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BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas , Biomarcadores Tumorais/sangue , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunotoxinas/efeitos adversos , Imunotoxinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer. METHODS: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging. RESULTS: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent. CONCLUSIONS: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.
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Anticorpos Monoclonais , Neoplasias da Próstata , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/farmacocinética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/patologia , Oligopeptídeos/metabolismo , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Avelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC). METHODS: In a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred. CONCLUSION: Avelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov NCT01772004; registered January 21, 2013.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: Metastatic melanoma patients were treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines. PATIENTS & METHODS: A total of 72 patients were enrolled in a single-arm Phase I/II (NCT00948480) trial or a randomized Phase II (NCT00436930). RESULTS: Toxicity was minimal. Median overall survival (OS) was 49.4 months; 5-year OS 46%. A 5-year OS was 72% for 18 recurrent stage 3 without measurable disease when treated and 53% for 30 stage 4 without measurable disease when treated. A total of 24 patients with measurable stage 4 when treated (median of four prior therapies) had an 18.5 months median OS and 46% 2-year OS. CONCLUSION: This dendritic cell vaccine was associated with encouraging survival in all three clinical subsets. Clinicaltrial.gov NCT00436930 and NCT00948480.
RESUMO
PURPOSE: Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study. MATERIAL AND METHODS: This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes<1000/mm3 or platelets<75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration). RESULTS: TRT interruptions > or =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (>70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration. CONCLUSION: Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.
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Neoplasias Pulmonares/radioterapia , Radioterapia/efeitos adversos , Radioterapia/métodos , Carcinoma de Pequenas Células do Pulmão/radioterapia , Antineoplásicos/administração & dosagem , Terapia Combinada , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Tamoxifeno/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. METHODS: Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections. RESULTS: Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to > 60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio = 0.304, p = 0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination. CONCLUSIONS: This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine. TRIAL REGISTRATION: Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009.
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Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Melanoma/terapia , Citocinas/sangue , Feminino , Humanos , Hipersensibilidade Tardia , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Análise de Sobrevida , Transplante Autólogo/efeitos adversosRESUMO
In patients with metastatic melanoma, sequential single-arm and randomized phase II trials with a therapeutic vaccine consisting of autologous dendritic cells (DCs) loaded with antigens from self-renewing, proliferating, irradiated autologous tumor cells (DC-TC) showed superior survival compared with similar patients immunized with irradiated tumor cells (TC). We wished to determine whether this difference was evident in cohorts who at the time of treatment had (1) no evidence of disease (NED) or (2) had detectable disease. Eligibility criteria and treatment schedules were the same for all three trials. Pooled data confirmed that overall survival (OS) was longer in 72 patients treated with DC-TC compared with 71 patients treated with TC (median OS 60 versus 22 months; 5-year OS 51% versus 32%, p=0.004). Treatment with DC-TC was associated with longer OS in both cohorts. Among 70 patients who were NED at the time that treatment was started, OS was better for DC-TC: 5-year OS 73% versus 43% (p=0.015). Among 73 patients who had detectable metastases, OS was better for DC-TC: median 38.8 months versus 14.7 months, 5-year OS 33% versus 20% (p=0.025). This approach is promising as an adjunct to other therapies in patients who have had metastatic melanoma.
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Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Imunoterapia/métodos , Melanoma/terapia , Células-Tronco Neoplásicas/transplante , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Carga Tumoral , Apresentação de Antígeno , Células Dendríticas/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Interferon gama/administração & dosagem , Masculino , Melanoma/imunologia , Melanoma/secundário , Antígenos Específicos de Melanoma/imunologia , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/imunologia , Neoplasias Cutâneas/imunologia , Taxa de Sobrevida , Células Tumorais Cultivadas/imunologiaRESUMO
The role of adjuvant therapy in the treatment of patients with high-risk malignant melanoma remains an area of intense investigation. The initial enthusiasm for high-dose interferon has been tempered by the results of more recent studies that allow for conflicting interpretations. Vaccine therapy trials have failed to clearly demonstrate a survival benefit, although several trials are currently ongoing. Recent studies of the role of chemotherapy suggest there may be combinations that have a survival benefit which deserve further study. This article will address patient selection and staging workup, and review options for treatment.
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Melanoma/terapia , Terapia Neoadjuvante , Neoplasias Cutâneas/terapia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Quimioterapia Adjuvante , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Interferons/administração & dosagem , Interferons/uso terapêutico , Melanoma/patologia , Melanoma/secundário , Estadiamento de Neoplasias , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios XRESUMO
The role of systemic chemotherapy in the treatment of patients with metastatic melanoma remains of questionable benefit. Despite encouraging phase II data from multiple institutions that suggested an improved overall response rate for patients treated with the Dartmouth regimen, recently completed phase III trials have failed to demonstrate a significant benefit in survival. Of concern is the fact that there have been relatively few new chemotherapeutic agents in the past several years that have demonstrated any activity in this disease. More recently there has been a shift away from combination chemotherapy to biochemotherapy. However, this approach has yet to be clearly defined as superior. The basis for optimism in the future in this field resides in the realm of molecular oncology. As mechanisms of resistance are identified, new molecules such as antisense oligonucleotides may provide the basis for increasing the sensitivity of melanoma to chemotherapeutic and/or immunotherapeutic treatments.
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Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/análogos & derivados , Melanoma/tratamento farmacológico , Melanoma/secundário , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carmustina/administração & dosagem , Carmustina/uso terapêutico , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Humanos , Compostos de Nitrosoureia/uso terapêutico , Paclitaxel/uso terapêutico , Tamoxifeno/administração & dosagem , TemozolomidaRESUMO
Only 10% of metastatic melanoma patients survive 5 years, even though many can achieve substantial tumor reduction by surgical resection and/or radiation therapy and/or systemic therapy. An effective, nontoxic, consolidation immunotherapy could benefit such patients. We initiated a randomized trial to compare 2 promising patient-specific immunotherapy cell products. Patients had to have a diagnosis of metastatic melanoma and availability of an autologous melanoma cell line. Patients were stratified by whether their most advanced stage had been regional or distant metastases, and by whether they had measurable disease at the time of treatment, then they were randomized to receive irradiated autologous proliferating tumor cells or autologous dendritic cells (DC) loaded with antigens from such cells. Both products were injected subcutaneously in 500 µg of granulocyte-macrophage colony stimulating factor, weekly for 3 weeks and then monthly for 5 months. Patients in the 2 arms did not differ in baseline characteristics. All patients received prescribed therapy. Treatment was well tolerated. At the time of initial analysis, with no patients lost to follow-up, 50% of patients deceased, and all surviving patients followed for at least 6 months after randomization, survival is superior in the DC arm (hazard ratio, 0.27; 95% confidence interval, 0.098-0.729) with median survival not reached versus 15.9 months, and 2-year survival rates of 72% versus 31% (P=0.007). This trial provides evidence that a DC vaccine is associated with longer survival compared with a tumor cell vaccine, and is consistent with previous data suggesting a survival benefit from this patient-specific immunotherapy.
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Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Imunoterapia/métodos , Melanoma/terapia , Células-Tronco Neoplásicas/transplante , Neoplasias Cutâneas/terapia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Masculino , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Análise de SobrevidaRESUMO
PURPOSE: During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration (VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings. PATIENTS AND METHODS: Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting. RESULTS: Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted. CONCLUSION: Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons.
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Ensaios Clínicos como Assunto , Instalações de Saúde , Neoplasias/terapia , Assistência ao Paciente/normas , Seleção de Pacientes , Resultado do Tratamento , Centros Médicos Acadêmicos , Serviços de Saúde Comunitária , Hospitais de Veteranos , Humanos , Qualidade da Assistência à SaúdeRESUMO
UNLABELLED: Between January 2001 and September 2007, we treated 54 metastatic melanoma patients with patient-specific tumor cell vaccines consisting of dendritic cells (DCS), derived from their peripheral blood cells that were cultured in interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor (GM-CSF), which had phagocytosed irradiated autologous tumor cells from a continuously proliferating, self-renewing, autologus tumor cell (TC) culture. The loaded DCs were injected subcutaneously in 500 microg of GM-CSF weekly x three, and then monthly for 5 months, for a total of up to 8 injections. The 34 men and 20 women had a median age of 50.5 years; 32 had M1c (visceral metastases and/or elevated lactate dehydrogenase) as their most advanced disease stage. Overall, 83% had received other systemic therapies, including interferon-alpha (n = 20), biochemotherapy (n = 19), GM-CSF (n = 19), chemotherapy (n = 16), IL-2 (n = 13), and other investigational vaccines (n = 7). Patients received an average of 7.4 vaccinations. Treatment was well-tolerated, with most patients experiencing only mild local pruritus and/or erythema. A positive delayed-type hypersensitivity reaction to purified autologous tumor cells was observed at baseline in only 1 of 54 patients, compared to 12 of 54 following vaccination (p = 0.001). The projected 5-year survival rate is an impressive 54% at a median follow-up of 4.5 years (range, 2.4-7.4) for the 30 surviving patients. This survival was superior to that observed following vaccination with irradiated TC in 48 melanoma patients in a previous trial (64 versus 31 months, p = 0.016). This patient-specific vaccine warrants further investigation, based on its safety and encouraging survival rates. ( CLINICAL TRIAL NUMBER: NCI-V01-1646).
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Antígenos de Neoplasias/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Células Dendríticas/transplante , Melanoma/imunologia , Melanoma/terapia , Adolescente , Adulto , Anticorpos/sangue , Antígenos CD/metabolismo , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Autoantígenos/uso terapêutico , Biomarcadores Tumorais/sangue , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Citocinas/sangue , Células Dendríticas/metabolismo , Progressão da Doença , Feminino , Gangliosídeos/sangue , Gangliosídeos/imunologia , Humanos , Hipersensibilidade Tardia/imunologia , Interferon gama/sangue , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Fagocitose/imunologia , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemAssuntos
Artrite Reumatoide/tratamento farmacológico , Imunossupressores/efeitos adversos , Segunda Neoplasia Primária/fisiopatologia , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Sobreviventes , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Neoplasias/imunologia , Segunda Neoplasia Primária/induzido quimicamenteRESUMO
Based on both clinical and laboratory data that suggested that tamoxifen (TAM) enhanced the effectiveness of cisplatin (DDP)-based chemotherapy regimens, the Cancer and Leukemia Group B (CALGB) designed and initiated a prospective, randomized phase III trial to test the efficacy of the addition of high-dose TAM to a standard chemoradiation regimen of DDP and etoposide (VP-16) in patients with limited-stage small cell lung cancer (LS-SCLC). Between August 6, 1993, and January 15, 1999, 319 patients with LSSCLC were accrued to CALGB 9235. Patients were randomized to receive chemotherapy with or without high-dose TAM. Treatment on the non-TAM containing arm (arm 1) included DDP (80 mg/m2 intravenously day 1 only) and VP-16 (80 mg/m2 intravenously days 1-3) given every 3 weeks for a total of 5 cycles. Patients treated on arm 2 received the identical chemotherapy regimen as described here with the addition of high-dose TAM (80 mg orally twice per day), which was given for 5 days each cycle starting 1 day before the DDP. Thoracic radiation (XRT) given at 200 cGy 5 days per week to a total dose of 50 Gy began on day 1 of cycle 4 of chemotherapy and overlapped with cycle 5. Prophylactic cranial irradiation was offered to all patients who achieved a complete response or near-complete response. A total of 307 patients are evaluable for response. After the completion of the chemoradiation portion of the treatment, the overall response rate (ORR) was 88% for 154 patients treated without tamoxifen and 84% for 153 patients treated with tamoxifen with complete response (CR) rates of 49% and 50%, respectively. The median failure-free survivals of 12.3 months and 10.5 months and the overall survivals of 20.6 months and 18.4 months, respectively, were not statistically significant between the 2 arms. Toxicity was similar with and without tamoxifen. This phase III trial failed to demonstrate a positive effect on either the response or survival for the addition of TAM to standard etoposide-cisplatin-radiation management for patients with LS-SCLC. However, these data continue to support a positive effect of chemoradiation in the treatment of patients with LS-SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/secundário , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/radioterapia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Irradiação Craniana , Fracionamento da Dose de Radiação , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Segunda Neoplasia Primária , Análise de Sobrevida , Tamoxifeno/administração & dosagemAssuntos
Melanoma/secundário , Doenças Vasculares Periféricas/complicações , Insuficiência Renal/complicações , Neoplasias Cutâneas/patologia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Doenças Vasculares Periféricas/terapia , Insuficiência Renal/terapiaRESUMO
BACKGROUND: Clouston syndrome is an autosomal dominant disorder characterized by nail dystrophy, partial or total alopecia, and hyperkeratosis of the palms and soles. OBJECTIVE: Although a variety of unusual cutaneous manifestations have been described, the incidence of melanoma in this population is unknown. METHODS: This article reports a case of in-transit metastatic subungual melanoma in a patient with Clouston syndrome successfully treated with hyperthermic limb perfusion with melphalan. RESULTS: Six months postperfusion, the patient is doing well, with resolution of the extremity erythema and edema. Followup ultrasonography revealed reduction in size of the eight subcutaneous nodules, with the largest measuring 3.3 cm in maximum diameter, representing nearly a 50% reduction in tumor volume postperfusion. CONCLUSION: Although melanoma has also been associated with some forms of ectodermal dysplasia, such as ectrodactyly--ectodermal dysplasia--clefting (EEC) syndrome, the incidence of melanoma in patients with Clouston syndrome is unknown. Thus far, to our knowledge, this is the first case report of melanoma arising in a patient with Clouston syndrome.