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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).

ABSTRACT: BACKGROUND:Up 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%). AIM:To assess long-term outcomes and late toxicity associated with CBOP/BEP. METHODS:Patients 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. RESULTS:Eighty-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. CONCLUSION:Although 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 REGISTRATION:ISRCTN 53643604.

SUBMITTER: Cafferty FH

PROVIDER: S-EPMC7045084 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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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).

Cafferty Fay H FH White Jeff D JD Shamash Jonathan J Hennig Ivo I Stenning Sally P SP Huddart Robert A RA

European journal of cancer (Oxford, England : 1990) 20200131

<h4>Background</h4>Up 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%).<h4>Aim</h4>To assess long-term outcomes and late toxicity associated with CBOP/BEP.<h4>Metho ...[more]

PMID: 32007714

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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: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.

Project description:ObjectiveLittle observational data exist regarding the use of cisplatin, etoposide, and bleomycin (BEP) chemotherapy regimen in patients with gestational trophoblastic neoplasia (GTN).MethodsThis is a retrospective study of 95 patients with GTN in our center from June/2010 to June/2018. All patients received at least 2 cycles of BEP chemotherapy. The primary outcomes were the rate of complete remission (CR) and overall survival (OS). The secondary outcomes were disease-free survival (DFS), pregnancy rates after BEP exposure, drug resistance rate, and other adverse events.ResultsOf the 95 patients included, 66 (69.5%) patients received BEP as primary treatment and 29 (30.5%) were Salvage chemotherapy. The median age at diagnosis was 37 years (range 29.75-46) and 34 years (range 27-40) in two groups, respectively. The median WHO prognostic scores were 6 (range 3.5-8), and 77.32% of patients were FIGO stage III-IV in the primary treatment group. The median WHO prognostic scores were 5 (range 3-9), and 66.55% of patients were FIGO stage III-IV in the salvage treatment group. Median cycles of BEP treatment were 4 (3, 5) and 3 (2, 4) in two groups, respectively. In the primary chemotherapy group, 18.2% received additional hysterectomy, 4.5% received UAE for vaginal bleeding, and 1.52% received whole-brain radiotherapy. In the salvage chemotherapy group, 20.7% received hysterectomy, 6.9% received lobectomy, 3.4% received hysteroscopic lesion resection, and 3.4% received whole-brain radiotherapy. CR rates to initial chemotherapy were 86.4%, including 87.9% in the primary chemotherapy group and 82.8% in the salvage chemotherapy group. No predictive factor of chemotherapy resistance was identified. The rate of 5 year-DFS was 96.52% (95% CI 86.78-99.12) in the primary chemotherapy group and 92.44% (95% CI 73.02-98.06) in the salvage chemotherapy group. The rate of 5 year-OS was 98.31% (95% CI 88.57-99.76) and 95.65% (95% CI 79.93-99.38) in the two groups, respectively. During the treatment, neutropenia, thrombocytopenia, anemia, and liver dysfunction occurred in 80.3%, 6.1%, 25.8%, and 50% primary chemotherapy patients and 82.8%, 31%, 10.3%, and 86.2% salvage chemotherapy patients. In patients with fertility requirements, live birth rates were 100% (10/10) in primary chemotherapy patients and 80% (4/5) in salvage chemotherapy patients.ConclusionsBEP regimen was effective in the treatment of GTINs. The treatment was well tolerated, with no safety concerns on patients' fertility.

Project description:BackgroundThe National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience.Material and methodsResponse and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data.ResultsBetween 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events.ConclusionEPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care.Implications for practiceFour cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.

Dataset Information

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).

Publications

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).

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