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A potential option for patients who do not have access to neoadjuvant immunotherapy

Clinical observations have demonstrated that microsatellite instability-high (MSI-H) and/or deficient MMR (dMMR) status are associated with favorable prognosis and no benefit from 5-Fluorouracil (5-FU)-based adjuvant chemotherapy in patients with resected stage II colorectal cancer (CRC). This study represents a systematic review and meta-analysis exploring the predictive role of MSI-H status in stage III CRC undergoing or not adjuvant chemotherapy. Published articles that evaluated the role of adjuvant chemotherapy in resected stage III CRC from inception to September 2020 were identified by searching the PubMed, EMBASE, and Cochrane Library databases. The random-effects model was conducted to estimate the pooled effect size of OS and DFS. The primary outcome of interest was OS. 21,590 patients with MSI-H/dMMR stage III CRC, from n = 17 retrospective studies, were analyzed. Overall, OS was improved with any adjuvant chemotherapy vs. any control arm (single-agent 5-FU or surgery alone): HR 0.42, 95% CI 0.26–0.66; P < 0.01. Conversely, DFS was not significantly improved (HR 0.7, 95% CI 0.45–1.09; P = 0.11). In patients with stage III MSI-H/dMMR CRC, adjuvant chemotherapy is associated with a significant OS improvement. Thus, MSI-H/dMMR status does represent a predictive factor for postoperative chemotherapy benefit in stage III CRC beyond its prognostic role.

A proliferative marker, expressed as the percentage of cells in a cell cycle, has been developed and used as a discriminant of more aggressive malignant phenotypes in early breast cancer (BC). The marker is usually expressed by the immunohistochemical staining of the cell cycle antigen Ki-67. It has not, however, yet been definitely evaluated, due to methodological concerns, which specific Ki-67 cut-off provide the strongest prognostic information in resected BC. We conducted a meta-analysis to explore the prognostic value of different cut-off levels of Ki-67 in terms of overall survival (OS) and disease-free survival (DFS) in early BC. The databases of PubMed, the ISI Web of Science, EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials, and CINHAL were used to identify the relevant literature. Data from studies reporting a hazard ratio (HR) and a 95 % confidence interval (CI) calculated as a multivariate analysis were pooled in a meta-analysis, with metaregression used to test for trends in predefined subgroups. All the statistical tests were 2-sided. Forty-one studies encompassing 64,196 BC patients were included in the analysis. Overall, n  = 25 studies were available for the OS analysis. The pooled HR for high versus low Ki-67 was 1.57 (95 % CI 1.33–1.87, P  < 0.00001). Twenty-nine studies were available for the DFS analysis. The pooled HR for high versus low Ki-67 was 1.50 (95 % CI 1.34–1.69, P  < 0.00001). When a cut-off of Ki-67 staining ≥ 25 % was used, the pooled HR for OS was 2.05 (95 % CI 1.66–2.53, P  < 0.00001), which was significantly different to studies where the cut-offs chosen were <25 %. In ER+ tumors, the HR for high versus low Ki-67 was similar and significant (HR = 1.51, 95 % CI 1.25–1.81, P  < 0.0001). We conclude that Ki-67 has an independent prognostic value in terms of OS in BC patients. The Ki-67 threshold with the greatest prognostic significance is as yet unknown, but a cut-off >25 % is associated with a greater risk of death compared with lower expression rates.

Introduction The 21-gene Oncotype DX Breast Recurrence Score® test, (Genomic Health, Redwood City CA) has not been formally evaluated in an older cohort with estrogen receptor (ER)-positive breast cancer (BC) in term of physicians’ treatment decisions. We determine the utility of Recurrence Score® (RS) result on adjuvant therapy prescription in elderly patients with resected early BC. Material and methods PONDx was a multicenter, prospective, observational study, and which investigated the real-life use of the Oncotype DX® test by physicians treating early BC patients in clinical practice. Results Data from the elderly extracted from 1724 BC patients who underwent Oncotype DX testing were available from 27 reference centers located in 6 regions of Italy (Lombardia, Lazio, Emilia Romagna, Campania, Abruzzo, and Marche). A total of 230 patients (13% of the total population) aged > 70 years were analyzed. The study primarily evaluated the impact of the Oncotype DX test on adjuvant treatment decisions. Physicians chosen chemotherapy plus endocrine therapy in 36% of elderly patients and 46% of those 50–70 years before the Oncotype DX test. After knowing the RS data, these rates fell to 23 and 33% (38 and 28% relative reduction, respectively). Conclusions 21-gene test may be helpful even in a relatively low-risk group as elderly patients and may avoid the toxicity of adjuvant chemotherapy in a significant amount. If the Oncotype DX test is currently adopted on a large scale among the elderly and may impact the general prognosis of elderly BC patients, it is challenging and still unproven.

ObjectiveThe preferred neoadjuvant treatment for gastroesophageal junction (GEJ) adenocarcinoma is still matter of debate. We conducted a meta-analysis to assess the different impact of neoadjuvant combined chemotherapy and radiotherapy (CTRT) versus chemotherapy (CT) alone.MethodsA comprehensive search was performed in EMBASE, PubMed, and Cochrane Library databases from inception to 30th June 2018. Studies comparing survival of patients who underwent CTRT or CT alone before surgery for GEJ adenocarcinoma were included. Hazard ratio (HR) for overall survival (OS) was extracted, and a random-effects model was used for pooled analysis. Median OS, 5-year OS, complete pathologic response (pCR), locoregional and distant failure rates were also calculated.Results22 studies including 18,260 patients were considered for the final analysis. The pooled results demonstrated that combined CTRT do not significantly reduce the risk of death (HR 0.95, 95% CI 0.84–1.07; P = 0.41) but has a positive impact on the risk of relapse (HR 0.85, 95% CI 0.75–0.97; P = 0.01) compared to CT alone. Addition of RT to CT alone significantly increased the odds of pCR by 2.8 (95% CI 2.27–3.47; P < 0.001) and reduced the risk of locoregional failure (OR 0.6, 95% CI 0.39–0.91; P = 0.01) but not the risk of distant metastases (OR 0.81, 95% CI 0.59–1.11; P = 0.19).ConclusionsIn this systematic review and meta-analysis comparing neoadjuvant CTRT with CT for adenocarcinoma of GEJ, we found no difference in terms of median OS, despite a higher pCR rate and a reduced risk of locoregional recurrences for the combined approach. Further studies, preferably large randomized clinical trials, are needed to confirm these results.

Background Current guidelines support the use of adjuvant chemotherapy (CT) following neoadjuvant chemoradiotherapy (CTRT) and surgery to treat rectal cancer, although clinical trials have provided little evidence that it is effective. We performed a systematic review of published studies to assess whether adjuvant CT improves outcome after neoadjuvant therapy and radical surgery in cases of rectal cancer. Materials and methods We conducted an electronic database search for randomized and nonrandomized studies in PubMed, EMBASE, Web of Science, Scopus and the Cochrane Register of Controlled Trials. We then carried out a meta-analysis by using the fixed- or random-effects models. The primary endpoint was 5-year overall survival (OS) reported as odds ratios (ORs) and 95 % confidence intervals (CIs). Results Two randomized controlled trials (RCTs), one pooled analysis of five RCTs and 10 retrospective studies that included a total of 5,457 patients matched our selection criteria. Meta-analysis showed that for rectal cancer patients treated with surgery and neoadjuvant CTRT, adjuvant CT improves 5-year OS (OR, 0.64; 95 % CI, 0.46–0.88; p  = 0.006) and 5-year disease-free survival (DFS) (OR, 0.71; 95 % CI, 0.6–0.83; p  < 0.0001). The 5-year OS benefit was significantly larger in downstaged patients and in retrospective series. A better DFS was instead noted in all studies due to a reduced risk of local relapse. Conclusions Amongst rectal cancer patients treated with neoadjuvant therapy and surgery, adjuvant CT seems to improve the 5-year DFS and OS rates and may be discussed with patients. However, the benefit derives mainly from retrospective evidence.

IntroductionSteroids are commonly used for managing brain edema in patients with glioblastoma multiforme (GBM), treated with surgery and concomitant temozolomide-based chemoradiotherapy (CTRT). The adverse effects of glucocorticoids include lymphopenia, hyperglycemia, and risk of infection. We report the results of a meta-analysis evaluating the effects of steroids on outcome when associated with the treatment of GBM.MethodsPubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with GBM and treated or not treated with steroids. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with the worst outcome in steroid users compared to non-users.ResultsTwenty-two publications were retrieved from studies selected for a total of 8,752 patients. In the primary analysis (n = 22 studies reporting data), OS was reduced in GBM patients taking steroids during treatment (HR = 1.54, 95% CI 1.37–1.75; p < 0.01). Similarly, PFS was inferior in steroid users in n = 9 studies with data available (HR = 1.28, 95% CI 1.1–1.49; p < 0.01).ConclusionsIn patients with GBM and treated with RT and/or CT, association with steroids significantly reduces survival and PFS. Use of the lowest dose of glucocorticoids for the shortest period needed to achieve the treatment goals and prevention of steroid-associated complications are essential aims of treatment of this disease.

Platinum agents such as cisplatin and carboplatin are DNA-damaging agents with activity in breast cancer (BC), particularly in the triple negative (TN) subgroup. The utility of platinum agents, in addition to standard neoadjuvant chemotherapy (NAC), is controversial. To assess the activity of platinum agents in patients with TNBC treated with NAC, we performed a systematic review and meta-analysis of all published studies. A search of PubMed, EMBASE, the Web of Science, SCOPUS, and the Cochrane Central Register of Controlled Trials was performed to identify studies that investigated platinum-based NAC in patients with TNBC. Random effect models were adopted to estimate the summary risk ratio (RR), and the publication bias was evaluated using a funnel plot and Egger’s regression asymmetry test. The primary endpoints were the pooled rate of the pathologic complete response (pCR) and the RR to obtain a pCR in patients treated versus not treated with NAC containing platinum agents. 28 studies were included (six randomized controlled trials and 22 retrospective or prospective studies) for a total of 1,598 TNBC patients. Overall, the pooled rate of pCR in patients treated with platinum-based NAC was 45 %. In randomized trials, NAC containing cisplatin or carboplatin significantly increased the rate of pCR compared with nonplatinum agents (RR = 1.45, 95 % CI 1.25–1.68; P  < 0.0001). Compared with non-TN, TNBCs were associated with a threefold increase in the pCR rate when treated with platinum-based NAC (RR 3.32, 95 % CI 2.39–4.61; P  < 0.0001). In conclusion, pCR rates increase significantly with the addition of cisplatin or carboplatin in TNBC compared with NAC containing no platinum drugs. TN status is a predictor of benefit from platinum-based NAC.

The gut microbiome has emerged as a critical determinant of immune-checkpoint inhibitor (ICI) efficacy. A narrative review of 95 clinical studies (2015–2025) shows that patients with greater gut microbial diversity and relative enrichment of commensals such as Akkermansia, Ruminococcus, and other short-chain fatty acid producers experience longer progression-free and overall survival, particularly in melanoma and non-small-cell lung cancer. Broad-spectrum antibiotics given within 30 days of ICI initiation and over-the-counter mixed probiotics consistently correlate with poorer outcomes. Early phase I/II trials of responder-derived fecal microbiota transplantation in ICI-refractory melanoma achieved objective response rates of 20–40%, while pilot high-fiber or plant-forward dietary interventions improved immunologic surrogates such as CD8+ tumor infiltration. Machine-learning classifiers that integrate 16S or metagenomic profiles predict ICI response with an area under the ROC curve of 0.83–0.92. Methodological heterogeneity across sampling, sequencing, and clinical endpoints remains a barrier, underscoring the need for standardization and larger, well-powered trials.

IntroductionImmune checkpoint inhibitors (ICIs) represent a cornerstone for the treatment of many advanced tumors. When 65 is considered as a cut-off age, ICIs are equally effective in younger and older patients. However, the efficacy of ICIs among patients aged ≥ 75 remains uncertain, since those patients were generally under-represented in clinical trials. We performed a pooled analysis of major randomized trials including data of outcome in very older population.Material and methodsWe searched PubMed, Embase, and the Cochrane Library for randomized controlled trials published from the inception of each database to November 22th, 2019. We only included (1) randomized studies comparing ICIs alone or in combinations with no ICIs, (2) studies reporting data of patients older than 75 years, (3) studies for solid tumors, and (4) studies with HR and 95% confidence interval (CI) available for OS based on 75 years as cut-off age. All data were expressed as the combination of HR and 95% CI, and P < 0.05 was considered to be statistically significant.ResultsA total of n = 8 publications for a total of n = 12 randomized studies were aggregated in the quantitative analysis. Overall, the pooled analysis showed a borderline significant OS benefit for ICIs compared to no ICIs arms (HR = 0.84, 95% CI 0.7–1; P = 0.05) in particular in first-line trials with HR = 0.77 (95%CI 0.61–0.96; P = 0.02).ConclusionWe conclude that ICIs may be offered in patients older than 75 years, providing a complete geriatric and clinical evaluation is performed in all subjects before starting therapy.