RESUMO
BACKGROUND: In the pivotal phase III RECOURSE trial, trifluridine/tipiracil (FTD/TPI) improved progression-free and overall survival (PFS, OS) of patients with pre-treated metastatic colorectal cancer (mCRC). Subsequently, the TALLISUR trial provided post-authorisation efficacy and safety data and patient-reported outcomes on quality of life (QoL) in a German patient cohort. The present analysis reports the final data on efficacy, safety and QoL and investigates the impact of baseline characteristics and associated prognostic subgroups on outcome. METHODS: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). To assess the primary endpoint, QoL, EORTC QLQ-C30 questionnaires were employed. Secondary endpoints included QoL assessed through EQ-5D-5L questionnaires, OS, PFS and safety. Additionally, 3 subgroups were defined according to a post-hoc analysis of the RECOURSE trial: best, good and poor prognostic characteristics (BPC, GPC, PPC). Patients with < 3 metastatic sites at inclusion and/or ≥ 18 months from diagnosis to inclusion were considered to have GPC. GPC patients without liver metastasis at inclusion were considered to have BPC. All remaining patients were considered to have PPC. RESULTS: Of 195 patients, 186 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. Treatment with FTD/TPI was associated with maintained QoL. For all patients, median OS was 6.9 months (95% CI 6.1 - 8.3) and for the defined subgroups (BPC n = 20 vs GPC n = 65 vs PPC n = 121) 12.2, 7.9 and 6.8 months (95% CI 6.0 - 18.2, 6.2 - 13.3, 5.4 - 8.1). The most frequent TEAEs were neutropenia (29.6%), anaemia (24.7%) and nausea (23.7%). Febrile neutropenia occurred in 1.1%. CONCLUSIONS: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression, but also with maintained QoL. Independent of other baseline characteristics such as ECOG performance status and age, low metastatic burden and indolent disease were factors associated with favourable outcome. CLINICAL TRIAL REGISTRATION: EudraCT-Number 2017-000292-83, first registration 19/06/2017.
Assuntos
Neoplasias Colorretais , Combinação de Medicamentos , Pirrolidinas , Qualidade de Vida , Timina , Trifluridina , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Trifluridina/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Idoso de 80 Anos ou mais , Metástase Neoplásica , Intervalo Livre de Progressão , Prognóstico , AlemanhaRESUMO
Biliary tract cancer is a highly heterogeneous group of gastrointestinal cancers, and the only curative treatment is surgery, which is only applicable at early stages of the malignancy. ADJUBIL, a phase II trial (NCT05239169), aims to evaluate immunotherapy with durvalumab and tremelimumab with or without capecitabine in adjuvant situations for biliary tract cancers. A total of 40 prospective patients will be randomly assigned following surgery, consisting of a two-arm feasibility pilot part with a pick-the-winner design with durvalumab and tremelimumab in combination with or without capecitabine.
This article describes the design of a phase II clinical trial called ADJUBIL, which evaluates the use of immunotherapy (durvalumab and tremelimumab) with or without classic chemotherapy (capecitabine) in biliary tract cancer patients who have undergone curative surgery. This type of treatment is also called adjuvant therapy, meaning it is used after the primary treatment. Biliary tract cancer is a rare type of liver cancer, often diagnosed late. Following surgery, patients may experience an early return of the disease, called tumor relapse. To avoid or delay tumor relapse, patients need extra treatment. Pure chemotherapy (capecitabine) is the standard after curative surgery. For patients with no option for cure, chemotherapy together with new powerful immunotherapy has become standard. This study will recruit 40 adult patients with tumor removal, who will be randomly divided into two groups. Half of them will be treated with immunotherapy only (durvalumab and tremelimumab). The other half will be treated with capecitabine together with immunotherapy. This study will continue for 12 months, but the treatment can be stopped if, for example, the tumor reoccurs or any possible side effect of the therapy is detected. The most effective treatment type will be selected. This type of selection is called pick-the winner.
Assuntos
Adjuvantes Imunológicos , Neoplasias do Sistema Biliar , Humanos , Adjuvantes Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Capecitabina/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum. METHODS: A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization. RESULTS: The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26-44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169). DISCUSSION: GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population.
Assuntos
Adenoma , Neoplasias Colorretais , Adenoma/prevenção & controle , Antioxidantes/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Método Duplo-Cego , Humanos , Extratos Vegetais/uso terapêutico , CháRESUMO
BACKGROUND: Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer. METHODS: We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing. FINDINGS: Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]). INTERPRETATION: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection. FUNDING: Eli Lilly and Company.
Assuntos
Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Indazóis/administração & dosagem , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/administração & dosagem , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de Tempo , RamucirumabRESUMO
Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-3 and platelet-derived growth factor receptor-a/-b. Thereby, it targets angiogenic escape mechanisms. The trial TyRosine kinase Inhibitor for the treatment of Chemorefractory Colorectal Cancer (TRICC-C) trial evaluates the addition of nintedanib to mFOLFOX6 (fluorouracil, folinic acid and oxaliplatin) in patients with metastatic colorectal cancer (mCRC). TRICC-C is a randomised controlled, double-blinded, phase II trial in mCRC patients that received a first-line non-oxaliplatin containing chemotherapy. Patients received mFOLFOX6 + nintedanib (F + N) (2 × 200 mg p.o./d, d1-d14) or mFOLFOX6 + placebo (F + P), in a 1:1 ratio. Primary endpoint was median progression free survival (mPFS) and secondary overall response rate (ORR), overall survival (OS) and safety. Fifty-three patients (27 F + N; 26 F + P) were randomised between 12/2012 and 5/2016 (scheduled n = 180). The trial was terminated prematurely due to slow accrual. The trial did not reach its primary endpoint but mPFS, median overall survival (mOS) and disease control rate (DCR) were numerically higher in the F + N arm compared to the F + P arm; however, the difference was not significant (mPFS: F + P: 4.6 months vs F + N: 8.1 months; HR 0.65; 95% CI 0.32-1.30; P = .2156; mOS: F + P: 9.9 months vs F + N: 17.1 months; HR 1.03, 95% CI 0.48-2.23; P = .9387; DCR: F + P: 50% vs F + N: 66,7%; P = .2709). Toxicity was moderate and only different for neutropenia (F + P: 11.5%, F + N: 19.2%) and gastrointestinal disorders (F + P: 65.4%, F + N: 84.6%). Final results show safety and a nonsignificant trend towards improved PFS and DCR for the combination of mFOLFOX6 + nintedanib in the second-line therapy of mCRC.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/administração & dosagem , Adenocarcinoma/mortalidade , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Intervalo Livre de Progressão , Terapia de Salvação/métodosRESUMO
BACKGROUND: Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. METHODS: The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < =p0 = 60% versus H1: p > =p1 = 80%, alpha = 0.05, beta = 0.1. DISCUSSION: This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET. TRIAL REGISTRATION: EudraCT: 2017-001207-68 . Date of registration: 2018.01.03.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Dacarbazina/administração & dosagem , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/irrigação sanguínea , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Projetos Piloto , Estudos Prospectivos , Fatores de Tempo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , RamucirumabRESUMO
OPINION STATEMENT: Pancreatic cancer is mainly diagnosed at an advanced, often metastatic stage and still has a poor prognosis. Over the last decades, chemotherapy of metastatic pancreatic cancer (mPDAC) has proven to be superior to a mere supportive treatment with respect to both survival and quality of life. Recently, even sequential treatment of mPDAC could be established. Options for first-line treatment are combination chemotherapy regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel when the performance status of the patient is good. For patients with poorer performance status, gemcitabine single-agent treatment is a valid option. Recently, the PARP inhibitor olaparib has been demonstrated to improve progression-free survival when used as a maintenance treatment in the subgroup of patients with mPDAC and a BRCA1/-2 germ line mutation having received at least 16 weeks of platinum-based chemotherapy. This group of patients also benefits from platinum-based chemotherapy combinations. Therefore, the BRCA1/-2 stats should be examined early in patients with mPDAC even when the occurrence of these mutations is only about 5% in the general Caucasian population. After the failure of first-line treatment, patients should be offered a second-line treatment if their ECOG permits further treatment. Here, the combination of 5-FU/FA plus nanoliposomal irinotecan has shown to be superior to 5-FU/FA alone with respect to overall survival. Immune checkpoint inhibitors like PD1/PD-L1 mAbs are particularly efficacious in tumors with high microsatellite instability (MSI-h). Limited data in mPDACs shows that only a part of the already small subgroup of MSI-H mPDACs (frequency about 1%) appears to benefit substantially from a checkpoint inhibitor treatment. The identification of further subgroups, e.g., tumors with DNA damage repair deficiency, gene fusions, as well as novel approaches such as tumor-organoid-informed treatment decisions, may further improve therapeutic efficacy.
Assuntos
Neoplasias Pancreáticas/terapia , Fatores Etários , Biomarcadores Tumorais , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Técnicas de Diagnóstico Molecular , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Retratamento , Resultado do TratamentoRESUMO
Gastrointestinal (GI) malignant neoplasms have a high global incidence and a huge impact on cancer-associated mortality. In the past years, excitement was growing among oncologists and patients alike for the use of immunotherapy, specifically immune checkpoint inhibitors. The approval of several PD-1/PD-L1 and CTLA-4 inhibitors radically changed the treatment landscape in many cancer types and established immune-oncology as a new treatment strategy against cancer. Despite major breakthrough reports, shortcomings of immune checkpoint inhibitors (ICI) have been observed, including primary and acquired treatment resistance, especially in patients receiving ICIs as a single treatment. Several immunotherapies for the treatment of GI tumors have recently emerged; however, checkpoint inhibition has not yet shown similar success in GI malignancies compared to other solid tumors. Various phase I-III trials focusing on immunotherapies for GI tumors have found only moderate to unsatisfactory objective response rates (ORR), ranging between 10â% and 25â%. In particular, negative studies have been reported in gastric and pancreatic cancer. Nevertheless, small subsets of cancers, such as DNA mismatch repair deficient (dMMR)/microsatellite instable (MSI) cancers, among others, seem to benefit from treatment with immune checkpoint inhibition. Routine testing for the rare molecular features that can predict response should be implemented in clinical routine for all GI tumors, and large scale clinical trials to identify predictive biomarkers are needed. This article will address the current use and evidence for immunotherapy in GI malignancies and future trends in this area for clinical practice.
Assuntos
Neoplasias Gastrointestinais/terapia , Imunoterapia/métodos , Receptor de Morte Celular Programada 1 , Neoplasias Gastrointestinais/patologia , Humanos , Fatores Imunológicos , Instabilidade de MicrossatélitesRESUMO
BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.
Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Carcinoma Ductal Pancreático/mortalidade , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Combinação de Medicamentos , Fluoruracila/uso terapêutico , Alemanha/epidemiologia , Humanos , Irinotecano , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante/métodos , Compostos Organometálicos/uso terapêutico , Oxaliplatina , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Adulto Jovem , GencitabinaRESUMO
Regorafenib (BAY 73-4506, Stivarga®) is an oral diphenylurea multi-kinase inhibitor that targets angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-ß, FGFR), and oncogenic receptor tyrosine kinases (KIT, RET, and RAF). Regorafenib is the first small-molecule multi-kinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Consequently, Regorafenib was FDA approved for this indication in 2012. In addition, Regorafenib treatment resulted in a significant improvement in progression-free survival (PFS) compared to placebo in patients with metastatic gastrointestinal stromal tumors (GIST) after progression on standard treatments and is also FDA-approved in this indication since 2013. In 2017, Regorafenib has been FDA approved for the treatment of patients with advanced hepatocellular carcinoma (HCC) previously treated with Sorafenib. In this situation, Regorafenib significantly improved PFS and overall survival (OS) compared to placebo. Regorafenib has also been examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), soft-tissue sarcoma (STS), and additional phase II trials ongoing (e.g., second- and third-line treatment for medullary thyroid cancer, NCT02657551).
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Animais , Humanos , Inibidores de Proteínas Quinases/farmacologiaRESUMO
At ASCO 2017, and subsequently the ESMO congress 2017, a number of studies were presented which, in part, may change the present standard of therapy in gastrointestinal oncology. The German FLOT4 trial established perioperative Docetaxel, Oxaliplatin and 5-Fluorouracil (5-FU) as the new treatment standard for resectable adenocarcinoma of the gastroesophageal junction and the stomach. In hepatocellular carcinoma (HCC), two large studies did not show a survival benefit for selective internal therapy (SIRT), so an increasing use of SIRT in HCC is not recommended. On the other hand, the multityrosinekinase inhibitor Lenvatinib seems to be a promising alternative to sorafenib in first line treatment of metastatic HCC. In early colon cancer-following the data from the large IDEA initiative-three months of capecitabine and oxaliplatin is recommended for low-risk stage III cancers (T1â-â3, N1), while in high-risk stage III cancers (T4 or N2) patients should still receive six months of oxaliplatin and a fluoropyrimidine. Aside from regular exercise, one study found that regular intake of tree nuts (at least 2 servings per week), may decrease the risk of recurrence. In first line metastatic colorectal cancer (mCRC), SIRT should not be applied, whereas in BRAF mutant cancers, the combination of irinotecan, cetuximab and vemurafenib seems to be a promising second line treatment option. In biliary tract cancer, after curative resection, six months of capecitabine is considered the new treatment standard. Finally, in pancreatic cancer, targeting the tumor stroma with pegylated hyaluronidase (PEGPH20) may be a new treatment option that needs to be proven in phase 3 studies.
Assuntos
Neoplasias Gastrointestinais , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Fluoruracila , Neoplasias Gastrointestinais/prevenção & controle , Neoplasias Gastrointestinais/terapia , Humanos , Neoplasias Hepáticas , Oncologia , Recidiva Local de Neoplasia , Estados UnidosRESUMO
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high risk of relapse even after curative-intended resection. There are no evidence-based recommendations for surveillance in actual guidelines. Given this situation and as a basis for prospective studies, we wanted to determine the current practice of surveillance after pancreatic cancer resection in German institutions. Methods A web-based questionnaire was sent in 2015 to 300 German institutions (hospitals, outpatient clinics, and private practices) experienced in the care of patients with PDAC. The questionnaire comprised 23 items including the respective institution, the level of care, the annual case load of pancreatic cancer surgery, the surveillance algorithms used, and the most frequently used means for surveillance as well as their evaluation by the users with respect to the effectiveness of these means. Additionally, we perform a review of the literature. Results The final analysis comprised 161 questionnaires (response rate 53.7â%). Mainly high-volume centers (82.5â% with >â300 hospital beds) participated. In 46.6â% of centers, more than 80â% of patients received adjuvant chemotherapy after surgery. Between 60â-â80â% of these patients completed the recommended 6 months of adjuvant treatment, and 47â% of the patients received the whole treatment (surgery, adjuvant therapy) and surveillance in the same center. Upon completion of adjuvant treatment, 96â% of centers survey their patients, and 82â% of these centers already employ diagnostic means during the course of adjuvant chemotherapy. The most commonly used diagnostic means were taking patient history, conducting physical examination, performing laboratory tests including CA19â-â9, and imaging. Of those employed, CA19â-â9 and imaging followed by patient history were considered the most efficient to detect disease relapse by the centers. Half of the institutions perform surveillance for 5 years after surgery. Conclusion This is the first systematic analysis of self-reported surveillance strategies used in Germany after resection of PDAC with curative intent. Surveillance after resection of PDAC with curative intent is common in Germany. Alterations of CA19â-â9 levels as well as imaging and taking patient history are considered the most efficient means to detect relapse of disease by the physicians participating in our survey.
Assuntos
Recidiva Local de Neoplasia , Neoplasias Pancreáticas , Inquéritos e Questionários , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Alemanha , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia , Vigilância da População , Estudos ProspectivosRESUMO
BACKGROUND: The current study was conducted to examine the activity of a docetaxel/oxaliplatin (DocOx) combination as second line treatment for advanced pancreatic ductal adenocarcinoma (Trial registration: NCT00690300. Registered June 2, 2008) METHODS: DocOx is a prospective, multi-center, single arm, phase II trial using docetaxel (75 mg/m(2), 60 min, d 1) and oxaliplatin (80 mg/m(2), 120 min, d 2) in 21-day cycles. The treatment period was scheduled for up to 8 cycles. Primary endpoint was tumor response according to RECIST 1.0. Secondary endpoints were progression free survival, overall survival, safety/toxicity, quality of life and clinical benefit. RESULTS: Data represent the intention to treat analysis of 44 patients with chemorefractory pancreatic cancer enrolled between 2008 and 2012 at five institutions in Germany. The primary endpoint of tumor response was achieved in 15.9% of the patients (7 partial remissions, no complete remission), with a disease control rate of 48% after the first two treatment cycles. Median progression free survival (PFS) was 1.82 months (CI 95% 1.5-3.96 months) and median overall survival (OS) was 10.1 months (CI 95% 5.1-14.1 months). CONCLUSIONS: This single-arm trial demonstrates that the combination of docetaxel and oxaliplatin yields promising results for the treatment of advanced pancreatic ductal adenocarcinoma patients. Selected patients had particular benefit from this treatment as indicated by long PFS and OS times. Even after 8 cycles of treatment with DocOx a partial response was observed in 2 patients and stable disease was observed in another 6 patients. The data obtained with the DocOx protocol compare well with other second line protocols such as OFF (oxaliplatin, 5-FU, leucovorin). The DocOx regimen could be an interesting option for patients who received gemcitabine as first line treatment for metastatic pancreatic cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Taxoides/administração & dosagem , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma Ductal Pancreático/patologia , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , OxaliplatinaRESUMO
Regorafenib (BAY 73-4506, Stivarga®) is an oral diphenylurea multikinase inhibitor that targets angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-ß, FGFR), and oncogenic receptor tyrosine kinases (KIT, RET, and RAF). Regorafenib is the first small-molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Consequently, regorafenib was FDA approved for this indication. In addition, regorafenib treatment resulted in a significant improvement in progression-free survival (PFS) compared with placebo in patients with metastatic gastrointestinal stromal tumors (GIST) after progression on standard treatments and is also an FDA approved indication. Currently, regorafenib is examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and soft tissue sarcoma (STS).
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Animais , Humanos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
PURPOSE: Sarcopenia is considered a negative prognostic factor in patients with malignant tumors. Among other diagnostic options, computed tomography (CT), which is repeatedly performed on tumor patients, can be of further benefit. The present study aims to establish a framework for classifying the impact of sarcopenia on the prognosis of patients diagnosed with esophageal or gastric cancer. Additionally, it explores the significance of CT radiomics in both diagnostic and prognostic methodologies. MATERIALS AND METHODS: CT scans of 83 patients with esophageal or gastric cancer taken at the time of diagnosis and during a follow-up period of one year were evaluated retrospectively. A total of 330 CT scans were analyzed. Seventy three of these patients received operative tumor resection after neoadjuvant chemotherapy, and 74% of the patients were male. The mean age was 64 years (31-83 years). Three time points (t) were defined as a basis for the statistical analysis in order to structure the course of the disease: t1 = initial diagnosis, t2 = following (neoadjuvant) chemotherapy and t3 = end of the first year after surgery in the "surgery" group or end of the first year after chemotherapy. Sarcopenia was determined using the psoas muscle index (PMI). The additional analysis included the analysis of selected radiomic features of the psoas major, quadratus lumborum, and erector spinae muscles at the L3 level. Disease progression was monitored according to the response evaluation criteria in solid tumors (RECIST 1.1). CT scans and radiomics were used to assess the likelihood of tumor progression and their correlation to sarcopenia. For machine learning, the established algorithms decision tree (DT), K-nearest neighbor (KNN), and random forest (RF) were applied. To evaluate the performance of each model, a 10-fold cross-validation as well as a calculation of Accuracy and Area Under the Curve (AUC) was used. RESULTS: During the observation period of the study, there was a significant decrease in PMI. This was most evident in patients with surgical therapy in the comparison between diagnosis and after both neoadjuvant therapy and surgery (each p < 0.001). Tumor progression (PD) was not observed significantly more often in the patients with sarcopenia compared to those without sarcopenia at any time point (p = 0.277 to p = 0.465). On average, PD occurred after 271.69 ± 104.20 days. The time from initial diagnosis to PD in patients "with sarcopenia" was not significantly shorter than in patients "without sarcopenia" at any of the time points (p = 0.521 to p = 0.817). The CT radiomics of skeletal muscle could predict both sarcopenia and tumor progression, with the best results for the psoas major muscle using the RF algorithm. For the detection of sarcopenia, the Accuracy was 0.90 ± 0.03 and AUC was 0.96 ± 0.02. For the prediction of PD, the Accuracy was 0.88 ± 0.04 and the AUC was 0.93 ± 0.04. CONCLUSIONS: In the present study, the CT radiomics of skeletal muscle together with machine learning correlated with the presence of sarcopenia, and this can additionally assist in predicting disease progression. These features can be classified as promising alternatives to conventional methods, with great potential for further research and future clinical application. However, when sarcopenia was diagnosed with PMI, no significant correlation between sarcopenia and PD could be observed.
RESUMO
INTRODUCTION: S-1 has been shown to be an effective adjuvant treatment option for East Asian patients who underwent gastrectomy for stage II/III gastric cancer. We conducted a phase I/II study to evaluate the feasibility, tolerability, and efficacy of administering S-1 in the adjuvant setting after R0-resection of adenocarcinoma of the stomach and esophagogastric junction (EGJ) in Caucasian patients. METHODS: In this single-cohort, open-label, phase I/II trial, we enrolled patients with locally advanced adenocarcinoma of the stomach or EGJ having undergone R0-resection with or without neoadjuvant treatment. One treatment cycle consisted of oral S-1 (30 mg/m2 bid) for 14 days. Cycles were repeated every 3 weeks for 18 cycles (54 weeks). Primary endpoint was feasibility and tolerability. Safety was evaluated according to the Common Toxicity Criteria Adverse Events (CTCAE) version 4.0. Secondary endpoints were 1-year relapse-free survival (RFS) rate, RFS, and overall survival (OS). RESULTS: Between October 2015 and February 2018, 32 patients were enrolled in 12 German centers, and 30 started adjuvant study treatment. Seventeen patients completed all 18 cycles. Two patients terminated study treatment early due to adverse events (AEs), 7 due to patient's or investigator's decision, and 4 due to recurrence or distant metastasis during adjuvant therapy. Dose levels were reduced to 25 mg/m2 in 9 patients and to 20 mg/m2 in 1 patient. Of patients completing all 18 cycles, 5 did so with reduced dosage of S-1. Documented grade ≥3 AEs were neutropenia, diarrhea, vomiting, polyneuropathy, palmar-plantar erythrodysaesthesia, and rash. Serious AEs were observed in 7 patients. Median RFS was 32.2 months. One-year RFS rate was 77%. Data on OS were still premature at the end of the study. CONCLUSION: Adjuvant treatment with S-1 for 1 year is a feasible and safe treatment option for Caucasian patients diagnosed with gastric adenocarcinoma or cancer of the EGJ after R0-resection.
Assuntos
Adenocarcinoma , Combinação de Medicamentos , Junção Esofagogástrica , Estudos de Viabilidade , Gastrectomia , Ácido Oxônico , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Tegafur/uso terapêutico , Tegafur/administração & dosagem , Masculino , Ácido Oxônico/uso terapêutico , Ácido Oxônico/administração & dosagem , Pessoa de Meia-Idade , Feminino , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Adenocarcinoma/cirurgia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Idoso , Quimioterapia Adjuvante , Adulto , Resultado do Tratamento , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidadeRESUMO
BACKGROUND: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. PATIENTS AND METHODS: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). RESULTS: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. CONCLUSIONS: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Fluoruracila , Leucovorina , Compostos Organoplatínicos , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Masculino , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Adulto , Metástase Neoplásica , Biomarcadores Tumorais/sangueRESUMO
BACKGROUND: A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination. METHODS: ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany. Patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma who had not been previously treated for advanced disease were enrolled. After an induction phase with three cycles of nab-paclitaxel-gemcitabine combination therapy (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients were randomly assigned (1:1) by stratified permuted block randomisation either to continue treatment with standard nab-paclitaxel-gemcitabine or to receive alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone. Patients and investigators were not masked to treatment allocation. Randomisation was done centrally by the study statistician using a computer-generated randomisation list, and was stratified by Karnofsky Performance Status and presence of liver metastases. The primary endpoint was the derivation of an unbiased point estimate and an associated confidence interval with a confidence coefficient of 80% for the hazard ratio (HR) for overall survival after randomisation, without testing a specific hypothesis, analysed by intention to treat in all patients who started randomised treatment. Safety was analysed according to treatment received. This trial is registered with ClinicalTrials.gov, NCT02564146, and is completed. FINDINGS: Between May 27, 2016, and May 27, 2021, 325 patients were enrolled. Following three cycles of induction treatment, 174 patients were randomly assigned: 85 to continue receiving standard nab-paclitaxel-gemcitabine, of whom 79 started treatment, and 89 to the alternating treatment schedule, of whom 88 started treatment. Of the 167 patients who started randomised treatment, 88 (53%) were female and 79 (47%) were male. Median overall survival after randomisation was 10·4 months (80% CI 9·2-12·0) in the group that received standard treatment and 10·5 months (10·2-11·1) in the group that received alternating treatment (HR 0·90, 80% CI 0·72-1·13; p=0·56). The most common adverse events of any grade were peripheral neuropathy (59 [74%] of 80 patients in the continuous treatment group vs 53 [62%] of 85 patients in the alternating treatment group) and fatigue (43 [54%] vs 44 [52%]). Treatment-emergent serious adverse events after randomisation occurred in 40 (50%) patients in the continuous treatment group and in 28 (33%) in the alternating treatment group. Fewer treatment-emergent adverse events of grade 3 or higher occurred in patients treated with alternating cycles compared with those receiving standard therapy, especially for peripheral neuropathy (17 [21%] patients in the continuous treatment group vs 12 [14%] in the alternating treatment group) and infections (16 [20%] vs nine [11%]). There were two treatment-related deaths after randomisation, both in the continuous treatment group (one multiple organ dysfunction syndrome, not treated after randomisation, and one interstitial lung disease). INTERPRETATION: Our findings suggest that a dose-reduced regimen with alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles is associated with similar overall survival to that for standard treatment with nab-paclitaxel-gemcitabine, but with improved tolerability. We therefore propose that a switch to the alternating schedule could be considered in a clinical setting for patients with metastatic pancreatic cancer who have at least stable disease after three cycles of nab-paclitaxel-gemcitabine treatment. FUNDING: Celgene/Bristol Myers Squibb.