Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a
mutation. The effect of combining maintenance olaparib and ...bevacizumab in patients regardless of
mutation status is unknown.
We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or
mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death.
Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval CI, 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had
mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have
mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab.
In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a
mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).
To assess the patterns and time trends in overall survival and progression-free survival treatment effects across randomized controlled trials (RCTs) in oncology.
A PubMed search for oncology network ...meta-analyses (NMAs) was carried (to September 30, 2021). Relevant hazard ratios were extracted for systemic treatments from RCTs in the NMAs. After removing duplicate results, relationships between treatment effects, year of publication, trial design, and other features were explored.
From 241 oncology NMAs, 2,109 unique eligible RCTs provided analyzable data. On average, there was a 12%–14% reduction in hazard for overall survival and 27%–30% reduction for progression-free survival, with substantial heterogeneity across different malignancies. Correlation between overall survival and progression-free survival treatment effects was modest (r = 0.60, 95% confidence interval, 0.56–0.64). Over time, there was a suggestive trend of increased progression-free survival treatment effect, although overall survival treatment effects remained steady. Only one in five trials met criteria for clinically meaningful improvements in overall survival. Among 300 randomly selected trials, mean absolute improvement was 1.6 months for median progression-free survival and 1.4 months for median overall survival.
Broad patterns across the past 50 years of oncology research suggest continuous progress has been made, but few results meet clinically meaningful thresholds for overall survival improvement.
Background
Survival differences between left‐sided colon cancer (LSCC) and right‐sided colon cancer (RSCC) has been previously reported with mixed results, with various study periods not accounting ...for other causes of mortality.
Purpose
We sought to assess the trends in colon cancer cause‐ specific survival (CSS) and overall survival (OS) based on sidedness.
Method
Fine‐Gray competing risk and Cox models were used to analyze Surveillance, Epidemiology, and End Results (SEER) population‐based cohort from 1975 to 2019. Various interval periods were identified based on the timeline of clinical adoption of modern chemotherapy (1975–1989, interval period A; 1990–2004, B; and 2005–2019, C).
Results
Of the 227,637 patients, 50.1% were female and 46.2% were RSCC. RSCC was more common for African Americans (51.5%), older patients (age ≥65; 51.4%), females (50.4%), while LSCC was more common among Whites (53.1%; p < 0.001), younger patients (age 18–49, 64.6%; 50–64, 62.3%; p < 0.001), males (58.1%; p < 0.001). The Median CSS for LSCC and RCC were 19.3 and 16.7 years respectively for interval period A (1975–1989). Median CSS for interval periods B and C were not reached (more than half of the cohort was still living at the end of the follow‐up period). Adjusted CSS was superior for LSCC versus RSCC for the most recent interval period C (HR 0.89; 0.86–0.92; p < 0.001). LSCC consistently showed superior OS for all study periods. Stage stratification showed worse CSS for localized and regional LSCC in the earlier study periods, but the risk attenuated over time. However, left sided distant disease had superior CSS per stage for all interval periods. OS was better for LSCC irrespective of stage, with gradual improvement over time.
Conclusion
LSCC was associated with superior survival compared to right sided tumors. With the adoption of modern chemotherapy regimens, prognosis between LSCC and RSCC became more divergent in favor of LSCC. Colon cancer clinical trials should strongly consider tumor sidedness as an enrollment factor.
The increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) ...are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials.
We systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival.
Thirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75).
One-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.
•This comprehensive systematic review and meta-analysis fulfill an unmet need by deciphering the prognostic role of Tumor Associated Macrophage (TAM) markers (CD68, CD163, CD204, CD206, iNOS, HLA-DR ...and CD11b) in HNSCC.•A low number of CD163+TAMs correlates to better overall survival, disease free survival and progression free survival.•CD163 is potentially a strong prognosticator of survival than CD68.•Limited studies have been conducted on the prognostic role of M1-like TAMs. This could potentially be attributed to the lack of a robust immunohistochemical marker for M1-like TAMs.
Head and neck squamous cell carcinoma (HNSCC) is an immunogenic cancer type, and tumor associated macrophages (TAMs) are a major component of the tumor microenvironment (TME). In this systematic review and meta-analysis, studies assessing tumor infiltration with CD68+, iNOS+, HLA-DR+, CD11b+, CD163+, CD206+, and CD204+TAMs were included, and correlation to survival hazard was studied. A low number of CD68+TAMs correlated to better overall survival (OS) in multivariate analysis (HR 1.36 95 %CI (1.07–1.72) P = .01). CD68+TAMs did not correlate to disease free survival (DFS), disease specific survival (DSS), progression free survival (PFS), or recurrence free survival (RFS). A low number of CD163+TAMs correlated to better OS in uni- and multivariate analysis (resp. HR 2.65 95 %CI (1.57–4.46) P = .01 and HR 2.42 95 %CI (1.72–3.41) P < .001). A low number of CD163+TAMs also correlated to better DFS and PFS, whereas a low number of CD204+TAMs only correlated to PFS. While IHC analysis of pan macrophage marker CD68 and M2-like marker CD163 both show prognostic utility in OS, CD163 is a stronger prognosticator, as indicated by multivariate meta-analysis. CD163+TAMs also correlate to DFS and PFS; outcomes that are more relevant to patients, thus showing promising results for future clinical implementation.
Tumor-infiltrating lymphocytes play an essential role in improving clinical outcome of neuroblastoma (NB) patients, but their relationship with other tumor-infiltrating immune cells in the T ...cell-inflamed tumors remains poorly investigated. Here we show that dendritic cells (DCs) and natural killer (NK) cells are positively correlated with T-cell infiltration in human NB, both at transcriptional and protein levels, and associate with a favorable prognosis. Multiplex imaging displays DC/NK/T cell conjugates in the tumor microenvironment of low-risk NB. Remarkably, this connection is further strengthened by the identification of gene signatures related to DCs and NK cells able to predict survival of NB patients and strongly correlate with the expression of PD-1 and PD-L1. In summary, our findings unveil a key prognostic role of DCs and NK cells and indicate their related gene signatures as promising tools for the identification of clinical biomarkers to better define risk stratification and survival of NB patients.
Abstract Objectives To assess the impact of neural invasion/NI on overall survival/OS and tumor recurrence in pancreatic ductal adenocarcinoma/PDAC. Summary background data NI is a histopathological ...hallmark of PDAC. Although some studies suggested an important role for NI on OS, disease-free/DFS and progression-free survival/PFS in PDAC, there is still no consensus on the actual role of NI on survival and local recurrence in PDAC. Methods Pubmed, Cochrane library, Ovid and Google Scholar were screened for the terms “pancreatic ductal adenocarcinoma”, “pancreatic cancer”, “survival”, “tumor recurrence” and “perineural invasion”. The P referred– R eporting- I tems-for- S ystematic-review-and- M eta- A nalysis/PRISMA-guidelines were used for systematic review and meta-analysis. Articles meeting predefined criteria were critically analysed on relevance, and meta-analyses were performed by pooling univariate and multivariate hazard ratios/HR. Results A total number of 25 studies on the influence of NI on tumor recurrence, and 121 studies analysing the influence of NI on survival were identified by systematic review. The HR of the univariate (HR 1.88; 95%-CI 1.71–2.07; p < 0.00001) and multivariate meta-analysis (HR 1.68; 95%-CI 1.47–1.92; p < 0.00001) showed a major impact of NI on OS. Likewise, NI was associated with decreased DFS (HR 2.53; 95%-CI: 1.67–3.83; p = 0.0001) and PFS (HR 2.41; 95%-CI: 1.73–3.37: p < 0.00001) multivariate meta-analysis. Conclusions Although the power of this study is limited by missing pathological procedures to assess the true incidence of NI, NI appears to be an independent prognostic factor for OS, DFS and PFS in PDAC. Therefore, NI should be increasingly considered in patient stratification and in the development of novel therapeutic algorithms.
BACKGROUND
Stomach cancer was a leading cause of cancer‐related deaths early in the 20th century and has steadily declined over the last century in the United States. Although incidence and death ...rates are now low, stomach cancer remains an important cause of morbidity and mortality in black, Asian and Pacific Islander, and American Indian/Alaska Native populations.
METHODS
Data from the CONCORD‐2 study were used to analyze stomach cancer survival among males and females aged 15 to 99 years who were diagnosed in 37 states covering 80% of the US population. Survival analyses were corrected for background mortality using state‐specific and race‐specific (white and black) life tables and age‐standardized using the International Cancer Survival Standard weights. Net survival is presented up to 5 years after diagnosis by race (all, black, and white) for 2001 through 2003 and 2004 through 2009 to account for changes in collecting Surveillance, Epidemiology, and End Results Summary Stage 2000 data from 2004.
RESULTS
Almost one‐third of stomach cancers were diagnosed at a distant stage among both whites and blacks. Age‐standardized 5‐year net survival increased between 2001 to 2003 and 2004 to 2009 (26.1% and 29%, respectively), and no differences were observed by race. The 1‐year, 3‐year, and 5‐year survival estimates were 53.1%, 33.8%, and 29%, respectively. Survival improved in most states. Survival by stage was 64% (local), 28.2% (regional), and 5.3% (distant).
CONCLUSIONS
The current results indicate high fatality for stomach cancer, especially soon after diagnosis. Although improvements in stomach cancer survival were observed, survival remained relatively low for both blacks and whites. Primary prevention through the control of well‐established risk factors would be expected to have the greatest impact on further reducing deaths from stomach cancer. Cancer 2017;123:4994‐5013. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
In this analysis of stomach cancer survival for 80% of the US population, age‐standardized 5‐year net survival remains low, but it improved slightly between 2001‐2003 and 2004‐2009. The differences between blacks and whites in pooled 5‐year survival for 37 states combined are not large. Primary prevention through control of well‐established risk factors will be an important public health action for the longer term.
Background
Because the addition of nimotuzumab to chemoradiation in patients with locally advanced head and neck cancer improved outcomes in a phase 2 study, the authors conducted a phase 3 study to ...confirm these findings.
Methods
This open‐label, investigator‐initiated, phase 3, randomized trial was conducted from 2012 to 2018. Adult patients with locally advanced head and neck cancer who were fit for radical chemoradiation were randomized 1:1 to receive either radical radiotherapy (66‐70 grays) with concurrent weekly cisplatin (30 mg/m2) (CRT) or the same schedule of CRT with weekly nimotuzumab (200 mg) (NCRT).The primary endpoint was progression‐free survival (PFS); key secondary endpoints were disease‐free survival (DFS), duration of locoregional control (LRC), and overall survival (OS). An intent‐to‐treat analysis also was performed.
Results
In total, 536 patients were allocated equally to both treatment arms. The median follow‐up was 39.13 months. The addition of nimotuzumab improved PFS (hazard ratio HR, 0.69; 95% CI, 0.53‐0.89; P = .004), LRC (HR, 0.67; 95% CI, 0.50‐0.89; P = .006), and DFS (HR, 0.71; 95% CI, 0.55‐0.92; P = .008) and had a trend toward improved OS (HR, 0.84; 95% CI, 0.65‐1.08; P = .163). Grade 3 through 5 adverse events were similar between the 2 arms, except for a higher incidence of mucositis in the NCRT arm (66.7% vs 55.8%; P = .01).
Conclusions
The addition of nimotuzumab to concurrent weekly CRT improves PFS, LRC, and DFS. This combination provides a novel alternative therapeutic option to a 3‐weekly schedule of 100 mg/m2 cisplatin in patients with locally advanced head and neck cancer who are treated with radical‐intent CRT.
The addition of nimotuzumab to concurrent weekly cisplatin and chemoradiotherapy improves outcomes. This combination provides a novel alternative therapeutic option to a 3 weekly schedule of 100 mg/m2 cisplatin in patients with head and neck cancer.
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