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

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

Effect of <it>KRAS</it> codon13 mutations in patients with advanced colorectal cancer (advanced CRC) under oxaliplatin containing chemotherapy. Results from a translational study of the AIO colorectal study group

<p>Abstract</p> <p>Background</p> <p>To evaluate the value of <it>KRAS</it> codon 13 mutations in patients with advanced colorectal cancer (advanced CRC) treated with oxaliplatin and fluoropyrimidines.</p> <p>Methods</p> <p>Tumor specimens from 201 patients with advanced CRC from a randomized, phase III trial comparing oxaliplatin/5-FU vs. oxaliplatin/capecitabine were retrospectively analyzed for <it>KRAS</it> mutations. Mutation data were correlated to response data (Overall response rate, ORR), progression-free survival (PFS) and overall survival (OS).</p> <p>Results</p> <p>201 patients were analysed for <it>KRAS</it> mutation (61.2% males; mean age 64.2 ± 8.6 years). <it>KRAS</it> mutations were identified in 36.3% of tumors (28.8% in codon 12, 7.4% in codon 13). The ORR in codon 13 patients compared to codon 12 and wild type patients was significantly lower (p = 0.008). There was a tendency for a better overall survival in <it>KRAS</it> wild type patients compared to mutants (p = 0.085). PFS in all patients was not different in the three <it>KRAS</it> genetic groups (p = 0.72). However, we found a marked difference in PFS between patients with codon 12 and 13 mutant tumors treated with infusional 5-FU versus capecitabine based regimens.</p> <p>Conclusions</p> <p>Our data suggest that the type of <it>KRAS</it> mutation may be of clinical relevance under oxaliplatin combination chemotherapies without the addition of monoclonal antibodies in particular when overall response rates are important.</p> <p>Trial registration number</p> <p>2002-04-017</p

Microsatellite instability (MSI-H) is associated with a high immunoscore but not with PD-L1 expression or increased survival in patients (pts.) with metastatic colorectal cancer (mCRC) treated with oxaliplatin (ox) and fluoropyrimidine (FP) with and without bevacizumab (bev): a pooled analysis of the AIO KRK 0207 and RO91 trials

Introduction!#!In a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab (the AIO KRK 0207 and R091 trials) we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS).!##!Methods!#!In total, 550 samples were analysed. Immunohistochemical analysis of the MMR proteins and additionally fragment length analysis was performed, molecular examinations via allele-discriminating PCR in combination with DNA sequencing. Furthermore PD-L1 and IS were assessed.!##!Results!#!MSI-H tumors were more frequent in right sided tumors (13.66% vs. 4.14%) and were correlated with mutant BRAF (p = 0.0032), but not with KRAS nor NRAS mutations (MT). 3.1% samples were found to be PD-L1 positive, there was no correlation of PDL1 expression with MSI-H status, but in a subgroup analysis of MSI-H tumors the percentage of PD-L1 positive tumors was higher than in MSS tumors (9.75% vs. 2.55%). 8.5% of samples showed a positive IS, MSI-H was associated with a high IS. The mean IS of the pooled population was 0.57 (SD 0.97), while the IS of MSI-H tumors was significantly higher (mean of 2.4; SD 1.4; p =&amp;lt; 0.0001).!##!Discussion!#!Regarding OS in correlation with MSI-H, PD-L1 and IS status we did not find a significant difference. However, PD-L1 positive mCRC tended to exhibit a longer OS compared to PD-L1 negative cancers (28.9 vs. 22.1 months)