RESUMEN
BACKGROUND: Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice. METHODS: Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA). RESULTS: Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. CONCLUSIONS: Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/genética , Anilidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Sorafenib/uso terapéutico , Análisis de Supervivencia , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , RamucirumabRESUMEN
BACKGROUND: Sorafenib has been shown to improve survival in patients with advanced hepatocellular carcinoma (HCC), however, full dose can be difficult to tolerate. The aim of this study was to determine whether sorafenib starting dose and mean dose intensity affect survival. METHODS: Patients treated with sorafenib for HCC from January 2008 to July 2016 in several Canadian provinces were included and retrospectively analyzed. The primary end point was overall survival (OS) of patients starting on sorafenib full dose compared to reduced dose. Secondary analysis compared OS with different mean dose-intensity groups. Survival outcomes were assessed with Kaplan-Meier curves and Cox proportional hazards models. A propensity score analysis was performed to account for treatment bias and confounding. RESULTS: Of 681 patients included, sorafenib was started at full dose in 289 patients (42%). Median survival for starting full and reduced dose was 9.4 months and 8.9 months (P = .15) respectively. After propensity score matching and adjusting for potential confounders there was still no difference in survival (HR 0.8, 95% CI, 0.61-1.06, P = .12). Almost half of the patients (45%) received a dose intensity < 50%. Median survival for mean dose intensity > 75%, 50%-75%, and < 50% were 9.5 months, 12.9 months, and 7.1 months (P = .005) respectively. In multivariable models, starting dose(HR 1.16, 95% CI 0.93-1.44, P = .180) and mean dose intensity were not associated with survival. CONCLUSIONS: Starting HCC patients on a reduced dose of sorafenib compared to full dose may not compromise survival. Mean dose-intensity of sorafenib may also not affect survival.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/uso terapéutico , Antineoplásicos/farmacología , Canadá , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Sorafenib/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND: The CELESTIAL, RESORCE, and REACH-2 trials showed survival benefit of cabozantinib, regorafenib, and ramucirumab, respectively, in hepatocellular carcinoma (HCC) patients treated with sorafenib who had good performance status (ECOG 0-1) and liver function (Child-Pugh-A). This study characterizes subsequent treatments received by HCC patients after sorafenib, and determines the proportion of patients eligible for novel therapies if strict eligibility criteria (SEC) were utilized compared to more liberal modified eligibility criteria (MEC, including ECOG 2, Child-Pugh-B7). METHODS: HCC patients who received sorafenib between 2008 and 2017 were included from the Canadian HCC CHORD Database. Patients were classified as eligible or ineligible based on available CELESTIAL, RESORCE, and REACH-2 trial SEC or MEC. Median overall survival (mOS) was assessed using the Kaplan-Meier method. RESULTS: A total of 730 patients were identified; and 172 (23.6%) received subsequent treatment. Patients who received subsequent treatment had longer mOS than those who did not (12.1 vs 3.3 months; P < .001). Using SEC, only 13.1% of patients would be eligible for cabozantinib, regorafenib, or ramucirumab. Expanding eligibility to include patients who meet MEC increased the proportion of eligible patients to 31.7%. Higher ineligibility for regorafenib and ramucirumab was driven by trial-specific criteria, including sorafenib intolerance (28%) for RESORCE and AFP <400 (58.9%) for REACH-2. CONCLUSIONS: A small proportion of real-world HCC patients would be eligible for cabozantinib, regorafenib, or ramucirumab if SEC in clinical trials were followed, while more than double would be eligible if MEC were applied. Patients who received subsequent treatment had improved mOS, regardless of whether they met SEC or MEC.
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Anilidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Sorafenib/uso terapéutico , Canadá , Carcinoma Hepatocelular/mortalidad , Ensayos Clínicos Fase III como Asunto , Bases de Datos Factuales , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , RamucirumabRESUMEN
BACKGROUND: Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS: A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS: Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION: CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).
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Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/fisiopatología , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Hígado/fisiopatología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/fisiopatología , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Sorafenib/efectos adversosRESUMEN
Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.
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Genes BRCA1 , Genes BRCA2 , Asesoramiento Genético , Mutación , Neoplasias Pancreáticas/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian-predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis. HCC cases were recruited in a comprehensive cancer center while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan-Meier curves, and log-rank tests. In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM-741 or BRM-1321) and risk of HCC was identified (P > 0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM-741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89-11.54 and BRM-1321 per variant allele aHR 4.09, 95%CI 2.22-7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45-fold increase in risk of death when compared to those who were double wild-type for the two polymorphisms. Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants.
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/patología , Femenino , Genotipo , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: To determine maximum tolerated dose (MTD) and toxicities of sorafenib combined with stereotactic radiotherapy (SBRT) or whole liver radiotherapy (WLRT) in patients with liver metastases. MATERIAL AND METHODS: Eligible patients had unresectable liver metastases. Sorafenib dose was escalated in 2 strata: I - SBRT: effective liver volume irradiated (Veff)<80% (30-60Gy in 6 fractions); II - WLRT: Veff>80% (21.6Gy in 6 fractions). Four weeks of sorafenib, with radiotherapy during weeks 2-3, was delivered at 3 escalating dose levels (200-400mg twice daily). Dose limiting toxicity was defined as any grade 3+ liver toxicity, or grade 4+ treatment-related toxicity. RESULTS: Thirty-three patients were treated: 18 in stratum I (median dose 42Gy), 15 in stratum II. The MTD was not reached. Grade 3+ toxicity was seen in 33% of patients, at a median of 10days. Two deaths from non-classic liver toxicity occurred post WLRT in stratum II. The median overall survival was 22.3 and 5.7months for strata I and II respectively. CONCLUSIONS: Sorafenib and 21.6Gy in 6 fraction WLRT resulted in unacceptably high rates of liver toxicity. Although sorafenib combined with SBRT was tolerable, the observed efficacy does not merit further clinical evaluation.
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Antineoplásicos/uso terapéutico , Quimioradioterapia , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adulto , Anciano , Quimioradioterapia/efectos adversos , Femenino , Humanos , Hígado/efectos de la radiación , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Estudios Prospectivos , Radiocirugia/efectos adversos , SorafenibRESUMEN
PURPOSE: The purpose of this study was to quantify unexpected liver volume reductions in patients treated with sorafenib prior to and during liver radiation therapy (RT). METHODS AND MATERIALS: Fifteen patients were treated in a phase 1 study of sorafenib for 1 week, followed by concurrent sorafenib-RT (in 6 fractions). Patients had either focal cancer (treated with stereotactic body RT [SBRT]) or diffuse disease (treated with whole-liver RT). Liver volumes were contoured and recorded at planning (day 0) from the exhale CT. After 1 week of sorafenib (day 8), RT image guidance at each fraction was performed using cone beam CT (CBCT). Planning liver contours were propagated and modified on the reconstructed exhale CBCT. This was repeated in 12 patients treated with SBRT alone without sorafenib. Three subsequent patients (2 sorafenib-RT and 1 non-sorafenib) were also assessed with multiphasic helical breath-hold CTs. RESULTS: Liver volume reductions on CBCT were observed in the 15 sorafenib-RT patients (median decrease of 68 cc, P=.02) between day 0 and 8; greater in the focal (P=.025) versus diffuse (P=.52) cancer stratum. Seven patients (47%) had reductions larger than the 95% intraobserver contouring error. Liver reductions were also observed from multiphasic CTs in the 2 additional sorafenib-RT patients between days 0 and 8 (decreases of 232.5 cc and 331.7 cc, respectively) and not in the non-sorafenib patient (increase of 92 cc). There were no significant changes in liver volume between planning and first RT in 12 patients with focal cancer treated with SBRT alone (median increase, 4.8 cc, P=.86). CONCLUSIONS: Liver volume reductions were observed after 7 days of sorafenib, prior to RT, most marked in patients with focal liver tumors, suggesting an effect of sorafenib on normal liver. Careful assessment of potential liver volume changes immediately prior to SBRT may be necessary in patients in sorafenib or other targeted therapies.
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Antineoplásicos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/radioterapia , Hígado/efectos de los fármacos , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Carga Tumoral/efectos de los fármacos , Adulto , Anciano , Contencion de la Respiración , Femenino , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Niacinamida/uso terapéutico , Tamaño de los Órganos/efectos de los fármacos , Planificación de la Radioterapia Asistida por Computador , Radioterapia Guiada por Imagen/métodos , Sorafenib , Factores de Tiempo , Tomografía Computarizada Espiral , Adulto JovenRESUMEN
INTRODUCTION/BACKGROUND: Targeted therapy has become the mainstay of treatment for mRCC. The efficacy of this therapy in the older population is poorly understood. PATIENTS AND METHODS: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. RESULTS: All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those ≥ 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.781-1.285) or shorter treatment duration (HR, 1.018; 95% CI, 0.827-1.252). The retrospective study design was the primary limitation. CONCLUSION: The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups.
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Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Bevacizumab , Carcinoma de Células Renales/mortalidad , Bases de Datos Factuales , Femenino , Humanos , Indoles/efectos adversos , Indoles/uso terapéutico , Neoplasias Renales/mortalidad , Masculino , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirroles/efectos adversos , Pirroles/uso terapéutico , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Estudios Retrospectivos , Sorafenib , Sunitinib , Resultado del TratamientoRESUMEN
BACKGROUND: The outcomes and prognosis of patients with brain metastases from advanced renal cell carcinoma (RCC) are not well characterized in the targeted-therapy era. METHODS: Data from patients with metastatic RCC (mRCC) and brain metastases treated with targeted therapy were collected through the International Metastatic Renal Cell Carcinoma Database Consortium from 7 cancer centers. RESULTS: Overall, 106 (15%) of 705 patients with mRCC had brain metastases. Forty-seven patients had brain metastases at the start of first-line anti-vascular endothelial growth factor therapy, and the rest developed metastases during follow-up. Of the patients with brain metastases, 12%, 42% and 29% were in the favorable, intermediate, and poor prognosis groups, respectively, per the Heng criteria. Ninety percent had cerebral metastases, 17% had cerebellar metastases, 37% had a Karnofsky performance status (KPS) <80%, and 80% had neurologic symptoms at presentation. The median largest size and number of brain metastases was 1.8 cm (range, 0.2-6.6 cm) and one (range, 1 to innumerable), respectively. The patients were treated with sunitinib (n = 77), sorafenib (n = 23), bevacizumab (n = 5), and temsirolimus (n = 1). Local disease treatment included whole brain radiotherapy (81%), stereotactic radiosurgery (25%), and neurosurgery (25%). On multivariable analysis, KPS < 80%, diagnosis to treatment with targeted therapy <1 year, and a higher number of brain metastases (>4) was associated with worse survival from the time of diagnosis with brain metastases. CONCLUSIONS: Patients with brain metastases from RCC are unlikely to be in the favorable risk group. KPS at the start of therapy, diagnosis to treatment time, and the number of brain metastases are prognostic factors for overall survival.
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Neoplasias Encefálicas/secundario , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Neoplasias Renales/mortalidad , Terapia Molecular Dirigida , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Bases de Datos Factuales , Humanos , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/uso terapéutico , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Sorafenib , Sunitinib , Sobrevida , Resultado del TratamientoRESUMEN
Presentation of the Case A 37-year-old woman presented at 35 weeks of gestation with her third child with failure to adequately gain weight and was noted by her obstetrician to have delay in the growth of her baby. Ultrasound of the abdomen incidentally revealed the presence of a liver lesion. After additional evaluation, she ultimately delivered her daughter at 36 weeks uneventfully. She subsequently underwent additional evaluation. Liver magnetic resonance imaging (MRI) revealed a 5-cm solitary solid mass in segment 4A of the liver, concerning for malignancy. Serum α-fetoprotein, carcinoembryonic antigen, cancer antigen (CA)19-9, CA15-3, and CA125 were all normal. Liver biopsy was positive for adenocarcinoma. The tumor cells demonstrated a phenotype suggesting a possible breast primary, although the immunohistochemistry did not support that diagnosis and the tumor was negative for mammaglobin, gross cystic disease fluid protein (GCDFP)-15, estrogen receptor (ER), and progesterone receptor (PR) (Table 1). The tumor was also CDX2 and cardiotrophin-1 negative, but cytokeratin (CK) 19 positive. Her endoscopic retrograde cholangiopancreatography, upper endoscopy, colonoscopy, breast mammogram, and breast MRI were completely normal. A positron emission tomography-computed tomography scan showed a fluorodeoxyglucose-avid 5.8-cm × 6.0-cm hypoattenuating lesion with peripheral enhancement involving segment 4 and segment 8 at the dome. In addition, central necrosis within the lesion was noted. The left main portal vein was mildly attenuated by the mass. She eventually underwent a left hepatectomy en bloc with caudate resection, portal lymphadenectomy, cholecystectomy, and omental pedicle flap. On exploration of the abdomen, no additional disease was noted. The final pathology revealed a 9.4-cm moderately to poorly differentiated adenocarcinoma of the intrahepatic bile ducts. Venous invasion was present. Perineural invasion was absent. The margins were negative. Thirteen lymph nodes were obtained, all of which were negative, consistent with a stage T2, N0, MX intrahepatic cholangiocarcinoma. The tumor was positive for CK7, CK19, and CA19-9 and negative for CK20, CDX2, CA125, ER, PR, GCDFP-15, synaptophysin, and chromogranin (Table 1). The uninvolved liver was unremarkable and a trichrome stain showed no fibrosis. Following an uneventful postoperative recovery, she was referred for consideration of adjuvant therapy.
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Quimioterapia Adyuvante/métodos , Colangiocarcinoma/patología , Colangiocarcinoma/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Neoplasias de los Conductos Biliares , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/cirugía , Biomarcadores/sangre , Biopsia , Antígeno Ca-125/sangre , Factor de Transcripción CDX2 , Capecitabina , Antígeno Carcinoembrionario/sangre , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Colangiopancreatografia Retrógrada Endoscópica , Citocinas/análisis , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Fluorodesoxiglucosa F18/análisis , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Glicoproteínas/genética , Glicoproteínas/metabolismo , Hepatectomía/métodos , Proteínas de Homeodominio/análisis , Humanos , Inmunohistoquímica , Queratina-20/análisis , Queratinas/análisis , Hígado/patología , Escisión del Ganglio Linfático , Imagen por Resonancia Magnética , Proteínas de Transporte de Membrana , Fenotipo , Vena Porta/patología , Vena Porta/cirugía , Embarazo , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , alfa-Fetoproteínas/análisis , GemcitabinaRESUMEN
INTRODUCTION: Treatment options for advanced hepatocellular cancer (HCC) are limited. Sorafenib, an orally active multi-kinase inhibitor, is the only systemic agent with a survival benefit in randomized studies. However, the gain in survival is modest and new treatment strategies are needed. CLINICAL CASES: We report two cases of advanced HCC treated with a combination of sorafenib and radiation therapy. Impressive and sustained clinical and radiological responses were seen. Treatment was well-tolerated in both cases with no unexpected toxicities reported. DISCUSSION: There is sound rationale for the combination of sorafenib and radiation therapy for treatment of HCC. These two cases suggest both feasibility and efficacy of this combination, in selected patients. Prospective studies addressing this combination are ongoing.
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Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma Hepatocelular/terapia , Quimioradioterapia/métodos , Neoplasias Hepáticas/terapia , Piridinas/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , SorafenibRESUMEN
PURPOSE: Vascular endothelial growth factor targeted therapy is a standard of care in patients with metastatic renal cell carcinoma. The role of cytoreductive nephrectomy in the era of novel agents remains poorly defined. MATERIALS AND METHODS: We retrospectively reviewed baseline characteristics and outcomes of 314 patients with anti-vascular endothelial growth factor therapy naïve, metastatic renal cell carcinoma from United States and Canadian cancer centers to study the impact of cytoreductive nephrectomy on overall survival. RESULTS: Patients who underwent cytoreductive nephrectomy (201) were younger (p < 0.01), and more likely to have a better Karnofsky performance status (p < 0.01), more than 1 site of metastasis (p = 0.04) and lower corrected calcium levels (p < 0.01) compared to those who did not undergo cytoreductive nephrectomy (113). On univariable analysis cytoreductive nephrectomy was associated with a median overall survival of 19.8 months compared to 9.4 months for patients who did not undergo cytoreductive nephrectomy (HR 0.44; 95% CI 0.32, 0.59; p < 0.01). On multivariable analysis and adjusting for established prognostic risk factors the overall survival difference persisted (adjusted HR 0.68; 95% CI 0.46, 0.99; p = 0.04) in favor of the cytoreductive nephrectomy group. In subgroup analyses stratified for favorable/intermediate/poor risk criteria, patients in the poor risk group had a marginal benefit (p = 0.06). Similarly patients with Karnofsky performance status less than 80% also had a marginal survival benefit (p = 0.08). CONCLUSIONS: In this retrospective study cytoreductive nephrectomy was independently associated with a prolonged overall survival of patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor targeted agents, although the benefit is marginal in those patients with poor risk features.
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Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/cirugía , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Nefrectomía/métodos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Bevacizumab , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Femenino , Humanos , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Estudios Retrospectivos , Sorafenib , Sunitinib , Tasa de Supervivencia , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
CONTEXT: In a randomized phase 3 trial, 400 mg of sorafenib twice daily prolonged overall survival of patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh A disease. In a phase 1 study, sorafenib combined with doxorubicin, 60 mg/m(2), was well tolerated by patients with refractory solid tumors. The combination of sorafenib and doxorubicin in patients with advanced HCC has not been evaluated in a phase 2 or 3 trial. OBJECTIVE: To evaluate the efficacy and safety of doxorubicin plus sorafenib compared with doxorubicin alone in patients with advanced HCC and Child-Pugh A disease. DESIGN, SETTING, AND PATIENTS: In a double-blind phase 2 multinational study, conducted from April 2005 to October 2006, 96 patients (76% male; median age, 65 years [range, 38-82 years]) with advanced HCC, Eastern Cooperative Oncology Group performance status 0 to 2, Child-Pugh A status, and no prior systemic therapy were randomly assigned to receive 60 mg/m(2) of doxorubicin intravenously every 21 days plus either 400 mg of sorafenib or placebo orally twice a day. The date of the last patient's follow-up was April 2008. MAIN OUTCOME MEASURE: Time to progression as determined by independent review. RESULTS: Following complete accrual, an unplanned early analysis for efficacy was performed by the independent data monitoring committee, so the trial was halted. The 2 patients remaining in the placebo group at that time were offered sorafenib. Based on 51 progressions, 63 deaths, and 70 events for progression-free survival, median time to progression was 6.4 months in the sorafenib-doxorubicin group (95% confidence interval [CI], 4.8-9.2), and 2.8 months (95% CI, 1.6-5) in the doxorubicin-placebo monotherapy group (P = .02). Median overall survival was 13.7 months (95% CI, 8.9--not reached) and 6.5 months (95% CI, 4.5-9.9; P = .006), and progression-free survival was 6.0 months (95% CI, 4.6-8.6) and 2.7 months (95% CI, 1.4-2.8) in these groups, respectively (P = .006). Toxicity profiles were similar to those for the single agents. CONCLUSIONS: Among patients with advanced HCC, treatment with sorafenib plus doxorubicin compared with doxorubicin monotherapy resulted in greater median time to progression, overall survival, and progression-free survival. The degree to which this improvement may represent synergism between sorafenib and doxorubicin remains to be defined. The combination of sorafenib and doxorubicin is not yet indicated for routine clinical use. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00108953.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Sorafenib , Resultado del TratamientoRESUMEN
OBJECTIVE: In this retrospective analysis of the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program in North America, we compared the safety and efficacy of sorafenib in patients aged ≥70 with those aged <70 years. METHODS: Patients were treated with oral sorafenib twice daily until the occurrence of disease progression or treatment intolerance. The primary objective of the ARCCS program was making sorafenib available to patients with advanced renal cell carcinoma (RCC) in the USA and Canada before marketing approval was obtained; the secondary objective was the evaluation of its safety and efficacy. RESULTS: Of the 2,504 patients enrolled in the ARCCS program who received at least 1 dose of sorafenib, 736 (29%) were aged ≥70 years. The most common grade ≥3 adverse events included rash/desquamation (5% in both groups), hand-foot skin reaction (8% in those aged ≥70 years vs. 10% in those <70 years of age), hypertension (5 vs. 4%) and fatigue (7 vs. 4%). Partial response was seen in 4% of the patients in both age groups. The median overall survival for the ≥70-year versus <70-year groups was also similar (46 vs. 50 weeks). CONCLUSIONS: There were no substantial differences in safety and efficacy between patients aged ≥70 and <70 years with advanced RCC treated with sorafenib.
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Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Piridinas/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Bencenosulfonatos/efectos adversos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Etnicidad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/efectos adversos , Estudios Retrospectivos , Seguridad , Sorafenib , Análisis de SupervivenciaRESUMEN
BACKGROUND: The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. METHODS: In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months. RESULTS: The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups. CONCLUSIONS: Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).
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Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Bencenosulfonatos/efectos adversos , Carcinoma de Células Renales/mortalidad , Ensayos de Uso Compasivo , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , América del Norte , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , SorafenibRESUMEN
PURPOSE: There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy. METHODS: Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS. RESULTS: The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73. CONCLUSION: This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Neoplasias Renales/mortalidad , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Bencenosulfonatos/uso terapéutico , Bevacizumab , Femenino , Humanos , Indoles/uso terapéutico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Pronóstico , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Sorafenib , Sunitinib , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Sorafenib, an oral multikinase inhibitor, prolonged progression-free survival when compared with placebo, as second-line therapy for patients with metastatic renal carcinoma (MRC). Grade 3/4 adverse events were reported in 12% of patients. This study presents sorafenib's efficacy and safety in a less selected cohort of patients enrolled in an expanded access program. METHODS: Patients with MRC received sorafenib 400 mg twice daily until disease progression. Tumor response was evaluated by RECIST criteria. Adverse events were graded by NCI common toxicity criteria. RESULTS: From November 2005 to August 2006, 58 patients were enrolled. The median progression-free survival was 7.5 months (95% CI: 5.4-11.3), and the best responses among 54 patients were 11 (20%) confirmed partial responses, 15 (28%) stable diseases for > or =6 months; 10 patients (18%) had early progression at 8 weeks. Grade 3/4 adverse events occurred in 37 patients (64%; 95% CI: 50%-76%), the most frequent being skin rash in 17 patients (29%), and hand-foot syndrome in 9 patients (15%). Thirty-six (62%) patients required dose reductions and/or treatment interruptions. CONCLUSIONS: Sorafenib is effective in a less selected patient population with MRC but leads to more toxicity than described previously.
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Bencenosulfonatos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bencenosulfonatos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Neoplasias Renales/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , Sorafenib , Análisis de SupervivenciaRESUMEN
BACKGROUND: The Intergroup 0116 study showed a survival benefit with adjuvant chemoradiotherapy (CRT) for resected gastric cancer. We report our experience using conformal radiotherapy (RT). METHODS AND MATERIALS: Eighty-two patients with resected gastric or gastroesophageal junction (GEJ) adenocarcinoma, Stage IB to IV (M0), were treated with 45 Gy in 25 fractions using a 5-field conformal technique. Chemotherapy was in accordance with the Intergroup 0116 study, or infusional 5-fluorouracil and cisplatin in a phase I/II trial. RESULTS: Mean age was 56.4 years. Median follow-up was 22.8 months. Grade 3 or greater acute toxicity (National Cancer Institute Common Terminology Criteria of Adverse Events, version 3.0) was noted in 57% of patients (upper gastrointestinal tract 34%, hematologic 33%). One patient died of neutropenic sepsis. Radiation Therapy Oncology Group Grade 3 late toxicity included esophageal strictures (3 patients) and small bowel obstruction (1 patient). Full course CRT was completed by 67% of patients. Of 26 patients who relapsed, 20 died. Site of first relapse was available on 23 patients: 8 locoregional and distant, 4 locoregional alone, 11 distant alone. Overall and relapse-free survival were 69% and 54% at 3 years. CONCLUSION: Adjuvant CRT for gastric cancer, even with conformal RT, is associated with significant toxicity. Survival was comparable to that reported in the Intergroup 0116 study.