A Phase III Randomized Study Comparing a Chemotherapy with Cisplatin and Etoposide to a Etoposide Regimen without Cisplatin for Patients with Extensive Small-Cell Lung Cancer.
ABSTRACT: INTRODUCTION:In a literature meta-analysis, we showed survival benefits for regimens including cisplatin [hazard ratio (HR) 0.61; 95% confidence interval (CI), 0.57-0.66] and for those including etoposide (HR 0.65; 0.61-0.69). That benefit was mainly observed when etoposide alone or in combination with cisplatin was included in the chemotherapy regimens. Our objective was to determine if chemotherapy with both drugs improves survival in comparison to a non-platinum regimen with etoposide. METHODS:Extensive small-cell lung cancer patients were randomized between cisplatin-etoposide (CE) and ifosfamide?+?etoposide + epirubicin regimen (IVE) between 2000 and 2013. RESULTS:176 and 170 eligible patients were allocated to CE and IVE (315 deaths were required before analysis), respectively. Objective response rates were not significantly different: 60% with CE and 59% with IVE. No statistically significant difference in median survival and 1-year and 2-year was observed with rates of 9.6?months, 31 and 5% for CE and 10?months, 39 and 9% for IVE, respectively. HR was 0.84 (95% CI 0.68-1.05, p?=?0.16). Only two prognostic factors for survival were retained in multivariate analysis: sex with HR?=?0.69 (95% CI 0.49-0.97, p?=?0.03) and performance status with HR?=?0.53 (95% CI 0.49-0.97, p?
Project description:Patients with poor and intermediate prognosis metastatic germ-cell tumours (MGCTs) are at a significant risk of relapse after standard platinum-based chemotherapy. Novel treatment regimens are required to improve survival. Dose intense, alternating combinations of drugs with known activity in germ-cell tumours represents one approach. In all, 43 patients with IGCCCG intermediate/poor prognosis MGCT were treated with a dose intense regimen alternating bleomycin, vincristine, cisplatin (BOP) with bleomycin, etoposide, cisplatin (BEP) to a maximum of three cycles. Data were collected on the maintenance of dose intensity, toxicity, response, progression-free (PFS) and overall survival (OS). The complete response rate was 58%; a further 7% of patients being rendered disease free by resection of viable residual tumour. With a median follow-up of more than 4 years in surviving patients, 3-year OS and PFS rates of 81% (95% CI: 66-91%) and 72% (95% CI: 56-83%) are seen, respectively. Bleomycin, vincristine, cisplatin (BOP)/bleomycin, etoposide, cisplatin (BEP) was well tolerated, with 86% of patients completing all planned courses. Toxicity was predominantly haematological with common toxicity criteria grade III neutropenia in 90% of patients. Cisplatin neuropathy and bleomycin-induced pulmonary toxicity represented the most significant nonhaematological toxicity. Bleomycin, vincristine, cisplatin (BOP)/bleomycin, etoposide, cisplatin (BEP) represents a practicable, well-tolerated, dose intense chemotherapy regimen with significant activity in intermediate and poor prognosis MGCT.
Project description: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.
Project description:<h4>Background</h4>Our goal was to organize the data from randomized controlled trials that evaluated first-line chemotherapy for chemo-naïve extensive disease small-cell lung cancer (ED-SCLC).<h4>Methods</h4>The protocol following PRISMA methodology was submitted as PROSPERO 154049. We included individually randomized trials comparing two or more chemotherapy regimens as the first-line treatment for chemo-naïve ED-SCLC regardless of the age, sex, performance status, co-morbidities, and organ functions written in the English language since 2000. Molecular targeted agents and immune checkpoint inhibitors were considered chemotherapy along with cytotoxic medications. We pooled the logarithm of hazard ratio (HR) and its standard error using the frequentist weighted least squares approach random-model network meta-analysis.<h4>Results</h4>A total of 46 eligible trials that involved 11,987 patients were included. The primary endpoint, HR of overall survival (OS, HRos) of the selected comparisons was as follows: carboplatin+amrubicin (HRos 0.56, 95% confidence interval (CI) 0.33-0.96), carboplatin+etoposide+atezolizumab (HRos 0.70, 95% CI 0.53-0.92), and carboplatin+irinotecan (HRos 0.73, 95% CI 0.58-0.91) were compared with carboplatin+etoposide. The carboplatin+etoposide+atezolizumab regimen was compared with carboplatin+irinotecan (HRos 0.97, 95% CI 0.68-1.37) and cisplatin+irinotecan regimen (HRos 0.87, 95% CI 0.58-1.31). "Selective carboplatin or cisplatin (CBDCA/CDDP)"+etoposide+durvalumab was compared with CBDCA/CDDP+etoposide (HRos 0.73, 95% CI 0.59-0.91). Platinum+etoposide+durvalumab was compared with platinum+irinotecan (HRos 0.88, 95% CI 0.67-1.15). Cumulative meta-analysis suggested that platinum+irinotecan was associated with better OS than platinum+etoposide as of 2010 through 40 out of 46 trials in our review that used platinum+etoposide as a reference regimen.<h4>Conclusion</h4>Patients treated with carboplatin+amrubicin, carboplatin+etoposide+atezolizumab, CBDCA/CDDP+etoposide+durvalumab, and platinum+irinotecan showed better HRos than those treated with platinum+etoposide, one of the standard regimens.
Project description:PURPOSE:Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC). MATERIALS AND METHODS:Patients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate. RESULTS:A total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ? 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable. CONCLUSION:The addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point.
Project description:BACKGROUND:It remains unknown which is the most preferable regimen used concurrently with thoracic radiation for locally advanced non-small cell lung cancer (NSCLC). We performed a network meta-analysis to address this important issue. METHODS:PubMed, Embase, Cochrane Library, Web of Science and major international scientific meetings were searched for relevant randomized controlled trials (RCTs). Overall survival (OS) data was the primary outcome of interest, and progression-free survival (PFS), and serious adverse events (SAEs) were the secondary outcomes of interests, reported as hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (CIs). RESULTS:14 RCTs with a total of 2975 patients randomized to receive twelve categories of treatments were included in the meta-analysis. Direct comparison meta-analysis showed that etoposide-cisplatin (EP) was more effective than paclitaxel-cisplatin/carboplatin (PC) in terms of OS (HR = 0.85, 95% CI: 0.77-0.94) and PFS (HR = 0.66, 95% CI: 0.47-0.95). In network meta-analysis, all regimen comparisons did not produce statistically significant differences in survival. Based on treatment ranking of OS and the benefit-risk ratio, S-1-cisplatin (SP) was likely to be the most preferable regimen for its best efficacy and low risk of causing SAEs. Uracil/tegafur-cisplatin (UP) and pemetrexed-cisplatin/carboplatin (PP) were ranked the second and third respectively. Gemcitabine-cisplatin (GP) and PC + Cetuximab (PC-Cet) appeared to be the worst and second-worst regimens for their poor efficacy and poor tolerability. CONCLUSIONS:Based on efficacy and tolerability, SP is likely to be the most preferable regimen used concurrently with thoracic radiation for locally advanced NSCLC, followed by UP and PP. Further direct head-to-head studies are needed to confirm these findings.
Project description:PURPOSE:To 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 METHODS:Patients 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. RESULTS:Accrual 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. CONCLUSION:T-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:INTRODUCTION:Metastatic breast cancer (MBC) with leptomeningeal metastases (LM) has dismal survival. We aim to determine if modern systemic therapy, especially the bevacizumab, cisplatin, and etoposide (BEEP) regimen, is beneficial to MBC LM patients. METHODS:We excerpted data from a prospectively collected cytopathology database for MBC patients who were diagnosed with LM by positive cerebrospinal fluid cytology. The primary outcome was OS from cytologically confirmed LM until death. Univariate and multivariate analyses were performed to elucidate prognostic factors. RESULTS:We identified 34 patients with cytologically confirmed LM. Treatments after LM diagnosis included: intrathecal methotrexate (82.4%), systemic chemotherapy (68%; BEEP n?=?19, others n?=?4), and whole brain radiotherapy (n?=?5, 14.7%). Three of seven HER2-positive patients (43%) also received intrathecal trastuzumab. OS was improved in 2014-2016 compared with 2011-2013 (13.57 vs 3.20 months, p?=?0.004), when 12/17 (71%) versus 7/17 (41%) patients received BEEP, respectively. In the multivariate model including all treatments, BEEP (HR 0.24, p?=?0.003) and intrathecal trastuzumab (HR 0.22, p?=?0.035), but not intrathecal methotrexate (HR 0.86, p?=?0.78), remained significant prognostic factors. CONCLUSIONS:MBC with LM is treatable-systemic BEEP are efficacious and may improve survival.
Project description:Introduction: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented. Methods: The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n=71) or no adjuvant treatment (OBS, n=62) [GSE14814] and 2) formalin-fixed paraffin-embedded (FFPE) pre-treatment tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine. Results: The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p=0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p=0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR=0.138 (95% CI:0.035-0.537), p=0.004) and multivariate analysis (HR=0.14 (95% CI:0.030-0.6), p=0.0081). No discrimination was found in the OBS cohort (HR=1.328, p=0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p=0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p=0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis. Conclusions: Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment. Overall design: A total of 95 pre-treatment non-small cell lung cancer samples were profiled for gene expression by using Affymetrix U133+2 platform. Raw cel data were preprocessed by RMA. Data from GSE14814 were used directly, without re-analysis.
Project description:Elevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer.Eligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed.Eight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3-9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0-10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF.BEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease.ClinicalTrials.gov identifying number NCT01281696 .
Project description:PURPOSE:To investigate the efficacy and safety of bevacizumab plus cisplatin and etoposide in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS:In this phase II trial, 63 patients were treated with bevacizumab 15 mg/kg plus cisplatin 60 mg/m(2) and etoposide 120 mg/m(2), which was followed by bevacizumab alone until death or disease progression occurred. The primary end point was the proportion of patients alive at 6 months without disease progression (ie, progression-free survival [PFS]). Secondary end points included overall survival (OS), objective response rate, and toxicity. Correlative studies were performed to explore the relationship between baseline and changes in plasma vascular endothelial growth factor (VEGF), soluble cell adhesion molecules (ie, vascular cell adhesion molecule [VCAM], intercellular cell adhesion molecule [ICAM], and E-selectin) and basic fibroblast growth factor and outcome. RESULTS:The 6-month PFS was 30.2%, the median PFS was 4.7 months, and OS was 10.9 months. The response rate was 63.5%. The most common adverse event was neutropenia (57.8%). Only one patient had grade 3 pulmonary hemorrhage. Patients who had high baseline VCAM had a higher risk of progression or death compared with those who had low baseline VCAM levels. No relationships between outcome and any other biomarkers were seen. CONCLUSION:The addition of bevacizumab to cisplatin and etoposide in patients with ED-SCLC results in improved PFS and OS relative to historical controls who received this chemotherapy regimen without bevacizumab. This regimen appears to be well tolerated and has minimal increase in toxicities compared with chemotherapy alone. Baseline VCAM levels predicted survival, but no other relationships among treatment, biomarkers, and outcome were identified.