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1.
Gynecol Oncol ; 156(1): 13-22, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708167

RESUMO

BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles. FINDINGS: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. INTERPRETATION: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). FUNDING: National Cancer Institute.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Peritoneais/patologia , Intervalo Livre de Progressão
2.
Gynecol Oncol ; 156(1): 23-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31791552

RESUMO

OBJECTIVE: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer. METHODS: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d. RESULTS: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm. CONCLUSIONS: Addition of ralimetinib to GC resulted in a modest improvement in PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
3.
Support Care Cancer ; 28(1): 221-227, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31016422

RESUMO

PURPOSE: Paclitaxel-associated acute pain syndrome (P-APS) affects 80% of patients undergoing therapy. Although it has been shown that prednisone administration for 5 days relieves P-APS, detailed results have not been reported thus far. Therefore, in this study, we evaluated the preventive effect of dexamethasone (DEX) administration against P-APS. METHODS: A total of 60 patients who received carboplatin (area under the curve; AUC = 5-6) plus paclitaxel (200 mg/m2) (plus bevacizumab 15 mg/kg, if non-squamous carcinoma of lung) were enrolled. Eight milligrams of DEX was orally administered on days 2 and 3 to the DEX group patients, and the frequency, severity, duration of P-APS, and other adverse effects in the first cycle were retrospectively evaluated and compared to those observed in control group patients, who were not administered DEX on days 2 and 3. RESULTS: No difference in terms of patient characteristics, except for type of cancer, was observed between groups. The results showed that the frequency of all grade P-APS was approximately 70% and there was no difference between groups. Frequency of ≥ G2 P-APS was 40% in the control group and 14% in the DEX group, demonstrating a significant reduction. Duration of P-APS was 5.8 days in the control group and 4.3 days in the DEX group, which tended to become shorter following additional DEX administration, although this was not significant. Adverse effects other than P-APS induced by chemotherapy were similar between the two groups. CONCLUSION: Additional DEX administration is safe and useful for the attenuation of the severity of P-APS.


Assuntos
Dor Aguda/induzido quimicamente , Dor Aguda/prevenção & controle , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dexametasona/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/efeitos adversos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioprevenção/métodos , Dexametasona/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Estudos Retrospectivos , Síndrome , Resultado do Tratamento
4.
Int J Cancer ; 146(2): 439-448, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31381147

RESUMO

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Indóis/administração & dosagem , Neoplasias Ovarianas/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos de Citorredução , Feminino , Seguimentos , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Ovário/cirurgia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Placebos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Adulto Jovem
5.
Gynecol Oncol ; 155(3): 406-412, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31677820

RESUMO

OBJECTIVE: Increased Vascular Endothelial Growth Factor Receptor (VEGF) expression in endometrial cancer (EC) is associated with a poor prognosis. Preliminary clinical data reported Bevacizumab effectiveness in EC both as single agent and in combination with chemotherapy. METHODS: In a phase II trial, patients with advanced (FIGO stage III-IV) or recurrent EC were randomized to receive Carboplatin-Paclitaxel standard dose for 6-8 cycles vs Carboplatin-Paclitaxel and Bevacizumab 15 mg/kg in combination with chemotherapy and maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS). RESULTS: 108 patients were randomized; PFS (10.5 vs 13.7 months, HR 0.84 p = 0.43), overall response rate (ORR 53.1% vs 74.4%) and overall survival (OS) (29.7 vs 40.0 months, HR 0.71 p = 0.24) resulted in a non-significant increase in Bevacizumab treated patients. The PFS increase became significant when an exploratory analysis with the Breslow test was used. Moreover, patients treated with Bevacizumab experienced a significant increase in 6-month disease control rate (70.4% vs 90.7%). Cardiovascular events were more frequent in the experimental arm ("de novo" grade ≥2 hypertension 21% vs 0% and grade ≥2 thromboembolic events 11% vs 2% in the Bevacizumab vs standard treatment arm, respectively). CONCLUSIONS: Bevacizumab combined with chemotherapy in the treatment of advanced/recurrent EC failed to demonstrate a significant increase in PFS in the MITO END-2 trial. Nevertheless, these preliminary data suggests some effectiveness of the antiangiogenic agent which merits further exploration in a larger population with a better molecular characterization.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos
6.
Lancet ; 394(10212): 1929-1939, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31590988

RESUMO

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Etoposídeo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Esquema de Medicação , Etoposídeo/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Carcinoma de Pequenas Células do Pulmão/mortalidade
7.
Cancer Sci ; 110(12): 3738-3745, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31608537

RESUMO

The prognosis of non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) is poor, and 5%-20% of those receiving chemotherapy experience ILD exacerbation. To evaluate the safety and efficacy of nab-paclitaxel plus carboplatin for NSCLC patients with ILD, we undertook a multicenter phase II study. Chemotherapy-naïve patients with advanced NSCLC and mild or moderate ILD received nab-paclitaxel (100 mg/m2 , days 1, 8, and 15) plus carboplatin (area under the curve = 6, day 1) every 3 weeks for 4 cycles (maximum, 6 cycles). Interstitial lung diseases were diagnosed based on criteria for fibrosing interstitial pneumonia. The primary endpoint was the prevalence of exacerbation-free ILD 28 days after completion of protocol treatment. Secondary endpoints were response rate, progression-free survival, overall survival, prevalence of exacerbation-free ILD, and toxicity. Ninety-four patients were enrolled, and 92 patients received any protocol treatment. Median age was 70 years, and 58% had nonsquamous histology. In the primary analysis, the prevalence of exacerbation-free ILD 28 days after protocol treatment was 95.7% (88/92; 90% confidence interval, 90.3-98.5), which met the primary endpoint. Response rate was 51% (95% confidence interval, 40%-62%). At the time of data cut-off, median progression-free survival was 6.2 months, and median overall survival was 15.4 months. The most common grade 3/4 adverse events were neutropenia (75%), leukopenia (53%), anemia (48%), and thrombocytopenia (20%). Two treatment-related deaths (1 each of pulmonary infection and ILD exacerbation) were observed. This study showed that a combination of nab-paclitaxel with carboplatin was tolerable in NSCLC patients with mild or moderate ILD in terms of safety. This study is registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN 000012989).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Doenças Pulmonares Intersticiais/complicações , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Doenças Pulmonares Intersticiais/epidemiologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Estudos Prospectivos
9.
BMC Cancer ; 19(1): 748, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362708

RESUMO

BACKGROUND: Primary retroperitoneal serous adenocarcinoma (PRSA) is an extremely uncommon malignancy exclusively reported in females. Due to the rarity of the disease, it is difficult to establish a standardized treatment. CASE PRESENTATION: We describe a unique case of PRSA in a 71-year-old male who presented with right-sided lower back pain and numbness. Magnetic resonance imaging identified a mass invading the adjacent psoas muscle and twelfth rib. Tissue biopsy confirmed poorly differentiated PRSA. Patient was initially treated with neoadjuvant carboplatin and paclitaxel chemotherapy regimen. This resulted in complete radiological resolution of the tumor. However, 12 weeks later, rapid recurrence was noted on follow-up CT scan. The patient was then treated with external radiotherapy with concurrent nivolumab, an anti-PD-1 antibody. The patient displayed a positive response to treatment with reduction in primary tumor and metastases and had a sustained disease control. CONCLUSION: Treatment with radiotherapy in combination with anti-PD-1 antibody could be an effective modality of management for PRSA.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cistadenocarcinoma Seroso/radioterapia , Cistadenocarcinoma Seroso/terapia , Imunoterapia/métodos , Nivolumabe/uso terapêutico , Neoplasias Retroperitoneais/radioterapia , Neoplasias Retroperitoneais/terapia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Cistadenocarcinoma Seroso/diagnóstico por imagem , Seguimentos , Humanos , Fatores Imunológicos/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Nivolumabe/farmacologia , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Retroperitoneais/diagnóstico por imagem , Resultado do Tratamento
10.
Anticancer Res ; 39(8): 4455-4462, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366544

RESUMO

BACKGROUND/AIM: Platinum-based chemotherapy often fails due to its severe adverse effects. The aim of this study was to examine the adverse effects profile and efficacy of dicycloplatin and compare them to those of cisplatin and carboplatin. MATERIALS AND METHODS: Cystoscopy surveillance of the first American cancer patient treated with dicycloplatin was performed quarterly. In vitro and in vivo studies were conducted using immunoblotting and flow cytometry to assess immune status of spleen and bone marrow of mice treated with dicycloplatin, cisplatin and carboplatin. RESULTS: The American patient did not suffer clinically significant myelosuppression; dicycloplatin has sustained remission in this patient to date. Experimental studies showed that dicycloplatin is less toxic to bone marrow and spleen of mice than cisplatin and carboplatin. CONCLUSION: Dicycloplatin is a promising drug in cancer chemotherapy with less aggressive side-effects than those typically associated with cisplatin and carboplatin. This is an important therapeutic advantage in cancer chemotherapy. Clinical investigation of dicycloplatin as an alternative to cisplatin or carboplatin is warranted.


Assuntos
Medula Óssea/efeitos dos fármacos , Glutamatos/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Baço/efeitos dos fármacos , Animais , Medula Óssea/patologia , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cistoscopia , Modelos Animais de Doenças , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Glutamatos/efeitos adversos , Humanos , Camundongos , Compostos Organoplatínicos/efeitos adversos , Baço/patologia
11.
Gynecol Oncol ; 154(3): 554-557, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31285082

RESUMO

OBJECTIVE: We evaluated the efficacy and safety of the combination of paclitaxel, carboplatin, and bevacizumab in patients with advanced or recurrent cervical cancer. METHODS: Subjects included patients with advanced or recurrent cervical cancer not amenable to curative treatment with surgery or radiation therapy. Treatment consisted of paclitaxel 175 mg/m2, carboplatin area under the curve 6 mg/mL/min, and bevacizumab 15 mg/kg every 21 days until disease progression, complete remission, or limiting toxicity. The primary endpoint was the objective response. RESULTS: In total, 34 patients received a median of 6 treatment cycles (range 2-25). The median follow-up period was 18.5 months (range 2-29). The objective response was 88% (95% confidence interval: 72.5%-96.7%). Seventeen patients (50%) experienced complete response, whereas 13 patients experienced (38%) partial response with a median duration of 6 months. Grades 3 and 4 hematologic toxicities manifested as neutropenia in 14 (41.2%), leukopenia in 14 (41.2%), anemia in 11 (32.4%), and thrombocytopenia in 9 (26.5%) patients. One patient who underwent prior pelvic irradiation developed grade 2 rectovaginal fistula. CONCLUSION: The combination of paclitaxel, carboplatin, and bevacizumab is effective and safe in patients with advanced or recurrent cervical cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos
12.
J Cancer Res Clin Oncol ; 145(9): 2335-2342, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31286241

RESUMO

PURPOSE: Clinical stage (CS) 1 testicular seminoma is cured in almost 100% of cases following either retroperitoneal radiotherapy, carboplatin monotherapy, or surveillance strategies. Little is known about potential long-term effects of carboplatin. We, therefore, examined late sequelae of this drug in seminoma patients. PATIENTS AND METHODS: We retrospectively identified 451 patients with CS1 testicular seminoma treated between 1994 and 2014, of whom 243 underwent carboplatin therapy [median follow-up (F/U) 96 months], 81 received radiotherapy (median F/U 142 months), and 127 underwent surveillance (median F/U 40 months). Satisfaction regarding management, as well as the following events during F/U, were analysed by questionnaire: subsequent malignant neoplasms (SMNs), cardiovascular events, arterial hypertension, peptic ulcer, tinnitus, peripheral neuropathy, hypogonadism, and infertility. The relative frequencies of the events were analysed using descriptive statistics. The frequency of observed SMNs was compared with the expected number. RESULTS: Patients receiving carboplatin tolerated the treatment less well (71.2%) than those under surveillance (81.9%). After carboplatin, 12 SMNs (5.0%) were noted vis-a-vis 5.0 expected. There were three cases of prostatic cancer and 3 melanomas among the SMNs. Half of these SMNs occurred early after treatment. Among the other health events, only reported hypogonadism (13.2%) appeared to be marginally increased in frequency. CONCLUSIONS: This study found a 2.4-fold higher than expected rate of SMN-and a slightly increased rate of hypogonadism-in the long-term period following carboplatin treatment. Although further studies are needed to confirm these preliminary findings, these results are probably informative for clinicians caring for seminoma patients.


Assuntos
Carboplatina/administração & dosagem , Seminoma/tratamento farmacológico , Seminoma/radioterapia , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/radioterapia , Adolescente , Adulto , Idoso , Carboplatina/efeitos adversos , Quimioterapia Adjuvante , Terapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Transtornos de Início Tardio/induzido quimicamente , Transtornos de Início Tardio/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segunda Neoplasia Primária/epidemiologia , Radioterapia Adjuvante , Estudos Retrospectivos , Seminoma/patologia , Neoplasias Testiculares/patologia , Resultado do Tratamento , Conduta Expectante , Adulto Jovem
13.
Int J Mol Sci ; 20(13)2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277262

RESUMO

Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca2+ concentration ([Ca2+]i); however, carboplatin pretreatment enhanced the increase in [Ca2+]i induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca2+]i and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca2+]i induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.


Assuntos
Carboplatina/farmacologia , Hiperalgesia/induzido quimicamente , Transdução de Sinais , Canal de Cátion TRPA1/metabolismo , Proteínas de Ancoragem à Quinase A/metabolismo , Animais , Carboplatina/efeitos adversos , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
BMC Cancer ; 19(1): 693, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307410

RESUMO

BACKGROUND: To evaluate the safety and efficacy of intra-arterial chemotherapy (IAC) for the primary or secondary treatment of infants diagnosed with advanced retinoblastoma before 3 months of age. METHODS: This single-center retrospective study included 39 infants (42 eyes) aged ≤3 months who were diagnosed with unilateral or bilateral advanced intraocular retinoblastoma (group D and E eyes) and received IAC as primary or secondary treatment between June 2012 and February 2017. Based on each patient's therapeutic history and response to chemotherapeutic drugs, melphalan, topotecan, and/or carboplatin were used for IAC. The main outcomes included the technical success rate for IAC, survival rates, and adverse events. RESULTS: In total, 29 and 13 eyes received IAC as primary and secondary treatments, respectively. Catheterization was successful in 136 of 137 procedures. All eyes in the secondary IAC group had previously received intravenous chemotherapy. The mean number of IAC sessions for each eye was 3 (range, 2-6). The 2-year ocular survival rates were 80.7% (95% confidence interval [CI], 58.9-91.7) in the primary IAC group and 91.7% (95% CI, 53.9-98.8) in the secondary IAC group. During the follow-up period, 1 patient with unilateral disease (group E) developed extraocular disease and died. The 2-year recurrence-free survival rates in the primary and secondary IAC groups were 71.9% (95% CI, 49.4-85.7) and 75.0% (95% CI, 40.8-91.2), respectively. During each catheterization procedure, the main complications included eyelid erythema (2.4%), fundus hemorrhage (11.9%), myelosuppression (7.7%), transient vomiting and hair loss (2.6%), and transient pancytopenia (2.6%). Prolonged complications included phthisis bulbi (19.0%), vision loss (19.0%), poor vision (9.5%), and cataract (2.4%). There was no case of stroke, neurological impairment, secondary malignant tumor, or metastasis. CONCLUSIONS: Our findings suggest that IAC, whether primary or secondary, is effective and fairly safe for the management of advanced retinoblastoma in infants aged < 3 months. However, adverse events related to intra-arterial injection and the visual outcomes cannot be neglected and require further investigation.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carboplatina/uso terapêutico , Etoposídeo/uso terapêutico , Infusões Intra-Arteriais/efeitos adversos , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Vincristina/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/efeitos adversos , Cateterismo/efeitos adversos , Pré-Escolar , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias da Retina/mortalidade , Retinoblastoma/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/efeitos adversos
15.
Pediatr Blood Cancer ; 66(11): e27914, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31342649

RESUMO

BACKGROUND: The present study sought to reduce the incidence of treatment complications of low-risk neuroblastoma by using image-defined risk factors (IDRFs) to inform the timing of surgical resection. PROCEDURES: Eligible patients included children (<18 years of age) with stage 1 or 2 disease, children (<365 days of age) with stage 3 disease, and infants with stage 4S disease. In IDRF-negative cases, treatment was completed with surgical resection alone. In IDRF-positive cases, the timing of surgery was determined based on the IDRFs after low-dose chemotherapy with 2-3 of the following four drugs: vincristine, cyclophosphamide, pirarubicin, and carboplatin. The outcome measures were overall survival, progression-free survival, and adverse events. This study was registered with the UMIN Clinical Trials Registry (number 000004355). RESULTS: Of the 60 patients screened between 2010 and 2013, 58 eligible patients were enrolled; 32 were identified as IDRF negative at diagnosis while 26 were identified as IDRF positive and underwent induction chemotherapy. The 3-year overall and progression-free survival rates of the 58 patients were 100% and 82.8% (95% confidence interval: 70.3-90.3), respectively. Neutropenia was the most frequently reported grade 3 or 4 chemotherapy-related form of toxicity (41.7%). With regard to surgical complications, 2.5% of all patients developed pleural effusion and ascites as early complications, while only 2.5% developed renal atrophy as a long-term complication. No fatal toxicities were observed. CONCLUSION: Using IDRFs to inform surgical decision making for the treatment of low-risk neuroblastoma improved prognosis and reduced the incidence of long-term complications.


Assuntos
Neuroblastoma/cirurgia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/etiologia , Criança , Pré-Escolar , Tomada de Decisão Clínica , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Ganglioneuroblastoma/diagnóstico por imagem , Ganglioneuroblastoma/tratamento farmacológico , Ganglioneuroblastoma/cirurgia , Humanos , Lactente , Recém-Nascido , Japão , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/tratamento farmacológico , Derrame Pleural/etiologia , Complicações Pós-Operatórias/etiologia , Intervalo Livre de Progressão , Estudos Prospectivos , Fatores de Risco , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Doenças Vasculares/etiologia , Vincristina/administração & dosagem , Vincristina/efeitos adversos
16.
Future Oncol ; 15(23): 2779-2790, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31293180

RESUMO

Aim: Platinum agents are DNA damaging agents with promising activity in breast cancers, especially in triple-negative subgroup. This meta-analysis was conducted to compare the treatments of platinum-based neoadjuvant chemotherapy (NAC) and standard NAC for triple-negative breast cancers (TNBCs). Materials & methods: Diverse electronic databases were searched to identify the randomized clinical trials that directly compared the treatments of platinum-based NAC versus NAC in TNBC patients. Toxicity of platinum-based regimens was further evaluated. Results: Addition of platinum agents significantly improved the pathological complete response rates in TNBC patients compared with the standard NAC. Unfortunately, platinum-based regimens were more likely to develop higher incidence of hematologic toxicities. Conclusion: Platinum-based NAC regimens could achieve significant pathological complete response improvement with well-tolerated toxicity in TNBC patients.


Assuntos
Antineoplásicos/uso terapêutico , Terapia Neoadjuvante/métodos , Compostos de Platina/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/efeitos adversos , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Feminino , Humanos , Compostos de Platina/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
17.
Dermatol Ther ; 32(4): e12981, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31168954

RESUMO

Serpentine supravenous hyperpigmentation (SSH) is a unique type of chemotherapy-associated drug eruption, characterized by hyperpigmentation along the superficial venous network. Histopathology reveals an increase in melanin production without destruction of basal cells of the epidermis or dermal inflammatory infiltrate. Herein, we describe a patient who developed SSH after repeated intravenous infusions with carboplatin and vinorelbine; two medications that have been uncommonly reported in association with SSH previously.


Assuntos
Carboplatina/efeitos adversos , Erupção por Droga/etiologia , Hiperpigmentação/induzido quimicamente , Vinorelbina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Erupção por Droga/diagnóstico , Erupção por Droga/patologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Vinorelbina/administração & dosagem
18.
Int J Hematol ; 110(3): 375-380, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31104212

RESUMO

The frequency of multiple primary malignant neoplasms (MPMN) is increasing due to population aging. Since consensus guidelines for the treatment of MPMN are lacking, treatment strategies are determined by disease status on a per-patient basis. In this report, we describe a case of MPMN with follicular lymphoma (FL) grade 1 that transformed to double-hit lymphoma during adjuvant chemotherapy for concurrent ovarian carcinoma. A 64-year-old woman was diagnosed with MPMN of FL and endometrioid carcinoma by staging laparotomy and lymph node biopsy. She received four cycles of adjuvant chemotherapy (carboplatin and paclitaxel) for endometrioid carcinoma, but during chemotherapy, the FL grade 1 transformed to double-hit lymphoma. We speculate that adjuvant chemotherapy for endometrioid carcinoma may have triggered the transformation of FL in the present case.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Endometrioide , Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Endometrioide/diagnóstico por imagem , Carcinoma Endometrioide/tratamento farmacológico , Quimioterapia Adjuvante/efeitos adversos , Feminino , Humanos , Linfoma Folicular/induzido quimicamente , Linfoma Folicular/diagnóstico por imagem , Pessoa de Meia-Idade , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/diagnóstico por imagem , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos
19.
Gynecol Oncol ; 154(1): 138-143, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31079832

RESUMO

OBJECTIVE: To evaluate hematologic adverse effect profiles associated with frontline platinum-based chemotherapy in ovarian cancer patients according to BRCA 1/2 mutational status. METHODS: Patients with high-grade serous ovarian cancer and a known BRCA mutational status who received in frontline 6 cycles of Carboplatin (AUC 5) plus Paclitaxel 175 mg/mq were retrospectively selected from our databases. Hematologic toxicity profiles of BRCA mutated patients were compared to non-mutated patients, according to EORTC Common Terminology Criteria for Adverse Events (CTCAE_4.02). RESULTS: Totally, 176 women of whom 58 (33%) were BRCA1/2 mutation carriers - 40 BRCA1 (69%) and 18 (31%) BRCA2 mutations carriers - and 118 (67%) non-carriers were identified. A significant higher frequency of thrombocytopenia (24% vs 5%; p < 0.001), anemia (21% vs 7%; p = 0.006) and neutropenia (62% vs 27%; p ≤0.001) was observed in BRCA mutated patients, resulting in a higher percentage of granulocyte-colony stimulating growth factors injection (12% versus 1%, p < 0.001) and dose delay (19% versus 27%, p = 0.005). The multivariate analysis confirmed that granulocyte-colony stimulating growth factors injection and dose delay were statistically significantly more frequent in BRCA mutated patients (OR 2.567, 95% CI 1.136-5.798, p = 0.035; OR 3.860, 95% CI 1.098-13.570, p = 0.023). Finally, the total number of hematologic adverse events compared between the two groups of patients during the entire treatment period showed a substantial higher rate of hematologic adverse events in BRCA mutated population. CONCLUSIONS: Germline BRCA 1/2 mutations are associated with a higher hematologic toxicity in patients with ovarian cancer who underwent platinum-based chemotherapy.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/genética , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Estudos de Coortes , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Predisposição Genética para Doença , Doenças Hematológicas/sangue , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Estudos Retrospectivos
20.
Expert Opin Drug Metab Toxicol ; 15(6): 487-497, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31116618

RESUMO

Introduction: Platinum-drugs (Cisplatin, Carboplatin, Oxaliplatin) are widely used in Medical Oncology departments to treat common neoplasms whose survival has greatly increased in the last few years. Thus, there is a growing population of cancer survivors who were treated with them and whose Quality of Life can be impaired by neurological late toxicities. Areas covered: Essential clinical information of natural history, predisposing factors, assessment issues and lacks in treatment for peripheral neurotoxicity are here reported. An overview of preclinical pathogenetic observations is also given to drive future drug discovery. Expert opinion: To unravel needs and lacks for platinum-induced neurotoxicity a great effort is still to be done. A coordinated and combined effort of clinical and preclinical researchers is required. The newborn multidisciplinary Toxic Neuropathy Consortium - Special Interest Group of the Peripheral Nerve Society - seems a virtuous alliance that might find answers to meet clinical and scientific needs in this field.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Animais , Antineoplásicos/administração & dosagem , Sobreviventes de Câncer , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Humanos , Neoplasias/patologia , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Qualidade de Vida
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