Sommeijer, Dirkje W.

Abstract Meta-analysis based on individual participant data (IPD) is a powerful methodology for synthesizing evidence by combining information drawn from multiple trials. Hitherto, its principal application has been in questions of clinical management, but an increasingly important use is in clarifying trials methodology, for instance in the selection of endpoints, as discussed in this review. In oncology, the Aide et Recherche en Cancérologie Digestive (ARCAD) Metastatic Colorectal Cancer Database is a leader in the use of IPD-based meta-analysis in methodological research. The ARCAD database contains IPD from more than 38 000 patients enrolled in 46 studies and continues to collect phase III trial data. Here, we review the principal findings of the ARCAD project in respect of endpoint selection and examine their implications for cancer trials. Analysis of the database has confirmed that progression-free survival (PFS) is no longer a valid surrogate endpoint predictive of overall survival in the first-line treatment of colorectal cancer. Nonetheless, PFS remains an endpoint of choice for most first-line trials in metastatic colorectal cancer and other solid tumors. Only substantial PFS effects are likely to translate into clinically meaningful benefits, and accordingly, we advocate an oncology research model designed to identify highly effective treatments in carefully defined patient groups. We also review the use of the ARCAD database in assessing clinical response including novel response metrics and prognostic markers. These studies demonstrate the value of IPD as a tool for methodological studies and provide a reference point for the expansion of this approach within clinical cancer research.

3520 Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values <0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p<.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p<.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p<0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.

Abstract Background Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. This study examines the effect of shared decision-making (SDM) training for medical oncologists on observed SDM in standardized patient assessments. Materials and Methods A randomized controlled trial comparing training with standard practice was conducted. Medical oncologists and oncologists-in-training (n = 31) participated in a video-recorded, standardized patient assessment at baseline (T0) and after 4 months (T1, after training). The training was based on a four-stage SDM model and consisted of a reader, two group sessions (3.5 hours each), a booster session (1.5 hours), and a consultation card. The primary outcome was observed SDM as assessed with the Observing Patient Involvement scale (OPTION12) coded by observers blinded for arm. Secondary outcomes were observed SDM per stage, communication skills, and oncologists’ satisfaction with communication. Results The training had a significant and large effect on observed SDM in the simulated consultations (Cohen's f = 0.62) and improved observed SDM behavior in all four SDM stages (f = 0.39–0.72). The training improved oncologists’ information provision skills (f = 0.77), skills related to anticipating/responding to emotions (f = 0.42), and their satisfaction with the consultation (f = 0.53). Conclusion Training medical oncologists in SDM about palliative systemic treatment improves their performance in simulated consultations. The next step is to examine the effect of such training on SDM in clinical practice and on patient outcomes. Implications for Practice Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. Hence, applying the premises of shared decision-making (SDM) is recommended. SDM is increasingly advocated based on the ethical imperative to provide patient-centered care and the increasing evidence for beneficial patient outcomes. Few studies examined the effectiveness of SDM training in robust designs. This randomized controlled trial demonstrated that SDM training (10 hours) improves oncologists’ performance in consultations with standardized patients. The next step is to examine the effect of training on oncologists’ performance and patient outcomes in clinical practice.

766 Background: Tumor-size-based endpoints such as depth of response have recently become a focus of investigations related to search for early on-treatment predictive markers for patients with colorectal cancer (Piessevaux et al. 2013; Cremolini et al., 2015; Heinemann et al., 2015). We evaluate the use of time-to-nadir (TTN) and depth-of-nadir (DoN) as potential surrogates for overall survival (OS). Methods: We have used the data from trials included in the ARCAD Advanced Colorectal Cancer Database. We have considered three sets of treatment comparisons: comparisons involving only chemotherapy agents (CT); involving anti-angiogenesic agents (ANG); and involving anti-EGFR agents (EGFR). For each of the sets separately, we applied a two-stage modelling approach (Renard et al. 2002) to jointly analyze the relative change of tumor size versus baseline (RCTS) and OS. In particular, in the first stage, a joint model for the repeated measurements of RCTS and OS was fitted to the data. Based on the model, treatment effects on OS and RCTS were estimated. Treatment effects on OS were expressed as log-hazard-ratios, while the effects on RCTS were expressed in terms of differences in the time-to-nadir (TTN) and in the depth of nadir (DoN). In the second stage, a linear regression was fitted through the estimated treatment effects on TTN/DoN and OS. The coefficient of determination (R2), computed by using the comparison-specific sample-size as weights, was used to quantify the strength of association between the treatment effects on TTN/DoN and OS. In particular, values of R2 larger than 0.75 were considered as indicating a good surrogate. Results: The CT set included 18 comparisons with 5726 pts. in total. For the treatment effects on TTN and OS, the value of R2 was estimated to be equal to 0.31, while for DoN and OS, it was equal to 0.01. For the ANG set (11 comparisons, 3964 pts.) the values of R2 were equal to 0.26 and 0.21, respectively, while for the EGFR set (16 comparisons, 4687 pts.) they were equal to 0.10 and 0.45, respectively. Conclusions: These preliminary results suggest that TTN and DoN are not good surrogates for OS in advanced colorectal cancer. More detailed analyses are ongoing and will be presented at the meeting.

666 Background: Early tumor shrinkage (ETS; ≥20% decrease from baseline) and early objective tumor response (EOTR; CR/PR by RECIST) are associated with improved PFS/OS to a similar extent than best overall response (BOR), confirmed response (ConfR) and non-progression rate (NPR; CR/PR/SD by RECIST) at the individual level in first-line mCRC (ASCO 2014, abstr 3538/3578). We assessed these RBEs at the trial level. Methods: Data were available on 12,185 pts enrolled in a total of 17 randomized trials of chemotherapy (CT) alone or with targeted agents (TAs). ETS, EOTR and NPR were assessed at 6/8/9 and 12 weeks (wks), whereas BOR and ConfR were ascertained within 26 wks from randomization. Association between treatment effects on RBEs and on PFS/OS was assessed by coefficients of determination (R2, adjusted for estimation errors) using a copula model). Results: None of the RBEs had consistently strong correlations with PFS or OS (Table). The number of trials was insufficient to obtain reliable estimates for antiangiogenics and anti-EGFR separately. Conclusions: Despite their individual-level associations with PFS and OS, RBEs do not appear to be surrogate endpoints in first-line mCRC, given their poor predictive ability. [Table: see text]