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1.
Int J Clin Oncol ; 25(3): 403-417, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31974683

RESUMO

BACKGROUND: The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 15 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Adulto , Antineoplásicos/farmacologia , Criança , Fusão Gênica , Hematologia , Humanos , Japão , Oncologia , Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Sociedades Médicas
2.
Int J Clin Oncol ; 25(2): 217-239, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31286289

RESUMO

BACKGROUND: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. METHODS: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. RESULTS: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. CONCLUSION: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Reparo de Erro de Pareamento de DNA/genética , Imunoterapia/métodos , Neoplasias/genética , Neoplasias/terapia , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Humanos , Japão , Oncologia , Terapia de Alvo Molecular , Receptor de Morte Celular Programada 1/antagonistas & inibidores
3.
Nagoya J Med Sci ; 81(3): 501-509, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31579340

RESUMO

The survey involves examining the applications from 142 institutions that have consented to make available all certification applications from 2015 and 2016 to a research project for building a certification system for an ethics committee run by the Agency for Medical Research and Development. The number of certified institutions is 20 (14.1%). In the applications from uncertified institutions, there are cases in which requirements of ethics guidelines are unmet, and there is insufficient information provided on regulation and procedure. An analysis of the committee members who can contribute as members of the general public (general public committee members) has indicated that the number of committee members who do not belong to an institution in which an ethics committee is instituted (external committee members) is 41 (95.7%) among the certified institutions and 224 (84.5%) among the uncertified institutions. The proportion of general public committee members drawn internally from institutions tends to be higher among uncertified institutions. While a separate committee examined conflicts of interest in research in 19 certified institutions (95.0%), such conflicts were found in 41 uncertified institutions (33.9%) by the ethics committee. The survey confirms that the challenge lies in increasing the number of external committee members and in further improving the system to manage conflicts of interest, and the education and training regime.


Assuntos
Comitês Consultivos/estatística & dados numéricos , Comitês de Ética em Pesquisa/estatística & dados numéricos , Pesquisa Biomédica/ética , Revisão Ética , Humanos , Japão
4.
Surg Oncol ; 29: 25-32, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31196490

RESUMO

OBJECTIVE: To examine clinico-pathological characteristics and outcomes of uterine carcinosarcoma (UCS) in women aged ≥80 years. METHODS: This is a secondary analysis of a previous multicenter retrospective study examining 906 women with stage I-IV UCS who underwent primary hysterectomy. Patient demographics, treatment types, tumor characteristics, and survival were examined across aged ≥80 (n = 82 [9.1%]), aged 60-79, (n = 526 [58.1%]), and aged <60 (n = 298 [32.9%]). RESULTS: Women in the aged ≥80 group were more likely to be Caucasian, undergo simple hysterectomy without lymphadenectomy, and receive no postoperative therapy (all, P < 0.05). Tumors in the aged ≥80 group were more likely to have high-grade carcinoma, heterologous sarcoma, and sarcoma dominance but less likely to have lympho-vascular space invasion (all, P < 0.05). Lymphadenectomy did not improve survival in the aged ≥80 group (P > 0.05), whereas lymphadenectomy was protective for survival in the younger groups (both, P < 0.05). Postoperative chemotherapy was associated with improved progression-free survival (PFS) in the aged ≥80 group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22-0.89, P = 0.021). With chemotherapy treatment, women in the aged ≥80 group had PFS similar to those in the aged 60-79 group (HR 0.97, 95%CI 0.51-1.83, P = 0.92). In contrast, without chemotherapy treatment, women in the aged ≥80 group had significantly decreased PFS compared to the aged 60-79 group (HR 1.62, 95%CI 1.09-2.40, P = 0.016). Similar associations were observed for postoperative radiotherapy. CONCLUSION: Nearly 10% of women with UCS are aged ≥80 that are characterized by aggressive tumor factors. Postoperative therapy but not extensive surgery may improve survival in this age group.


Assuntos
Carcinossarcoma/patologia , Quimioterapia Adjuvante/mortalidade , Histerectomia/mortalidade , Excisão de Linfonodo/mortalidade , Radioterapia Adjuvante/mortalidade , Neoplasias Uterinas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinossarcoma/mortalidade , Carcinossarcoma/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/terapia
5.
Int J Clin Oncol ; 24(10): 1284-1291, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31127479

RESUMO

PURPOSE: To compare the efficacy, safety, and tolerability profiles of pegylated liposomal doxorubicin and carboplatin (PLDC) with those of gemcitabine and carboplatin (GC) for the treatment of patients with platinum-sensitive recurrent ovarian cancer. METHODS: Ovarian cancer patients with recurrence > 6 months after first-line platinum and taxane-based therapies were randomly assigned to PLDC [pegylated liposomal doxorubicin 30 mg/m2 plus carboplatin area under the curve (AUC) 5 mg/mL/min on day 1] every 4 weeks or GC (gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin AUC 4 mg/mL/min on day 1) every 3 weeks for at least 6 cycles. The primary endpoint was progression-free survival, and overall response rate, overall survival, toxicity, and dose administration were secondary endpoints. RESULTS: One-hundred patients (49 PLDC; 51 GC) were randomly assigned. Over a median follow-up of 24 months, the median progression-free survival was 12.0 months (95% CI 9.2-15.0) for PLDC and 9.8 months (8.9-12.3) for GC [HR 0.69 (0.455-1.047)] with a difference of 2.2 months. The response rate was 57.1% (41.0-72.3) for PLDC and 56.4% (39.6-72.2) for GC. No obvious differences in toxicity (G3/4) were noted between arms. The median relative dose intensity of planned dose per week was 88.9% for pegylated liposomal doxorubicin and 53.1% for gemcitabine (p < 0.0001). CONCLUSIONS: PLDC and GC are both good treatment candidates for platinum-sensitive recurrent ovarian cancer patients; however, the dose intensity was lower for GC than for PLDC. PLDC had a more favorable risk-benefit profile than that of GC for patients.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma Mucinoso/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Polietilenoglicóis/administração & dosagem , Prognóstico , Taxa de Sobrevida , Adulto Jovem
6.
Int J Clin Oncol ; 24(5): 575-582, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30580379

RESUMO

BACKGROUND: The aim of this study was to evaluate the effects of treatment with both three-dimensional radiotherapy (3DRT) and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors. METHODS: We conducted a retrospective multi-institutional chart review of postoperative uterine cervical cancer patients with high-risk prognostic factors who had been treated with both 3DRT and weekly 40-mg/m2 cisplatin from 2007 to 2012. Each participating hospital provided detailed information regarding patient characteristics, treatment outcomes, and treatment complications. RESULTS: The eligible 96 patients were analyzed. The median follow-up period was 61 months. The 3-year relapse-free survival, overall survival (OS), and locoregional relapse-free survival (LRFS) rates were 76%, 90%, and 88%, respectively. In multivariate analysis, the histological finding of either adenocarcinoma or adenosquamous carcinoma was a significant risk factor for both OS and LRFS. The percentage of patients with grade ≥ 3 acute hematologic toxicity, acute lower gastrointestinal toxicity (GIT), and late lower GIT were 45%, 19%, and 17%, respectively. CONCLUSIONS: The outcomes of concurrent chemoradiotherapy (CCRT) using weekly 40-mg/m2 cisplatin are similar to those in the previous studies that used several chemotherapy regimens. However, postoperative CCRT using 3DRT had a high level of late GIT.


Assuntos
Quimiorradioterapia/efeitos adversos , Cisplatino/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/radioterapia , Carcinoma Adenoescamoso/cirurgia , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/cirurgia
8.
Surg Oncol ; 27(3): 433-440, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30217299

RESUMO

OBJECTIVE: To examine significance of sarcoma dominance (SD) patterns in uterine carcinosarcoma (UCS). METHODS: This is a secondary analysis of multicenter retrospective study examining women with stages I-IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. RESULTS: SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P < 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35-1.69, and hetero/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homo/non-dominance (all, P < 0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P > 0.05). CONCLUSION: In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy.


Assuntos
Adenocarcinoma de Células Claras/patologia , Carcinossarcoma/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Neoplasias Uterinas/patologia , Adenocarcinoma de Células Claras/cirurgia , Carcinossarcoma/cirurgia , Cistadenocarcinoma Seroso/cirurgia , Neoplasias do Endométrio/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Uterinas/cirurgia
9.
Ann Surg Oncol ; 25(12): 3676-3684, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30105438

RESUMO

PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.


Assuntos
Carcinossarcoma/secundário , Neoplasias Uterinas/patologia , Carcinossarcoma/mortalidade , Carcinossarcoma/cirurgia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Projetos Piloto , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/cirurgia
10.
Ann Surg Oncol ; 25(9): 2756-2766, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29971677

RESUMO

OBJECTIVE: The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS: This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I-IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS: Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36-2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39-2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION: In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.


Assuntos
Vasos Sanguíneos/patologia , Carcinossarcoma/patologia , Carcinossarcoma/terapia , Vasos Linfáticos/patologia , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Humanos , Histerectomia , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Intervalo Livre de Progressão , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida
11.
Int J Gynecol Cancer ; 28(1): 2-10, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-26588236

RESUMO

OBJECTIVE: The recent phase 3 trial AGO-OVAR16 demonstrated that pazopanib maintenance improved median progression-free survival in patients with ovarian cancer whose disease did not progress during first-line treatment. However, this improvement was not seen in the subset of East Asian patients. The current analysis evaluated the efficacy and safety of pazopanib maintenance in East Asian patients from AGO-OVAR16 and a separate East Asian study. MATERIALS AND METHODS: East Asian patients from AGO-OVAR16 (n = 209) and the East Asian study (N = 145) were randomized 1:1 to receive pazopanib 800 mg/d or placebo for up to 24 months. The primary end point for each study was progression-free survival by RECIST (Response Evaluation Criteria in Solid Tumors) based on investigator assessment. Clinical and genetics data were analyzed separately by study or pooled according to separate predetermined statistical plans. RESULTS: Pazopanib maintenance had a detrimental effect on median progression-free survival versus placebo in East Asian patients from the combined studies (n = 354; 17.9 vs 21.5 months; hazard ratio, 1.114; 95% confidence interval, 0.818-1.518; P = 0.4928). Pazopanib maintenance showed a disadvantage in overall survival in East Asian patients from AGO-OVAR16 versus placebo (hazard ratio, 1.706; 95% confidence interval, 1.010-2.883; P = 0.0465); overall survival analysis was not performed in the East Asian study because of insufficient event numbers. Pazopanib-treated patients had a significantly higher incidence of grade 3 or higher hypertension (27%) and neutropenia (13%) versus placebo. CONCLUSIONS: The treatment effect of maintenance pazopanib in East Asian patients seemed to differ from that in non-Asian patients. In study-specific and pooled analyses, none of the potential factors analyzed could satisfactorily explain the different efficacy results of pazopanib in East Asian patients.


Assuntos
Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Método Duplo-Cego , Extremo Oriente , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto Jovem
12.
J Surg Oncol ; 117(3): 488-496, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29044542

RESUMO

BACKGROUND AND OBJECTIVES: To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. METHODS: This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. RESULTS: The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. CONCLUSION: Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Carcinossarcoma/mortalidade , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/mortalidade , Carboplatina/administração & dosagem , Carcinossarcoma/patologia , Carcinossarcoma/cirurgia , Estudos de Casos e Controles , Quimioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Estudos Retrospectivos , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
13.
Gynecol Oncol ; 148(2): 267-274, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29248197

RESUMO

OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P=0.012), non-Asian race (HR 6.28, P<0.001), large body habitus (HR per kg/m2 1.04, P=0.014), residual disease at surgery (HR 3.04, P=0.003), tumor size ≥5cm (HR 2.73, P=0.003), and stage IV disease (HR 2.12, P=0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P<0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P=0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46, 95%CI 1.05-2.04, P=0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population.


Assuntos
Carcinossarcoma/cirurgia , Complicações Pós-Operatórias/etiologia , Neoplasias Uterinas/cirurgia , Tromboembolia Venosa/etiologia , Idoso , Carcinossarcoma/mortalidade , Carcinossarcoma/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasia Residual , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/patologia , Estudos Retrospectivos , Fatores de Risco , Carga Tumoral , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia , Tromboembolia Venosa/mortalidade
14.
Oncotarget ; 8(41): 71181-71187, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050354

RESUMO

The efficacy of nivolumab is greater than that of other anti-melanoma drugs, so nivolumab-based combined therapies that enhance anti-tumor immune responses in patients with metastatic melanoma are of great interest to dermato-oncologists. As we have previously reported, IFN-ß enhances the anti-tumor immune response of anti-PD-1 antibodies against B16F10 melanoma in vivo. To explore the potential of this property of IFN-ß as part of a combination therapy for the treatment of metastatic melanoma patients, we performed a phase 1 trial, using a traditional rule-based 3 + 3 design, on patients with advanced melanoma. The nivolumab dose was fixed at 2 mg/kg, every 3 weeks. IFN-ß was administered to three groups at doses of 1 million, 2 million, and 3 million units, respectively. Dose-limiting toxicities were defined as any grade 3-5 adverse events occurring between day 0 and day 42 that might possibly be related to nivolumab and IFN-ß. Of the nine patients who received this combined therapy, none experienced dose-limiting toxicities, and all completed the treatment phase of the study. Patient follow-up continued for 6 months following the final treatment. There were two complete responses (22%) and one partial response (11%), all of which occurred in patients who had received monthly IFN-ß immediately prior to the study. In this study, we determined the safe dose of IFN-ß, when combined with nivolumab, to be 3 million units. To determine the efficacy of this combination therapy, further phase II trials are required.

15.
Gynecol Oncol ; 147(3): 565-571, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29056442

RESUMO

OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P<0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P=0.02). When stratified by disease-free interval, women with a disease-free interval ≥6months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P=0.002); conversely, in women with a disease-free interval <6months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P=0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P=0.019). CONCLUSION: Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6months.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Carcinossarcoma/mortalidade , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Compostos Organoplatínicos/administração & dosagem , Estudos Retrospectivos , Terapia de Salvação , Taxoides/administração & dosagem , Estados Unidos/epidemiologia , Neoplasias Uterinas/mortalidade
16.
Cancer Chemother Pharmacol ; 80(2): 355-361, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28656383

RESUMO

PURPOSE: We report a phase II clinical study of the combination of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in platinum- and taxane-resistant recurrent ovarian cancer, based on the recommended doses determined in a phase I trial. METHODS: PLD was administered intravenously at a dose of 30 mg/m2 on day 3. CPT-11 was administered intravenously at a dose of 80 mg/m2 on days 1 and 15, according to the recommendations of the phase I study. A single course of chemotherapy lasted 28 days, and patients underwent at least 2 courses until disease progression. The primary endpoint was antitumor efficacy, and the secondary endpoints were adverse events, progression-free survival (PFS), and overall survival (OS). RESULTS: The response rate was 32.3% and the disease control rate was 64.5%. Grade 3 and 4 neutropenia, anemia, and a decrease in platelet count were observed in 17 (54.9%), 3 (9.7%), and 1 patient (3.2%), respectively. In terms of grade 3 or higher non-hematologic toxicities, grade 3 nausea occurred in 1 patient (3.2%), vomiting in 3 patients (9.7%), and grade 3 diarrhea and fatigue in 1 patient (3.2%). The median PFS and OS rates were 2 months and not reached, respectively. Of the 11 patients with a treatment-free interval (TFI) of ≥3 months, the response rate was 63.3%, and the median PFS was 7 months. CONCLUSIONS: The treatment outcomes for the 31 patients enrolled in this study were unsatisfactory. However, sub-analysis suggested that patients with a TFI of ≥3 months had a good response rate and PFS. This suggests that CPT-11/PLD combination therapy may be a chemotherapy option for platinum-resistant recurrent ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Irinotecano , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Compostos de Platina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento
17.
Gynecol Oncol ; 145(1): 78-87, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28215838

RESUMO

BACKGROUND: To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS: We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS: The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36). CONCLUSION: Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia/métodos , Carcinossarcoma/terapia , Histerectomia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Uterinas/terapia , Carcinossarcoma/patologia , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Neoplasias Uterinas/patologia
18.
Gynecol Oncol ; 144(2): 329-335, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27931750

RESUMO

OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.


Assuntos
Carcinossarcoma/induzido quimicamente , Antagonistas de Estrogênios/efeitos adversos , Tamoxifeno/efeitos adversos , Neoplasias Uterinas/induzido quimicamente , Idoso , Neoplasias da Mama/tratamento farmacológico , Carcinossarcoma/mortalidade , Carcinossarcoma/patologia , Carcinossarcoma/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia
19.
Int J Clin Oncol ; 21(4): 735-740, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26782958

RESUMO

OBJECTIVE: The aim of this study was to compare the efficacy of nedaplatin-based concurrent chemoradiotherapy (CCRT) with that of cisplatin-based CCRT in patients with cervical cancer. METHODS: The medical records of patients with cervical cancer who had undergone CCRT between 2003 and 2007 were retrospectively reviewed. Of these, 129 patients were treated postoperatively with CCRT (n = 52) or primary CCRT (n = 77). A total of 29 patients were treated with nedaplatin-based postoperative CCRT and 23 patients were treated with cisplatin-based postoperative CCRT. A total of 28 patients were treated with nedaplatin-based postoperative CCRT, and 49 patients were treated with cisplatin-based postoperative CCRT. Progression-free survival (PFS) and overall survival (OS) were compared between the treatment groups. RESULTS: With postoperative CCRT, there were no significant differences in recurrence rate (P = 1.0000), PFS (log-rank: P = 0.8503), and OS (log-rank: P = 0.8926) between the two treatment groups. With primary CCRT, there were no significant differences in PFS (log-rank: P = 0.7845) and OS (log-rank: P = 0.3659). The frequency of acute toxicity was not significantly different between the cisplatin-based postoperative CCRT group and the nedaplatin-based postoperative CCRT group. CONCLUSIONS: Nedaplatin-based postoperative CCRT is an effective and well-tolerated regimen for both early-stage and advanced-stage cervical cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Japão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia
20.
Int J Gynecol Cancer ; 26(3): 561-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26825829

RESUMO

OBJECTIVE: We conducted this study to evaluate the efficacy and safety of adjuvant chemotherapy using taxane plus carboplatin (CBDCA) for high-risk stage IB-IIB patients with uterine cervical non-squamous cell carcinoma after radical hysterectomy. METHODS: Thirty-seven patients were eligible. Pelvic lymph node involvement and/or parametrial invasion were defined as high-risk factors. The patients were treated with 6 cycles of paclitaxel (PTX, 175 mg/m(2)) or docetaxel (DTX, 60 mg/m(2)) followed by CBDCA (area under the curve, 6) every 3 weeks. The primary end point was 2-year progression-free survival (PFS) rate, and the secondary end point was the assessment of adverse events. RESULTS: Twenty-two patients received PTX/CBDCA (TC) chemotherapy, and the remaining 15 patients underwent DTX/CBDCA (DC) chemotherapy. The 2-year PFS rate was 62.1% (95% confidence interval, 44.6%-75.5%). Patients receiving DC chemotherapy showed a better 2-year PFS rate compared to those with TC chemotherapy, but the difference was not statistically significant (80.0% vs 50.0%, P = 0.1400). The most common grade 3/4 adverse events were hematologic toxicities, which were generally well tolerable. Nonhematologic toxicity was generally mild. CONCLUSIONS: Taxane and CBDCA combination chemotherapy, especially DC chemotherapy, may be one of the useful adjuvant treatments for high-risk stage IB-IIB patients with uterine cervical non-squamous cell carcinoma after radical hysterectomy.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma Mucinoso/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Adenoescamoso/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Adenoescamoso/patologia , Carcinoma Adenoescamoso/cirurgia , Quimioterapia Adjuvante , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Histerectomia , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Taxoides/administração & dosagem , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia
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