RESUMO
BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.
Assuntos
Neoplasias Nasofaríngeas , Platina , Humanos , Neoplasias Nasofaríngeas/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Docetaxel , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of renal cell carcinoma was published in 2019 with an update planned for 2021. It was therefore decided by both the ESMO and the Singapore Society of Oncology (SSO) to convene a special, virtual guidelines meeting in May 2021 to adapt the ESMO 2019 guidelines to take into account the ethnic differences associated with the treatment of renal cell carcinomas in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with renal cell carcinoma representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Ásia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/terapia , Seguimentos , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , OncologiaRESUMO
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Seguimentos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Oncologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapiaRESUMO
The transfer constant K trans is commonly employed in dynamic contrast-enhanced MRI studies, but the utility and interpretation of K trans as a potential biomarker of tumor vasculature remains unclear. In this study, computer simulations based on a comprehensive tracer kinetic model with multiple pathways was used to provide clarification on the interpretation and application of K trans. Tissue concentration-time curves pertaining to a wide range of transport conditions were simulated using the multiple-pathway (MP) model and fitted using the generalized kinetic (GK) and extended GK models. Relationships between K trans and plasma flow F p, vessel permeability PS and extraction rate EF p under various transport conditions were assessed by correlation and regression analysis. Results show that the MP model provides an alternative two-tier interpretation of K trans based on the vascular transit time. K trans is primarily associated with F p and EF p respectively, in the slow and rapid vascular transit states, independent of the magnitude of PS. The relative magnitudes of PS and F p only serve as secondary constraints for which K trans can be further associated with EF p and PS in the slow and rapid transit states, respectively.
Assuntos
Simulação por Computador , Meios de Contraste , Imageamento por Ressonância Magnética , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Meios de Contraste/metabolismo , Humanos , Aumento da Imagem , Cinética , Permeabilidade , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , SorafenibeRESUMO
Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) allows functional characterisation of tissue perfusion characteristics and acts as a biomarker for tumour angiogenesis. It involves serial acquisition of MRI images before and after injection of contrast, as such, tissue perfusion and permeability can be assessed based on the signal enhancement kinetics. The ability to evaluate whole tumour volumes in a non-invasive manner makes DCE MRI especially attractive for potential oncological applications. Here we provide an overview of the current research involving DCE MRI as a biomarker for the diagnosis and characterisation of malignancies, prediction of the therapeutic response and survival outcomes, as well as radiation therapy planning.
Assuntos
Meios de Contraste , Imageamento por Ressonância Magnética/métodos , Neoplasias/diagnóstico , Animais , HumanosRESUMO
BACKGROUND & AIMS: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sirolimo/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Resultado do TratamentoRESUMO
Compartmental tracer kinetic models currently used for analysis of dynamic contrast-enhanced MRI data yield poor fittings or parameter values that are unphysiological in necrotic regions of the tumor, as these models only describe microcirculation in perfused tissue. In this study, we explore the use of Fick's law of diffusion as an alternative method for analysis of dynamic contrast-enhanced MRI data in the necrotic regions. Xenografts of various human cancer cell lines were implanted in 14 mice that were subjected to dynamic contrast-enhanced MRI performed using a spoiled gradient recalled sequence. Tracer concentration was estimated using the variable flip angle technique. Poorly perfused and necrotic tumor regions exhibiting delayed and slow enhancement were identified using a k-means clustering algorithm. Tracer behavior in necrotic regions was shown to be consistent with Fick's diffusion equation and the in vivo gadolinium diffusivity was estimated to be 2.08 (±0.88) × 10(-4) mm(2)/s. This study proposes the use of gadolinium diffusivity as an alternative parameter for quantifying tracer transport within necrotic tumor regions.
Assuntos
Meios de Contraste , Gadolínio DTPA , Neoplasias Hepáticas Experimentais/patologia , Imageamento por Ressonância Magnética/métodos , Transplante de Neoplasias , Animais , Linhagem Celular Tumoral , Meios de Contraste/farmacocinética , Difusão , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Quimiorradioterapia , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/terapia , Adulto , Idoso , Biomarcadores Tumorais/genética , Cisplatino/administração & dosagem , Análise Mutacional de DNA , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Gefitinibe , Expressão Gênica , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Hibridização in Situ Fluorescente , Masculino , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Quinazolinas/administração & dosagem , Fatores de Risco , Fumar , Resultado do TratamentoRESUMO
BACKGROUND: The vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation. METHODS: Patients with non-small-cell lung cancer (NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition. RESULTS: Thirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse. CONCLUSIONS: Radiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.