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The incidence of CNS progression in patients with high-risk regional melanoma (stages IIIAN2a-IIIC) is not well characterized. Data from the S0008 trial provided an opportunity to examine the role of CNS progression in treatment failure and survival. All patients were surgically staged. Following wide excision and full regional lymphadenectomy, patients were randomized to receive adjuvant biochemotherapy (BCT) or high-dose interferon alfa-2B (HDI). CNS progression was retrospectively identified from data forms. Survival was measured from date of CNS progression. A total of 402 eligible patients were included in the analysis (BCT: 199, HDI: 203). Median follow-up (if alive) was over 7 years (range: 1 month to 11 years). The site of initial progression was identifiable in 80% of relapsing patients. CNS progression was a component of systemic melanoma relapse in 59/402 patients (15% overall). In 34/402 patients (9%) CNS progression represented the initial site of treatment failure. CNS progression was a component of initial progression in 27% of all patients whose melanoma relapsed (59/221). The risk of CNS progression was highest within 3 years of randomization. The difference in CNS progression rates between treatment arms was not significant (BCT = 25, HDI = 34, P = 0.24). Lymph node macrometastases strongly associated with CNS progression (P = 0.001), while ulceration and head and neck primaries were not significant predictors. This retrospective analysis of the S0008 trial identified a high brain metastasis rate (15%) in regionally advanced melanoma patients. Further studies are needed to establish whether screening plus earlier treatment would improve survival following CNS progression.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/secundario , Interferón-alfa/uso terapéutico , Melanoma/secundario , Melanoma/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Cisplatino/administración & dosificación , Dacarbazina/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Melanoma/complicaciones , Estadificación de Neoplasias , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Neoplasias Cutáneas/complicaciones , Úlcera Cutánea/etiología , Tasa de Supervivencia , Vinblastina/administración & dosificaciónRESUMEN
Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient's prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988-2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35-0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10-0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00-9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.
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PURPOSE: In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16-20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment. MATERIALS AND METHODS: All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months. RESULTS: 391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48-1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39-1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09-0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23-0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable. CONCLUSIONS: Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses.
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Carcinoma de Células Renales/tratamiento farmacológico , Interleucina-2/uso terapéutico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Estudios de Cohortes , Femenino , Humanos , Interleucina-2/administración & dosificación , Interleucina-2/farmacología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Análisis de SupervivenciaRESUMEN
Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml(-1)). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.
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Genoma Humano/genética , Melanoma/genética , Melanoma/patología , Células Neoplásicas Circulantes/patología , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
BACKGROUND: Trebananib, an investigational peptibody, binds to angiopoietin 1 and 2, thereby blocking their interaction with Tie2. PATIENTS AND METHODS: This open-label phase I study examined trebananib 3 mg/kg or 10 mg/kg intravenous (I.V.) once weekly plus sorafenib 400 mg twice per day or sunitinib 50 mg once per day in advanced RCC. Primary end points were adverse event incidence and pharmacokinetics. RESULTS: Thirty-seven patients were enrolled. During trebananib plus sorafenib administration (n = 17), the most common treatment-related adverse events (TRAEs) included rash (n = 12; 71%), diarrhea (n = 12; 71%), hypertension (n = 11; 65%), and fatigue (n = 11; 65%); grade ≥ 3 TRAEs (n = 7; 41%); and 2 patients (12%) had peripheral edema. During trebananib plus sunitinib administration (n = 19), the most common TRAEs included diarrhea (n = 14; 74%), fatigue (n = 13; 68%), hypertension (n = 11; 58%), and decreased appetite (n = 11; 58%); grade ≥ 3 TRAEs (n = 13; 68%); and 8 (42%) patients had peripheral edema. Trebananib did not appear to alter the pharmacokinetics of sorafenib or sunitinib. No patient developed anti-trebananib antibodies. Objective response rates were 29% (trebananib plus sorafenib) and 53% (trebananib plus sunitinib). CONCLUSION: The toxicities of trebananib 3 mg/kg or 10 mg/kg I.V. plus sorafenib or sunitinib in RCC were similar to those of sorafenib or sunitinib monotherapy, with peripheral edema being likely specific to the combinations. Antitumor activity was observed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Proteínas Angiogénicas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Femenino , Humanos , Indoles/administración & dosificación , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Pirroles/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Sorafenib , Sunitinib , Resultado del TratamientoRESUMEN
Merkel cell carcinoma (MCC) is a highly aggressive skin malignancy. The growing incidence and recognition of this cancer in elderly or immunosuppressed individuals suggests that it is becoming an increasing clinical challenge. MCC recently has been demonstrated to have a probable viral pathogenesis related to a novel member of the polyomavirus (termed Merkel cell polyomavirus [MCV]). The molecular pathogenesis of viral carcinogenesis is currently being worked out in MCC. Current diagnostic and therapeutic strategies are discussed, with an eye toward the future development of molecularly targeted treatments.
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Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/terapia , Infecciones por Polyomavirus/complicaciones , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , Carcinoma de Células de Merkel/patología , Carcinoma de Células de Merkel/virología , Ensayos Clínicos como Asunto , Humanos , Poliomavirus/genética , Poliomavirus/metabolismo , Infecciones por Polyomavirus/patología , Infecciones por Polyomavirus/virología , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/virologíaRESUMEN
A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real-time information that can inform the care of every patient with cancer as well as connect patients with their entire medical teams. The rapid learning system will form a continuous cycle of learning: securely capturing data from every patient at the point of care, drawing on evidence-based guidelines, and evaluating quality of care against those standards and the outcomes of other patients. Clinical trials are another area in which collaboration is critical. Increasing clinical trial participation will require commitment across the cancer community from physicians, patients, insurers, hospitals, and industry. A 2010 report by the Institute of Medicine described challenges to participation in trials by both physicians and patients and provided recommendations for revitalizing clinical trials conducted through the National Cancer Institute's Cooperative Group Program. ASCO has pledged its support for the full implementation of these recommendations. More broadly, ASCO recently outlined a bold vision for translational and clinical cancer research for the next decade and made recommendations to achieve that vision. Accelerating Progress Against Cancer: ASCO's Blueprint for Transforming Clinical and Translational Research, released in November, calls for a research system that takes full advantage of today's scientific and technologic opportunities and sets a high-level agenda for policy makers, regulators, and advocates. Cancer research has transformed cancer care in the past forty years, and this year's Clinical Cancer Advances illustrates how far we have come in the past year alone. We now have a tremendous opportunity to use today's knowledge and collaborate across all facets of cancer care to conquer this deadly disease. Michael P. Link, MD President American Society of Clinical Oncology.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Ensayos Clínicos como Asunto/tendencias , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Calidad de Vida , Cuidado Terminal , Adulto , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Niño , Aprobación de Drogas , Detección Precoz del Cáncer/métodos , Escolaridad , Femenino , Predisposición Genética a la Enfermedad , Reforma de la Atención de Salud , Política de Salud/tendencias , Accesibilidad a los Servicios de Salud , Disparidades en Atención de Salud , Cuidados Paliativos al Final de la Vida , Humanos , Inmunoterapia , Masculino , Oncología Médica/tendencias , Mutación , Neoplasias/metabolismo , Neoplasias/mortalidad , Neoplasias/prevención & control , Medicina de Precisión , Prevención Primaria/métodos , Radioterapia Adyuvante , Investigación/tendencias , Prevención Secundaria/métodos , Factores Socioeconómicos , Tomografía Computarizada por Rayos X , Estados Unidos/epidemiologíaRESUMEN
5-Aza-2'-deoxycytidine (decitabine) is a drug targeting the epigenetic abnormalities of tumors. The basis for its limited efficacy in solid tumors is unresolved, but may relate to their indolent growth, their p53 genotype or both. We report that the primary molecular mechanism of decitabine-depletion of DNA methyltransferase-1 following its "suicide" inactivation-is not absolutely associated with cell cycle progression in HCT 116 colon cancer cells, but is associated with their p53 genotype. Control experiments affirmed that the secondary molecular effects of decitabine on global and promoter-specific CpG methylation and MAGE-A1 mRNA expression were S-phase dependent, as expected. Secondary changes in CpG methylation occurred only in growing cells ~24-48 h after decitabine treatment; these epigenetic changes coincided with p53 accumulation, an index of DNA damage. Conversely, primary depletion of DNA methyltransferase-1 began immediately after a single exposure to 300 nM decitabine and it progressed to completion within ~8 h, even in confluent cells arrested in G 1 and G 2/M. Our results suggest that DNA repair and remodeling activity in arrested, confluent cells may be sufficient to support the primary molecular action of decitabine, while its secondary, epigenetic effects require cell cycle progression through S-phase.
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Antimetabolitos Antineoplásicos/farmacología , Azacitidina/análogos & derivados , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Epigénesis Genética/efectos de los fármacos , Azacitidina/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Islas de CpG/efectos de los fármacos , ADN (Citosina-5-)-Metiltransferasa 1 , Daño del ADN , Metilación de ADN , Decitabina , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Antígenos Específicos del Melanoma/genética , Fase S , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
INTRODUCTION: Many cancers are associated with inferior vena cava (IVC) obstruction, but very few cancers have the ability to propagate within the lumen of the renal vein or the IVC. Renal cell carcinoma is the most common of these cancers. Renal cancer with IVC extension has a high rate of recurrence and a low five year survival rate. CASE PRESENTATION: A 62-year-old Caucasian woman previously in good health developed the sudden onset of severe reflux symptoms and right-sided abdominal pain that radiated around the right flank. A subsequent ultrasound and CT scan revealed a right upper pole renal mass with invasion of the right adrenal gland, liver, left renal vein and IVC. This appeared to be consistent with stage III renal cancer with IVC extension. Metastatic nodules were believed to be present in the right pericardial region; the superficial anterior abdominal wall; the left perirenal, abdominal and pelvic regions; and the left adrenal gland. The pattern of these metastases, as well as the invasion of the liver by the tumor, was thought to be atypical of renal cancer. A needle biopsy of a superficial abdominal wall mass revealed a surprising finding: The malignant cells were diagnostic of large-cell, B-cell non-Hodgkin's lymphoma. The lymphoma responded dramatically to systemic chemotherapy, which avoided the need for nephrectomy. CONCLUSION: Lymphomas only rarely progress via intraluminal vascular extension. We have been able to identify only one other case report of renal lymphoma with renal vein and IVC extension. While renal cancer would have been treated with radical nephrectomy and tumor embolectomy, large-cell B-cell lymphomas are treated primarily with chemotherapy, and nephrectomy would have been detrimental. It is important to remember that, rarely, other types of cancer arise from the kidney which are not derived from the renal tubular epithelium. These may be suspected if an atypical pattern of metastases or unusual invasion of surrounding organs is present. A preoperative or intraoperative biopsy may be helpful in these cases.
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Despite increasing use of "targeted therapy," interleukin-2 (IL-2) is unique, because this cytokine can induce long-term remissions in 5% to 7% of patients with metastatic melanoma and renal cancer. Clinical use of IL-2 is limited by severe toxicities, such as hypotension and vascular leak syndrome (VLS). Nitric oxide seems to be involved in the pathogenesis of these toxicities. On the basis of previous studies, we hypothesized that the endothelial nitric oxide synthase (eNOS) is the major source of nitric oxide. Mice with a knockout of the eNOS isoenzyme were treated with IL-2 (800,000 IU twice daily for 5 d). Blood pressure and vascular leak were measured. Inhibitors of superoxide, nitric oxide, and soluble guanylate cyclase were used to probe the mechanism. These experiments showed that IL-2 treatment increased eNOS messenger ribonucleic acid expression and nitric oxide metabolite excretion in eNOS knockout mice. Unlike normal and inducible nitric oxide synthase knockout mice, eNOS knockout mice proved resistant to IL-2-induced hypotension and vascular leak. Although hypotension seems to be mediated by superoxide or peroxynitrite, vascular leak seemed to be mediated by nitric oxide. Inhibition of guanylate cyclase and cyclic guanylate monophosphate formation during IL-2 treatment using methylene blue (MB)-inhibited vascular leak. MB treatment did not interfere with IL-2-induced antitumor mechanisms. Our experiments established that eNOS is a key mediator of IL-2-induced VLS and hypotension. A clinical trial of MB infusion during IL-2 therapy is currently being planned.
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Guanilato Ciclasa/metabolismo , Interleucina-2 , Óxido Nítrico Sintasa de Tipo III , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Síndrome de Fuga Capilar/inducido químicamente , Síndrome de Fuga Capilar/metabolismo , Carcinoma de Células Renales/tratamiento farmacológico , GMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Humanos , Hipotensión/inducido químicamente , Hipotensión/metabolismo , Interleucina-2/efectos adversos , Interleucina-2/farmacología , Manganeso , Melanoma/tratamiento farmacológico , Azul de Metileno/farmacología , Ratones , Ratones Endogámicos , Ratones Noqueados , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Compuestos Organometálicos/farmacología , ARN Mensajero/biosíntesis , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Guanilil Ciclasa Soluble , Superóxidos/metabolismo , omega-N-Metilarginina/farmacologíaRESUMEN
OBJECTIVE: Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. METHODS: Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate. RESULTS: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. CONCLUSION: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Dacarbazina/efectos adversos , Dacarbazina/farmacocinética , Demografía , Femenino , Humanos , Ipilimumab , Estimación de Kaplan-Meier , Subgrupos Linfocitarios/inmunología , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
OBJECTIVE: We reviewed the imaging studies of patients with known metastatic renal cell carcinoma (RCC) in order to more accurately assess where retroperitoneal lymphadenopathy occurs. METHODS: The database of patients with metastatic RCC was reviewed and 101 patients were found from 2002 to 2006. Each patient's CT scans were then reviewed. Twenty-seven retroperitoneal sections were defined for each patient, with 3 positions in each of the x-, y-, and z-axis. Lymph nodes greater than 1 cm were then counted for each section. RESULTS: Of the 101 patients, 31, of whom 28 qualified, were found to have retroperitoneal lymphadenopathy of a least 1 cm or greater. Two-thirds of nodes (87 out of 124) exhibited a suprahilar, intra-aortocaval, and retro-aortocaval trend of lymph node enlargement. Three patients (11%) had isolated infrahilar nodes, while 8 patients (29%) exhibited a skip lesion pattern by imaging criteria. Only 4 patients (14%) were noted to have lymph nodes that were confined to the ipsilateral (paraaortic or paracaval) nodes in the perihilar and infrahilar region, which would be readily accessible during renal surgery. CONCLUSIONS: Lymphatic drainage in RCC is ill-defined, likely due to multiple lymphatic outflow channels. However, after a review of retroperitoneal lymphadenopathy imaging in patients with known metastatic RCC, there does seem to be a cephalad, posterior, and medial drainage pattern.
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Carcinoma de Células Renales/diagnóstico por imagen , Neoplasias Renales/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Enfermedades Linfáticas/diagnóstico por imagen , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/complicaciones , Neoplasias Renales/patología , Ganglios Linfáticos/patología , Enfermedades Linfáticas/etiología , Espacio Retroperitoneal/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Disseminated metastatic disease, including brain metastases, is commonly encountered in malignant melanoma. The classical treatment approach for melanoma brain metastases has been neurosurgical resection followed by whole brain radiotherapy. Traditionally, if lesions were either too numerous or surgical intervention would cause substantial neurologic deficits, patients were either treated with whole brain radiotherapy or referred to hospice and supportive care. Chemotherapy has not proven effective in treating brain metastases. Improvements in surgery, radiosurgery, and new drug discoveries have provided a wider range of treatment options. Additionally, recently discovered mutations in the melanoma genome have led to the development of "targeted therapy." These vastly improved options are resulting in novel treatment paradigms for approaching melanoma brain metastases in patients with and without systemic metastatic disease. It is therefore likely that improved survival can currently be achieved in at least a subset of melanoma patients with brain metastases.
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BACKGROUND: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. METHODS: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. RESULTS: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. CONCLUSIONS: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/administración & dosificación , Hexanonas/administración & dosificación , Melanoma/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Imatinib mesylate (Gleevec) was evaluated as a treatment for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) based on the identification of strong c-KIT staining of these neoplasms. METHODS: Eligibility included patients with measurable metastatic or unresectable MCC, c-KIT (CD117) expression and a Zubrod performance status of 0 to 2. Imatinib 400 mg daily was administered orally in 28-day cycles to 23 patients. RESULTS: Overall, imatinib was well tolerated with grade 1 or 2 nausea, diarrhea, and hematologic toxicity as the most frequent side effects. A partial response was seen in 1 patient (4%; 95% CI: 0%-22%). Median progression-free survival was 1 month (95% CI: 1-2 months). Median overall survival was 5 months (95% CI: 2-8 months). One patient achieved a partial response and another had prolonged disease stabilization while receiving treatment. CONCLUSIONS: The majority of patients progressed rapidly within 1 to 2 cycles of treatment. The observed progression-free survival and overall survival were not adequate to conclude that this agent was active in advanced MCC, and thus the planned second stage of patient accrual was not opened.
Asunto(s)
Carcinoma de Células de Merkel/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Benzamidas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Estudios de Factibilidad , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Análisis de SupervivenciaRESUMEN
BACKGROUND: nab-Paclitaxel (ABI-007, Abraxane), a 130-nM, albumin-bound (nab) particle form of Cremophor-free paclitaxel, is approved for metastatic breast cancer. In the current study, the efficacy and safety of nab-paclitaxel were evaluated in previously treated and chemotherapy-naive patients with metastatic melanoma (MM). METHODS: Patients with histologically or cytologically confirmed, measurable MM were enrolled. nab-Paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m(2) (in previously treated patients) or 150 mg/m(2) (in chemotherapy-naive patients). RESULTS: Thirty-seven patients were treated in each cohort. The response rate was 2.7% in the previously treated cohort and 21.6% in the chemotherapy-naive cohort; the response plus stable disease rate was 37.8% and 48.6% in the previously treated and chemotherapy-naive cohorts, respectively. The median progression-free survival (PFS) was 3.5 months and 4.5 months, and the median survival was 12.1 months and 9.6 months, respectively. The probability of being alive and free of disease progression at 6 months was 27% for the previously treated cohort and 34% for the chemotherapy-naive cohort; the probability of surviving 1 year was 49% and 41%, respectively, for the previously treated and chemotherapy-naive cohorts. Approximately 78% of the previously treated patients and 49% of the chemotherapy-naive patients were treated without dose reduction. Eight (22%) chemotherapy-naive patients discontinued therapy because of toxicities. Drug-related toxicities included grade 3 to 4 (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue. CONCLUSIONS: nab-Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy-naive patients with MM. The response rate, PFS, and survival compared favorably with current standard dacarbazine therapy and combination therapies for melanoma. nab-Paclitaxel therapy of MM should be investigated further in controlled clinical trials. Cancer 2010. (c) 2010 American Cancer Society.
Asunto(s)
Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Paclitaxel/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Paclitaxel Unido a Albúmina , Albúminas/efectos adversos , Albúminas/uso terapéutico , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Melanoma/mortalidad , Metástasis de la Neoplasia , Paclitaxel/efectos adversos , Neoplasias Cutáneas/mortalidadRESUMEN
This overview of the current state of melanoma research and treatment and directions for moving forward represents the consensus of discussions between expert panelists at the First and Second Global Workshops on Melanoma held in Fajardo, Peurto Rico on November 30-December 1, 2007 and Clearwater Beach, Florida on November 19-20, 2008.
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Investigación Biomédica , Congresos como Asunto , Melanoma , Antineoplásicos/uso terapéutico , Apoptosis/fisiología , Biomarcadores/metabolismo , Ensayos Clínicos como Asunto , Consenso , Femenino , Humanos , Sistema Inmunológico/fisiología , Masculino , Melanoma/tratamiento farmacológico , Melanoma/fisiopatología , Melanoma/prevención & control , Transducción de Señal/fisiologíaRESUMEN
A storm of inflammatory cytokines is released during treatment with pro-inflammatory cytokines, such as interleukin-2 (IL-2), closely approximating changes initially observed during sepsis. These signals induce profound changes in neurologic function and cognition. Little is known about the mechanisms involved. We evaluated a number of experimental methods to quantify changes in brain blood vessel integrity in a well-characterized IL-2 treatment mouse model. Measurement of wet versus dry weight and direct measurement of small molecule accumulation (e.g. [(3)H]-H(2)O, sodium fluorescein) were not sensitive or reliable enough to detect small changes in mouse brain vascular permeability. Estimation of brain water content using proton density magnetic resonance imaging (MRI) measurements using a 7T mouse MRI system was sensitive to 1-2% changes in brain water content, but was difficult to reproduce in replicate experiments. Successful techniques included use of immunohistochemistry using specific endothelial markers to identify vasodilation in carefully matched regions of brain parenchyma and dynamic contrast enhanced (DCE) MRI. Both techniques indicated that IL-2 treatment induced vasodilation of the brain blood vessels. DCE MRI further showed a 2-fold increase in the brain blood vessel permeability to gadolinium in IL-2 treated mice compared to controls. Both immunohistochemistry and DCE MRI data suggested that IL-2 induced toxicity in the brain results from vasodilation of the brain blood vessels and increased microvascular permeability, resulting in perivascular edema. These experimental techniques provide us with the tools to further characterize the mechanism responsible for cytokine-induced neuropsychiatric toxicity.
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Encéfalo/irrigación sanguínea , Interleucina-2/toxicidad , Enfermedades Vasculares/inducido químicamente , Animales , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Permeabilidad Capilar/efectos de los fármacos , Femenino , Inmunohistoquímica , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Ratones Endogámicos C3H , Tamaño de los Órganos/efectos de los fármacos , Organismos Libres de Patógenos Específicos , Enfermedades Vasculares/inmunologíaRESUMEN
Twenty-five years ago treatment for metastatic renal cancer was generally ineffective. Over the intervening period, cytokines such as interferon-alpha and interleukin-2 gained prominence in the treatment of metastatic renal cancer. These agents produced clinical responses in a minority of patients with metastatic renal cancer, albeit with substantial toxicity. Over the last 3 years, there has been a substantial increase in our understanding of kidney cancer at the molecular level. This has led to major breakthroughs in the management of this once untreatable disease. Substantial gains in progression free and overall survival have occurred as a consequence. This issue of The Cancer Journal has been devoted to reviewing clinical progress in the treatment of metastatic renal cancer, with an eye toward current needs and the likely future directions of the field.