RESUMO
BACKGROUND: In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response. METHODS: We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 79877428. RESULTS: Median survival of patients allocated to control strategy A was 13.9 months. Median survival of each of the other groups was longer (B-ir 15.0, B-ox 15.2, C-ir 16.7, and C-ox 15.4 months). However, log-rank comparison of each group against control showed that only C-ir--the first-line combination strategy including irinotecan--satisfied the statistical test for superiority (p=0.01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less (HR=1.06, 90% CI 0.97-1.17). INTERPRETATION: Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Prognóstico , Análise de SobrevidaRESUMO
Response evaluation in the assessment of potential new anti-cancer therapies is undergoing intense investigation and change. Current imaging techniques most commonly used in early phase clinical trials are limited to providing reliable and reproducible anatomical data demonstrating a change in size and reduction in tumour volume thereby inferring patient benefit. Current imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) by their nature require computer programs and software. This is a constantly evolving field and upgraded technology enables faster acquisition times for scans, greater anatomical detail and accurate volumetric data to be acquired. Dynamic studies allow contrast agents to be visualised in any given structure over time, so blood flow, blood volume and permeability can be assessed thereby demonstrating function. The advent of many new anti-cancer agents with novel modes of action such as anti-angiogenesis agents act by preventing the development of a suitable blood supply to sustain tumour growth. Such agents do not actively destroy tumour cells so do not exhibit a 'cytocidal' effect as traditional anti-cancer agents do but prevent tumour growth, so can be regarded as 'cytostatic' agents. Therefore, traditional response evaluation criteria may not be appropriate to assess drug efficacy or 'activity' in achieving patient benefit. New techniques have also been developed so the 'function' or metabolism can be demonstrated and tumour serum markers and other factors also require consideration rather than relying on a single modality alone. This article reviews the current accepted response criteria and highlights some newer techniques which will almost certainly play a major role in the assessment of new anti-cancer therapy, particularly in the development of cytostatic agents which are playing an ever increasing role.
Assuntos
Citostáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Desenho de Fármacos , Humanos , Imageamento por Ressonância Magnética , Neoplasias/diagnóstico , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
PURPOSE: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted. RESULTS: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n = 8). Dose-limiting toxicities were observed at 600 mg twice a day (n = 3): G3 rash (n = 2) and G4 γ-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1-2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n = 1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients. CONCLUSIONS: OSI-930 is safe and well tolerated, with pharmacokinetic-pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity.