for metastases. RESULTS: Neoadjuvant therapy was delivered to 185 patients with borderline resectable pancreatic cancer who were not enrolled in competing clinical trials; 13 (7%) patients received chemoradiation, 12 (7%) received chemotherapy, and 160 (86%) received both. Of the 185 patients, 115 (62%) completed all intended neoadjuvant therapy and surgery; 81 (70%) of 115 underwent pancreaticoduodenectomy; and vascular reconstruction was performed in 51 (44%). A margin negative resection was achieved in 111 (97%) of 115 patients, and 83 (72%) were node negative. Median overall survival for all 185 patients was 20 months; 31 months for the 115 patients who completed all neoadjuvant therapy and surgery as compared to 13 months for the 70 patients who were not resected (P < .0001). CONCLUSION: After neoadjuvant therapy, surgical resection was performed in 62% of patients with borderline resectable pancreatic cancer. Those who normalized preoperative serum carbohydrate antigen 19-9 and had node negative pathology achieved the longest survival. To further improve median survival for all patients, we are incorporating adaptive approaches to neoadjuvant therapy sequencing based on objective assessments of response.
Assuntos
Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Comorbidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. PATIENTS AND METHODS: Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation. RESULTS: Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. CONCLUSIONS: The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients. CLINICAL TRIAL REGISTRY NO: NCT01647828.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Gerenciamento Clínico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Receptor Notch2/antagonistas & inibidores , Receptor Notch3/antagonistas & inibidores , Resultado do Tratamento , GencitabinaRESUMO
To evaluate the safety and efficacy of infliximab administered with gemcitabine to treat cancer cachexia and to explore a functional measure of clinical benefit, investigators involved in this multicenter, phase II, placebo-controlled study randomized 89 patients with stage II-IV pancreatic cancer and cachexia to receive either placebo or 3 mg/ kg or 5 mg/kg of infliximab at weeks 0, 2, and 4 and then every 4 weeks to week 24; patients also received 1,000 mg/m2 of gemcitabine weekly from weeks 0-6 and then for 3 of every 4 weeks until their disease progressed. The primary endpoint was change in lean body mass (LBM) at 8 weeks from baseline; major secondary endpoints included overall survival, progression-free survival, Karnofsky performance status, and 6-minute walk test distance. In addition, quality of life was measured. The mean change in LBM at 8 weeks was +0.4 kg for patients receiving placebo, +0.3 kg for those receiving 3 mg/kg of infliximab, and +1.7 kg for those receiving 5 mg/kg of infliximab. No statistically significant differences in LBM or secondary endpoints were observed among the groups. Safety findings were similar in all groups. Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated with statistically significant differences in safety or efficacy when compared with placebo.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Caquexia/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Feminino , Humanos , Infliximab , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Placebos , Prognóstico , Taxa de Sobrevida , GencitabinaRESUMO
BACKGROUND: Patients with locally advanced pancreatic cancer have historically been considered inoperable. The purpose of this report was to determine resectability rates for patients with locally advanced pancreatic cancer based on our recently described definitions of type A and type B locally advanced pancreatic cancer. METHODS: An institutional prospective pancreas cancer database was queried for consecutive patients with locally advanced pancreatic cancer treated between January 2009 and June 2017. All pretreatment imaging was re-reviewed and patients were categorized as locally advanced pancreatic cancer type A or type B. Demographics, induction therapy, resection type, and outcomes were reviewed. RESULTS: We identified 108 consecutive patients; 12 were excluded from analysis due to the absence of available pretreatment imaging or they had not yet completed all intended neoadjuvant therapy. Of the remaining 96 patients (45 type A, 51 type B), disease progression occurred in 19 (20%) during induction therapy and 30 (31%) were deemed inoperable at final preoperative restaging. Therefore, 47 (49%) of 96 patients were taken to surgery and 40 (42%) underwent successful resection (28 [62%] of 45 type A and 12 [24%] of 51 type B); an RO resection was achieved in 32 (80%). Metastatic disease was found intraoperatively (6 at laparoscopy, 1 at laparotomy) in 7 (15%) of 47 patients. There were no mortalities; 6 (15%) patients experienced major postoperative complications. Resected patients had a median overall survival of 38.9 months. CONCLUSION: Locally advanced pancreatic cancer can be dichotomized into type A and B with distinctly different probabilities of completing all therapy to include surgery; thereby allowing goals of therapy to be established at the time of diagnosis. Multimodality therapy that includes surgery can be accomplished in selected patients with locally advanced pancreatic cancer and is associated with a median overall survival that approximates earlier stages of disease. (Surgery 2017;160:XXX-XXX.).
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Adenocarcinoma/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Adenocarcinoma/classificação , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pâncreas/irrigação sanguínea , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Wisconsin/epidemiologiaRESUMO
Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.