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BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.
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BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Trifluridina/uso terapéutico , Uracilo/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Países Bajos , Neutropenia/inducido químicamente , Pronóstico , Pirrolidinas , Timina , Resultado del Tratamiento , Trifluridina/efectos adversos , Uracilo/efectos adversos , Uracilo/uso terapéuticoRESUMEN
Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.Asunto(s)
Antineoplásicos/efectos adversos
, Antineoplásicos/farmacocinética
, Neutropenia/genética
, Variantes Farmacogenómicas
, Polimorfismo de Nucleótido Simple
, Taxoides/efectos adversos
, Taxoides/farmacocinética
, Adolescente
, Adulto
, Anciano
, Anciano de 80 o más Años
, Antineoplásicos/administración & dosificación
, Bases de Datos Genéticas
, Docetaxel
, Femenino
, Predisposición Genética a la Enfermedad
, Humanos
, Inactivación Metabólica/genética
, Masculino
, Proteínas de Transporte de Membrana/genética
, Proteínas de Transporte de Membrana/metabolismo
, Tasa de Depuración Metabólica/genética
, Persona de Mediana Edad
, Modelos Genéticos
, Neutropenia/inducido químicamente
, Farmacogenética
, Fenotipo
, Factores de Riesgo
, Índice de Severidad de la Enfermedad
, Taxoides/administración & dosificación
, Adulto Joven
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BACKGROUND: A circulating tumor cell (CTC) count is an established prognostic factor in metastatic breast cancer (MBC). Besides enumeration, CTC characterization promises to improve outcome prediction and treatment guidance. Having shown the feasibility of quantifying clinically relevant mRNA transcripts in CTCs, we determined the prognostic value of CTC gene expression in MBC. PATIENTS AND METHODS: CTCs were isolated and enumerated from blood of 197 MBC patients who were about to start first-line systemic therapy. Of these, 180 were assessable for quantification of mRNA expression by RT-qPCR in relation to time-to-treatment failure (TTF). A prognostic CTC gene profile was generated by leave-one-out cross validation in a 103 patient discovery set and validated in 77 patients. Additionally, all 180 patients were randomly divided into two equal sets to discover and validate a second prognostic profile. RESULTS: CTC count predicted for TTF at baseline {≥5 versus <5 CTCs/7.5 ml blood, hazard ratio (HR) 2.92 [95% confidence interval (CI) 1.71-4.95] P < 0.0001}. A 16-gene CTC profile was generated in the first discovery set, which identified patients with death or TTF <9 months versus those with a better outcome. In multivariate analysis, the 16-gene profile was the only factor associated with TTF [HR 3.15 (95% CI 1.35-7.33) P 0.008]. Validation of this profile in the independent patient set pointed into the same direction, but was not statistically significant. A newly generated 8-gene profile showed similarly favorable test characteristics as the 16-gene profile, but did not significantly pass validation either. CONCLUSION: A 16-gene CTC profile was identified, which provided prognostic value on top of CTC count in MBC patients. However, validation of this profile in an independent cohort, nor of a second profile, reached statistical significance, underscoring the need to further fine-tune the still promising approach of CTC characterization.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica/métodos , Células Neoplásicas Circulantes , Adulto , Bélgica/epidemiología , Neoplasias de la Mama/epidemiología , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Países Bajos/epidemiología , Pronóstico , Estudios ProspectivosRESUMEN
PURPOSE: To construct a model to predict preference-adjusted EuroQol 5D (EQ-5D) health utilities for patients with metastatic castrate-resistant prostate cancer (mCRPC) using the disease-specific health-related quality of life (HRQoL) measure, functional assessment of cancer therapy-prostate (FACT-P). METHODS: HRQoL data were collected from patients with mCRPC who were enrolled in an observational study conducted in 47 centers across six European Union countries. Utility values were generated using a UK-specific EQ-5D value set. The predictive validity of the five FACT-P subscales, patient demographics, comorbidities and prior chemotherapy was tested using ordinary least squares (OLS), median, Gamma and Tobit multivariate regression models. RESULTS: FACT-P and EQ-5D questionnaires were completed by 602 (86 %) patients. Mean age [standard deviation (SD)] was 72.1 (7.9) years, mean time from diagnosis (SD) was 5.4 (4.4) years, and mean time since failure of androgen deprivation therapy (SD) was 1.0 (1.6) years. At study inclusion, 39 % of patients were chemotherapy-naïve, 37 % were undergoing chemotherapy, and 24 % were post-chemotherapy. Mean FACT-P and EQ-5D utility values were 104 and 0.66, respectively. OLS regression was the best-performing model, explaining 61.2 % of the observed EQ-5D variation. All FACT-P subscales were significantly predictive; the physical and functional well-being subscales had the highest explanatory value (coefficient 0.023 and 0.001, respectively, p < 0.0001). The other variables did not add additional explanatory value. CONCLUSIONS: The algorithm developed enables translation of cancer-specific HRQoL measures to preference-adjusted health status in patients with mCRPC. The function may be useful in calculating EQ-5D scores when EQ-5D data have not been gathered directly.
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Algoritmos , Estado de Salud , Manejo del Dolor , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Calidad de Vida , Corticoesteroides/uso terapéutico , Anciano , Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Estudios Transversales , Difosfonatos/uso terapéutico , Docetaxel , Europa (Continente) , Humanos , Masculino , Modelos Teóricos , Dolor/tratamiento farmacológico , Cuidados Paliativos , Neoplasias de la Próstata Resistentes a la Castración/patología , Encuestas y Cuestionarios , Taxoides/uso terapéuticoRESUMEN
BACKGROUND: The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide. METHODS: In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m(-2) per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers. RESULTS: Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide. CONCLUSION: Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m(-2) per cycle, every 3 weeks) is 800 mg daily.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ifosfamida/uso terapéutico , Neoplasias/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Células Endoteliales/citología , Femenino , Humanos , Ifosfamida/efectos adversos , Ifosfamida/farmacocinética , Indazoles , Masculino , Persona de Mediana Edad , Factor de Crecimiento Placentario , Proteínas Gestacionales/sangre , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adulto JovenRESUMEN
BACKGROUND: There is new interest in platinum-based treatment of patients with metastatic castration resistant prostate cancer (mCRPC), to which a subgroup responds. Although platinum sensitivity is suggested to be associated with aggressive disease features and distinct molecular profiles, identification of responders is a clinical challenge. In this study, we selected patients who displayed PSA progression during cabazitaxel monotherapy, for combined cabazitaxel and carboplatin treatment. METHODS: In this retrospective study, mCRPC patients received carboplatin and cabazitaxel after biochemical progression following at least 2 cabazitaxel monotherapy cycles. We assessed PSA response, Time to PSA Progression (TTpsa) and Time to Radiographic Progression (TTrad). For a subset of patients, mutational analysis of BRCA-1, BRCA-2, ATM, PTEN, P53 and RB1 was performed. RESULTS: Forty-five patients were included, after a median of 4 (3-6) cycles of cabazitaxel monotherapy. Patients received a median of 3 (2-5) cycles of combined cabazitaxel and carboplatin, on which 12 (26.6%) patients had a PSA decline ≥ 50% from baseline. TTpsa was 2 (1-5) months and TTrad 3 (2-6) months. Adverse events were predominantly grade 1-2. Of the 29 (64.4%) patients evaluable for molecular signature, 6 (13.3%) had BRCA1, BRCA2 or ATM mutations and 12 (26.7%) had a PTEN, P53 or RB1 mutations. The occurrence of these mutations was not associated with any clinical outcome measure. CONCLUSIONS: In this study we showed that patients with PSA progression during cabazitaxel monotherapy could benefit from the addition of carboplatin to cabazitaxel, while prospective identification of these patients remains a clinical challenge.
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Neoplasias de la Próstata Resistentes a la Castración , Taxoides , Masculino , Humanos , Carboplatino/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Antígeno Prostático Específico , Resultado del Tratamiento , Estudios Retrospectivos , Estudios Prospectivos , Proteína p53 Supresora de Tumor/genética , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: The recommended treatment for a subset of patients with metastatic prostate cancer (mPC) changed from androgen deprivation therapy (ADT) to combinations with chemotherapy such as docetaxel. Implementation of new evidence from trials is however complex and challenging. We investigated the effect of multidisciplinary team meetings (MDTs) on adopting the newest emerging combination therapy in patients with mPC and assessed the overall survival of chemohormonal therapy in a real-world setting. METHODS: All mPC patients diagnosed between October 2015 and April 2016 in the Netherlands were identified from the population-based Netherlands Cancer Registry (n = 962). Logistic regression analyses were performed to examine the role of patient- and tumor characteristics, with special emphasis on MDTs, on receiving chemohormonal therapy versus ADT monotherapy. Kaplan-Meier survival curves were used to assess overall survival (OS). RESULTS: As many patients received ADT monotherapy as chemohormonal therapy (both n = 452). Being discussed in a MDT as patient, younger age, less comorbidities, a better performance status and high-volume disease were significantly associated with receiving chemohormonal therapy compared to ADT monotherapy. After adjustment for these factors, the presence of a MDT was independently associated with the administration of chemohormonal therapy (OR 2.77, 95% CI 1.68-4.59). The 2-year OS was 82.1% (95% CI: 78.5-85.6%) for patients receiving chemohormonal therapy and 59.9% (95% CI: 55.4-64.4%) for patients receiving ADT monotherapy. CONCLUSION: Being discussed in a MDT is independently associated with the administration of chemohormonal therapy in this group of patients with mPC. This supports the hypothesis that implementation of innovative treatment options is facilitated by an organizational structure with MDTs.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/efectos adversos , Docetaxel , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Grupo de Atención al PacienteRESUMEN
Differences in the clinical course and treatment responses in individual patients with advanced renal cell carcinoma (RCC) can largely be explained by the different genomics of this disease. To improve the personalized treatment strategy and survival outcomes for patients with advanced RCC, the genomic make-up in patients with advanced RCC was investigated to identify putative actionable variants and signatures. In this prospective multicenter study (NCT01855477), whole-genome sequencing (WGS) data of locally advanced and metastatic tissue biopsies and matched whole-blood samples were collected from 91 patients with histopathologically confirmed RCC. WGS data were analyzed for small somatic variants, copy-number alterations and structural variants. For a subgroup of patients, RNA sequencing (RNA-Seq) data could be analyzed. RNA-Seq data were clustered on immunogenic and angiogenic gene expression patterns according to a previously developed angio-immunogenic gene signature. In all patients with papillary and clear cell RCC, putative actionable drug targets were detected by WGS, of which 94% were on-label available. RNA-Seq data of clear cell and papillary RCC were clustered using a previously developed angio-immunogenic gene signature. Analyses of driver mutations and RNA-Seq data revealed clear differences among different RCC subtypes, showing the added value of WGS and RNA-Seq over clinicopathological data. By improving both histological subtyping and the selection of treatment according to actionable targets and immune signatures, WGS and RNA-Seq may improve therapeutic decision making for most patients with advanced RCC, including patients with non-clear cell RCC for whom no standard treatment is available to data. Prospective clinical trials are needed to evaluate the impact of genomic and transcriptomic diagnostics on survival outcome for advanced RCC patients.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Transcriptoma , Estudios Prospectivos , GenómicaRESUMEN
BACKGROUND: Enzalutamide, registered for the treatment of metastatic castration-resistant prostate cancer (mCRPC), is an inducer of multiple CYP-enzymes. Enzalutamide itself is mainly converted by CYP2C8 to the active metabolite N-desmethylenzalutamide (NDME). Due to a pharmacokinetic interaction, combining enzalutamide with a moderate CYP2C8 inhibitor might result in higher enzalutamide concentrations. Addressing this interaction is challenging since pharmacokinetic data are missing. CASE PRESENTATION: We present a case of a Caucasian male with mCRPC who was treated with enzalutamide and a moderate CYP2C8 inhibitor, clopidogrel, concomitantly. Plasma trough levels (Ctrough) of enzalutamide and its active metabolite N-desmethylenzalutamide (NDME) were determined and compared when treated with and without clopidogrel. The sum concentration of enzalutamide and NDME was not affected by coadministration of a moderate CYP2C8 inhibitor. Both treatments were well tolerated and no major side effect were observed. CONCLUSION: This case report shows that enzalutamide can be safely prescribed while cotreated with a moderate CYP2C8-inhibitor, without reducing the dose. More research is warranted to make a statement about the effect of enzalutamide on clopidogrel.
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Neoplasias de la Próstata Resistentes a la Castración , Benzamidas , Clopidogrel/uso terapéutico , Citocromo P-450 CYP2C8 , Humanos , Masculino , Nitrilos , Feniltiohidantoína/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
BACKGROUND: Cisplatin (cDDP) has regained interest for metastatic breast cancer (MBC) patients, given the platinum sensitivity in subtypes and better manageable toxicity. Here, the primary aim was to determine whether molecular characteristics of circulating tumor cells (CTCs) could identify patients responding to cDDP and to describe the outcomes to cDDP monotherapy in a large group of MBC patients pretreated with anthracycline- and taxane-based treatments. METHODS: Based on cell line data, a CTC-cDDP-sensitivity profile was generated. Applying an A'Herns single-stage phase II design, further investigation was considered worthwhile if 5/10 patients with a favorable profile responded to cDDP. Patients received 70mg/m2 cDDP every three weeks, CTCs were enumerated and the CTC-cDDP-sensitivity profile was determined. In total, 65 heavily pretreated MBC patients (77% received ≥2 lines of previous chemotherapy for MBC) were eligible for the per-protocol analysis. Primary endpoint was response rate, secondary endpoints included best observed response, progression-free survival (PFS) and overall survival (OS). RESULTS: The best observed response during cDDP therapy was a partial response in 7% and stable disease in 56% of the patients. None of the patients with a favorable CTC-cDDP-sensitivity profile had a response. The median baseline CTC count was 8 (range 0-3254). Patients with <5 CTCs had a better PFS and OS than patients with ≥5 CTCs (median PFS 4.5 months (95%CI 2.38-6.62) vs. 2.1 months [(95%CI 1.34-2.80)(p=0.009)] and median OS 13.1 months (95%CI 9.89-16.33) vs. 5.6 months [(95%CI 3.60-7.64)(p=0.003)]. No other factors than CTC count were associated with outcome to cDDP therapy, including triple-negative breast cancer versus ER-positive tumors. CONCLUSIONS: The CTC-cDDP-sensitivity profile was unable to select patients responding to cDDP monotherapy. In an unselected group of heavily pretreated MBC patients, cDDP yields outcomes comparable to other chemotherapeutic regimens for heavily pretreated MBC patients. CTC count was the only factor associated with outcome in these patients. CLINICAL TRIAL REGISTRATION: (https://www.trialregister.nl/trial/3885, identifier NTR4046).
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BACKGROUND: This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide. METHODS: Patients with advanced solid tumours, good performance score, good organ function, and no standard therapy available were eligible. Continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g m(-2) for 3 days or 6 g m(-2) for 5 days, administered every 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed. RESULTS: With growth-factor support, the MTD of sunitinib combined with either ifosfamide schedule was 12.5 mg in 32 patients enrolled. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed. CONCLUSION: With growth-factor support, the MTD of sunitinib with both ifosfamide schedules was 12.5 mg. Ifosfamide produced decreased sunitinib blood levels because of CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this also holds true for anti-tumour activity needs to be further explored.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ifosfamida/administración & dosificación , Indoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Pirroles/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Ifosfamida/efectos adversos , Ifosfamida/farmacocinética , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Dosis Máxima Tolerada , Pirroles/efectos adversos , Pirroles/farmacocinética , SunitinibRESUMEN
BACKGROUND: Although urinary adverse events after treatment of prostate cancer (CaP) are common, population-based studies on functional outcomes are scarce. The aim of this study is to evaluate the occurrence of urinary incontinence (UI) and erectile dysfunction (ED) in daily clinical practice using a nationwide Dutch cohort of patients with localized or locally advanced CaP. BASIC PROCEDURES: Patients were invited to complete the EPIC-26 questionnaire before treatment (baseline) and at 12 and 24 months after diagnosis. We calculated the mean EPIC-26 domain scores, stratified by treatment modality (i.e., radical prostatectomy, external radiotherapy, and no active treatment), and the proportions of patients with UI (defined as ≥ 2 pads per day) and ED (defined as erections not firm enough for sexual intercourse). Logistic regression modeling was used to explore the factors related to UI and ED after surgery. MAIN FINDINGS: In total 1,759 patients participated in this study. Patients undergoing radical prostatectomy experienced clinically relevant worsening in the urinary incontinence domain. After excluding patients who reported UI at baseline, 15% of patients with prostatectomy reported UI 24 months after diagnosis. Only comorbidity was associated with UI in surgically treated patients. Regardless of treatment, patients reported a clinically significant reduced sexual functioning over time. Before treatment, 54% of patients reported ED. Among the 46% remaining patients, 87% of patients treated with radical prostatectomy reported ED 24 months after diagnosis, 41% after radiotherapy, and 46% in patients without active treatment. Bilateral nerve-sparing surgery was the only factor associated with ED after 24 months. PRINCIPAL CONCLUSIONS: UI and ED frequently occur in patients with localized and locally advanced CaP, in particular after radical prostatectomy. The higher occurrence rate of UI and ED, compared with clinical trial participants, supports the importance of real-world data, which can be used for local treatment recommendations and patient information, but also to evaluate effects of future initiatives, such as treatment centralization and research aimed at improving functional outcomes.
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Disfunción Eréctil/epidemiología , Complicaciones Posoperatorias/epidemiología , Prostatectomía , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Incontinencia Urinaria/epidemiología , Anciano , Estudios de Cohortes , Humanos , Masculino , Estadificación de Neoplasias , Países Bajos , Neoplasias de la Próstata/patologíaRESUMEN
Until the publication of two pivotal trials, there were no treatment options available that did prolong the overall survival in men with hormone refractory prostate cancer (HRPC). Currently, docetaxel-based cytotoxic treatment is considered as a standard of care in all the patients with progressive metastatic HRPC. The use of this treatment regimen renders an equal survival benefit in all the subgroups of patients; however, there is a substantial difference in the overall survival between the subgroups. This review addresses the optimal timing of the cytotoxic treatment in asymptomatic patients with HRPC.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides/uso terapéutico , Docetaxel , Resistencia a Antineoplásicos , Humanos , Masculino , Neoplasias Hormono-Dependientes/mortalidad , Nomogramas , Neoplasias de la Próstata/mortalidadRESUMEN
As the incidence of invasive breast cancer, mainly developing at older age, is rising, the absolute number of elderly developing metastatic disease is also increasing. In view of improved life expectancy, sociocultural changes and better supportive measures for chemotherapy-induced toxicity, there is an increasing request for the administration of chemotherapy in elderly. At the moment, medical oncologists are still reluctant to use chemotherapy in elderly partly because of concern about increased toxicity and poor tolerability of this patient cohort, and the inability to appropriately select elderly that may benefit from chemotherapy. The question is whether this attitude remains justified. In this review, the current status of clinical research in the area of metastatic breast cancer regarding toxicity and activity of chemotherapy in older breast cancer patients is discussed. Further, data on pharmacokinetics are emphasised as age-related physiologic changes may affect these features with consequences for toxicity and decision-making. Moreover, data on assessment tools trying to characterise the 'functional age' are reviewed. In general, the literature data are scarce and hampered by major limitations, while pharmacokinetic data indicate that a different approach in older breast cancer patients does not always seem justified. To increase our knowledge aiming at optimisation of cancer treatment in elderly, there is a clear necessity for prospective, well-designed studies with emphasis on the particular requirements of older patients and incorporation of pharmacokinetic and -dynamic evaluation of cytotoxic agents used in this specific group. As in other research areas, maximal progress will be achieved by joined efforts of co-operative research groups.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Actitud Frente a la Salud , Neoplasias de la Mama/metabolismo , Quimioterapia Adyuvante , Toma de Decisiones , Femenino , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-ß-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2-deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.
Asunto(s)
Glucurónidos/farmacología , Glucurónidos/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/farmacocinética , Anciano , Animales , Transporte Biológico/efectos de los fármacos , Perros , Femenino , Glucurónidos/administración & dosificación , Células HEK293 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones Noqueados , Persona de Mediana Edad , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Niacinamida/administración & dosificación , Niacinamida/farmacocinética , Niacinamida/farmacología , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Compuestos de Fenilurea/administración & dosificación , Rifampin/farmacología , SorafenibRESUMEN
PURPOSE: There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. METHODS: In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. RESULTS: Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m(2), while for D1w MTD, it was 20 mg/m(2). In the D3w schedule, the administration of pazopanib led to a 33% lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m(2); P = 0.019) and >50% increase in AUC(0-∞) (mean 1,602 vs 2,414 ng*h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. CONCLUSIONS: Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Docetaxel , Interacciones Farmacológicas , Femenino , Humanos , Indazoles , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Taxoides/administración & dosificaciónRESUMEN
INTRODUCTION: The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC. PATIENTS AND METHODS: Data from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾ 50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel. RESULTS: From the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase. CONCLUSION: Our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Molecular Dirigida/métodos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Anciano , Anciano de 80 o más Años , Androstenos/administración & dosificación , Benzamidas , Supervivencia sin Enfermedad , Docetaxel , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/análogos & derivados , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Taxoides/administración & dosificación , Resultado del TratamientoRESUMEN
A prospective study of repaired vertical peripheral tears of the meniscus in fifty patients (nine women and forty-one men) was carried out from January 1977 to June 1980. All tears were confirmed preoperatively by arthroscopy. Forty-three medial and seven lateral menisci were repaired. Fifteen tears were treated within two weeks and thirty-five were operated on as long as seven years after injury. Only eight patients had a meniscal tear that was not accompanied by injuries of either the anterior cruciate ligament or the collateral ligaments, or both. At a mean follow-up of eighteen months (range, six to thirty-nine months), forty-two patients (84 per cent) had clinically apparent healing of the sutured meniscal tear. Repeat arthroscopy was done in twenty-seven (64 per cent) of these patients, four to twenty-nine months (mean, twelve months) after the operation. The arthroscopy proved that all of these repaired tears had healed. Eight patients had a second tear after the initial repair: four were reruptures at the sutured area and four were new ruptures in another area of the meniscus and were associated with fresh trauma. All of these patients subsequently had an arthroscopic meniscectomy.