Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomized controlled trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4533-4533
Author(s):  
Ulrich Ronellenfitsch ◽  
Katrin Jensen ◽  
Svenja Seide ◽  
Meinhard Kieser ◽  
Matthias Schwarzbach ◽  
...  
Keyword(s):  
Neoadjuvant Therapy ◽  
Treatment Effect ◽  
Treatment Effects ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Surrogate Endpoint ◽  
Threshold Effect ◽  
Free Survival ◽  
Gastroesophageal Adenocarcinoma ◽  
Surrogate Threshold Effect

4533 Background: Disease-free survival (DFS) is an appealing surrogate endpoint for overall survival (OS) in trials on neoadjuvant or adjuvant cancer therapy, because it is available faster and with less follow-up effort. The aim of this study was to assess if DFS can be a valid surrogate endpoint for OS when comparing neoadjuvant treatment followed by surgery to surgery alone for gastroesophageal adenocarcinoma. Methods: Individual patient data (IPD) from eight randomized controlled trials (n = 1,126 patients) which compared neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma were used for the analysis. Correlation between OS-time and DFS-time was calculated. Kaplan-Meier survival curves and corresponding hazard ratios (HRs) for treatment effects were separately determined for each trial. Subsequently, HRs were pooled in a meta-analysis using a random-effects model. An error-in-variables linear regression model was used to compare observed and predicted values. The minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS was estimated by calculating the surrogate threshold effect. Results: OS-time correlated strongly with DFS-time. HRs for OS and DFS were highly similar for all single trials. The meta-analysis yielded almost identical overall HRs for treatment effects on OS and DFS. The determination coefficient for the association between HRs for OS and DFS was 0.912 (95% confidence interval 0.75-1.0), indicating a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect was calculated at 0.79, indicating that a future trial yielding a hazard ratio for the treatment effect on DFS < 0.79 could be expected with a 95% probability to yield a hazard ratio for the treatment effect on OS < 1. Conclusions: DFS and OS strongly correlate both after neoadjuvant therapy followed by surgery and after surgery alone for gastroesophageal adenocarcinoma. Likewise, the treatment effects on the two endpoints are very similar. Consequently, DFS can be regarded an appropriate surrogate endpoint for OS in trials on neoadjuvant therapy for gastroesophageal adenocarcinoma.

Progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in advanced/recurrent gastric cancer (AGC) treatment: Individual-patient-data (IPD) based meta-analysis of randomized trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16506-e16506
Author(s):  
Koji Oba ◽  
Xavier Paoletti ◽  
Yung-Jue Bang ◽  
Olivier Bouché ◽  
Michel Ducreux ◽  
...  
Keyword(s):  
Treatment Effects ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Surrogate Endpoint ◽  
Threshold Effect ◽  
Patient Data ◽  
Individual Level ◽  
Measurable Disease ◽  
Surrogate Threshold Effect ◽  
The Individual

e16506 Background: In 2013, the GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research through International Collaboration) evaluated the surrogacy of PFS based on IPD of 4,069 patients from 20 randomized trials of AGC. Treatment effects on PFS and on OS were only moderately correlated, and we could not validate PFS as a surrogate endpoint for OS. More recent trials, with refined inclusion criteria and higher standards for evaluating progression, may allow for a more accurate estimate of the correlation. The 2nd round of the GASTRIC sought to re-evaluate the surrogacy of PFS for OS in AGC. Methods: The GASTRIC database was updated with trials published after 2010 which used RECIST (Response Evaluation Criteria in Solid Tumors). Since the proportional hazards assumption was questionable for PFS, we primarily used mean-time ratio as a treatment effect measure, estimated by using the log-logistic model. Using the meta-analytic approach, correlations between PFS and OS at the individual level (Rindiv), and between treatment effects on PFS and on OS at the trial level (Rtrial), were estimated using Spearman’s rank-correlation and estimation-error-adjusted regression, respectively. Surrogate threshold effect was estimated as well. Results: We analyzed 10,912 patient data (1st round 4,069 patients from 20 trials and 2nd round 6,843 patients from 17 trials). Overall, moderate correlations were found at the individual level (Rindiv = 0.75, 95%CI = 0.75 to 0.76 in Hougaard copula) and at the trial level (Rtrial = 0.77, 95%CI = 0.32 to 1.00), respectively. Surrogate threshold effect was equal to 1.29, i.e., observing 29% increase in mean PFS time would predict a significant increase of the OS time. In the subgroup of patients with measurable disease in the 2nd round dataset (4,866 patients), Rtrial was higher and equal to 0.93 (95%CI = 0.70 to 1.00), with STE equal to 1.21. These results were same for 1st and 2nd line trials. Conclusions: The meta-analysis indicates a strong correlation between treatment effects (expressed as log-mean-ratios) on PFS and OS in patients with measurable disease.

Event-Free Survival Is a Surrogate for Overall Survival in Patients Treated for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3744-3744 ◽  
Author(s):  
Richard F. Schlenk ◽  
Hartmut Döhner ◽  
Konstanze Döhner ◽  
Arnold Ganser ◽  
Michael Heuser ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Effect ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Effects ◽  
Regression Line ◽  
Threshold Effect ◽  
Coefficient Of Determination ◽  
Surrogate Threshold Effect ◽  
Acute Myeloid

Abstract Purpose: We evaluated whether event-free survival (EFS) can be used as a surrogate for overall survival (OS) in patients treated for acute myeloid leukemia. Material: We carried out a meta-analysis of individual patient data from four randomized clinical trials carried out under the auspices of the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG): AMLHD 98B (Schlenk et al. Leukemia 2004 18:1798-803; n=254), AMLSG 06-04 (NCT00151255, n=189), AMLSG 07-04 (NCT00151242, n=1,100) and AMLSG 12-09 (NCT01180322, n=268). Some of these trials addressed multiple therapeutic questions, which resulted in a total of 7 independent treatment comparisons. Methods: A two-level modelling approach was used to estimate the association between EFS and OS, and between the treatment effects on EFS and on OS. At the individual level, a copula was fitted to model the joint distribution of EFS and OS, and Spearman's rank correlation coefficient (rho) was used to quantify the association between the endpoints. At the trial-level, a linear regression was fitted through the estimated treatment effects (Weibull-model-based log hazard ratios) on EFS and OS, taking into account the estimation error. The coefficient of determination (R²) was used to quantify the association between the treatment effects. The surrogate threshold effect (STE) was estimated as the treatment effect on EFS that would predict a significant treatment effect on OS. Results: A total of n=1,811 patients were included in the analysis. Spearman's correlation coefficient was equal to 0.76 (standard error, SE, 0.015). The coefficient of determination (R²) of the linear regression between log hazard ratios on EFS and on OS was equal to 0.97 (SE 0.13). The intercept of the regression line was equal to -0.04 (SE 0.04) and the slope was equal to 0.80 (SE 0.21). The surrogate threshold effect was equal to 0.90. Using an alternative method of estimation of treatment effects, marginal proportional hazards models for EFS and OS, the R² was equal to 0.98 (SE 0.21), the intercept of the regression line was equal to -0.02 (SE 0.05), the slope was equal to 0.82 (SE 0.28), and the surrogate threshold effect was equal to 0.89. Further results for different subsets of patients, for example, those with activating FLT3 mutations, will be presented at the meeting. Interpretation: In this population of intensively-treated AML patients, there was a tight association between the treatment effect on EFS and OS, suggesting that the former can be used as a surrogate for the latter in clinical trials assessing the efficacy of new treatments. The surrogate threshold effect of about 0.90 and the regression analysis suggest that a reduction of at least 10% in the risk of an event would reliably predict a reduction of approximately 8% in the risk of death. Disclosures Schlenk: Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Teva: Honoraria, Research Funding; AROG: Honoraria, Research Funding; Amgen: Research Funding; Böhringer Ingelheim: Honoraria; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Buyse:IDDI: Employment; Novartis: Research Funding. Burzykowski:IDDI: Employment; Novartis: Research Funding.

scholarly journals The Prognostic Significance of Combined Pretreatment Fibrinogen and Neutrophil-Lymphocyte Ratio in Various Cancers: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Rongqiang Liu ◽  
Shiyang Zheng ◽  
Qing Yuan ◽  
Peiwen Zhu ◽  
Biao Li ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Meta Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Regression Analyses ◽  
Free Survival ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Meta Regression

Purpose. The prognostic value of a new scoring system, termed F-NLR, that combines pretreatment fibrinogen level with neutrophil-lymphocyte ratio has been evaluated in various cancers. However, the results are controversial. The purpose of this study was to comprehensively analyze the prognostic value of F-NLR score in patients with cancers. Methods. An integrated search of relevant studies was conducted by screening the PubMed and Embase databases. Pooled hazard ratios, with 95% confidence intervals (CIs), for overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) were calculated to estimate the prognostic significance of F-NLR score in patients with various tumors. A random effects model was used for comprehensive analysis, and subgroup and meta-regression analyses were used to explore sources of heterogeneity. Results. Thirteen articles reporting data from of 4747 patients were included in the study. Pooled analysis revealed that high F-NLR score was significantly associated with poor OS ( HR = 1.77 ; 95% CI, 1.51–2.08) and poor DFS/PFS ( HR = 1.63 ; 95% CI, 1.30–2.05). Subgroup and meta-regression analyses did not alter the prognostic role of F-NLR score in OS and DFS/PFS. Conclusions. Increased F-NLR score is significantly associated with poor prognosis in patients with cancers and can serve as an effective prognostic indicator.

scholarly journals Clinical significance of tumor-stroma ratio in head and neck cancer: a systematic review and meta-analysis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Alhadi Almangush ◽  
Rasheed Omobolaji Alabi ◽  
Giuseppe Troiano ◽  
Ricardo D. Coletta ◽  
Tuula Salo ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Clinical Significance ◽  
Neck Cancer ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Tumor Stroma ◽  
Free Survival ◽  
Hematoxylin And Eosin ◽  
Meta Analyses

Abstract Background The clinical significance of tumor-stroma ratio (TSR) has been examined in many tumors. Here we systematically reviewed all studies that evaluated TSR in head and neck cancer. Methods Four databases (Scopus, Medline, PubMed and Web of Science) were searched using the term tumo(u)r-stroma ratio. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were followed. Results TSR was studied in nine studies of different subsites (including cohorts of nasopharyngeal, oral, laryngeal and pharyngeal carcinomas). In all studies, TSR was evaluated using hematoxylin and eosin staining. Classifying tumors based on TSR seems to allow for identification of high-risk cases. In oral cancer, specifically, our meta-analysis showed that TSR is significantly associated with both cancer-related mortality (HR 2.10, 95%CI 1.56–2.84) and disease-free survival (HR 1.84, 95%CI 1.38–2.46). Conclusions The assessment of TSR has a promising prognostic value and can be implemented with minimum efforts in routine head and neck pathology.

scholarly journals Rise and fall of total mesorectal excision with lateral pelvic lymphadenectomy for rectal cancer: an updated systematic review and meta-analysis of 11,366 patients

2021 ◽  
Author(s):  
Gabriele Anania ◽  
Richard Justin Davies ◽  
Alberto Arezzo ◽  
Francesco Bagolini ◽  
Vito D’Andrea ◽  
...  
Keyword(s):  
Systematic Review ◽  
Rectal Cancer ◽  
Total Mesorectal Excision ◽  
Neoadjuvant Therapy ◽  
Functional Outcomes ◽  
Meta Analysis ◽  
Neoadjuvant Chemoradiotherapy ◽  
Disease Free Survival ◽  
Mesorectal Excision ◽  
Timeline Analysis

Abstract The role of lateral lymph node dissection (LLND) during total mesorectal excision (TME) for rectal cancer is still controversial. Many reviews were published on prophylactic LLND in rectal cancer surgery, some biased by heterogeneity of overall associated treatments. The aim of this systematic review and meta-analysis is to perform a timeline analysis of different treatments associated to prophylactic LLND vs no-LLND during TME for rectal cancer. Methods A literature search was performed in PubMed, SCOPUS and WOS for publications up to 1 September 2020. We considered RCTs and CCTs comparing oncologic and functional outcomes of TME with or without LLND in patients with rectal cancer. Results Thirty-four included articles and 29 studies enrolled 11,606 patients. No difference in 5-year local recurrence (in every subgroup analysis including preoperative neoadjuvant chemoradiotherapy), 5-year distant and overall recurrence, 5-year overall survival and 5-year disease-free survival was found between LLND group and non LLND group. The analysis of post-operative functional outcomes reported hindered quality of life (urinary, evacuatory and sexual dysfunction) in LLND patients when compared to non LLND. Conclusion Our publication does not demonstrate that TME with LLND has any oncological advantage when compared to TME alone, showing that with the advent of neoadjuvant therapy, the advantage of LLND is lost. In this review, the most important bias is the heterogeneous characteristics of patients, cancer staging, different neoadjuvant therapy, different radiotherapy techniques and fractionation used in different studies. Higher rate of functional post-operative complications does not support routinely use of LLND.

scholarly journals Clinical and prognostic significances of cancer stem cell markers in gastric cancer patients: a systematic review and meta-analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mahdieh Razmi ◽  
Roya Ghods ◽  
Somayeh Vafaei ◽  
Maryam Sahlolbei ◽  
Leili Saeednejad Zanjani ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Clinical Outcomes ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stem Cell Markers ◽  
Free Survival

Abstract Background Gastric cancer (GC) is considered one of the most lethal malignancies worldwide, which is accompanied by a poor prognosis. Although reports regarding the importance of cancer stem cell (CSC) markers in gastric cancer progression have rapidly developed over the last few decades, their clinicopathological and prognostic values in gastric cancer still remain inconclusive. Therefore, the current meta-analysis aimed to quantitatively re-evaluate the association of CSC markers expression, overall and individually, with GC patients’ clinical and survival outcomes. Methods Literature databases including PubMed, Scopus, ISI Web of Science, and Embase were searched to identify the eligible articles. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were recorded or calculated to determine the relationships between CSC markers expression positivity and overall survival (OS), disease-free survival (DFS)/relapse-free survival (RFS), disease-specific survival (DSS)/ cancer-specific survival (CSS), and clinicopathological features. Results We initially retrieved 4,425 articles, of which a total of 66 articles with 89 studies were considered as eligible for this meta-analysis, comprising of 11,274 GC patients. Overall data analyses indicated that the overexpression of CSC markers is associated with TNM stage (OR = 2.19, 95% CI 1.84–2.61, P = 0.013), lymph node metastasis (OR = 1.76, 95% CI 1.54–2.02, P < 0.001), worse OS (HR = 1.65, 95% CI 1.54–1.77, P < 0.001), poor CSS/DSS (HR = 1.69, 95% CI 1.33–2.15, P < 0.001), and unfavorable DFS/RFS (HR = 2.35, 95% CI 1.90–2.89, P < 0.001) in GC patients. However, CSC markers expression was found to be slightly linked to tumor differentiation (OR = 1.25, 95% CI 1.01–1.55, P = 0.035). Sub-analysis demonstrated a significant positive relationship between most of the individual markers, specially Gli-1, Oct-4, CD44, CD44V6, and CD133, and clinical outcomes as well as the reduced survival, whereas overexpression of Lgr-5, Nanog, and sonic hedgehog (Shh) was not found to be related to the majority of clinical outcomes in GC patients. Conclusion The expression of CSC markers is mostly associated with worse outcomes in patients with GC, both overall and individual. The detection of a combined panel of CSC markers might be appropriate as a prognostic stratification marker to predict tumor aggressiveness and poor prognosis in patients with GC, which probably results in identifying novel potential targets for therapeutic approaches.

scholarly journals P22 Are Elderly Patients at Increased Perioperative Morbidity and Mortality from Oesophagectomy for Oesophageal Cancer? A Systematic Mapping Review and Meta-Analysis

BJS Open ◽  
2021 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
Rohan R Gujjuri ◽  
Muhammed Elhadi ◽  
Hamza Umar ◽  
Manjunath S Subramanya ◽  
Richard P T Evans ◽  
...  
Keyword(s):  
Elderly Population ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
The Elderly ◽  
Pulmonary Complications ◽  
Cardiac Complications ◽  
Anastomotic Leaks ◽  
Free Survival ◽  
Younger Patients ◽  
Disease Free

Abstract Introduction Oesophagectomy is being increasingly performed in an ageing population that is observing a concomitant growth in the life expectancy. However, the risks are poorly quantified, and this study aims to review current evidence to further quantify the postoperative of oesophagectomy in the elderly population compared to younger patients. Methods A systematic electronic search was conducted for studies reporting oesophagectomy in the elderly population. Meta-analysis was performed using random-effects modelling to compute odds ratios (OR) and 95% confidence intervals (CI). Primary outcome was overall complications and secondary outcomes included anastomotic leaks, cardiac complications, pulmonary complications, overall and disease-free survival. Meta-regression was performed to identify study-, hospital- and patient-level factors confounding study findings. Results This review included 37 eligible studies involving 61,723 patients. Increasing age was significantly associated with increased rates of overall complications (OR: 1.67, CI 95%: 1.42 – 1.97), cardiac complications (OR: 1.62, CI 95%: 1.10 – 2.40), pulmonary complications (OR: 1.44, CI 95%: 1.11 – 1.87) and decreased 5-year overall survival (OR: 1.36, CI 95%: 1.11 – 1.66) and 5-year disease-free survival (OR: 1.66, CI 95%: 1.40 – 1.97). Rates of anastomotic leaks showed no difference between elderly and younger patients (OR: 1.06, CI 95%: 0.71 – 1.59). Conclusion Postoperative outcomes such as overall complications, 5-year overall survival and disease-free survival appear to significantly worse in all age cut-offs in this meta-analysis. Sarcopenia and frailty act as better predictors of postoperative outcomes than chronological age. This study confirms the preconceived suspicions of increased risks in elderly patients following oesophagectomy and will aid future pre-operative counselling and informed consent.

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