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Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Retais , Humanos , Prognóstico , Neoplasias Colorretais/patologia , Panitumumabe , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Leucovorina/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
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.
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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
Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases.Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).
Metastatic colorectal cancer (mCRC) is cancer of the colon or rectum that has spread to other parts of the body, most often to the liver, lungs and abdomen. People with mCRC that has worsened after initial treatment have limited options. Zanzalintinib is a novel oral investigational drug that can slow or stop cancer growth. It works by blocking certain proteins that play important roles in the development, growth and spread of cancer. Zanzalintinib may also help improve the effectiveness of another class of cancer drugs called immune checkpoint inhibitors (ICIs), which work by activating the patient's immune system to fight cancer. Here, we describe the design of STELLAR-303, an ongoing study that is comparing the effects of combining zanzalintinib and an ICI drug called atezolizumab with an approved treatment for mCRC called regorafenib. About 900 participants with mCRC will be enrolled in the study worldwide. To be included in the study, participants must have mCRC that worsened after previous therapies and must not have a high level of microsatellite instability, which is a specific feature of some mCRCs. Participants will be randomly given one of the two treatments. The main goal of the study is to evaluate zanzalintinib plus atezolizumab compared with regorafenib by measuring the length of time participants are alive after starting treatment, specifically in patients with mCRC that has not spread to the liver. Additionally, the study will look at the side effects with each treatment. The study is currently seeking participants.
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Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/µL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice.
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Doenças Transmissíveis , Neoplasias Hematológicas , Hematologia , Infecções Fúngicas Invasivas , Humanos , Antifúngicos/uso terapêutico , Citocromo P-450 CYP3A , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/prevenção & controle , Infecções Fúngicas Invasivas/microbiologia , Doenças Transmissíveis/tratamento farmacológico , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Oncologia , Triazóis/uso terapêuticoRESUMO
Chemotherapy-induced nausea and the subsequent vomiting (CINV) are adverse effects of cancer treatment associated with considerable burden for the patient. CINV has a significant negative impact on quality of life. The consequent loss of fluids and electrolytes can lead to impaired renal function or weight loss, which may lead to hospitalization. If CINV later results in anticipatory vomiting, this complicates both CINV prophylaxis and further chemotherapy, which can endanger the continuation of cancer treatment. The introduction of high-dose dexamethasone as well as 5HT3 and NK1 receptor antagonists has led to a significant improvement of CINV prophylaxis since the 1990s. Recommendations on CINV prophylaxis are in available in guidelines. Adherence to these guidelines results in better outcomes.
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Antieméticos , Antineoplásicos , Neoplasias , Humanos , Antieméticos/efeitos adversos , Qualidade de Vida , Vômito/induzido quimicamente , Vômito/prevenção & controle , Vômito/tratamento farmacológico , Náusea/induzido quimicamente , Náusea/prevenção & controle , Náusea/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Voriconazole has been recommended as primary treatment for patients with invasive aspergillosis. Intravenous and tablet formulations of posaconazole that have improved systemic absorption could be an effective alternative to voriconazole. We aimed to assess non-inferiority of posaconazole to voriconazole for the primary treatment of invasive aspergillosis. METHODS: We did a randomised, prospective, double-blind, double-dummy, controlled trial comparing posaconazole (intravenous or oral posaconazole 300 mg twice on day 1, followed by 300 mg once a day for days 2-84) with voriconazole (6 mg/kg intravenous or 300 mg oral twice on day 1 followed by 4 mg/kg intravenously or 200 mg orally twice a day for days 2-84) for 12 weeks or less in the primary treatment of invasive aspergillosis. Participants were from 91 study sites in 26 countries, were aged 13 years or older, weighed at least 40 kg, and met criteria for proven, probable, or possible fungal disease. Participants were randomly assigned (1:1) via a computer-generated randomisation schedule with stratification by risk status. The primary endpoint was cumulative all-cause mortality up until day 42 in the intention-to-treat (ITT) population (defined as randomly assigned participants who received ≥1 dose of study drug), with a 10% non-inferiority margin. The ITT population was also evaluated for safety. This study is registered with ClinicalTrials.gov, NCT01782131, and EudraCT, 2011-003938-14. FINDINGS: Between Oct 25, 2013, and Sept 10, 2019, of 653 individuals assessed for eligibility, 575 ITT participants were randomly assigned and received one or more doses of study drug (n=288 [50%] posaconazole, n=287 [50%] voriconazole). Mortality up until day 42 was 15% (44 of 288) in the posaconazole group and 21% (59 of 287) in the voriconazole group (treatment difference -5·3% [95% CI -11·6 to 1·0]; p<0·0001). Mortality up until day 42 in the full-analysis-set subpopulation (ITT participants with proven or probable invasive aspergillosis) supported this conclusion: 31 (19%) of 163 participants in the posaconazole group and 32 (19%) of 171 participants in the voriconazole group (treatment difference 0·3% [95% CI -8·2 to 8·8]). The most frequently reported treatment-related adverse events (incidence >3%) were increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT), nausea, hypokalaemia, and vomiting in the posaconazole group and increased ALT, AST, or alkaline phosphatase, hallucination, increased γ-glutamyltransferase peptidase, nausea, and blurred vision in the voriconazole group. The overall incidence of treatment-related adverse event rates in the ITT population was 30% for posaconazole and 40% for voriconazole (treatment difference -10·2% [95% CI -17·9 to -2·4]). INTERPRETATION: Posaconazole was non-inferior to voriconazole for all-cause mortality up until day 42 in participants with invasive aspergillosis. Posaconazole was well tolerated, and participants had fewer treatment-related adverse events than in the voriconazole group. This study supports the use of posaconazole as a first-line treatment for the condition. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.
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Antifúngicos/administração & dosagem , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Triazóis/administração & dosagem , Voriconazol/administração & dosagem , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Antifúngicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Aspergilose Pulmonar Invasiva/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Triazóis/efeitos adversos , Voriconazol/efeitos adversos , Adulto JovemRESUMO
The aim of the study was to investigate the predictive impact of extracranial metastatic patterns on course of disease and survival in patients with colorectal cancer (CRC) and brain metastasis (BM). A total of 228 patients (134 male [59%], 94 female [41%]) with histologically proven CRC and BM were classified into different groups according to extracranial metastatic patterns. Time intervals to metastatic events and survival times from initial CRC diagnosis, extracranial and intracranial metastasis were analyzed. Extracranial organs mostly affected were liver (102 of 228 [44.7%]) and lung (96 of 228 [42.1%]). Liver and lung metastases were detected in 31 patients (13.6%). Calculated over the entire course of disease, patients with lung metastasis showed longer overall survival (OS) than patients with liver metastasis or patients without lung metastasis (43.9 vs 34.6 [P = .002] vs 35.0 months [P = .002]). From the date of initial CRC diagnosis, lung metastasis occurred later in CRC history than liver metastasis (24.3 vs 7.5 months). Once lung metastasis was diagnosed, BM occurred faster than in patients with liver metastasis (15.8 vs 26.0 months; Δ 10.2 months). Accordingly, OS from the diagnosis of liver metastasis was longer than from lung metastasis (27.1 vs 19.6 months [P = .08]). Once BM was present, patients with lung metastasis lived longer than patients with liver metastasis (3.8 vs 1.1 months [P = .028]). Shortest survival times in all survival categories analyzed revealed patients with concurrent liver and lung metastasis. Patients with CRC and BM form a heterogeneous cohort where extracranial metastasis to liver or lungs predicts survival.
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Neoplasias Encefálicas/secundário , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Neoplasias Encefálicas/diagnóstico , Estudos de Coortes , Neoplasias Colorretais/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Masculino , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico , Fatores de TempoRESUMO
To ensure the safety of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT), evidence-based recommendations on infectious complications after HDC/ASCT are given. This guideline not only focuses on patients with haematological malignancies but also addresses the specifics of HDC/ASCT patients with solid tumours or autoimmune disorders. In addition to HBV and HCV, HEV screening is nowadays mandatory prior to ASCT. For patients with HBs antigen and/or anti-HBc antibody positivity, HBV nucleic acid testing is strongly recommended for 6 months after HDC/ASCT or for the duration of a respective maintenance therapy. Prevention of VZV reactivation by vaccination is strongly recommended. Cotrimoxazole for the prevention of Pneumocystis jirovecii is supported. Invasive fungal diseases are less frequent after HDC/ASCT, therefore, primary systemic antifungal prophylaxis is not recommended. Data do not support a benefit of protective room ventilation e.g. HEPA filtration. Thus, AGIHO only supports this technique with marginal strength. Fluoroquinolone prophylaxis is recommended to prevent bacterial infections, although a survival advantage has not been demonstrated.
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Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Hepacivirus/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/prevenção & controle , Hepatite C/prevenção & controle , Pneumocystis carinii/metabolismo , Pneumonia por Pneumocystis/prevenção & controle , Alemanha , Hematologia , Hepatite B/sangue , Anticorpos Anti-Hepatite B/sangue , Hepatite C/sangue , Humanos , Oncologia , Pneumonia por Pneumocystis/sangue , Guias de Prática Clínica como Assunto , RNA Viral/sangue , Sociedades Médicas , Transplante Autólogo , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter-related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients.
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Infecções Relacionadas a Cateter/diagnóstico , Infecções Relacionadas a Cateter/terapia , Hematologia/normas , Oncologia/normas , Guias de Prática Clínica como Assunto/normas , Sociedades Médicas/normas , Infecções Relacionadas a Cateter/epidemiologia , Cateteres Venosos Centrais/normas , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/terapia , Gerenciamento Clínico , Alemanha/epidemiologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , HumanosRESUMO
Aim: To determine quality of life, effectiveness and safety of oral netupitant-palonosetron (NEPA)-based antiemetic prophylaxis in the real-world setting. Materials & methods: Prospective, noninterventional study in adults receiving highly or moderately emetogenic chemotherapy and NEPA for three cycles. NEPA was administered per summary of product characteristics. Results: A total of 2429 patients enrolled, 2173 were evaluable. 'No impact on daily life' due to vomiting was reported by 85%/82% of patients in the highly emetogenic chemotherapy/moderately emetogenic chemotherapy groups in cycle 1, with rates of 54%/59% for nausea. Overall, complete response rate was 89%/87%/83% in the acute/delayed/overall phases. NEPA was well tolerated. Conclusion: NEPA had beneficial effects on the quality of life of a heterogeneous group of cancer patients and was safe and effective in the real-world setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Náusea/etiologia , Náusea/prevenção & controle , Palonossetrom/uso terapêutico , Piridinas/uso terapêutico , Vômito/etiologia , Vômito/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Palonossetrom/administração & dosagem , Palonossetrom/efeitos adversos , Estudos Prospectivos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient's risk factors (eg length and depth of granulocytopenia) and the expected side effects. OBJECTIVES: Since the last edition of recommendations for 'Treatment of invasive fungal infections in cancer patients' of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possible invasive fungal diseases (IFDs) towards pre-emptive therapy of probable IFD. METHODS: The guideline was prepared by German clinical experts for infections in cancer patients in a stepwise consensus process. MEDLINE was systematically searched for English-language publications from January 1975 up to September 2019 using the key terms such as 'invasive fungal infection' and/or 'invasive fungal disease' and at least one of the following: antifungal agents, cancer, haematological malignancy, antifungal therapy, neutropenia, granulocytopenia, mycoses, aspergillosis, candidosis and mucormycosis. RESULTS: AFT of IFDs in cancer patients may include not only antifungal agents but also non-pharmacologic treatment. In addition, the armamentarium of antifungals for treatment of IFDs has been broadened (eg licensing of isavuconazole). Additional antifungals are currently under investigation or in clinical trials. CONCLUSIONS: Here, updated recommendations for the treatment of proven or probable IFDs are given. All recommendations including the levels of evidence are summarised in tables to give the reader rapid access to key information.
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Antifúngicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Hematologia/organização & administração , Infecções Fúngicas Invasivas/tratamento farmacológico , Neoplasias/complicações , Guias de Prática Clínica como Assunto , Agranulocitose/complicações , Agranulocitose/microbiologia , Neoplasias Hematológicas/complicações , Hematologia/métodos , Humanos , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/etiologia , Neoplasias/microbiologiaRESUMO
BACKGROUND: Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016. METHODS: We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting. RESULTS: In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population. CONCLUSION: The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals.
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Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Timina/efeitos adversos , Timina/uso terapêutico , Trifluridina/efeitos adversos , Trifluridina/uso terapêutico , Idoso , Ensaios de Uso Compassivo/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Invasive fungal diseases (IFD) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non-Aspergillus moulds are increasingly identified in case of documented IFD. For definite diagnosis of IFD, a combination of diagnostic tools have to be applied, including conventional mycological culture and non-conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFDs with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions.
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Infecções Fúngicas Invasivas/diagnóstico , Antifúngicos/uso terapêutico , Fungos/genética , Fungos/isolamento & purificação , Fungos/fisiologia , Alemanha , Hematologia , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Oncologia , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. METHODS: This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. FINDINGS: 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). INTERPRETATION: Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.
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Antifúngicos/uso terapêutico , Micoses/tratamento farmacológico , Nitrilas/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Voriconazol/uso terapêutico , Administração Oral , Adulto , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Aspergilose/tratamento farmacológico , Aspergilose/mortalidade , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Micoses/mortalidade , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Voriconazol/administração & dosagem , Voriconazol/efeitos adversosRESUMO
PURPOSE: To report planned final overall (OS) and progression-free survival (PFS) analyses from the phase II PEAK trial (NCT00819780). METHODS: Patients with previously untreated, KRAS exon 2 wild-type (WT) metastatic colorectal cancer (mCRC) were randomised to mFOLFOX6 plus panitumumab or bevacizumab. The primary endpoint was PFS; secondary endpoints included OS, objective response rate, duration of response (DoR), time to response, resection and safety. Treatment effect by tumour RAS status was a prespecified objective. Exploratory analyses included early tumour shrinkage (ETS) and depth of response (DpR). RESULTS: One hundred seventy patients had RAS WT and 156 had RAS WT/BRAF WT mCRC. Median PFS was longer for panitumumab versus bevacizumab in the RAS WT (12.8 vs 10.1 months; hazard ratio (HR) = 0.68 [95% confidence intervals (CI) = 0.48-0.96]; p = 0.029) and RAS WT/BRAF WT (13.1 vs 10.1 months; HR = 0.61 [95% CI = 0.42-0.88]; p = 0.0075) populations. Median OS (68% OS events) for panitumumab versus bevacizumab was 36.9 versus 28.9 months (HR = 0.76 [95% CI = 0.53-1.11]; p = 0.15) and 41.3 versus 28.9 months (HR = 0.70 [95% CI = 0.48-1.04]; p = 0.08), in the RAS WT and RAS WT/BRAF WT populations, respectively. Median DoR (11.4 vs 9.0 months; HR = 0.59 [95% CI = 0.39-0.88]; p = 0.011) and DpR (65.0 vs 46.3%; p = 0.0018) were improved in the panitumumab group. More panitumumab patients experienced ≥30% ETS at week 8 (64 vs 45%; p = 0.052); ETS was associated with improved PFS/OS. No new safety signals occurred. CONCLUSIONS: First-line panitumumab + mFOLFOX6 increases PFS versus bevacizumab + mFOLFOX6 in patients with RAS WT mCRC.
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Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Demografia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Panitumumabe , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Antiemetic guidelines recommend co-administration of targeted prophylactic medications inhibiting molecular pathways involved in emesis. NEPA is a fixed oral combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3 RA. NEPA showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with oral PALO in a single chemotherapy cycle; maintenance of efficacy/safety over continuing cycles is the objective of this study. METHODS: This study is a multinational, double-blind study comparing a single oral dose of NEPA vs oral PALO in chemotherapy-naïve patients receiving anthracycline/cyclophosphamide-based chemotherapy along with dexamethasone 12 mg (NEPA) or 20 mg (PALO) on day 1. The primary efficacy endpoint was delayed (25-120 h) complete response (CR: no emesis, no rescue medication) in cycle 1. Sustained efficacy was evaluated during the multicycle extension by calculating the proportion of patients with overall (0-120 h) CR in cycles 2-4 and by assessing the probability of sustained CR over multiple cycles. RESULTS: Of 1455 patients randomized, 1286 (88 %) participated in the multiple-cycle extension for a total of 5969 cycles; 76 % completed ≥4 cycles. The proportion of patients with an overall CR was significantly greater for NEPA than oral PALO for cycles 1-4 (74.3 vs 66.6 %, 80.3 vs 66.7 %, 83.8 vs 70.3 %, and 83.8 vs 74.6 %, respectively; p ≤ 0.001 each cycle). The cumulative percentage of patients with a sustained CR over all 4 cycles was also greater for NEPA (p < 0.0001). NEPA was well tolerated over cycles. CONCLUSIONS: NEPA, a convenient, guideline-consistent, fixed antiemetic combination is effective and safe over multiple cycles of chemotherapy.
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Antieméticos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Isoquinolinas/administração & dosagem , Náusea/tratamento farmacológico , Piridinas/administração & dosagem , Quinuclidinas/administração & dosagem , Vômito/tratamento farmacológico , Adulto , Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/tratamento farmacológico , Palonossetrom , Vômito/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC). METHODS: 154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression. RESULTS: Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease. Median response duration was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) (hazard ratio (HR): 0.16). Median progression-free survival was longer in RAS WT vs MT (11.2 vs 7.3 months; HR, 0.37) and was also longer in RAS WT/BRAF WT vs RAS or BRAF MT (13.2 vs 6.9 months; HR, 0.25). Incidence of adverse events was similar regardless of RAS/BRAF status, and no new safety signals were noted. Among patients with RAS WT tumours, ORR was 67% with high AREG expression and 38% with low AREG expression. CONCLUSIONS: First-line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas ras/genética , Anfirregulina/genética , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/metabolismo , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Ensaios Clínicos Fase II como Assunto , Intervalo Livre de Doença , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Panitumumabe , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
Invasive aspergillosis (IA) is a life-threatening complication in hematological cancer patients. Voriconazole (VCZ) is the established first-line treatment of IA. VCZ has a nonlinear pharmacokinetic profile and exhibits considerable variability of drug exposure. Therefore, therapeutic drug monitoring (TDM) of VCZ may help to improve treatment results in IA patients, but evidence-based data on the clinical use of TDM in patients treated with VCZ for IA are scarce. Evidence-based guidance is needed to support decisions on the use of TDM in routine VCZ therapy of IA. Our present analysis assessed published studies for evidence-based criteria for TDM of VCZ to improve efficacy and safety of IA therapy in cancer patients. Literature searches of MEDLINE and Cochrane database were performed. We identified 27 clinical studies reporting on the use of plasma level monitoring and/or TDM for VCZ. For each study, strength of recommendation and quality of evidence were categorized according to predefined criteria. A number of studies were published on plasma level monitoring (PLM) and TDM in VCZ therapy of IA. Across studies, VCZ levels >5-5.5 mg/L were found to be associated with toxicity, while reaching minimum levels of >1-2 mg/L appeared to improve efficacy. Timing, frequency, and intervention thresholds and dosage increments of VCZ for adjustment of plasma levels remain to be established. Currently, there is still no conclusive evidence for recommendations in routine clinical practice. More data from prospective randomized studies with TDM are desirable to provide a solid evidence basis for these approaches.
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Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Voriconazol/uso terapêutico , Aspergilose/complicações , Aspergilose/epidemiologia , Prática Clínica Baseada em Evidências , Humanos , Neoplasias/complicações , Neoplasias/epidemiologiaRESUMO
Current guidelines recommend the combination of a neurokinin-1 (NK1) receptor antagonist (RA) and a 5-hydroxytryptamine-3 (5-HT3) RA, together with corticosteroids, in order to prevent chemotherapy-induced nausea and vomiting with anthracycline-cyclophosphamide and highly emetogenic chemotherapy, and it is to be considered with moderately emetogenic chemotherapy. Netupitant and palonosetron (NEPA) is a fixed-dose combination of netupitant, a novel, highly selective NK1 RA, and palonosetron, a new-generation 5-HT3 RA, targeting two major emetic pathways in a single oral capsule. In clinical trials, NEPA administered on day 1 together with dexamethasone was highly effective and well tolerated in the prevention of chemotherapy-induced nausea and vomiting in patients with solid tumors undergoing moderately emetogenic chemotherapy or highly emetogenic chemotherapy. NEPA offers maximal convenience, and as a simple guideline-based regimen, has the potential to improve adherence to guidelines.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Isoquinolinas/administração & dosagem , Náusea/tratamento farmacológico , Náusea/etiologia , Neoplasias/complicações , Piridinas/administração & dosagem , Quinuclidinas/administração & dosagem , Vômito/tratamento farmacológico , Vômito/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Isoquinolinas/efeitos adversos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Neoplasias/tratamento farmacológico , Palonossetrom , Piridinas/efeitos adversos , Piridinas/química , Piridinas/farmacocinética , Quinuclidinas/efeitos adversos , Quinuclidinas/química , Quinuclidinas/farmacocinética , Antagonistas do Receptor 5-HT3 de Serotonina , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinética , Resultado do TratamentoRESUMO
PURPOSE: This study aims to compare the efficacy and safety of oral palonosetron with intravenous (IV) palonosetron for the prevention of cisplatin-related chemotherapy-induced nausea and vomiting (CINV). METHODS: A multinational, randomized, double-blind study enrolling adult chemotherapy-naive patients with malignant solid tumors scheduled to receive cisplatin-based highly emetogenic chemotherapy (HEC). Patients received oral palonosetron (0.50 mg) or IV palonosetron (0.25 mg), each with oral dexamethasone. The primary objective was to demonstrate non-inferiority in terms of patients with a complete response (CR, no emesis/no rescue medication) within the acute phase (0-24 h after chemotherapy administration). RESULTS: Of the 743 patients randomized, 739 received study medications and 738 were included in the full analysis set. The CR rate in the acute phase was high for both groups (oral 89.4 %; IV 86.2 %). As this difference in proportions (stratum-adjusted Cochran-Mantel-Haenszel method) was 3.21 % (99 % confidence interval (CI) -2.74 to 9.17 %), non-inferiority was demonstrated (since the lower limit of the 99 % CI was closer to zero than the predefined margin of 15 %). Treatment-emergent adverse events (TEAEs) related to the study drug were rare (oral 3.2 %; IV 6.5 %). No TEAEs related to study drug leading to discontinuation were reported. CONCLUSION: Non-inferiority of oral versus IV palonosetron was demonstrated. The CR rate in the acute phase was >86 % in both patient groups. The safety profiles were comparable.