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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: Paclitaxel in combination with ramucirumab is the standard of care second-line therapy in gastro-esophageal adenocarcinoma (GEA). As the number of taxane pretreated patients in the perioperative or first-line setting is increasing, it is unknown whether these patients benefit from re-applying a taxane in using the combination of paclitaxel and ramucirumab. Furthermore, the rates of neurotoxicity with first-line FOLFOX or FLOT range from 30%-70%, making second-line taxane-containing therapy less suitable to a meaningful portion of patients. This patient group is likely to benefit from a taxane-free second-line chemotherapy regimen, such as FOLFIRI and ramucirumab (FOLFIRI-Ram). Therefore, the RAMIRIS phase III trial evaluates the effects of the regimen of FOLFIRI-Ram in the second-line treatment after a taxane-based chemotherapy in patients with advanced GEA. METHODS: The RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B). The Phase II is already closed with 111 enrolled patients. In the phase III, 318 taxane-pretreated patients with advanced GEA will be recruited and randomized 1:1 to FOLFIRI (5-FU 2400 mg/m2 over 46 h i.v., irinotecan 180 mg/m2 i.v.; 5-FU 400 mg/m2 bolus; leucovorin 400 mg/m2 i.v.; on day 1 and 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm A) or paclitaxel 80 mg/m2 (days 1, 8, 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm B). The primary endpoints are overall survival (OS) and objective overall response rate (ORR). Secondary endpoints are progression-free survival (PFS), disease control rate and safety and quality of life as assessed by EORTC-QLQ-C30 questionnaire. DISCUSSION: The already completed RAMIRIS phase II demonstrated feasibility and efficacy of FOLFIRI-Ram. Especially docetaxel-pretreated patients seemed to markedly benefit from FOLFIRI-Ram, with favorable response- and PFS rates and lower toxicity. This offers a rationale for the phase III trial. If the RAMIRIS III trial transfers and confirms the results, they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA. TRIAL REGISTRATION: NCT03081143 Date of registration: 13.11.2015.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina , Junção Esofagogástrica/patologia , Fluoruracila , Irinotecano , Leucovorina , Paclitaxel , Qualidade de Vida , Neoplasias Gástricas/patologia , RamucirumabRESUMO
BACKGROUND: Older patients with metastatic pancreatic cancer may suffer increased toxicity from intensive chemotherapy. Treatment individualization by geriatric assessment (GA) might improve functional outcome. METHODS: We performed a multicenter, phase IV, open label trial in patients ≥70 years with metastatic pancreatic adenocarcinoma. Patients underwent GA and were assigned to one of three categories based on their scores: Go-Go, Slow-Go, or Frail. These categories were intended to guide physician's treatment decisions when choosing to treat patients with nab-paclitaxel/gemcitabine (arm A), gemcitabine (arm B), or best supportive care (arm C). Primary objective was a stable (loss of five points or less) Barthel's Activities of Daily Living (ADL) score during chemotherapy; secondary endpoints included GA scores during therapy, safety, quality of life, response and survival rates. RESULTS: Thirty-two patients were enrolled in the trial in six centers in Germany (out of 135 planned), resulting in termination due to low recruitment. Fifteen patients were allocated to nab-paclitaxel/gemcitabine, fifteen to gemcitabine, and two to best supportive care by their physicians, although according to their GA scores 29 patients (91%) were categorized as Slow-Go and three (9%) as Go-Go. Thus, fifteen of 32 (47%) patients were misclassified and given a course of treatment inconsistent with their GA scores. Median progression-free survival (PFS) were 3.3 months and 9.1 months and median time to quality-of-life deterioration 13 days and 29 days in the nab-paclitaxel/gemcitabine and gemcitabine monotherapy arms, respectively. Serious adverse events were reported in 11 (78.6%) patients in the nab-paclitaxel/gemcitabine and 8 (53.3%) patients in the gemcitabine arm. CONCLUSIONS: Clinical evaluations by investigators differed markedly from geriatric assessments, leading to potential overtreatment. In our modest sample size study, those patients undergoing more intensive therapy had a less favorable course.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Atividades Cotidianas , Adenocarcinoma/tratamento farmacológico , Idoso , Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Avaliação Geriátrica , Humanos , Sobretratamento , Paclitaxel , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Neoplasias PancreáticasRESUMO
UNLABELLED: We herein report the case of a male patient with acute myeloid leukemia with fatal outcome attributable to pharmacokinetics of pegfilgrastim. CASE REPORT: An unexplained blast proliferation in a patient with acute myeloid leukemia following cytotoxic induction chemotherapy was investigated in depth. Myeloblast hyperstimulation was likely related to pegfilgrastim, the long half-life of which extended the duration of side-effects, resulting in massive and rapidly fatal leukemia cell proliferation. CONCLUSION: Pegfilgrastim can cause unexpected deleterious effects in acute myeloid leukemia. We, thus, recommend administering drugs with a shorter half-life, such as filgrastim or lenograstim, to reduce infection incidence in patients receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia.
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Crise Blástica/induzido quimicamente , Proliferação de Células/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Evolução Fatal , Filgrastim , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Prognóstico , Proteínas Recombinantes/efeitos adversosRESUMO
Severe prolonged neutropenia, allogeneic hematopoietic stem cell or solid-organ transplantation, corticosteroids or other T cell suppressive agents, and other severe immunosuppressive factors have for many years been considered to predispose patients to invasive aspergillosis. Other conditions such as impaired innate immunity, diabetes, renal impairment, progression of the underlying malignancy, prior respiratory disease, and nosocomial or environmental exposure to fungal spores or climatic factors have recently been considered additional risk factors of invasive aspergillosis. The multiplicity of risk factors as well as the obvious synergy between them renders risk stratification difficult. An international, large-scale, multicenter, epidemiological study is necessary to develop a risk score.
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Aspergilose/tratamento farmacológico , Aspergilose/imunologia , Antifúngicos/uso terapêutico , Aspergilose/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Neutropenia/etiologia , Neutropenia/imunologia , Fatores de RiscoRESUMO
OBJECTIVES: The aim of our study was to assess the adherence to labelling and international guidelines for antifungal prescribing. METHODS: A retrospective study was performed in intensive care units in addition to the oncology and haematology department, which covered 70% of antifungal consumption at Hautepierre Hospital, Strasbourg, France. On reviewing medical charts, the antifungal prescription was examined in relation to the recommendations of indication, dosage, risk of drug-drug interactions and, where appropriate, antifungal susceptibility testing. Treatments were considered appropriate, inappropriate or debatable. RESULTS: Between January and April 2007, 199 treatments were given for 179 different episodes in 133 adult patients. Treatments were prescribed for pre-emptive or targeted therapy (nâ=â90, with 60 for candidiasis, 26 for aspergillosis and 4 for other mould diseases), empirical therapy (nâ=â17) and primary (nâ=â81) or secondary (nâ=â11) prophylaxis. Fluconazole accounted for 67% of prescriptions, followed by voriconazole (19%), caspofungin (10%), posaconazole (2%), conventional or liposomal amphotericin B (2%), itraconazole (<1%) and terbinafine (<1%). Indication and dosage were found to be appropriate in 65% and 62% of cases, inappropriate in 22% and 21%, and debatable in 13% and 17%, respectively. The overall (by combining all assessment criteria) rate of inappropriate use was 40%. The overall survival rate at 12 weeks was highest in patients receiving appropriate therapy (81% versus 72% and 68% in the debatable and inappropriate therapy groups, respectively), with between-group differences not being significant (Pâ=â0.49). CONCLUSIONS: Our evaluation revealed a high proportion of inappropriate or debatable use of antifungal agents, while highlighting significant issues, such as inadequate dosage or indications.
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Antifúngicos/uso terapêutico , Fidelidade a Diretrizes/estatística & dados numéricos , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , França , Neoplasias Hematológicas/complicações , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Serviço Hospitalar de Oncologia , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto JovemRESUMO
Three lipid formulations of amphotericin B have been developed: amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B. These three compounds differ by their lipid composition and therefore by their physical characteristics, their pharmacokinetics, and their safety and efficacy profile. There is a consensus to accept reduced toxicity of these formulations, especially reduced, but not absence of, renal toxicity as compared to amphotericin B deoxycholate. Few well-designed studies have been conducted and none of them demonstrated convincingly superiority in term of efficacy of any of the lipid preparations over amphotericin B deoxycholate. Recently a double blind randomized study compared a standard dose of 3 mg/kg/d of liposomal amphotericin B and a loading dose (10 mg/kg/d for 14 days and then the standard dose) in primary therapy of invasive filamentous fungal infections, mainly aspergillosis. Response rate at end of randomized therapy as well as survival at 12 weeks was numerically superior in the standard dose arm but this difference was not statistically significant. Lack of benefit of high dose liposomal amphotericin B in aspergillosis cannot yet be extrapolated to other filamentous fungal infections. Nephrotoxicity was substantially higher in the loading dose arm and this contraindicates its use in clinical practice.