RESUMO
Surufatinib, is a potent inhibitor of vascular endothelial growth factor receptors 1-3; fibroblast growth factor receptor-1; colony-stimulating factor 1 receptor. This Phase 1/1b escalation/expansion study in US patients with solid tumors evaluated 5 once daily (QD) surufatinib doses (3 + 3 design) to identify maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate safety and efficacy at the RP2D in 4 disease-specific expansion cohorts including pancreatic neuroendocrine tumors [pNET] and extrapancreatic NETs [epNET]. MTD and RP2D were 300 mg QD (escalation [n = 35]); 5 patients (15.6%) (Dose Limiting Toxicity [DLT] Evaluable Set [n = 32]) had DLTs. Pharmacokinetics were dose proportional. Estimated progression-free survival (PFS) rates at 11 months were 57.4% (95% confidence interval [CI]: 28.7, 78.2) and 51.1% (95% CI: 12.8, 80.3) for pNET and epNET expansion cohorts, respectively. Median PFS was 15.2 (95% CI: 5.2, not evaluable) and 11.5 (95% CI: 6.5,11.5) months. Response rates were 18.8% and 6.3%. The most frequent treatment-emergent adverse events (both cohorts) were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%). Pharmacokinetics, safety, and antitumor efficacy of 300 mg QD oral surufatinib in US patients with pNETs and epNETs are consistent with previously reported studies in China and may support applicability of earlier surufatinib studies in US patients. Clinical trial registration: Clinicaltrials.gov NCT02549937.
Assuntos
Neoplasias , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Tumores Neuroectodérmicos Primitivos/induzido quimicamente , Dose Máxima TolerávelRESUMO
PURPOSE: To compare disease-free survival (DFS) after maintenance therapy with the selective protein kinase C ß (PKCß) inhibitor, enzastaurin, versus placebo in patients with diffuse large B-cell lymphoma (DLBCL) in complete remission and with a high risk of relapse after first-line therapy. PATIENTS AND METHODS: This multicenter, phase III, randomized, double-blind, placebo-controlled trial enrolled patients who were at high risk of recurrence after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients (N = 758) with stage II bulky or stage III to IV DLBCL, three or more International Prognostic Index risk factors at diagnosis, and a complete response or unconfirmed complete response after 6 to 8 cycles of R-CHOP were assigned 2:1 to receive oral enzastaurin 500 mg daily or placebo for 3 years or until disease progression or unacceptable toxicity. Primary end point was DFS 3 years after the last patient entered treatment. Correlative analyses of biomarkers, including cell of origin by immunohistochemistry and PKCß expression, with efficacy outcomes were exploratory objectives. RESULTS: After a median follow-up of 48 months, DFS hazard ratio for enzastaurin versus placebo was 0.92 (95% CI, 0.689 to 1.216; two-sided log-rank P = .541; 4-year DFS, 70% v 71%, respectively). Independent of treatment, no significant associations were observed between PKCß protein expression or cell of origin and DFS or overall survival. CONCLUSION: Enzastaurin did not significantly improve DFS in patients with high-risk DLBCL after achieving complete response to R-CHOP. Achievement of a complete response may have abrogated the prognostic significance of cell of origin by immunohistochemistry.
Assuntos
Indóis/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteína Quinase C beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Doxorrubicina/uso terapêutico , Feminino , Humanos , Indóis/efeitos adversos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Proteína Quinase C beta/análise , Proteínas Proto-Oncogênicas c-bcl-2/análise , Rituximab , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin-bound agent that demonstrated activity in a phase 2 melanoma study. METHODS: In this open-label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin-corrected exposure of 1200-6400 h (hour).µg/mL on day 1) or paclitaxel (80 mg/m(2) on days 1, 8, and 15) every 28 days as second-line treatment. RESULTS: The study was placed on clinical hold after randomization of 336 patients when a safety review indicated an imbalance of possibly drug-related deaths in the tasisulam arm. Efficacy results for tasisulam versus paclitaxel revealed a response rate of 3.0% versus 4.8%, a median progression-free survival of 1.94 months versus 2.14 months (P = .048), and a median overall survival of 6.77 months versus 9.36 months (P = .121). The most common drug-related grade ≥3 laboratory toxicities (graded according to Common Terminology for Adverse Events [version 3.0]) were thrombocytopenia (18.9%) for patients treated with tasisulam and neutropenia/leukopenia (8.7%) among those receiving paclitaxel. There were 13 possibly related deaths reported to occur on the study, with the majority occurring during cycle 2 in the setting of grade 4 myelosuppression, all in the tasisulam arm. Investigation of the unexpectedly high rate of hematologic toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin-corrected exposure in cycle 2. CONCLUSIONS: Although the study was stopped early because of safety issues in the tasisulam arm, tasisulam was considered unlikely to be superior to paclitaxel, and paclitaxel activity in the second-line treatment of melanoma was much lower than expected. The toxicity imbalance was attributed to an unexpectedly low tasisulam clearance in a subset of patients, underscoring the importance of pharmacokinetic monitoring of compounds with complex dosing, even in late-phase studies.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Término Precoce de Ensaios Clínicos , Melanoma/tratamento farmacológico , Melanoma/secundário , Paclitaxel/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Neutropenia Febril Induzida por Quimioterapia/diagnóstico , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucopenia/induzido quimicamente , Leucopenia/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Resultado do TratamentoRESUMO
INTRODUCTION: Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs). METHODS: Patients with LC (any histology) who had received WBRT for BMs were randomized to receive oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placebo. The primary endpoint was time to progression (TTP) of BMs. RESULTS: Fifty-four patients received enzastaurin and 53 patients received placebo. The median TTP of BMs was (months) enzastaurin: 6.9 (95% confidence interval [CI]: 3.4-11.9); placebo: 4.9 (95% CI: 3.6-not assessable); p=0.82. Median overall survival (OS) was (months) enzastaurin: 3.8 (95% CI: 2.6-5.6); placebo: 5.1 (95% CI: 3.7-5.7); p=0.47. Median progression-free survival (PFS) was (months) enzastaurin: 2.2 (95% CI: 1.1-2.3); placebo: 2.0 (95% CI: 1.3-2.3); p=0.75. The overall response rate (ORR) for extracranial disease was enzastaurin: 0%; placebo: 4.5% (p=0.49) and for intracranial disease was enzastaurin: 9.3%; placebo 6.8% (p=0.71). Grade 4 hematologic treatment-emergent adverse events were (enzastaurin vs. placebo) thrombocytopenia (5.6% vs. 1.9%) and neutropenia (5.6% vs. 0%). There was 1 treatment-related death in each arm (enzastaurin: unknown cause; placebo: pulmonary embolism). No significant differences in health-related quality of life (HRQoL) were observed. CONCLUSIONS: Enzastaurin was well tolerated but did not improve TTP of BMs, ORR, OS, PFS, or HRQoL after WBRT in LC patients with BMs.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Indóis/uso terapêutico , Neoplasias Pulmonares/patologia , Quimioterapia de Manutenção , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/radioterapia , Progressão da Doença , Feminino , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do TratamentoRESUMO
This work was conducted to find out new potential serum markers and study their role as predictive factors in patients with metastatic melanoma. Serum samples from 68 patients with stage IV malignant melanoma were collected just before current treatment and screened for 79 different cytokines by using a multi-cytokine array. Angiogenin, which is a protein capable of promoting angiogenesis, was found to be markedly elevated among a sub-group of patients with progressive disease (PD) and thus was subjected to further analysis. The mean serum angiogenin level was 270 ng/ml and the median 236 ng/ml (STD 163 ng/ml). Concentrations were significantly higher among men than in women (P = 0.031), whereas patient's age, site of the primary tumour, Clark's or Breslow's classifications were not associated with angiogenin levels. Patients with only lymph node metastases had markedly lower angiogenin levels than those with metastases at other sites (P = 0.05). High angiogenin levels were significantly (P = 0.015; Kruskal-Wallis) associated with poor treatment response with chemoimmunotherapy. Treatment-related survival (TRS) was shorter (10 months) in patients with above-median values than in those with below-median levels (19 months, P = NS). Cox multivariate regression model was used to control for the confounding by the classical prognostic factors of melanoma (age, sex, disease burden, performance score, site of metastases). Disease burden was the only variable that remained in the model as a significant independent predictor of TRS (P = 0.044). These data suggest that serum angiogenin levels might be of predictive value in the evaluation of treatment response for patients with stage IV melanoma.
Assuntos
Melanoma/sangue , Ribonuclease Pancreático/sangue , Neoplasias Cutâneas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Resultado do Tratamento , Carga TumoralRESUMO
This randomized phase II study was designed to compare the efficacy and tolerability of dacarbazine (DTIC) and bleomycin, vincristine, lomustine and DTIC (BOLD) combined with natural interferon-alpha (nIFN-alpha) or recombinant interferon-alpha2b (rIFN-alpha2b) in patients with advanced melanoma. The treatment arms were: A, DTIC plus nIFN-alpha; B, BOLD plus nIFN-alpha; C, DTIC plus rIFN-alpha2b; D, BOLD plus rIFN-alpha2b. One hundred and eight patients were randomized, of whom 106 were eligible to be analysed for efficacy. Overall, 56% of patients had abdominal visceral and/or bone involvement. The response rates were 8% (2/25) in arm A, 13% (4/31) in arm B, 12% (3/25) in arm C and 24% (6/25) in arm D. The differences were not statistically significant by the usual chi-squared test. However, when analysed using the Cochran-Armitage trend test, the one-sided P values were close to significant (0.085 and 0.033). All of the eight complete responses occurred in patients with soft tissue and/or lung metastases and the BOLD regimens produced six of them. There were no significant differences in survival (arm A, 11.1 months; arm B, 9.8 months; arm C, 9.1 months; arm D, 7.5 months; P=0.62). BOLD was more toxic than DTIC. With the present sample size, there were no statistically significant differences in efficacy between the arms, but there was a trend towards a higher response rate with BOLD plus rIFN-alpha2b. Patients with soft tissue or lung metastases may achieve more complete responses with BOLD regimens.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon Tipo I/uso terapêutico , Interferon-alfa/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Feminino , Humanos , Lomustina/administração & dosagem , Lomustina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Recombinantes , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
We have observed that an early increase in the CD4+/CD8+ ratio of metastatic melanoma patients during chemoimmunotherapy is the most favourable independent prognostic factor. In this study, 87 patients with metastatic melanoma were monitored for peripheral blood lymphocyte subsets (CD4+ and CD8+) before and during chemoimmunotherapy (dacarbazine, vinblastine, lomustine and bleomycin or dacarbazine alone plus interferon-alpha) to confirm our previous observation. Blood samples were systematically obtained from patients who received either of these chemoimmunotherapies. The frequencies of peripheral blood lymphocyte subsets were monitored by flow cytometry using monoclonal antibodies OKT4 (CD4+, T-helper cells) and OKT8 (CD8+, T-suppressor cells). The overall response rate was 46.5%, and the median overall survival was 9.3 months. Patients with pre-treatment CD4+ levels above the mean level, who later responded to therapy, had a median survival of 28.1 months vs. 10.2 months for responders with low pre-treatment CD4+ levels (P=0.053, log-rank test). Responders with decreasing CD8+ levels had a median survival of 27.8 months vs. 10.8 months for responders with increasing CD8+ levels (P=0.04, log-rank test). Similarly, responding patients with an increasing CD4+/CD8+ ratio had a median survival of 28.1 months vs. 10.5 months for those with decreasing ratios (P=0.002, log-rank test). Non-responders showed no difference in median survival irrespective of low or high pre-treatment CD4+ lymphocytes, increasing or decreasing CD8+ levels, or increasing or decreasing CD4+/CD8+ ratios. This follow-up study confirms that the monitoring of CD4+ and CD8+ lymphocytes may provide important predictive and prognostic information in metastatic melanoma patients receiving chemoimmunotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Adulto , Idoso , Bleomicina/administração & dosagem , Dacarbazina/administração & dosagem , Feminino , Humanos , Interferon-alfa/administração & dosagem , Lomustina/administração & dosagem , Metástase Linfática , Masculino , Melanoma/tratamento farmacológico , Melanoma/secundário , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , Vimblastina/administração & dosagemRESUMO
The expression pattern of integrin-type cell adhesion receptors is often changed during malignant transformation. In the present work, we studied the prognostic significance of beta1 and alphav integrin chains for survival of patients with metastatic melanoma. The expression levels of beta1 integrin were also compared with those of Bcl-2, an anti-apoptotic protein, the presence of which is associated with treatment response and survival in melanoma. The expression of beta1 and alphav integrins in 68 melanoma metastases obtained from 55 patients treated with combined chemoimmunotherapy was studied by immunohistochemistry using anti-beta1 and anti-alphav antibodies. The patients were divided into two groups (using a cut-off point of >/= 81%) for beta1 integrin expression levels and into three categories (negative/low, median, high) for alphav integrin expression levels. All tumours were positive for beta1 integrin, and the tumours (n = 6) which had the highest alphav score were also strongly positive for beta1 (94%; P = 0.0055). Patients (n = 43) with 80% or less beta1 integrin-positive tumour cells in their samples had a median disease-free survival (DFS) of 17.0 months, and patients (n = 12) with 81% or more beta1 integrin-positive tumour cells had a DFS of only 5.7 months (P = 0.0001). Patients (n = 32) with low alphav integrin expression levels had shorter DFS (median 12.3 months; P = 0.0146) than patients (n = 20) with median expression levels (median 16.7 months; P = 0.0146). However, three patients who had a very strong alphav expression in their tumours had a median DFS of only 1.8 months (P = 0.0146). Median level expression of beta1 integrin was associated with the presence of Bcl-2 in tumour cells (P = 0.0033). Our results suggest that beta1 and alphav integrin chains are independently expressed in metastatic melanoma and may have an effect on the metastatic potential of melanoma cells.
Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Integrina alfaV/metabolismo , Integrina beta1/metabolismo , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunoterapia , Antígeno Ki-67/metabolismo , Masculino , Melanoma/secundário , Melanoma/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida , Fatores de TempoRESUMO
PURPOSE: The RAS-RAF-mitogen-activated protein kinase pathways mediate the cellular response to growth signals. In melanocytes, BRAF is involved in cAMP-dependent growth signals. Recently, activating mutations in the BRAF gene, were reported in a large proportion of melanomas. We have studied mutations in the BRAF gene and their association with clinical parameters. EXPERIMENTAL DESIGN: We analyzed exons 1, 11, and 15 of the BRAF gene and exons 1 and 2 of the N-ras gene for mutations in 38 metastatic melanomas by PCR-single-strand conformation polymorphism and direct sequencing. Kaplan-Meier survival and multivariate analyses were used to correlate mutations with various clinical parameters. RESULTS: Mutations in exon 15 of the BRAF gene were detected in 26 (68%) melanomas. In 25 cases, mutation involved the "hot spot" codon 600(2)of the BRAF gene. Three melanomas without a BRAF mutation carried amino acid substituting base changes at codon 61 of the N-ras gene. In a multivariate proportional hazard (Cox) model, BRAF mutation, along with the stage of metastatic melanomas, showed a statistically significant hazard ratio of 2.16 (95% confidence interval 1.02-4.59; chi(2) for the model 6.94, degrees of freedom 2, P = 0.03) for diminished duration of response to the treatment. In a Kaplan-Meier survival model, cases with BRAF mutation showed longer disease-free survival (median of 12 months) than cases without mutation (median of 5 months), although this association was not statistically significant (Log-rank test P = 0.13). CONCLUSIONS: Our results, besides confirming the high frequency of BRAF mutations in metastatic melanomas, also underline the potential importance of these mutations in disease outcome.
Assuntos
Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas c-raf/genética , Adulto , Idoso , Sequência de Bases , Éxons , Feminino , Genes ras/genética , Humanos , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise Multivariada , Metástase Neoplásica , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas B-raf , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: To identify factors that independently contribute to overall survival in Stage IVB uveal melanoma and to subcategorize by prognosis. METHODS: Data of 91 consecutive patients who died of metastatic uveal melanoma in 1985-2000 were analyzed by Kaplan-Meier and Cox regression analysis. Main covariates were participation in annual review, symptoms, Karnofsky index, metastatic burden, liver function tests, and age. Time on chemotherapy was modeled as a confounder. A working formulation for staging patients according to predicted survival was designed. RESULTS: Of the 91 patients, 85% underwent annual liver imaging and function tests, 63% were asymptomatic, and 73% received chemotherapy. The median survival period was 8.4 months (95% confidence interval [CI], 6.3-11.8). Karnofsky index, largest dimension of the largest metastasis, metastatic burden, serum transaminase, lactate dehydrogenase, and alkaline phosphatase (AP) levels, and time on chemotherapy were strongly (P < 0.001) associated with survival. Symptoms (P = 0.031) and regular review (P = 0.081) were weakly associated with survival. Karnofsky index (P = 0.013), the largest dimension of the largest metastasis (P = 0.003), and serum AP level (P = 0.042) retained independent significance, adjusting for time on chemotherapy. Predicted median survival calculated for relevant covariate combinations was divided into three periods (> or =12 months vs. 6-11 months vs. < 6 months). Observed median survival for Stage IVBa was 14.9 months (95% CI, 11.7-21.3), for Stage IVBb 8.9 months (95% CI, 2.7-13.7), and for Stage IVBc 2.0 months (95% CI, 1.0-3.7). CONCLUSION: The model and working formulation for categorization can be tested as an aid in patient counseling and as a tool in design and analysis of clinical trials.
Assuntos
Melanoma/mortalidade , Melanoma/secundário , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Feminino , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Melanoma/sangue , Melanoma/terapia , Pessoa de Meia-Idade , Modelos Teóricos , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias Uveais/sangue , Neoplasias Uveais/terapiaRESUMO
BACKGROUND: A Phase II trial comprising patients with metastatic uveal melanoma (Stage IVB) was undertaken to determine the activity of bleomycin, vincristine, lomustine, and dacarbazine (BOLD) chemotherapy with human leukocyte interferon, as well as the progression-free and overall survival of the patients according to the substage before treatment. METHODS: Twenty-two patients with histologically proven metastatic uveal melanoma received 15 mg of bleomycin (Days 2 and 5), 1 mg/m(2) vincristine (Days 1 and 4), 200 mg/m(2) dacarbazine (Days 1 to 5), and 80 mg lomustine (Day 1) every 4 weeks together with a leukocyte interferon preparation (3 x 10(6) IU daily for 6 weeks followed by 6 x 10(6) IU three times per week). RESULTS: Of 20 evaluable patients, 3 (15%; 95% confidence interval [CI] 0-38) obtained a partial objective response in hepatic and extrahepatic sites and 11 (55%; 95% CI 32-77) showed stable disease after receiving more than two cycles. The median progression-free survival was 4 months (95% CI 2-10) and the median overall survival was 12 months (95% CI 8-22). Eleven patients who had favorable pretreatment characteristics (Stage IVBa) survived a median of 17 months (95% CI 4-37) whereas 10 patients with less favorable characteristics (Stage IVBb) survived a median of 11 months (95% CI 1-23). Moderate toxicity occurred with this outpatient regimen. CONCLUSIONS: The BOLD/human leukocyte interferon regimen had modest activity against metastatic uveal melanoma in hepatic and extrahepatic sites. The median overall survival approached that reported for more aggressive intrahepatic therapy regimens. Substage differences can significantly impact study outcomes. Therefore, substage information should be reported to facilitate comparisons between studies.
Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon-alfa/farmacologia , Melanoma/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Injeções Intravenosas , Interferon-alfa/administração & dosagem , Lomustina/administração & dosagem , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Resultado do Tratamento , Neoplasias Uveais/patologia , Vincristina/administração & dosagemRESUMO
OBJECTIVE: The antiapoptotic protein Bcl-2 is supposed to influence the treatment responsiveness of different malignancies. In the present study the prognostic and predictive significance of Bcl-2 expression for survival and response to an administered therapy was explored in patients with metastatic melanoma. Also, the correlation between Bcl-2 expression and proliferation activity of tumor cells was defined to examine the regulatory role of Bcl-2 in proliferation. MATERIALS AND METHODS: Sixty metastatic melanomas obtained from patients treated with chemoimmunotherapy were examined by immunohistochemistry with anti-Bcl-2 and anti-Ki-67 (MIB-1) antibodies. Proliferation activity was expressed in percentages as MIB-1 index. RESULTS: The presence of Bcl-2 immunoreactivity was associated with a significantly lower MIB-1 index (p = 0.016), and a longer disease-free survival (p = 0.004). The lack of Bcl-2 expression was related to a higher response rate to therapy in comparison to a diffuse and focal pattern of Bcl-2 expression (p = 0.017). Although the presence of Bcl-2 immunoreactivity as such did not correlate with survival after the initiation of chemoimmunotherapy, the focal Bcl-2 expression pattern was strongly associated with a worse prognosis compared to a diffuse expression or a lack of Bcl-2 staining (p < 0.0001). CONCLUSIONS: Our results support the role of Bcl-2 in the regulation of cell proliferation and suggest that an increase of metastatic potential and progression of malignant melanoma is associated with a loss of Bcl-2 expression. The lack of Bcl-2 expression could be a predictor of the response to chemoimmunotherapy, whereas the Bcl-2 expression pattern, possibly indicating the heterogeneity of the tumors, might be a potential prognostic factor for survival after the initiation of therapy.
Assuntos
Neoplasias Pulmonares/metabolismo , Melanoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Antígenos Nucleares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunoterapia , Antígeno Ki-67 , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Melanoma/mortalidade , Melanoma/secundário , Melanoma/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Prognóstico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading extracellular matrix. Their role has been emphasized in tumor invasion, metastasis and tumor-induced angiogenesis. We studied the expression of collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) in 70 melanoma metastases obtained from 56 patients treated with combined chemoimmunotherapy. The patients were divided into 2 groups using a cut-off point of 0% for MMP-1 expression and 20% for MMP-3 expression. We found that patients with MMP-1 positive metastases (n = 38) had significantly shorter disease-free survival compared to patients with MMP-1 negative metastases (n = 18) (median 11.2 vs. 17.0 months, p = 0.0383). The disease-free survival of patients with high levels of MMP-3 expression in their metastases (> or = 20% positive tumor cells, n = 14) was also significantly shorter compared to patients with lower levels of expression (n = 42) (median 5.1 vs. 14.0 months, p = 0.0294). The expression of MMP-13 did not correlate to survival parameters. We also found that the presence of melanin, a pigment produced by melanocytes, correlated with high expression levels of MMP-1 (p = 0.0002), MMP-3 (p < 0.0001) and MMP-13 (p = 0.0009). The high expression levels of MMP-13 were also associated with the presence of visceral metastases (p = 0.0284). Our findings suggest that MMP-1 and -3 may have a special role in melanoma metastasis formation and thus they could be used to measure the biological activity of the disease.