RESUMO
PURPOSE: The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achieving high-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aim of this study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-related adverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK. METHODS: We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durable response to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression. HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEs and survival. HRQoL data was compared with two norm-based datasets. RESULTS: Eighty-four metastatic melanoma survivors were eligible and 87% (N = 73) completed the SF-36. ICI-related toxicity of any grade occurred in 92% of patients and 43% had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients required steroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyond steroids. Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical role functioning and general health compared with the normative population. There was a trend towards inferior scores in patients with previous exposure to ipilimumab compared with those never exposed to ipilimumab. CONCLUSIONS: Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicity and experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population's unique survivorship needs.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Melanoma/terapia , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , SobreviventesRESUMO
Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).
Assuntos
Antineoplásicos , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Antineoplásicos/efeitos adversos , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Pirimidinas/efeitos adversosRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2-6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2-3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. METHODS/DESIGN: REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL. Trial Registration ISRCTN79455488. NCT04913025 EUDRACT #: 2021-002060-47. CTA 31330/0008/001-0001; MREC approval: 21/LO/0593. REFINE Protocol version 4.0.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Nivolumabe/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Qualidade de Vida , Neoplasias Renais/tratamento farmacológico , ImunoterapiaRESUMO
Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.
Assuntos
Neoplasias Encefálicas , Melanoma , Humanos , Melanoma/patologia , Mutação , Evolução Molecular , DNARESUMO
Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants.
Assuntos
COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , SARS-CoV-2 , Neoplasias Hematológicas/tratamento farmacológicoRESUMO
Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Neoplasias , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , Estudos Clínicos como Assunto , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Imunidade , SARS-CoV-2RESUMO
Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.
Assuntos
Vacinas contra COVID-19/efeitos adversos , Neoplasias Colorretais/metabolismo , Síndrome da Liberação de Citocina , COVID-19/metabolismo , COVID-19/prevenção & controle , Humanos , Masculino , SARS-CoV-2/isolamento & purificaçãoRESUMO
ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T CD8-Positivos , Carcinoma de Células Renais/genética , Ensaios Clínicos Fase II como Assunto , Retrovirus Endógenos/genética , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Renais/genética , Nivolumabe/farmacologia , Estudos Prospectivos , Análise de Sequência de RNA , Análise de Célula Única , Evasão Tumoral , Microambiente Tumoral , Sequenciamento do ExomaRESUMO
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer.
RESUMO
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.
Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , Neoplasias/complicações , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/mortalidade , Feminino , Seguimentos , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/imunologia , Estudos Prospectivos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto JovemRESUMO
Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.
Assuntos
Vacina BNT162/imunologia , COVID-19/prevenção & controle , ChAdOx1 nCoV-19/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Vacina BNT162/administração & dosagem , COVID-19/sangue , COVID-19/imunologia , ChAdOx1 nCoV-19/administração & dosagem , Feminino , Humanos , Imunidade Celular , Imunogenicidade da Vacina , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/complicações , Estudos Prospectivos , Linfócitos T/imunologiaRESUMO
CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wildtype (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic.
Assuntos
Imunidade Adaptativa/imunologia , Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacina BNT162/administração & dosagem , Vacina BNT162/imunologia , COVID-19/complicações , COVID-19/epidemiologia , Vacinas contra COVID-19/administração & dosagem , ChAdOx1 nCoV-19/administração & dosagem , ChAdOx1 nCoV-19/imunologia , Feminino , Humanos , Imunogenicidade da Vacina/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Estudos Prospectivos , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Linfócitos T/imunologia , Linfócitos T/virologia , Vacinação/métodosRESUMO
Sorafenib, a multi-targeted kinase inhibitor, is approved in Europe for the treatment of patients with advanced renal cell carcinoma whose treatment with an interferon or interleukin-2-based therapy has previously failed, or who are unsuitable for such therapy. Unlike some first-generation anti-cancer therapies, sorafenib is generally associated with moderate and manageable adverse events. Some of the most common adverse events include a hand-foot skin reaction, diarrhoea and rash. As nurses provide an interface between the patient and the clinical team, it is important that they understand how sorafenib-related adverse events impact on patients. It is equally vital that nurses are able to recognize and manage these adverse events. Our experience has shown that with patient education, early reporting, monitoring and treatment, the adverse events of sorafenib therapy can be easily and effectively managed. Optimal adverse event management helps ensure treatment compliance and ensures that patients receive maximum benefit from therapy.
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Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Alopecia/induzido quimicamente , Alopecia/enfermagem , Carcinoma de Células Renais/enfermagem , Diarreia/induzido quimicamente , Diarreia/enfermagem , Toxidermias/etiologia , Toxidermias/enfermagem , Fadiga/induzido quimicamente , Fadiga/etiologia , Feminino , Humanos , Neoplasias Renais/enfermagem , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Educação de Pacientes como Assunto , Compostos de Fenilureia , SorafenibeAssuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Neoplasias Hematológicas/imunologia , Imunização Secundária , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/complicações , COVID-19/epidemiologia , Neoplasias Hematológicas/complicações , Humanos , Imunogenicidade da Vacina , Neoplasias/complicações , Neoplasias/imunologia , Avaliação de SintomasRESUMO
The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2-3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/administração & dosagem , Progressão da Doença , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Vemurafenib , Adulto JovemRESUMO
PURPOSE: As a group of European nurses familiar with treating patients with renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) using targeted/chemo- therapies, we aimed to review strategies for managing adverse events (AEs) associated with one targeted therapy, sorafenib. METHOD: Focusing on the AEs we considered the most difficult to manage (hand-foot skin reaction [HFSR], diarrhoea, fatigue and mucositis/stomatitis), we reviewed the literature to identify strategies relevant to sorafenib. Given the paucity of published work, this included strategies concerning targeted agents in general. This information was supplemented by considering the wider literature relating to management of these AEs in other tumour types and similar toxicities experienced during conventional anti-cancer therapy. Together with our own experience, this information was used to compile an AE management guide to assist nurses caring for patients receiving sorafenib. RESULTS: Our collated experience suggests the most commonly reported AEs with sorafenib and other targeted agents are HFSR, diarrhoea, fatigue, rash and mucositis/stomatitis; these generally have an acute (appearing at â¼0-1 months) or delayed onset (appearing at â¼3 months). Most management strategies in the literature were experience-based rather than arising from controlled studies. However, strategies based on controlled studies are available for HFSR and mucositis/stomatitis. CONCLUSIONS: Evidence, especially from controlled studies, is sparse concerning management of AEs associated with sorafenib and other targeted agents in RCC/HCC. However, recommendations can be made based on the literature and clinical experience that encompasses targeted and conventional therapies, particularly in the case of non-specific toxicities e.g. diarrhoea and fatigue.
Assuntos
Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Diarreia/enfermagem , Toxidermias/enfermagem , Fadiga/enfermagem , Terapia de Alvo Molecular/efeitos adversos , Mucosite/enfermagem , Avaliação em Enfermagem/métodos , Piridinas/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Diarreia/induzido quimicamente , Toxidermias/etiologia , Europa (Continente) , Fadiga/induzido quimicamente , Dermatoses do Pé/induzido quimicamente , Dermatoses do Pé/enfermagem , Dermatoses da Mão/induzido quimicamente , Dermatoses da Mão/enfermagem , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mucosite/induzido quimicamente , Niacinamida/análogos & derivados , Compostos de Fenilureia , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sociedades de Enfermagem , SorafenibeAssuntos
Antineoplásicos/efeitos adversos , Indóis/efeitos adversos , Melanoma/tratamento farmacológico , Paniculite/induzido quimicamente , Paniculite/diagnóstico , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/efeitos adversos , Adulto , Antineoplásicos/administração & dosagem , Diagnóstico Diferencial , Eritema Nodoso/diagnóstico , Feminino , Ácido Glutâmico , Humanos , Indóis/administração & dosagem , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Sulfonamidas/administração & dosagem , Valina , VemurafenibRESUMO
PURPOSE: Tumor necrosis factor alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti-TNF-alpha monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC. PATIENTS AND METHODS: Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-alpha, CCL2, and interleukin-6 (IL-6) were measured before and during treatment. RESULTS: TNF-alpha and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF-alpha at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-alpha, IL-6, and CCL2 and poor survival (< 12 months). CONCLUSION: This is the first direct clinical evidence suggesting that TNF-alpha may be a therapeutic target in RCC. Plasma levels of TNF-alpha, IL-6, and CCL2 may have predictive and prognostic significance.