Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Estudos Multicêntricos como Assunto , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias Urogenitais/tratamento farmacológico , Austrália/epidemiologia , Bleomicina/administração & dosagem , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Nova Zelândia/epidemiologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Neoplasias Urogenitais/diagnóstico , Neoplasias Urogenitais/epidemiologiaRESUMO
PURPOSE: The phase II TACTIC trial prospectively selected patients with KRAS wild-type advanced biliary tract cancer for first-line treatment with panitumumab and combination chemotherapy. METHODS: Of 78 patients screened, 85 % had KRAS wild-type tumours and 48 were enrolled. Participants received cisplatin 25 mg/m(2) and gemcitabine 1000 mg/m(2) on day 1 and day 8 of each 21-day cycle and panitumumab 9 mg/kg on day 1 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or request to discontinue. The primary endpoint was the clinical benefit rate (CBR) at 12 weeks (complete response, partial response, or stable disease). CBR of 70 % was considered to be of clinical interest. Secondary outcomes were progression-free survival, time to treatment failure, overall survival, CA19.9 response and safety. RESULTS: Thirty-four patients had a clinical benefit at 12 weeks, an actuarial rate of 80 % (95 % CI 65-89 %). 46 % had a complete or partial response. Median progression-free survival was 8.0 months (95 % CI 5.1-9.9) and median overall survival 11.9 months (95 % CI 7.4-15.8). Infection accounted for 27 % of the grade 3 or 4 toxicity, with rash (13 %), fatigue (13 %), and hypomagnesemia (10 %) among the more common grade 3 or 4 non-haematological toxicities. CONCLUSION: A marker-driven approach to patient selection was feasible in advanced biliary tract cancer in an Australian population. The combination of panitumumab, gemcitabine, and cisplatin in KRAS wild-type cancers was generally well tolerated and showed promising clinical efficacy. Further exploration of anti-EGFR therapy in a more selected population is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Seleção de Pacientes , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/patologia , Antígeno CA-19-9/sangue , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Panitumumabe , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. PATIENTS AND METHODS: Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. RESULTS: Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. CONCLUSION: Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Bleomicina/administração & dosagem , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/secundário , Prognóstico , Neoplasias Testiculares/patologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The purpose of this trial was to compare adjuvant 5-flurouracil, alpha-interferon and interleukin-2 to observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma (RCC) in terms of disease free survival, overall survival and quality of life (QoL). PATIENTS AND METHODS: Patients 8weeks post nephrectomy for RCC, without macroscopic residual disease, with stage T3b-c,T4 or any pT and pN1 or pN2 or positive microscopic margins or microscopic vascular invasion, and no metastases were randomised to receive adjuvant treatment or observation. QoL was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQC-30). Treatment delivery and toxicity were monitored. The trial was designed to detect an increase in 3year disease free survival (DFS) from 50% on observation to 65% on treatment (hazard ratio (HR)=0.63) with 90% power and two-sided alpha=0.05. RESULTS: From 1998 to 2007, 309 patients were randomised (155 to observation; 154 to treatment). 35% did not complete the treatment, primarily due to toxicity (92% of patients experienced ⩾grade 2, 41% ⩾grade 3). Statistically significant differences between the arms in QoL parameters at 2months disappeared by 6months although there was suggestion of a persistent deficit in fatigue and physical function. Median follow-up was 7years (maximum 12.1years). 182 patients relapsed or died. DFS at 3years was 50% with observation and 61% with treatment (HR 0.84, 95% confidence interval (CI) 0.63-1.12, p=0.233). 124 patients died. Overall survival (OS) at 5years was 63% with observation and 70% with treatment (HR 0.87, 95% CI 0.61-1.23, p=0.428). CONCLUSIONS: The treatment is associated with significant toxicity. There is no statistically significant benefit for the regimen in terms of disease free or overall survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/patologia , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Incidência , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Neoplasias Renais/patologia , Masculino , Recidiva Local de Neoplasia/patologia , Nefrectomia , Qualidade de Vida , Recidiva , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing. PATIENTS AND METHODS: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS). RESULTS: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value. CONCLUSIONS: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.
Assuntos
Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Área Sob a Curva , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Quimioterapia de Indução , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: To perform a subset analysis of patients with partially platinum-sensitive recurrent ovarian cancer (ROC) who received either CD [carboplatin-pegylated liposomal doxorubicin (PLD)] or CP (carboplatin-paclitaxel) in the CALYPSO trial. PATIENTS AND METHODS: CALYPSO, an international phase III, non-inferiority trial, enrolled women with ROC that relapsed >6 months following first- or second-line therapy. Patients were randomized to CD or CP. Patients with a treatment-free interval of >6 and ≤ 12 months were evaluated for progression-free survival (PFS), the primary end point of CALYPSO trial, and safety. RESULTS: A total of 344 partially platinum-sensitive patients were included (N = 161, CD and N = 183, CP). The hazard ratio for PFS was 0.73 (95% confidence interval: 0.58-0.90; P = 0.004 for superiority) in favor of CD. Median PFS times were 9.4 months (CD) and 8.8 months (CP). Toxicities more common with CP versus CD included grade 3/4 neutropenia (50% versus 39%; P = 0.015), grade 2 alopecia (86% versus 9%; P < 0.001), neuropathy and hypersensitivity reactions. Hand-foot syndrome was more common with CD; however, grade 3/4 reactions were low (one patient in each arm). CONCLUSION: Carboplatin-PLD has a more favorable risk-benefit profile than CP in patients with partially platinum-sensitive ROC and should be considered an effective treatment option for these patients.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Paclitaxel/efeitos adversos , Compostos de Platina/uso terapêutico , Polietilenoglicóis/efeitos adversos , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. METHODS: This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours. RESULTS: Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles. CONCLUSIONS: CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Contagem de Células , Células Endoteliais , Feminino , Humanos , Queratina-18/análise , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Fator de von Willebrand/análise , Fator de von Willebrand/imunologiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m(-2)) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day(-1) (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day(-1) (cohort 2b; the erlotinib dose was escalated to 100 mg day(-1) in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100-150 mg day(-1), with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Docetaxel , Cloridrato de Erlotinib , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Peritoneais/mortalidade , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Taxoides/administração & dosagem , Taxoides/efeitos adversosRESUMO
Female Japanese macaques (Macaca fuscata) in the Arashiyama population near Kyoto, Japan, are unusual, in that they exhibit what many would consider to be male-typical sexual characteristics. Specifically, they mount other females within the context of temporary, but exclusive, sexual relationships (i.e., homosexual consortships) and they sometimes exhibit a preference for female sexual partners, even when given the choice of a sexually motivated male alternative. In this study, we examined whether female Japanese macaques also exhibited male-typical patterns of courtship behaviour during homosexual consortships. Data were collected on courtship behaviour during heterosexual and homosexual consortships in free-ranging Japanese macaques from the Arashiyama (Japan) population. We analyzed the occurrence of 12 different courtship behaviours during 3374 heterosexual inter-mount intervals and 1412 homosexual inter-mount intervals. Sex differences between heterosexually consorting males and females existed for only two of the 12 courtship behaviours we investigated: inclined-back presentations and sexual vocalizations. Dominant and subordinate homosexually consorting females were sex-typical in their expression of inclined-back presentations and sexual vocalizations. Consequently, facultative same-sex sexual partner preference, mounting and consortships do not co-occur with male-typical patterns of courtship behaviour in female Japanese macaques.
Assuntos
Copulação/fisiologia , Macaca/fisiologia , Comportamento Sexual Animal/fisiologia , Animais , Comportamento de Escolha/fisiologia , Corte , Feminino , Masculino , Preferência de Acasalamento Animal/fisiologia , Caracteres SexuaisRESUMO
BACKGROUND: Previous studies have indicated an association between obesity and poor survival in several tumour types, including ovarian cancer. We sought to test the hypothesis that obesity reduces survival in a large, well-characterised and relatively homogeneous cohort of ovarian cancer patients. PATIENTS AND METHODS: The relationship between body mass index (BMI) and overall survival (OS) and progression-free survival (PFS) in 1067 patients participating in the Scottish Randomised Trial in Ovarian Cancer I trial was assessed. All patients received first-line carboplatin/taxane chemotherapy. The dose of carboplatin was determined by a measured glomerular filtration rate (GFR), ensuring accurate dosing in all categories of BMI and the dose of taxane was not capped. Patients were assigned to one of four categories: underweight (BMI < 18.5), ideal weight (BMI 18.5-24.9), overweight (BMI 25-29.9) or obese (BMI >or= 30). RESULTS: There were neither statistically significant differences in PFS or OS between these four groups nor were there any differences in taxane or carboplatin dose intensity. Furthermore, there was no association between BMI and tumour stage or grade at presentation, or completeness of debulking surgery. CONCLUSIONS: Obese patients with epithelial ovarian cancer do not have a poorer prognosis, provided that they receive optimal doses of chemotherapy based on measured GFR and actual body weight.
Assuntos
Índice de Massa Corporal , Carcinoma/mortalidade , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma/complicações , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Sobrepeso/complicações , Paclitaxel/administração & dosagem , Análise de Sobrevida , Taxoides/administração & dosagem , Magreza/complicaçõesRESUMO
Two studies were carried out to evaluate heat-killed Mycobacterium vaccae SRL172 as an immunotherapeutic agent for patients with metastatic, post-nephrectomy, renal cell carcinoma. In the first study, 60 patients in France and the UK received injections of SRL172, and their survival was compared with that of historical controls who had been treated either with biological response modifiers (IL-2, IFN-alpha) or chemotherapy. In the second study, 36 patients were randomised to receive treatment with IL-2 alone or IL-2 plus SRL172. Survival and adverse events related to the treatments were assessed and compared between treatment groups. The first study showed that those treated with SRL172 alone survived equally as long as those receiving IL-2 or IFN-alpha and both treatment groups survived longer than those on chemotherapy (p<0.001), a result supported by Cox's proportional hazards regression analysis. The second study, stopped early due to drug supply issues, showed that the addition of SRL172 to IL-2 made no difference to survival compared to IL-2 alone, in the limited numbers treated. Adverse events occurring in those receiving SRL172 in the first study were mild and in the second study those receiving IL-2 alone had significantly more adverse events than those receiving SRL172 plus IL-2 (p<0.001). It is concluded that SRL172 may have activity in metastatic renal cancer and has very low toxicity, making it worthy of further study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Bacterianas/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Renais/terapia , Imunoterapia/métodos , Neoplasias Renais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vacinas Bacterianas/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-2/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosAssuntos
Neoplasias Abdominais/terapia , Cardiopatias Congênitas/complicações , Seminoma/terapia , Síndrome de Williams/complicações , Neoplasias Abdominais/complicações , Neoplasias Abdominais/diagnóstico , Adulto , Humanos , Masculino , Seminoma/complicações , Seminoma/diagnóstico , Síndrome de Williams/diagnósticoRESUMO
The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m(-2) (arm A, n=51) or docetaxel 60 mg m(-2) with irinotecan 200 mg m(-2) (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58-81%; P=0.079; arm B 67% (90% CI 55-78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3-4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3-4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carboplatina/administração & dosagem , Carcinoma/patologia , Progressão da Doença , Docetaxel , Esquema de Medicação , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Infusões Intravenosas , Irinotecano , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Análise de Sobrevida , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
The feasibility of sequential carboplatin followed by docetaxel-based therapy for untreated ovarian cancer was determined. Patients received four q3w cycles of carboplatin AUC 7, then four q3w cycles of either docetaxel 100 mg m(-2) (day 1) (arm A); docetaxel 75 mg m(-2) (day 8) and gemcitabine 1250 mg m(-2) (days 1,8) (arm B) or docetaxel 25 mg m(-2) and gemcitabine 800 mg m(-2) (both given weekly (days 1,8,15)) (arm C). A total of 44 patients were randomised to each treatment arm. None of the arms demonstrated an eight cycle completion rate (70.5/72.7/45.5% in arms A/B/C, respectively), which was statistically greater than 60% (P=0.102, P=0.056, P=0.982) which was our formal feasibility criteria, although only the completion rate in arm C was clearly worse than this level. The overall response rate (ORR) after carboplatin was 65.7% in 70 evaluable patients. In evaluable patients, ORRs after docetaxel-based cycles were: arm A 84.0% (21 out of 25); arm B 77.3% (17 out of 22); arm C 69.6% (16 out of 23). At follow-up (median 30 months), median progression-free survival times were: arm A 15.5 months (95% CI: 10.5-20.6); arm B 18.1 months (95% CI: 15.9-20.3); arm C, 13.7 months (95% CI: 12.8-14.6). Neutropenia was the predominant grade 3-4 haematological toxicity: 77.8/85.7/54.4% in arms A/B/C, respectively. Dyspnoea was markedly increased in both gemcitabine-containing arms (P=0.001) but was worse in arm C. Although just failing to rule out eight cycle completion rates less than 60%, within the statistical limitations of these small cohorts, the overall results for arms A and B are encouraging. Larger phase III studies are required to test these combinations.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Carboplatina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Docetaxel , Esquema de Medicação , Dispneia/induzido quimicamente , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Análise de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento , GencitabinaRESUMO
In essence, dose densification is "accelerated therapy" (a commonly used phrase in radiotherapeutics) and is a form of dose intensification because the amount of drug per unit time (dose intensity = mg/m(2)/week) is increased. There is general consensus that increasing platinum dose intensity in ovarian carcinoma has not been proven despite a dozen or more randomized trials evaluating up to twofold increases in dose intensity. Few randomized trials in ovarian carcinoma have compared weekly "dose dense" chemotherapy with more conventional dosing schedules although there are plenty of phase II studies. In these, dose densification of single agent therapy, for some drugs at least, appears to be relatively well tolerated, with encouraging levels of activity in patients purportedly refractory to the same agents when scheduled in the standard way. However, many studies ostensibly evaluating "dose density" do not actually evaluate this entity, but actually split the standard 3-weekly dose into weekly fragments thus maintaining the same dose intensity. Furthermore, as the aim of treatment in recurrent ovarian cancer is palliation, weekly treatments are less convenient, are probably less cost effective, and have different dose-limiting toxicities. This article will review the clinical data supporting dose density as a therapeutic maneuver in ovarian cancer.