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A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974).

ABSTRACT: BACKGROUND:To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor-prognosis germ-cell cancer (GCC). PATIENT AND METHODS:Patients with poor-prognosis GCC were assigned to receive either BEP or VIP followed by HD-CT. To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but closed with 137, due to slow accrual. RESULTS:One hundred thirty-one patients were included in this analysis. The complete response rates in the HD-CT and in the BEP arm did not differ: (intention to treat) 44.6% versus 33.3% (P = 0.18). There was no difference in FFS between the two treatment arms (P = 0.057, 66 events). At 2 years, the FFS rate was 44.8% [95% confidence interval (CI) 32.5-56.4] and 58.2%, respectively (95% CI 48.0-71.9); but this 16.3% (standard deviation 7.5%) difference was not statistically significant (P = 0.060). Overall survival did not differ between the two groups (log-rank P > 0.1, 47 deaths). CONCLUSION:This study could not demonstrate that high-dose chemotherapy given as part of first-line therapy improves outcome in patients with poor-prognosis GCC.

SUBMITTER: Daugaard G

PROVIDER: S-EPMC3082158 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974).

Daugaard G G Skoneczna I I Aass N N De Wit R R De Santis M M Dumez H H Marreaud S S Collette L L Lluch J R G JRG Bokemeyer C C Schmoll H J HJ

Annals of oncology : official journal of the European Society for Medical Oncology 20101108 5

<h4>Background</h4>To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor-prognosis germ-cell cancer (GCC).<h4>Patient and methods</h4>Patients with poor-prognosis GCC were assigned to receive either BEP or VIP followed by HD-CT. To show a 15% improvement in a 1-y ...[more]

PMID: 21059637

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Project description:PurposeTo compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC).Patients and methodsPatients were randomly assigned to receive either T-BEP or standard BEP. Patients assigned to the T-BEP group received paclitaxel 175 mg/m(2) in a 3-hour infusion. Patients who were administered T-BEP received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. The study was designed as a randomized open-label phase II/III study. To show a 10% improvement in 3-year progression-free survival (PFS), the study aimed to recruit 498 patients but closed with 337 patients as a result of slow accrual.ResultsAccrual was from November 1998 to April 2009. A total of 169 patients were administered BEP, and 168 patients were administered T-BEP. Thirteen patients in both arms were ineligible, mainly as a result of a good prognosis of GCC (eight patients administered BEP; six patients administered T-BEP) or a poor prognosis of GCC (one patient administered BEP; four patients administered T-BEP). PFS at 3 years (intent to treat) was 79.4% in the T-BEP group versus 71.1% in the BEP group (hazard ratio [HR], 0.73; CI, 0.47 to 1.13; P [log-rank test] = 0.153). PFS at 3 years in all eligible patients was 82.7% versus 70.1%, respectively (HR, 0.60; CI: 0.37 to 0.97) and was statistically significant (P = 0.03). Overall survival was not statistically different.ConclusionT-BEP administered with G-CSF seems to be a safe and effective treatment regimen for patients with intermediate-prognosis GCC. However, the study recruited a smaller-than-planned number of patients and included 7.7% ineligible patients. The primary analysis of the trial could not demonstrate statistical superiority of T-BEP for PFS. When ineligible patients were excluded, the analysis of all eligible patients demonstrated a 12% superior 3-year PFS with T-BEP, which was statistically significant.

Project description:BackgroundData suggests that males experience less toxicity and poorer survival than females treated for Ewing's sarcoma. We instituted an intra-patient dose escalation (DE) policy with Vincristine/Doxorubicin/Cyclophosphamide (VDC) alternating with Ifosfamide/Etoposide (IE) based on hematological nadirs and report its feasibility and safety.MethodsA retrospective review of adherence to DE guidelines and toxicities was conducted for patients who received DE with VDC/IE over 3 years at a single cancer center. Absolute neutrophil counts (ANC) was collected on days 8, 12 and 15 for cycles 1-6. DE of 10%/cycle was applied if ANC?>?1.5×109/L and platelet?>?100×109/L on all blood results. The primary endpoint was the proportion of patients who received appropriate DE. The secondary endpoint was to assess morbidity, changes in hematologic nadirs between gender and age and a comparison with a prior cohort of ESFT patients who did not receive DE. Gender comparisons were assessed via independent 2-sample t-tests assuming unequal variances. Within cycle changes in hematologic nadirs were assessed using repeated measures ANOVA. Relapse free survival and overall survival (OS) curves were estimated using the Kaplan-Meier method.Results23 patients were identified (mean age: 27; range 17-54). 91 decisions for DE were made (1 decision excluded because of progressive disease) with 90% concordance with guidelines. No adverse outcomes occurred as a result of the inappropriate escalation. Grade 3/4 febrile neutropenia (FN) during VDC and IE was 26.1% (6/23 patients) and 17.4% respectively with no difference for those who were DE. Males were less neutropenic after C1 and C3 of VDC compared to females (P-value C1?=?0.003; C3?=?0.005). VDC was associated with greater neutropenia on day 8 whereas IE had greater neutropenia on day 12 (P-value <0.001). During VDC, a non statistical difference in neutropenia was seen for individuals aged 15-25 (n?=?13) compared with older individuals (P-value?=?0.09). OS comparison for those with localized disease with a prior cohort who were not DE showed similar outcomes (P-value?=?0.37).ConclusionsDE is deliverable without increased adverse outcomes. Males have less myelosuppression during VDC, and should be especially considered for DE.

Project description:BackgroundRelapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma.MethodsWe conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0-1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1-3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1-3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete.FindingsBetween Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28-45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7-4·1), 32 (74%; 95% CI 58·8-86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3-4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3-4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients.InterpretationOur data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young (<60 years), transplantation-eligible patients for second-line therapy.FundingSeagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.

Dataset Information

A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974).

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A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974).

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