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BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nivolumab/uso terapéutico , Sorafenib/uso terapéutico , Anciano , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/psicología , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/psicología , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Sorafenib/efectos adversosRESUMEN
OBJECTIVE: In the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy. METHODS: CELESTIAL randomised (2:1) patients with advanced HCC and Child-Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (<3 months, 3 to <6 months and ≥6 months). RESULTS: Of patients who had received only prior sorafenib, 331 were randomised to cabozantinib and 164 to placebo; 136 patients had received sorafenib for <3 months, 141 for 3 to <6 months and 217 for ≥6 months. Cabozantinib improved OS relative to placebo in the overall second-line population who had received only prior sorafenib (median 11.3 vs 7.2 months; HR=0.70, 95% CI 0.55 to 0.88). This improvement was maintained in analyses by prior sorafenib duration with longer duration generally corresponding to longer median OS-median OS 8.9 vs 6.9 months (HR=0.72, 95% CI 0.47 to 1.10) for prior sorafenib <3 months, 11.5 vs 6.5 months (HR=0.65, 95% CI 0.43 to 1.00) for 3 to <6 months and 12.3 vs 9.2 months (HR=0.82, 95% CI 0.58 to 1.16) for ≥6 months. Cabozantinib also improved PFS in all duration subgroups. Safety data were consistent with the overall study population. CONCLUSION: Cabozantinib improved efficacy outcomes versus placebo in the second-line population who had received only prior sorafenib irrespective of duration of prior sorafenib treatment, further supporting the utility of cabozantinib in the evolving treatment landscape of HCC. CLINICAL TRIAL NUMBER: NCT01908426.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Anciano , Anciano de 80 o más Años , Anilidas , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piridinas , Sorafenib/uso terapéutico , Adulto JovenRESUMEN
Background: There has been an increasing requirement for fresh tumor tissue to enroll in clinical trials in order to look for specific biomarkers. This has been shown to increase screening duration and increase screen failure rates. It was important to corroborate these results in other centers. Methods: This study is a non-randomized retrospective analysis of patients in one subset of patients seen by research nurses who operated in the standard head/neck and lung team not including patients in the phase 1 program. All patients were enrolled in clinical trials from January 16, 2013 to May 28, 2018 at USC Norris Comprehensive Cancer Institute in Los Angeles. Patients who were required to give fresh research biopsies prior to intervention were part of the research biopsy group. Results: In total, 76 patients were analyzed in this study. Thirty-three patients were in the research biopsygroup and 43 patients were in the no biopsy group. Trials that required a fresh biopsy had a longer median screening duration (30 vs. 14 days) than trials that did not require a biopsy (p < 0.0001). Conclusions: Our study shows that requiring biopsies prior to clinical trial treatment results in a statistically significant delay in treatment. The informed consent forms that were part of clinical trials involving mandatory research biopsies did not reflect this delay in treatment. However, these delays did not result in a statistically significant decrease in number of days on trial or days until progression of disease.
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BACKGROUND: Insufficient recruitment of participants remains a critical roadblock to successful clinical research, particularly clinical trials. Social media provide new ways for connecting potential participants with research opportunities. Researchers suggest that the social network Twitter may serve as a rich avenue for exploring how patients communicate about their health issues and increasing enrollment in cancer clinical trials. However, there is a lack of evidence that Twitter offers practical utility and impact. OBJECTIVE: This pilot study aimed to examine the feasibility and impact of using Twitter monitoring data (ie, user activity and their conversations about cancer-related conditions and concerns expressed by Twitter users in Los Angeles County) as a tool for enhancing clinical trial recruitment at a comprehensive cancer center. METHODS: We will conduct a mixed-methods interrupted time series study design with a before-and-after social media recruitment intervention. On the basis of a preliminary analysis of eligible trials, we plan to onboard at least 84 clinical trials across 6 disease categories: breast cancer, colon cancer, kidney cancer, lymphoma, non-small cell lung cancer, and prostate cancer that are open to accrual at the University of Southern California (USC) Norris Comprehensive Cancer Center. We will monitor messages about these 6 cancer conditions posted by Twitter users in Los Angeles County. Recruitment for the trials will occur through the Twitter account (@USCTrials). Primary study outcomes-feasibility and acceptance of the social media intervention among targeted Twitter users and the study teams of the onboarded trials-will be assessed using qualitative interviews and the 4-point Likert scale and by calculating the proportion of targeted Twitter users who engaged with outreach messages. Second, impact of the social media intervention will be measured by calculating the proportion of enrollees in trials. The enrollment rate will be compared between the active intervention period and the prior 10 months as historical control for each disease trial group. This study has been funded by the National Center for Advancing Translational Science through a Clinical and Translational Science Award. Study approval was obtained from the clinical investigations committee at USC Norris and the institutional review board at USC. RESULTS: Recruitment on Twitter started in February 2018. Data collection will be completed in November 2018. CONCLUSIONS: This pilot project will provide preliminary data and practical insight into the application of publicly available Twitter data to identify and recruit clinical trial participants across 6 cancer disease types. We will shed light on the acceptance of the social media intervention among Twitter users and study team members of the onboarded trials. If successful, the findings will inform a multisite randomized controlled trial to determine the efficacy of the social media intervention across different locations and populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03408561; https://clinicaltrials.gov/ct2/show/NCT03408561 (Archived by WebCite at http://www.webcitation.org/72LihauzW). REGISTERED REPORT IDENTIFIER: RR1-10.2196/9762.
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OBJECTIVES: To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 90 patients with advanced HCC, Child-Pugh class A-B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. RESULTS: The median OS was 8.55 months (95% CI: 7.00-13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69-12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57-1.47). The median EFS was 4.37 months (95% CI: 2.99-7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84-4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42-1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5-15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9-13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53-1.46). CONCLUSIONS: There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/patología , Supervivencia sin Enfermedad , Clorhidrato de Erlotinib/efectos adversos , Humanos , Neoplasias Hepáticas/patología , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib , Resultado del TratamientoRESUMEN
There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. SGI-110 can also act as a dual inhibitor to down-regulate polycomb repressive complex 2 (PRC2) genes by demethylating their gene bodies, resulting in reactivation of PRC2 repressed genes without involvement of DNA methylation. Furthermore, it can up-regulate endogenous retroviruses to reactivate immune pathways. Finally, about 48% of frequently altered genes in primary HCC tumors can be reversed by SGI-110 treatment. CONCLUSION: Our integrative analysis has successfully linked the antitumor effects of SGI-110 to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets, and provided a rationale for combination treatments of SGI-110 with immune checkpoint therapies.
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Azacitidina/análogos & derivados , Carcinoma Hepatocelular/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/tratamiento farmacológico , Metiltransferasas/genética , Azacitidina/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral/efectos de los fármacos , Metilación de ADN , Inhibidores Enzimáticos/farmacología , Epigenómica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Terapia Molecular Dirigida , Sensibilidad y EspecificidadRESUMEN
PURPOSE: The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC). METHODS: Eligible patients with no prior systemic therapy for advanced HCC and Child-Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design. Dose limiting toxicity (DLT) was defined as treatment-related grade 3 or 4 non-hematologic toxicity (except for a subset of manageable toxicities) or any grade 4 hematologic toxicities. RESULTS: In 21 patients enrolled, there were 3 DLTs; grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis. The maximum tolerated dose of cixutumumab was 4 mg/kg IV weekly with standard dose sorafenib. Eighteen of 21 (86%) patients had grade 3 or above toxicities attributed to treatment. One patient also experienced grade 4 colonic perforation and grade 5 peritonitis. The median number of cycles completed was 4 (0-26). Of 16 patients evaluable for response, 81% achieved stable disease. The median progression free survival was 6.0 months (95% CI 3.6-undefined) and the median overall survival was 10.5 months (95% CI 7.1-undefined). CONCLUSIONS: While the combination of cixutumumab and sorafenib had a toxicity profile similar to that of sorafenib monotherapy, it manifested limited clinical efficacy in unselected patients with HCC.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Supervivencia sin Progresión , Sorafenib/efectos adversosRESUMEN
PURPOSE: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. RESULTS: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of â¼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. CONCLUSIONS: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. ©2015 AACR.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Difenilamina/análogos & derivados , Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/uso terapéutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Terapia Combinada/métodos , Difenilamina/efectos adversos , Difenilamina/sangre , Difenilamina/farmacocinética , Difenilamina/uso terapéutico , Femenino , Semivida , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/metabolismo , Niacinamida/efectos adversos , Niacinamida/sangre , Niacinamida/farmacocinética , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/sangre , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib , Sulfonamidas/efectos adversos , Sulfonamidas/sangreRESUMEN
PURPOSE: The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. PATIENTS AND METHODS: Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. RESULTS: A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. CONCLUSION: This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/radioterapia , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/radioterapia , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Conductos Biliares Extrahepáticos/patología , Capecitabina , Quimioradioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , GemcitabinaRESUMEN
OBJECTIVES: Gallbladder and cholangiocarcinomas represent a heterogeneous group of malignant diseases that commonly present at an advanced stage and have limited therapeutic options. Based on the role of the Ras-Raf-Mek-Erk pathway and the VEGF axis in biliary carcinomas, we conducted a phase II study of sorafenib in patients with advanced biliary cancers. METHODS: Eligible patients had no prior therapy for metastatic or unresectable disease. Sorafenib was administered at 400 mg po twice daily continuously. RESULTS: The study was terminated after the first stage of accrual due to failure to meet the primary objective. A confirmed response rate of 0% (0%-11%) was observed. Thirty-nine percent of patients demonstrated stable disease (including 2 with unconfirmed PR). PFS was 3 months (95% CI: 2-4 months) and OS 9 months (95% CI: 4-12 months). The most common grade 3 and 4 toxicities included hand-foot skin reaction (13%), bilirubin elevation (13%), venous thromboembolism (10%), AST/ALT elevation (10%) and elevated alkaline phosphatase (10%). CONCLUSION: While treatment with sorafenib did not result in objective responses, patients with biliary cancers receiving this drug had some therapeutic benefit. Additional studies with sorafenib in combination with chemotherapy or other targeted agents may be warranted.
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Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/cirugía , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/cirugía , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/efectos adversos , Colangiocarcinoma/patología , Supervivencia sin Enfermedad , Femenino , Neoplasias de la Vesícula Biliar/patología , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Piridinas/efectos adversos , Sorafenib , Resultado del TratamientoRESUMEN
PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating intracellular folate levels, which affects DNA synthesis and methylation. Two MTHFR gene polymorphisms, C677T and A1298C, are linked to altered enzyme activity. Several studies have shown these two polymorphisms to be associated with response to fluorouracil (FU) -based treatment in advanced colon cancer patients, but data are inconsistent and contradictory. Meanwhile, epidemiologic studies demonstrated that these MTHFR polymorphisms were associated with cancer risk in a sex-specific manner. We tested the hypothesis of whether these two polymorphisms are associated with sex-specific clinical outcome in metastatic colon cancer patients treated with FU-based chemotherapy. PATIENTS AND METHODS: This study included 318 patients (177 men and 141 women) with metastatic colon cancer treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Peripheral blood samples were collected from each patient, and genomic DNA was extracted from WBCs. Two MTHFR gene polymorphisms (C677T and A1298C) were tested by fluorogenic 5'-nuclease assay. RESULTS: The A1298C polymorphism showed statistically significant differences in overall survival (OS) in female, but not male, patients with metastatic colon cancer (log-rank test, P = .038). Among females, OS was greater for patients with the A/A genotype (n = 67; median OS, 18.4 months) compared with patients with the A/C genotype (n = 50; median OS, 13.9 months) or C/C genotype (n = 10; median OS, 15.6 months). CONCLUSION: Although preliminary, these data support the role of the A1298C polymorphism in MTHFR as prognostic marker in female patients with metastatic colon cancer. Further studies are needed to confirm these findings.
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Neoplasias del Colon/mortalidad , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Fluorouracilo/uso terapéutico , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Tasa de SupervivenciaRESUMEN
Recurrence is a significant clinical problem for patients with rectal cancer treated with adjuvant chemoradiation. Previous studies have suggested that determining intratumoral gene expression of key genes may be helpful in predicting clinical outcome of patients with gastrointestinal malignancies undergoing chemotherapy. The role of molecular predictors for prediction of recurrence in the setting of adjuvant chemoradiotherapy is not well established. The present study was designed to identify a genetic profile that would be associated with recurrence in patients with rectal cancer treated with adjuvant chemoradiation therapy. A retrospective study with a longitudinal cohort and a cross-sectional cohort of 67 patients with locally advanced rectal cancer who underwent cancer resection, followed by 5-fluorouracil (5-FU) plus pelvic radiation was conducted. Total RNA was extracted from formalin-fixed, paraffin-embedded, laser-captured-microdissected tissue. We determined mRNA levels of genes involved in the 5-FU pathway (thymidylate synthase, dihydropyrimidine dehydrogenase), DNA-repair (excision-repair cross-complementing factor 1, Rad51), angiogenesis/radiation sensitivity [vascular endothelial growth factor (VEGF)] and radio-sensitivity [epidermal growth factor receptor (EGFR)] in tumor tissue and tumor-adjacent normal tissue by quantitative reverse transcriptase-polymerase chain reaction. In univariate analysis, only intratumoral gene expression level of VEGF (P = 0.055) was associated with recurrence, whereas elevated mRNA expression levels of thymidylate synthase (P = 0.008), VEGF (P = 0.023) and EGFR (P = 0.004) in tumor-adjacent normal tissue were significantly associated with recurrence. Multivariate analysis using recursive partitioning indicated that distinct groups of recurrence could be defined by elevated mRNA expression levels of VEGF, EGFR in tumor-adjacent normal tissue, and Rad51 in tumor tissue. These data suggest that the genetic profile of the tumor-adjacent normal tissue may be associated with treatment failure, indicating that tumor microenvironment may be more important in the development of recurrence of rectal tumors than formerly expected.
Asunto(s)
Recurrencia Local de Neoplasia/genética , Neoplasias del Recto/genética , Adulto , Anciano , Quimioterapia Adyuvante , Estudios Transversales , Femenino , Fluorouracilo/uso terapéutico , Perfilación de la Expresión Génica , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Proyectos Piloto , ARN Mensajero/metabolismo , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Estudios RetrospectivosRESUMEN
The mechanism of action of 5-fluorouracil (5-FU) and its pharmacologic behavior are influenced by its mode of administration. Several clinical studies have been conducted with the purpose of evaluating the difference between the continuous (CI 5-FU) and the bolus infusion of 5-FU (BI 5-FU). We focus our review on the studies relevant to the treatment of colorectal cancer, both in the adjuvant and metastatic setting. While individual trials fail to show a survival benefit for CI 5-FU, a meta-analyses of 7 trials shows an improvement in overall survival (OS) over BI 5-FU in metastatic colorectal cancer treatment. All trials in the same setting reveal a different toxicity profile for CI 5-FU that is generally more favorable than BI 5-FU. In the adjuvant setting, CI 5-FU allows the duration of therapy to be shortened by half without compromising the efficacy. CI 5-FU is the regimen of choice when given concurrently with radiation. When given in combination with other cytotoxic agents, CI 5-FU seems to be associated with less toxicity and potentially higher efficacy. Oral fluoropyrimidines, especially capecitabine, appear to behave in similar manner to CI 5-FU and may offer a convenient alternative to the usage of infusion pumps and indwelling catheters. While clinical trials are ongoing to compare capecitabine to CI 5-FU, we believe that CI 5-FU should be offered to patients in the United States given its favorable toxicity profile and higher efficacy in several settings.