Poor Prognosis Germ Cell Tumors Research Articles

Paraneoplastic Hyperthyroidism in Advanced Testicular Non-Seminomatous Germ Cell Tumors: Prevalence and Clinical Management

Introduction: Paraneoplastic hyperthyroidism (PH) has been reported in patients with testicular germ cell tumors (GCTs), sporadically. This disorder is caused by extremely elevated serum levels of beta-human chorionic gonadotropin (bHCG). To date, little is known about the prevalence of PH, and its clinical features are poorly understood. The aim of the present study was to analyze the relative frequency and clinical features of PH in GCTs and evaluate their effects on therapeutic outcomes. Methods: A cohort of 438 patients treated for testicular GCT from 2017 to 2023 was retrospectively analyzed for histology, age, clinical stage, and presence of PH. The clinical features of the patients with PH were evaluated descriptively. The relative frequency of PH was compared among the subgroups using descriptive statistical methods. Results: Three patients with PH were identified; all had clinical symptoms of hyperthyroidism, suppressed serum levels of thyroid-stimulating hormone (TSH), and increased levels of tri-iodothyronin (fT3). All the patients had advanced, metastasized, and non-seminomatous GCTs. Serum bHCG levels ranged from 225,00 U/L to 1,520,000 U/L. The prevalence of PH was 0.7% in the entire GCT population and 60% in those with very high bHCG serum levels. All the patients received standard cisplatin-based chemotherapy along with thyrostatic treatment. The clinical symptoms of the hyperthyroidism rapidly disappeared. TSH levels normalized with decreasing bHCG levels. The PH treatment did not affect the therapeutic outcomes of the patients. Conclusion: PH may occur in 0.7% of all patients with GCT but may be present in up to 60% of patients with very high levels of bHCG. Measuring serum levels of TSH and fT3 should be performed in addition to routine diagnostic measures in all patients with poor prognosis GCTs. Thyrostatic medication is recommended for patients with the clinical symptoms of hyperthyroidism. Early recognition of hyperthyroidism and prompt intervention will reduce comorbidity and help optimize therapeutic outcomes.

DNA damage levels in peripheral blood mononuclear cells before and after first cycle of chemotherapy have comparable prognostic values in germ cell tumor patients.

Germ cell tumors (GCTs) represent the most frequent solid malignancy in young men. This malignancy is highly curable by cisplatin (CDDP)-based chemotherapy. However, there is a proportion of patients having a poor prognosis due to refractory disease or its relapse. No reliable biomarkers being able to timely and accurately stratify poor prognosis GCT patients are currently available. Previously, we have shown that chemotherapy-naïve GCT patients with higher DNA damage levels in peripheral blood mononuclear cells (PBMCs) have significantly worse prognosis compared to patients with lower DNA damage levels. DNA damage levels in PBMCs of both chemotherapy-naïve and first cycle chemotherapy-treated GCT patients have been assessed by standard alkaline comet assay and its styrene oxide (SO)-modified version. These levels were correlated with clinico-pathological characteristics. We re-confirm prognostic value of DNA damage level in chemotherapy-naïve GCT patients and reveal that this prognosticator is equally effective in GCT patients after first cycle of CDDP-based chemotherapy. Furthermore, we demonstrate that SO-modified comet assay is comparably sensitive as standard alkaline comet assay in case of patients who underwent first cycle of CDDP-based chemotherapy, although it appears more suitable to detect DNA cross-links. We propose that DNA damage levels in PBMCs before and after first cycle of CCDP-based chemotherapy are comparable independent prognosticators for progression-free and overall survivals in GCT patients. Therefore, their clinical use is highly advised to stratify GCT patients to identify those who are most at risk of developing disease recurrence or relapse, allowing tailoring therapeutic interventions to poor prognosis individuals, and optimizing their care management and treatment regimen.

Prognostic value of circulating cell-free DNA in association with choriocarcinoma syndrome development in patients with germ cell tumors.

424 Background: Germ cell tumors (GCTs) represent a highly curable malignancy; however, a small portion of patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with high mortality rate shortly after the chemotherapy start. The aim of this study was to assess the prognostic value of circulating cell-free – extracellular DNA (ecDNA) in patients with GCTs and its association with CS development and outcome. Methods: This study included 23 patients with poor-prognosis GCTs treated from November 2002 to May 2018 at the National Cancer Institute in Slovakia. Pre-treatment total ecDNA, nuclear (ncDNA) and mitochondrial DNA (mtDNA) were quantified in plasma using fluorometry and real-time PCR and analyzed in association with CS development and survival. Results: Four (17%) patients developed CS and all of them died due to ARDS shortly after the chemotherapy start. Total ecDNA, but not ncDNA or mtDNA were associated with CS development. Four out of 11 (37%) patients with high plasma ecDNA developed CS compared to 0 out of 12 (0%) patients with low plasma ecDNA (p = 0.037). In univariate analysis, higher concentration of ecDNA also positively correlated with ECOG PS ≥2, metastatic lung involvement ≥50%, weight loss ≥10%, hemoglobin ≤100 g/l, and neutrophil to lymphocyte ratio ≥ 3.3 at the time of presentation. Patients with low ecDNA had significantly better PFS (HR = 0.35, 95% CI 0.11-1.17, p = 0.043) and OS (HR = 0.26, 95% CI 0.06-1.20, p = 0.032) compared to patients with high pretreatment concentration of ecDNA. Conclusions: In this study we have proved that quantitative analysis of plasma ecDNA has prognostic value for CS development in patients treated due to GCTs. Further research focused on the biology of ecDNA may help us to understand its role as a biomarker, but also a potentially treatable pathogenic factor for choriocarcinoma syndrome development.

713P Assessment of bleomycin pulmonary toxicity in men with poor-prognosis non-seminomatous germ-cell tumors treated in the GETUG 13 phase III trial

In 2014, the GETUG 13 trial has established the role of early intensified treatment for men with poor prognosis germ-cell tumors (GCT) and unfavorable tumor marker decline (Fizazi K, Lancet Oncol 2014). Patients with unfavorable marker decline were randomized after 1 cycle of BEP to receive either 3 additional BEP or dose-dense chemotherapy with personalized cumulative doses of bleomycin (potentially exceeding the 300 mg recommended threshold) based on serial lung function assessments. We assessed pulmonary toxicity of this strategy.

Long-term outcomes with intensive induction chemotherapy (carboplatin, bleomycin, vincristine and cisplatin/bleomycin, etoposide and cisplatin) and standard bleomycin, etoposide and cisplatin in poor prognosis germ cell tumours: A randomised phase II trial (ISRCTN53643604)

BackgroundUp to 50% of men with poor prognosis, non-seminoma germ cell tumours (GCTs) die with standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. An intensive regimen, CBOP/BEP (carboplatin, bleomycin, vincristine and cisplatin/BEP), met response targets in a randomised, phase II trial (74% complete response or partial response marker negative, 90% confidence interval (CI) 61%–85%). AimTo assess long-term outcomes and late toxicity associated with CBOP/BEP. MethodsPatients with poor prognosis extracranial GCT were randomised to 4xBEP or CBOP/BEP (2xCBOP, 2xBO, 3xBEP with 15,000iu of bleomycin). Low-dose, stabilising chemotherapy before entry was permitted. Response rates (primary outcome) were reported previously. Here, we report secondary outcomes: progression-free survival (PFS), overall survival (OS) and late toxicity. Prognostic factors and the impact of marker decline are assessed in exploratory analysis. ResultsEighty-nine patients (43 CBOP/BEP) were randomised. After median 63 months follow-up, 3-year PFS is 55.7% (95% CI: 39.7%, 69.0%) for CBOP/BEP and 38.7% (95% CI: 24.7%, 52.4%) for BEP (hazard ratio [HR]: 0.59 (0.33, 1.06), p = 0.079). Three-year OS is 65.0% (48.8%, 77.2%) and 58.5% (43.0%, 71.2%), respectively (HR: 0.79 (0.41, 1.52), p = 0.49). Twelve-month toxicity was affected by subsequent treatments, with no clear differences between arms. Stabilising chemotherapy was associated with poorer PFS (HR: 2.09 (1.14, 3.81), p = 0.017), whereas unfavourable marker decline, in 60 (70%) patients, was not. ConclusionAlthough not powered for PFS, results for CBOP/BEP are promising. Impact on OS was less clear (and will be affected by subsequent therapy). Further study in an international phase III trial is warranted. Trial registrationISRCTN 53643604.

GCT-67 - Long term follow-up of the MRC TE23 randomized phase II trial of intensive induction chemotherapy (CBOP/BEP) in poor prognosis germ cell tumours (GCT) (CRUK/05/014; ISRCTN53643604)

GCT-67 - Long term follow-up of the MRC TE23 randomized phase II trial of intensive induction chemotherapy (CBOP/BEP) in poor prognosis germ cell tumours (GCT) (CRUK/05/014; ISRCTN53643604)

915P - Long term follow-up of the MRC TE23 randomized phase II trial of intensive induction chemotherapy (CBOP/BEP) in poor prognosis germ cell tumours (GCT) (CRUK/05/014; ISRCTN53643604)

Background: Up to 50% of men with poor prognosis non-seminoma GCT die with standard BEP chemotherapy. An intensive regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), met response targets in a phase II, multicentre, open-label, randomized trial (74% with complete response or partial response marker negative, 90% CI 61% to 85%; primary outcome). Here, we report long term outcomes and prognostic factors. Methods: Patients with extracranial GCT and IGCCCG poor prognosis features were randomised to 4xBEP or CBOP/BEP (2xCBOP, 2xBO, 3xBEP with bleomycin dose 15,000iu). Low-dose, stabilising chemotherapy prior to entry was permitted. This analysis focuses on progression-free survival (PFS), overall survival (OS) and toxicity (all secondary outcomes), and exploratory analysis of prognostic factors and the impact of marker decline (as defined in GETUG13). Results: 89 patients (43 CBOP/BEP) were randomised. After median 63 months follow-up, 3-year PFS is 55.7% (95% CI 39.7%, 69.0%) for CBOP/BEP arm, 38.7% (24.7%, 52.4%) for BEP (HR 0.59 (0.33, 1.06), p = 0.079). 3-year OS is 65.0% (48.8%, 77.2%) and 58.5% (43.0%, 71.2%) respectively (HR 0.79 (0.41, 1.52), p = 0.49). 12-month toxicity was affected by subsequent treatments, with no clear differences between arms. There was no grade ≥3 toxicity in the CBOP/BEP arm. In multivariate models, use of pre-protocol chemotherapy was the only factor associated with poorer PFS (HR2.09 (1.14, 3.81), p = 0.017). Mediastinal primary (HR 2.13 (1.02, 4.46), p = 0.045) and use of pre-protocol chemotherapy (HR 3.40 (1.74, 6.63), p < 0.001) were associated with poorer OS. Unfavourable marker decline, in 60 (70%) patients, was not associated with other prognostic factors, nor with long term outcomes (HR 0.82 (0.44, 1.53), p = 0.54 for PFS). Conclusions: The trial was not powered to compare PFS and OS, but PFS results for CBOP/BEP are promising, and similar to the intensive arm of GETUG13. Impact on OS was less clear (and will be affected by subsequent therapy). Use of pre-protocol chemotherapy was associated with poorer outcomes. Further study in an international phase III trial is warranted. Clinical trial identification: ISRCTN53643604. Legal entity responsible for the study: Medical Research Council, UK. Funding: Cancer Research UK (grant no CRUK/05/014). Disclosure: R.A. Huddart: Stock or other ownership interests: Cancer Centre London LLP; Consulting or advisory role: MSD, Roche, Bristol-Myers Squibb; Speaker’s bureau: Roche, Elekta; Research funding: MSD, Elekta; Travel expenses: Roche, MSD. All other authors have declared no conflicts of interest.

Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases

BackgroundThe GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. MethodsWe conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. ResultsWith a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. ConclusionsBrain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2–3 months of chemotherapy.

Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors (GCT).

4504Background: Until 2014, standard treatment for poor-prognosis GCT was 4 BEP plus surgery and cure was achieved in only 50% of patients (pts) (IGCCCG 1997). The tumor marker decline rate identif...

Clinical Outcomes of Metastatic Poor Prognosis Germ Cell Tumors: Current Perspective From a Referral Center

BackgroundSurvival estimates with first-line treatment for patients with metastatic poor prognosis germ cell tumors (GCT) are still suboptimal in the literature. We conducted a retrospective study to evaluate the outcome of patients referred to our tertiary cancer center. Patients and MethodsA retrospective analysis was conducted on patients who received at least first-line chemotherapy at our center. Distribution of clinical characteristics was evaluated in the periods < 1997, 1997 to 2001, 2001 to 2006, and 2007 to 2013. The Kaplan–Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariable and multivariable Cox models with prespecified clinical variables were undertaken for PFS and OS. All tests and confidence intervals were 2-sided and set at a P = .05 level of significance. ResultsBetween 1982 and 2013, 168 patients were identified. The median age was 27 years (interquartile range [IQR], 22-34). The presence of liver, bone, or brain metastases trended to greater incidence from 1997 onward (27.5% < 1997 to 55.6% in 2007-2013; χ2P = .054). Median follow-up was 102 (IQR, 63-166) months. Global 5-year PFS was 48.5% (95% confidence interval [CI], 41.5-56.8) and OS was 63.2% (95% CI, 56.0-71.2). In multivariable analysis, treatment period was not significantly associated with either PFS (overall P = .229) or OS (overall P = .216). ConclusionIn this single-center series of consecutive poor prognosis GCT we could observe greater PFS and OS than the historical estimates. This observation was independent from the period of treatment. Based on the present results, studies focused on improving the outcome in the sole poor-risk cohort should be discouraged. Results were biased by their retrospective quality.

High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study

BackgroundIn the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). Patients and methodsPatients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m2), 2 courses of cisplatin and HD-etoposide (2.4 g/m2) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. ResultsFrom December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7–165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8–72.8] and 54.8% (95% CI 41.6%–72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9–79.0) and 59.3% (95% CI 46.1–76.3). One toxic death (PEB arm) was recorded. ConclusionsThe study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. ClinicalTrials.govNCT02161692.

Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial

Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve progression-free survival for patients with germ-cell tumours. In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin [20 mg/m(2) per day for 5 days], etoposide [100 mg/m(2) per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18-21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m(2) over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m(2) over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m(2) over 2 h on day 1), intravenous ifosfamide (2 g/m(2) over 3 h on days 10, 12, and 14), plus mesna (500 mg/m(2) at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10-14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00104676. Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49-68) in the Unfav-dose-dense group versus 48% (38-59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44-1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57-81) in the Fav-BEP group (HR 0·66, 95% CI 0·49-0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3-4 neurotoxic events (seven [7%] vs one [1%]) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1-2 febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (one [1%] in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. Institut National du Cancer (Programme Hospitalier de Recherche Clinique).

859P - Clinical Outcomes of Poor Prognosis Germ Cell Tumors (Gct): an Analysis of a Series from a Single Referral Center

ABSTRACT Aim: Outcomes of first-line treatment (Tx) for patients (pts) with metastatic poor prognosis GCT are still suboptimal in literature. However, the low incidence of disease and the increasing effectiveness of salvage therapy are issues against further clinical research in the field. We conducted a retrospective study to evaluate the impact of Tx period on prognosis of pts referred to our tertiary cancer center. Methods: A retrospective analysis was conducted on pts receiving at least first-line chemotherapy (CT) at our center. Distribution of frequencies of clinical characteristics were evaluated in the periods 1000 IU/ml, HCG > 1000 IU/l. All tests and confidence intervals were two-sided and set at p = 0.05 level of significance. Results: Between the years 1982 and 2013, 168 pts have been identified. Median age was 27 yrs (IQR: 22-34). No clinical factor had significantly different distribution over time, only LBB metastases trended to higher frequency from 1997 onwards (27.5% Conclusions: In this single-center series of poor prognosis GCT we could not demonstrate an effect on Tx period on survival. The slight differences in PFS on UVA are likely due to modest discrepancies in distribution of clinical variables (LBB). The global picture is that of a stable and very high cure-rate. Based on these results, attempts to improve the outcome exclusively in this field should be discouraged. Results are biased by their retrospective quality. Disclosure: All authors have declared no conflicts of interest.

A Randomised Phase 2 Trial of Intensive Induction Chemotherapy (CBOP/BEP) and Standard BEP in Poor-prognosis Germ Cell Tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604)

BackgroundStandard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required. ObjectiveTo explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial. Design, setting, and participantsWe conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres. InterventionBEP (bleomycin 30 000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15 000 IU). Outcome measurements and statistical analysisPrimary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates. Results and limitationsA total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61–85) with CBOP/BEP, 61% with BEP (90% CI, 48–73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33–1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS. ConclusionsThe primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial. Patient summaryIn this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration. Trial registrationISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604.

Patterns of relapse in poor-prognosis germ cell tumors in the GETUG 13 trial: Implications for assessment of brain progression.

365 Background: GETUG 13 investigated personalized chemotherapy based on tumor marker decline in patients with poor-prognosis GCT and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavorable decline (Fizazi K, ASCO 2013). We investigated the pattern of relapse for patients included in GETUG 13. Methods: We conducted an analysis of relapse events in patients from GETUG 13 and an unfavorable decline of tumor markers (n=203). Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic CT scan and an MRI of the brain: 22 patients (10%) had evidence of brain metastases at presentation. Results: With a median follow-up of 4.1 years (0.3 ; 8.8 years) when the analysis was performed, a progression event was observed in 94/203 patients (46%). First event consisted in a marker progression only in 41 patients (43%), a radiographic progression only in 29 patients (31%), a mix progression on both markers and imaging in 11 patients (12%), and death in 13 patients (14%). In patients with radiographic progression only, brain was the predominant site (n=16/29, 55%). Among all patients who experienced a radiographic progression (as first and subsequent progression event, n=58), brain only was the site of progression in 26 patients (45%): 12/30 (40%) in patients treated with BEP and 14/28 (50%) in those treated with dose-dense chemotherapy. Conclusions: Brain metastases develop often, early, and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and treatment of brain metastases in these patients, for example by integrating a systematic brain MRI after 2-3 months of chemotherapy.

A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: Results of GETUG 13.

LBA4500 Background: Poor-prognosis GCT (IGCCCG, J Clin Oncol 1997) remains a challenge with no improvement in the 50% survival demonstrated in phase III trials for 25 years. Day 21 serum tumor marker decline rate identified a subgroup of patients (pts) with a better outcome (J Clin Oncol 2004, 22: 3868-76). The hypothesis we tested in this study is that treatment allocation based on early tumor marker decline will improve the progression-free survival (PFS). Methods: Pts with IGCCCG poor-prognosis GCT were treated with a first cycle of BEP. AFP and hCG were assessed at day 18–21: 1) Pts with a favorable decline continued BEP for a total of 4 courses (Fav-BEP); 2) Pts with an unfavorable decline were randomized to receive either BEP (Unfav-BEP) or a dose-dense regimen (Unfav-dose-dense), consisting of paclitaxel-BEP plus day-10 oxaliplatin x 2 cycles, followed by 2 cycles of cisplatin, ifosfamide, and continuous infusion bleomycin (depending on lung function) + G-CSF. The primary endpoint was PFS (hypothesis: 20% difference, type 1 error: 5%, power 80%, 196 randomized pts needed). Results: 263 pts were enrolled and 254 were evaluable at day 21 (6 early deaths, 3 withdrawals): 51 pts (20%) had favorable tumor marker decline and 203 had unfavorable decline (randomized: 105 Unfav-dose-dense arm, 98 Unfav-BEP). The prognostic value of early tumor marker decline (Fav-BEP vs Unfav-BEP) was confirmed: 70% vs 48% for 3-year PFS (p=0.01), and 84% vs 65% for overall survival (OS) (p=0.02). The 3-year PFS was 59% in the Unfav-dose-dense arm vs 48% in the Unfav-BEP arm (p=0.05; HR: 0.66 [0.44-1.00]). 3-year OS was 73% and 65%, respectively. More ≥ grade 2 neurotoxicity (21% vs 4%) and more hematotoxicity occurred in the dose-dense arm, with no excess febrile neutropenia (17% each arm) or toxic deaths (1 each arm). Salvage high-dose chemotherapy + stem-cell transplant were required in 6% in the Unfav-dose-dense arm and 16% in the Unfav-BEP arm (p=0.01). Conclusions: An algorithm of individualized treatment intensification determined by the rate of early tumor marker decline reduces the risk of progression or death in men with poor-prognosis GCT. Clinical trial information: NCT00104676.

A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: Results of GETUG 13.

LBA4500 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

858P - Addition of Darbepoetin Alfa to Sequential High Dose Vip Chemotherapy for Patients with Advanced Metastatic Germ Cell Cancer

ABSTRACT Background High-dose VIP chemotherapy (HD-VIP) plus ABSCT given as first line treatment might be a strategy in patients with advanced germ cell tumors (GCT) with poor prognosis. The objective of the trial was to investigate the addition of darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC) transfusions. Methods This was a randomized, open-label multicenter phase 2 study conducted in 20 hospitals. Darbepoetin 2,25 mcg/kg weekly or 500 mcg Q3W s.c., started with HD-VIP (dose level 6), was applied in arm B (arm A: HD-VIP alone). The primary objective was freedom from blood transfusions (FFT). Secondary objectives included objective remission rate (ORR) after chemotherapy, 24-mos PFS and OS, median course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety. Results Between 7/2003 and 11/2008 108 pts were allocated to the study, and 102 were included in the intention-to-treat (ITT) analysis. By March 2012, the median follow-up time after randomization was 62 (range, 3–100) mos for surviving patients. Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3, respectively. No differences in baseline Hb, severity of anemia, number of RBC transfusions and area under the curve of Hb levels during HD-VIP was observed. Pts assigned to darbepoetin had similar treatment toxicity compared to those assigned to HD-VIP alone. 5-year OS in arm A was 74.0% compared to 63.0% (P = .18) in Arm B. 5-year DFS was 60.5% in arm A vs 53.1% in Arm B (P = 0.54). Darbepoetin was generally well tolerated with 2 pts discontinuing treatment due to thrombosis. A per-protocol (PP) analysis revealed comparable outcomes (OS 74.4 vs 67.5, P = 0.38; DFS 60.4 vs 58.3, P = 0.70). Conclusions Based on ITT and PP analysis, the addition of darbepoetin alfa to HD-VIP compared to HD-VIP alone does not appear to impact FFT, ORR, and survival in poor prognosis GCT pts (NCT00204633). Disclosure All authors have declared no conflicts of interest.

789O - The TAXIF II Protocol Final Results: A Phase II Trial of High-Dose Chemotherapy Supported by Haematopoietic Stem Cell Transplantation in Patients with Disseminated Germ-Cell Tumors Failing Chemotherapy and with Adverse Prognostic Factors

ABSTRACT Background High-dose chemotherapy (HDCT) has been shown to circumvent resistance in poor-prognosis germ cell tumors (GCT), mainly for patients whose relapses occur more than 4 weeks after cisplatin-based CT. Patients and methods This multicentric phase II trial was addressed to patients with poor-prognosis non-refractory GCTs. The main objectives were to determine the complete response rate and to monitor treatment-associated toxicities. Patients with adverse prognostic factors failing CT were to receive 2 cycles combining Epirubicin and Paclitaxel (EpiTax), followed by 3 consecutive HDCT [one using a Paclitaxel/Thiotepa association, 2 using the 5-day Ifosfamide-Carboplatine-Etoposide regimen]. Inclusion criteria included seminomatous GCT in relapse after 2 lines of CT, non-seminomatous GCT in relapse after 1 or 2 lines, partial remission after 1 line, primary mediastinal GCT in first relapse. Peripheral blood stem cells were collected after the EpiTax cycles. Results Between 09/2004 and 12/2007, 45 patients were included: 45 received 1 HDCT, 39 two HDCT, 29 patients received the complete protocol. Sixteen patients did not received the entire protocol, 8 (53%) for toxic side effects. Two patients (4.4%) died of toxicities, 17 (37.7%) of disease progression. For a median follow-up time of 26 months (4–51 m), the final overall response rate was 66,7% (CR, 20,6%). The median PFS was 16 months (95%CI, 9-NA) and the median OS was 32 months (95%CI, 32–49). The 2-year PFS was a plateau set up at 50% (95%CI, 32-67%) and the 2-year OS was 71% (95%CI, 52–83%). Conclusion The TAXIF II protocol was highly effective in non-refractory GCT patients failing CT. Disclosure F. Selle: consultancy for roche and Pharmamar. All other authors have declared no conflicts of interest.

Addition of darbepoetin alfa to sequential high-dose VIP chemotherapy for patients with advanced metastatic germ cell cancer.

e15026 Background: High-dose VIP chemotherapy plus ABSCT given as first line treatment might be a strategy in patient with advanced germ cell tumors (GCT) with poor prognosis. The objective of the trial was to investigate the addition of darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC) transfusions. Methods: This was a randomized, open-label multicenter phase 2 study conducted in 20 hospitals. Darbepoetin 2.25 mcg/kg weekly or 500 mcg Q3W s.c., started with high dose VIP (dose level 6) was applied in arm B (arm A: HD-VIP alone). The primary objective was freedom from blood transfusions (FFT). Secondary objectives included objective remission rate (ORR) after chemotherapy, 24 mos PFS and OS, median course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety. Results: Between 7/2003 and 11/2008 108 pts were allocated to the study, and 106 were included in the intention-to-treat (ITT) analysis. By March 2011 the median follow-up time after randomization was 20 mos. Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3, respectively. No differences in baseline Hb, severity of anemia, no of RBC transfusions and area under the curve of Hb levels during HD-VIP was observed. Pts assigned to darbepoetin had similar treatment toxicity compared to those assigned to HD-VIP alone. 24-mos OS in arm A was 86.3% compared to 67.8% (p=.064) in Arm B. 2-year RFS was 66.8% in arm A vs 55.5% in Arm B (p=0.45). Darbopoetin was generally well tolerated with 2 pts discontinuing treatment due to thrombosis. Since compliance to study protocol was generally poor (6 out of 55 pts never received study drug during HD-VIP) a per-protocol analysis is in preparation. Conclusions: Based on ITT analysis, the addition of darbepoetin alfa to the high dose regimen compared to HD-VIP alone does not appear to impact on FFT, ORR, and 2-year survival rate in poor prognosis GCT pts (NCT00204633).