RESUMO
AIMS: Primary mediastinal germ cell tumours (PMGCTs) are rare mediastinal neoplasms, and their diagnosis can be challenging, owing to small biopsy samples. The aim of this study was to develop a diagnostic algorithm using immunohistochemical staining, with a focus on novel markers, and molecular analysis of isochromosome 12p [i(12p)]. METHODS AND RESULTS: Paraffin-embedded tissues of 32 mediastinal tumours were analysed with immunohistochemical staining for sal-like transcription factor 4 (SALL4), Lin-28 homologue A (LIN28), octamer-binding transcription factor 3/4 (OCT3/4), D2-40, cluster of differentiation 117 (CD117), sex-determining region Y-box 17, sex-determining region Y-box 2 (SOX2), cluster of differentiation 30, the ß-subunit of human chorionic gonadotropin (ß-hCG), GATA-binding protein 3 (GATA3), forkhead box protein A2 (FOXA2), glypican-3 (GPC3), α-fetoprotein (AFP), terminal deoxynucleotidyl transferase (TdT), nuclear protein of the testis (NUT), and pan-cytokeratin. Quantitative real-time polymerase chain reaction was performed to investigate the i(12p) status. Fifteen seminomas, seven teratomas, one yolk sac tumour, one choriocarcinoma and seven mixed PMGCTs were diagnosed. Each entity had different immunohistochemical staining patterns, which helped to distinguish them: OCT3/4, D2-40, CD117 and TdT for seminoma; OCT3/4 and SOX2 for embryonal carcinoma; FOXA2, GPC3 and AFP for yolk sac tumour; and ß-hCG and GATA3 for choriocarcinoma. Mature teratomas stained positively for pan-cytokeratin in epithelial components and focally for SALL4, SOX2, GATA3, D2-40, and FOXA2. Furthermore, a NUT carcinoma mimicking a PMGCT was diagnosed, showing strong nuclear SOX2 staining and speckled nuclear NUT staining. i(12p) was detected in 24 of 27 PMGCTs (89%). CONCLUSION: A diagnostic algorithm is of great importance for a reliable diagnosis of PMGCT in, usually small, tissue biopsy samples. Therefore, a combination of three to four antibodies to identify the correct histological subtype is usually necessary, in addition to morphological features. The i(12p) status serves as an additional option to indicate a germ cell origin in selected cases.
Assuntos
Neoplasias do Mediastino/diagnóstico , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Adolescente , Adulto , Idoso , Algoritmos , Biomarcadores Tumorais/metabolismo , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Patologia Molecular , Adulto JovemRESUMO
PURPOSE: To report on the clinical characteristics, outcome, and frequency of peritoneal carcinosis (PC) in patients with advanced germ cell tumors (GCT), a multicenter registry analysis was carried out. METHODS: A multicenter registry analysis was conducted by the German Testicular Cancer Study Group (GTCSG) with international collaborators. Data was collected and analyzed retrospectively. Patients were eligible for inclusion if PC was diagnosed either by radiologic or histopathologic finding during the course of disease. Descriptive and explorative statistical analysis was carried out with cancer-specific survival (CSS) as primary study endpoint. RESULTS: Collaborators from ten GCT expert centers identified 28 GCT (0.77%) patients with PC after screening approximately 3767 GCT patient files and one case was contributed from a cancer registry request. Patients were diagnosed from 1997 to 2019 at a median age of 37 years (interquartile range, 13). Two patients (7%) presented with stage I and 27 patients (93%) with synchronous metastatic disease at first diagnosis. The primary histology was seminoma in seven (27%) and non-seminoma in 21 patients (72%). PC was detected after a median of 15.3 months from primary diagnosis (range 0-177) and two consecutive treatment lines (range 0-5), respectively. The median CSS from the time of detection of PC was 10.5 months (95%Confidence Interval 0.47-1.30) associated with an overall 2-year CSS rate of 30%. CONCLUSION: PC represents a rare tumor manifestation in GCT patients and was primarily associated with the occurrence of advanced cisplatin-refractory disease conferring to a dismal prognosis.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Adulto , Humanos , Masculino , Sistema de Registros , Estudos Retrospectivos , Neoplasias Testiculares/patologiaRESUMO
PURPOSE: Testicular germ cell tumours (GCTs) represent the most common malignancy in young adult males with two thirds of all cases presenting with clinical stage I (CSI). Active surveillance is the management modality mostly favoured by current guidelines. This systematic review assesses the treatment results in CSI patients concerning recurrence rate and overall survival in non-seminoma (NS) and pure seminoma (SE) resulting from surveillance in comparison to adjuvant strategies. METHODS/SYSTEMATIC REVIEW: We performed a systematic literature review confining the search to most recent studies published 2010-2021 that reported direct comparisons of surveillance to adjuvant management. We searched Medline and the Cochrane Library with additional hand-searching of reference lists to identify relevant studies. Data extraction and quality assessment of included studies were performed with stratification for histology (NS vs. SE) and treatment modalities. The results were tabulated and evaluated with descriptive statistical methods. RESULTS: Thirty-four studies met the inclusion criteria. In NS patients relapse rates were 12 to 37%, 0 to 10%, and 0 to 11.8% for surveillance, chemotherapy and for retroperitoneal lymph node dissection (RPLND) while overall survival rates were 90.7-100%, 91.7-100%, and 97-99.1%, respectively. In SE CSI, relapse rates were 0-22.3%, 0-5%, and 0-12.5% for surveillance, radiotherapy, chemotherapy, while overall survival rates were 84.1-98.7%, 83.5-100%, and 92.3-100%, respectively. CONCLUSION: In both histologic subgroups, active surveillance offers almost identical overall survival as adjuvant management strategies, however, at the expense of higher relapse rates. Each of the management strategies in CSI GCT patients have specific merits and shared-decision-making is advised to tailor treatment.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Seminoma , Neoplasias Testiculares , Masculino , Adulto Jovem , Humanos , Orquiectomia/métodos , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Testiculares/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Seminoma/patologia , Excisão de Linfonodo/métodos , Quimioterapia Adjuvante/métodosRESUMO
PURPOSE: In this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors. METHODS: This work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety. RESULTS: Relapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10-15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success. CONCLUSIONS: Patients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients' survival.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Testiculares/patologia , Terapia de Salvação , Cisplatino/uso terapêutico , Estudos Retrospectivos , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Transplante Autólogo , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológicoRESUMO
PURPOSE: The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options. METHODS: A systematic review was performed. Only randomized clinical trials and comparative studies published from January 2010 until February 2021 were included. Search items included: seminoma, CS IIA, CS IIB and therapy. Outcome parameters were relapse rate (RR), relapse-free (RFS), overall and cancer-specific survival (OS, CSS). Additionally, acute and long-term side effects including secondary malignancies (SMs) were analyzed. RESULTS: Seven comparative studies (one prospective and six retrospective) were identified with a total of 5049 patients (CS IIA: 2840, CS IIB: 2209). The applied treatment modalities were radiotherapy (RT) (n = 3049; CS IIA: 1888, CSIIB: 1006, unknown: 155) and chemotherapy (CT) or no RT (n = 2000; CS IIA: 797, CS IIB: 1074, unknown: 129). In CS IIA, RRs ranged from 0% to 4.8% for RT and 0% for CT. Concerning CS IIB RRs of 9.5%-21.1% for RT and of 0%-14.2% for CT have been reported. 5-year OS ranged from 90 to 100%. Only two studies reported on treatment-related toxicities. CONCLUSIONS: RT and CT are the most commonly applied treatments in CS IIA/B seminoma. In CS IIA seminomas, RRs after RT and CT are similar. However, in CS IIB, CT seems to be more effective. Survival rates of CS IIA/B seminomas are excellent. Consequently, long-term toxicities and SMs are important survivorship issues. Alternative treatment approaches, e.g., retroperitoneal lymph node dissection (RPLND) or dose-reduced sequential CT/RT are currently under prospective investigation.
Assuntos
Segunda Neoplasia Primária , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Seminoma/radioterapia , Seminoma/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Neoplasias Testiculares/radioterapia , Neoplasias Testiculares/tratamento farmacológico , Segunda Neoplasia Primária/patologiaRESUMO
BACKGROUND AND PURPOSE: Hemiscrotectomy with en bloc orchidectomy represents a radical primary, completion, or salvage option in men with inguinoscrotal cancers. We describe our surgical technique and peri-operative and oncological outcomes. PATIENTS AND METHODS: Retrospective cohort study of 16 men treated at a supra-regional referral centre with open radical hemiscrotectomy with or without en bloc orchidectomy between 2010 and 2020. Peri-operative and survival outcomes were analysed. RESULTS: Radical hemiscrotectomy with or without en bloc orchidectomy was performed on 16 patients comprising 7 well-differentiated liposarcomas, 4 dedifferentiated liposarcomas, 2 leiomyosarcomas, 1 mesothelioma, 1 rhabdomyosarcoma and 1 mammary type myofibroblastoma. Primary hemiscrotectomy was performed in four, completion hemiscrotectomy in nine and salvage hemiscrotectomy in three. The median hospital stay was 2 days [interquartile range (IQR) 2-4]. Four patients (25%) had post-operative complications including wound infection or haematoma. During a median follow-up of 18 months (IQR 2-66), one patient (6%) died following a recurrence in the pelvis and retroperitoneum. DISCUSSION: and Conclusions If careful dissection is performed, radical hemiscrotectomy and en bloc orchidectomy is a radical but safe procedure with a short hospital stay. Haematoma and infection represent the main complications, and within limited follow-up most men showed no recurrence.
Assuntos
Recidiva Local de Neoplasia , Orquiectomia , Humanos , Masculino , Recidiva Local de Neoplasia/cirurgia , Encaminhamento e Consulta , Estudos Retrospectivos , Resultado do Tratamento , Reino UnidoRESUMO
AIMS: Malignant germ cell tumours (GCTs) of the testis are rare neoplasms, but the most common solid malignancies in young men. World Health Organization guidelines divide GCTs into five types, for which numerous immunohistochemical markers allow exact histological subtyping in the majority of cases. In contrast, a germ cell origin is often hard to prove in metastatic GCTs that have developed so-called somatic malignant transformation. A high percentage, up to 89%, of GCTs are characterised by the appearance of isochromosome 12p [i(12p)]. Fluorescence in-situ hybridisation has been the most common diagnostic method for the detection of i(12p) so far, but has the disadvantages of being time-consuming, demanding, and not being a stand-alone method. The aim of the present study was to establish a quantitative real-time polymerase chain reaction assay as an independent method for detecting i(12p) and regional amplifications of the short arm of chromosome 12 by using DNA extracted from formalin-fixed paraffin-embedded tissue. METHODS AND RESULTS: A cut-off value to distinguish between the presence and absence of i(12p) was established in a control set consisting of 36 tumour-free samples. In a training set of 149 GCT samples, i(12p) was detectable in 133 tumours (89%), but not in 16 tumours (11%). In a test set containing 27 primary and metastatic GCTs, all 16 tumours with metastatic spread and/or somatic malignant transformation were successfully identified by the detection of i(12p). CONCLUSION: In summary, the qPCR assay presented here can help to identify, further characterise and assign a large proportion of histologically inconclusive malignancies to a GCT origin.
Assuntos
Isocromossomos/genética , Neoplasias Embrionárias de Células Germinativas/genética , Transformação Celular Neoplásica , Humanos , Hibridização in Situ Fluorescente , Neoplasias Embrionárias de Células Germinativas/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
PURPOSE: The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients. METHODS: Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR). RESULTS: The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p ≤ 0.001), respectively. CONCLUSIONS: LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.
Assuntos
L-Lactato Desidrogenase/sangue , Seminoma/sangue , Seminoma/mortalidade , Neoplasias Testiculares/sangue , Neoplasias Testiculares/mortalidade , Adolescente , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Seminoma/patologia , Taxa de Sobrevida , Neoplasias Testiculares/patologia , Adulto JovemRESUMO
OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.
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Neoplasias Embrionárias de Células Germinativas/terapia , Tumores do Estroma Gonadal e dos Cordões Sexuais/terapia , Neoplasias Testiculares/terapia , Adulto , Assistência ao Convalescente , Humanos , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Cuidados Paliativos , Guias de Prática Clínica como Assunto , Qualidade de Vida , Neoplasias Testiculares/patologiaRESUMO
INTRODUCTION: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages. METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements. RESULTS: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma. CONCLUSION: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Adulto , Preservação da Fertilidade , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Embrionárias de Células Germinativas/terapia , Guias de Prática Clínica como Assunto , Prognóstico , Neoplasias Testiculares/classificação , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/terapiaRESUMO
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). MATERIALS AND METHODS: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. RESULTS: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. CONCLUSION: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.
Assuntos
COVID-19/epidemiologia , Institutos de Câncer/estatística & dados numéricos , Neoplasias Embrionárias de Células Germinativas/terapia , COVID-19/prevenção & controle , Canadá/epidemiologia , Institutos de Câncer/tendências , Europa (Continente)/epidemiologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Oncologistas/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Padrões de Prática Médica/tendências , SARS-CoV-2 , Inquéritos e Questionários , Telemedicina/tendênciasRESUMO
BACKGROUND: Testicular type II germ cell tumours (GCTs) are an exemplar of a curable cancer and the most common malignancy in males aged ≤35 years. Even in metastatic stages, about 70% of patients can be cured by cisplatin-based chemotherapy and multimodal treatments. For patients failing platinum-based standard therapy, prognosis is poor and novel biomarkers and therapeutic options are urgently needed. OBJECTIVES: Discussion of desired histopathological information to guide urologists' and oncologists' decision making in the treatment of male GCTs. MATERIAL AND METHODS: A narrative review of histopathological key features of male GCT tissue samples for clinical decision making. RESULTS: Histopathological workup is crucial to identify (i) a GCT origin in cancers of unknown primary based on isochromosome 12p (i(12p)) detection, (ii) the different type II GCT subtypes, and (iii) risk factors, i.e. lymphovascular or rete testis invasion, among others. Proper histopathological diagnosis is indispensable for guideline-endorsed, histology-driven, and risk-adapted treatment decisions, hereby helping to maintain treatment success while reducing the therapeutic burden and potential long-term sequelae of multimodal treatments. For refractory patients failing standard treatment options, prognosis remains poor and, so far, neither predictive or prognostic biomarkers nor novel therapeutic targets have been established. CONCLUSIONS: Close interaction and interdisciplinary discussion of histopathologic and radiologic findings and established risk factors including serum tumour markers is crucial for successful treatment including intensified strategies, where necessary, or prevention of overtreatment, where possible.
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Neoplasias Embrionárias de Células Germinativas , Oncologistas , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/terapia , Patologistas , Prognóstico , Neoplasias Testiculares/terapiaRESUMO
PURPOSE OF REVIEW: Prognosis of patients with refractory or multiply relapsed germ cell cancer (GCC) is dismal with a life expectancy of a few months only. Thus, new targets and treatment options are urgently needed. Here, we review and discuss the biological basis and first clinical results of immune-checkpoint inhibition by targeting programed death 1 (PD-1) or its ligand (PD-L1) in treatment-refractory GCCs. RECENT FINDINGS: There is a biological rationale to evaluate immune-checkpoint inhibitors in refractory GCCs, as PD-L1 is often expressed and refractory tumors often display mismatch repair deficiency or microsatellite instability. However, the first published clinical phase II trial evaluating pembrolizumab in unselected refractory nonseminoma patients was closed early due to lacking clinical activity. On the contrary, single-case reports have shown meaningful activity in some patients. SUMMARY: To date, targeted treatments, including current immunotherapy approaches, have only shown very limited activity. Although immune-checkpoint inhibition provides an effective treatment option for various malignancies based on large randomized clinical trials, data on the use of this immunotherapy in refractory GCC are scarce as results of ongoing trials are pending.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Cisplatino/uso terapêutico , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Neoplasias Embrionárias de Células Germinativas/metabolismo , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Testiculares/metabolismoRESUMO
Despite high cure rates, about 20% of patients with advanced germ cell tumors (GCTs) fail cisplatin-based chemotherapy. High levels of DNA methylation have been identified in GCTs and linked to cisplatin resistance. Here, we examined the effects of DNA hypomethylating 5-azacitidine (5-aza) on two embryonal carcinoma cell lines (NCCIT, 2102Ep) and their cisplatin-resistant isogenic derivatives. Effects on cell viability and cisplatin sensitivity were assessed by the trypan blue exclusion method. Western blotting was used to examine induction of apoptosis 5-aza and results were validated by flow cytometry. Single agent treatment with 5-aza strongly impacted viability and induced apoptosis at low nanomolar concentrations, both in cisplatin-sensitive and -resistant cell lines. 5-aza exerted an immediate apoptotic response, followed by a prolonged inhibitory effect on cell viability and cell-cycle progression. Sequential treatment with 5-aza and cisplatin reduced cellular survival of the cisplatin-resistant sublines already at nanomolar concentrations, suggesting a partial restoration of cisplatin sensitivity by the compound. 5-aza demonstrated anti-tumor activity as a single agent at low nanomolar concentrations in GCT cells, irrespective of cisplatin-sensitivity. 5-aza may also have the potential at least to partially restore cisplatin-sensitivity in non-seminoma cells, supporting the hypothesis that combining DNA demethylating agents with cisplatin-based chemotherapy may be a valid therapeutic approach in patients with refractory GCTs.
Assuntos
Apoptose/efeitos dos fármacos , Azacitidina/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Apoptose/genética , Biomarcadores , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Metilação de DNA , Humanos , Concentração Inibidora 50 , MasculinoRESUMO
PURPOSE: In general, 50 % up to 80 % of metastasized germ cell tumor patients can be cured by platinum-based chemotherapy. However, 3-5 % of patients will still die of platinum-refractory disease and new systemic treatment options are needed to improve treatment success in this difficult setting. This review aims to give an overview on treatment options and current developments in the field of platinum-refractory male germ cell tumors. METHODS: A comprehensive literature search was conducted searching PubMed, Medline, Cochrane and Embase to identify clinical trials regarding the treatment of platinum-refractory disease. ASCO, EAU and ESMO conference proceedings were searched to identify unpublished results of relevant trials. Comprehensive review papers were hand searched for additional references. Clinicaltrials.gov was checked for ongoing clinical trials in the field of platinum-refractory germ cell tumors. RESULTS: Outcome of platinum-refractory disease remains poor. Single-agents with reasonable activity are gemcitabine, oxaliplatin and paclitaxel, but complete remissions resulting in long-term survival could not be achieved. The triple-combination of gemcitabine, oxaliplatin and paclitaxel followed by resection of residual masses provides the best outcomes with objective responses in 51 % of patients and long-term survival in approximately 10-15 %. To date, no molecularly targeted agent has shown reasonable activity. CONCLUSIONS: Treatment options for platinum-refractory disease are limited, but a small subset of patients may achieve long-term disease-free survival by multimodal treatment. The potential of novel targeted agents, i.e. by immune-checkpoint-inhibition remains to be defined.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Humanos , Masculino , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Paclitaxel/administração & dosagem , Terapia de Salvação , GencitabinaRESUMO
PURPOSE: We comprehensively reviewed current efforts and advances in the field of chemotherapeutic and biologically targeted treatment options after the failure of cisplatin based, first line regimens for urothelial carcinoma. MATERIALS AND METHODS: We searched MEDLINE®, Central®, and meeting abstracts of ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology) to identify original articles, reviews and retrospective analyses on second line treatment of urothelial carcinoma. Articles were included in analysis if they described prospective phase II/III studies or larger high quality retrospective studies of second line treatment of urothelial carcinoma. RESULTS: Although considered a chemosensitive disease, most patients with advanced or metastatic urothelial carcinoma relapse after cisplatin based first line treatment. Today none of the commonly used drugs, ie paclitaxel, carboplatin and/or gemcitabine, are approved by the FDA (Food and Drug Administration) for second line systemic treatment. In Europe vinflunine plus best supportive care is the only option approved by the EMA (European Medicines Agency) with moderate clinical efficacy. Responses to combined chemotherapy approaches are often better but associated with remarkable toxicity. In patients who respond well to first line treatment and, thus, are considered cisplatin sensitive readministration of a platinum based combination regimen may be an option. To date targeted therapies do not have a role in second line treatment of urothelial cancer. Immunotherapeutic strategies to target the PD-1/PD-L1 axis are emerging. In a recent phase I trial evaluating the PD-L1 targeted monoclonal antibody MPDL3280A a promising 43% response rate with good tolerability was achieved, which led to an immediate breakthrough therapy designation by the FDA. Combining chemotherapy with targeted agents, eg weekly paclitaxel and pazopanib, also shows promising activity in this prognostically poor treatment situation. CONCLUSIONS: Response rates and survival are poor after second line chemotherapy for advanced or metastatic urothelial carcinoma. To improve outcomes of salvage treatment novel biologically targeted drugs as monotherapy or as part of a combination with conventional cytostatics are urgently needed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fatores Biológicos/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma de Células de Transição/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Humanos , Indazóis , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Pirimidinas/administração & dosagem , Terapia de Salvação , Sulfonamidas/administração & dosagem , Neoplasias da Bexiga Urinária/patologia , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , GencitabinaRESUMO
PURPOSE: Testicular germ cell tumor (GCT) and its treatment may cause distressing long-term symptoms. We aimed to examine self-reported symptom frequency and distress as well as the impact of demographic and medical characteristics in GCT survivors. METHODS: A total of 164 GCT survivors receiving follow-up care at the University Cancer Center Hamburg and a specialized private practice facility were interviewed at a median time of 11.6 years after first diagnosis. Metastatic disease was present in 48 % of the patients and relapse had occurred in 17 %. The patients completed the short form of the Memorial Symptom Assessment Scale (MSAS-SF) assessing 28 physical and 4 psychological symptoms. RESULTS: The mean number of physical symptoms was 4.5 (SD = 4.3) (psychological symptoms M = 1.4, SD = 1.4; total M = 5.9, SD = 5.2). The most frequent physical symptoms were lack of energy (49 %), feeling drowsy (42 %), sleeping problems (36 %), and difficulty in concentration (32 %). Lack of energy was experienced as highly distressing by 21 % of the patients. The most frequent psychological symptoms were irritability (47 %) and being worried (42 %). The number of physical symptoms was associated with higher age, lower socioeconomic status, and shorter time since diagnosis in multivariate regression analyses controlling for metastatic vs. localized disease, relapse, extent of surgery, number of chemotherapy cycles, and radiotherapy. CONCLUSIONS: GCT survivors suffered from a significant number of long-term symptoms. Fatigue-related symptoms were most frequent and perceived as highly distressing. Continuous attention toward fatigue is necessary throughout follow-up care to offer support in time, particularly in more vulnerable patients of higher age and lower socioeconomic status.
Assuntos
Neoplasias Embrionárias de Células Germinativas/diagnóstico , Sobreviventes/psicologia , Neoplasias Testiculares/diagnóstico , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/mortalidade , Estresse Psicológico/psicologia , Neoplasias Testiculares/mortalidade , Adulto JovemAssuntos
Neoplasias Embrionárias de Células Germinativas , Teratoma , Humanos , Excisão de Linfonodo , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Prognóstico , Teratoma/tratamento farmacológico , Teratoma/cirurgiaRESUMO
Since the introduction of cisplatin-based combination chemotherapy, patients with metastatic germ cell tumours achieve very high cure rates of >80%. Nevertheless, about 30% of patients relapse despite guideline-endorsed first-line treatment. Of these, again about 50% of patients can still achieve cure with platinum-based salvage chemotherapy and eventually post-chemotherapy residual mass resection.Salvage chemotherapy generally involves platinum-based combination chemotherapy, either as conventional dose cisplatin-based combinations again or as high-dose chemotherapy with subsequent autologous stem cell transplantation.To date, high level evidence from randomised trials supporting the use of salvage high-dose chemotherapy for all patients relapsing after first-line treatment remains lacking, but a large international retrospective registry study had shown a 15% overall survival benefit for patients undergoing salvage high-dose chemotherapy.In this article, we summarise the available literature on the different salvage treatment approaches and discuss these in the light of current treatment guideline recommendations for the management of testicular cancer.
RESUMO
Treatment de-escalation strategies in patients with seminoma with retroperitoneal metastases are being investigated in ongoing clinical trials. Primary retroperitoneal lymph node dissection conducted by expert surgeons may avoid any cytotoxic treatment and related long-term side effects in ≥70% of patients with clinical stage IIA/B seminoma.