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LESSONS LEARNED: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma.Patients treated with 10 mg per day dose were most likely to require dose reductions.Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. BACKGROUND: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). METHODS: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. RESULTS: A total of 53 patients were enrolled in cohort 1 (n = 24) and cohort 2 (n = 29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. CONCLUSION: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.
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Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Adulto JovemRESUMO
BACKGROUND: Inadequate physician training may be a barrier to physician-patient discussions of advance directives (ADs). DESCRIPTION: The purpose of this study was to determine the effects of an ADs course, which includes completing a directive, on medical students' perceived knowledge of and preparedness for discussing ADs with patients. All 4th-year medical students completed a 10-hr bioethics course comprising interactive lecture and small-group discussion formats. Curriculum content included ethical and legal aspects of ADs. An 8-item survey with free-text entry was administered 1 month after course completion. Internal consistency reliability of survey scores was determined. Two authors independently coded the free-text comments and reached consensus on underlying themes. EVALUATION: Of the 89 students who completed the survey (response rate 80%), 87 (98%) felt more knowledgeable and 88 (99%) better equipped to counsel patients about ADs. Forty-two (47%) reported they had counseled others to complete ADs during the month after the course. Internal consistency reliability of survey scores was very good (Cronbach's alpha =.78). Dominant themes of responses to the question, "What was the most eye opening, troubling, or difficult aspect about filling out your advance directive?" included difficulties articulating wishes, legal language, selecting a surrogate, and facing mortality. CONCLUSIONS: These findings suggest an ADs course that includes completing a directive enhances medical students' empathy for and preparedness to discuss ADs with patients.
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Diretivas Antecipadas , Atitude do Pessoal de Saúde , Educação de Graduação em Medicina/organização & administração , Relações Profissional-Paciente , Estudantes de Medicina/estatística & dados numéricos , Adulto , Competência Clínica , Currículo , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Educação de Pacientes como Assunto , Adulto JovemRESUMO
The purpose of this study was to explore whether cancer patients, who are actively receiving cancer therapy and who sometimes have only a few months to live, have anxieties or concerns that arise as a result of not being able to care for their pets during their illness or after their demise. A survey was developed and utilized among such patients to assess whether they had pet-related concerns and anxieties and to determine whether they desired more information on available pet-related resources. Three hundred nine patients completed the survey, and 170 (55%) had a pet(s). The majority described that their pets helped them during their cancer. Only 4% of all patients and 7% of the pet owners desired more information on community resources for pet care, and 80% of pet owners had family members who were already helping them with pet care. Cancer patients appear to benefit from their pets and report few pet-related concerns. Healthcare providers at other medical centers should consider determining whether their patients have needs and anxieties related to caring for their pets and whether educational efforts should be put forth to focus on such issues.
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Animais Domésticos , Antineoplásicos/uso terapêutico , Ansiedade , Vínculo Humano-Animal , Saúde Mental , Neoplasias/tratamento farmacológico , Neoplasias/psicologia , Terapia Assistida com Animais , Animais , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Patients with schizophrenia sometimes receive substandard medical care. This study explored such disparities among lung cancer patients with underlying schizophrenia. METHODS: This retrospective study focused on patients with pre-existing schizophrenia (or in some instances schizoaffective disorder) and a lung cancer diagnosis made between 1980 and 2004. 'Disparity' was defined as a patient's having been prescribed less aggressive therapy for a potentially curable cancer based on state-of-the-art treatment standards for the time and for the cancer stage. Qualitative methods were used to assess healthcare providers' decision-making. RESULTS: 29 patients were included. The median age was 59 years; 38% were men. Twenty-three had non-small cell lung cancer and 6 small cell lung cancer; 17 had potentially curable cancers. Five of 17 had a 'disparity' in cancer care: (1) no cancer therapy was prescribed because of chronic obstructive pulmonary disease; (2) no cancer therapy was prescribed because of infection; (3) no chemotherapy was prescribed because the patient declined it; radiation was provided; (4) no chemotherapy was prescribed because of the patient's schizophrenia symptoms; radiation was administered; and (5) no surgery was performed because of disorientation from a lobotomy; radiation was prescribed. Comments from healthcare providers suggest reflection and ethical adjudication in decision-making. CONCLUSION: Schizophrenia was never the sole reason for no cancer treatment in patients with potentially curable lung cancer. This study provides the impetus for others to begin to assess the effect of schizophrenia on lung cancer management in other healthcare settings.
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Carcinoma Pulmonar de Células não Pequenas/psicologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Pequenas/psicologia , Carcinoma de Células Pequenas/terapia , Disparidades em Assistência à Saúde/ética , Neoplasias Pulmonares/psicologia , Neoplasias Pulmonares/terapia , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Adulto , Idoso , Atitude do Pessoal de Saúde , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/epidemiologia , Comorbidade , Ética Médica , Medicina Baseada em Evidências , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Preconceito , Prognóstico , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/epidemiologia , Estudos Retrospectivos , Esquizofrenia/epidemiologiaRESUMO
There are voluminous data acknowledging the validity of the animal/human bond. Pharmacologic, endocrinologic, immunologic, and psychologic studies have clearly documented the impact of the companion animal on the health and well-being of patients and families, especially in the medical setting. Our paper is, to our knowledge, the first study outlining the mechanics, engineering concepts, and background of providing the appropriate facility to connect the hospitalized patient with their companion animal. We have summarized the peer-reviewed research in this critical area.
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Terapia Assistida com Animais , Gatos , Cães , Planejamento Ambiental , Hospitalização , Vínculo Humano-Animal , Animais de Estimação , Animais , Engenharia , Hospitais , HumanosRESUMO
Critical to the clinical management of a patient with malignant melanoma is an understanding of its natural history. As with most malignant disorders, prognosis is highly dependent on the clinical stage (extent of tumor burden) at the time of diagnosis. The patient's clinical stage at diagnosis dictates selection of therapy. We review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. Although much work remains to be done to improve the survival of patients with melanoma, clinically meaningful results seem within reach.
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Melanoma/patologia , Melanoma/terapia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Humanos , Linfonodos/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , PrognósticoRESUMO
Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.
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Melanoma , Neoplasias Cutâneas , Diagnóstico Diferencial , Humanos , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/patologia , Melanoma/prevenção & controle , Fatores de Risco , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/prevenção & controleRESUMO
The optimal surveillance for patients with resected high-risk melanoma is controversial. Select locoregional or oligometastatic recurrences can be cured with salvage resection. Data on the ability of PET/CT to detect such recurrences are sparse. We evaluated whether surveillance PET/CT in patients with resected stage III-IV melanoma led to detection of clinically occult recurrences amenable to curative-intent salvage treatment. We retrospectively identified 1429 melanoma patients who underwent PET/CT between January 2008 and October 2012 at Mayo Clinic (Rochester, Minnesota). A total of 1130 were excluded because of stage I-II, ocular or mucosal melanoma, incomplete resection, PET/CT not performed for surveillance or performed at a different institution, and records not available. A total of 299 patients were eligible. Overall, 162 (52%) patients developed recurrence [locoregional: 77 (48%), distant: 85 (52%)]. The first recurrence was clinically occult in 98 (60%) and clinically evident in 64 (40%). Clinically evident recurrences were more often superficial (skin, subcutaneous, or nodal) or in the brain, whereas clinically occult recurrences more often visceral. Overall, 90% of all recurrences were detected by 2.8 years. In all, 70% of patients with recurrence underwent curative-intent salvage treatment (locoregional: 94%, distant: 48%), with similar rates for clinically occult versus clinically evident recurrences (66 vs. 75%, P=0.240). Overall survival was superior among those who underwent curative-intent salvage treatment [5.9 vs. 1.2 years; hazard ratio=4.27, 95% confidence interval (CI)=2.68-6.80; P<0.001], despite 79% developing recurrence again. PET/CT had high sensitivity (88%, 95% CI=79.94-93.31%), specificity (90%, 95% CI=88.56-91.56%), and negative predictive value (99%, 95% CI=98.46-99.52%). However, the positive predictive value was only 37% (95% CI=31.32-43.68%). In patients with resected stage III-IV melanoma, surveillance PET/CT detected a large proportion of clinically occult recurrences amenable to curative-intent salvage treatment. Despite a high rate of second relapse, curative-intent salvage treatment was associated with superior overall survival. Even though PET/CT had high sensitivity, specificity, and negative predictive value, positive predictive value was poor, highlighting the need for histologic confirmation of PET/CT-detected abnormalities.
Assuntos
Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Dendritic cells (DCs) have been used as vaccines in clinical trials of immunotherapy of cancer and other diseases. Nonetheless, progress towards the use of DCs in the clinic has been slow due in part to the absence of standard methods for DC preparation and exposure to disease-associated antigens. Because different ex vivo exposure methods can affect DC phenotype and function differently, we studied whether electroporation-mediated transfection (electrotransfection) of myeloid DCs with in vitro expanded RNA isolated from tumor tissue might be feasible as a standard physical method in the preparation of clinical-grade DC vaccines. METHODS: We prepared immature DCs (IDCs) from CD14+ cells isolated from leukapheresis products and extracted total RNA from freshly resected melanoma tissue. We reversely transcribed the RNA while attaching a T7 promoter to the products that we subsequently amplified by PCR. We transcribed the amplified cDNA in vitro and introduced the expanded RNA into IDCs by electroporation followed by DC maturation and cryopreservation. Isolated and expanded mRNA was analyzed for the presence of melanoma-associated tumor antigens gp100, tyrosinase or MART1. To test product safety, we injected five million DCs subcutaneously at three-week intervals for up to four injections into six patients suffering from stage IV malignant melanoma. RESULTS: Three preparations contained all three transcripts, one isolate contained tyrosinase and gp100 and one contained none. Electrotransfection of DCs did not affect viability and phenotype of fresh mature DCs. However, post-thaw viability was lower (69 +/- 12 percent) in comparison to non-electroporated cells (82 +/- 12 percent; p = 0.001). No patient exhibited grade 3 or 4 toxicity upon DC injections. CONCLUSION: Standardized preparation of viable clinical-grade DCs transfected with tumor-derived and in vitro amplified mRNA is feasible and their administration is safe.
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Small cell lung cancer is highly sensitive to chemotherapy, and a survival advantage with its use is well established. However, whether chemotherapy also confers such benefits to patients with severe organ dysfunction has not been extensively studied. The goal of this study was to provide further guidance for clinical decision-making. Medical records from small cell lung cancer patients who were seen at a single tertiary care institution between 1994 and 2002 were reviewed. All patients with severe organ dysfunction were identified. The latter was defined as creatinine >/=3mg/dl, total bilirubin>/=3mg/dl, and/or platelet count=50 x10(6) per milliliter. An in depth review of treatment and outcome in this patient subgroup was then undertaken. A total of 993 small cell lung cancer patients were seen during this period, and 25 (2.5%) had severe organ dysfunction. Eleven had been treated with chemotherapy, 11 had not, and this information was not retrievable in 3. Cyclophosphamide, etoposide (oral or intravenous), paclitaxel, cisplatin, or carboplatin were prescribed as single agents or in combination; 8 of 11 patients received an initial dose reduction. With chemotherapy, three patients normalized their bilirubin, and one manifested a notable drop. Median survival was 150 days for chemotherapy-treated patients but only 10 days for those who did not receive it. One patient died a few days after chemotherapy; three others were hospitalized immediately thereafter; and two were lost to follow up. In five patients, no notable adverse events were noted in the medical record. These preliminary findings suggest that, even in the presence of severe organ dysfunction, a subgroup of small cell lung cancer patients can tolerate chemotherapy, normalize their laboratory parameters, and go on to live for several months.
Assuntos
Carcinoma de Células Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Insuficiência de Múltiplos Órgãos/diagnóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bilirrubina/metabolismo , Carboplatina/administração & dosagem , Carcinoma de Células Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Creatinina/metabolismo , Ciclofosfamida/administração & dosagem , Tomada de Decisões , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Contagem de Plaquetas , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The animal-human bond refers to an emotional, almost existential, relationship between animals and people. From the time of antiquity, domestic animals were an important source of economic vitality, but with the changing cultural landscape, the companion animal has become a faithful friend. Overwhelming anecdotal evidence supports the healing power of this relationship. We summarize the emerging literature on the neurobiochemical and cardiovascular benefits of companion pet ownership. We address the peer-reviewed data from myriad journal articles assessing the impact of the companion animal on the quality and often the length of life of select patients.
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Terapia Assistida com Animais , Vínculo Humano-Animal , Qualidade de Vida , Animais , Cães , Humanos , Longevidade , Minnesota , Animais de EstimaçãoRESUMO
KW-2189, a semisynthetic duocarmycine antibiotic has been shown to exert antiproliferative effects against human tumor cell lines in vitro and animal tumor models in vivo. Phase I studies identified myelosuppression as the most noteworthy adverse effect. Presented are two concurrent phase II studies assessing the antitumor and toxicity profile of KW-2189 in metastatic melanoma patients. One of the studies accrued patients with a history of prior melanoma therapy and the other accrued patients without a history of prior melanoma therapy. KW-2189 was administered at 0.4 mg/m2 to previously treated patients and 0.5 mg/m2 to the previously untreated. Treatment was administered intravenously on day 1 of a 6-week cycle. Thirty previously untreated and 15 previously treated patients were accrued. The toxicity profiles of the both groups of patients were similar. Of the 15 previously treated patients, 8 completed once cycle of treatment, 2 completed 2 cycles, and 5 completed 3 cycles. Dose modification for neutropenia/ thrombocytopenia was necessary in six patients. Among the previously untreated cohort (30 patients), 16 completed 1 cycle, 5 completed 2 cycles, 4 completed 3 cycles, 3 completed 4 cycles, and 2 completed 6 cycles. Doses were modified (neutropenia or thrombocytopenia) in 11 patients. None of the 15 previously treated patients responded to therapy. Four patients remained stable during two cycles. Five of the previously untreated patients achieved a partial remission/regression. Response duration ranged from 2.8 to 16.6 months. Overall objective response rate was 17%. Regarding survival, one previously treated patient is still alive 2.9 years after study entry, and three previously untreated patients are still alive 1.6, 2.3, and 2.9 years after study entry. The 1-year survival rate for previously treated patients is 27% and for the untreated patients is 23%. In summary, the lack of significant antitumor activity of KW-2189 and its associated toxicity suggest that further testing of this regimen in patients with stage IV melanoma is not warranted.
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Antibióticos Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Duocarmicinas , Humanos , Melanoma/patologia , Taxa de SobrevidaRESUMO
A randomized, double-blind, placebo-controlled phase III clinical trial was performed to assess megestrol acetate (Megace) as a postsurgical adjuvant therapy for patients with locally advanced malignant melanoma. Patients whose tumors were greater than 1.7 mm thick and had no regional lymph node involvement and patients with regional lymph node involvement were randomized to receive either 160 mg twice per day oral suspension of megestrol acetate or placebo. Treatment was administered for a maximum of 2 years or until disease progression. The study accrued 262 eligible patients. All but two patients were followed until death or a minimum of 4.5 years. Disease progression was documented in 156 patients. Neither progression-free survival (PFS) nor overall survival (OS) was found to differ between the treatments. The median PFS was 2.4 years in the megestrol acetate arm and 2.3 years in the placebo arm. Multivariate analysis revealed a significantly decreased PFS for patients with four or more positive regional lymph nodes and metachronous nodal disease. Median OS was 5.3 years in the megestrol acetate arm and 3.9 years in the placebo arm. Multivariate analysis revealed that OS was significantly decreased for patients 70 years of age or older with four or more positive lymph nodes. Adjuvant therapy with megestrol acetate oral suspension administered at a dose of 160 mg twice a day for 2 years was not found to be effective in prolonging PFS or OS in patients with surgically resected, locally advanced melanoma.
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Antineoplásicos/uso terapêutico , Acetato de Megestrol/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Método Duplo-Cego , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Melanoma/cirurgia , Pessoa de Meia-Idade , Análise Multivariada , Análise de SobrevidaRESUMO
OBJECTIVE: Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents (temozolomide [TMZ]) and inhibition of tumor angiogenesis. METHODS: We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/wk) and 200 mg/m/d of TMZ for 5 days each cycle. RESULTS: Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%-59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). CONCLUSIONS: The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Everolimo , Feminino , Humanos , Quimioterapia de Indução , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Temozolomida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: The current study was undertaken to explore whether older age predicts adverse event rates in metastatic melanoma patients participating in cancer clinical trials. METHODS: Six phase II studies conducted at our institution for patients with metastatic disease were used in these pooled analyses: 1) ABT-510; 2) bortezomib, paclitaxel, and carboplatin; 3) everolimus; 4) bevacizumab, paclitaxel, carboplatin; 5) carboplatin and abraxane; and 6) temozolomide and everolimus. In total, 233 patients, 64 elderly (≥ 70 years) and 169 younger, were analyzed for age-based differences in grade 2 or worse adverse events and other clinical outcomes. RESULTS: Despite the fact that older patients had slightly worse performance scores, based on age, no differences in rates of adverse events were observed. Only worse baseline performance score predicted a higher rate of adverse events: patients with performance scores of one or worse were almost 4 times more likely to experience adverse events. Median cancer progression free survival and overall survival were comparable between older and younger patients. CONCLUSION: These findings suggest that concern for adverse event rates should not preclude the enrollment of elderly melanoma patients to cancer clinical trials. Such patients should continue to be monitored carefully for tumor response and toxicity.
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Thus far, peptide vaccines used to stimulate tumor-specific immune responses in patients with melanoma have been largely unsuccessful. Granulocyte-macrophage colony-stimulating factor and interleukin-2 are immune-potentiating cytokines that have improved vaccine responses in preclinical models. We hypothesized that higher doses of granulocyte-macrophage colony-stimulating factor and addition of low-dose interleukin-2 might augment responses to vaccine antigens. Patients with resected stage II, III, or IV melanoma were treated with vaccines containing three melanoma-associated peptides [MART-1a, gp100(207-217), and survivin], along with 300 or 500 mcg granulocyte-macrophage colony-stimulating factor in Montanide ISA. Cohorts of patients received low-dose subcutaneous interleukin-2 on days 7-20 after vaccination. Induction of a response was defined as either doubling of cytotoxic T lymphocyte frequency from baseline or increase in frequency from undetectable (<0.05%) to detectable. Leukocyte subsets and plasma cytokines were analyzed before and after vaccination. Cytotoxic T lymphocyte responses to MART-1a, gp100(207-217), and survivin were induced in 11, 16, and 14 of 19 patients, respectively. Responses were not higher in patients receiving 500 mcg granulocyte-macrophage colony-stimulating factor or low-dose interleukin-2 than in patients receiving 300 mcg granulocyte-macrophage colony-stimulating factor only. Interleukin-2 treatment (in nine patients) led to increases in natural killer cells and T regulatory cells compared with no interleukin-2 treatment (nine patients). Multiple plasma cytokines were transiently induced during vaccination. Neither increasing the dose of granulocyte-macrophage colony-stimulating factor nor addition of low-dose interleukin-2 resulted in an increase in the frequency of vaccine-specific cytotoxic T lymphocytes to a melanoma peptide vaccine. The increase in T regulatory cells associated with interleukin-2 treatment suggests that interleukin-2 may be immunosuppressive in this setting.
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Adjuvantes Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Interleucina-2/uso terapêutico , Melanoma/terapia , Vacinas de Subunidades Antigênicas/uso terapêutico , Adulto , Vacinas Anticâncer/imunologia , Estudos de Coortes , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Proteínas Inibidoras de Apoptose/imunologia , Interleucina-2/imunologia , Antígeno MART-1/imunologia , Masculino , Melanoma/imunologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Projetos Piloto , Survivina , Vacinas de Subunidades Antigênicas/imunologia , Adulto Jovem , Antígeno gp100 de Melanoma/imunologiaRESUMO
OBJECTIVES: Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic antitumor immunity. To improve the clinical and immunologic efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma. METHODS: We conducted a dose-escalation clinical trial of HLA-A2 patients with metastatic melanoma to the lung treated with aerosolized granulocyte macrophage colony stimulating factor (GM-CSF) (500-2000 microg/dose, with increments of 250 microg/dose/cohort) twice/d on days 1 to 7 and 15 to 21 every 28 days until progression or severe toxicity to find a dose where a majority of patients develop antitumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined. RESULTS: The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which a majority of patients (> or =3 of 5) demonstrated significant up-regulation of antitumor immunity. Three of 16 patients who were tetramer positive for at least one melanoma antigen (eg, MART-1) pretreatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pretreatment developed an IR against gp100. The greatest changes in antitumor immunity occurred at the highest dose levels. CONCLUSIONS: A dose of aerosolized GM-CSF capable of inducing antitumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in antitumor T cell IRs was achieved at the highest doses of GM-CSF.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Administração por Inalação , Adulto , Aerossóis , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/metabolismo , Relação Dose-Resposta a Droga , Feminino , Antígeno HLA-A2/imunologia , Humanos , Imunofenotipagem , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Antígeno MART-1 , Masculino , Dose Máxima Tolerável , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Proteínas Recombinantes , Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Resultado do TratamentoRESUMO
OBJECTIVES: Thrombospondins are natural inhibitors of angiogenesis, tumor metastases, and tumor growth (melanoma). ABT-510 is a synthetic analog of thrombospondin-1, well tolerated in phase I studies. We conducted a phase II trial evaluating the clinical efficacy of ABT-510 and its effects on biomarkers of angiogenesis and immunity in patients with metastatic melanoma (MM). PATIENTS AND METHODS: A 2-stage phase II clinical trial was conducted to assess the clinical efficacy, safety, and pharmacodynamic effects (angiogenesis and immunity) of ABT-510 in patients with stage IV melanoma. The primary endpoint was 18-week treatment failure rate. Patients self-administered 100 mg of ABT-510 subcutaneously twice daily. Blood samples were collected at baseline and every 3 weeks while on therapy. Eligible patients demonstrated measurable disease, good performance status and no evidence of intracranial metastases. Correlative laboratory studies evaluated biomarkers of angiogenesis and immunity. RESULTS: Twenty-one patients were enrolled. Most patients were stage M1c (71%) and all had prior therapy for MM. Only 3 of the first 20 patients enrolled were progression free and on treatment at 18 weeks resulting in early termination of the study. Decreases in peripheral blood VEGF-A levels and VEGF-C levels, and CD146 and CD34/133 counts relative to pretreatment were detected. Limited changes in antitumor T cell immunity were observed. CONCLUSIONS: ABT-510 therapy administered at 100 mg twice/day in patients with MM did not demonstrate definite clinical efficacy. Further dose escalation or combination with cytotoxic therapy may be more effective therapeutically.
Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombospondina 1 , Resultado do TratamentoRESUMO
BACKGROUND: Patients with metastatic melanoma (MM) have very few therapy options. Based on reports of responses to paclitaxel and carboplatin (PC), 31 patients with MM were treated with PC. METHODS: Data regarding patients treated with PC were abstracted from medical records. Clinical outcomes as determined by the treating oncologist were used for this analysis. Response determination was retrospectively confirmed using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Thirty-one patients with MM were treated with PC. Patients had a median of 2 previous therapies, with the majority (29; 94%) having failed prior temozolomide (TMZ) or dacarbazine (DTIC) therapy. The most commonly used regimen was weekly paclitaxel (at a dose of 100 mg/m(2)) and carboplatin (area under the curve 2) administered on Days 1, 8, and 15 of a 28-day cycle. An objective partial response was noted in 8 patients (26%) with an additional 6 patients (19%) having stable disease; therefore, a clinical benefit was noted in 45% of those patients treated. The median time to disease progression for the entire group was 3 months (range, 0-7 mos), with a median overall survival of 7.8 months (range, 1-14 mos). The clinical benefit derived by the 14 patients, which lasted for a median of 5.7 months (range, 2.5-7.3 mos), was considered to be clinically significant. At the time of last follow-up, eight patients continued to receive PC therapy. CONCLUSIONS: The PC combination appears to have definite and clinically meaningful activity when used as second-line therapy after TMZ or DTIC. Further evaluation of this regimen, alone or as a 'backbone' for other agents, needs to be considered.