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1.
Cancers (Basel) ; 11(2)2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699934

RESUMO

Uveal melanoma is a common intraocular malignant tumor that is uniformly fatal once metastatic. No effective adjuvant therapy currently exists to reduce the risk of distant metastasis after definitive treatment of the primary lesion. Immunotherapy has been used effectively in the adjuvant setting in locally advanced cutaneous melanoma. We performed a Phase I/II clinical trial of adjuvant ipilimumab in high-risk primary uveal melanoma with distant metastasis-free survival (DMFS) as the primary objective. A total of 10 patients with genomically high-risk disease were treated: three at a dose of 3 mg/kg and seven at 10 mg/kg. Two of the seven patients at the higher dose had to discontinue therapy secondary to grade 3 toxicity. At 36 months follow-up, 80% of patients had no evidence of distant disease (95% CI, 58.7⁻100). With recent advancements in CTLA-4 inhibition, PD-1 inhibition, and combined checkpoint blockade, immunotherapy is a promising avenue of treatment in uveal melanoma. Further clinical trials are needed to elucidate the role of immunotherapy in the adjuvant setting.

2.
Am J Clin Oncol ; 41(11): 1132-1136, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29509591

RESUMO

OBJECTIVES: Hepatic arterial infusion (HAI) of cytotoxic chemotherapy is a strategy to deliver high dose of anticancer therapy to liver metastases that derive their blood supply from the hepatic artery. Metastatic melanoma (MM) has a high incidence of liver metastases, with uveal subtype in particular exhibiting a predilection for liver dissemination. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated efficacy in MM and first-pass hepatic metabolism. Therefore, we hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end organ of interest, with minimal systemic exposure. PATIENT AND METHODS: We performed a single-institution open-label phase I/II study of HAI of nab-paclitaxel in MM patients with liver metastasis. Patients received treatment every 21 days at 4 different dose levels. The primary objective of the phase I portion of the study was safety and determination of the maximum-tolerated dose. The primary objective of the phase II portion of the study was overall response rate per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0. RESULTS: A total of 30 patients were treated between 2009 and 2013, 16 of whom had uveal melanoma. The maximum-tolerated dose was 220 mg/m and 19 patients were treated at this dose. There was 1 patient (5%) with a partial response at this dose, and 8 patients (42%) with stable disease at this dose. CONCLUSIONS: HAI nab-paclitaxel demonstrates rare objective responses in melanoma patients with liver metastases. This treatment should be studied in combination with checkpoint blockade or other novel treatments to enhance meaningful responses but should not be considered effective monotherapy.

3.
Cancer Immunol Immunother ; 66(10): 1359-1366, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28612140

RESUMO

Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH ≤2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m2 orally days 1-4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Dacarbazina/análogos & derivados , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Dacarbazina/administração & dosagem , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Feminino , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/farmacologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Temozolomida
4.
Melanoma Res ; 26(6): 604-608, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27540836

RESUMO

TPI 287 is a synthetic taxane derivative with structural modifications allowing for central nervous system penetration and potential circumvention of multidrug resistance efflux pump mechanisms. The aim of this phase I study was to determine the maximum tolerated dose of the combination of TPI 287 and temozolomide in metastatic melanoma. Patients with stage IV unresectable or recurrent stage III melanoma were eligible. Stable untreated or treated brain metastases were allowed. Patients with previous taxane exposure were excluded. TPI 287 was administered intravenously on days 1, 8, and 15 and temozolomide was taken orally daily on days 1-5 of a 28-day cycle. Responses were assessed every two cycles according to WHO criteria. A total of 21 patients were enrolled. The maximum tolerated dose of the combination at this schedule was determined to be 125 mg/m intravenous of TPI 287 and 110 mg/m of oral temozolomide. The dose-limiting toxicity was neuropathy and six patients experienced grade III neuropathy. All patients were evaluable for tumor response. There were no complete responses; there were two partial responses and seven patients had stable disease (overall response rate 9.5% and disease control rate 42.9%). Three patients had stable disease in the brain despite progressive extracranial disease. The combination of TPI 287 and temozolomide is well tolerated in patients with metastatic melanoma, with the exception of neuropathy. The central nervous system penetration of both agents makes this a rational combination for further testing in primary and metastatic brain lesions.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Temozolomida
6.
Oncotarget ; 6(14): 12809-21, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25980577

RESUMO

Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 - 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71- 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 - 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 - 0.85). Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with 1% of mutant cfDNA (BRAF, EGFR, KRAS, or PIK3CA) had a shorter median survival compared to 33 patients with

Assuntos
DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Feminino , Genes erbB-1/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto Jovem
7.
Case Rep Oncol Med ; 2015: 427163, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25874144

RESUMO

Many types of cancers metastasize to the eye. However, uveal melanoma metastasizing to the contralateral choroid is very rare. We report the case of a 68-year-old man with history of treated uveal melanoma of the right eye that developed metastasis to the liver and the choroid of the left eye. Ten years earlier, he was diagnosed to have uveal melanoma of the right eye and was initially treated with plaque radiotherapy. Two years later, upon progression of the disease in the right eye he had enucleation of the eye. We describe the patient's clinical history, the diagnosis of recurrent disease in the contralateral eye, therapy of the left eye, and systemic metastasis. In addition, we reviewed the published medical literature and described the recent advances in the management of uveal melanoma.

8.
South Med J ; 108(3): 158-63, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25772049

RESUMO

OBJECTIVES: According to reports in the clinical literature, metastatic uveal melanoma in young adults has not been well studied. This article describes the clinical characteristics and natural history of patients who were diagnosed as having uveal melanoma in the first 4 decades of life. METHODS: This was a chart review of patients aged 40 years or younger who were treated for metastatic uveal melanoma. The eligibility criteria included an established diagnosis of primary uveal melanoma that was treated with localized plaque radiation therapy or enucleation, the presence of radiologically confirmed systemic tumor metastasis, and available therapy and follow-up information. Sixty-five patients met the eligibility criteria and were included in our study. RESULTS: The interval between the time of diagnosis of the primary tumor to the diagnosis of systemic metastasis and the median survival duration from diagnosis of the primary and metastatic disease were significantly longer than were those of patients with uveal melanoma patients overall. CONCLUSIONS: Patients with uveal melanoma who are diagnosed within the first 4 decades of life have a better prognosis than do patients with uveal melanoma overall; however, the prognosis of patients with metastatic uveal melanoma remains poor.


Assuntos
Melanoma/diagnóstico , Neoplasias Uveais/diagnóstico , Adolescente , Adulto , Fatores Etários , Progressão da Doença , Enucleação Ocular , Feminino , Seguimentos , Humanos , Masculino , Melanoma/mortalidade , Melanoma/radioterapia , Melanoma/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias Uveais/mortalidade , Neoplasias Uveais/radioterapia , Neoplasias Uveais/cirurgia , Adulto Jovem
9.
J Invest Dermatol ; 135(2): 508-515, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25148578

RESUMO

The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , GTP Fosfo-Hidrolases/genética , Genes p53 , Humanos , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-kit/genética
10.
J Pediatr Hematol Oncol ; 36(7): 552-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25089601

RESUMO

BACKGROUND: This study compares the natural history and treatment outcomes of cutaneous melanoma in teenagers and young adults to determine if exclusion of teenagers from investigative trials is justified. PATIENTS AND METHODS: This is a chart review of patients between the ages of 13 and 40 years treated at The University of Texas MD Anderson Cancer Center for melanoma. Data related to the natural history and treatment outcomes were collected. Statistical tools were used to compare characteristics between teenagers and young adults. Cox proportional hazard models were utilized to examine the association between age group and overall survival. RESULTS: Of the 476 patients, 109 were teenagers and 367 were young adults. Both groups had comparable disease stage, pathology, and rates of metastasis. Initial disease stage and pathology significantly influenced survival. Sixty-six of 452 patients with skin melanoma developed metastasis. Teenagers survived better than young adults from diagnosis of the skin primary and after development of systemic metastasis. Teenagers tolerated and benefited from interleukin-2-based systemic therapy and targeted therapies as well as the young adults. CONCLUSIONS: Because of the similarities in natural history and treatment outcomes between teenage and young adult patients, it is recommended that teenage patients be officially enrolled on adult melanoma therapeutic trials.


Assuntos
Melanoma/tratamento farmacológico , Melanoma/mortalidade , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Adolescente , Adulto , Distribuição por Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bases de Dados Factuais , Feminino , Humanos , Interleucina-2/uso terapêutico , Masculino , Melanoma/patologia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Adulto Jovem
11.
Eur J Cancer ; 50(12): 2099-107, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24930625

RESUMO

BACKGROUND: To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM). METHODS: Eligible patients received ramucirumab (10mg/kg) + dacarbazine (1000 mg/m(2)) (Arm A) or ramucirumab only (10mg/kg) (Arm B) every 3 weeks. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), overall response and safety. FINDINGS: Of 106 randomised patients, 102 received study treatment (Arm A, N=52; Arm B, N=50). Baseline characteristics were similar in both arms. Median PFS was 2.6 months (Arm A) and 1.7 months (Arm B); median 6-month PFS rates were 30.7% and 17.9% and 12-month PFS rates were 23.7% and 15.6%, respectively. In Arm A, 9 (17.3%) patients had partial response (PR) and 19 (36.5%), stable disease (SD); PR and SD in Arm B were 2 (4.0%) and 21 (42.0%), respectively. Median OS was 8.7 months in Arm A and 11.1 months in Arm B. Patients in both arms tolerated the treatment with limited Grade 3/4 toxicities. INTERPRETATION: Ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Dacarbazina/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/efeitos adversos , Feminino , Humanos , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Neoplasias Cutâneas/secundário , Análise de Sobrevida , Adulto Jovem , Ramucirumab
12.
Melanoma Res ; 24(4): 342-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24743052

RESUMO

The primary objective of this study was to determine the safety, toxicity, and maximum tolerated dose of nanoparticle albumin-bound (nab)-paclitaxel as part of biochemotherapy for metastatic melanoma and to determine whether substituting nab-paclitaxel for less potent agents could increase response rates and duration. Treatment consisted of intravenous cisplatin (20 mg/m) on days 1-4, oral temozolomide (250 mg/m) on days 1-3, subcutaneous interferon-α (5×10 IU/m) on days 1-5, and continuous intravenous interleukin-2 (9×10 IU/m) for 96 h on days 1-4. A standard 3+3 dose escalation method was used; the nab-paclitaxel starting dose was 100 mg/m on day 1 and 70 mg/m on day 5. The treatment cycle was repeated every 3 weeks and toxicity was assessed weekly. Ten patients were enrolled. Dose-limiting toxicities included diarrhea, transaminasemia, and neutropenia. The maximum tolerated dose was not identified because the nab-paclitaxel dose on day 1 at the lowest planned dose (80 mg/m) caused dose-limiting toxicity in two of five patients. Of the nine patients who were evaluable for response, five had a partial response. The median time to disease progression was 5.30 months and the median overall survival was 8.73 months. Six patients developed central nervous system metastasis at a median of 5.33 months after treatment initiation. Biochemotherapy including nab-paclitaxel according to the doses and schedule regimen used in the present study has significant toxicity. Substituting dacarbazine with temozolomide did not prevent central nervous system metastasis in patients with metastatic melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Cisplatino/administração & dosagem , Estudos de Coortes , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Relação Dose-Resposta a Droga , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interleucina-2/administração & dosagem , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Temozolomida , Adulto Jovem
13.
Melanoma Res ; 24(3): 237-43, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24667300

RESUMO

In a previous large randomized, open-label study, retrospective subset analysis revealed that the addition of the Bcl-2 antisense oligonucleotide oblimersen to dacarbazine (Dac) significantly improved overall survival, progression-free survival, and the response rate in chemotherapy-naive patients with advanced melanoma and normal baseline serum lactate dehydrogenase (LDH) levels. To confirm and expand on this observation, we conducted a prospective double-blind, placebo-controlled study to determine whether oblimersen augmented the efficacy of Dac in advanced melanoma patients with low-normal baseline LDH levels. A total of 314 chemotherapy-naive patients were randomly assigned to receive Dac (1000 mg/m(2)) preceded by a 5-day continuous intravenous infusion of either oblimersen sodium (7 mg/kg/day) or placebo every 21 days for less than eight cycles. Co-primary efficacy endpoints were overall survival and progression-free survival. Response and progression of the disease were assessed by independent blinded review of computed tomography scan images. No difference in overall nor progression-free survival was observed between the Dac-oblimersen and Dac-placebo groups. Although the overall (17.2 vs. 12.1%) and durable (10.8 vs. 7.6%) response rates numerically favored Dac-oblimersen over Dac-placebo, they did not differ significantly (P=0.19 and 0.32, respectively). The incidence of hematologic adverse events, particularly thrombocytopenia and neutropenia, was higher in the Dac-oblimersen group than in the Dac-placebo group. Withdrawals from the study because of treatment-related adverse events were low (i.e. <2.5%) in both groups. The addition of oblimersen to Dac did not significantly improve overall survival nor progression-free survival in patients with advanced melanoma and low-normal levels of LDH at baseline.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Infusões Intravenosas , Masculino , Melanoma/diagnóstico por imagem , Melanoma/genética , Melanoma/metabolismo , Melanoma/mortalidade , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/administração & dosagem , Estudos Prospectivos , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Tionucleotídeos/administração & dosagem , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Clin Lymphoma Myeloma Leuk ; 14(3): 197-202, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24417913

RESUMO

BACKGROUND: Vincristine sulfate liposome injection (VSLI) facilitates vincristine dose intensification and densification, is active in untreated and relapsed lymphoma, and has been approved in the United States for relapsed and refractory acute lymphoblastic leukemia. Cancer- and concomitant chemotherapy-related anemia, neutropenia, and thrombocytopenia in patients with hematologic malignancy have complicated the evaluation of hematologic toxicity related to new drugs. PATIENTS AND METHODS: We assessed the hematologic toxicity of VSLI 2.25 mg/m(2) administered every 14 (cohort 1) or 7 (cohort 2) days in 54 patients with metastatic uveal melanoma, a cancer not known to involve the bone marrow. RESULTS: Cohort 2 received a greater median number of VSLI doses (6 vs. 4) within a shorter median period (5.7 vs. 8.7 weeks), resulting in a larger median cumulative exposure (22.6 vs. 17.7 mg) and near doubling of the median dose density (2.2 vs. 4.0 mg/wk) compared with cohort 1. Despite greater VSLI exposure and dose density, cohort 2 had a lower median decrease from baseline in the neutrophil count and a greater increase from baseline in the platelet count compared with cohort 1. Hematologic adverse events (AEs) were uncommon and mostly grade 1 or 2 in severity. No grade 4 hematologic AEs developed. CONCLUSION: VSLI at its approved dose resulted in a low incidence of clinically meaningful hematologic toxicity. A near doubling of the median dose density did not have an identifiable effect on the reported incidence and severity of hematologic AEs. VSLI could be well suited for use combined with myelosuppresive drugs and for patients unable to tolerate peripheral blood cytopenia.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Contagem de Células Sanguíneas , Índices de Eritrócitos/efeitos dos fármacos , Melanoma/sangue , Melanoma/tratamento farmacológico , Neoplasias Uveais/sangue , Neoplasias Uveais/tratamento farmacológico , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Lipossomos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento , Neoplasias Uveais/patologia
15.
Melanoma Res ; 24(1): 54-60, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24121189

RESUMO

The objectives of this study were to determine the cumulative incidence and timing of new brain metastases over the course of systemic therapy for metastatic melanoma and to identify prognostic factors for brain metastases. Chemo-naive patients underwent computed tomography or MRI of the brain every 6 weeks. The cumulative incidence of confirmed brain metastases was calculated at 12-week intervals. Univariable and multivariable competing risk regression models were used to assess the association between the development of brain metastases and potential risk factors of interest. Cumulative incidence with competing risk and competing risk regression was used to assess the brain metastasis-free interval from the time of diagnosis of stage IV disease. The clinical characteristics of the 315 patients with brain metastases were compared with those of 370 brain metastasis-free patients. Among patients with brain metastases, a significantly higher proportion had stage M1b and M1c disease at diagnosis compared with stage M1a and a greater proportion had metastatic disease in three or more visceral sites. Significantly shorter brain metastasis-free intervals were found in these patients compared with patients with M1a disease and those with no visceral metastases. More than 80% of the 230 patients who developed brain metastases during systemic therapy had their brain metastases confirmed within 60 weeks from the onset of advanced melanoma. Imaging studies at 12-week intervals for 60 weeks after the diagnosis of advanced melanoma will detect brain metastases in most of the patients who will eventually develop them.


Assuntos
Neoplasias Encefálicas/secundário , Melanoma/patologia , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Melanoma/tratamento farmacológico , Melanoma/secundário , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Adulto Jovem
16.
Invest New Drugs ; 32(2): 279-86, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23756764

RESUMO

BACKGROUND: Preclinical data have shown that lenalidomide and sorafenib target endothelial cells, inhibiting growth of ocular melanoma cells in a xenograft model. We conducted a Phase I study of lenalidomide and sorafenib in patients with advanced cancer. METHODS: During the escalation phase, lenalidomide (days 1-21) and sorafenib (days 1-28) were given orally once daily at the following respective doses: level 1 (10 mg, 200 mg); level 2 (10 mg, 400 mg); level 3 (20 mg, 400 mg); and level 4 (25 mg, 400 mg) (1 cycle = 28 days). A "3 + 3" study design was used. RESULTS: Forty-one patients were treated (median age: 50 years). The most common diagnoses were adenoid cystic carcinoma (N = 9), ovarian adenocarcinoma (N = 7), and melanoma (N = 6); 142 cycles (median: 3) were administered. No dose-limiting toxicities were noted. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related toxicities were neutropenia, thrombocytopenia, skin rash, and thromboembolism. Of 38 patients who were evaluable for response, stable disease (SD) was noted in 53 % of patients (SD ≥6 months: 16 %). Tumor types with SD ≥ 6 months were as follows: ocular melanoma, 2/2 (100 %); other melanoma, 1/4 (25 %); adenoid cystic carcinoma, 2/9 (22 %); and ovarian cancer, 1/6 (17 %). The median progression-free survival duration was 3.5 months (95 % CI, 1.9-5.0), and the median overall survival duration was 12.3 months (95 % CI, 10.1-14.5). CONCLUSIONS: Lenalidomide and sorafenib was well tolerated and associated with disease stabilization for ≥6 months in patients with melanoma, adenoid cystic carcinoma, and ovarian adenocarcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Lenalidomida , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Sorafenibe , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Adulto Jovem , Quinases raf/antagonistas & inibidores
17.
J Clin Aesthet Dermatol ; 6(5): 27-37, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23710269

RESUMO

BACKGROUND: Vemurafenib, a selective BRAF inhibitor that has antineoplastic activity in patients with unresectable or metastatic malignant melanoma whose tumor harbors a BRAF V600E mutation, has multiple drug-associated cutaneous adverse effects. PURPOSE: To provide a detailed and comprehensive review of reported changing or new pigmented lesions in oncology patients who have been treated with vemurafenib. METHODS: The new appearance of melanocytic nevi on normal-appearing skin after initiating treatment with vemurafenib is described in two men with metastatic malignant melanoma whose tumors demonstrated a BRAF V600E mutation. Using the PubMed database, an extensive literature search was performed for the following topics: vermurafenib, nevus, nevi, melanoma, pigmented lesion, cutaneous, adverse effect, side effect. The results of the search were used to secure all reports of new or changing pigmented lesions after initiating treatment with vemurafenib. RESULTS: Vemurafenib is associated with both changes in existing pigmented lesions (including involution, alteration of color and size, and progression to melanoma) and the onset of new melanocytic lesions-nevi (in 5 patients) and primary melanomas (in 2 patients). Visual examination, dermoscopic evaluation, and reflectance confocal microscopy have been used to document the changes in existing or new melanocytic lesions subsequent to initiating treatment with vermurafenib. Histopathology analysis has shown these lesions to usually be either dysplastic nevi or new primary melanomas. CONCLUSION: Vemurafenib-treated patients can develop new pigmented lesions (such as nevi) and/or morphological changes in their existing melanocytic lesions (such as involution, increase in size, or alternation of color). In addition, they can develop new primary malignant melanomas that either occur de novo on normal-appearing skin or develop in pre-existing melanocytic lesions. Therefore, total body skin examination should be considered prior to initiating treatment with vemurafenib. Regularly scheduled follow-up skin examinations are also recommended for patients while they are receiving this drug. In addition, for patients who are being treated with vemurafenib, either dermoscopic or photographic or visual modalities should be used to evaluate new or changing pigmented lesions. Also, biopsy for histopathology should be considered for vemurafenib-treated patients who develop new pigmented lesions or whose existing melanocytic lesions have morphological changes in size or color.

18.
J Immunother ; 36(4): 276-86, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23603862

RESUMO

Peptide vaccination against tumor-associated antigens remains one of the most common methods of immunization in cancer vaccine clinical trials. Although peptide vaccination has been reported to increase circulating antigen-specific T-cells, they have had limited clinical efficacy and there is a necessity to increase their capacity to generate strong antitumor responses. We sought to improve the clinical efficacy of peptide-based vaccines in cancer immunotherapy of metastatic melanoma using a LHRH agonist (leuprolide) as adjuvant. Seventy HLA-A*0201 stage IIb-IV melanoma patients were vaccinated with class I HLA-A*0201-restricted gp100209-2M peptide and stratified for HLA-DP4 restriction. HLA-DP4 patients were also vaccinated with class II HLA-DP4-restricted MAGE-3243-258 peptide. Patients from both groups were randomized to receive 2 doses of leuprolide or not. Here we report the increase in PBMC TREC levels at week 24 after peptide vaccination, which was independent of the leuprolide treatment. This change was mirrored by a small increase in the TREC-enriched CD8CD45RAROCD27CD103, but not the TREC-enriched CD4CD45RAROCD31 T-cell population. Serum concentration of 2 important factors for thymopoiesis was measured: insulin growth factor 1 (IGF-1) levels were not changed, whereas a moderate increase in IL-7 levels was noted in the sera of all patients 6 weeks after vaccination. Increased expression of CD127 (IL-7 receptor-α) at week 24, compared with baseline, was only seen in the CD8CD45RAROCD27CD103 T-cell population. Our results suggest that leuprolide has no effect on thymic output when used as peptide vaccine adjuvant, but IFA-based peptide vaccination may unexpectedly affect the thymus by increasing thymic output of new T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Leuprolida/uso terapêutico , Melanoma/imunologia , Melanoma/terapia , Vacinas de Subunidades Antigênicas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Antineoplásicos Hormonais/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Feminino , Humanos , Interleucina-7/sangue , Contagem de Linfócitos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/química , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , Receptores de Antígenos de Linfócitos T/metabolismo , Resultado do Tratamento , Vacinas de Subunidades Antigênicas/administração & dosagem , Adulto Jovem , Antígeno gp100 de Melanoma/química , Antígeno gp100 de Melanoma/imunologia
19.
Am J Clin Oncol ; 36(5): 443-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22706174

RESUMO

CONTEXT: Metastatic uveal melanoma recurrence after ≥10 years is not well studied in the clinical literature. This study describes the clinical characteristics and natural history of patients with delayed tumor recurrence. OBJECTIVE: To describe the characteristics of patients with delayed systemic recurrence of uveal melanoma and the natural history of the disease after recurrence. EVIDENCE ACQUISITION: This is a chart review of patients treated between 1994 and 2008 at The University of Texas, MD Anderson Cancer Center for uveal melanoma whose disease recurred ≥10 years after treatment of the primary tumor. RESULTS: Of 463 patients treated for metastatic uveal melanoma, 305 developed systemic recurrence within 5 years from the time of diagnosis of primary melanoma, 97 developed systemic recurrences between 5 and 10 years, whereas 61 patients developed metastasis after ≥10 years. The interval between primary to first systemic metastasis was a significant independent predictor of survival time from first systemic metastasis. The median survival time for patients with delayed metastatic recurrence after ≥10 years was significantly longer than for patients who had intermediate or early systemic recurrence. Levels of lactate dehydrogenase, serum alkaline phosphatase, serum albumin, age, M-stage, and performance status at time of recurrence, as well as sex were also independent predictors of survival time from systemic recurrence. CONCLUSIONS: Longer time interval between primary and first systemic metastasis is significantly correlated with prolonged survival. Patients who survive ≥10 years without tumor metastasis after treatment for primary uveal melanoma cannot be considered cured. Prognosis remains poor for patients with metastatic uveal melanoma.


Assuntos
Neoplasias Hepáticas/mortalidade , Melanoma/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Uveais/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Fatores de Tempo , Neoplasias Uveais/patologia , Neoplasias Uveais/terapia , Adulto Jovem
20.
Clin Cancer Res ; 18(24): 6758-70, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23032743

RESUMO

PURPOSE: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. EXPERIMENTAL DESIGN: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. RESULTS: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. CONCLUSION: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.


Assuntos
Imunoterapia Adotiva , Interleucina-2/uso terapêutico , Subpopulações de Linfócitos/transplante , Melanoma/terapia , Neoplasias Cutâneas/terapia , Linfócitos T Citotóxicos/transplante , Células Cultivadas , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Indução de Remissão , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Telômero/metabolismo , Transplante Autólogo , Resultado do Tratamento , Carga Tumoral/imunologia
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