Quality of life and cost of strategies of two chemotherapy lines in metastatic colorectal cancer: results of the FFCD 2000-05 trial.

Objectives: This study compared the cost and quality of life (QoL) of 407 advanced colorectal cancer patients, randomly assigned to receive LV5FU2 followed by FOLFOX6 (sequential strategy) or FOLFOX6 followed by FOLFIRI (combination strategy). Methods: Costs were compared from the French health insurance perspective, until the end of the second line of treatment. Consumed resources, collected during the trial, included medicines, hospitalizations, examinations, and transportation. Valuations were made using 2009 and 2016 tariffs. QoL was assessed using the QLQ-C30 questionnaire and clinically significant variations were searched. Results: In 2009, the mean cost per patient was significantly lower for the sequential strategy compared to the combination strategy (18,061€ and 23,119€, p = 0.001). In 2016, the difference was no longer significant (16,876€ and 18,090€, p = 0.41) because oxaliplatin and irinotecan became generics. The QoL analysis (292 patients) showed that there was significantly less improvement of global health status in the sequential strategy than in the combination strategy (29% and 42%; p = 0.02) during first-line therapy. No significant differences were observed for emotional functioning (p = 0.45) and physical functioning (p = 0.07) or during second-line therapy. Conclusion: The choice to treat patients with advanced colorectal cancer using one or the other strategy cannot be based on costs or QoL.

Extrapolation of Survival Curves from Cancer Trials Using External Information.

BACKGROUND: Estimates of life expectancy are a key input to cost-effectiveness analysis (CEA) models for cancer treatments. Due to the limited follow-up in Randomized Controlled Trials (RCTs), parametric models are frequently used to extrapolate survival outcomes beyond the RCT period. However, different parametric models that fit the RCT data equally well may generate highly divergent predictions of treatment-related gain in life expectancy. Here, we investigate the use of information external to the RCT data to inform model choice and estimation of life expectancy. METHODS: We used Bayesian multi-parameter evidence synthesis to combine the RCT data with external information on general population survival, conditional survival from cancer registry databases, and expert opinion. We illustrate with a 5-year follow-up RCT of cetuximab plus radiotherapy v. radiotherapy alone for head and neck cancer. RESULTS: Standard survival time distributions were insufficiently flexible to simultaneously fit both the RCT data and external data on general population survival. Using spline models, we were able to estimate a model that was consistent with the trial data and all external data. A model integrating all sources achieved an adequate fit and predicted a 4.7-month (95% CrL: 0.4; 9.1) gain in life expectancy due to cetuximab. CONCLUSIONS: Long-term extrapolation using parametric models based on RCT data alone is highly unreliable and these models are unlikely to be consistent with external data. External data can be integrated with RCT data using spline models to enable long-term extrapolation. Conditional survival data could be used for many cancers and general population survival may have a role in other conditions. The use of external data should be guided by knowledge of natural history and treatment mechanisms.

[New applications for individual participant data meta-analyses of randomized trials]. / Les nouvelles applications des méta-analyses d'essais randomisés sur données individuelles.

Meta-analyses of randomized trials using individual-participant data, which represent the highest level of evidence for the evaluation of a treatment effect, are now used in different contexts in clinical research. This article aims at reviewing some of these new applications. Meta-analyses are increasingly used in economic evaluation, which implies new measure outcomes of the treatment effect, as well as in biomarkers evaluations thanks to their higher statistical power and the possibility to validate findings on independent data. This article also considers the perspectives opened up by new data sources, such as randomized trials registers, and data sharing policies.

Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study.

OBJECTIVE: In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. METHODS: We used IPD from the Meta-Analysis of Radiotherapy in Lung Cancer concerning 2,000 patients with locally advanced non-small cell lung cancer, included in ten trials. We considered methods either used in the field of meta-analysis or in economic evaluation but never applied to assess the rmstD for economic evaluation using IPD meta-analysis. Methods were classified into two approaches. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial. RESULTS: The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. The estimated rmstDs ranged from 1.7 month to 2.5 months, and mean ICERs ranged from € 24,299 to € 34,934 per life-year gained depending on the chosen method. At a ceiling ratio of € 25,000 per life year-gained, the probability of the experimental treatment being cost-effective ranged from 31% to 68%. CONCLUSIONS: This case study suggests that the method chosen to estimate the rmstD from IPD meta-analysis is likely to influence the results of cost-effectiveness analyses.

Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis.

BACKGROUND: In investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, overall survival (OS) is considered the gold standard endpoint. However, the disadvantage of using OS as the endpoint is that it requires an extended follow-up period. We sought to investigate whether disease-free survival (DFS) is a valid surrogate for OS in trials of adjuvant chemotherapy for gastric cancer. METHODS: The GASTRIC group initiated a meta-analysis of individual patient data collected in randomized clinical trials comparing adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. Surrogacy of DFS was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints. External validation of the prediction based on DFS was also evaluated. RESULTS: Individual patient data from 14 randomized clinical trials that included a total of 3288 patients were analyzed. The rank correlation coefficient between DFS and OS was 0.974 (95% confidence interval [CI] = 0.971 to 0.976). The coefficient of determination between the treatment effects on DFS and on OS was as high as 0.964 (95% CI = 0.926 to 1.000), and the surrogate threshold effect based on adjusted regression analysis was 0.92. In external validation, the six hazard ratios for OS predicted according to DFS were in very good agreement with those actually observed for OS. CONCLUSIONS: DFS is an acceptable surrogate for OS in trials of cytotoxic agents for gastric cancer in the adjuvant setting.

Cost effectiveness of modified fractionation radiotherapy versus conventional radiotherapy for unresected non-small-cell lung cancer patients.

INTRODUCTION: Modified fractionation radiotherapy (RT), delivering multiple fractions per day or shortening the overall treatment time, improves overall survival for non -small-cell lung cancer (NSCLC) patients compared with conventional fractionation RT (CRT). However, its cost effectiveness is unknown. Therefore, we aimed to examine and compare the cost effectiveness of different modified RT schemes and CRT in the curative treatment of unresected NSCLC patients. METHODS: A probabilistic Markov model was developed based on individual patient data from the meta-analysis of radiotherapy in lung cancer (N = 2000). Dutch health care costs, quality-adjusted life years (QALYs), and net monetary benefits (NMBs) were compared between two accelerated schemes (very accelerated RT [VART] and moderately accelerated RT [MART]), two hyperfractionated schemes (using an identical (HRT) or higher (HRT) total treatment dose than CRT) and CRT. RESULTS: All modified fractionations were more effective and costlier than CRT (1.12 QALYs, &OV0556;24,360). VART and MART were most effective (1.30 and 1.32 QALYs) and cost &OV0556;25,746 and &OV0556;26,208, respectively. HRT and HRT yielded less QALYs than the accelerated schemes (1.27 and 1.14 QALYs), and cost &OV0556;26,199 and &OV0556;29,683, respectively. MART had the highest NMB (&OV0556;79,322; 95% confidence interval [CI], &OV0556;35,478-&OV0556;133,648) and was the most cost-effective treatment followed by VART (&OV0556;78,347; 95% CI, &OV0556;64,635-&OV0556;92,526). CRT had an NMB of &OV0556;65,125 (95% CI, &OV0556;54,663-&OV0556;75,537). MART had the highest probability of being cost effective (43%), followed by VART (31%), HRT (24%), HRT (2%), and CRT (0%). CONCLUSION: Implementing accelerated RT is almost certainly more efficient than current practice CRT and should be recommended as standard RT for the curative treatment of unresected NSCLC patients not receiving concurrent chemo-radiotherapy.

Validation of a risk-assessment scale and a risk-adapted monitoring plan for academic clinical research studies--the Pre-Optimon study.

CONTEXT: Good Clinical Practice regulates monitoring activities in clinical research. Due to question and design diversity, and limited resources, on-site monitoring is often less intensive in the academic context, and variable. Standardization is needed, and relies on definition and validation of tools accounting for risk. OBJECTIVE: To define, and validate tools, to implement a risk-based monitoring strategy for academic clinical research. METHODS: Working groups of experienced professionals searched the literature, and built a consensus risk-assessment scale (RAS), and a risk-adapted monitoring plan (RAMP). We allocated 200 protocols to 49 assessors. We assessed the RAS relevance vs. a visual analogue scale (VAS), and its reproducibility through Kraemer's kappa, and intraclass correlation coefficient (ICC) from a random proportional odds model. We identified sources of disagreement through a logistic regression. We described assessors' difficulties during assessment. We applied the RAMP to 10 protocols per risk level, and rated its feasibility (0 = easy to 4 = impossible). RESULTS: RAS and RAMP were defined in 4 levels. RAS relevance was good: RAS-risk levels were evenly distributed on VAS-risk (0.6, 2.6, 5.6, and 7.9). Reproducibility was moderate to good: kappa=0.48, ICC=0.70. Major disagreements (36%) arose from decision-makers, rather than hands-on managers. Most difficulties occurred in ill-written protocols (17%). RAMP was easily feasible for most protocols (mean score: 0.2 to 0.9). We proposed a standard synopsis for evaluation purpose. CONCLUSION: We defined, and validated risk-based tools. This risk-adapted strategy will be compared to an intensive one in a randomized trial, Optimon, to define a standard of practice for academic clinical research.

Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.

PURPOSE: The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. RESULTS: The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5'UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5'UTR genotypes, respectively. Conversely, patients with the TS-5'UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). CONCLUSION: A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

Cost-effectiveness analysis of first-line chemotherapies in metastatic colorectal cancer. Results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 randomized trial.

BACKGROUND: The De Gramont regimen (or high-dose LV5FU2, HD-LV5FU2) is considered a standard treatment for metastatic colorectal cancer. The aim of the study was to evaluate the efficacy and the costs of three regimens as compared to HD-LV5FU2: raltitrexed (R), LV5FU2 with a lower dose of folinic acid (LD-LV5FU2), and weekly infusional 5FU (WI-FU). METHODS: An economic analysis was performed prospectively as part of a randomized trial comparing first-line chemotherapy regimens in 294 patients with unresectable metastatic colorectal cancer. The primary endpoint was event-free survival (EFS). Direct medical costs were computed from the health system viewpoint using 2001 unit costs. RESULTS: None of the three regimens improved EFS as compared to HD-LV5FU2. R was less effective and more toxic. The mean total cost per patient was euro 15,970 for HD-LV5FU2. The cost of R (10,687 euro) was lower than that of HD-LV5FU2 (p = 0.008). The cost of LD-LV5FU2 (14,888 euro) and of WI-FU (13,760 euro) was not significantly different from that of HD-LV5FU2. CONCLUSION: The lower efficacy and increased toxicity of R made it a clinically inferior regimen despite its easy administration and lower cost. The HD-LV5FU2 protocol remains a better treatment. LD-LV5FU2 appeared a good alternative regimen because it reduced costs without jeopardizing its efficacy. The WI-FU regimen did not show a significant difference in terms of efficacy, but suggested toxicity to be slightly increased.

Clinical research infrastructures and networks in France: report on the French ECRIN workshop.

A meeting was organised in Paris on 13 September 2004, to provide an in-depth description of the state of the art in institutional clinical research infrastructures and their environment in France. This meeting was scheduled within the ECRIN (European Clinical Research Infrastructures Network) project, funded by the European Union (6th Framework Programme). Ten items were addressed: (i) centres and networks; (ii) funding and sponsoring of clinical research; (iii) ethics; (iv) legislation and regulation; (v) adverse-event reporting and drug dispensing; (vi) methodology, data management and data monitoring; (vii) quality management and audits; (viii) communication with investigators, sponsors and participants; (ix) transparency and registration of clinical studies; and (x) education and careers. This description, together with parallel workshops held in other countries using a similar pattern, helped prepare a comparative analysis enabling better identification of the bottlenecks for multinational research in Europe, and define the most relevant approaches to harmonisation and the services required to support the role of sponsors in transnational studies.