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Background: Replacement of carmustine (BCNU) in the BEAM regimen (BCNU, etoposide, cytarabine, melphalan) with bendamustine (BendaEAM) before autologous stem cell transplantation (ASCT) is feasible in lymphoma. However, randomised trials are lacking. Here, we present the first trial addressing this topic. Methods: This multicentre, randomised, phase 2 study (BEB-trial) conducted at four haematological centres in Austria and Switzerland compares BEAM with BendaEAM in patients with relapsed lymphoma. Both regimens were administered intravenously before ASCT, in BEAM according to the standard protocol (300 mg/m2 BCNU on day -6), in BendaEAM, BCNU was replaced by 200 mg/m2 bendamustine given on days -7 and -6. Eligible patients were aged 18-75 years and had mantle cell lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma in first or second remission or chemosensitive relapse. The primary endpoint of the study was to evaluate whether replacement of BCNU by bendamustine reduces lung toxicity, defined as a decrease of the diffusion capacity of the lung for carbon monoxide by at least 20% at three months after ASCT. Data analyses were performed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02278796, and is complete. Findings: Between April 20, 2015, and November 28, 2018, 108 patients were enrolled; of whom 53 were randomly assigned to receive BendaEAM (36 male, 17 female) and 55 to receive BEAM (39 male, 16 female). All patients engrafted rapidly. Lung toxicity did not differ between groups (BendaEAM: n = 8, 19.5%; BEAM: n = 11, 25.6%; risk difference = -6.1%: 95% confidence interval: -23.9% to 11.7%). Acute toxicities of at least grade 3 were comparable in both groups (BendaEAM: 35.8%, BEAM: 30.9%). Overall survival (BendaEAM: 92.5%, BEAM: 89.1%) and complete remission (BendaEAM: 76.7%, BEAM: 74.3%) after 1 year (median follow-up: 369 days) were similar. No difference in quality of life was observed. Interpretation: Results were similar for both regimens in terms of survival and response rates. A phase 3 non-inferiority study is required to investigate whether BendaEAM can be considered as an alternative to BEAM. Funding: Mundipharma.
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OBJECTIVES: To investigate physiotherapists' current knowledge and practice in the management of patients with lateral elbow tendinopathy, to explore associations between the participants' education and management preferences and to identify potential evidence-to-practice gaps by making comparisons with recent research recommendations. DESIGN: An on-line cross-sectional survey. SUBJECTS: Registered physiotherapists working in Greece with previous experience in the management of lateral elbow tendinopathy. RESULTS: Three hundred and seventy eight responses met the inclusion criteria. Most responders (70.4%-91.5%) use pain provocation tests for the diagnosis of the condition, while a limited proportion uses patient rated outcome measures (6.9%-13%). Supervised exercise is the mainstay of rehabilitation (92.6%), followed by adjunctive research recommended treatment techniques such as manual therapy (72%) and advice (59.5%). Up to 83.6% of participants use adjunctive treatment techniques that are not recommended or without research recommendation (such as electrophysical agents, ice etc.). Physiotherapists with post-graduate education in musculoskeletal physiotherapy are almost three times more likely to choose only research recommended treatment approaches. There is a lack of consensus in an optimal exercise programme (type, volume, duration etc.) in patients with lateral elbow tendinopathy. CONCLUSION: Despite research recommendations a limited use of patient rated outcome measures in lateral elbow tendinopathy is recorded. Supervised exercise is the first line treatment option for most physiotherapists, although the optimal application is still unclear. A large proportion of physiotherapists apply adjunctive treatment techniques that are either ineffective or poorly researched suggesting a substantial evidence-to-practice gap. Better access to knowledge, organisational and peer-support can potentially help to bridge this gap.
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Tendinopatia do Cotovelo , Fisioterapeutas , Tendinopatia , Estudos Transversais , Tendinopatia do Cotovelo/terapia , Grécia , Humanos , Fisioterapeutas/educação , Tendinopatia/diagnóstico , Tendinopatia/terapiaRESUMO
Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in â¼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.
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Neoplasias do Sistema Digestório/tratamento farmacológico , Hipóxia/tratamento farmacológico , Fosfatos de Inositol/uso terapêutico , Administração Intravenosa , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias do Sistema Digestório/patologia , Feminino , Humanos , Fosfatos de Inositol/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Unresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma. METHODS: Twelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m2 gemcitabine and predefined doses of cisplatin 25 mg/m2 on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1-14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported. RESULTS: The determined MTD for gemcitabine was 800 mg/m2. Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1-49), and median progression-free survival 10.1 months (range 2-40). CONCLUSIONS: Intravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Artéria Hepática , Adulto , Idoso , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Floxuridina/administração & dosagem , Seguimentos , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , GencitabinaRESUMO
BACKGROUND: High rates of venous thromboembolic events (VTEs), mainly in advanced disease, are reported for patients with cancer of the upper gastrointestinal tract (stomach, pancreas) and for treatment with cisplatin. METHODS: Exploratory analysis of VTEs reported as adverse events and serious adverse events in a prospective, randomised, multicentre, multimodal phase III trial according to VTEs reported as adverse events and severe adverse events. Patients with resectable oesophageal cancer (T2N1-3, T3-4aNx) were randomized to 2 cycles of chemotherapy with docetaxel 75 mg/m2, cisplatin 75 mg/m2 followed by chemo-radiotherapy (CRT) and subsequent surgery (control arm) or the same treatment with addition of cetuximab (investigational arm). RESULTS: VTEs occurred in 26 of 300 patients included in the trial, resulting in an incidence rate (IR) of 8.7% [95% CI 5.7-12.4%]. A total of 29 VTEs were reported:13 (45%) VTEs were grade 2, 13 (45%) grade 3 and three (10%) fatal grade 5 events. 72% (21/29) of all VTEs occurred preoperatively (IR 6.7%): 14% (4/29) during chemotherapy and 59% (17/29) during CRT. In multivariable logistic regression only adenocarcinoma (IR 11.1%, 21/189 patients) compared to squamous cell cancer (IR 4.5%, 5/111 patients) was significantly associated with VTE-risk during treatment, OR 2.9 [95%CI 1.0-8.4], p = 0.046. Baseline Khorana risk score was 0 in 73% (19/26), 1-2 in 23% (6/26) and 3 in only 4% (1/26) of patients with VTEs. CONCLUSION: A high incidence of VTEs during preoperative therapy of resectable oesophageal cancer is observed in this analysis, especially in patients with adenocarcinoma. The role of prophylactic anticoagulation during neoadjuvant therapy in resectable esophageal cancer should be further evaluated in prospective clinical trials. According to our data, which are in line with other analysis of VTE-risk in patients with oesophageal cancer patients treated with neoadjuvant cisplatin-based chemotherapy and CRT, prophylactic anticoagluation could be considered balanced against individual bleeding risks, especially in patients with adenocarcinoma. In addition to the established risk factors, oesophageal adenocarcinoma treated with neoadjuvant cisplatin-based therapy may be regarded as a high-risk situation for VTEs. TRIAL REGISTRATION: Registered at clinicaltrials.gov, NCT01107639, on 21 April 2010.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Esofágicas/terapia , Tromboembolia/epidemiologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Neoplasias Esofágicas/patologia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tromboembolia/induzido quimicamente , Resultado do TratamentoRESUMO
This update on plasma cell myeloma has been elaborated by a Swiss expert panel as a result of the plethora of new data on the treatment of plasma cell myeloma reported recently. It adds new insights to the more extensive review that was published 3 years ago and may help clinicians on decision making for their patients. The new recommendations for distinguishing plasma cell myeloma from smouldering myeloma are briefly presented, including a section on contemporary imaging studies with this respect. Former panel recommendations that remain unchanged by new results will not be discussed in detail as the major focus of this review is on treatment-relevant new developments.
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Mieloma Múltiplo , Guias de Prática Clínica como Assunto , Humanos , SuíçaRESUMO
The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enrolled in the observational Swiss Blood Stem Cell Transplantation Registry. The median age was 67 years (65-77). Single ASCT was performed in 344 (88.7%) patients, with 259 patients (75.3%) receiving a melphalan dose of 200 mg/m2 (MEL200), and 85 patients (24.7%) receiving lower doses (MELlow) (median 140 mg/m2, range 70-180 mg/m2). MEL200 patients were slightly younger, and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and KPS. Overall mortality at day 100 was 1.5% without differences between the MEL groups (p = 0.621). Median progression-free survival (PFS) in the MEL200 and the MELlow group was 27.7 and 22.1 months, respectively (p = 0.294). Median overall survival (OS) in the MEL200 and in MELlow group was 91.2 and 61.2 months (p = 0.015). However, multivariate analysis showed no significant association of the melphalan dose and OS (HR 0.734; CI95% 0.264-2.038; p = 0.553). In conclusion, our data reveal no significant differences in safety and PFS for elderly myeloma patients treated with MEL200 or with lower MEL doses.
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Transplante de Células-Tronco Hematopoéticas , Melfalan/administração & dosagem , Mieloma Múltiplo , Sistema de Registros , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Fatores de Risco , Taxa de SobrevidaRESUMO
Selective digestive decontamination (SDD) with the oral, non-absorbable antimicrobial substances gentamicin, vancomycin and amphotericin B was optionally used at our institution to reduce the risk of gastrointestinal tract derived infections in multiple myeloma (MM) patients undergoing high-dose chemotherapy with subsequent autologous stem cell transplantation (HDCT/ASCT). The majority of patients received sulfamethoxazole-trimethoprim as pneumocystis pneumonia prophylaxis. From 203 patients receiving their first HDCT/ASCT between 2009 and 2015, we compared retrospectively 90 patients receiving SDD to 113 patients not receiving SDD. The administration of SDD was associated with a reduction of bacterial infections after HDCT/ASCT (overall: 8% versus 24%, p = .002; gram-negative pathogens: 1% versus 11%, p = .006) and less use of systemic antibiotics (62% versus 77%, p = .022). Omission of SDD was an independent risk factor for developing neutropenic fever and bloodstream infections. SDD could be an option to reduce bacterial infections in patients undergoing HDCT/ASCT that needs to be tested in prospective trials.
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Anti-Infecciosos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Gastroenterite/tratamento farmacológico , Gastroenterite/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/complicações , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/etiologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Mieloma Múltiplo/terapia , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Sepse/tratamento farmacológico , Sepse/etiologia , Transplante Autólogo , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Nelfinavir/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Pathologic response to neoadjuvant chemotherapy (neoCTX) is a prognostic factor in many cancer types, and early prediction would help to modify treatment. In patients with gastric and esophagogastric junction (AEG) cancer, the accuracy of FDG PET-CT to predict early pathologic response after neoadjuvant chemotherapy (neoCTX) is currently not known. METHODS: From a consecutive cohort of 72 patients, 44 patients with resectable, locally-advanced gastric cancer or AEG Siewert type II and III received neoCTX after primary staging with endoscopic ultrasound, PET-CT and laparoscopy. Overall, 14 patients did not show FDG uptake, and the remaining 30 were restaged by PET-CT 14 days after the first cycle of neoCTX. Metabolic response was defined as decrease of tumor standardized uptake value (SUV) by ≥35%. Major pathologic regression was defined as less than 10% residual tumor cells. RESULTS: Metabolic response after neoCTX was detected in 20/30 (66.7%), and non-response in 10/30 (33.3%) patients. Among metabolic responders, n = 10 (50%) showed major and n = 10 (50%) minor pathologic regression. In non-responders, n = 9 (90%) had minor and 1 (10%) a major pathologic regression. This resulted in a sensitivity of 90.9%, specificity 47.3%, positive predictive value 50%, negative predictive value 90% and accuracy of 63.3%. CONCLUSION: Response PET-CT after the first cycle of neoCTX does not accurately predict overall pathologic response. However, PET-CT reliably detects non-responders, and identifies patients who should either immediately proceed to resection or receive a modified multimodality therapy. TRIAL REGISTRATION: The trial was registered and approved by local ethics committee PB_2016-00769.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Gástricas/diagnóstico por imagem , Adulto , Idoso , Cárdia/diagnóstico por imagem , Cárdia/patologia , Cárdia/cirurgia , Endossonografia , Junção Esofagogástrica/diagnóstico por imagem , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18/administração & dosagem , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Valor Preditivo dos Testes , Prognóstico , Compostos Radiofarmacêuticos/administração & dosagem , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Resultado do TratamentoRESUMO
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.
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Gelatinases/genética , Neoplasias Pulmonares/terapia , Proteínas de Membrana/genética , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Receptor de Morte Celular Programada 1/genética , Serina Endopeptidases/genética , Adulto , Idoso , Animais , Antígenos CD28/imunologia , Antígenos CD28/uso terapêutico , Endopeptidases , Feminino , Gelatinases/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ativação Linfocitária/imunologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/imunologia , Masculino , Proteínas de Membrana/imunologia , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Pessoa de Meia-Idade , Fosforilação Oxidativa , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Serina Endopeptidases/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.
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Sequential high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is a curative option in relapsing germ cell tumor (GCT) patients, and complete remission (CR) after the first ASCT (early CR2) is associated with favorable outcome. Prognostic factors predicting early CR2 have not been investigated so far. We analyzed consecutive patients with a first relapse of GCT treated with three sequential cycles of carboplatin/etoposide-based HDCT with ASCT in the two largest academic centers in Switzerland. The cohort comprised 96 relapsing GCT patients, with 19 (19.8%) patients achieving early CR2 after the first HDCT cycle. The median progression-free survival and overall survival were not reached in patients achieving early CR2, whereas they were 9.6 months (P = 0.0301) and 34.8 months (P = 0.0684) for patients missing early CR2. Patients with early CR2 more often had CR1 after first-line bleomycin, etoposide, and cisplatin chemotherapy (68.4 vs. 31.6%; P = 0.0037) and an interval longer than 2 years between initial diagnosis and first HDCT (36.8 vs. 15.6%; P = 0.0373), but less often a histology of mixed nonseminomatous tumor (46.8 vs. 21.1%; P = 0.0418). These data suggest that response to first-line chemotherapy, late relapse, and histology are associated with achieving early CR2 after a first HDCT with ASCT in relapsing GCT patients.
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Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Terapia de Salvação/métodos , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Embrionárias de Células Germinativas/patologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC. METHODS: Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed. RESULTS: Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3-100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50-100) for cisplatin and 100% (IQR 75-100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0-33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8-62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts. CONCLUSION: Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients. TRIAL REGISTRATION: The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/cirurgia , Quimioterapia Adjuvante/métodos , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , GencitabinaRESUMO
Standard of care for untreated mantle cell lymphoma (MCL) is still debated. At the University Hospital Zurich, advanced MCL in physically fit patients is treated either with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone induction followed by consolidating high-dose chemotherapy and autologous stem cell support (R-CHOP/HD-ASCT), or with rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate-cytarabine (R-hyper-CVAD/MTX-AraC) without consolidating HD-ASCT upon physicians' and patients' choice. We retrospectively analysed the outcome and therapy tolerance in patients with MCL treated with R-CHOP/HD-ASCT or R-hyper-CVAD/MTX-AraC at the University Hospital Zurich between January 1996 and January 2016. Forty-three patients were included; 29 patients received R-CHOP/HD-ASCT and 14 patients R-hyper-CVAD/MTX-AraC. Mean age at diagnosis was 54.4 years (range 38-68 years). Thirty-five patients (81.4%) completed the entire first-line therapy (n = 24 in the R-CHOP/HD-ASCT group, n = 11 in the R-hyper-CVAD group). Of those, all patients responded and 97% achieved a complete remission (CR). With a mean follow-up of 5.7 years 10-year progression-free survival (PFS) for all patients was 32% and overall survival (OS) was 76%, with no difference between the two therapy groups. Complication-induced hospitalisation rate, haematological toxicity and economic burden were significantly higher in the R-hyper-CVAD therapy group. In contrast, quality of life and global health state were better in the R-hyper-CVAD therapy group. Both first-line therapies showed similar outcome with a median OS longer than 10 years. Due to significantly lower haematological toxicity and lower economic burden, we recommend R-CHOP/HD-ASCT as first-line therapy in fit adult patients with advanced MCL.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Citarabina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Hospitalização/estatística & dados numéricos , Linfoma de Célula do Manto/terapia , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/economia , Citarabina/efeitos adversos , Citarabina/economia , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/economia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/economia , Esquema de Medicação , Feminino , Hospitalização/economia , Humanos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/psicologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/economia , Qualidade de Vida/psicologia , Indução de Remissão , Estudos Retrospectivos , Rituximab , Análise de Sobrevida , Transplante Autólogo , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/economiaRESUMO
BACKGROUND: KRAS mutation occurs in â¼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. RESULTS: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). CONCLUSIONS: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Quimiorradioterapia/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Radioterapia Adjuvante/efeitos adversos , Neoplasias Retais/genética , SorafenibeRESUMO
Vinorelbine combined with filgrastim at a dose of 10 µg/kg of body weight (BW) per day is a reliable and well-tolerated regimen for mobilization of hematopoietic progenitor cells (HPCs) in patients with multiple myeloma. This prospective, randomized, phase II study was initiated to assess the feasibility of a reduced filgrastim dosage. Vinorelbine was combined with either standard-dose filgrastim (10 µg/kg BW per day) or reduced-dose filgrastim (5 µg/kg BW per day). Leukapheresis sessions were planned to start at day 8 and were continued until the predefined target amount of 4 × 106 HPCs/kg BW was collected. The study demonstrated the feasibility of vinorelbine combined with reduced daily filgrastim with a mean of 1.29 leukapheresis sessions necessary per patient (95% confidence interval, .95 to 1.7). All patients could start leukapheresis as planned at day 8, and the collection success rate was 100% for the whole patient collective after a maximum of 2 leukapheresis sessions. No statistically significant differences with regard to the amount of HPCs collected between the 2 groups were observed (P = .99). Accordingly, no differences were seen with regard to length of hospitalization for autotransplant (P = .34) and duration of neutrophil (P = .93) and platelet engraftment (P = .42). Patients receiving reduced-dose filgrastim reported significantly lower peak pain values in a numeric analogue scale (P = .01), and the costs were significantly lower than in patients undergoing standard-dose chemomobilization (P = .001). Vinorelbine 35 mg/m2 plus filgrastim 5 µg/kg BW once per day until completion of HPC collection is feasible and appears to be advantageous with respect to the severity of pain intensity and treatment costs.
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Filgrastim/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Vinorelbina/administração & dosagem , Idoso , Autoenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Estudos ProspectivosRESUMO
PURPOSE: Following a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine-chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer. METHODS: In this 3 + 3 dose escalation study, patients received a single weekly standard dose of intravenous gemcitabine, followed by single weekly oral intake of 100, 200 or 300 mg of chloroquine. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Immune status was evaluated by RT-PCR to measure the relative expression of immune-related genes in peripheral blood mononuclear cells (PBMCs). RESULTS: Overall, nine patients [median age 72 years; interquartile range (IQR), 68-78 years] were treated. No dose-limiting toxicities as defined in the protocol were observed. Three patients experienced partial response, and two patients had stable disease. The median time to progression was 4 months (95% CI 0.8-7.2), and the median overall survival was 7.6 months (95% CI 5.3-9.9). Among 86 assayed immune genes, three were significantly differentially expressed in PBMCs from responding versus non-responding patients: interferon-gamma receptor-1, toll-like receptor 2, and beta-2 microglobulin. CONCLUSIONS: The addition of chloroquine to gemcitabine was well tolerated and showed promising effects on the clinical response to the anti-cancer chemotherapy. Based on these initial results, the efficacy of the gemcitabine-chloroquine combination should be further assessed.
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Antimaláricos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Cloroquina/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Antimaláricos/administração & dosagem , Antimaláricos/farmacologia , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Cloroquina/administração & dosagem , Cloroquina/farmacologia , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , GencitabinaRESUMO
OBJECTIVES: To report survival following different operative strategies and perioperative chemotherapy in patients with synchronous colorectal liver metastases in a tertiary academic referral centre. METHODS: We performed a retrospective analysis, based on a prospective database, of patients who presented with synchronous colorectal liver metastases. Follow-up data were obtained from medical records, letters or telephone contacts. The main endpoint was overall survival. An additional event of interest was postoperative mortality according to treatment strategy. Predefined variables were analysed to identify associated risk factors. RESULTS: Overall, 109 patients undergoing liver resection for synchronous colorectal liver metastases between 2000 and 2010 were identified. The majority of patients had resection of the primary tumour first (n = 82), the classic approach; notably fewer were treated according to a combined (n = 20) or a reverse "liver first" strategy (n = 7). Most patients (92%) received preoperative, interval and/or postoperative chemotherapy. Median overall survival of the entire population was 33.6 months (interquartile range [IQR] 11-92.7 months). Patients undergoing classic surgery had a median overall survival of 40.3 months (IQR 14.9-96.6 months). The 3-year survival rates of the three patient groups were 53% in the classic, 47% in the combined and 58% in the reverse group. The lowest rate of 180-day mortality (9%) was after the classic surgical approach. On a multivariate Cox proportional hazards regression analysis, patient age >60 years (hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.1-3.9; p = 0.018), R2-status (HR 2.08, 95% CI 1.03-4.2; p = 0.040), and >4 liver metastases (HR 2.4, 95% CI 1.2-4.6; p = 0.011) were associated significantly with worse overall survival. CONCLUSIONS: In patients undergoing surgical resection for synchronous colorectal liver metastases, promising survival rates could be achieved, irrespective of the chosen surgical strategy. The presence of five or more liver metastases, patient age over 60 years and R2-status were found to be adverse risk factors.
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Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Taxa de Sobrevida , Anticorpos Monoclonais/administração & dosagem , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Feminino , Hepatectomia/métodos , Hepatectomia/mortalidade , Humanos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: In 2009, international nutritional societies published practice guidelines on screening and nutritional support for patients undergoing stem cell transplantation. Little is known about how these guidelines are implemented in clinical practice. We performed a nationwide survey with the aim of understanding current practice patterns, differences between clinical practice, and international recommendations as well as barriers to the use of nutritional therapy. METHODS: We performed a qualitative survey including all centers across Switzerland offering allogeneic (n = 3) or autologous (n = 7) stem cell transplantation. We focused on in-house protocols pertaining to malnutrition screening, indications for nutritional support, types of nutritional therapy available and provided, and recommendations regarding neutropenic diets. RESULTS: All centers offering allogeneic, and most of the centers offering autologous transplantation, had a malnutrition screening tool, mainly the nutritional risk score (NRS 2002) method. Only one center does not provide nutritional support. There is wide variation regarding start and stop of nutritional therapy as well as route of delivery, with five centers recommending parenteral nutrition and five centers recommending enteral nutrition as a first step. Although all centers offering allogeneic transplantation, and approximately every other autologous transplant center, used a neutropenic diet, specific recommendations regarding the type of food and food handling showed significant variation. CONCLUSION: This Swiss survey found wide variation in the use of nutritional therapy in patients undergoing stem cell transplantation, with low adherence overall to current practice guidelines. Understanding and reducing barriers to guideline implementation in clinical practice may improve clinical outcomes. Close collaboration of centers will facilitate future research needed to improve current practice and ensure high quality of treatment.