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Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds an E3 ubiquitin ligase and ER to directly trigger ubiquitination of ER and its subsequent proteasomal degradation. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated with clinical activity in pretreated patients with ER+/HER2- advanced breast cancer. The global, randomized Phase III VERITAC-2 study compares efficacy and safety of vepdegestrant versus fulvestrant in adults with ER+/HER2- advanced breast cancer after treatment with a CDK4/6 inhibitor plus endocrine therapy. Progression-free survival by blinded independent central review (primary end point) will be assessed in the intention-to-treat population and ESR1 mutation-positive subpopulation. Secondary end points include overall survival, tumor response, safety, pharmacokinetics, patient-reported outcomes, and circulating tumor DNA biomarkers.Clinical trial registration: NCT05654623 (ClinicalTrials.gov).
VERITAC-2 is a clinical trial comparing vepdegestrant, a new drug that degrades estrogen receptors, to an existing treatment called fulvestrant in patients with ER+/HER2- advanced breast cancer: Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer grows in response to estrogen, a hormone in the body, and has low levels or no HER2 protein. People living with ER+/HER2- advanced breast cancer that has grown, spread to another part of the body, or cannot be removed by surgery are often treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapies, but their cancer may get worse on these treatments and new treatments are needed. Fulvestrant, an endocrine therapy that attaches to estrogen receptors, lowers estrogen's effect on tumors and can slow or stop cancer growth. Vepdegestrant, a new medicine being tested for ER+ breast cancer, is a PROteolysis TArgeting Chimera (PROTAC) protein degrader that attaches to estrogen receptors and causes them to be tagged for removal by the cell's natural protein disposal system. By removing estrogen receptors, vepdegestrant may cause tumors to stop growing or shrink.This paper describes the Phase III VERITAC-2 clinical study comparing vepdegestrant versus fulvestrant in people living with ER+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor and endocrine therapy.Patients will be randomly assigned to receive vepdegestrant (a pill taken once daily by mouth) or fulvestrant (a shot given into the muscle). The purpose of the study is to find out how long people live without their cancer getting worse with vepdegestrant or fulvestrant. VERITAC-2 will also look at how long people live during the study, side effects people may experience, and the overall well-being of people throughout the study.
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Introduction: The development of precision medicine and targeted therapies have revolutionized cancer treatment. Historically, treatment was chosen based on the tumor-histology, but can now be tailored to patient-specific biomarkers. Investigations have shown up to 40% of cancer patients who undergo molecular testing have an actionable biomarker with a drug currently available, and that patients benefit from these drugs. In 2018, larotrectinib became the first drug developed and approved exclusively as a tumor-agnostic therapy. Because of advancement in precision medicine, biomarker testing has become a standard of care in a variety of tumors and its use is increasing.Areas covered: We discuss the landscape of biomarker testing in the context of soft tissue sarcomas and thyroid cancer, two rare diseases with historically high unmet needs in their subpopulations. We summarize historical data and contemporary applications.Expert opinion: The paradigm shift in oncology treatment toward precision medicine, including tumor-agnostic agents, is experiencing substantial momentum but still facing challenges. A gap exists between guideline recommendations for biomarker testing and clinical application, resulting in compromised access and suboptimal outcomes. Future progress will require routine access to testing and expanding treatment options coupled with awareness, predictability, and strategies to address resistance mechanisms.
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Biomarcadores Tumorais/metabolismo , Sarcoma/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Humanos , Terapia de Alvo Molecular , Medicina de Precisão/métodos , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Sarcoma/patologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: Over the past decade, oncology therapies have trended toward orally administered regimens, and there has been growing attention on evaluation of factors that affect adherence. There has not been a rigorous investigation of factors associated with adherence to intravenous (i.v.) and oral anticancer drugs in the setting of metastatic colorectal cancer (mCRC). OBJECTIVES: To (a) assess potential patient-specific factors related to adherence to mCRC chemotherapy regimens and (b) compare adherence with IV versus oral dosage forms. METHODS: A retrospective analysis was performed using the Optum Oncology Management claims database. Patients aged 18 years and older diagnosed with mCRC between July 1, 2004, and December 31, 2010, who were insured by a commercial health plan were included in the study. Adherence to i.v. and oral chemotherapy regimens was assessed using the National Comprehensive Cancer Network (NCCN) guidelines as the standard for expected cycle/regimen duration. The most commonly prescribed chemotherapy regimens were assessed. Adherence was evaluated using the medication possession ratio (MPR), calculated as the number of days a patient was covered by their chemotherapy regimen, according to NCCN guidelines, divided by the number of days elapsed from the first to the last infusion of that regimen. For most analyses, the MPR was considered a continuous variable that could take on values between 0 and 1. In other analyses, a dichotomous categorical variable designated if the MPR was at least 0.8 versus less than 0.8. The Wilcoxon rank sum, Kruskal-Wallis, and Student's t-test were used to detect differences in continuous measures between patients receiving oral capecitabine therapy versus i.v. chemotherapy. The chi square test (X(2) test) or Fisher's exact test was used to assess differences in the dichotomous MPR variable. Generalized estimating equation (GEE) models were used for regimen-level analyses to account for correlated responses within individuals. RESULTS: A total of 6,780 patients were included in the analysis, virtually all (98%) with commercial insurance coverage and the remaining (2%) with Medicare Advantage. Patients with mCRC received 17,095 regimens of chemotherapy, including 2,252 regimens of oral capecitabine. Of the 17,095 regimens, 6,780 (40%) were first-line regimens (i.e., the first time mCRC was treated for a given patient). The most common chemotherapy regimen, regardless of line of therapy, was FOLFOX (2,991 regimens, 17.5% of all regimens used). FOLFOX-based therapies with or without bevacizumab were the most common regimens for first- and second-line chemotherapy, while oral capecitabine treatment was the most commonly prescribed regimen for patients in third- or fourth-line therapy. Overall, medication adherence across all regimens was relatively high, with a mean MPR of 0.87 (SD = 0.17). Evaluation of the distribution of i.v. and oral capecitabine regimens revealed that 28% of all regimens were associated with an MPR of less than 0.8. The average MPR was clinically similar, but statistically higher for i.v. chemotherapy regimens (0.881) compared with oral capecitabine regimens (0.799; P < 0.0001). In the multivariable GEE model, lung or liver metastases were associated with a higher MPR, while lower Charlson Comorbidity Index and oral anticancer therapy were associated with lower MPR. Furthermore, as line of therapy increased, the difference in MPR between patients receiving oral capecitabine and i.v. chemotherapy increased. CONCLUSIONS: This analysis determined that adherence with i.v. chemotherapy regimens was clinically similar, but statistically higher, compared to oral capecitabine therapy. The difference in adherence rates between the 2 routes of administration increased as the line of anticancer regimen increased. These results suggest that there should be an increased focus on improving adherence rates in patients receiving oral capecitabine.
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Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Adesão à Medicação , Metástase Neoplásica/tratamento farmacológico , Administração Intravenosa , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Masculino , Medicare Part C , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Estados UnidosRESUMO
BACKGROUND: We performed a retrospective analysis of data from a phase II study evaluating sorafenib in patients with advanced hepatocellular carcinoma (HCC) to assess differences in safety and efficacy based on Child-Pugh (CP) status (A/B). METHODS: Patients received sorafenib 400 mg PO bid. We analyzed safety, pharmacokinetic (PK), and efficacy data in the two CP groups. RESULTS: Ninety-eight patients were CP A; 38 were CP B, with a median duration of therapy of 4 and 1.8 months, respectively. Grade 3/4 adverse events in the CP A and B groups, respectively, included hyperbilirubinemia (14% and 53%), ascites (3% and 5%), and encephalopathy (3% and 13%). Median overall survival (OS) in the CP A group was 9.5 months, compared with 3.2 months in the CP B population. Responses were limited in both groups. AUC and C(max) values were comparable between the two groups. CONCLUSIONS: Due to the lack of randomization against placebo or no therapy in this study, it is unclear if the more frequent worsening of liver cirrhosis and outcome of CP B patients are drug related or due to disease progression, or both. As expected, outcome was poorer in patients with CP B than in those with CP A cirrhosis. The hyperbilirubinemia seen in both groups may be at least partly related to inhibition of UGT1A1 by sorafenib. PK profiles were similar in the two groups. More data are needed to confirm and more fully understand the safety and efficacy of sorafenib in patients with advanced HCC and CP B cirrhosis.
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BACKGROUND: The phase III Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) indicated that sorafenib is effective and well tolerated in advanced renal cell carcinoma patients. However, few data have been published on the safety of long-term sorafenib treatment. A retrospective subgroup analysis was performed to evaluate the efficacy and safety of sorafenib in patients in TARGET who received treatment for >1 year. METHODS: The present subgroup analysis (based on the September 2006 database with updated safety analysis) evaluated the efficacy and safety of sorafenib in all patients in the sorafenib arm of TARGET who were treated for >1 year. The assessments included the overall survival, progression-free survival (PFS), disease control rate (DCR), and safety. The patients remained on therapy post-progression at the discretion of the investigator. RESULTS: In TARGET, 169 patients received treatment with sorafenib for >1 year. The median PFS of patients in this subpopulation was 10.9 months from the date of randomisation, with a DCR of 92%. The most commonly reported treatment-related adverse events of any grade were diarrhoea (74%), rash/desquamation (51%), hand-foot skin reaction (49%), alopecia (39%), and fatigue (38%). Adverse events were mild to moderate, and presented early in the course of the treatment; there were no unexpected toxicities associated with the long-term administration of sorafenib. CONCLUSIONS: Results of this subgroup analysis of patients enrolled in TARGET who received treatment for >1 year indicate that long-term treatment with sorafenib is associated with continued efficacy and a well-tolerated safety profile.
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Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Sorafenibe , Adulto JovemRESUMO
PURPOSE: Mature survival data and evaluation of vascular endothelial growth factor (VEGF) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study in patients with renal cell carcinoma (RCC) are reported. PATIENTS AND METHODS: Nine hundred three previously treated patients were randomly assigned to receive sorafenib versus placebo. On demonstration of progression-free survival (PFS) benefit with sorafenib, patients assigned to placebo were offered sorafenib. Overall survival (OS) was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The relationships between baseline VEGF level and prognosis and efficacy were evaluated. RESULTS: The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 v 15.2 months, respectively; hazard ratio [HR] = 0.88; P = .146); however, when post-cross-over placebo survival data were censored, the difference became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029). Adverse events at 16 months after cross over were similar to those previously reported. Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status (P < .0001), Memorial Sloan-Kettering Cancer Center score (P < .0001), and PFS and OS in univariate (PFS, P = .0013; OS, P = .0009) and multivariate (PFS, P = .0231; OS, P = .0416) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib (P = .0145). Both high-VEGF (P < .01) and low-VEGF (P < .01) groups benefited from sorafenib. CONCLUSION: Although an OS benefit was not seen on a primary intent-to-treat analysis, results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib, suggesting an important cross-over effect. VEGF levels are prognostic for PFS and OS in RCC. The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC.
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Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzenossulfonatos/efeitos adversos , Carcinoma de Células Renais/sangue , Estudos Cross-Over , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Método Duplo-Cego , Fadiga/induzido quimicamente , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Náusea/induzido quimicamente , Niacinamida/análogos & derivados , Compostos de Fenilureia , Prognóstico , Piridinas/efeitos adversos , Sorafenibe , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: The perception that older cancer patients may be at higher risk than younger patients of toxic effects from cancer therapy but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials and the known toxic effects of cytotoxic chemotherapy. It is not known how older patients respond to targeted therapy. METHODS: This retrospective subgroup analysis of data from the phase 3, randomized Treatment Approach in Renal Cancer Global Evaluation Trial examined the safety and efficacy of sorafenib in older (age >or=70 years, n = 115) and younger patients (age <70 years, n = 787) who received treatment for advanced renal cell carcinoma. Patient demographics and progression-free survival were recorded. Best tumor response, clinical benefit rate (defined as complete response plus partial response plus stable disease), time to self-reported health status deterioration, and toxic effects were assessed by descriptive statistics. Health-related quality of life was assessed with a Cox proportional hazards model. Kaplan-Meier analyses were used to summarize time-to-event data. RESULTS: Median progression-free survival was similar in sorafenib-treated younger patients (23.9 weeks; hazard ratio [HR] for progression compared with placebo = 0.55, 95% confidence interval [CI] = 0.47 to 0.66) and older patients (26.3 weeks; HR = 0.43, 95% CI = 0.26 to 0.69). Clinical benefit rates among younger and older sorafenib-treated patients were also similar (83.5% and 84.3%, respectively) and were superior to those of younger and older placebo-treated patients (53.8% and 62.2%, respectively). Adverse events were predictable and manageable regardless of age. Sorafenib treatment delayed the time to self-reported health status deterioration among both older patients (121 days with sorafenib vs 85 days with placebo; HR = 0.66, 95% CI = 0.43 to 1.03) and younger patients (90 days with sorafenib vs 52 days with placebo; HR = 0.69, 95% CI = 0.59 to 0.81) and improved quality of life over that time. CONCLUSIONS: Among patients with advanced renal cell carcinoma receiving sorafenib treatment, outcomes of older (>or=70 years) and younger (<70 years) patients were similar.
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Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Intervalo Livre de Doença , Humanos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Qualidade de Vida , Estudos Retrospectivos , SorafenibeRESUMO
BACKGROUND: TZT-1027, a novel chemotherapeutic agent, is derived from dolastatin 10, and blocks cells during G2/M-phase by interfering with microtubule assembly and stability. TZT-1027 has exhibited potential cytotoxic activity in several human cancer cell lines (in vitro) and also demonstrated antitumor activity in human xenografts (in vivo). In addition, Phase I clinical investigations suggested activity in STS (soft-tissue sarcoma). METHODS: Eligible patients were those who had histologic evidence of locally advanced or metastatic STS and who had received 1 prior treatment regimen with an anthracycline-based chemotherapy for metastatic disease. Subjects received intravenous infusions of TZT-1027 over 1 hour on Day 1 and Day 8 of each 21-day treatment course. Efficacy was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Twenty-nine patients were enrolled and 28 patients received at least 1 course of study drug and were eligible for efficacy and safety evaluation. The median age of the patients was 48 years (range, 23-73 years) and the median baseline Eastern Cooperative Oncology Group (ECOG) performance status was 1 (range, 0-2). A total of 67 courses (range, 1-9 courses; median, 2 courses) of TZT-1027 were administered. No patient in the study demonstrated an objective response to treatment. Of 6 patients (21.4%) who experienced disease stabilization, 1 continued to have stable disease for 9.3 months. The median time to tumor progression was 44 days (95% confidence interval [95% CI], 43.0-54.0) and the median survival was 178 days (95% CI, 134.0-317.0). The most commonly reported toxicities were neutropenia, fatigue, and constipation. CONCLUSIONS: TZT-1027 was found to be safe and well tolerated, and the hematologic toxicities observed were consistent with preclinical toxicology and Phase I study findings. No confirmed responses were seen in the current study.
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Antineoplásicos/uso terapêutico , Oligopeptídeos/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Antraciclinas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Constipação Intestinal/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversosRESUMO
OBJECTIVES: The primary aim of this study was to investigate the expression of apoptotic and cell cycle regulators p53, p21, p27, bax, and bcl-2 in uterine leiomyosarcoma in order to identify molecular pathways that possibly could be important in the development of leiomyosarcoma. A secondary aim was to examine if the apoptotic and cell cycle regulatory protein expression profile of uterine leiomyosarcoma is potentially useful for clinical prognostic purposes. METHODS: A tissue microarray representing 36 uterine leiomyosarcomas and 19 uterine leiomyomas was created with 3 representative cores from each tumor. Immunohistochemical staining was performed for bcl-2, bax, p21, p27, and p53 using standard techniques. Staining was scored 0-12 for each marker, 0-3 being negative and 4-12 positive. Outcome analyses were performed only for leiomyosarcomas. First recurrence was determined from the time of initial diagnosis. Survival was determined from the time of initial diagnosis to last follow-up. RESULTS: Associations were found between disease type (leiomyosarcoma vs. leiomyoma) and the positivity status of p21 (43% vs. 0%, P < 0.001), p53 (54% vs. 0%, P < 0.001), and bax (34% vs. 94%, P < 0.001). bcl-2-positive leiomyosarcoma was associated with a longer time to recurrence (P = 0.02) in a univariate analysis. In a multivariate analysis, tumor stage was the only independent significant prognostic factor (P = 0.002). CONCLUSION: The significant differential expression of apoptotic and cell cycle regulatory proteins in uterine leiomyosarcoma as compared to benign smooth muscle tumors suggests that pathways involving these proteins may be important in the development of malignant disease and, therefore, could be potential targets for molecular therapies.
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Apoptose/fisiologia , Biomarcadores Tumorais/biossíntese , Proteínas de Ciclo Celular/biossíntese , Ciclo Celular/fisiologia , Leiomiossarcoma/metabolismo , Leiomiossarcoma/patologia , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
Introduction. The role of vinorelbine in specific soft tissue sarcoma subtypes is unclear. We present retrospective single institution experience with single-agent vinorelbine in subjects with metastatic soft tissue malignancies. Methods. Fifty-eight patients were treated with single agent intravenous vinorelbine between April 1997 and December 2004. Doxorubicin had been administered previously to 53 subjects (91%), and the median number of lines of previous chemotherapy was 3 (range 0-7). Results. Patients received a median 6 doses of vinorelbine (range 1-65). The overall response rate was 6% (3 patients: 1 angiosarcoma, 1 epithelioid sarcoma, and 1 embryonal rhabdomyosarcoma). Fourteen patients (26%) experienced a best result of stable disease. Median time to progression was 1.8 months (95% confidence intervals 1.5-2.1 months, Kaplan-Meier estimate). Eight patients experienced grade 3 or 4 toxicity, most commonly febrile neutropenia. Conclusion. Vinorelbine demonstrates limited activity in a heavily pretreated group of soft-tissue sarcoma patients. Prospective investigation may be considered for selected sarcoma subtypes.
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PURPOSE: To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. RESULTS: A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. CONCLUSION: The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Doxorrubicina/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do TratamentoRESUMO
OBJECTIVE: Temozolomide has been studied in soft-tissue sarcomas with varying dosing schedules. We review the Memorial Sloan-Kettering Cancer Center (MSKCC) experience in women with metastatic or unresectable leiomyosarcoma treated with continuous daily dose (CDD) or bolus-dose (BD) temozolomide. We include a literature review of temozolomide activity in leiomyosarcoma patients. METHODS: After obtaining Institutional Review Board approval, we identified women with recurrent leiomyosarcoma treated with temozolomide at MSKCC from 9/2001 to 9/2004. Patients were treated daily with dosages ranging from 50 to 75 mg/m(2) for 6 out of 8 weeks or for 5 days every 4 weeks with 150-300 mg/m(2) daily. All patients were evaluated at least every month for toxicity and response. We reviewed patients' charts for age at diagnosis, stage, performance status, prior treatments, temozolomide dose and schedule, best response to treatment, and treatment delays or dose reductions due to toxicity. RESULTS: Twelve patients were treated with CDD temozolomide (median age, 54 years; range, 35-72 years). All patients had previously received doxorubicin; 11 had received >/=2 previous chemotherapy regimens. One patient achieved a prolonged partial response for 4 cycles; 4 demonstrated stabilization of disease for 2-5+ cycles. Seven patients were treated with BD temozolomide (median age, 50 years; range, 43-63 years). All patients received previous doxorubicin and received >/=2 previous chemotherapy regimens. Four patients achieved stabilization of disease for 3, 5, 6, and 16 cycles, respectively. One patient achieved a near complete response for 13 cycles and continues to be followed off therapy for 10+ months. CONCLUSIONS: Temozolomide has promising therapeutic benefit and is well tolerated in patients with metastatic unresectable leiomyosarcoma. Further investigation of temozolomide in leiomyosarcoma patients is warranted.
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Antineoplásicos Alquilantes/administração & dosagem , Dacarbazina/análogos & derivados , Dacarbazina/administração & dosagem , Leiomiossarcoma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Idoso , Esquema de Medicação , Feminino , Humanos , Leiomiossarcoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Temozolomida , Neoplasias Uterinas/patologiaRESUMO
PURPOSE: YKL-40 is a secreted glycoprotein (chitinase family). We compared YKL-40 with two ovarian cancer serum markers, CA125 and CA15-3, for the detection of early-stage ovarian cancer. MATERIALS AND METHODS: Serum YKL-40 levels were assayed by enzyme-linked immunosorbent assay for 46 healthy subjects, 61 high-risk individuals, 33 patients with benign gynecologic processes, and 50 preoperative patients subsequently diagnosed with predominantly early-stage ovarian cancer. Serum CA125 and CA15-3 values were obtained. RESULTS: Median YKL-40 level was 28 ng/mL (range, 15 to 166 ng/mL) for healthy subjects, 36 ng/mL (range, 9 to 69 ng/mL) for high-risk individuals without prior cancer, 44.5 ng/mL (range, 5 to 133 ng/mL) for high-risk patients with prior breast cancer, and 38 ng/mL (range, 5 to 67 ng/mL) for individuals with benign gynecologic processes (P = NS). Median preoperative YKL-40 level for ovarian cancer patients was 94 ng/mL (range, 17 to 517 ng/mL; P <.0001 compared with normal and high-risk). YKL-40 was elevated (>/= 62 ng/mL) in 36 (72%) of 50 patients compared with 23 (46%) of 50 and 13 (26%) of 50 patients for CA125 and CA15-3 (P <.008). Twenty (65%) of 31 early-stage patients had elevated serum YKL-40 levels compared with 11 (35%) of 31 and four (13%) of 31 patients for CA125 and CA15-3 (P =.039). YKL-40 levels increased with stage (P <.005), regardless of grade, histology, or patient age. Patients with early-stage tumors with YKL-40 values more than 80 ng/mL had a worse prognosis (71% recurrence v no recurrence [P =.034]). CONCLUSION: YKL-40 may represent a novel marker for the detection of early-stage ovarian cancer. YKL-40 levels in early-stage patients may also predict disease recurrence and survival. The utility of YKL-40 in detection of early-stage ovarian cancer deserves further investigation.
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Biomarcadores Tumorais/análise , Glicoproteínas/análise , Recidiva Local de Neoplasia , Estadiamento de Neoplasias/métodos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Adipocinas , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoantígenos/análise , Proteína 1 Semelhante à Quitinase-3 , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lectinas , Pessoa de Meia-Idade , Prognóstico , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
BACKGROUND: Benign uterine leiomyomata (LMA) are hormonally responsive neoplasms. To the authors' knowledge, little is known regarding the hormonal expression patterns of leiomyosarcomas (LMSs) of the uterus. The objective of the current study was to assess the immunohistochemical (IHC) patterns of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) expression in LMA and LMS of the uterus using a tissue microarray. The authors also sought to assess the prognostic value of ER, PR, and AR expression in LMS. METHODS: Between January 1991 and March 2001, 25 patients were identified with primary uterine LMS for whom tissue was available. A tissue microarray was created with 3 representative cores from each of the LMS cases, as well as from 19 cases with benign uterine LMA. IHC staining was scored as follows: negative (0-1) and positive (2-3). Outcome analyses were performed for LMS only. First recurrence was determined from the time of the initial diagnosis. Survival was determined from the time of the initial diagnosis to last follow-up. RESULTS: ER, PR, and AR positivity in LMA compared with LMS was as follows: ER, 78% versus 40% (P = 0.03); PR, 88% versus 38% (P = 0.001); and AR, 32% versus 40% (P = 0.75). There was no difference noted with regard to IHC expression based on stage of LMS. The median overall survival for patients with LMS was 23.5 months (95% confidence interval, 19.5, NR). When adjusted for stage, PR and AR were found to be predictive of a lower risk of recurrence (P = 0.01 and P = 0.035, respectively). ER, PR, and AR were not found to be associated with overall survival after adjustment for stage. Tumor stage was found to be associated with survival (P = 0.005). CONCLUSIONS: The rate of ER and PR expression was found to be significantly less in uterine LMS compared with LMA. ER, PR, and AR expression was observed in approximately 30-40% of uterine LMS cases. In the current series, PR and AR expression appeared to be associated with disease-free survival but were not found to correlate with overall survival.
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Leiomioma/metabolismo , Leiomiossarcoma/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias Uterinas/metabolismo , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Over the past 20 years in the United States, esophageal cancer has shown the most rapid rate of increase of any solid tumor malignancy. Esophageal cancer is an aggressive disease, and poor survival is achieved with surgery or chemoradiation therapy alone. Ongoing trials are investigating the use of preoperative chemoradiation followed by surgical resection. Chemoradiation employing a combination of cisplatin and a continuous infusion of 5-fluorouracil (5-FU) is the most commonly used therapy. The significant gastrointestinal toxicity of traditional cisplatin/5-FU-based regimens has prompted the evaluation of new agents in combined-modality therapy. The Memorial Sloan-Kettering Cancer Center has conducted chemoradiation trials with weekly paclitaxel/cisplatin and irinotecan/cisplatin, and the results suggest that this regimen has the potential to improve the therapeutic index without compromising efficacy. Randomized trials are now being conducted to evaluate the tolerance and efficacy of paclitaxel/cisplatin in comparison with paclitaxel/5-FU combined with radiotherapy in locally advanced esophageal cancer. The incorporation of these non-5-FU-based therapies with novel biologic agents is planned.
Assuntos
Camptotecina/análogos & derivados , Neoplasias Esofágicas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/cirurgia , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Terapia Neoadjuvante , Paclitaxel/administração & dosagemRESUMO
OBJECTIVE: There is no standard treatment for recurrent epithelial ovarian cancer (EOC). As there are no curative options, many oncologists choose to treat women who recur with carboplatin, particularly if they are deemed to have platinum-sensitive disease. However, particularly in the era of platinum-taxane treatment as primary therapy, the utility of this treatment has not been established, nor is it clear whether the results of single-agent treatment are equivalent to that of combination therapy. We sought to determine the outcomes for patients with platinum-sensitive EOC who were treated with carboplatin-taxane therapy and received single-agent carboplatin (C) as second chemotherapy. In addition, we sought to compare these results to the outcomes in women who received carboplatin and paclitaxel (C + T) at first relapse. PATIENTS AND METHODS: We identified 24 patients using our electronic institutional database with a histologically confirmed diagnosis of ovarian cancer that had a complete response to platinum-paclitaxel chemotherapy, relapsed greater than 6 months after treatment, and received single-agent carboplatin as second-line chemotherapy. We performed a subsequent comparison between a subgroup of this cohort and one that met the same inclusion criteria but received C + T at relapse between January 1998 and December 2000. RESULTS: Eighteen patients were evaluable for response, and all were available for analysis of survival end points. For evaluable patients, the overall response rate was 39% (complete, 11%; partial, 28%). Twenty-two percent had stable disease. Six (25%) patients experienced a hypersensitivity reaction, including 1 who required hospitalization. The median overall survival was 22 months. The 2-year overall survival rate was 49%. Stratification by treatment-free interval (TFI) showed a 25% for a TFI between 6 and 12 months and 43% for a TFI > 12 months. When a subgroup of these women (18/24) was compared to a cohort that received C + T (29), the combination was associated with a higher complete and overall response rate, 7 and 36% for C versus 45 and 71% for C + T (P = 0.02). The overall survival in women who received C was 26 months versus 42 months in the women who received C + T (P < 0.02). CONCLUSION: Carboplatin as a single agent is effective therapy for recurrent ovarian cancer in women who recur following treatment with carboplatin and paclitaxel, and the treatment-free interval predicts response to single-agent carboplatin. However, our secondary analysis suggests that carboplatin and paclitaxel may produce a higher response rate and a survival benefit compared to C alone. This supports the conclusions of ICON4, which recently reported both overall and progression-free survival benefits with C + T over C in women with platinum-sensitive recurrent disease.
Assuntos
Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Estudos RetrospectivosRESUMO
BACKGROUND: A 96-hour infusion schedule of paclitaxel demonstrates tolerability and antitumor activity in lung cancer and breast cancer refractory to short-duration infusion paclitaxel. Given the activity of paclitaxel in esophageal cancer, a phase II trial of 96-hour infusion paclitaxel in esophageal cancer was undertaken. METHODS: Both adenocarcinoma and squamous cell histology were included. Paclitaxel was administered at 140 mg/m2 over 96 hours every 21 days. Patients who had metastatic disease to the liver and transaminases greater than two times normal value received 120 mg/m2. Response to treatment was evaluated after the first two cycles and subsequently every third cycle. RESULTS: Ten men and four women were entered. All were eligible for response and had stage IV disease. Thirteen patients were previously treated. All 13 received prior short-duration paclitaxel-containing chemotherapy regimens. Eleven patients had adenocarcinoma and three squamous cell cancer. Patients completed a mean of two cycles (range one to eight) prior to disease progression. No major responses were observed. Toxicity was minimal and included grade 3/4 neutropenia in 14% of patients. One patient with adenocarcinoma demonstrated stable disease for 28 weeks. CONCLUSION: No major activity was observed in a population of previously treated patients. Ninety-six-hour paclitaxel in metastatic esophageal cancer is generally well tolerated with minimal toxicity; however, it is ineffective in previously treated patients. Further evaluation of this schedule of paclitaxel in combination with concurrent radiotherapy, where its radiosensitizing potential may be useful, is ongoing in locally advanced esophageal cancer.