Schmoll, Hans‐Joachim

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]

659 Background: Prospective survival prediction of patients with metastatic colorectal cancer is difficult. Prognosis estimation based on readily available clinicopathologic factors has the potential to inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for OS and PFS in mCRC using the multi-trial ARCAD database. Methods: Data from 19,678 mCRC pts accrued to 24 first line randomized phase III clinical trials since 1997 were used to construct and validate Cox models for PFS and OS, stratified by treatment arm within each study. Candidate variables included age, gender, BMI, performance status, colon vs. rectal cancer, prior chemotherapy, number of metastatic sites, sites of metastases (liver, lung, lymph nodes), and baseline bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil:lymphocyte ratio (dNLR). Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions considered if p<0.001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated using a 10% holdout sample from each trial. Results: Nomograms for OS and PFS including remaining variables were well calibrated with C-indices of 0.66 and 0.60, respectively. Evaluation of external validity revealed good concordance; 71% and 67% respectively between predicted (> vs. <50% probability) and actual (yes/no) 1-year OS and 6-month PFS, and median 1-year OS and 6-month PFS predictions fell within the actual 95% Kaplan-Meier intervals. Gender, liver and lung metastases, and dNLR were not prognostic for OS; prior chemo, colon vs. rectum, dNLR, liver and lymph node metastases, and gender did not predict for PFS. No clinically relevant pairwise interactions were identified. Conclusions: The proposed nomograms are well calibrated and internally and externally valid. These tools have the potential to aid prognostication and patient/physician communication, and balance risk in randomized trials in mCRC.

Purpose Fluorouracil plus leucovorin (FU + LV) adjuvant chemotherapy reduced the risk of recurrence and death across all time points in a pooled analysis of 20,898 patients with colon cancer from 18 randomized studies. The impact of oxaliplatin added to FU + LV on the time course of recurrence and survival remains unknown. Patients and Methods A total of 12,233 patients enrolled to the randomized trials C-07, C-08, N0147, MOSAIC (Adjuvant Treatment of Colon Cancer), and XELOXA (Adjuvant XELOX) were pooled to examine the impact of oxaliplatin and tumor-specific factors on the time course of recurrence and death. For each end point, continuous-time risk was modeled over 6 years post treatment in all oxaliplatin-treated patients and patients concurrently randomized to FU + LV with or without oxaliplatin; the latter analyses supported time-dependent treatment comparisons. Results Addition of oxaliplatin significantly reduced the risk of recurrence within the first 14 months post treatment for patients with stage II disease and within the first 4 years for patients with stage III disease. Oxaliplatin also significantly reduced risk of death from 2 to 6 years post treatment for patients with stage III disease, with no differences in timing of outcomes between treatment groups (ie, oxaliplatin did not simply postpone recurrence or death compared with FU + LV alone). Patients with stage II disease receiving oxaliplatin did not exhibit a significant reduction in risk of death in the first 6 years post treatment. Recurrence risk peaked near 14 months for both treatments, and risk of recurrence and death increased with increased tumor and nodal burden. Conclusions These analyses support the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy in patients with stage III disease and underscore the need for adequate surveillance of patients with colon cancer during the first 3 years after adjuvant therapy.

Purpose In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear. Patients and Methods Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted). Results BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m 2 , and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m 2 had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect. Conclusion Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.

PurposeProgression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.MethodsIndividual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.ResultsForty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.ConclusionIn modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.