RESUMO
The quantitative immunofluorescence assay of serous ovarian cancer tissue for the expression of estrogen receptors (ERα and ERß) revealed a higher expression level of ERß in comparison with ERα in all surgical tumor samples investigated. Significant differences in the expression level of the markers were detected "from tumor to tumor." A high expression level of both ERα (≥ 25%) and ERß (≥ 44%) in the tumor predicts a significantly longer progression-free survival time (p < 0.01) in the patients after the first line of platinum and taxane-based adjuvant chemotherapy.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Neoplasias Ovarianas/diagnóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Imunofluorescência , Humanos , Prognóstico , TranscriptomaRESUMO
The differences in expression of ERCC1 were estimated between tumor specimens embedded into paraffin blocks and surgical biopsy specimens of non-small cell lung cancer as well as breast and ovarian cancers. Concordance or differences not higher than 20% were observed in 73% of the cases. The number of the cases with more significant differences in ERCC1 expression was less than 17%. The results show that ERCC1 detection in surgical biopsy specimens by flow cytometry is the more preferable method due to reduced preanalytical phase of the analysis.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Citometria de Fluxo/métodos , Técnicas de Diagnóstico Molecular/métodos , Neoplasias Ovarianas/metabolismo , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Citometria de Fluxo/normas , Humanos , Técnicas de Diagnóstico Molecular/normas , Neoplasias Ovarianas/patologia , Inclusão em Parafina/métodos , Inclusão em Parafina/normasRESUMO
Using the model of breast cancer Ehrlich ascites tumor in mice, we showed that a sigle intraperitoneal injection of cardiac glycoside digoxin 1 h before the intraperitoneal injection of cisplatin increased the anticancer effect of the cytostatic drug more than twice when recalculated for the dose. It is assumed that the modifying effect of digoxin is determined by the direct inhibition of glycolysis in tumor cells. Taking into account the design of the study, we consider promising the clinical evaluation of the effectiveness of digoxin as a modifier of cisplatin efficiency in intracavitary therapy of ascites cancers with pleural and abdominal dissenmination.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Ehrlich/tratamento farmacológico , Cisplatino/farmacologia , Digoxina/farmacologia , Animais , Neoplasias da Mama/metabolismo , Carcinoma de Ehrlich/metabolismo , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Glicólise/efeitos dos fármacos , Camundongos Endogâmicos CBA , Transplante de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Lung cancer is a major cause of mortality in Russia. This study aimed to document the characteristics, clinical management, EGFR mutation status and outcomes of patients with non-small-cell lung cancer (NSCLC) throughout the Russian Federation to inform future management decisions. METHODS: This non-interventional, prospective cohort study (clinicaltrials.gov NCT01069835) was conducted at 33 sites across the Russian Federation. Patients with confirmed NSCLC were enrolled and followed for up to 12 months or until death. Investigators collected information on patient and disease characteristics, diagnosis and treatment patterns, clinical outcomes and adverse events (AEs). A logistic regression model was used to evaluate characteristics affecting tumor EGFR mutation status. RESULTS: Data were analyzed from 838 patients. Most (78.4%) were male and Caucasian (98%), mean age was 58.7 years and 26.5% were never-smokers. Squamous-cell carcinoma (54.3%) was the most prevalent histology, followed by adenocarcinoma (31%). Most patients presented with advanced disease (23.7% with stage IIIA, 14.1% with stage IIIB, 25.4% with stage IV) and 10.1% of patients had EGFR-mutation-positive tumors. EGFR mutation was significantly associated with female gender, never smoking, age and adenocarcinoma histology. First- or second-line chemotherapy had been performed in 370 and 96 patients, respectively, and median progression-free survival was 35 and 19.4 weeks, respectively. For 813 patients, 194 AEs were reported at visit 1. A median of two AEs was reported for patients who had at least one AE. Study limitations include potential site selection bias, short observation period, small sample size and inclusion of fewer than average stage III-IV patients. CONCLUSIONS: This study contributes to a better understanding of prognostic and predictive factors of NSCLC in the Russian Federation, which will enable optimal treatment selection in future clinical practice. Epidemiology of EGFR mutations in this NSCLC cohort was similar to other studies of NSCLC in Caucasian populations.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Prospectivos , Federação RussaRESUMO
BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part). METHODS: Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed. RESULTS: Phase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78-1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77-1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52-1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvß6 expression was associated with longer OS in arms A [HR 0.55 (0.30-1.00)] and B [HR 0.41 (0.21-0.81)] than in arm C. CONCLUSION: The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT01008475.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Cetuximab , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Integrina alfaV/biossíntese , Integrina alfaV/imunologia , Irinotecano , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaAssuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Neoplasias Ovarianas/metabolismo , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Células HeLa , Humanos , Neoplasias Ovarianas/diagnósticoRESUMO
AIM: AZD8931 is an oral equipotent inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling. This Phase I, open-label study evaluated the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD8931 in patients with advanced solid tumors (NCT00637039). METHODS: Patients received AZD8931 as a single oral dose followed by 4 days of observation, then twice-daily dosing for 21 consecutive days. Using a standard 3 + 3 design, AZD8931 doses were escalated from 40 mg bid until the maximum tolerated dose (MTD) was established. RESULTS: Twenty-eight patients received AZD8931 (n = 5, 40 mg bid; n = 8, 80 mg bid; n = 6, 160 mg bid; n = 6, 240 mg bid; n = 3, 300 mg bid). Ovary (n = 8) and breast (n = 5) were the most common primary tumor types. The most frequent adverse events were treatment-emergent cutaneous (n = 27) and diarrhea (n = 21). Dose-limiting toxicities (DLTs) were identified in one patient in the 240 mg bid cohort (Grade 3 rash) and two patients in the 300 mg bid cohort (Grade 3 and 4 diarrhea). The pharmacokinetic profile of AZD8931 supported twice-daily dosing. AZD8931 was rapidly absorbed (median tmax 1-3 h), was well distributed and had moderate to high clearance with an elimination half-life of approximately 11 h. Exposure appeared to increase approximately proportionally with dose up to 160 mg. Of 21 patients evaluable for response at day 21, 12 had stable disease and nine had disease progression. CONCLUSION: The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment.
Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-3/antagonistas & inibidores , Transdução de Sinais , Adulto , Idoso , Demografia , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/administração & dosagem , Quinazolinas/sangue , Quinazolinas/farmacocinética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND: This phase II study investigated whether a lower-than-approved dose of capecitabine, plus docetaxel (XT), would improve tolerability versus standard-dose XT without compromising efficacy. PATIENTS AND METHODS: Women aged ≥18 years with locally advanced/metastatic breast cancer resistant to anthracycline-based chemotherapy in the (neo)adjuvant, first- or second-line metastatic setting were eligible. Patients were randomly assigned to receive standard-dose XT (capecitabine 1250 mg/m(2) twice daily, days 1-14; docetaxel 75 mg/m(2), day 1 every 3 weeks) or low-dose XT (capecitabine 825 mg/m(2) twice daily, days 1-14; docetaxel as above). The primary objective was to demonstrate non-inferiority of low-dose to standard-dose XT in terms of progression-free survival (PFS). RESULTS: 470 patients were randomly allocated in a 1 : 1 ratio to standard-dose or low-dose XT. Median PFS was 7.9 versus 5.8 months [hazard ratio 1.16, 95% confidence interval (CI) 0.95-1.43] in the standard-dose and low-dose arms, respectively. The upper limit of the 95% CI was above the predefined non-inferiority margin (1.35, P = 0.078). Secondary efficacy end points were consistent with PFS. The frequency and severity of adverse events was similar in both treatment arms. CONCLUSIONS: Non-inferiority of low-dose to standard-dose XT in terms of PFS was not demonstrated; this may be due to regional subgroup effects.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Docetaxel , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Adulto JovemRESUMO
In trials in triple negative breast cancer (TNBC), oestrogen and progesterone receptor negativity should be defined as < 1% positive cells. Negativity is a ratio of <2 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less. In routine practice, immunohistochemistry is acceptable given stringent quality assurance. Triple negativity emerging after neoadjuvant treatment differs from primary TN and such patients should not enter TNBC trials. Patients relapsing with TN metastases should be eligible even if their primary was positive. Rare TN subtypes such as apocrine, adenoid-cystic and low-grade metaplastic tumours should be excluded. TN and basal-like (BL) signatures overlap but are not equivalent. Since the significance of basal cytokeratin or EGFR overexpression is not known and we lack validated assays, these features should not be used to subclassify TN tumours. Tissue collection in trials is mandatory so the effect on outcome of different tumour phenotypes and BRCA mutation can be explored. No prospective studies have established that TN tumours have particular sensitivity or resistance to any specific chemotherapy agent or radiation. TNBC patients should be treated according to tumour and clinical characteristics.
Assuntos
Neoplasias da Mama/terapia , Metástase Neoplásica , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Feminino , Genes erbB-2/fisiologia , Humanos , Estadiamento de Neoplasias , Projetos de PesquisaRESUMO
AIM: To describe surgical outcomes in patients with HER2-positive locally advanced (LABC) or inflammatory breast cancer (IBC) participating in the NeOAdjuvant Herceptin (NOAH) study (ISRCTN86043495). PATIENTS AND METHODS: A total of 235 patients with HER2-positive disease were randomized to neoadjuvant trastuzumab plus chemotherapy (doxorubicin plus paclitaxel, followed by paclitaxel, followed by cyclophosphamide, methotrexate and fluorouracil) or neoadjuvant chemotherapy alone. Of these patients, 228 received their allocated treatment (115 received trastuzumab plus chemotherapy and 113 received chemotherapy alone) and were potentially eligible for surgery. Mastectomy was required for all patients with IBC and was recommended for all patients with LABC. However, breast-conserving therapy could be considered for patients with peripheral neoplasms measuring ≤ 4 cm in diameter at diagnosis, with a favorable ratio of tumor to breast volume, or at the patient's request if there had been a good response to treatment. RESULTS: As previously reported, the addition of trastuzumab to neoadjuvant chemotherapy improved the overall, complete and pathological complete response to therapy and significantly improved event-free survival (the primary endpoint of the study). Trastuzumab also enabled more patients to have breast conserving surgery (BCS) (23% versus 13% respectively) without an apparent detrimental effect on local disease control (no patient treated with trastuzumab plus chemotherapy had experienced a local recurrence after BCS at the time of analysis). CONCLUSIONS: Although this was not an aim of the trial, neoadjuvant trastuzumab given concurrently with chemotherapy enabled 23% of patients with HER2-positive LABC/IBC to avoid mastectomy (including a small number of patients with IBC).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/patologia , Neoplasias Inflamatórias Mamárias/cirurgia , Mastectomia Segmentar/métodos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Medição de Risco , Análise de Sobrevida , Trastuzumab , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) in patients with poor-prognosis nonseminomatous germ cell tumor (NSGCT). Paclitaxel is an active treatment of nonseminomatous germ cell tumors. METHODS: The present study was an open-label, single-center, Phase II study. Chemotherapy-naive patients received T-BEP (paclitaxel 175 mg/m2 [day 2], cisplatin 20 mg/m2 [days 1-5], etoposide 100 mg/m2 [days 1-5], bleomycin 30 IU [days 1, 3, and 5]), and granulocyte colony-stimulating factor 300 µg (days 6-10). The number of cycles (range 4-6) was dependent on the normalization of tumor markers. Secondary resection was planned for patients with tumor marker-negative partial remission. Assessments included radiologic response, tumor markers, and safety. The primary endpoint was progression-free survival (PFS) 1 year after chemotherapy. RESULTS: Of 51 patients, 49 completed chemotherapy and were evaluable for response: 12 (25%) had a complete response, 29 (59%) were marker-negative (tumor marker normalization) and 3 (6%) were marker-positive (tumor marker decrease for ≥1 month) incomplete responders, and 5 (10%) had progressive disease. A total of 37 patients underwent secondary resection. After the treatment of 27 patients, an unplanned analysis showed inappropriate toxicity at cycle 1 (grade 3-4 infection [6 patients] resulting in 2 toxic deaths), which led to treatment modification (BEP [cycle 1], T-BEP [subsequent cycles]), with no further toxic deaths observed. Grade 3-4 adverse events included neutropenia (71%), febrile neutropenia (33%), and infection (14%). During the first year after chemotherapy, 1 patient was lost to follow-up, and 21 patients relapsed. The PFS rate at 1 year after chemotherapy was 58% (29 of 50 patients). CONCLUSIONS: T-BEP did not improve PFS in patients with poor-prognosis NSGCT. The administration of T-BEP from cycle 1 resulted in excessive toxicity but was administered safely from cycle 2.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/secundário , Prognóstico , Adulto JovemRESUMO
BACKGROUND: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6-12 months platinum-free interval (PFI)] is unclear. PATIENTS AND METHODS: within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup. RESULTS: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45-0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43-0.82; P = 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months). CONCLUSION: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6-12 months).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Compostos Organoplatínicos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Recidiva , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Resultado do TratamentoRESUMO
BACKGROUND: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6-12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy. PATIENTS AND METHODS: a detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted. RESULTS: similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357). CONCLUSION: the superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Recidiva , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina , Resultado do TratamentoRESUMO
BACKGROUND: This retrospective study was carried out to evaluate the prognostic significance of clinical factors in patients treated for metastatic gastric cancer with second-line chemotherapy. PATIENTS AND METHODS: We evaluated the prognostic significance of various clinical factors in 126 patients, who were treated with second-line chemotherapy. RESULTS: Median progression-free and overall survival (OS) for second-line chemotherapy were 3.3 and 5.3 months, respectively, with an overall response rate of 11.1%. Multivariate analysis identified three independent prognostic factors: performance status: Eastern Cooperative Oncology Group zero to one [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.7-5.4], hemoglobin (Hb) level: >/=10 g/dl (HR 2.2, 95% CI 2.1-2.4) and time-to-progression (TTP) under first-line therapy: >/=5 months (HR 0.5, 95% CI 0.3-0.8). From the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: good (n = 40), intermediate (n = 36) and poor risk group (n = 56). The median survival for good, intermediate and poor risk groups were 13.5, 6.0 and 2.9 months, respectively, whereas the 1-year OS rates were 50.2%, 14.2% and 2.6%, respectively (P = 0.00001). CONCLUSIONS: With inadequate data from randomized controlled trials at the moment, our report indicates that second-line chemotherapy is effective and beneficial in patients with good performance status, higher Hb level along with higher TTP under first-line therapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma de Células em Anel de Sinete/patologia , Cisplatino/administração & dosagem , Docetaxel , Etoposídeo/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Estadiamento de Neoplasias , Neoplasias Ovarianas/secundário , Neoplasias Peritoneais/secundário , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Taxoides/administração & dosagemRESUMO
BACKGROUND: Locally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points. PATIENTS AND METHODS: These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy. RESULTS: Among 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31-not reached] versus 24 months (95% CI: 13-42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41-0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12-59) versus 11 months (95% CI: 8-14) for PF (HR: 0.66; 95% CI: 0.45-0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37-0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030). CONCLUSIONS: In locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Neoplasias Hipofaríngeas/terapia , Neoplasias Laríngeas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/mortalidade , Neoplasias Hipofaríngeas/patologia , Neoplasias Hipofaríngeas/radioterapia , Neoplasias Hipofaríngeas/cirurgia , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirurgia , Laringectomia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Medição de Risco , Taxoides/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
The basic principle of targeted therapy formulated about ten years ago consists in the design and application of drugs specifically directed against well-defined targets that are critical for tumor survival and not compromising for normal organs and tissues. The past decade has been marked by the appearance of an immense diversity of novel antitumor agents with claimed targeted action. Unfortunately, despite indisputable progress in clinical settings, some popular drugs against solid tumors (e.g. bevacizumab, trastuzumab, erlotinib, gefitinib) nominally assigned to targeted-action drugs, cannot actually be classified with this group being nonconforming to a priori stated goals of targeted therapy. The state-of-the-art and current problems in targeted therapy of solid tumors are reviewed.
Assuntos
Antineoplásicos/uso terapêutico , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: The purpose of this study was to validate a prognostic index [surgical complete response 1 (sCR1)] in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: Data and specimens from 61 patients with normalized tumor markers and postchemotherapy viable nonteratomatous NSGCT treated in 13 institutions were collected. RESULTS: With a median follow-up of 5.4 years, the 5-year progression-free survival (PFS) rate was 65%; the 5-year overall survival (OS) rate was 72%. Favorable PFS was predicted by a complete resection, <10% of viable malignant cells, and a good International Germ Cell Consensus Classification group at presentation. Patients were assigned to one of three risk groups defined in sCR1: no risk factor (good risk), one risk factor (intermediate risk) and two to three risk factors (poor risk group). The 5-year PFS rate was 92%, 78%, and 42%, respectively (P = 0.002) (as compared with 90%, 76%, and 41% in the original sCR1 study). The 5-year OS rate was 90%, 86%, and 52%, respectively (P = 0.009) (as compared with 100%, 83%, and 51% in the original sCR1 study). Postoperative chemotherapy did not appear to improve OS compared with surveillance and treatment only at relapse. CONCLUSION: In patients with postchemotherapy viable NSGCT, a complete resection of residual masses should be rigorously pursued. These data validate the sCR1 prognostic index. Given their excellent outcome, patients in the favorable group may not require postoperative chemotherapy.