RESUMEN
Cardiac metastases from head and neck cancer are rare. We present 2 patients with primary head and neck cancer found to have cardiac metastases. Electrocardiograms showed a persistent acute infarction pattern due to myocardial tumor infiltration. No cardiac symptoms were present. Both patients died of metastatic disease.
Asunto(s)
Neoplasias de Cabeza y Cuello/patología , Neoplasias Cardíacas/secundario , Infarto del Miocardio/diagnóstico , Anciano , Diagnóstico Diferencial , Ecocardiografía , Electrocardiografía , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Infarto del Miocardio/fisiopatologíaRESUMEN
BACKGROUND: Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC. METHODS: Sequential cohorts of 3 to 6 patients with advanced RCC received dose-escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained. RESULTS: Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed. CONCLUSIONS: The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Pirroles/administración & dosificación , Sirolimus/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/secundario , Everolimus , Femenino , Humanos , Indoles/farmacocinética , Neoplasias Renales/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pirroles/farmacocinética , Sirolimus/administración & dosificación , Sirolimus/farmacocinética , SunitinibRESUMEN
Sunitinib is associated with a robust objective response rate in patients with metastatic clear cell renal cell carcinoma (RCC). The primary objective of this phase II clinical trial was to assess the overall response rate for sunitinib in patients with papillary metastatic RCC as well as other non-clear cell histologies. A Simon 2-stage design was used to determine the number of papillary metastatic RCC patients for enrollment, and allowed for descriptive response data for other non-clear cell histologies. Twenty-three patients were enrolled, including 8 with papillary renal cell carcinoma (RCC) and the remainder with other non-clear cell histologies (unclassified in 5 patients). All patients received 50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2). The trial was stopped early because of slow accrual; no responses were observed in the 8 patients with papillary RCC. In the 22 evaluable patients, best response to sunitinib included a partial response in 1 patient with unclassified RCC, stable disease in 15, and progression in 6. The median progression-free survival was 5.5 months (95% CI, 2.5-7.1) in all 23 patients, and 5.6 months for the 8 papillary patients (95% CI, 1.4-7.1). The robust objective responses sunitinib had produced in clear cell RCC could not be demonstrated in this study comprised of patients with non-clear cell histologies.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Papilar/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma Papilar/mortalidad , Carcinoma Papilar/secundario , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Supervivencia sin Enfermedad , Esquema de Medicación , Terminación Anticipada de los Ensayos Clínicos , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirroles/administración & dosificación , Pirroles/efectos adversos , Sunitinib , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib. We evaluated the association of sunitinib-induced HTN with antitumor efficacy and HTN-associated adverse events in patients with metastatic renal cell carcinoma. METHODS: This retrospective analysis included pooled efficacy (n = 544) and safety (n = 4917) data from four studies of patients with metastatic renal cell carcinoma who were treated with sunitinib 50 mg/d administered on a 4-week-on 2-week-off schedule (schedule 4/2). Blood pressure (BP) was measured in the clinic on days 1 and 28 of each 6-week cycle. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods; hazard ratios (HRs) for survival were also estimated by a Cox proportional hazards models using HTN as a time-dependent covariate. Efficacy outcomes were compared between patients with and without HTN (maximum systolic BP [SBP] ≥140 mm Hg or diastolic BP [DBP] ≥90 mm Hg). Adverse events were also compared between patients with and without HTN (mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg). All P values were two-sided. RESULTS: Patients with metastatic renal cell carcinoma and sunitinib-induced HTN defined by maximum SBP had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all). Similar results were obtained when comparing patients with vs without sunitinib-induced HTN defined by maximum DBP. In a Cox proportional hazards model using HTN as a time-dependent covariate, PFS (HR of disease progression or death = .603, 95% CI = .451 to .805; P < .001) and OS (HR of death = .332, 95% CI = .252 to .436; P < .001) were improved in patients with treatment-induced HTN defined by maximum SBP; OS (HR of death = .585, 95% CI = .463 to .740; P < .001) was improved in patients with treatment-induced HTN defined by maximum DBP, but PFS was not. Few any-cause cardiovascular, cerebrovascular, ocular, and renal adverse events were observed. Rates of adverse events were similar between patients with and without HTN defined by mean SBP; however, hypertensive patients had somewhat more renal adverse events (5% vs 3%; P = .013). CONCLUSIONS: In patients with metastatic renal cell carcinoma, sunitinib-associated HTN is associated with improved clinical outcomes without clinically significant increases in HTN-associated adverse events, supporting its viability as an efficacy biomarker.
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Antineoplásicos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Carcinoma de Células Renales/tratamiento farmacológico , Hipertensión/inducido químicamente , Indoles/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Pirroles/efectos adversos , Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/secundario , Factores de Confusión Epidemiológicos , Supervivencia sin Enfermedad , Humanos , Indoles/administración & dosificación , Estimación de Kaplan-Meier , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Pirroles/administración & dosificación , Estudios Retrospectivos , Factores de Riesgo , Sunitinib , Resultado del TratamientoRESUMEN
OBJECTIVES: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors with proven clinical benefit in patients with metastatic renal cell carcinoma (RCC). This phase I/II study investigated sunitinib in combination with an epidermal growth factor receptor inhibitor, gefitinib, in patients with metastatic RCC. METHODS: In phase I, patients received sunitinib 37.5 or 50 mg in 6-week cycles (4 weeks on treatment, 2 off) plus gefitinib 250 mg, both once daily, to determine the sunitinib maximum tolerated dose (MTD). Pharmacokinetics was assessed for both drugs. In phase II, patients received sunitinib MTD plus gefitinib to evaluate the safety and antitumor activity of this combination. RESULTS: Forty-two patients were enrolled: 11 in phase I, and 31 in phase II. In phase I, 2 dose-limiting toxicities were observed with sunitinib 50 mg (grade 2 left ventricular ejection fraction decline and grade 3 fatigue), and 37.5 mg was declared the MTD. Thirteen patients treated at the MTD achieved a partial response (objective response rate: 37%; 95% confidence interval, 22-55) and 12 (34%) had stable disease. Median progression-free survival was 11 months (95% confidence interval, 6-17). The most commonly reported grade 3/4 treatment-related adverse event was diarrhea (14%), the only grade 3/4 adverse event to occur in >2 patients. Pharmacokinetic analyses did not indicate any drug-drug interactions. CONCLUSIONS: In metastatic RCC, sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy with an acceptable safety profile. Dosing, pharmacokinetic profile, and safety support study of sunitinib plus an epidermal growth factor receptor inhibitor in other tumor types.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Gefitinib , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Neoplasias Renales/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Pirroles/administración & dosificación , Pirroles/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Sunitinib , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Both bevacizumab and sunitinib target the vascular endothelial growth factor pathway and demonstrate activity against advanced renal cell carcinoma (RCC). In this phase I study, the maximum-tolerated dose (MTD) and safety of sunitinib in combination with bevacizumab were examined in patients with advanced RCC. PATIENTS AND METHODS: Three cohorts of three to six patients were treated with escalated doses of daily oral sunitinib (ie, 25 mg, 37.5 mg, 50 mg) for 4 weeks followed by a 2-week break and with fixed doses of bevacizumab (10 mg/kg) intravenously once every 2 weeks. Dose-limiting toxicities (DLTs) were assessed during the first cycle to determine the MTD, and an expanded cohort was treated to obtain additional safety information. RESULTS: Of 26 study participants, 25 received treatment at one of three dose levels. Grade 4 hemorrhage, identified as a DLT, occurred in one patient in each of cohorts 2 and 3. The MTD was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of adverse events. One complete and 12 partial responses were observed, which provided an objective response rate of 52%. CONCLUSION: In this phase I trial of patients with metastatic RCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension and vascular and hematologic toxicities at the highest dose level. We do not plan to pursue additional study of this regimen at these doses in patients with RCC.