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1.
Invest New Drugs ; 40(5): 1080-1086, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35763178

RESUMO

BACKGROUND: Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs. METHODS: Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report. RESULTS: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1-6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7-1.5 months), and median overall survival was 2.9 months 95% CI (1.5-4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. CONCLUSIONS: This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Cisplatino/uso terapêutico , Dissulfiram/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico
2.
Invest New Drugs ; 39(6): 1664-1670, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34052929

RESUMO

Background Patients with multiple relapsed/refractory germ cell tumours (GCTs) have an extremely poor prognosis. PARP (poly-ADP-ribose polymerase) is overexpressed in GCTs compared to normal testes, and PARP overexpression is an early event in GCT development. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and the PARP inhibitor veliparib in patients with multiple relapsed/refractory GCTs. Methods Fifteen patients with multiple relapsed/refractory GCTs were enrolled in this phase II study from October 2016 to October 2020. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 every 3 weeks; carboplatin at a target AUC of 4 on day 1 every 3 weeks; and veliparib at a dose of 250 mg b.i.d. throughout. The primary end point was 12-month progression-free survival (PFS). Results The median number of treatment cycles was 4 (range 2-8). Twelve-month PFS was achieved in 1 (6.7 %) patient. The median PFS was 3.1 months (95 % CI 2.2-3.9), and the median overall survival was 10.5 months (95 % CI 8.9-11.1). Partial remission was achieved in 4 (26.7 %) patients, and disease stabilization was observed in 5 (33.3 %) patients. A favourable response was achieved in 3 (20.0 %) patients. Treatment was well tolerated; however, 11 (73.3 %) patients experienced grade 3/4 neutropenia, 10 (66.7 %) experienced thrombocytopenia, 5 (33.3 %) anaemia and 2 (13.3 %) febrile neutropenia. Conclusions This study failed to achieve its primary endpoint, and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib for multiple relapsed/refractory GCTs. ClinicalTrials.gov Identifier: NCT02860819, registered August 9, 2016.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/uso terapêutico , Carboplatina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Adulto Jovem , Gencitabina
3.
BMC Cancer ; 20(1): 779, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32819309

RESUMO

BACKGROUND: Survivors of germ-cell tumors (GCT) may suffer from long-term adverse consequences. Our study was conducted to assess a long-term sexual functioning in GCT survivors. METHODS: GCT survivors (N = 170) from the National Cancer Institute in Slovakia completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire 9-year median follow up (range 5-32) as a primary exploratory aim. Study groups consisted of 17 survivors (10%) who had active surveillance (AS, controls), and 153 (90%) survivors who received treatment beyond orchiectomy (Tx), including cisplatin-based chemotherapy (CT, N = 132; 78%), radiotherapy to the retroperitoneal lymph nodes (RT, N = 12; 7%) or both (CTRT, N = 9; 5%). RESULTS: In univariate analysis, treatment of any type resulted in difficulty to maintain erection during sexual intercourse compared to patients treated with AS (P = 0.04). Survivors who received CTRT had lower ability to achieve orgasm during sexual activities (P = 0.04) and they reported disappointment with their overall quality of sex life (P = 0.002). The number of attempts to initiate sexual intercourse did not differ. Sexual relationships caused none or mild anxiety and the desire to be sexually active was higher after CTRT (P = 0.05). Multivariable analysis confirmed that orgasmic dysfunction after ≥400 mg/m2 of cisplatin and issues in maintaining erection after Tx were independent of retroperitoneal lymph-node dissection (P = 0.03 and P = 0.04, respectively). Survivors were disappointed with the quality of sex life and had stronger desire to be sexually active independent of age, (P = 0.01 and P = 0.05, respectively). CONCLUSIONS: This study identified an impairment in sexual function may represent an issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy were associated with disappointment and stronger sexual desire, while a higher cumulative dose of cisplatin may be responsible for orgasmic dysfunction.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Embrionárias de Células Germinativas/terapia , Disfunções Sexuais Fisiológicas/epidemiologia , Neoplasias Testiculares/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobreviventes de Câncer/psicologia , Quimiorradioterapia Adjuvante/efeitos adversos , Cisplatino/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/complicações , Neoplasias Embrionárias de Células Germinativas/mortalidade , Orquiectomia/efeitos adversos , Orgasmo/efeitos dos fármacos , Orgasmo/efeitos da radiação , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/efeitos da radiação , Estudos Prospectivos , Qualidade de Vida , Autorrelato/estatística & dados numéricos , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual/efeitos da radiação , Disfunções Sexuais Fisiológicas/diagnóstico , Disfunções Sexuais Fisiológicas/etiologia , Eslováquia/epidemiologia , Neoplasias Testiculares/complicações , Neoplasias Testiculares/mortalidade , Fatores de Tempo , Adulto Jovem
4.
Invest New Drugs ; 37(4): 748-754, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152292

RESUMO

Background Germ cell tumors (GCTs) are highly curable diseases; however, not all patients can be cured. Patients in their second relapse have especially poor prognoses. PD-L1 expression is significantly higher in GCTs than in normal testicular tissue, and high PD-L1 expression is associated with a poor prognosis. This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs. Methods In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10 mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if <8 of 15 patients had 12-week PFS, the study was to be terminated. Here, we report the results of the first stage of the trial. Results From November 2017 to January 2018, 8 patients with a median age of 29 years (range, 22 to 52 months) were enrolled. Patients were pretreated with a median of 5 (range, 1 to 6) previous lines of platinum-based therapies; 5 tumors (62.5%) were absolutely refractory to cisplatin, and 5 patients (62.5%) had visceral nonpulmonary metastases. At a median follow-up period of 2.6 months (range, 0.3 to 14.4), all the patients experienced disease progression, and 7 patients (87.5%) died. The twelve-week PFS was 0%, median PFS was 0.9 months (95% CI 0.5-1.9), and median OS was 2.7 months (95% CI 1.0-3.3). Avelumab was well tolerated, and no severe adverse events were observed. Conclusions This study failed to achieve its primary endpoint. Our data suggest a lack of avelumab efficacy in unselected multiple relapsed/refractory GCTs.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Intervalo Livre de Progressão , Adulto Jovem
5.
Ann Oncol ; 27(2): 300-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26598537

RESUMO

BACKGROUND: Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. PATIENTS AND METHODS: Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. RESULTS: None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. CONCLUSIONS: In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/sangue , Coriocarcinoma/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Testiculares/patologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/mortalidade , Pesquisa Translacional Biomédica , Adulto Jovem
6.
BMC Cancer ; 16: 597, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27487789

RESUMO

BACKGROUND: Germ cell neoplasia in situ (GCNIS), is preinvasive stage of testicular germ cell tumours (TGCTs). Fibrillins, which are integral components of microfibrils are suggested to be involved in cancer pathogenesis and maintenance of embryonic stem cells pluripotency. The aim of this study was to examine fibrillin-1 (FBN-1) expression in TGCTs patients. METHODS: Surgical specimens from 203 patients with TGCTs were included into the translational study. FBN-1 expression was evaluated in the tumour tissue, in GCNIS and in adjacent non-neoplastic testicular tissue in all available cases. Tissue samples were processed by the tissue microarray method. FBN-1 was detected by immunohistochemistry using goat polyclonal antibody and the expression was evaluated by the multiplicative quickscore (QS). RESULTS: The highest FBN-1 positivity was detected in GCNIS (mean QS = 11.30), with overexpression of FBN-1 (QS >9) in the majority (77.1 %) of cases. Expression of FBN-1 in all subtypes of TGCTs was significantly lower in comparison to expression in GCNIS (all p <0.001). Seminoma had significantly higher expression compared to EC, ChC and TER (all p <0.05), but not to YST (p = 0.84). In non-neoplastic testicular tissue the FBN-1 positivity was very low (mean QS = 0.02). Sensitivity, specificity, positive and negative predictive value of FBN-1 expression for diagnosis of GCNIS were 97.1, 98.8, 98.6 and 97.7 %. CONCLUSIONS: FBN-1 is overexpressed in TGCTs and especially in GCNIS when compared to non-neoplastic testicular tissue in patients with germ cell tumors and could be involved in germ cell neoplasia in situ development.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma in Situ/diagnóstico , Fibrilina-1/biossíntese , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Testiculares/diagnóstico , Humanos , Imuno-Histoquímica , Masculino , Sensibilidade e Especificidade , Análise Serial de Tecidos
7.
Neoplasma ; 56(4): 291-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19473054

RESUMO

Despite progress in primary treatment of patients with advanced ovarian cancer, the majority develop recurrence of the disease. A platinum salt treatment, either as monotherapy or in combination with another cytostatic agent, is indicated for patients who have relapsed 6 or more months after primary treatment and thus have platinum-sensitive relapse. Because repeated use of paclitaxel treatment may lead to substantial neurotoxicity, the combination of gemcitabine with carboplatin represents a suitable treatment option, which is widely used in common clinical practice in the Czech Republic and Slovakia. This non-interventional, prospective study observed the effectiveness and tolerability of second-line treatment with gemcitabine and carboplatin in patients with platinum-sensitive relapse of ovarian cancer in routine clinical practice. The primary endpoint was to evaluate the survival and secondary endpoints were to evaluate time to disease progression, objective tumor response rate, and treatment toxicity. Patients were enrolled to planned second-line treatment with gemcitabine and carboplatin (gemcitabine 1000 mg/m2 and carboplatin AUC 5 on Day 1, and gemcitabine 1000 mg/m2 on Day 8 of a 21-day cycle) for platinum-sensitive relapse of ovarian cancer as a part of routine clinical practice and followed for 12 months. The events (death, tumor progression), tumor response, and maximal grades of toxicity were recorded according to common clinical practice. Survival time (using Kaplan-Meier analysis) and objective tumor response rate were calculated using data forms, and a subgroup analysis was performed using log rank tests for time-to-event endpoints; p-values were also calculated. Response rates were calculated for the whole population; for the subgroups, the Fisher's exact test was performed and only p-values were calculated. Between January 2004 and June 2005, 53 patients were enrolled in the study. The median age was 57 years and 96% of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and 1 at baseline. Approximately 91% of patients were originally diagnosed with stage III or IV; 60% of patients had disease free intervals (DFIs) of 12 or more months from previous therapy, and the additional 40% less than 12 months. The 1-year survival rate was 83%. Median survival time was not determined within the 12-month period following the start of the treatment study due to the limited duration of follow-up. Objective tumour response rate was 67.3%. Most common reasons for discontinuation of therapy were "Planned treatment completed" (53%) and "Tumor progression" (11%). Most common toxicities were leukopenia, anaemia, neutropenia, and thrombocytopenia; grades 3 and 4 of these toxicity types did not exceed 30%. Febrile neutropenia was recorded in two patients. Most common non-haematological toxicities were nausea and vomiting, fatigue, and neuropathy; grades 3 and 4 of these were below 6%. Results on time to disease progression are not published due to inconsistent statistical analysis of reported data. Based on this observation from routine clinical practice, which corresponds with previously published results from controlled clinical trials, the gemcitabine and carboplatin combination seems to be a suitable therapeutic option for patients with platinum-sensitive relapse of ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/secundário , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/secundário , Feminino , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem , Gencitabina
8.
Neoplasma ; 54(3): 240-5, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17447857

RESUMO

First line treatment of patients pts with poor-prognosis GCT, using BEP, is unsatisfactory. T-BEP (paclitaxel followed by BEP) demonstrated promising efficacy in the group of pts with intermediate and poor prognosis GCT. We present the results achieved with 1st line T-BEP in pts with poor-prognosis CGT. Twenty-four pts received T-BEP as initial therapy. Three pts (12.5%) had primary mediastinal GCT. Four cycles of T-BEP were given 21 days apart. Paclitaxel 175 mg/m2 was administered on day 1 before administration of BEP. The administration of G-CSF was not scheduled. Surgical resection of all radiographic residua was considered. All pts were assessable for response. Complete or partial response with negative tumor markers was achieved in 13 pts (54.2%; CI 95%: 34.3-74.1%). Median follow-up is 35.6 months. Median survival was not achieved and median time-to-progression is 9.5 months. Myelosuppression was the major toxicity with Gr3-4 granulocytopenia experienced in 52.1% of all courses. There were two treatment-related deaths due to sepsis. Patients treated with 1st line T-BEP didn't achieve higher response rate or time to progression. However, the overall survival observed in our study is surprisingly long. We do not recommend using this regimen without G-CSF support due to substantial toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adulto , Bleomicina/administração & dosagem , Carcinoma Embrionário/tratamento farmacológico , Carcinoma Embrionário/secundário , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/secundário , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Paclitaxel/administração & dosagem , Prognóstico , Estudos Prospectivos , Teratocarcinoma/tratamento farmacológico , Teratocarcinoma/secundário , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/secundário
9.
Bratisl Lek Listy ; 108(2): 100-3, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17685010

RESUMO

Four large randomized trials to assess efficacy and toxicity of trastuzumab in adjuvant systemic therapy of breast cancer have been initiated. Results clearly demonstrate, that adjuvant treatment of trastuzumab significantly improves outcomes for women with HER2 positive breast cancer. The clinically most significant adverse events of trastuzumab are serious-infusion related reactions and cardiotoxicity. Benefit for patient should be considered according to advantage versus risk (Tab. 1, Fig. 2, Ref. 17) Full Text (Free, PDF) www.bmj.sk.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Quimioterapia Adjuvante , Feminino , Humanos , Receptor ErbB-2 , Trastuzumab
10.
Bratisl Lek Listy ; 106(11): 362-5, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16541622

RESUMO

The treatment options for early stage breast cancer include local-regional and systemic therapy. Surgery and radiotherapy can minimize the risk of local recurrence, while systemic adjuvant chemotherapy and hormonal treatment is related to prolongation of survival rate. Several prognostic factors were identified. The dominant prognostic factor is lymph node involvement with cancer. The decision regarding treatment must be made according to risk versus benefit for every patient. The absolute benefit of systemic treatment is major in patients with intermediate and poor prognosis (Tab. 3, Fig. 2, Ref. 10).


Assuntos
Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Humanos , Recidiva Local de Neoplasia
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