RESUMEN
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.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Dacarbazina/análogos & derivados , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/farmacología , Dacarbazina/administración & dosificación , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Femenino , Humanos , Ipilimumab/administración & dosificación , Ipilimumab/farmacología , Masculino , Melanoma/patología , Persona de Mediana Edad , Neoplasias Cutáneas/patología , TemozolomidaRESUMEN
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.
Asunto(s)
Melanoma/diagnóstico , Neoplasias de la Úvea/diagnóstico , Adolescente , Adulto , Factores de Edad , Progresión de la Enfermedad , Enucleación del Ojo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/mortalidad , Melanoma/radioterapia , Melanoma/cirugía , Pronóstico , Estudios Retrospectivos , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/radioterapia , Neoplasias de la Úvea/cirugía , Adulto JovenRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Lenalidomida , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Sorafenib , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/análogos & derivados , Adulto Joven , Quinasas raf/antagonistas & inhibidoresRESUMEN
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.
Asunto(s)
Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Adolescente , Adulto , Distribución por Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bases de Datos Factuales , Femenino , Humanos , Interleucina-2/uso terapéutico , Masculino , Melanoma/patología , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Spindle cell melanoma represents a rare but distinct subset of melanoma, and its genomic spectrum has not been fully defined. METHODS: We searched our institutional database for patients with a diagnosis of pure spindle cell-type melanoma whose tumors had been analyzed for BRAF, NRAS, and KIT mutations using pyrosequencing technique. RESULTS: We identified 24 patients with spindle cell melanoma, including 10 patients with desmoplastic melanoma, whose tumors had been analyzed for at least one of the three genes. The median Breslow thickness was 2.6 mm, and the most common site of the primary melanoma was the trunk, followed by the head and neck region. BRAF, NRAS and KIT genomic sequencing was performed successfully in 20, 18 and 14 patients, respectively. Among the 20 melanomas with completed BRAF-sequencing analysis, 6 (30%) harbored a mutation, of which 5 (83%) had a V600E mutation and 1 (17%) had a V600R mutation. None of the melanomas harbored NRAS or KIT mutations. CONCLUSION: As has been reported in other common types of melanoma, V600 BRAF mutation is the most common mutation of those tested in spindle cell melanoma. NRAS or KIT mutation appears to be rare, if not completely absent.
Asunto(s)
Neoplasias de Cabeza y Cuello/genética , Melanoma/genética , Proteína Oncogénica p21(ras)/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Mutación , Proteína Oncogénica p21(ras)/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Treatment of metastatic melanoma with interleukin-2-based biochemotherapy involves administration of a combination of moderately and highly emetogenic chemotherapies over 5 days. Corticosteroids for the prevention of biochemotherapy-induced nausea and vomiting (CINV) are contraindicated because they cause lysis of LAK cells produced in response to interleukin-2. Palonosetron is a long-acting, highly potent, second-generation serotonin receptor antagonist. The recommended dosing schedule of palonosetron for the control of CINV due to biochemotherapy is not known. METHODS: In a phase II design, treatment-naïve patients with metastatic melanoma undergoing the first cycle of biochemotherapy were randomized to receive palonosetron 0.25 mg intravenously for CINV prophylaxis on either days 1 and 4 (schedule 1) or days 1, 3, and 5 (schedule 2). All patients received dacarbazine on day 1, cisplatin, vinblastine, and interleukin-2 on days 1-4, and interferon alpha-2b on days 1-5. We evaluated and compared, by palonosetron dosing schedule, the pattern and the severity of CINV during the first 7 days of treatment and the duration of the 21-day cycle as well as the impact on daily function with the Functional Living Index-Emesis. RESULTS: Thirty patients (median age 53 years) were enrolled. Eighteen (60%) were men. A consistent trend of a better control of both nausea and vomiting favoring schedule 2 was observed during the first 7 days and throughout the cycle. Significantly more patients experienced nausea on any day during the first 7 days on schedule 1 (mean number of episodes 8.1 ± 1.5) than on schedule 2 (mean number of episodes 5.6 ± 2.3, p = 0.028). The impact on daily function was similar between the two groups. CONCLUSIONS: Both dosing schedules of palonosetron were tolerated well. Alternate day dosing of palonosetron was more effective in controlling CINV in this patient population.
Asunto(s)
Antieméticos/uso terapéutico , Antineoplásicos/uso terapéutico , Interleucina-2/efectos adversos , Isoquinolinas/uso terapéutico , Náusea/prevención & control , Quinuclidinas/uso terapéutico , Antagonistas de la Serotonina/uso terapéutico , Vómitos/prevención & control , Antieméticos/administración & dosificación , Antineoplásicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interleucina-2/uso terapéutico , Isoquinolinas/administración & dosificación , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Náusea/inducido químicamente , Palonosetrón , Quinuclidinas/administración & dosificación , Antagonistas de la Serotonina/administración & dosificación , Vómitos/inducido químicamenteRESUMEN
We reviewed the medical records of 42 patients with cutaneous melanoma metastatic to the liver who underwent hepatic artery chemoembolization (HACE) at our institution. HACE resulted in radiologic response (38.9%) or disease stabilization (47.2%) in most patients. The median overall survival (OS) and time to progression (TTP) of liver disease were 7.7 and 6 months, respectively. Patient's age, lactate dehydrogenase (LDH) levels, type of treatment, number of extrahepatic metastatic sites, and response to therapy were found to be significant predictors of OS after HACE. Prolonged survival was seen in patients who responded to HACE (p = .034).
Asunto(s)
Quimioembolización Terapéutica , Neoplasias Hepáticas/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/patología , Quimioembolización Terapéutica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Arteria Hepática , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Melanoma/irrigación sanguínea , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Neoplasias Cutáneas/mortalidad , Texas , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma. METHODS: Patients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 microg/dose) and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH) to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB). The gamma-interferon (IFNgamma) ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8. RESULTS: Among 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions) had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNgamma-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant setting, 11 with stage IV melanoma at baseline had a progression-free and overall survival of 45% and 82%, respectively, with a median follow-up of 10 years. CONCLUSION: Treatment with autologous tumor-derived HSPPC-96 was feasible and safe at all doses tested. Observed immunological effects and antitumor activity were modest, precluding selection of a biologically active dose. Nevertheless, the 25-microg dose level was shown to be practical for further study.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Proteínas de Choque Térmico/uso terapéutico , Melanoma , Adolescente , Adulto , Anciano , Animales , Vacunas contra el Cáncer/inmunología , Proteínas de Choque Térmico/inmunología , Humanos , Inmunoterapia/métodos , Estimación de Kaplan-Meier , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Masculino , Melanoma/inmunología , Melanoma/patología , Melanoma/prevención & control , Persona de Mediana Edad , Metástasis de la Neoplasia , Adulto JovenRESUMEN
INO-1001 is a PARP-1 inhibitor that interrupts the repair process of N-methylpurines generated by temozolomide. We evaluated the pharmacokinetics of INO-1001 and determined its safety when used with temozolomide at 200 mg/m(2)/day x 5 days every 4 weeks. We enrolled 12 adult patients, in cohorts of 3-6 patients, into the study. INO-1001 at doses of 100, 200 and 400 mg was given intravenous for 1 hr q 12 hr for 10 doses. INO-1001 had a moderate clearance, volume of distribution and a relatively short terminal half-life. Myelosuppression and elevation of liver transaminases were dose-limiting toxicities (DLTs) of INO-1001 at 400 mg.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/secundario , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Administración Oral , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Enfermedades de la Médula Ósea/inducido químicamente , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Reparación de la Incompatibilidad de ADN , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Dacarbazina/farmacocinética , Dacarbazina/farmacología , Esquema de Medicación , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/farmacocinética , Indoles/farmacología , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/fisiología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/fisiología , TemozolomidaRESUMEN
This retrospective analysis aimed to identify the prognostic factors that influenced long-term survival of patients with metastatic melanoma. The medical records for 616 chemo-naive patients who were treated with systemic therapy on eight phase II/III clinical trials were reviewed. Clinical characteristics, disease stage, metastatic sites, baseline serum albumin, LDH, and response to treatment were compared between the treatment groups and significant prognostic factors were identified. Cox proportional-hazards regression analysis identified treatment with biochemotherapy, younger age, normal baseline serum albumin and LDH levels, ECOG P.S. < 2 and absence of visceral metastasis as favorable prognostic factors for long-term survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/mortalidad , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Interferones/administración & dosificación , Interleucina-2/administración & dosificación , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/sangre , Masculino , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Albúmina Sérica/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Factores de Tiempo , Resultado del Tratamiento , Neoplasias de la Úvea/metabolismo , Neoplasias de la Úvea/patologíaRESUMEN
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.
RESUMEN
Vincristine sulfate liposomes injection (VSLI) is a liposomal formulation of vincristine encapsulated in sphingosomes composed of sphinogomyelin and cholesterol (58/42; mol/mol). The pharmacokinetics and urinary excretion of VSLI were evaluated in 12 patients with metastatic melanoma after single-dose (2.0 mg/m2 every 2 weeks = 1 cycle) and multiple-dose (cycle 3, pharmacokinetics only) administrations (intravenous infusion over 1 hour). After VSLI infusion, total (released and encapsulated) vincristine concentrations in plasma remained relatively constant for 3 to 12 hours and thereafter declined, with interpatient variability seen in the rate of decline resulting in monoexponential or biexponential profiles. The area under the plasma concentration-time curve from time zero to infinity of total vincristine in plasma ranged from 4933 to 40495 h.ng/mL and total clearance ranged from 131 to 445 mL/h. The volume of distribution at steady state was 2650 +/- 731 mL, indicating VSLI was mainly confined within the plasma. The released vincristine concentrations in plasma were below the level of quantitation in 95% of samples. The pharmacokinetic parameters were similar between cycles 1 and 3, and trough plasma levels of total vincristine were below the level of quantitation of 1 ng/mL. Approximately 8% of the injected dose was excreted in the urine as unchanged vincristine (7%) or N-desformylvincristine (0.8%). Overall, VSLI exhibited a longer circulation half-life and higher area under the plasma concentration-time curve compared to conventional vincristine, whereas its route of elimination remained unchanged.
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Antineoplásicos Fitogénicos/farmacocinética , Melanoma/orina , Vincristina/farmacocinética , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/orina , Preparaciones de Acción Retardada , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Liposomas , Masculino , Melanoma/sangre , Melanoma/tratamiento farmacológico , Melanoma/patología , Persona de Mediana Edad , Neoplasias Cutáneas/orina , Vincristina/administración & dosificación , Vincristina/sangre , Vincristina/orinaRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Neoplasias Cutáneas/patología , Taxoides/administración & dosificación , Taxoides/efectos adversos , TemozolomidaRESUMEN
PURPOSE: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. RESULTS: Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. CONCLUSION: Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores Inmunológicos/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/secundario , Adulto , Cisplatino/administración & dosificación , Dacarbazina/administración & dosificación , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Interleucina-2/administración & dosificación , Interleucina-2/uso terapéutico , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Análisis de Supervivencia , Vinblastina/administración & dosificaciónRESUMEN
PURPOSE: To evaluate the outcome and toxicity of a sphincter-sparing treatment strategy in the management of patients with anal-rectal melanoma. PATIENTS AND METHODS: Between 1989 and 2000, 23 patients with invasive anal-rectal melanoma were managed with sphincter-sparing surgical resection and adjuvant radiation. Surgery consisted of primary local excision, as well as dissection for patients with documented regional nodal disease. Adjuvant radiation was delivered using a hypofractionated regimen of 30 Gy in five fractions over 2.5 weeks. Adjuvant systemic therapy was delivered to nine patients: cytotoxic chemotherapy in seven and immunotherapy in two. RESULTS: After a median follow-up of 32 months, 15 patients had relapsed and 15 patients had died. The actuarial 5-year overall, disease-specific, disease-free, and distant metastasis-free survival rates were 31%, 36%, 37%, and 35%, respectively. The actuarial 5-year local and regional nodal control rates were 74% and 84%, respectively. No patient had locoregional failure as the sole site of failure and no patient required salvage abdominoperineal resection (APR). By univariate analysis, patients with nodal disease at presentation had a decreased actuarial 5-year disease-specific (0% v 45%, P =.004), disease-free (0% v 45%, P <.001), and distant metastasis-free survival (0% v 42%, P <.001). The actuarial complication-free survival rate was 71%. Two patients developed mild scrotal edema (grade 1), and four patients developed moderate proctitis requiring prolonged medical management (grade 2). CONCLUSION: Sphincter-sparing local excision and adjuvant radiation is well tolerated and can effectively control local-regional disease while avoiding the functional morbidity of APR.
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Neoplasias del Ano/radioterapia , Neoplasias del Ano/cirugía , Melanoma/radioterapia , Melanoma/cirugía , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Ano/patología , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Metástasis Linfática , Masculino , Melanoma/secundario , Persona de Mediana Edad , Invasividad Neoplásica , Radioterapia Adyuvante , Neoplasias del Recto/patología , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
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.
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The Abstract is incorrect in PubMed. The corrected Abstract is provided here.
RESUMEN
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 KRAS mutant DNA (4.8 vs. 7.3 months, p=0.008). Similarly, 67 patients with >1% of mutant cfDNA (BRAF, EGFR, KRAS, or PIK3CA) had a shorter median survival compared to 33 patients with = 1% of mutant cfDNA (5.5 vs. 9.8 months, p = 0.001), which was confirmed in multivariable analysis. [Corrected]
Asunto(s)
ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Fosfatidilinositol 3-Quinasa Clase I , Análisis Mutacional de ADN , Femenino , Genes erbB-1/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto JovenRESUMEN
PURPOSE: To evaluate the outcome and treatment-related toxicity for patients with axillary lymph node metastases from malignant melanoma treated with surgery and radiation, with or without systemic therapy. MATERIALS AND METHODS: The medical records of 89 consecutive patients with axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients underwent axillary dissection and postoperative radiation to a median dose of 30 Gy at 6 Gy/fraction delivered twice weekly. In 3 patients referred with microscopic residual disease, a single boost (4-6 Gy) was given to a reduced field. All but 2 patients were referred because their axillary dissections revealed features believed to predict a 30-50% risk of subsequent axillary recurrence: lymph nodes >/=3 cm in size (54 patients), >/=4 lymph nodes positive (44), the presence of extracapsular extension (69), recurrent disease after initial surgical resection (23), or multiple risk factors (77). Fifty-one patients received systemic therapy before or after radiation therapy. RESULTS: At a median follow-up of 63 months, 47 patients had relapsed and 43 patients had died. The actuarial overall and disease-free survival rates at 5 years were 50% and 46%, respectively. The actuarial axillary control and distant metastasis-free survival rates at 5 years were 87% and 49%, respectively. Univariate analysis revealed that the probability of axillary control was inferior when the axillary disease measured >6 cm in size (72% vs. 93%, p = 0.02), the location of the primary tumor was unknown (74% vs. 93%, p = 0.02), the axillary failure occurred within 18 months from diagnosis of the primary melanoma (84% vs. 100%, p = 0.04), or the Breslow thickness was >4 mm (80% vs. 96%, p = 0.04). Additionally, there was an inferior distant metastasis-free and disease-free survival when there were >2 nodes positive for metastatic disease, the primary lesion had a Breslow thickness >4 mm, or the axillary failure occurred within 18 months from diagnosis of the primary melanoma. On multivariate analysis, the significantly inferior distant metastasis-free and disease-free survival seen when >2 nodes were positive or the recurrence occurred within 18 months remained significant. The small number of axillary failures precluded multivariate analysis for axillary control; however, stratified analysis suggested that size >6 cm was the factor most closely associated with subsequent axillary failure. Twenty-six patients developed treatment-related arm edema. Classification according to the severity of edema yielded 5-year actuarial arm edema rates of 21%, 19%, and 1%, for Grade 1 (transient or asymptomatic), Grade 2 (requiring medical intervention), or Grade 3 (requiring surgical intervention) edema, respectively. CONCLUSION: Adjuvant radiation therapy using a hypofractionated regimen resulted in an 87% 5-year axillary control rate, superior to the 50-70% local control achieved with surgery alone for lymph node metastases from melanoma when high-risk features are present. Improvements are needed for patients with bulky nodal masses >6 cm in size. Mild-to-moderate arm edema was common, but manageable. The degree to which radiotherapy adds to the risk of arm edema after axillary dissection alone cannot be addressed in the present analysis.
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Metástasis Linfática/radioterapia , Melanoma/radioterapia , Melanoma/secundario , Neoplasias Cutáneas/radioterapia , Neoplasias Cutáneas/secundario , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Brazo , Axila , Edema/etiología , Estudios de Seguimiento , Humanos , Escisión del Ganglio Linfático , Irradiación Linfática , Melanoma/mortalidad , Melanoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Dosificación Radioterapéutica , Radioterapia Adyuvante , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/cirugía , Tasa de SupervivenciaRESUMEN
The management of patients with metastatic malignant melanoma remains difficult. Conventional chemotherapy has been disappointingly ineffective. Dacarbazine (DTIC) is considered to be one of the most active single agents with a response rate of approximately 15-20%. Many patients who initially respond to treatment subsequently relapse. Clearly, there is a need for improvement, and the evaluation of new agents is warranted. This article reviews current phase II studies of single-agent taxanes and their combinations in patients with metastatic melanoma, and examines the likely impact of taxanes on treatment strategies. Response rates from phase II trials with single-agent taxanes vary from 3.3% to 17%. Prolonged durations of disease control are observed. Combinations of taxanes with DTIC, temozolomide, cisplatin, carboplatin and tamoxifen have demonstrated response rates from 12% to 41%, suggesting that they are at least as effective as various other combination regimens. Encouraging results have been produced in the second-line metastatic setting. Taxanes, both as single agents and in combinations, may be a treatment option for some patients with metastatic melanoma, especially in the second-line setting.