Primary Mediastinal Nonseminomatous Germ Cell Tumors Research Articles

Malignant Teratoma Arising From Mediastinal Non-Seminomatous Germ Cell Tumor: A Rare Case Report

Introduction: Primary mediastinal non-seminomatous germ cell tumors (NSGCT) have a worse prognosis than gonadal germ cell tumors (GCTs). Malignant transformation of teratomatous components of GCT to a somatic malignancy is rare.
 Materials and methods: A case of primary mediastinal NSGCT with malignant transformation of a teratoma was seen in a 23 years old male. Resected tumor specimen was received. Tissue processing was done and sections were prepared for Histo Pathological Examination.
 Results: Histopathology confirmed NSGCT with yolk sac and teratomatous components. Chemotherapy for GCT transiently normalized serum tumor markers with little effect on the mediastinal mass. Incomplete resection of the residual tumor revealed intermediate grade chondosarcoma. Here we discuss this rare case.
 Conclusion: malignant transformation to chondrosarcoma is a rare possibility which needs to be considered while managing the patient of Primary Mediastinal Germ Cell Tumors (PMGCT)

Salvage high-dose chemotherapy (HDCT) for relapsed primary mediastinal nonseminomatous germ-cell tumors (PMNSGCT).

5032 Background: Patients with PMNSGCT have high relapse rates after first-line therapy. Historical outcomes in this subset with standard-dose salvage chemotherapy or HDCT+bone marrow transplant (BMT) have been poor. The use of peripheral-blood stem-cell transplant (PBSCT) has allowed for more rapid engraftment and the ability to start the 2nd course 3-4 weeks after the 1st course of HDCT. We report survival outcomes of salvage HDCT+PBSCT in relapsed PMNSGCT. Methods: Between 2004-January 2021, 32 pts with relapsed PMNSGCT were treated with HDCT+PBSCTx2 utilizing our institutional regimen: carboplatin 700 mg/m2 + etoposide 750 mg/m2, for 3 consecutive days, followed by PBSCT. Median time between cycle1 day1 to cycle2 day1 was 3.2 wks (range, 2.6-4.6). Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) analysis. Results: Median age was 30. At the start of HDCT, median AFP was 192 (range, 4-17130) and hCG 1.5 (range, 0.6-15711). First-line therapy was standard germ cell tumor chemotherapy such as bleomycin-etoposide-cisplatin (BEP) or etoposide-ifosfamide-cisplatin (VIP). HDCT was 2nd line in (26, 81.3%) and 3rd line in (6, 18.8%). Eighteen (56.3%) pts had platinum-refractory disease defined as progression within 4 weeks of 1st line chemo. Twenty-three (72%) patients had extra mediastinal metastases (mets) at the start of HDCT. Metastatic sites included pulmonary (17), lymph nodes (2), liver (3), bone (2), brain (1). Median follow-up time from start of HDCT was 1 yr (range, 0.02-14.1). Twenty-six (81%) pts completed both cycles, while 6 (19%) completed only one cycle due to toxicity or progression. The estimated 2-yr PFS was 30.7 (95% CI, 15.8-46.9) and 2-yr OS was 35.2 (95% CI, 18.9-51.9). At the most recent follow-up, 9 (28%) pts were continuously no evidence of disease (NED), including 2 pts who had surgical resection of teratoma following HDCT. Median follow-up from the start of HDCT for the NED pts was 4.6 yrs (range, 1-14.1). Five of the NED pts had extra mediastinal mets, and 2 had platinum-refractory disease. Among the 9 NED pts, HDCT was 2nd line in 7 (77.8%) and 3rd line in 2 (22.2%). These results compare favorably to historical data with standard-dose chemotherapy or HDCT+BMT in relapsed primary mediastinal GCT with salvage rates < 10% (Hartmann et al., JCO 19:1641-1648, 2001). Grade ≥3 toxicity, as previously described in our study (Adra et al., JCO 35:1096-1102, 2017), occurred in 8 (25%) pts. There were two treatment-related deaths. Conclusions: HDCT+PBSCT is a safe and effective salvage therapy in pts with relapsed PMNSGCT with curative potential. In our opinion, these complicated patients are best managed at tertiary centers with expertise in medical oncology, stem cell transplantation, and thoracic surgical oncology.

Peri-treatment adverse events of primary mediastinal non-seminomatous germ cell tumors.

Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) are rare but life-threatening thoracic cancers. We report our experience from eight patients with peri-treatment adverse events. By analyzing changes in tumor extent, serum tumor markers, and pathologies between diagnosis and transfer, those events could be attributed to postbiopsy respiratory insufficiency, growing teratoma syndrome, secondary histiocytic malignancy, and PMNSGCT progression. Subjecting patients to respiratory therapy, conventional or high-dose chemotherapy, and surgery controlled the disease, with five of the eight patients surviving disease free. These outcomes indicate that integrated appropriate and timely approaches are important in tackling peri-treatment adverse events.

Survival Outcomes of Patients With Primary Mediastinal Germ Cell Tumors: A Retrospective Single-institutional Experience

Primary mediastinal non-seminomatous germ cell tumors (PMNSGCTs) are occasionally complicated by a hematologic malignancy, as with somatic-type malignant tumors called germ cell tumors with somatic-type malignancy (GCTSTM) and are known to have a poor prognosis. Data obtained between September 1997 and February 2020 for patients with mediastinal germ cell tumor at our institution were retrospectively analyzed. Key outcome measures included survival rates and the clinical features of non-seminoma cases. Of 16 patients, 9 had pure seminoma, and 7 had non-seminoma. At the median follow-up of 56.2 months, the 5-year survival rate was significantly higher in patients with seminoma (100%) than in those with non-seminoma (37%) (log-rank test, p=0.0153). Regarding PMNSGCT, two patients evolved into GCTSTM and three had concomitant hematological malignancies. Patients with PMNSGCTs, GCTSTM complications, and hematologic malignancies showed poor survival, suggesting the need for the development of treatment strategies.

Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor.

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients.

Abstract 5169: Tissue analysis of NAD(P)H: quinone oxidoreductase (NQO1) and catalase expression in patients with germ cell tumors (GCT)

Abstract Background: Testicular germ cell tumor (GCT) is the most common cancer in young men between 15 and 35 years of age. Cisplatin-based combination chemotherapy will cure 70% of patients with metastatic GCT. Patients who relapse can still be cured with salvage standard-dose or high-dose chemotherapy. However, about 15% of patients with relapsed/refractory GCT are incurable. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase elevated in several tumor types compared to normal tissue. NQO1 detoxifies quinones and reduces oxidative stress. NQO1 bioactivatable drugs induce DNA damage in cells overexpressing NQO1, but not in cells lacking it, hence delivering tumor-selective damage and cell death. Alterations in catalase expression can cause cytoprotection. The ratio of NQO1:catalase activities is presumed to be a predictive marker for therapeutic activity of NQO1 bioactivatable drugs. There is no existing data on NQO1 or catalase expression in GCTs. Methods: Patients with testicular or extra-gonadal GCT who had surgery between January 2016 and December 2018 were identified from the Indiana University Melvin and Bren Simon Cancer Center Tissue Bank database. Patients with non-seminomatous GCT (NSGCT) of testis or primary mediastinal NSGCT were selected and specimens obtained. Immunohistochemistry staining was performed on tumor tissue to determine the quantity and intensity of NQO1 and catalase expression. Results: NQO1 and catalase expression were determined in 16 patients. Thirteen specimens stained moderately to strongly positive for NQO1. Only 1 specimen stained negative. Conversely, no specimen stained strongly positive for catalase, and only 2 stained moderately positive. Fourteen specimens were catalase deficient or only mildly positive for catalase. The details of the immunostaining is summarized in the table below. Immunohistochemistry staining for NQO1 and catalase in GCTImmunostainNegative(0)Mildly positive (<10%)Moderately positive (10-50%)Strongly positive (>50%)NQO1Quantity01114Intensity0547Combined score1267CatalaseQuantity3472Intensity31120Combined score7720 Conclusions: NSGCTs appear to have high levels of NQO1 and deficiency of catalase. NQO1 bioactivatable agents could serve as a potential therapeutic approach in patients with refractory testicular GCTs. Citation Format: Neda Hashemi Sadraei, Nabil Adra, Constance Temm, Kenneth A. Kesler, Muhammad T. Idrees, David A. Boothman, Lawrence Einhorn. Tissue analysis of NAD(P)H: quinone oxidoreductase (NQO1) and catalase expression in patients with germ cell tumors (GCT) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5169.

Response to guadecitabine (SGI-110) combined with cisplatin and gemcitabine (GCG) in platinum refractory germ cell tumors (GCTs).

e17057 Background: Treatment options for platinum refractory GCTs are limited. Platinum resistance derives, in part, from tumour suppressor gene promotor methylation. In vitro, this reverses on co-administration of a DNA hypomethylating agent. Guadecitabine is a next generation hypomethylating agent. SPIRE is a phase Ib/IIa clinical trial to establish a GCG dose/schedule. Methods: We report 2 platinum refractory GCT patients (pts) treated (txd) in SPIRE with GCG (guadecitabine 20 mg/m2, SC, day (D) 1-5; cisplatin 70 mg/m2, IV, D8; gemcitabine 1000 mg/m2, IV, D8 + 15; filgrastim 300 μg, SC, D15-21; q21). Results: Pt 1: 21 yo man, testicular mixed GCT (seminoma/malignant teratoma intermediate). Prior tx: 2001, orchidectomy; 2005, 3 x BEP (bleomycin, etoposide, cisplatin) + retroperitoneal lymph node dissection. 2015, 2 x TI (paclitaxel, ifosfamide), 3 x TIP (cisplatin, ifosfamide, paclitaxel); 2016, 3 x HDCE (high dose carboplatin/ etoposide + autologous stem cell transplantation); 2017, 6 x GOP (gemcitabine, oxaliplatin, paclitaxel). In 2017, received 6 x GCG in SPIRE for CT confirmed lung metastases (mets) and rising β-hCG (human chorionic gonadotropin). Response: RECIST stable disease with metabolic CR on PET in lungs and > 90% β-hCG reduction. In Cycle 6, pt developed symptomatic brain mets, treated with WBRT (40Gy, 20#) + cyberknife to the six mets completed 2018. Since 2018, ongoing complete marker and radiologic (brain and systemic) remission (20 months). Pt 2: 44 yo man, primary mediastinal non-seminomatous GCT. Prior tx: 2008, 4 x BEP + mediastinal mass resection; 2015, 4 x TIP; 2016, 1 x HDCE. In 2017, received 5 x GCG in SPIRE for a PET avid mediastinal/pulmonary relapse and AFP (alpha-fetoprotein) rise. Response: RECIST stable and > 50% AFP reduction for 6 months (subsequent progression with intracerebral metastasis). Treatment was well tolerated. Grade 4 neutropenia/ thrombocytopenia occurred in both and febrile neutropenia in pt 1. Both required a 25% dose reduction in Cis/Gem. Conclusions: GCG produced exceptional clinical responses in both platinum refractory GCT pts. Prospective evaluation is warranted. Clinical trial information: 16332228.

Clinical features and outcomes of secondary somatic malignancy (SSM) associated with primary mediastinal nonseminomatous germ cell tumors (PM-NSGCT).

531 Background: The incidence of secondary somatic malignancy (SSM) arising from teratoma is increased in 2 settings; late relapse and primary mediastinal nonseminomatous germ cell tumors (PM-NSGCT). Here, we report the clinical features and outcomes of patients with SSM in the setting of PM-NSGCT. Methods: Between 1985 and 2018, 29 patients with PM-NSGCT and SSM who had sufficient clinical follow-up to evaluate outcome were identified. Clinical and pathologic parameters were reviewed. The Kaplan-Meier method was used to estimate overall survival (OS) from time of SSM diagnosis and the log rank test to compare estimates. Results: Median age was 28 years (range 18-59) and all patients were male. Most presented with local symptoms (n=24, 83%), elevated tumor markers (n=26, 90%), and disease isolated to the mediastinum (n=25, 86%). A total of 39 SSM histologies were present in the 29 cases, with 8 (28%) having 2 (n=6) or 3 (n=2) SSM histologies; 25 (86%) also had viable non-teratomatous GCT in the mediastinal mass. Sarcoma was found in all 29 cases including rhabdomyosarcoma (n=15), angiosarcoma (n=6), sarcoma NOS (n=5), spindle cell (n=4), PNET (n=3), and other (n=3). Non-sarcoma histologies (n=1 each) included AML, SCC, and neuroblastoma. Most patients received GCT-directed chemotherapy followed by an attempt at surgical resection (90%). With a median follow-up of 2 years for survivors, median OS was 1.8 years (95% CI 0-3.9 years), with 18 patients succumbing to disease. Complete surgical resection was achieved in 23 men (79%) and was associated with superior OS (3.1 vs. 0.3 years, p=0.005). At relapse or progression, 11 received SSM histology-directed and 7 GCT-directed chemotherapy with no difference in OS (1.3 vs. 1.2 years, p=0.993). 7 patients developed SSM in the form of leukemia, a finding associated with significantly inferior OS (0.3 vs. 3.0 years, p=0.009). Conclusions: Sarcoma is the predominant SSM histology associated with PM-NSGCT and portends a poor prognosis even with initially localized disease. Complete resection following chemotherapy is critical to achieving long-term survival whereas SSM in the form of leukemia portends especially poor outcome.

MTE 23.02 Mediastinal Germ Cell Tumor

MTE 23.02 Mediastinal Germ Cell Tumor

A Suggested Prognostic Reclassification of Intermediate and Poor-Risk Nonseminomatous Germ Cell Tumors

BackgroundThe International Germ Cell Cancer Collaborative Group (IGCCCG) classification has been used since 1997 to allocate metastatic germ cell tumors (GCTs), but its applicability needs an update. We aimed to revisit the outcomes of intermediate and poor risk nonseminomatous GCTs (NSGCTs). Patients and MethodsIndividual patient-level data from the databases of 2 institutions were collected. Outcomes of consecutive patients who received first-line chemotherapy from 1990 to 2014 were used. The Kaplan–Meier method was used to estimate relapse-free (RFS) and overall survival (OS). Cox regression analyses were used to evaluate potential prognostic factors of RFS and OS univariably. Forward stepwise selection was used to construct a multivariable model. A risk factor (RF) model was then constructed and compared with IGCCCG classification using the concordance statistics (CS). ResultsA total of 647 patients were identified. Four RFs for OS in the multivariable model were identified: primary mediastinal NSGCT (P < .001), brain metastases (P < .001), lung metastases (P = .016), and age at the time of diagnosis (P = .003). CS were improved on the basis of the number of RF (0, 1, 2, and 3 or 4) compared with IGCCCG (RFS: 0.63 vs. 0.58; OS: 0.65 vs. 0.59). For intermediate risk, there were no differences between 3 (n = 25) and 4 cycles of cisplatin, etoposide, and bleomycin (BEP; n = 159) or BEP × 3 + etoposide and cisplatin (EP) × 1 (n = 31) for RFS (P = .35) and OS (P = .061). ConclusionAn improved risk stratification was obtained for intermediate and poor risk GCTs. Our reclassification system might provide an aid for a reclassification attempt of all GCT patients. Our prognostic model might be offered to clinicians to improve their ability to assess patient prognosis, enhance stratification, and inform patients.

Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014

Based on the risk stratification from the International Germ Cell Cancer Collaborative Group (IGCCCG), only 14% of patients with metastatic germ-cell tumors (GCT) had poor-risk disease with a 5-year progression-free survival (PFS) rate of 41% and a 5-year overall survival (OS) rate of only 48%. This analysis attempts to identify prognostic factors for patients with poor-risk disease. We conducted a retrospective analysis of all patients with GCT diagnosed and treated at Indiana University from 1990 to 2014. Clinical and pathological characteristics were available for all patients and all of them were treated with cisplatin-etoposide-based chemotherapy. Cox proportional hazards models were used to target significant predictors of disease progression and mortality. A significance level of 5% was used in the analysis. We identified 273 consecutive patients with poor-risk GCT (PRGCT). Median follow-up time was 8 years (range 0.03-24.5). The 5-year PFS and OS rates were 58% [95% confidence interval (CI) 51% to 63%] and 73% (95% CI 67% to 78%), respectively. In multivariate survival analyses, multiple risk factors were associated with disease progression, including liver metastasis, brain metastasis, primary mediastinal nonseminomatous GCT (PMNSGCT), and elevation in logarithmic β-hCG. Significant predictors of mortality were PMNSGCT [hazard ratio (HR) 4.63, 95% CI 2.25-9.56; P < 0.001], brain metastasis (HR 3.30, 95% CI 1.74-6.23; P < 0.001), and increasing age (HR 1.03, 95% CI 1.01-1.06; P = 0.02). Patients with PMNSGCT, brain metastasis, or with increasing age are at higher risk of death than their counterparts. This contemporary cohort (1990-2014) of 273 patients with PRGCT had improved PFS and OS outcomes than those from the historical IGCCCG group of patients (1975-1990).

Phase II Clinical Trial of Oxaliplatin and Bevacizumab in Refractory Germ Cell Tumors

Salvage chemotherapy has curative potential in germ cell tumors (GCTs). However, novel therapies are still needed for patients failing to be cured with standard salvage chemotherapy. Bevacizumab in combination with chemotherapy has clinical activity in many solid tumors. This is the first study of bevacizumab with oxaliplatin in refractory GCT patients. Patients with metastatic GCT with progressive disease after second-line or later salvage chemotherapy were eligible. Prior high-dose chemotherapy and paclitaxel and/or gemcitabine were required unless primary mediastinal nonseminomatous GCT or late relapse. Patients received oxaliplatin-85 mg/m and bevacizumab-10 mg/kg every 2 weeks for a maximum of 14 cycles. Twenty-nine patients were enrolled and evaluated. Nine patients were late relapses and 5 had primary mediastinal nonseminomatous GCT. Median number of prior chemotherapy regimens was 4. There was no grade 4 and only 1 grade 3 toxicity. Although the primary endpoint of 12 months disease-free survival was not achieved, 8 patients (27.6%) had objective response including 1 complete remission. Median duration of remission was 5 months (range, 4 to 22 mo). Oxaliplatin plus bevacizumab was well tolerated in heavily pretreated GCTs with manageable adverse events. There was modest clinical activity but only 1 patient achieved complete remission.

A Prognostic Model Including Pre- and Postsurgical Variables to Enhance Risk Stratification of Primary Mediastinal Nonseminomatous Germ Cell Tumors: The 27-Year Experience of a Referral Center

BackgroundPrimary mediastinal germ cell tumors (PMGCTs) poorly benefit from chemotherapy and half of patients die because of disease progression. Enhancing the risk stratification might result in tailoring a more personalized treatment strategy from the time of diagnosis. Patients and MethodsBetween the years 1985 and 2012, 86 patients with PMGCT were treated at our center. Cox proportional hazards regression analysis was conducted in the population of nonseminomas to examine the prognostic effect of candidate factors on progression-free and OS. OS curves were compared using the Kaplan–Meier method and the log-rank test. ResultsMean age was 29.8 years (range, 15-63 years). Twenty-five patients (29.1%) had lung and 8 (9.3%) liver, bone, or brain metastases. Twelve patients (13.9%) received upfront high-dose chemotherapy and 45 patients (52.3%) underwent surgery after chemotherapy. Cox analyses included 61 evaluable primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs). The final model of factors indicating a poor prognosis included the combination of surgery and histological response (overall P = .011) and lung metastases (hazard ratio, 3.03; 95% confidence interval, 1.12-8.15; P = .028). The model showed a bootstrap-corrected Harrel c-statistic for OS of 0.66. A risk stratification model based on the combination of these factors and accounting for a 50% 5-year survival cutoff identified 2 groups (poor prognosis, n = 33 vs. good prognosis, n = 28) with distinct OS curves (P < .001). Preoperative serum tumor marker level was not associated with the final histology (P = .853, χ2 test). Results were limited by small numbers. ConclusionPatients with PMNSGCT included 2 subpopulations with distinct prognosis, and therapeutic improvements are needed for patients with poor-risk features.

Enhancing risk stratification in primary mediastinal nonseminomatous germ cell tumors (PMNSGCT): A 27-year experience at a tertiary cancer center.

373 Background: Mediastinal GCTs and PMNSGCTs poorly benefit from CT and half of patients (pts) still die for disease. Enhancing the risk stratification may result in tailoring a personalized treatment strategy since diagnosis. Methods: Between 1985 and 2012, 87 pts with PM-GCT were treated at our center. Of them, pure seminomatous histology was excluded. Cox proportional hazards regression analysis was conducted to examine the prognostic impact of these candidate factors on overall survival (OS): type of 1st-line CT (high [HDCT] vs conventional dose [CDCT]), post-CT surgery, type of baseline elevated serum tumor marker (STM), presence of lung or liver-bone-brain metastases (LBB), STM response (still elevated vs normal or normalized), and histology (viable cancer [VC] vs necrosis/teratoma [NT]). OS curves were compared by Kaplan Meier method with the log-rank test. Results: The study included 68 cases with PMNSGCT. Median age was 28.5 yrs (IQR: 23-35). 12 pts (17.7%) presented with mediastinal syndrome, 23 (33.8%) had lung and 7 (10.3%) LBB metastases. 12 pts received upfront HDCT and 45 pts (66.2%) underwent post-CT surgery. The final model of poor prognostic factors included no surgery (HR: 8.74, 95%CI, 1.77-43.01), surgery + VC (HR: 6.97, 95%CI, 1.46-33.30), and lung metastases (HR: 2.92, 95%CI, 0.99-8.64). The model demonstrated moderate discriminatory ability for OS (c-statistic=0.68). A risk stratification model based on the combination of these factors and accounting for a 50% five-year survival cutoff identified 2 groups (poor prognosis, N=28 vs good prognosis, N=26) with distinct overall survival curves (p&lt;0.001). Pre-operative STM and final histology were not associated (p=0.574 at Chi squared test). 5-yr OS after receiving 2nd line CT (n=25) was 18.7% (95%CI, 7.9-44.5). Results are limited by small numbers. Conclusions: Pts with PMNSGCT classified as having a good prognosis in this model had a fairly high survival estimate, while a strategy of consolidation CT for pts with poorest risk features warrants investigation, once the model is confirmed. The effect of surgery on survival was independent of post-CT STM, which also poorly predicted final histology.

Salvage high-dose chemotherapy for primary mediastinal nonseminomatous germ cell tumors: Single institute experience.

e15503 Background: Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) bear a worse prognosis than stage-matched testicular primaries, with a five year survival rate of 50%. In contrast to relapsed testicular NSGCT, retrospective analyses have not shown benefit to high-dose chemotherapy and autologous stem-cell transplant (HDCT/ ASCT) in PMNSGCT patients. Since publication of these studies, advancements in treatment regimens and supportive care have occurred, with emerging evidence suggesting HDCT/ASCT may benefit patients with PMNSGCT - both as first-line sequential treatment after standard-dose chemotherapy and at relapse. Objectives: Review the experience of patients presenting with PMNSGCT to a regional referral cancer center as a quality control assessment. Assess the benefit of salvage HDCT/ASCT to relapsed PMNSGCT patients. Methods: Patients presenting with PMNSGCT from 1980-2010 were abstracted from a Provincial cancer registry and records were retrospectively reviewed. Data includes patient demographics, cancer treatments and outcomes. Results: Fourteen male patients (median age 29; range: 17-54 years) with PMNSGCT were identified. Seven of 13 (54%) patients remain continuously disease-free with 1 patient lost to follow-up. Mean duration of follow-up in these patients is 57 (34-100) months. Three patients died having received ≤ 1 cycle of chemotherapy; exclusion of these patients results in a treatment failure rate of 30%. Six of the 7 cancer-free patients required salvage surgery. Three patients received tandem HDCT/ASCT (carboplatin 550 mg/m2 and etoposide 150 mg/m2daily for 4 days) at subsequent relapse despite second-line chemotherapy. Two remain disease-free at 45 and 74 months respectively, while the third patient died of their disease 14 months post-transplant. Conclusions: Our experience with PMNSGCT is generally consistent with published outcomes in that ≈50% of patients are cured. However, in this series 2/3 heavily pretreated patients were salvaged with HDCT/ASCT, refuting the published historical experience. This study is limited by its small sample size, but provides impetus to re-examine HDCT/ASCT for high-risk patients.

Salvage Therapy with High-Dose Chemotherapy and Peripheral Blood Stem Cell Transplant in Patients with Primary Mediastinal Nonseminomatous Germ Cell Tumors

Salvage therapy with high-dose chemotherapy (HDCT) and bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) has curative potential in patients with recurrent germ cell tumor. However, patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs) have had poor results with any form of salvage chemotherapy including HDCT. We switched from BMT to PBSCT in 1996. One hundred sixteen of 184 patients (63%) with recurrent or refractory germ cell tumors treated from 1996 to 2004 were alive and continuously disease-free. PMNSGCTs were excluded from that study because of poor results in the patient population with HDCT and BMTs. In 2006, we resumed treating patients with recurrent PMNSGCT with 2 consecutive courses of HDCT consisting of carboplatin 700 mg/m2 × 3 plus etoposide 750 mg/m2 × 3 and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells with a second course 3 to 4 weeks later. Twelve patients were treated: 11 as initial salvage chemotherapy and 1 as fourth-line therapy. Eight of the 12 patients had major thoracic resections at the time of the relapse after initial chemotherapy. Three of the 12 patients achieved complete remission (CR; 10, 15, and 50 months' duration). One patient remains continuously with no evidence of disease (NED) at 50 months. An additional patient is currently NED at 52 months with HDCT and subsequent surgery. Median survival for the 12 patients was 11 months (range, 4-52 months). Results with tandem transplant for recurrent PMNSGCT remain poor compared to primary testis cancer, but durable CR and probable cure can be achieved in a small subset of patients with PMNSGCT. In our opinion, salvage surgical resection if anatomically feasible is the preferred option for patients with PMNSGT progressing after initial chemotherapy.

Phase II study of everolimus (E) in refractory germ cell tumors (GCTs).

TPS4677 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients (pts) develop disease recurrence. Because of insufficient results in the treatment of relapsed GCTs, evaluation of new treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in GCTs development, but is associated with disease progression. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these pts could have greater benefit from mTOR inhibition. Methods: In December 2011, National Cancer Institute of Slovakia launched an one arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of E in pts with refractory GCTs. The primary objective is to determine the efficacy of E in patients with refractory GCTs. Secondary objectives includes favourable response rate, time to progression and safety. The pts with radiological and/or serological proof of relapsed GCTs, who were not amenable to be cured by chemotherapy or surgery and who failed at least two platinum-based regimens or one platinum regimen in case of platinum-refractory disease or primary mediastinal non-seminomatous GCTs were eligible. All other standard inclusion and exclusion criteria for study of salvage treatment in refractory GCTs pts were applied. E will be administered at a dose of 10mg daily until progression or unacceptable toxicity. Assuming a response rate of clinical interest of ≥40%, a minimal response rate of 20%, a probability of 5% for rejecting an active drug, and a probability of 20% to further evaluate an ineffective drug, 18 pts will be enrolled into the first cohort. If &lt;4 responses will be observed, the study will be terminated, otherwise, it will be continued with a second cohort of 20 pts.

Resection of Primary Mediastinal Non-Seminomatous Germ Cell Tumors: A 28-Year Experience at Memorial Sloan-Kettering Cancer Center

Surgical resection of residual tumor mass in responders to platinum-based chemotherapy has evolved as the preferred treatment of primary mediastinal nonseminomatous germ cell tumors (PMNGCTs). We reviewed a single institution's operative experience with these rare tumors. We reviewed charts of patients resected for PMNGCT at Memorial Sloan-Kettering Cancer Center between July 1980 and April 2008. Analyses included Kaplan-Meier survival with univariate log-rank comparisons and Cox multivariate regression. Fifty-seven patients were identified and followed up for a median of 5.3 years. Fifty-four of them received platinum-based preoperative chemotherapy, and 28 (49%) had limited stage I/II disease. Preoperative tumor markers normalized or decreased in 79% of patients. The most common surgical approach was anterolateral thoracotomy with partial sternotomy ("hemiclamshell," 38.6%). An R0 resection was achieved in 91% of the patients with a major morbidity of 17.5% and no postoperative deaths. The median overall survival was 31.5 months. Factors correlating with better survival on univariate analyses were necrosis or teratoma versus residual cancer on final pathology (p = 0.001), R0 resection (p = 0.03), normalized or decreased postchemotherapy/preoperative tumor markers (p < 0.001), normalized postoperative tumor markers (p = 0.004), stage I/II disease (p = 0.03), and surgery after 2000 versus 1980-1999 (p = 0.01). An exploratory multivariate analysis suggests that normalized or decreased postchemotherapy/preoperative tumor markers is the strongest independent predictor of improved survival. In a cohort of PMNGCT patients in which 91% of the patients underwent complete posttherapy resection, response to chemotherapy, measured by normalized or decreased preoperative tumor markers, was the strongest predictor of improved survival.

Salvage therapy with high-dose chemotherapy (HDCT) and peripheral blood stem cell transplant (PBSCT) in patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCT).

e15119 Background: Salvage therapy with high dose chemotherapy (HDCT) and bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) has curative potential in patients with recurrent germ cell tumor. Patients with primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) have had poor results with any form of salvage chemotherapy including HDCT. From 1986 to 1996, we included 13 patients with PMNSGCT in our series treated with HDCT and BMT. All died from progressive cancer. Methods: We switched from BMT to PBSCT in 1996, allowing more rapid engraftment and earlier initiation of the second course of HDCT with tandem transplant. 116 of 184 (63%) patients with recurrent or refractory germ cell tumors treated from 1996 to 2004 were alive and continuously disease free (NEJM 357:340-348, 2007). PMNSGCT patients were excluded. In 2006, we resumed treating patients with recurrent PMNSGCT with salvage HDCT with PBSCT. Carboplatin 700mg/m2 x 3 plus etoposide 750mgs/m2 x3 were given with second course 3-4 weeks later. Results: 12 patients were treated, 11 as initial salvage chemotherapy and one as 4th line therapy. Eight patients had major thoracic resections prior to HDCT. 3 of the 12 achieved complete remission (52, 12 and 12 weeks duration) but all have relapsed. 10 of the 12 have died; one is lost to follow-up at 44 weeks, and one patient is currently disease free at 176 weeks from HDCT, treated with subsequent salvage surgery. However, he developed secondary acute myeloid leukemia and underwent allogeneic BMT. Median survival for the 12 patients was 41 weeks (range 14-176). Conclusions: In our experience with tandem transplant, recurrent PMNSGCT continues to have a low probability for cure.

Phase II clinical trial of oxaliplatin and bevacizumab in refractory metastatic germ cell tumors (GCT).

4579 Background: Salvage chemotherapy with Ifosfamide based regimen or high dose chemotherapy (HDCT) has curative potential in GCTs. We still need novel therapies for patients where cure is not possible. Oxaliplatin has single agent activity in refractory GCTs. Bevacizumab in combination with chemotherapy has activity in many solid tumors but has not been studied in GCTs. This is the first study of bevacizumab in refractory GCT patients. Methods: Patients with serologically or histologically proven metastatic GCT who have failed cisplatin based combination chemotherapy and progressed on salvage therapy were eligible. Prior HDCT and paclitaxel plus gemcitabine were required unless late relapse or primary mediastinal non-seminomatous GCT (NSGCT). Oxaliplatin was given 85 mg/m2 and bevacizumab 10 mg/kg every 2 weeks with a maximum of 14 cycles. Results: 25 total patients have been enrolled with 24 evaluable and 1 too early to evaluate. 9 were late relapses and 5 with primary mediastinal NSGCT. Median number of previous chemotherapies was 4 including 13 with prior HDCT. Median number of cycles administered was 5. There were 7 (29%) objective responders. Median duration of response was 6 months (range 4 to 22 months). Of these 7 patients 3 had normalization of HCG and/or AFP. One additional patient had serologic response (>1 log reduction in HCG) for 5 months with stable radiographic lesions. Median survival was 8 months (range 2 to 40 months). Four patients had Grade 3 adverse events (peripheral neuropathy, hypertension, seizures and DVT). Conclusions: Oxaliplatin plus bevacizumab has promising activity in heavily pretreated GCTs with manageable toxicity.