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BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.
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Carcinoma de Células Renales , Inmunoterapia , Neoplasias Renales , Humanos , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Masculino , Neoplasias Renales/patología , Neoplasias Renales/inmunología , Neoplasias Renales/terapia , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Femenino , Persona de Mediana Edad , Pronóstico , Recuento de Linfocitos , Anciano , Inmunoterapia/métodos , Linfopenia , Estudios Retrospectivos , Bases de Datos Factuales , AdultoRESUMEN
[This corrects the article DOI: 10.1155/2020/1385978.].
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PURPOSE: In metastatic breast cancer (MBC) population treated with capecitabine monotherapy, we investigated clinical-pathological features as possible biomarkers for the oncological outcome. METHODS: Retrospective study of consecutive MBC patients treated at University Hospitals Leuven starting capecitabine between 1999 and 2017. The primary endpoint was the durable response (DR), defined as non-progressive disease for > 52 weeks. Other main endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). RESULTS: We included 506 patients; mean age at primary breast cancer diagnosis was 51.2 years; 18.2% had de novo MBC; 98.8% were pre-treated with taxanes and/or anthracycline. DR was reached in 11.6%. Patients with DR, as compared to those without DR, were more likely oestrogen receptor (ER) positive (91.5% vs. 76.8%, p = 0.010) at first diagnosis, had a lower incidence of lymph node (LN) involvement (35.6% vs. 49.9%, p = 0.039) before starting capecitabine, were more likely to present with metastases limited to ≤ 2 involved sites (54.2% vs. 38.5%, p = 0.020) and time from metastasis to start of capecitabine was longer (mean 3.5 vs. 2.7 years, p = 0.020). ORR was 22%. Median TTP and OS were 28 and 58 weeks, respectively. In multivariate analysis (only performed for TTP), ER positivity (hazard ratio (HR) = 0.529, p < 0.0001), HER2 negativity (HR = 0.582, p = 0.024), absence of LN (HR = 0.751, p = 0.008) and liver involvement (HR = 0.746, p = 0.013), older age at capecitabine start (HR = 0.925, p < 0.0001) and younger age at diagnosis of MBC (HR = 0.935, p = 0.001) were significant features of longer TTP. CONCLUSION: Our data display relevant clinical-pathological features associated with DR and TTP in patients receiving capecitabine monotherapy for MBC.
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Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Capecitabina/uso terapéutico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Solitary fibrous tumor (SFT) is a rare variant of soft tissue sarcoma (STS). Materials and Methods. We reviewed SFT patients (pts) treated at our institution between 12/1990 and 09/2017. RESULTS: We identified 94 pts with a median follow-up (mFU) of 4.7 years (range: 0.1-21.53). Primary sites were the chest (33%), abdomen (21.3%), brain (12.8%), and extremities (9.6%); 6.4% of pts presented with synchronous metastasis. Median overall survival (mOS) from the first diagnosis was 56.0 months (m) (0.3-258.3). Doege-Potter syndrome was seen in 2.1% of pts. Primary resection was performed in 86 pts (91.5%). Median progression-free survival was 34.1 m (1.0-157.1), and 43% of pts stayed SFT-free during FU. Local recurrence occurred in 26.7% after a mFU of 35.5 m (1.0-153.8), associated with an OS of 45.1 m (4.7-118.2). Metachronous metastasis occurred in 30.2% after a mFU of 36.0 m (0.1-157.1). OS in metastatic pts was 19.0 m (0.3-149.0). Systemic therapy was given to 26 pts (27.7%) with inoperable/metastatic disease. The most common (57.7%) upfront therapy was doxorubicin, achieving responses in 13.3% of pts with a PFS of 4.8 m (0.4-23.8). In second line, pts were treated with ifosfamide or pazopanib, the latter achieving the highest response rates. Third-line treatment was heterogeneous. CONCLUSION: SFT is an orphan malignancy with a highly variable clinical course and a considerable risk of local failure and metachronous metastasis. Surgery is the only curative option; palliative systemic therapy is used in inoperable/metastatic cases but achieves low response rates. The highest response rates are seen with pazopanib in second/third line.
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Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Conclusions: Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy.
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Anilidas/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Nivolumab/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Anciano , Carcinoma de Células Renales/mortalidad , Bases de Datos Factuales , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Masculino , Resultado del TratamientoRESUMEN
PURPOSE: We aimed to investigate the role of palbociclib, a first-in-class cyclin-dependent kinase 4 and 6 inhibitor, in postmenopausal women with highly pretreated endocrine therapy-resistant metastatic breast cancer (MBC). METHODS: Between 28 September 2015 and 14 March 2017, a compassionate use program was established in the University Hospitals Leuven in which 82 postmenopausal women with estrogen receptor-positive, HER2-negative MBC were included after at least four lines of systemic treatment. The efficacy and safety analysis was performed in 82 patients who had received at least one dose of palbociclib and who had at least 6-month follow-up at the data cut-off point. The primary objective was the evaluation of efficacy of the combination of palbociclib and endocrine therapy with clinical benefit as primary endpoint, defined as the absence of progressive disease and being on treatment for at least 6 months. Secondary objectives were the evaluation of toxicity and the identification of potential predictors for clinical benefit. RESULTS: The median age of the patients was 67.1 years (range 34.8-85.9) at the time of inclusion. The average duration of treatment was 5.6 months (range 1-19), with a median progression-free survival of 3.17 (95% CI 2.76-4.70) months. At the data cut-off point, 10 patients were still on treatment with palbociclib. In this highly pretreated setting, 34 patients experienced no progressive disease within 6 months, resulting in an overall clinical benefit rate (CBR) of 41.5%. 20.7% (17/82) showed stable disease for ≥ 9 months and 13.4% for ≥ 12 months. None of the investigated predicting factors were significantly associated with clinical benefit at 6 months. For 43.9% of the patients, treatment delay or dose reduction was indicated. CONCLUSIONS: Palbociclib in combination with endocrine therapy shows an unexpectedly high CBR and favorable safety profile in heavily pretreated endocrine-resistant estrogen receptor-positive, HER2-negative MBC patients.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Retratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. PATIENTS AND METHODS: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. RESULTS: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). CONCLUSION: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.
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Osteonecrosis de los Maxilares Asociada a Difosfonatos/tratamiento farmacológico , Conservadores de la Densidad Ósea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Factor A de Crecimiento Endotelial Vascular/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Osteonecrosis de los Maxilares Asociada a Difosfonatos/patología , Conservadores de la Densidad Ósea/farmacología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacología , Factor A de Crecimiento Endotelial Vascular/farmacología , Adulto JovenRESUMEN
BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.
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Neoplasias Óseas/patología , Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Osteoprotegerina/genética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor Activador del Factor Nuclear kappa-B/genética , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Neoplasias Óseas/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Femenino , Genes src/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proto-Oncogenes Mas , Ligando RANK/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Terapia Recuperativa/métodos , Anciano , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Estudios Retrospectivos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
INTRODUCTION: Despite guidelines and recommendations, a large proportion of patients with cancer still have inadequate pain control. Transdermal opioid administration can overcome problems such as swallowing and compliance, because only one application every three days is needed. Transdermal buprenorphine was documented to provide effective pain relief in cancer and non-cancer patients. A ceiling effect was described in animals at supratherapeutic dose levels. OBJECTIVES: This prospective observational pilot study was designed to explore the need for doses of transdermal buprenorphine beyond the recommended maximum dose of 140 microg/h, in a cohort of palliative patients with cancer pain. METHODS: 36 consecutive palliative patients with uncontrolled cancer pain were prescribed transdermal buprenorphine after having received adequate information on the disease, its evolution, the pain and the drug. They gave written informed consent for participation in this observational study. Pain intensity and use of breakthrough medication were registered by the patient and the health care provider. RESULTS: Pain was judged to be satisfactory controlled, by the patient and the health care providers, in 21 of 28 evaluable patients at a dose lower than or equal to 140 microg/h. The success rate was higher in the hospitalized patient group. The observation of adequate pain control in two patients treated with doses up to 210 microg/h supports the hypothesis that buprenorphine dose titration above 140 microg/h can be clinically effective and well tolerated. This also refutes the assumption of a clinically relevant ceiling effect. CONCLUSIONS: Transdermal buprenorphine control cancer pain in the majority of palliative patients.
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Analgésicos Opioides/administración & dosificación , Buprenorfina/administración & dosificación , Neoplasias/complicaciones , Dolor/tratamiento farmacológico , Dolor/etiología , Administración Cutánea , Adulto , Femenino , Humanos , Masculino , Manejo del Dolor , Dimensión del Dolor , Cuidados Paliativos , Proyectos Piloto , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Accurate prediction of outcome for metastatic renal cell carcinoma (mRCC) patients receiving targeted therapy is essential. Most of the available models have been developed in patients treated with cytokines, while most of them are fairly complex, including at least five factors. We developed and externally validated a simple model for overall survival (OS) in mRCC. We also studied the recently validated International Database Consortium (IDC) model in our data sets. METHODS: The development cohort included 170 mRCC patients treated with sunitinib. The final prognostic model was selected by uni- and multivariate Cox regression analyses. Risk groups were defined by the number of risk factors and by the 25th and 75th percentiles of the model's prognostic index distribution. The model was validated using an independent data set of 266 mRCC patients (validation cohort) treated with the same agent. RESULTS: Eastern Co-operative Oncology Group (ECOG) performance status (PS), time from diagnosis of RCC and number of metastatic sites were included in the final model. Median OS of patients with 1, 2 and 3 risk factors were: 24.7, 12.8 and 5.9 months, respectively, whereas median OS was not reached for patients with 0 risk factors. Concordance (C) index for internal validation was 0.712, whereas C-index for external validation was 0.634, due to differences in survival especially in poor-risk populations between the two cohorts. Predictive performance of the model was improved after recalibration. Application of the mRCC International Database Consortium (IDC) model resulted in a C-index of 0.574 in the development and 0.576 in the validation cohorts (lower than those recently reported for this model). Predictive ability was also improved after recalibration in this analysis. Risk stratification according to IDC model showed more similar outcomes across the development and validation cohorts compared with our model. CONCLUSION: Our model provides a simple prognostic tool in mRCC patients treated with a targeted agent. It had similar performance with the IDC model, which, however, produced more consistent survival results across the development and validation cohorts. The predictive ability of both models was lower than that suggested by internal validation (our model) or recent published data (IDC model), due to differences between observed and predicted survival among intermediate and poor-risk patients. Our results highlight the importance of external validation and the need for further refinement of existing prognostic models.
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Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Modelos Estadísticos , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/secundario , Estudios de Cohortes , Unión Europea , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Pronóstico , Sunitinib , Análisis de SupervivenciaRESUMEN
BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Polimorfismo de Nucleótido Simple , Pirroles/uso terapéutico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Metástasis de la Neoplasia , Estudios Retrospectivos , Sunitinib , Resultado del TratamientoRESUMEN
BACKGROUND: The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ). METHODS: Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk. RESULTS: Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates. CONCLUSION: Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Neoplasias Renales/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Neoplasias Óseas/patología , Carcinoma de Células Renales/patología , Difosfonatos/administración & dosificación , Difosfonatos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Indoles/administración & dosificación , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Osteonecrosis/inducido químicamente , Compuestos de Fenilurea/administración & dosificación , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirroles/administración & dosificación , Estudios Retrospectivos , Sorafenib , Sunitinib , Resultado del TratamientoRESUMEN
BACKGROUND: In pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours. METHODS: In this phase I study successive patient cohorts received docetaxel 60 or 75mg/m(2) every 3weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle. RESULTS: Twenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75mg/m(2) in combination with SU-014813 50mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy. CONCLUSIONS: Oral SU-014813 50mg/day with docetaxel 75mg/m(2) is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Cohortes , Docetaxel , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Humanos , Dosis Máxima Tolerada , Melanoma/tratamiento farmacológico , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Proyectos de Investigación , Seguridad , Taxoides/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib. PATIENTS AND METHODS: We reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST). RESULTS: Two hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P<0.0001) and 19.5 versus 38.5 months (P<0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P<0.0001) and OS (P=0.001). CONCLUSION: The presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Neoplasias Óseas/secundario , Carcinoma de Células Renales/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Estudios Retrospectivos , Sunitinib , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Embryonal rhabdomyosarcoma (RMS) is a rare malignant mesenchymal tumour that is believed to arise from cells committed to a skeletal muscle lineage. The head and neck region is among the most frequent locations for embryonal RMS in adults. We present a retrospective review of seven patients treated in our institution between 2000 and 2008. The age at diagnosis ranged from 19 to 41 years. One patient received primary surgery followed by adjuvant radiotherapy. Six inoperable patients were treated along a single chemotherapy protocol: the VIA-VIP regimen (a combination of vincristine, ifosfamide and doxorubicin (VIA) in alternation with etoposide, ifosfamide and cisplatin (VIP) administered in 3-weekly cycles), followed by local therapy, involving radiation therapy and/or surgery. An objective response to chemotherapy was observed in all six patients. Three out of seven patients remain disease-free with a median follow up of 4.5 years. Although the prognosis of head and neck embryonal RMS is worse in adults than in children, a multimodality treatment combining surgery, radiotherapy and intensive chemotherapy is feasible and effective in this population.
Asunto(s)
Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/terapia , Rabdomiosarcoma Embrionario/diagnóstico , Rabdomiosarcoma Embrionario/terapia , Adulto , Terapia Combinada , Femenino , Humanos , Masculino , Resultado del Tratamiento , Adulto JovenAsunto(s)
Adenocarcinoma/secundario , Neoplasias Endometriales/patología , Neoplasias Pulmonares/secundario , Pulmón/patología , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Biopsia , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Acetato de Medroxiprogesterona/uso terapéutico , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
We describe a patient in whom cutaneous vasculitis appeared after 4 days of ciprofloxacin administration. On clinical examination, papular and purpuric lesions were limited to the left axillary zone of the thorax. Skin biopsy did not show the classic leukocytoclastic image but rather a mononuclear infiltrate of the vessel walls. Except a mild increase in inflammatory parameters, there were neither autoantibodies nor biological abnormalities, and the complement level was normal. These findings suggest that ciprofloxacin-induced vasculitis displays histopathological and serologic heterogeneity.