RESUMO
Background: The real-world impact of tyrosine kinase inhibitors (tkis) in clinical practice for gastrointestinal stromal tumour (gist) has not been extensively reported. We sought to assess how outcomes have changed over the eras and to evaluate the effect of access to imatinib and sunitinib on survival in patients with unresectable or metastatic gist in British Columbia. Methods: Patients with metastatic or unresectable gist were allocated to one of three eras: pre-2002, 2002-2007, and post-2007 based on treatment availability (pre-imatinib, post-imatinib, and post-sunitinib). Overall survival (os) and progression-free survival (pfs) were compared between eras. Univariate and multivariate analyses were performed to determine the effects of tumour, patient, and treatment characteristics on survival outcomes. Results: Of 657 patients diagnosed with gist throughout British Columbia during 1996-2016, 196 had metastatic disease: 23 in the pre-imatinib era, 67 in the post-imatinib era, and 106 in the post-sunitinib era. A significant increase in os, by 53.6 months (p = 0.0007), and pfs, by 29.1 months (p = 0.044), was observed after the introduction of imatinib. The introduction of sunitinib did not significantly affect os or pfs. Conclusions: Implementation of tkis has drastically improved survival outcomes for patients with metastatic gist by up to 4.55 years in the real-world setting. Our study demonstrates that implementation of tkis in clinical practice has outperformed their benefit predicted in clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia , Adulto JovemRESUMO
BACKGROUND: Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers. METHODS: Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively. RESULTS: Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1-20%), with a median progression-free survival of 2 months (95% CI: 2-3), and median overall survival of 6 months (95% CI: 3-8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash. CONCLUSIONS: Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/tratamento farmacológico , Neoplasias da Vesícula Biliar/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Sorafenibe , Falha de Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: The survival benefit for single-agent anti-epidermal growth factor receptor (egfr) therapy compared with combination therapy with irinotecan in KRAS wildtype (wt) metastatic colorectal cancer (mcrc) patients in the third-line treatment setting is not known. The objective of the present study was to describe the characteristics of, and to compare survival outcomes in, two cohorts of patients treated with either singleagent panitumumab or combination therapy with cetuximab and irinotecan. METHODS: The study enrolled patients with KRAS wt mcrc previously treated with both irinotecan and oxaliplatin who had received either panitumumab or combination cetuximab-irinotecan before April 1, 2011, at the BC Cancer Agency (bcca). Patients were excluded if they had received anti-egfr agents in earlier lines of therapy. Data were prospectively collected, except for performance status (ps), which was determined by chart review. Information about systemic therapy was extracted from the bcca Pharmacy Database. RESULTS: Of 178 eligible patients, 141 received panitumumab, and 37 received cetuximab-irinotecan. Compared with patients treated with cetuximab-irinotecan, panitumumab-treated patients were significantly older and more likely to have an Eastern Cooperative Oncology Group (ecog) ps of 2 or 3 (27.7% vs. 2.7%, p = 0.001). Other baseline prognostic variables and prior and subsequent therapies were similar. Median overall survival was 7.7 months for the panitumumab group and 8.3 months for the cetuximab-irinotecan group. Multivariate analysis demonstrated that survival outcomes were similar regardless of the therapy selected (hazard ratio: 1.28; p = 0.34). An ecog ps of 2 or 3 compared with 0 or 1 was the only significant prognostic factor in this treatment setting (hazard ratio: 3.37; p < 0.01). CONCLUSIONS: Single-agent panitumumab and cetuximab-irinotecan are both reasonable third-line treatment options, with similar outcomes, for patients with chemoresistant mcrc.
RESUMO
BACKGROUND: The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ≥70 years and <60 years were compared in SWOG0030. METHODS: Twenty-nine unresectable colorectal cancer patients were stratified to either ≥70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared. RESULTS: Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ≥70 years patients (P<0.05). No difference in 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females. CONCLUSION: Increases in capecitabine Cmax and AUC was observed in patients ≥70 years when compared with younger patients who were >60 years.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fatores Etários , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Área Sob a Curva , Capecitabina , Neoplasias Colorretais/metabolismo , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Feminino , Floxuridina/sangue , Fluoruracila/sangue , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Taxa de Filtração Glomerular , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
BACKGROUND: Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric carcinoma; however, relatively little is known about the role of HER2 in the natural history of this disease. PATIENTS AND METHODS: Patients enrolled in the INT-0116/SWOG9008 phase III gastric cancer clinical trial with available tissue specimens were retrospectively evaluated for HER2 gene amplification by FISH and overexpression by immunohistochemistry (IHC). The original trial was designed to evaluate the benefit of postoperative chemoradiation compared with surgery alone. RESULTS: HER2 gene amplification rate by FISH was 10.9% among 258 patients evaluated. HER2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER2 amplification and treatment with respect to both disease-free survival (DFS) (P = 0.020) and overall survival (OS) (P = 0.034). Among patients with HER2-non-amplified cancers, treated patients had a median OS of 44 months compared with 24 months in the surgery-only arm (P = 0.003). Among patients with HER2-amplified cancers, there was no significant difference in survival based on treatment arm. HER2 status was not a prognostic marker among patients who received no postoperative chemoradiation. CONCLUSION: Patients lacking HER2 amplification benefited from treatment as indicated by both DFS and OS. CLINICAL TRIAL: INT-0116/SWOG9008 phase III.
Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Junção Esofagogástrica/patologia , Amplificação de Genes , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Quimiorradioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Feminino , Fluoruracila/uso terapêutico , Gastrectomia , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The objective of the study was to describe patterns of care of patients with gastrointestinal stromal tumors (GISTs) in the United States in the tyrosine kinase inhibitor (TKI) era. PATIENTS AND METHODS: From November 2004 through March 2009, data were collected regarding demographics, diagnostic history, treatment, relapse, and survival of 882 patients with GIST from 122 community and academic medical practices. RESULTS: The most common first-line treatment for the 719 patients presenting with localized GIST was surgery (87%). Use of adjuvant imatinib increased after June 2007; 47% of patients enrolled in the registry considered by the investigator to be at high risk for recurrence received adjuvant imatinib after June 2007 versus 18% before. Overall, 56% of patients received imatinib and 11% received sunitinib. The utilization of targeted therapy increased over time (45% and 0.4% of patients received imatinib and sunitinib, respectively, in 2006 versus 56% and 11%, respectively, in 2009). CONCLUSIONS: These are the first GIST registry data from the TKI era. The use of targeted therapy for GIST has increased in accordance with updated treatment guidelines. Diagnosis of GIST has evolved with increased use of KIT testing. The duration of targeted therapy in the adjuvant therapy setting is similar in community and academic practices.
Assuntos
Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/terapia , Padrões de Prática Médica , Centros Médicos Acadêmicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/epidemiologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/epidemiologia , Hospitais Comunitários , Humanos , Mesilato de Imatinib , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sistema de Registros , Sunitinibe , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%-45% of gastric cancers, making them potential targets. PATIENTS AND METHODS: The primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days. RESULTS: The study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6-3.1) months and OS was 4.8 (3.2-7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS. CONCLUSIONS: Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Quinazolinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Lapatinib , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol and docetaxel, given to patients with non-resectable, incurable pancreatic cancer. PATIENTS AND METHODS: Twenty-five patients were enrolled onto this phase II study. Patients were treated with oral calcitriol 0.5 microg/kg on day 1, followed by docetaxel 36 mg/m(2) IV on day 2, administered weekly for three consecutive weeks, followed by 1 week without treatment. Patients followed a low-calcium diet and increased their hydration. The primary end-point of the trial was time-to-progression. RESULTS: Three of 25 patients attained a partial response (12%, 95% CI 3 to 31) and seven (28%) achieved stable disease. Median time-to-progression was 15 weeks, and median overall survival was 24 weeks. Toxicities observed (hyperglycemia, fatigue) were mostly attributable to the docetaxel or its pre-treatment. CONCLUSIONS: This regimen of high-dose calcitriol with docetaxel may have activity in incurable pancreatic cancer, with a modest increase in TTP when compared to historical findings using single-agent docetaxel. However, results do not appear superior to those seen with gemcitabine, with or without erlotinib.
Assuntos
Antineoplásicos/farmacologia , Calcitriol/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Taxoides/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Calcitriol/administração & dosagem , Calcitriol/efeitos adversos , Agonistas dos Canais de Cálcio/administração & dosagem , Agonistas dos Canais de Cálcio/efeitos adversos , Agonistas dos Canais de Cálcio/farmacologia , Cálcio da Dieta , Progressão da Doença , Docetaxel , Quimioterapia Combinada , Fadiga/induzido quimicamente , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Taxa de Sobrevida , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC. PATIENTS AND METHODS: Eligible patients with ACC were randomized in double-blind fashion to receive placebo or TMTX (110 mg/m2) intravenously (i.v.) followed 24 h later by i.v. LCV 200 mg/m2, and 5-FU 500 mg/m2 plus oral LCV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumor response, quality of life (QoL) and toxicity. RESULTS: A total of 382 eligible patients were randomized. Significant toxicities were noted more frequently with TMTX/5-FU/LCV. Diarrhea was the most common grade 3 or 4 side-effect (41% and 28% on the TMTX and placebo arms, respectively). QoL scores and response rates did not differ between treatment arms. PFS was 5.3 months and 4.4 months in the TMTX and placebo arms, respectively (P = 0.77; Wilcoxon). OS was 15.8 months and 16.8 months, respectively (P = 0.73; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LCV worsened grade 3 or 4 diarrhea. The inclusion of TMTX did not yield any significant improvements in response rate, PFS or OS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Trimetrexato/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Taxa de Sobrevida , Fatores de Tempo , Trimetrexato/efeitos adversosRESUMO
BACKGROUND: Two randomised studies were performed with trimetrexate (TMTX) as a biochemical modulator of 5-fluorouracil (5-FU)/leucovorin (LV) in advanced colorectal cancer (ACC), one in Europe and one in the United States. Both studies were similarly designed to detect a statistically significant difference in progression-free survival (PFS). Overall survival (OS), however, was later adopted as the primary outcome measure for approvability of agents for first-line treatment of ACC. Therefore, an integrated analysis of survival data from the European and USA trials was performed to detect a clinically relevant difference in survival. PATIENTS AND METHODS: The experimental arm was identical in both studies and consisted of TMTX 110 mg/m2 intravenously (i.v.) followed 24 h later by i.v. LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. The 5-FU dose in the control arm was 600 mg/m2 in the European study and 500 mg/m2 in the USA study, and the USA study was placebo-controlled. Treatment was given weekly for 6 weeks every 8 weeks. RESULTS: A total of 746 patients were analysed. Median OS was 13.0 months for 5-FU/LV and 14.6 months for TMTX/5-FU/LV (P = 0.15; Wilcoxon). Median PFS was 4.4 months and 5.4 months, respectively (P = 0.07; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LV does not improve the outcome for patients with ACC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Análise de Sobrevida , Trimetrexato/uso terapêutico , Progressão da Doença , Feminino , Humanos , Masculino , Taxa de Sobrevida , Fatores de TempoRESUMO
Six patients with incurable malignancies were originally treated with vitamin E, 3200 IU/day for fourteen days, followed by the same dose of vitamin E daily plus LCV (20 mg/m2 i.v. bolus daily x 5) with 5FU (425 mg/m2 i.v. bolus immediately following LCV). The same schedule of LCV and 5FU was repeated 4 weeks later, then every 5 weeks indefinitely. When 3 of the first 6 had grade 3/4 toxicity, six more patients were treated on the identical drugs and schedule. Seven of twelve total patients had one or more grade 3/4 toxicities. Neutropenia, abdominal pain, and diarrhea were most common. No patient had a documented response, though seven patients did have stable disease. Though the combination of vitamin E and chemotherapy was toxic, this trial demonstrated maximal therapeutic doses of vitamin E can be combined with standard 5FU and LCV, without significantly increasing the side effects of the chemotherapy itself.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Vitamina E/uso terapêutico , Dor Abdominal/induzido quimicamente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Diarreia/induzido quimicamente , Dinoprosta/análogos & derivados , Dinoprosta/urina , Relação Dose-Resposta a Droga , F2-Isoprostanos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Neutropenia/induzido quimicamente , Vitamina E/administração & dosagem , Vitamina E/efeitos adversosRESUMO
Gastrointestinal stromal tumors (GISTs) are mesenchymal gut tumors that differ dramatically from other histologically similar neoplasms, such as leimomyomas, leiomyosarcomas (LMS), and neural tumors. Complete surgical removal remains the best current therapy for GISTs, but even major resections are associated with recurrence in approximately 90% of cases. GISTs are remarkably resistant to irradiation and standard chemotherapy; there is no role for treatment with those modalities. Treatment of advanced GIST patients with STI571, a novel selective tyrosine kinase inhibitor, results in remission rates that approach 60% and overall tumor control rates of 85%. Selected groups of patients, as based on tumor mutational status, have response rates as high as 80%. To date, STI571 therapy remains the only systemic treatment for GISTs to have meaningful clinical activity. Though other molecularly targeted therapies exist in oncology (eg, trastuzumab), STI571 is one of the first that applies a drug specifically designed to inhibit the product of a constitutively-activating mutation that drives pathogenesis of a solid tumor. Its use can serve as a paradigm for designing molecularly targeted therapies for other malignancies.
Assuntos
Neoplasias Gastrointestinais/terapia , Neoplasias de Tecido Conjuntivo/terapia , Antineoplásicos/uso terapêutico , Benzamidas , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Terapia Combinada , Procedimentos Cirúrgicos do Sistema Digestório , Inibidores Enzimáticos/uso terapêutico , Métodos Epidemiológicos , Neoplasias Gastrointestinais/epidemiologia , Humanos , Mesilato de Imatinib , Imunoterapia , Metástase Neoplásica , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/antagonistas & inibidores , Recidiva Local de Neoplasia/cirurgia , Neoplasias de Tecido Conjuntivo/epidemiologia , Piperazinas/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-kit/análise , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: A phase II study testing the safety and efficacy of irinotecan (CPT-11). 5-fluorouracil (5-FU), and leucovorin (LCV) was conducted in patients with advanced gastric adenocarcinomas. PATIENTS AND METHODS: Patients with metastatic or recurrent adenocarcinoma of the gastroesophageal junction (GEJ) or stomach were entered onto this study. Previous chemotherapy for metastatic disease was not allowed. Treatment consisted of repeated 6-week cycles comprising CPT-11 125 mg/m2 intravenously (i.v.) followed immediately by LCV 20 mg/m2 i.v. and 5-FU 500 mg/m2 i.v., all given weekly for four weeks followed by a two-week rest. RESULTS: Thirty-eight patients were enrolled and 36 eligible patients received protocol therapy. Grade 3-5 toxicities consisted primarily of neutropenia (36%) and diarrhea (28%). Neutropenic infection was observed in 14% of patients, with 3 (8%) dying of neutropenic sepsis. The overall response rate was 22% (95% confidence interval [CI] 8.5% to 35.5%). Median survival was 7.6 months, and median time to progression was 4.4 months. CONCLUSION: This weekly regimen of CPT-11 with bolus 5-FU/LCV is active in patients with advanced adenocarcinomas of the stomach or gastroesophageal junction. While rates of grade 3-4 neutropenia and diarrhea were similar to those observed historically in patients receiving this regimen for colorectal cancer, neutropenic fever/sepsis appeared to be more frequent, and dose modifications were substantial. Future trials of this combination in patients with gastric cancer should decrease the absolute starting drug doses and/ or employ altered scheduling that better accommodates the pattern of toxicity.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Junção Esofagogástrica/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neutropenia/induzido quimicamente , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
A 52-year-old man with retroperitoneal nodal, lung, and liver metastases from choriocarcinoma received chemotherapy with etoposide, cisplatin, and bleomycin. Within 48 hours of starting treatment, he had hypotension, hypoxemia, and anuria. Laboratory values showed hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidosis. He was placed on mechanical ventilation, and hemodialysis was instituted, with marked improvement in renal function. A second, shortened course of chemotherapy with carboplatin and etoposide was given 21 days later. However, on hospital day 48, the patient died of progressive pulmonary insufficiency and cardiac arrest. This represents the first reported case of acute tumor lysis syndrome after systemic chemotherapy for advanced nonseminomatous germ cell cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Coriocarcinoma/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Síndrome de Lise Tumoral/etiologia , Acidose/etiologia , Doença Aguda , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Bleomicina/efeitos adversos , Coriocarcinoma/secundário , Cisplatino/efeitos adversos , Etoposídeo/efeitos adversos , Evolução Fatal , Parada Cardíaca/etiologia , Humanos , Hiperpotassemia/etiologia , Hipocalcemia/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Insuficiência Respiratória/etiologia , Ácido Úrico/sangueRESUMO
BACKGROUND: The aim of this study was to confirm the activity and assess the safety profile of multitargeted antifolate (MTA) for patients with metastatic colorectal adenocarcinoma. METHODS: Forty-six patients were enrolled in the study, 35 with colon and 11 with rectal carcinoma. Adjuvant therapy was allowed if completed 1 year previously. Patients received MTA 600 mg/m(2) as a 10-minute intravenous infusion once every 21 days. Blood samples were taken every cycle for pharmacokinetic and vitamin metabolite assays. RESULTS: Among 39 patients eligible for efficacy analysis, 1 complete response and 5 partial responses were identified, for an overall response rate of 15.4% (95% confidence interval [CI], 4.1-26. 7%) for all patients. Fifteen patients had stable disease, with 9 living longer than 1 year. The median survival was 16.2 months (95% CI, 10.5-17.0%); 65% of patients were alive at 1 year, and the median time to progression was 4.4 months (range, 3.2-5.7 months). The main toxicities were hematologic, with common toxicity criteria (CTC) Grades 3 or 4 noted as follows: thrombocytopenia (18%), neutropenia (55%), and anemia (18%). Nonhematologic toxicities included Grade 2 or 3 skin reaction (53%), ameliorated by dexamethasone, and Grade 3 transaminases (23%). Dose omissions were not required and 21% of doses were reduced. CONCLUSIONS: MTA has clear activity in patients with colorectal carcinoma, and encouraging survival times were noted. MTA was well tolerated in this patient group, but myelosuppression was frequent. Toxicity may be increased with folate deficiency.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Neoplasias Retais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Neoplasias do Colo/patologia , Feminino , Glutamatos/efeitos adversos , Glutamatos/farmacologia , Guanina/efeitos adversos , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Pemetrexede , Neoplasias Retais/patologia , Análise de Sobrevida , Trombocitopenia/induzido quimicamenteRESUMO
Over the past 10 years, a number of topoisomerase I inhibitors have entered into clinical trials and several of these have been evaluated in phase II and III studies to determine their activity in patients with advanced colorectal cancer. The most extensively studied of these has been irinotecan (CPT-II). In phase II trials in patients with colorectal cancer that was recurrent or refractory to 5-Ruorouracil (5-FU)based front-line therapy, response rates of 14% to 22% and median survival times of 8 to 10 months have been consistently reported by groups from Japan, Europe, and the United States using avariety of drug administration schedules Two recently reported phase III trials comparing CPT-II against infusional 5-FU or best supportive care demonstrated that CPT-II confers a survival advantage over either of the two other approaches. In front-line treatment of colorectal cancer, CPT-II produces response rates of 19% to 32% and median survival times of 11 to 12 months, figures quite similar to those achievable with bolus 5-FU and leucovorin. Further evaluation in the front-line setting has concentrated on the integration of CPT-II with 5-FU-based regimens. The role of other topoisomerase I inhibitors in colorectal cancer has been more difficult to characterize. Using a standard daily x 5 schedule, topotecan has little objective activity against relapsed or refractory colorectal cancer. Infusional topotecan appears more promising in the treatment of patients with advanced colorectal cancer. The development of an oral formulation of topotecan may make this approach more feasible and is likely to undergo dinical evaluation in the near future. Phase II evaluation of 9-aminocamptothecin (9-AC) has focused on infusional schedules of varying lengths Despite this, little antitumor activity has been observed against colorectal cancer. Other topoisomerase I inhibitors, such as DX-8951f and 9-nitrocamptothecin (9-NC, RFS2000), have not been formally tested in phase II trials against colorectal cancer. In summary, extensive evaluation of topoisomerase I inhibitors has identified a significant degree of variability in clinical activity in patients with advanced colorectal cancer. To date, only one topoisomerase I inhibitor, CPT-II, has demonstrated a level of activity sufficient for it to become an integral component of treatment for patients with 5-FU-refractory colorectal cancer. Current and future studies will focus on the development of front-line regimens combining CPT-II and 5-FU for treatment of patients with advanced-stage disease, moving topoisomerase I inhibitors into the adjuvant therapy setting, and developing combined modality regimens of surgery, radiation, and topoisomerase I inhibitors for patients with locally advanced colorectal cancer.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Inibidores da Topoisomerase I , Animais , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/farmacologia , Humanos , Irinotecano , Topotecan/farmacologia , Topotecan/uso terapêuticoRESUMO
Fluorinated pyrimidines have long been used as radiosensitizers in combined-modality therapy for solid tumors. Nonetheless, the most commonly used drug, 5-fluorouracil (5-FU), is inconvenient to administer, particularly when given by continuous intravenous infusion. Continuous infusion 5-FU does offer a survival advantage over bolus in the treatment of large bowel tumors. This holds true regardless of whether radiation therapy is concomitantly given. UFT, a combination of uracil and tegafur (in a molar ratio of 4:1), is an attractive alternative. Trials to date suggest at least chemotherapeutic equivalence compared to 5-fluorouracil, and UFT is much simpler to administer. UFT is administered orally and can safely be combined with oral leucovorin. There is profound scientific rationale for using UFT with radiation therapy, and early trials in gastrointestinal malignancies demonstrate the safety and efficacy of the combination. Further studies will determine the optimal timing and uses for concomitant UFT and radiation therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Radiossensibilizantes/uso terapêutico , Administração Oral , Animais , Ensaios Clínicos como Assunto , Terapia Combinada , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/radioterapia , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Radiossensibilizantes/farmacologia , Tegafur/uso terapêutico , Uracila/uso terapêuticoRESUMO
BACKGROUND: Traditional teaching maintains that patients with primary colorectal adenocarcinoma require timely resection to prevent bleeding, perforation, or obstruction. The true benefits of primary tumor resection remain undocumented for patients presenting with metastatic disease, however. We postulated that resection of primary colorectal tumors could be avoided safely in a select population of asymptomatic colorectal cancer patients presenting with incurable stage IV disease. METHODS: A retrospective review of the Vanderbilt University Hospital tumor registry was performed for the years 1985 to 1997. During this period, 955 patients presented for management of primary colorectal cancer. From this group, all patients with stage IV disease at the time of diagnosis were identified. Patients who initially underwent resection of their primary lesion were included in the resection group; those who underwent initial nonoperative primary tumor management were included in the nonresection group. Data were obtained regarding age, extent of disease, nonsurgical therapy, tumor-specific complications, and palliative surgical procedures. Surgery-free survival and overall survival were analyzed using the Kaplan-Meier method. For patients with liver metastases, hepatic tumor burden was defined as either H1 (<25% parenchymal replacement), H2 (25% to 50%), or H3 (>50%) disease. RESULTS: Sixty-six patients were included in the resection group, and 23 patients with intact asymptomatic primary colorectal lesions were included in the nonresection group. Among patients with hepatic metastases, most of the patients in both groups had H1 disease. Ten patients in the resection group and 3 patients in the nonresection group presented with exclusively extrahepatic metastases. In the nonresection group, primary therapy included chemotherapy in 13 patients, external beam radiation therapy in 1 patient, and combination chemoradiation in 9 patients. The median survival in the nonresection group was 16.6 months. The 2-year actuarial survival was 18%, and the surgery-free survival was 91.3%. Only 2 of 23 patients (8.7%) managed without resection eventually developed obstruction at the primary tumor site requiring emergent diversion. There were no episodes of tumor-related hemorrhage or perforation. For the resection group, the operative morbidity was 30.3%, and the perioperative mortality rate was 4.6%. The median survival in the resection group was 14.5 months (P = 0.59, log-rank test vs. nonresection group). CONCLUSIONS: Selected patients with asymptomatic primary colorectal tumors who present with incurable metastatic disease may safely avoid resection of their primary lesions, with an anticipated low rate of hemorrhage, perforation, or obstruction before death from systemic disease. No survival advantage is gained by resection of an asymptomatic primary lesion in the setting of incurable stage IV colorectal cancer.
Assuntos
Adenocarcinoma/terapia , Neoplasias Colorretais/terapia , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) in Western populations has historically been associated with poor survival. METHODS: In this study, we conducted a 7-year retrospective analysis of patients with HCC undergoing transcatheter arterial chemoembolization (TACE) at our institution and examined demographics, outcomes, and complications. RESULTS: During the period of study, 39 patients (25 male [64%], mean age 58 [range 17 to 86]) underwent a total of 78 chemoembolization treatments. During the same time period, an additional 31 patients received supportive care only. The majority of patients had late stage disease (American Joint Committee on Cancer stage III, IVa, or IVb) with no statistical difference noted between the two groups (P = 0.2). However, patients receiving supportive care only had significantly worse hepatic dysfunction by Child's classification (P = 0.005). Twenty-nine patients (74%) had documented cirrhosis, with hepatitis C being the most common cause in 11 of 29 (38%). In patients undergoing TACE, overall actuarial survival was 35%, 20%, and 11% at 1, 2, and 3 years with a median survival of 9.2 months, significantly improved over the group receiving supportive care only (P < 0.0001). Median survival for the group receiving supportive care was less than 3 months. Neither age nor stage had a significant impact on survival. The most common complications of TACE included transient nausea, abdominal pain, vomiting, and fever. CONCLUSIONS: TACE is a safe and effective therapeutic option for selected patients with HCC not amenable to surgical intervention.