RESUMO
BACKGROUND: Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. METHODS: Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. RESULTS: Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. CONCLUSION: One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.
Assuntos
Ensaios Clínicos Fase III como Assunto , Terapias Complementares , Metástase Neoplásica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Terapias Complementares/efeitos adversos , Terapias Complementares/estatística & dados numéricos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metástase Neoplásica/terapia , Qualidade de Vida , Estudos RetrospectivosRESUMO
PURPOSE: This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition of concurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Eligible patients with stage III-IVB nonkeratinizing NPC were randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100 mg/m2) concurrent with RT, followed by 3 cycles of cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/day for 4 days). All of the patients were irradiated with conventional fractionation to ≥66 Gy. The median follow-up was 13.9 years. RESULTS: Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P = .016), progression-free survival rate (PFS: 56% vs 44%, P = .008), and overall survival rate (OS: 60% vs 50%, P = .044). There was no significant increase in overall late toxicity rate (51% vs 48%, P = .34) or noncancer deaths (19% vs 16%, P = .52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrent cycles had a significant increase in hearing impairment (40% vs 24%, P = .017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P = .037) and maximal survival gain. CONCLUSION: The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase in hearing impairment. This is a useful hypothesis that warrants further validation.
Assuntos
Quimiorradioterapia Adjuvante/métodos , Quimiorradioterapia/métodos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adolescente , Adulto , Idoso , Cisplatino/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the long-term therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P = .01) and progression-free survival rates (56% vs 42%; P = .006) because of superior locoregional control (87% vs 74%; P = .003), whereas the impact on distant control remained insignificant (68% vs 65%; P = .24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P = .20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P = .047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123:4147-4157. © 2017 American Cancer Society.
Assuntos
Carcinoma/mortalidade , Carcinoma/terapia , Quimiorradioterapia Adjuvante/mortalidade , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/patologia , Quimiorradioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/mortalidade , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Fluoruracila/administração & dosagem , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Radioterapia/efeitos adversos , Fatores de TempoRESUMO
PURPOSE: Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy. METHODS AND MATERIALS: Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m2/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m2) during weeks 1, 3, 5, and 7, and an additional week 9 dose in the final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2. RESULTS: Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m2 cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks. CONCLUSION: Cisplatin can be safely delivered with 5-FU-based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.
Assuntos
Antineoplásicos/administração & dosagem , Quimiorradioterapia Adjuvante/métodos , Cisplatino/administração & dosagem , Fluoruracila/administração & dosagem , Radiossensibilizantes/administração & dosagem , Radioterapia Guiada por Imagem , Neoplasias Gástricas/terapia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Qualidade de Vida , Radiossensibilizantes/efeitos adversos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgiaRESUMO
Epidermal growth factor receptor (EGFR) is over-expressed in nearly all cases of squamous cell carcinoma of the head and neck (SCCHN), and is an important driver of disease progression. EGFR targeted therapies have demonstrated clinical benefit for SCCHN treatment. In this report, we investigated the pre-clinical efficacy of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, both alone and in combination with ionizing radiation (IR), a primary curative modality for SCCHN. One normal oral epithelial (NOE) and three SCCHN (FaDu, UT-SCC-8, UT-SCC-42a) cell lines were used to conduct cell viability, clonogenic survival, cell cycle, and immunoblotting assays in vitro, using increasing doses of Dacomitinib (10-500 nM), both with and without IR (2-4 Gy). The FaDu xenograft model was utilized for tumor growth delay assays in vivo, and immunohistochemical analyses were conducted on extracted tumors. A dose-dependent reduction in cell viability and clonogenic survival after Dacomitinib treatment was observed in all three SCCHN models. Treatment led to a significant reduction in EGFR signalling, with a subsequent decrease in phosphorylation of downstream targets such as ERK, AKT, and mTOR. In vivo, Dacomitinib treatment delayed tumor growth, while decreasing phospho-EGFR and Ki-67 immunoexpression. These effects were further enhanced when combined with IR, both in vitro and in vivo. The preclinical data support the further evaluations of Dacomitinib combined with IR for the future management of patients with SCCHN.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Quinazolinonas/uso terapêutico , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Avaliação Pré-Clínica de Medicamentos , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Quinazolinonas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) was conventional-fractionation radiotherapy plus concurrent-adjuvant chemotherapy as recommended by the Intergroup-0099 Study. This combined analysis of the NPC-9901 and the NPC-9902 Trials aims to provide more comprehensive data to evaluate the efficacy of the Intergroup-0099 regimen and the contributing factors. METHODS: Eligible patients with stage III-IVB non-keratinizing NPC were randomly assigned to radiotherapy-alone (RT(i) group: 218 patients) or chemoradiotherapy (CRT(i) group: 223 patients) using cisplatin (100mg/m(2)) for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg/m(2)/day for 4 days) for three cycles. The median follow-up was 6.1 years. FINDINGS: Comparison by intention-to-treat showed that the CRT(i) group achieved significant improvement in overall failure-free rate (FFR), locoregional-FFR and cancer-specific survival (p ≤ 0.019); but the improvements for distant-FFR and overall survival (OS) were statistically insignificant (p ≥ 0.14). Further exploratory studies based on actual treatment showed that an additional improvement achieved was a significant gain in OS (CRT(a) versus RT(a) group: 72% versus 63% at 5-year, p=0.037). Multivariate analyses showed that the dose of cisplatin during the concurrent phase had significant impact on locoregional-FFR and OS, while that of fluorouracil during the adjuvant phase was significant for distant-FFR. The 5-year locoregional-FFR for patients who received 0-1, 2 and 3 concurrent cycles were 79%, 88% and 88%, respectively; the corresponding distant-FFR by adjuvant cycles were 68%, 78% and 77%, respectively. INTERPRETATION: Our results support the current practice of adding concurrent cisplatin plus adjuvant cisplatin-fluorouracil to radiotherapy for treating patients with locoregionally advanced NPC. The concurrent phase is important for locoregional control and survival, cisplatin 200mg/m(2) in two concurrent cycles might be adequate. Additional chemotherapy using fluorouracil-containing combination contributed to improving distant control.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adolescente , Adulto , Idoso , Carcinoma , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: To evaluate the therapeutic benefits by adding chemotherapy (+C) and/or accelerated-fractionation (AF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma. MATERIALS AND METHODS: From 1999 to 2004, 189 eligible patients were randomized to one of four treatment groups (CF/CF+C/AF/AF+C). The number of fractions/week was 5 for the CF groups and 6 for the AF groups. Patients in the +C groups were given concurrent cisplatin plus adjuvant cisplatin and fluorouracil. RESULTS: The AF+C group achieved significantly higher failure-free rate (88% at 5-year) than the CF group (63%; p=0.013), the AF group (56%; p=0.001) and the CF+C group (65%; p=0.027). As compared with CF alone, the increase in late toxicity was statistically insignificant (36% vs. 20%; p=0.25). Deaths due to cancer progression decreased (7% vs. 33%; p=0.011) but deaths due to incidental causes increased (9% vs. 2%; p=0.62). Improvement in overall survival reached borderline significance (85% vs. 66%; p=0.058). CONCLUSIONS: Concurrent-adjuvant chemotherapy combined with AF significantly reduced failure and cancer-specific deaths. Although the increase in major late toxicity and incidental deaths were statistically insignificant, a subtle increase in non-cancer deaths narrowed the overall survival gain.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fracionamento da Dose de Radiação , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Estadiamento de Neoplasias , Cooperação do PacienteRESUMO
Molecular-targeted agents are increasingly used for the treatment of cancer. However, the attrition rate for drugs that enter early clinical trials is higher than for other branches of internal medicine, suggesting that preclinical development has not been successful in identifying agents that can modify the outcome of human cancer. New preclinical strategies including genetically engineered mouse models and small-interfering RNAs are being used to evaluate novel agents, and have aided in the development of compounds, such as inhibitors of phosphatidylinositol 3-kinase or poly(ADP-ribose) polymerase. In addition, these techniques have helped in the identification of promising combinations of targeted drugs. In this Review, we describe methods for the preclinical evaluation of novel agents, their limitations, and strategies for improvement.
Assuntos
Antineoplásicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/normas , Avaliação Pré-Clínica de Medicamentos/tendências , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/classificação , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Camundongos , Proteínas de Neoplasias/metabolismoRESUMO
BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/patologia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Hong Kong/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Estadiamento de Neoplasias , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Razão de Chances , Radioterapia Adjuvante , Suicídio/estatística & dados numéricos , Resultado do TratamentoRESUMO
The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography-computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1-10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of >or=4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Biomarcadores Farmacológicos/análise , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Quinazolinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/farmacocinética , Biomarcadores Farmacológicos/metabolismo , Estudos de Coortes , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Piridinas/farmacocinética , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Sorafenibe , Resultado do TratamentoRESUMO
Investigation and utilization of molecularly targeted agents has induced a number of drug adverse effects that are not typically associated with conventional chemotherapy. QT interval prolongation, a cardiac toxicity that increases the risk of fatal arrhythmia, is associated with several novel oncology therapies. Classes of molecularly targeted agents with described QT effects include histone deacetylase inhibitors, multitargeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. Concurrently, guidelines for monitoring the QT-prolonging effects of drugs under development have become increasingly rigorous. Although these guidelines apply to anticancer agents, they were not specifically designed for the oncology patient population. This article will review the pathophysiology of QT prolongation, methods of preclinical QT assessment, and current guidelines for QT evaluation in early phase trials. Additionally, molecularly targeted agents with QT effects will be summarized, and mechanisms of addressing this toxicity in the context of oncology drug development will be explored.
Assuntos
Antineoplásicos/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Animais , Ensaios Clínicos Fase I como Assunto/normas , Ensaios Clínicos Fase II como Assunto/normas , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Eletrocardiografia , Humanos , Síndrome do QT Longo/fisiopatologia , Guias de Prática Clínica como Assunto , Vigilância de Produtos Comercializados , Fatores de Risco , Estados Unidos , United States Food and Drug AdministrationRESUMO
PURPOSE: To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had Assuntos
Antineoplásicos/uso terapêutico
, Benzenossulfonatos/uso terapêutico
, Carcinoma de Células Escamosas/tratamento farmacológico
, Neoplasias de Cabeça e Pescoço/tratamento farmacológico
, Neoplasias Nasofaríngeas/tratamento farmacológico
, Piridinas/uso terapêutico
, Adulto
, Idoso
, Carcinoma de Células Escamosas/mortalidade
, Carcinoma de Células Escamosas/secundário
, Progressão da Doença
, Intervalo Livre de Doença
, Feminino
, Neoplasias de Cabeça e Pescoço/mortalidade
, Neoplasias de Cabeça e Pescoço/patologia
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Neoplasias Nasofaríngeas/mortalidade
, Neoplasias Nasofaríngeas/patologia
, Recidiva Local de Neoplasia
, Niacinamida/análogos & derivados
, Compostos de Fenilureia
, Inibidores de Proteínas Quinases/uso terapêutico
, Sorafenibe
, Taxa de Sobrevida
, Quinases raf/antagonistas & inibidores
RESUMO
PURPOSE: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. EXPERIMENTAL DESIGN: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. RESULTS: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. CONCLUSIONS: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Quinazolinas/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/farmacocinética , Receptores ErbB/fisiologia , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Piridinas/farmacocinética , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , SorafenibeRESUMO
PURPOSE: To compare the benefit achieved by concurrent chemoradiotherapy (CRT) and/or accelerated fractionation (AF) vs. radiotherapy (RT) alone with conventional fractionation (CF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All patients were irradiated with the same RT technique to > or =66 Gy at 2 Gy per fraction, conventional five fractions/week in the CF and CF+C (chemotherapy) arms, and accelerated six fractions/week in the AF and AF+C arms. The CF+C and AF+C patients were given the Intergroup 0099 regimen (concurrent cisplatin plus adjuvant cisplatin and 5-fluorouracil). RESULTS: Between 1999 and April 2004, 189 patients were randomly assigned; the trial was terminated early because of slow accrual. The median follow-up was 2.9 years. When compared with the CF arm, significant improvement in failure-free survival (FFS) was achieved by the AF+C arm (94% vs. 70% at 3 years, p = 0.008), but both the AF arm and the CF+C arm were insignificant (p > or = 0.38). Multivariate analyses showed that CRT was a significant factor: hazard ratio (HR) = 0.52 (0.28-0.97), AF per se was insignificant: HR = 0.68 (0.37-1.25); the interaction of CRT by AF was strongly significant (p = 0.006). Both CRT arms had significant increase in acute toxicities (p < 0.005), and the AF+C arm also incurred borderline increase in late toxicities (34% vs. 14% at 3 years, p = 0.05). CONCLUSIONS: Preliminary results suggest that concurrent chemoradiotherapy with accelerated fractionation could significantly improve tumor control when compared with conventional RT alone; further confirmation of therapeutic ratio is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adulto , Idoso , Carcinoma/patologia , Cisplatino/administração & dosagem , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Fracionamento da Dose de Radiação , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: The Intergroup 0116 study showed a survival benefit with adjuvant chemoradiotherapy (CRT) for resected gastric cancer. We report our experience using conformal radiotherapy (RT). METHODS AND MATERIALS: Eighty-two patients with resected gastric or gastroesophageal junction (GEJ) adenocarcinoma, Stage IB to IV (M0), were treated with 45 Gy in 25 fractions using a 5-field conformal technique. Chemotherapy was in accordance with the Intergroup 0116 study, or infusional 5-fluorouracil and cisplatin in a phase I/II trial. RESULTS: Mean age was 56.4 years. Median follow-up was 22.8 months. Grade 3 or greater acute toxicity (National Cancer Institute Common Terminology Criteria of Adverse Events, version 3.0) was noted in 57% of patients (upper gastrointestinal tract 34%, hematologic 33%). One patient died of neutropenic sepsis. Radiation Therapy Oncology Group Grade 3 late toxicity included esophageal strictures (3 patients) and small bowel obstruction (1 patient). Full course CRT was completed by 67% of patients. Of 26 patients who relapsed, 20 died. Site of first relapse was available on 23 patients: 8 locoregional and distant, 4 locoregional alone, 11 distant alone. Overall and relapse-free survival were 69% and 54% at 3 years. CONCLUSION: Adjuvant CRT for gastric cancer, even with conformal RT, is associated with significant toxicity. Survival was comparable to that reported in the Intergroup 0116 study.
Assuntos
Adenocarcinoma/radioterapia , Radioterapia Conformacional , Neoplasias Gástricas/radioterapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Epirubicina/administração & dosagem , Junção Esofagogástrica , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Análise de SobrevidaRESUMO
PURPOSE: Three Phase II studies of preoperative radiotherapy and concurrent 5FU chemotherapy were undertaken. The primary endpoints were acute toxicity and pathologic complete response rate (pCR). Secondary endpoints were local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). METHODS AND MATERIALS: A total of 134 patients with adenocarcinoma of the rectum (clinical T3/T4 or N1/N2) were treated. The initial cohort received 40 Gy in 20 fractions, the second 46 Gy in 23 fractions, and the third 50 Gy in 25 fractions. 5FU (225 mg/m2/day) was given continuously throughout radiotherapy. A total of 121 patients underwent surgical resection. RESULTS: Treatment was well tolerated. Grade 3/4 acute toxicity was observed in 13%, 4%, and 14% of patients in the 40 Gy, 46 Gy, and 50 Gy cohorts, respectively (p = 0.20). pCR was documented in 15%, 23%, and 33% of patients, respectively (p = 0.07). The 2-year actuarial LRFS was 72%, 90%, and 89% (p = 0.02); DFS was 62%, 84%, and 78% (p = 0.02); and OS was 72%, 94%, and 92%, respectively (p = 0.03). CONCLUSIONS: All treatment schedules were well tolerated. There was a trend toward increased pCR with higher doses. A statistically significant increase in LRFS, DFS, and OS was seen with radiation doses of 46 Gy and greater, but there was no difference between 46 Gy and 50 Gy.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Antimetabólitos Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fluoruracila/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Dosagem Radioterapêutica , Radioterapia Adjuvante/efeitos adversos , Neoplasias Retais/mortalidade , Neoplasias Retais/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVES: This study evaluates the efficacy and toxicity of single-agent irinotecan following hepatectomy for metachronous colorectal metastases, and examines the predictive value of p27 and p53 expression and of microsatellite instability (MSI) status. METHODS: Twenty-nine patients, previously treated with 5-fluorouracil, with operable hepatic colorectal metastases underwent hepatectomy and received adjuvant irinotecan (thrice weekly) for 6 planned cycles. Metastases were examined for p53 and p27 expression by immunohistochemistry and for MSI using mono- and dinucleotide markers. RESULTS: The starting dose of irinotecan was 350 mg/m2 (in 3 patients), 300 mg/m2 (n = 14), and 250 mg/m2 (n = 12). Four patients failed to complete 6 cycles (2 progressive disease and 2 toxicity). Grade > or =3 toxicity was experienced in 8% of cycles (13 of 165). The estimated median relapse-free survival (RFS) was 45.2 months. RFS at 18 months was estimated to be 59% (95% confidence interval [CI], 43-80), 2-year overall survival (OS) was 85% (95% CI, 72-99.8), and the median follow-up was 27.9 months. Six patients (21%) have died; median OS has not been reached. In univariate analyses, p27 and MSI status were not predictive for RFS while p53 approached statistical significance (P = 0.051). Duration of chemotherapy was the only significant predictive factor (P = 0.006). CONCLUSION: The tolerability of this regimen after major liver resection supports further evaluation of irinotecan-based adjuvant chemotherapy in this group of patients.
Assuntos
Adenocarcinoma/secundário , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Adenocarcinoma/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Biomarcadores Tumorais/análise , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Terapia Combinada , Inibidor de Quinase Dependente de Ciclina p27/análise , DNA de Neoplasias/análise , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Gastroenteropatias/induzido quimicamente , Humanos , Irinotecano , Tábuas de Vida , Neoplasias Hepáticas/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Neutropenia/induzido quimicamente , Análise de Sobrevida , Resultado do Tratamento , Proteína Supressora de Tumor p53/análiseRESUMO
The Ras-Raf-MEK-ERK (ERK) pathway is a logical therapeutic target because it represents a common downstream pathway for several key growth factor tyrosine kinase receptors which are often mutated or overexpressed in human cancers. Although considered mainly growth-promoting, in certain contexts, this pathway also seems to be apoptosis-suppressing. Several novel agents targeting this pathway have now been developed and are in clinical trials. One of the most interesting new agents is BAY 43-9006. Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties. To date, encouraging results have been seen with BAY 43-9006, particularly in renal cell cancers which are highly vascular tumors. This review will provide an overview of the ERK signaling pathway in normal and neoplastic tissue, with a specific focus on novel therapies targeting the ERK pathway at the level of Raf kinase.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-raf/metabolismo , Animais , Apoptose , Benzenossulfonatos/farmacologia , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Modelos Biológicos , Neovascularização Patológica , Niacinamida/análogos & derivados , Oligonucleotídeos Antissenso/farmacologia , Compostos de Fenilureia , Fosforilação , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridinas/farmacologia , Transdução de Sinais , Sorafenibe , Fatores de Tempo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
With an increasing number of targeted agents available for testing, clinical trials must be rationally designed based on sound knowledge of the molecular mechanisms linking target and disease, fortified by strong preclinical data demonstrating how this relationship is modified by the targeted agent. Patients and resources are precious and should be expended judiciously on clinical trials that are well planned. Although traditional trial designs and endpoints may not be adequate for developing contemporary targeted drugs, transiting directly from phase I to phase III testing should be avoided except in distinct circumstances. Increased research efforts should be spent on the prospective evaluation and validation of novel biologic endpoints and innovative clinical designs, such that promising targeted agents can be effectively developed to benefit the care of cancer patients.