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PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , América Latina , Consenso , SunitinibRESUMEN
Cancer is primarily a disease in which late diagnosis is linked to poor prognosis, and unfortunately, detection and management are still challenging. Circulating tumor cells (CTCs) are a potential resource to address this disease. Cell fusion, an event discovered recently in CTCs expressing carcinoma and leukocyte markers, occurs when ≥2 cells become a single entity (hybrid cell) after the merging of their plasma membranes. Cell fusion is still poorly understood despite continuous evaluations in in vitro/in vivo studies. Blood samples from 14 patients with high-grade serous ovarian cancer (A.C. Camargo Cancer Center, São Paulo, Brazil) were collected with the aim to analyze the CTCs/hybrid cells and their correlation to clinical outcome. The EDTA collected blood (6 mL) from patients was used to isolate/identify CTCs/hybrid cells by ISET. We used markers with possible correlation with the phenomenon of cell fusion, such as MC1-R, EpCAM and CD45, as well as CEN8 expression by CISH analysis. Samples were collected at three timepoints: baseline, after one month (first follow-up) and after three months (second follow-up) of treatment with olaparib (total sample = 38). Fourteen patients were included and in baseline and first follow-up all patients showed at least one CTC. We found expression of MC1-R, EpCAM and CD45 in cells (hybrid) in at least one of the collection moments. Membrane staining with CD45 was found in CTCs from the other cohort, from the other center, evaluated by the CellSearch® system. The presence of circulating tumor microemboli (CTM) in the first follow-up was associated with a poor recurrence-free survival (RFS) (5.2 vs. 12.2 months; p = 0.005). The MC1-R expression in CTM in the first and second follow-ups was associated with a shorter RFS (p = 0.005). CEN8 expression in CTCs was also related to shorter RFS (p = 0.035). Our study identified a high prevalence of CTCs in ovarian cancer patients, as well as hybrid cells. Both cell subtypes demonstrate utility in prognosis and in the assessment of response to treatment. In addition, the expression of MC1-R and EpCAM in hybrid cells brings new perspectives as a possible marker for this phenomenon in ovarian cancer.
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Cistadenocarcinoma Seroso , Células Neoplásicas Circulantes , Neoplasias Ováricas , Femenino , Humanos , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor/metabolismo , BrasilRESUMEN
The discovery of predictive biomarkers in metastatic colorectal cancer (mCRC) is essential to improve clinical outcomes. Recent data suggest a potential role of circulating tumor cells (CTCs) as prognostic indicators. We conducted a follow-on analysis from a prospective study of consecutive patients with mCRC. CTC analysis was conducted at two timepoints: baseline (CTC1; before starting chemotherapy), and two months after starting treatment (CTC2). CTC isolation/quantification were completed by ISET® (Rarecells, France). CTC expressions of drug resistance-associated proteins were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Seventy-five patients were enrolled from May 2012 to May 2014. A CTC1 cut-off of >1.5 CTCs/mL was associated with an inferior median OS compared to lower values. A difference of CTC2-CTC1 > 5.5 CTCs/mL was associated with a reduced median PFS. By multivariate analysis, CTC1 > 1.5 CTCs/mL was an independent prognostic factor for worse OS. Multi-drug resistance protein-1 (MRP-1) expression was associated with poor median OS. CTC baseline counts, kinetics, and MRP-1 expression were predictive of clinical outcomes. Larger studies are warranted to explore the potential clinical benefit of treating mCRC patients with targeted therapeutic regimens guided by CTC findings.
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Colorectal cancer is a common and often deadly cancer. Circulating tumor cells (CTCs) have been implicated as a potentially valuable prognosis factor. The detection of circulating tumor microemboli (CTM) and of simple blood component parameters that reflect inflammatory status, such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), may provide information about tumor progression. The aim of this study was to explore the importance of CTCs, CTM, PLR, and NLR prospectively in non-metastatic colon cancer progression. CTCs were enriched using ISETâ (Isolation by SizE of Tumor cells) and identified by immunocytochemical exclusion of leukocytes. We evaluated CTCs and blood cell parameters in a cohort of 69 stage I-III colon cancer patients (52.2% men; median age, 61 years; age range, 19-87 years) at a baseline timepoint prior to resection surgery. The median of CTC levels at baseline was 20 cells/8â¯mL (0-94) and higher levels were associated with CTM presence (pâ¯=â¯0.02). CTM were found in 18 (26.1%) patients. Of 18 stage I patients, 33.3% had CTM and of 51 stages II or III patients, 13.7% had CTM (pâ¯=â¯0.08). Patients with a high PLR (>124) were mostly (75.6%) diagnosed with high-risk stages II/III cancer (stages I/low-risk II, 24.4%; pâ¯=â¯0.014). All 8 patients that had disease recurrence during follow-up had a high PLR (pâ¯=â¯0.02â¯vs. low PLR). NLR was not significantly associated with disease stage or recurrence. The present results indicate that CTCs and PLR analyses may be clinically useful for colon cancer management and risk stratification.
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BACKGROUND: Although multiple therapies have emerged for the treatment of metastatic renal cell carcinoma (mRCC), it is unclear whether application of these agents is consistent in developed and developing countries. We sought to determine patterns of care for mRCC in Brazil as a representative developing country. MATERIAL AND METHODS: A commercial database was used to acquire information pertaining to patients with mRCC receiving treatment at private or public hospitals in Brazil between March 2013 and October 2016. Basic clinical and demographic criteria were available, as well as information to ascertain the International Metastatic Renal Cell Carcinoma Database Consortium risk. Treatment-related data across multiple lines of therapy were collected. RESULTS: Of 4,379 patients assessed, 3,990 (91%) had metastatic disease, and 26%, 48%, and 26% of patients had good, intermediate, and poor International Metastatic Renal Cell Carcinoma Database Consortium risk disease, respectively. Although 3,149 patients (79%) received first-line therapy, only 641 (20%) and 152 (5%) received second- and third-line therapy, respectively. In the first-line setting, vascular endothelial growth factor-directed agents represented the most commonly used therapy, whereas in the second-line setting, vascular endothelial growth factor- and mammalian target of rapamycin-directed agents were used with similar frequency. Marked differences were seen in receipt of systemic therapy on the basis of treatment in private or public hospitals. CONCLUSION: Relative to developed countries, marked attrition is noted between each subsequent line of therapy in Brazil. Patterns of care also vary greatly in private and public settings, pointing to financial constraints as a potential cause for discordances in treatment.
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Carcinoma de Células Renales/terapia , Neoplasias Renales/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Adulto JovenRESUMEN
Circulating tumor cells are important markers of tumor progression and can reflect tumor behavior in metastatic colorectal cancer (mCRC). Identification of proteins that confer resistance to treatment is an important step to predict response and better selection of treatment for patients. Multidrug resistance-associated protein 1 (MRP1) and Multidrug resistance-associated protein 4 (MRP4) play a role in irinotecan-resistance, and Excision Repair Cross-Complementation group 1 (ERCC1) expression can confer resistance to platinum compounds. Here, we included 34 patients with mCRC and most of them received FOLFIRI or FOLFOX chemotherapy (91.1%). CTCs were isolated by ISET(®) Technology and identified in 30 patients (88.2%), with a median of 2.0 CTCs/mL (0-31.0). We analyzed the immunocytochemical expression of MRP1, MRP4 and ERCC1 only in patients who had previously detectable CTCs, accordingly to treatment received (n = 19, 15 and 13 patients, respectively). Among patients treated with irinotecan-based chemotherapy, 4 out of 19 cases with MRP1 positive CTCs showed a worse progression free survival (PFS) in comparison to those with MRP1 negative CTCs (2.1 months vs. 9.1 months; p = 0.003). None of the other proteins studied in CTCs had significant association with PFS. We analyzed also histological sections of primary tumors and metastases by immunohistochemistry, and found no association with clinicopathological characteristics or with PFS. Our results show MRP1 as a potential biomarker of resistance to treatment with irinotecan when found in CTCs from mCRC patients. This is a small proof-of-principle study and these early findings need to be validated in a larger cohort of patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Expresión Génica , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Clasificación del Tumor , Metástasis de la Neoplasia , Proyectos Piloto , Pronóstico , Análisis de SupervivenciaRESUMEN
Câncer de pulmão acomete 1,8 milhões de pessoas no mundo, com 1,6 milhões de óbitos decorrentes. É a principal neoplasia em incidência e mortalidade, com 56% dos casos diagnosticados já em fase avançada. Apesar do grande avanço no desenvolvimento de novos tratamentos para doença avançada na última década, faltam biomarcadores validados para a prática clínica, com valor prognóstico e preditivo de resposta a esses tratamentos. A detecção de CTCs no sangue periférico desses pacientes tem se mostrado como possível biomarcador em câncer de pulmão não pequenas células (CPNPC). Objetivo: O intuito desse estudo foi avaliar detecção de células tumorais circulantes (CTCs) em pacientes com CPNPC metastático, quanto ao valor prognóstico (correlação com sobrevida global (SG) e livre de progressão (SLP)) e preditivo (resposta radiológica). Método e Pacientes: Amostras de sangue para detecção de CTCs pelo método ISET (Rarecells Paris, France) foram coletadas antes do primeiro ciclo da nova quimioterapia, após 8 semanas do início e 16 semanas após o início, coincidindo com avaliação radiológica de resposta ao tratamento. Foram incluídos pacientes com diagnóstico de CPNPC metastático ao diagnóstico, ou que apresentaram recidiva após tratamento de doença localizada e que iriam iniciar novo tratamento sistêmico. Resultados: A amostra foi constituída por 32 pacientes, sendo 17 (53,1%) homens e 15 (46,9%) mulheres. O tipo histológico mais comum foi adenocarcinoma (n= 26; 81,25%). CTCs foram detectadas em 78,2% (25) dos pacientes no início do tratamento, em 85,2% (23) dos pacientes após 8 semanas e em 76,2% (16) após 16 semanas. Foi considerado como cut-off a mediana de contagem de CTCs por 8mL de sangue em cada momento, cujo valor foi de 16 CTCs/8mL. Houve uma tendência a maiores SLP e SG entre os pacientes com níveis abaixo da mediana comparados aos pacientes com níveis iguais ou superiores a ela (p=0,083 e p=0,45) após 8 semanas do início do tratamento. Quando avaliada cinética das CTCs nos momentos baseline e após 8 semanas nos pacientes submetidos a doublet de platina, houve diferença em SLP entre os pacientes que evoluíram com diminuição de CTCs ou se mantiveram indetectáveis (8,48 meses) comparados com aqueles cujos níveis aumentaram (3,42 meses; p=0,047). Não houve correlação entre contagem de CTCs e resposta radiológica. Conclusão: CTCs são detectáveis em alta porcentagem de pacientes com CPNPC metastático. Houve uma tendência a maior SLP e SG entre os pacientes com níveis abaixo da mediana, especialmente após 8 semanas do tratamento (CTC2). Houve uma maior SLP entre os pacientes cujos níveis se mantiveram indetectáveis ou diminuíram suas contagens ao longo do tratamento, versus aqueles que aumentaram na população submetida a doublet de platina.
Lung cancer occurs in approximately 1,8 million people and causes 1,6 million deaths worldwide. It is the main cancer in incidence and mortality, with 56% of cases diagnosed in advanced stage. In spite of the great improvement in developing new drugs for advanced disease in the last decade, it lacks biomarkers validated for clinical practice, with prognostic value and predictive of response to those new treatments. Detection of circulating tumor cells (CTCs) in peripheral blood of these patients has emerged as a potential biomarker for non-small cell lung cancer (NSCLC). Objective: The aim of this study was to evaluate detection of circulating tumor cells in patients with metastatic non-small cell lung cancer in terms of prognosis (disease-free survival (DFS) and overall survival(OS)) and prediction of radiographic response. Methods and patients: Blood samples for detection of CTCs by ISET method (Rarecells Paris,France) were collected before the first cycle of the new chemotherapy, 8 weeks after the beginning and 16 weeks after the beginning, matching radiographic evaluation.Patients with metastatic or relapsed non-small cell lung cancer, candidates to a new systemic treatment were included. Results: 32 patients were included, 17 of them men (53,1%) and 15 women (46,9%). The most common histology was adenocarcinoma (n=26, 81,25%). CTCs were detectable in 78,2% (25) of patients at the beginning of treatment, in 85,2% (25) of patients 8 weeks after, and in 76,2% (16) after 16 weeks. Median of CTCs/8mL was considered cut-off point for each time, which was 16 CTCs/8mL. There was a trend in longer disease-free survival and overall survival in those patients whose CTCs level were under median, compared to those equal or above it (p value = 0,083 and 0,45) after eight weeks of chemotherapy. When comparing CTC's kinetics at baseline and 8 weeks after treatment with platinum doublets, there was a difference in disease-free survival in those patients with decrease of CTC's levels or whose levels remained undetectable (8,48 months), comparing to an increase (3,42 months; p=0,047). There was no correlation between CTC's levels and radiographic response. Conclusion: CTCs are detectable in a high percentage of patients with metastatic NSCLC. There was a trend of higher DFS and OS in patients with CTC's levels above median, especially after 8 weeks of treatment (CTC2). A higher DFS was observed in patients whose CTC's levels decreased after 8 weeks of treatment or remained undetectable, in those submitted to doublet platinum.