Management Of Germ Cell Tumors Research Articles

Current outstanding challenges in germ cell tumors.

Despite the remarkable advances in the treatment of germ cell tumors (GCT), several challenges remain. This review aims to highlight some of these challenges and provide guidance on how to navigate through them. Patients with International Germ Cell Cancer Collaborative Group poor risk disease have worse prognosis and investigating novel therapeutic interventions are warranted in this population. Patients with brain metastases require a multidisciplinary approach by a group of clinicians experienced in the management of germ cell tumors. Patients with platinum refractory disease have poor prognosis and development of novel treatment options is urgently needed. Conventional tumor markers including alpha fetoprotein and human chorionic gonadotropin remain standard. Development of novel biomarkers to detect minimal residual disease or teratoma is needed. Management of patients with GCT requires a multidisciplinary approach. Patients should preferably be evaluated at tertiary care centers with expertise in the management of this disease.

Testicular cancer in 2023: Current status and recent progress.

Testicular germ cell tumor (GCT) is the most common solid tumor in adolescent and young adult men. Progress in the management of GCT has been made in the last 50 years, with a substantial improvement in cure rates for advanced disease, from 25% in the 1970s to nearly 80%. However, relapsed or platinum-refractory disease occurs in a proportion, 20% of whom will die from disease progression. This article reviews the current evidence-based treatments for extracranial GCT, the acute and chronic toxic effects that may result, and highlights contemporary advances and progress in the field.

The Role of Circulating Tumor DNA and Cell-Free DNA in the Management of Germ Cell Tumors: A Narrative Review

Liquid biopsy has demonstrated success as a diagnostic, prognostic, and therapy response monitoring tool in various cancers and could represent a rapid and minimally invasive alternative or complementary test for testicular germ cell tumors (GCTs). This article aims to review the current state of the research into circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) in testicular GCTs.Studies have confirmed the presence of ctDNA and cfDNA can be identified in peripheral blood samples of patients with testicular GCTs. Further research has attempted to optimize the methods for ctDNA detection in plasma to improve the sensitivity of these tests; however, a single method with high sensitivity and reliability has yet to be established. Previous studies have employes different methods for detecting cfDNA, including spectrophotometry, capillary electrophoresis, quantitative polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR), and whole genome sequencing. These studies have various elements of cfDNA examined such as total cfDNA quantity, methylation patterns, and specific mutations. Additional studies have investigated the efficacy of cfDNA detection in combination with other tests including miRNA analysis.The application of cfDNA as a biomarker has been rapidly expanding in several malignancies. However, there is a relative paucity of research on the clinical utility of cfDNA in testicular cancer, and many questions remain about the significance and feasibility of this biomarker in GCTs. Cell-free DNA shows promise as a biomarker to enhance detection and disease monitoring in testicular cancer, but robust studies are needed to develop an optimal and reproducible method for cfDNA detection in order to determine its clinical application in testicular cancer.

Balancing efficacy with long-term side-effects: can we safely de-escalate therapy for germ cell tumors?

ABSTRACT Introduction The success in the management of germ cell tumors has encouraged researchers to pay more attention on long-term side effects and other survivorship issues. The de-escalation of treatment is intended to reduce side effects but must be balanced against any compromise of efficacy. Cisplatin-based therapy is the cornerstone of treatment for germ cell tumors. However, they can result in acute and long-term side effects, including ototoxicity, neurotoxicity, nephrotoxicity, and increased risk of second malignancies. Areas covered This review discusses approaches of de-escalation including biomarker-directed treatment using microRNAs, surveillance for immature teratoma, the use of carboplatin monotherapy for seminoma, and the option of non-cisplatin-based approaches in relapsed germ cell tumors. Expert opinion While the results with the current standard options in terms of cancer control are very good, the price being paid in terms of long-term side effects is considerable.

Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.

PURPOSEThe classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium.MATERIALS AND METHODSData on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients.RESULTSCompared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH.CONCLUSIONPFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.

Real-world application of pre-orchiectomy miR-371a-3p test in testicular germ cell tumor (GCT) management.

387 Background: Current serum tumor markers (STMs) for testicular germ cell tumor (GCT) are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) GCT management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable GCT among patients undergoing partial or radical orchiectomy. Methods: Serum samples were collected from 69 consecutive patients pre-orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional STMs (AFP/β-hCG/LDH) between viable GCT patients and those without viable GCT on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. Kruskal-Wallis test and linear and ordinal regression models were used for analysis. Results: For detecting viable GCT, combined conventional STMs had a specificity of 100%, sensitivity of 58%, and area under the curve (AUC) of 0.79 (Table). The miR-371a-3p test showed a specificity of 100%, sensitivity of 93%, and AUC of 0.978. Median relative expression of miR-371a-3p in viable GCT patients was >6,800-fold higher than in patients lacking viable GCT. MiR-371a-3p levels correlated with composite stage (CS) (p=0.006), and, among CS I patients, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p<0.0001). Six patients received orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable GCT by the miR-371a-3p test. Conclusions: If validated, the miR-371a-3p test can be used in conjunction with conventional STMs to aid clinical decision-making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation. [Table: see text]

Pearls and perils in the management of germ cell tumors.

Research and innovation over the past half century have rendered testicular cancer a highly curable malignancy. Challenges and uncertainty remain in several aspects related to the management and surveillance of patients with germ cell tumors (GCT). Long-term effects of treatment on survivors of testicular cancer remain as continued areas of interest. This review aims to highlight pearls and perils in the management of patients with GCT. Uncertainty remain regarding complex aspects of first-line and salvage treatments of GCT, interpretation of tumor markers in cases of α-fetoprotein levels less than 25 ng/ml, plateau of β-human chorionic gonadotropin (hCG) levels in patients with initial hCG greater than 50 000 mIU/ml, supportive therapies throughout chemotherapy regimens, and long-term survivorship of patients who underwent surgery or received platinum-based chemotherapy. This review aims to highlight challenges that remain in GCT, review the emerging data in these areas, and provide our institutional opinion on the management in several aspects of GCT. Testicular cancer continues to present challenging clinical scenarios with respect to treatment, surveillance, and long-term management of patients. We review the data and share our institutional knowledge in several challenging areas related to the management of GCT.

Intricacies of Radiographic Assessment in Testicular Germ Cell Tumors.

Testicular germ cell tumors (GCTs) are malignancies with a unique biology, pathology, clinical appearance, and excellent outcomes. A correct radiographic assessment of GCTs is extremely important for the clinical management in several typical scenarios. Advancements in the field of diagnostic medicine bring an increasing number of sophisticated imaging methods to increase the performance of imaging studies. The conventional computed tomography (CT) remains the mainstay of diagnostic imaging in the management of GCTs. While certain improvements in the sensitivity and specificity are suggested with magnetic resonance (MR) imaging with lymphotrophic nanoparticles in evaluating retroperitoneal lymph nodes during the staging procedure, further exploration in larger prospective studies is needed. A common diagnostic dilemma is assessing the post-chemotherapy residual disease in GCTs. Several studies have consistently shown advantages in the utility of positron emission tomography (PET) scanning in post-chemotherapy residual retroperitoneal lymph nodes in patients with seminoma, but not with non-seminoma. Recommendations suggest that seminoma patients with a residual disease in the retroperitoneum larger than 3 cm should be subjected for PET scanning with 18-fluorodeoxyglucose. Relatively high sensitivity, specificity and a negative predictive value (80–95%) may guide clinical decision to spare these patients of high morbidity of an unnecessary surgery. However, a positive predictive value of around 50% renders PET scanning difficult to interpret in the case of positive finding. These patients often require extremely difficult surgical procedures with the high risk of post-operative morbidity. Therefore, seminoma patients with PET positive residual masses larger than 3 cm still remain a serious challenge in the decision making of nuclear medicine specialist, oncologists, and urologic surgeons. In this article, we aim to summarize data on controversial dilemmas in staging procedures, active surveillance, and post-chemotherapy assessment of GCTs based on the available published literature.

The Past and Future of Biomarkers in Testicular Germ Cell Tumors

Testicular germ cell tumor (GCT) is the most common malignancy in 18- to 40-year-old men. Unlike most other cancers, GCT is frequently curable even when metastatic. These tumors can be classified histologically into seminoma and non-seminoma, which determines treatment. Therefore, successful treatment requires accurate diagnosis, classification, and monitoring. Serum tumor markers, including lactate dehydrogenase, α-fetoprotein, and β-human chorionic gonadotropin, aid in the classification and staging of GCTs. These markers therefore play a critical role in the decision-making process when managing GCT patients. However, there exist many scenarios in which these markers fail to perform adequately. This is particularly true in the case of seminoma, where only 10% to 15% will have elevated serum tumor markers. Non-specific elevation of these markers is also a common occurrence, complicating the interpretation of borderline positive results, particularly in follow-up. To bridge this gap in performance, next generation biomarkers are being investigated. In this review, we consider the role of conventional serum tumor markers in GCT management and discuss recent advances in the next generation of biomarkers, with a focus on circulating microRNAs. We discuss the value that circulating microRNAs could bring as an addition to currently used markers, as well as potential weaknesses, in GCT management.

Pediatric Germ Cell Tumors: An Experience of 7 Years in a Tertiary Hospital of Bangladesh

Introduction: Germ cell tumors are a group of tumors with different clinical presentation and histological and biological characteristics. Malignant germ cell tumors occur at all ages with a trend of bimodal distribution in infancy and adolescence.
 Objective: To evaluate the demographic characteristics, distribution of different types of germ cell tumor, treatment modalities and outcome of germ cell tumor in children in a tertiary care hospital of Bangladesh.
 Methods: In this retrospective study, data regarding age and sex distribution, location, types of tumors, management of germ cell tumor in children were retrieved from the medical records of pediatric oncology department in NICRH, Dhaka from 2008 to 2014.
 Results: Out of total 87 patients female were 50 and male 37. Most of the patients were up to 5 years of age. The gonadal germ cell tumors (80%) were more than extragonadal tumor (20%) in both male and female patients. The most common germ cell tumor was dysgerminoma (32%) followed by yolk sac tumor (29.8%) and teratoma (19.5%). Yolk Sac Tumor (51.4%) was the most common in male and dysgerminoma (56%) the commonest in female. Out of 87, seventy two (82.7%) received chemotherapy following surgery. Among those 72 patients who received chemotherapy 49 (68 %) patients completed their treatment. Until the last follow up 71.4% patients remained alive and tumor free.
 Conclusion: Germ cell tumors are the most variable tumor of all childhood malignancies that has difference in age, sex, location and histological subtypes. Gonadal tumors have better prognosis than extragonadal tumors in both the sex.
 DS (Child) H J 2019; 35(2) : 119-122

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic: A Survey of International Expertise Centers.

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). 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. 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. 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. 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.

So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma?

The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.

The role of micro-RNAs in management of germ cell tumors: future directions.

miRNAs 371 and 302/367 clusters are abundantly secreted in the blood of patients with active germ cell malignancy (aGCM), both seminoma and nonseminoma. The serum concentration of those micro-RNAs correlates with tumor burden and to the activity of specific treatments; therefore, representing attractive biomarkers for the diagnosis and follow-up of patients with germ cell tumors. This review summarizes the most relevant evidence supporting their clinical validity in germ cell tumors. Several retrospective studies have reported high sensitivity and specificity of those micro-RNAs in identifying aGCM prior to the orchiectomy or in patients with metastatic germ cell tumor prior to or during chemotherapy. Most recently, few prospective studies have confirmed their clinical validity during the follow-up of patients after surgery and/or chemotherapy. Large studies are panned across the spectrum of germ cell tumors to assess their clinical utility and several efforts to identify biomarkers of teratoma are underway. The integration of those micro-RNAs in the management of germ cell tumors has the potential to refine the therapeutic decision, especially in some clinical situations characterized by high uncertainty, such as clinical stage I, clinical stage IIA with normal tumor markers and residual disease postchemotherapy.

GCT-44 - An overview of circulating microRNAs for the management of germ cell tumours

GCT-44 - An overview of circulating microRNAs for the management of germ cell tumours

AB013. Management of germ cell tumors: a case with growing teratoma syndrome

: The growing teratoma syndrome in patients with anterior mediastinal germ cell tumors were rare. Here, we report a patient with primary anterior mediastinal malignant mixed germ cell tumor that exhibited growing teratoma syndrome after initiation chemotherapy. A 28-year-old man is admitted to the hospital complaining of dyspnea. Chest computed tomography (CT) showed a huge heterogeneous anterior mediastinal mass (20 cm in longest direction). The tumor compressed the left lung, heart and great vessels. The α-fetoprotein (AFP) is higher than 3,000 ng/mL, the β-human chorionic gonadotropin (β-HCG) level is increased to 49.7 ng/mL. Core-needle biopsy confirmed the diagnosis of teratoma with nonseminomatous germ cell tumors. The patient was administered two rounds of bleomycin, etoposide, cisplatin (BEP) chemotherapy, but the mass grew despite Serum AFP was rapidly declining (171 ng/mL). And CT scan revealed a notable enlargement of the tumor. Surgical tumor resection was performed through a median sternotomy. The tumor was adherent to the pericardium, bilateral mediastinum pleura, left upper lobe, and left phrenic nerve. The tumor was completely resected including pericardiectomy, resection of the left phrenic nerve, and left upper lobectomies. The pathologic examination revealed malignant mixed germ cell tumor with extensive areas of chemotherapy-induced necrosis which was consisted with mature teratoma, immature teratoma and embryonal carcinoma. The patient was alive without recurrence at 6 months after two rounds of adjuvant chemotherapy.

Germ Cell Tumors in Adolescents and Young Adults

Germ cell tumors (GCTs) are rare in childhood, representing only 3.5% of childhood cancers, but a common malignancy in adolescents and young adults (AYAs), accounting for 13.9% of neoplasms in adolescents between age 15 and 19 years. The overall outcomes of patients treated for GCTs are excellent. However, as seen in other cancers, outcomes for AYA patients are significantly worse. Understanding the reasons for this observation has led to different approaches to diagnosis, staging, and treatment. The Malignant Germ Cell International Consortium was created to bring together pediatric, gynecologic, and testicular cancer specialists to promote research initiatives and provide evidence-based approaches in the management of GCTs across different age groups. Collaboration between multiple subspecialties is essential to further understand the disease continuum, the underlying biologic characteristics, and the development of appropriate therapeutic approaches. This review focuses on the unique characteristics of patients with extracranial GCTs in the AYA group.

A step forward in identifying the right human chorionic gonadotropin assay for testicular cancer.

Clinical practice guidelines for the management of germ cell tumors recommend the measurements of human chorionic gonadotropin (hCG) and/or free hCGβ subunit for earlier diagnosis/recognition of the residual disease, for the prognostic evaluation and for the post-chemotherapy surveillance. However, the marketed hCG assays are validated and approved only for pregnancy purposes, with the sole exception of the Elecsys 'hCG+β' assay (Roche Diagnostics), cleared in Europe for oncological application. Theoretically, the hCG assay design for oncological purposes should fulfil the recommendations of the International Society of Oncology and Biomarkers requiring the use of antibodies displaying an equimolar recognition of both intact hCG and hCGβ monomer. Further analytical requirements should also be considered, such as optimal analytical sensitivity to allow an early tumor detection and low cross-reactivity for luteinizing hormone (LH). For the Elecsys assay, the detection limit (0.2 U/L) and the reported cross-reactivity for LH (0.12%) may be considered adequate if compared with the recommended requirements. Another issue is the definition of decision limits for oncologic purposes. After 3 years of clinical experience using the Elecsys assay in the oncology setting, we were able to define limits partitioned by sex and age as follows: males <50 years, 0.3 U/L; males >50 years, 2.3 U/L; female <50 years, 2.1 U/L; female >50 years, 5.6 U/L. There is an urgent need to disseminate appropriate educational information and to boost the clinical use of selective, highly sensitive and precise assays, specifically manufactured for cancer application.

Ten year overview of germ cell tumours treated within the Anglian Germ Cell Cancer Collaborative Group (AGCCCG) (2005-2015): Outcomes and the impact of specialist multidisciplinary review on decision making.

e16538Background: The AGCCCG is a well established UK network for the management of germ cell tumours covering a catchment area of over 7.4 million people and is hosted by St Bartholomew’s Hospital...

State-of-the-Art Management of Germ Cell Tumors.

The state of the art management of germ cell tumors (GCT) in 2018 does not include novel agents targeting genomic alterations or exciting immunologic-based approaches but rather the avoidance of pitfalls in everyday practice. The relative rarity of GCT and high curability with correct management create the "perfect storm" for high-stakes errors to occur. This review focuses on several common pitfalls that should be avoided in staging and management of early-stage and advanced GCT in order to maximize patient outcomes. A particularly frequent misstep is to base treatment decisions on pre- rather than postorchiectomy tumor markers that, depending on marker directionality, can lead to either undertreatment with potentially inferior outcomes or overtreatment with excess toxicity. Another common mistake is the failure to consider the unique ability of GCT to differentiate and the distinct biology of teratoma (chemoresistance and lack of increased glucose uptake compared with normal tissue), which exerts a pervasive influence on nonseminoma management. This may lead to inappropriate use of PET scan to evaluate the postchemotherapy residual mass and, if negative, the conclusion that surgery is not needed whereas (FDG-negative) teratoma should be removed. It could also result in administration of additional unnecessary chemotherapy to patients with marker normalization but without robust radiographic response after 3 to 4 cycles of BEP. Finally, oncologists should strive to maintain standard chemotherapy doses, not substitute carboplatin for cisplatin, and refer to expert centers when expertise (e.g., RPLND) is not available locally in order to achieve optimal cure rates in advanced disease.

Managing seminomatous and nonseminomatous germ cell tumors.

In the present review, we summarize the recent developments in the management of germ cell tumors (GCTs). Treatment-related acute and late-onset toxicity remains a key challenge in the management of GCTs, with recent evidence showing that the adverse health outcomes of etoposide and cisplatin for four cycles in comparison to bleomycin, etoposide, and cisplatin for three cycles appear to be similar. Recent data showed that multidisciplinary clinic approach and management in experienced academic centers were associated with improved overall survival in GCT patients. There are currently multiple conventional-dose chemotherapy options for salvage therapy in patients with refractory or recurrent disease. In addition, more efficacious high-dose chemotherapy regimens continue to be developed. The role of salvage conventional-dose chemotherapy versus high-dose chemotherapy is currently being investigated prospectively. Recent reports suggested that brentuximab vedotin could be a potential salvage option for cluster of differentiation 30 positive refractory GCTs. On the other hand the results of the first phase II clinical trial investigating pembrolizumab in refractory GCTs were disappointing showing no clinical activity.Finally, deep exploration of the immune profile of GCTs using immunohistochemistry and gene expression profiling has identified that advanced GCT stage was associated with decreased T-cell and Natural killer-cell signatures, whereas T regulatory, neutrophil, mast cell, and macrophage signatures increased with advanced stage. Even though these results indicated that activated T-cell infiltration correlated with seminoma histology and good prognosis, and could be used in the future as a biomarker, this approach needs to be validated in a large cohort. Remaining challenges to be addressed include minimizing therapeutic toxicity, and improving outcomes in patients with refractory/recurrent GCTs.