scholarly journals Building External Control Arms From Patient-Level Electronic Health Record Data to Replicate the Randomized IMblaze370 Control Arm in Metastatic Colorectal Cancer

2021 ◽  
pp. 450-458
Author(s):  
Carsten Schröder ◽  
Marcus Lawrance ◽  
Chen Li ◽  
Christelle Lenain ◽  
Shivani K. Mhatre ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
External Control ◽  
Standardized Mortality Ratio ◽  
Electronic Health Record Data ◽  
Patient Level ◽  
Randomized Control ◽  
Electronic Health

PURPOSE External control (EC) arms derived from electronic health records (EHRs) can provide appropriate comparison groups when randomized control arms are not feasible, but have not been explored for metastatic colorectal cancer (mCRC) trials. We constructed EC arms from two patient-level EHR-derived databases and evaluated them against the control arm from a phase III, randomized controlled mCRC trial. METHODS IMblaze370 evaluated atezolizumab with or without cobimetinib versus regorafenib in patients with mCRC. EC arms were constructed from the Flatiron Health (FH) EHR-derived de-identified database and the combined FH/Foundation Medicine Clinico-Genomic Database (CGDB). IMblaze370 eligibility criteria were applied to the EC cohorts. Propensity scores and standardized mortality ratio weighting were used to balance baseline characteristics between the IMblaze370 and EC arms; balance was assessed using standardized mean differences. Kaplan-Meier method estimated median overall survival (OS). Cox proportional hazards models estimated hazard ratios with bootstrapped 95% CIs to compare differences in OS between study arms. RESULTS The FH EC included 184 patients; the CGDB EC included 108 patients. Most characteristics were well-balanced (standardized mean difference < 0.1) between each EC arm and the IMblaze370 population. Median OS was similar between the IMblaze370 control arm (8.5 months [95% CI, 6.41 to 10.71]) and both EC arms: FH (8.5 months [6.93 to 9.92]) and CGDB (8.8 months [7.85 to 9.92]). OS comparisons between the IMblaze370 experimental arm and the FH EC (hazard ratio, 0.85 [0.64 to 1.14]) and CGDB EC (0.86 [0.65 to 1.18]) yielded similar results as the comparison with the IMblaze370 control arm (1.01 [0.75 to 1.37]). CONCLUSION EC arms constructed from the FH database and the CGDB closely replicated the control arm from IMblaze370. EHR-derived EC arms can provide meaningful comparators in mCRC trials when recruiting a randomized control arm is not feasible.

scholarly journals Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database

2017 ◽  
Vol 35 (17) ◽  
pp. 1929-1937 ◽  
Author(s):  
Lindsay A. Renfro ◽  
Richard M. Goldberg ◽  
Axel Grothey ◽  
Alberto Sobrero ◽  
Richard Adams ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
External Validation ◽  
Cox Proportional Hazards ◽  
Early Mortality ◽  
Phase Iii ◽  
Cancérologie Digestive ◽  
The Impact

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.

Influence of dietary insulin scores on survival in patients with metastatic colorectal cancer (mCRC): Findings from CALGB (Alliance) 80405.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3568-3568
Author(s):  
Katherine DiNardo ◽  
Chao Ma ◽  
Fang-Shu Ou ◽  
Chen Yuan ◽  
Brendan John Guercio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Proportional Hazards ◽  
Energy Content ◽  
Insulin Response ◽  
Continuous Variable ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Dietary Recommendations

3568 Background: Diets inducing an elevated insulin response have been associated with increased recurrence and mortality in patients with non-metastatic colorectal cancer, but it remains unknown if postprandial hyperinsulinemia also affects progression and mortality in mCRC patients. The goal of this study was to assess the influence of dietary insulin load (DIL) and dietary insulin index (DII) on survival of mCRC patients. Methods: This was a prospective cohort study of 1,177 patients with previously untreated mCRC enrolled in a phase III trial of systemic chemotherapy plus biologics who reported dietary intake within one month after chemotherapy initiation. DIL was calculated as a function of food insulin index and the energy content of individual foods reported on a food frequency questionnaire. DII was calculated by dividing DIL by total energy intake. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and treatment-related adverse events (TRAEs). The primary statistical test was a test for trend, which was performed using the median value for each quintile of dietary insulin score as a continuous variable. Cox proportional hazards regression was used to adjust for potential confounders including assigned treatment arm, known prognostic factors, comorbidities, body mass index, and physical activity. Results: Higher DIL was significantly associated with worse OS (ptrend = 0.04); patients in the highest quintile survived 34.1 months, compared to 27.7 months in the lowest quintile (Cox hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.99 - 1.51). Higher DII was non-significantly associated with worse OS (HR 1.18, 95% CI 0.94 - 1.48, ptrend = 0.09). There was no significant association between dietary insulin scores and PFS. The influence of dietary insulin scores on survival did not differ significantly by various molecular markers involved in the insulin signaling pathway, including C-peptide, adiponectin, IGF-1, IGFBP-3, and IGFBP-7. Higher dietary insulin scores were significantly associated with greater risk of any TRAE. Those with a DIL greater than the median had a 75.4% rate of any TRAE, compared to 70.8% in those with a DIL less than or equal to the median (HR 1.19, 95% CI 1.03 - 1.38, p=0.02); the most significant associations were with neutropenia (HR 1.30, 95% CI 1.05 - 1.61, p=0.01) and diarrhea (HR 1.43, 95% CI 1.00 - 2.06, p=0.05). Conclusions: Higher DIL was significantly associated with worse OS, and both higher DIL and DII were significantly associated with increased TRAEs, in patients with previously untreated mCRC. These findings may inform future dietary recommendations for patients with mCRC. Further investigation into the molecular mechanisms underlying these associations is warranted. Clinical trial information: NCT00265850.

scholarly journals Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group

2017 ◽  
Vol 28 (6) ◽  
pp. 1288-1293 ◽  
Author(s):  
J.J.M. Kwakman ◽  
L.H.J. Simkens ◽  
J.M. van Rooijen ◽  
A.J. van de Wouw ◽  
A.J. ten Tije ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Phase Iii Trial ◽  
Cancer Group ◽  
First Line Treatment

Dose-escalation strategy in refractory metastatic colorectal cancer: A change in terms of cost-effectiveness

2021 ◽  
pp. 107815522199254
Author(s):  
Jacopo Giuliani ◽  
Francesco Fiorica ◽  
Giovanni Ponturo ◽  
Maurizio Azzurro ◽  
Andrea Ruzzenente ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cost Effectiveness ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Lower Cost ◽  
Cost Effective ◽  
Phase Iii ◽  
Controlled Trials ◽  
Pivotal Phase ◽  
Randomized Controlled

The analysis was conducted to assess the pharmacological costs of regorafenib and trifluridine/tipiracil in the treatment of refractory metastatic colorectal cancer (mCRC). Pivotal phase III randomized controlled trials (RCTs) of regorafenib and trifluridine/tipiracil in the treatment of refractory mCRC were considered. We have also considered the ReDOS trial, in order to verify if the dose-escalation strategy (practice changing for regorafenib) could influences the results. Differences in OS (expressed in months) between the different arms were calculated and compared with the pharmacological costs (at the Pharmacy of our Hospital and expressed in euros (€)) needed to get one month of OS. Trifluridine/tipiracil resulted the less expensive, with 1167.50 €per month OS-gained. The ReDOS trial further reduce costs with 510.41 €per month OS-gained in favour of regorafenib with the escalation-dose strategy. Both regorafenib and trifluridine/tipiracil can be considered economically sustainable treatments for refractory mCRC, apparently with a lower cost of trifluridine/tipiracil. The adoption of a dose-escalation strategy (ReDOS trial) could reverse the situation making regorafenib more cost-effective than trifluridine/tipiracil.

scholarly journals Quality-of-life findings from a randomised phase-III study of XELOX vs FOLFOX-6 in metastatic colorectal cancer

2009 ◽  
Vol 102 (1) ◽  
pp. 59-67 ◽  
Author(s):  
T Conroy ◽  
M Hebbar ◽  
J Bennouna ◽  
M Ducreux ◽  
M Ychou ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Iii ◽  
Phase Iii Study

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 57-57
Author(s):  
Hideaki Bando ◽  
Daisuke Kotani ◽  
Masahito Kotaka ◽  
Akihito Kawazoe ◽  
Toshiki Masuishi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Braf V600e ◽  
Phase Iii ◽  
Fixed Dose ◽  
Wild Type ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

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