Search

Background: Frontline immune checkpoint inhibitors (ICI)-based regimens in non-oncogene-addicted non-small-cell lung cancer (NSCLC) have been deeply investigated. To rank the available therapeutic options, we carried out a systematic review and Bayesian meta-analysis. Methods: A comprehensive search for randomized controlled trials (RCTs) of ICI regimens, and a pairwise and a network meta-analysis (NMA) with an all-comers and a stratified strategy were conducted. Endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (TRAEs). Results: Nineteen RCTs involving 17 treatment regimens were included. For the all-comers population, pembrolizumab/ chemotherapy (CT) and cemiplimab were most likely the best treatments. For programmed death-ligand 1 (PD-L1) < 1% nivolumab/ipilimumab with/without CT, for PD-L1 > 1% and 1%-49% pembrolizumab/CT and for PD-L1 > 50% cemiplimab ranked first for OS. In non-squamous (NSQ), pembrolizumab with/without CT ranked first for OS; cemiplimab ranked worse than the unselected population. In squamous (SQ), pooled hazard ratio (HR) showed a better chance in improving efficacy for combination strategy, while monotherapy did not, except for cemiplimab that ranked second. Atezolizumab/CT/bevacizumab ranked first in most subgroups for PFS. Direct comparison showed a non-statistically significant benefit of ICI regimens for the liver metastases cohort in OS, with a good ranking for pembrolizumab/CT and atezolizumab/bevacizumab/CT. Regarding brain metastases, all ICI regimens demonstrated an improvement in OS and PFS compared to CT. Nivolumab/ipilimumab/CT ranked better in this subset. Conclusions: Our meta-analysis updated on the most recent findings demonstrates that different ICI treatments rank differently in specific NSCLC settings (histology, biomarker and clinical presentation) offering a novel challenging scenario for clinical decision making and research planning.

Ovarian cancer is the leading cause of death among gynecological tumors. Carboplatin/paclitaxel represents the cornerstone of front-line treatment. Instead, there is no consensus for management of recurrent/progressive disease, in which pegylated liposomal doxorubicin (PLD) ± carboplatin is widely used. We performed a systematic review and metaanalysis to evaluate impact of PLD-based compared with no-PLD-based regimens in the ovarian cancer treatment. Data were extracted from randomized trials comparing PLD-based treatment to any other regimens in the January 2000-January 2013 time-frame. Study end-points were overall survival (OS), progression free survival (PFS), response rate (RR), CA125 response, and toxicity. Hazard ratios (HRs) of OS and PFS, with 95% CI, odds ratios (ORs) of RR and risk ratios of CA125 response and grade 3-4 toxicity, were extracted. Data were pooled using fixed and random effect models for selected endpoints. Fourteen randomized trials for a total of 5760 patients were selected and included for the final analysis, which showed no OS differences for PLD-based compared with other regimens (pooled HR: 0.94; 95% CI: 0.88-1.02; P = 0.132) and a significant PFS benefit of PLD-based schedule (HR: 0.91; 95% CI: 0.86-0.96; P = 0.001), particularly in second-line (HR: 0.85; 95% CI: 0.75-0.91) and in platinum-sensitive (HR: 0.83; 95% CI: 0.74-0.94) subgroups. This work confirmed the peculiar tolerability profile of this drug, moreover no difference was observed for common hematological toxicities and for RR, CA125 response. PLD-containing regimens do not improve OS when compared with any other schedule in all phases of disease. A marginal PFS advantage is observed only in platinum-sensitive setting and second-line treatment. © 2014 Landes Bioscience.

Background: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Gemcitabine is the mainstay treatment for advanced disease. However, almost all up-to-date trials, that evaluated the benefit of gemcitabine-combination schedules, failed to demonstrate an improvement in overall survival (OS). In this study, we performed a systematic review and a meta-analysis of randomised clinical trials (RCTs) to investigate the efficacy and safety of gemcitabine-based combination regimens as compared to gemcitabine alone in the management of pancreatic cancer. Methods: Clinical trials were collected by searching different databases (PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library) and abstracts from major cancer meetings. We considered period ranging from January 1997 to January 2012. Primary end-point was OS, secondary end-points were response rate (RR), disease control rate (DCR) and safety. Hazard ratios (HRs) of OS, odds-ratios (ORs) of RR, DCR and risk ratios of grade 3-4 toxicity rates (TRs), were extracted as presented in retrieved studies and used for statistical analysis. Meta-analytic estimates were derived using random-effects model. Findings: Thirty-four trials for a total of 10,660 patients were selected and included in the final analysis. The analysis showed that combination chemotherapy confers benefit in terms of OS (HR: 0.93; 95% confidence interval (CI): 0.89-0.97; p = 0.001). ORs for both RR and DCR demonstrated a significant advantage for combination therapy (OR for RR: 0.60, 95%CI: 0.47-0.76, p < 0.001; OR for DCR: 0.79; 95%CI: 0.66-0.93; p = 0.006). Toxicities were more frequent with the combination treatment and significance in terms of risk ratio was reached for diarrhoea (0.53, 95%CI: 0.36-0.79), nausea (0.74, 95%CI: 0.56-0.96), neutropenia (0.71, 95%CI: 0.59-0.85) and thrombocytopenia (0.57, 95%CI: 0.43-0.75). Interpretation: The combination chemotherapy as compared to gemcitabine alone significantly improves OS in advanced pancreatic cancer (APC). However, this advantage is marginal whereas the treatment-related toxicity is increased, suggesting the use of gemcitabine-based combination regimens only in selected patient populations. New prospective trials, based on translational approaches and innovative validated biomarkers, are eagerly awaited on this topic. © 2012 Elsevier Ltd. All rights reserved.

Aim A systematic review and meta-analysis from literature has been performed to assess the impact of targeted therapy in advanced pancreatic cancer. Methods By searching different literature databases and major cancer meetings proceedings, data from all randomized clinical trials designed to investigate molecular targeted agents in the treatment of advanced pancreatic cancer were collected. The time-frame between January 2007 and March 2015 was selected. Data on predefined end-points, including overall survival, progression-free survival in terms of Hazard Ratio and response-rate were extracted and analyzed by a random effects model. Pooled data analysis was performed according to the DerSimonian and Laird test. The occurrence of publication bias was investigated through Begg's test by visual inspection of funnel plots. Results Twenty-seven randomized clinical trials for a total of 8205 patients were selected and included in the final analysis. A significant benefit was demonstrated for anti-EGFR agents on overall survival (HR = 0.880; 95% confidence interval (CI) 0.797–0.972; p = 0.011). In the pooled analysis no benefit on overall survival (OS: pooled HR = 0.957; 95%CI 0.900–1.017; p = 0.153), or progression-free survival (PFS: pooled HR = 0.908; 95%CI 0.817–1.010; p = 0.075) for targeted-based therapies as compared to conventional treatments could be demonstrated. No advantage was reported in response-rate (OR for RR = 1.210; 95%CI 0.990–1.478; p = 0.063). Begg's funnel plot showed no evidence of publication bias. Conclusion The use of molecular targeted agents does not translate into clinical benefit. Therefore, our work highlights the need to identify predictive factors for patient selection and rationally designed clinical trials.

Despite major therapeutic advancements, multiple myeloma (MM) is still incurable and relapsed/refractory multiple myeloma (RRMM) remains a challenge; the rational choice of the most appropriate regimen in this setting is currently undefined. We performed a systematic review and 2 standard pairwise meta-analyses to evaluate the efficacy of regimens that have been directly compared with bortezomib or immunomodulatory imide drugs (IMiDs) in head-to-head clinical trials and a network meta-analysis (NMA) to determine the relevance of each regimen on the basis of all the available direct and indirect evidence. Sixteen trials were included in the pairwise meta-analyses, and 18 trials were included in the NMA. Pairwise meta-analyses showed that a 3-drug regimen (bortezomib- or IMiD-based) was superior to a 2-drug regimen in progression-free-survival (PFS) and overall response rate (ORR). NMA showed that an IMiD backbone associated with anti-MM monoclonal antibodies (mAbs) (preferably) or proteasome inhibitors had the highest probability of being the most effective regimen with the lowest toxicity. The combination of daratumumab, lenalidomide, and dexamethasone ranked as the first regimen in terms of activity, efficacy, and tolerability according to the average value between surface under the cumulative ranking curve of PFS, overall survival, ORR, complete response rate, and safety. This is the first NMA comparing all currently available regimens evaluated in published randomized trials for the treatment of RRMM, but our results need to be interpreted taking into account differences in their patient populations. Our analysis suggests that IMiDs plus new anti-MM mAb–containing regimens are the most active therapeutic option in RRMM.

The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/ label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m 2, day 1); oxaliplatin (85 mg/m2, day 2); levofolinate (100 mg/m2, days 1-2), 5-fluorouracil (5-FU) (400 mg/m2 in bolus followed by 24 h infusion at 800 mg/m2,days 1-2), sc. GM-CSF (100 μg, days 3-7); sc. aldesleukin (0 ° 5 MIU bi-daily, days 8-14 and 17-30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9 ° 23 (95% confidence interval (CI), 6 ° 9-11.5) vs. median 5.70 (95% CI, 3.38-8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35-0.77), P=0 ° 002] and response rate [66.1% (95% CI, 0.41-0.73) vs. 37 °0% (95% CI, 0.28-0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09-25.18) vs. 14.57mo (95% CI, 9.07-20.07); HR: 0 ° 79 (95% CI, 0.52-1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4+ T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3+CD4 +CD25+ FoxP3+) T cells. Taken together, these findings provide proofof- principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC. Copyright © 2014 by Lippincott Williams & Wilkins.

Background Ovarian cancer (OC) is the sixth most common cancer in women. Currently, carboplatin/paclitaxel ± bevacizumab is the cornerstone of front-line treatment. Conversely, the therapeutic options for recurrent or progressive disease are not well defined. For platinum-sensitive patients the best therapeutic approach is still a re-challenge with a platinum-based regimen. Pegylated liposomal doxorubicin (PLD), is considered one of the most active therapeutic options for recurrent or progressive OC. In this retrospective mono-institutional analysis, we evaluated the impact of PLD on the outcome of OC patients. Patients and methods We performed the retrospective study on a cohort of 108 patients with histologically confirmed serous papillary OC, followed at our Institution between 2001 and 2011. 80 patients were in stage III/IV and 55 of them received a second-line treatment. Thirty patients were treated with PLD. Both groups (PLD-treated versus PLD-untreated) underwent a median of 3 treatment lines and were prognostically balanced. The median follow-up was 60 months. Survival endpoints, toxicity and correlations between patients’ baseline characteristics and treatment efficacy were evaluated. Results Patients who had undergone PLD treatment (PLD group) showed a median overall survival (OS) of 45 months as compared to 65 months of patients not treated with PLD (PLD-free group) (HR 2.50 [0.95-6.67; p = 0.06]). Moreover, the median progression-free survival was 6 months in the PLD group versus 10 months in the PLD-free group (HR 1.75 [0.94-3.34; p = 0.07]). The overall objective response rate in II line treatment was 43% (13% in PLD group versus 57% in PLD-free group). Furthermore, we investigated survival endpoints in platinum-refractory patients who received PLD at least once during the course of disease. No OS advantage was achieved by PLD administration when compared to other therapeutic options (30 versus 32 months; HR 1.16 [0.31-4.34; p = 0.81]). No difference in term of toxicity was observed among different groups. Conclusions No evidence of superiority if PLD was compared to alternative agents was found in this analysis, particularly in the platinum-refractory setting. Our findings indicate a modest therapeutic activity of PLD in OC. Analysis of cost/benefit of PLD in OC is eagerly awaited.