Abstract 372: Disease-free survival and overall survival from colon cancer is improved with fluorescence-guided surgery in metastatic mouse models

Abstract Background Disease-free survival with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence, in patients who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from nine randomized studies conducted between 1998 and 2009 were included; three trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18,396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (pT1-3 & pN1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high/deficient mismatch repair tumors. Trial level correlation between 3-year DFS and 5-year OS remained strong (R2 =0.82, 95% CI = 0.67 to 0.98; R2 =0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusion Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

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Abstract 726: Fluorophore-conjugated antibodies improve surgical resection of pancreatic cancer leading to prolonged disease-free survival and overall survival in orthotopic mouse models.

10.1158/1538-7445.am2013-726 ◽

2013 ◽

Author(s):

Cristina A. Metildi ◽

Sharmeela Kaushal ◽

Mark A. Talamini ◽

George A. Luiken ◽

Robert M. Hoffman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Surgical Resection ◽

Mouse Models ◽

Disease Free Survival ◽

Free Survival ◽

Disease Free

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Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

Cancers ◽

10.3390/cancers12102960 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2960 ◽

Cited By ~ 2

Author(s):

Ivana Manini ◽

Federica Caponnetto ◽

Emiliano Dalla ◽

Tamara Ius ◽

Giuseppe Maria Della Pepa ◽

...

Keyword(s):

Growth Kinetic ◽

Disease Free Survival ◽

Free Survival ◽

Guided Surgery ◽

Adjuvant Therapies ◽

Fluorescence Guided Surgery ◽

Similar Phenotype ◽

Cancer Inflammation ◽

Disease Free ◽

Glioma Microenvironment

The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALA-PALE) and healthy tissue (ALA−) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA− samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment.

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Endpoints in adjuvant trials: A systematic review of the literature in colon cancer and proposed definitions for future trials

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4018 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4018-4018

Author(s):

M. E. Buyse ◽

K. J. Punt ◽

C. H. Köhne ◽

P. Hohenberger ◽

R. Labianca ◽

...

Keyword(s):

Systematic Review ◽

Colon Cancer ◽

Overall Survival ◽

Disease Free Survival ◽

Review Of The Literature ◽

Free Survival ◽

Medical Oncologists ◽

Starting Point ◽

Definition Of ◽

Disease Free

4018 Background: Disease-free survival (DFS) is the primary endpoint of most trials testing adjuvant treatments. However many other endpoints are used. There is much confusion about these endpoints since different definitions were used among trials, or no definitions were provided at all. Moreover there is no consensus on either the definition of each endpoint or on the most relevant among these endpoints. This creates difficulties when comparing the results of various trials. Methods: Adjuvant trials in colon cancer were used as a model. A systematic review was performed on published adjuvant studies in colon cancer from 1997–2006, and the definitions of endpoints other than overall survival (OS) were recorded. A panel of medical oncologists, surgical oncologists, and a statistician, all with expertise in randomised trials in colorectal cancer, aimed to reach consensus on the definition of the various endpoints as well as to select the most relevant among these. Results: A total of 52 studies were identified. In addition to overall survival 8 other endpoints were used, and both the definition of these endpoints as well as the starting point differed considerably among these studies. No definition was provided for the endpoint in 19 (37%) studies and for the starting point in 30 (58%) studies. The panel reached consensus on the definition of each endpoint ( table ), and agreed that DFS, defined as the time from randomisation to any event irrespective of cause was considered to be the most relevant endpoint for adjuvant studies. The date of randomisation was considered to be the most appropriate starting point. Conclusions: The proposed guideline will help in the design of future adjuvant studies in colon cancer, and will achieve the uniformity required to facilitate cross-study comparisons. It may serve as a model for adjuvant studies in other solid tumors. [Table: see text] No significant financial relationships to disclose.

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Overall survival (OS) and updated disease-free survival (DFS) results of the NSABP C-08 trial assessing bevacizumab (B) in stage II and III colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.3508 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 3508-3508 ◽

Cited By ~ 3

Author(s):

C. J. Allegra ◽

G. A. Yothers ◽

M. J. O'Connell ◽

S. Sharif ◽

N. J. Petrelli ◽

...

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

Disease Free Survival ◽

Stage Ii ◽

Free Survival ◽

Disease Free

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Cochrane systematic review and meta-analysis of adjuvant chemotherapy for stage II colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3548 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3548-3548

Author(s):

Brandon Matthew Meyers ◽

Humaid Obaid Al-Shamsi ◽

Alvaro Tell Figueredo

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

Adjuvant Chemotherapy ◽

Meta Analysis ◽

Disease Free Survival ◽

Stage Ii ◽

Cochrane Systematic Review ◽

Free Survival ◽

Stage Ii Colon Cancer ◽

Disease Free

3548 Background: Colon cancer is potentially curable by surgery in the early stages of the disease. Adjuvant chemotherapy improves disease-free and overall survival in patients with stage III disease, but the magnitude of benefit in stage II colon cancer is less clear. A previous Cochrane systematic review and meta-analysis (SR/MA) found improved disease-free, but not overall survival (Figueredo et al., 2008). An updated SR/MA was performed to determine the effects of adjuvant chemotherapy on disease-free and overall survival in patients with stage II colon cancer. Methods: Relevant databases (MEDLINE, EMBASE, and Cochrane) were independently searched by all authors, using the same search strategy employed in the original study (1/1988 to 9/2012). Randomized trials containing data on stage II colon cancer patients undergoing adjuvant 5-fluorouracil (5FU) chemotherapy versus observation were included. Pooled results were expressed as hazard ratios (HR) whenever possible, or risk ratios (RR), with 95% confidence intervals (95%CI) using a random effects model. Results: Seven studies were identified, and included in the final SR/MA. Six of the 7 studies were included in the disease-free survival analysis (n=4587). Adjuvant 5FU was associated with better disease-free survival (RR 0.84 (95%CI 0.75-0.94)). All 7 studies (n=5353) were included in the overall survival analysis showing an improvement with adjuvant 5FU (HR 0.87 (95%CI 0.78-0.97)). There was no evidence of heterogeneity across the studies (I2 = 0% for all analyses). Conclusions: In stage II colon cancer, adjuvant 5FU chemotherapy statistically improves both disease-free and overall survival. Our SR/MA demonstrates, for the first time, an overall survival advantage with adjuvant chemotherapy in stage II colon cancer.

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Adjuvant Therapy for Stage II Colon Cancer: A Systematic Review From the Cancer Care Ontario Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group

Journal of Clinical Oncology ◽

10.1200/jco.2004.03.087 ◽

2004 ◽

Vol 22 (16) ◽

pp. 3395-3407 ◽

Cited By ~ 218

Author(s):

Alvaro Figueredo ◽

Manya L. Charette ◽

Jean Maroun ◽

Melissa C. Brouwers ◽

Lisa Zuraw

Keyword(s):

Systematic Review ◽

Colon Cancer ◽

Overall Survival ◽

Adjuvant Therapy ◽

Meta Analysis ◽

Disease Free Survival ◽

Stage Ii ◽

Free Survival ◽

Stage Ii Colon Cancer ◽

Disease Free

Purpose To develop a systematic review that would address the following question: Should patients with stage II colon cancer receive adjuvant therapy? Methods A systematic review was undertaken to locate randomized controlled trials comparing adjuvant therapy to observation. Results Thirty-seven trials and 11 meta-analyses were included. The evidence for stage II colon cancer comes primarily from a trial of fluorouracil plus levamisole and a meta-analysis of 1,016 patients comparing fluorouracil plus folinic acid versus observation. Neither detected an improvement in disease-free or overall survival for adjuvant therapy. A recent pooled analysis of data from seven trials observed a benefit for adjuvant therapy in a multivariate analysis for both disease-free and overall survival. The disease-free survival benefits appeared to extend to stage II patients; however, no P values were provided. A meta-analysis of chemotherapy by portal vein infusion has also shown a benefit in disease-free and overall survival for stage II patients. A meta-analysis was conducted using data on stage II patients where data were available (n = 4,187). The mortality risk ratio was 0.87 (95% CI, 0.75 to 1.01; P = .07). Conclusion There is preliminary evidence indicating that adjuvant therapy is associated with a disease-free survival benefit for patients with stage II colon cancer. These benefits are small and not necessarily associated with improved overall survival. Patients should be made aware of these results and encouraged to participate in active clinical trials. Additional investigation of newer therapies and more mature data from the presently available trials should be pursued.

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