Effect of Risk Classification Discrepancy Between the MSKCC and IMDC Models on Prognosis in Patients with Metastatic Renal Cell Carcinoma - Beyond the Abstract
The survival rate of patients with mRCC has improved remarkably since the introduction of molecular-targeted therapy.1-9 Prognoses of patients with mRCC have been stratified in several classification tools, such as the MSKCC risk classification, the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification. Although the IMDC classifications was developed in the era of molecular-targeted therapy, the MSKCC risk classification was still widely used and reported in association with prognosis, even in the era of molecular-targeted therapy.10,11 Several studies externally validated the predictive accuracy of the MSKCC and IMDC models for prognosis in patients with mRCC treated with molecular-targeted drugs. This suggested that both the MSKCC and IMDC models could predict prognosis in patients with mRCC treated with molecular-targeted therapy.12,13 Although there is statistical feasibility between the risk models, there is a difference in the number of risk factors between the IMDC and MSKCC models. Indeed, the impact of risk group disagreement between the models remains unclear. We therefore investigated the impact of risk group disagreement on prognosis in real-world Japanese patients treated with first-line TKIs.
We retrospectively evaluated 176 patients with metastatic renal-cell carcinoma who were treated with TKIs as first-line therapy in 5 hospitals between October 2008 and August 2018. The risk group disagreement between the MSKCC and the IMDC models was evaluated using criteria of agreement (identical risk group in both MSKCC and IMDC models), upgrade (MSKCC-favorable to IMDC-intermediate, or MSKCC-intermediate to IMDC-poor), and downgrade (MSKCC-intermediate to IMDC-favorable, or MSKCC-poor to IMDC-intermediate). The agreement of risk stratification between the models was evaluated using the Cohen κ coefficient. Oncologic outcomes were compared between the agreement and disagreement groups.
The median age was 68 years. The number of patients with agreement and disagreement was 135 (77%) of 176 and 41 (23%) of 176, respectively. The Cohen k coefficient for the agreement of the 2 risk models was substantial with the k value of 0.613. The IMDC model significantly increased the number of patients in the poor risk group compared to the MSKCC model (P < 0.001). Of 41 patients with disagreement, reclassification from MSKCC-intermediate to IMDC-poor risk group was most frequent (34/176, 19%). There were significant differences in PFS (P = 0.002), CSS (P = 0.005), and OS (P = 0.004) between the agreement and disagreement groups. Respectively. IPTW-adjusted Cox regression analyses showed significant differences in PFS (HR = 1.86, P = 0.025), CSS (HR = 1.71, P = 0.040), and OS (HR = 1.75, P = 0.028) between the agreement and disagreement groups.
The major reason for risk group disagreement was neutrophil count greater than the upper limit of normal (88%, P < 0.001). In addition, there were significant differences in the abnormal value of hemoglobin (less than the lower limit of normal), serum calcium concentration (> 10 mg/dL), and C-reactive protein (CRP; > 0.3 mg/dL) between the 2 groups. Patients with abnormal serum calcium concentration were significantly fewer in the disagreement group (2%) than that of agreement group (15%). Univariate analysis for PFS and OS showed that neutrophil count and CRP were significantly associated with both poor PFS and OS.
In this study, we first show the oncologic outcomes of disagreement between the MSKCC and IMDC models in patients with treatment-naive mRCC. Majority of patients (39/41, 95%) experienced upgrade from MSKCC-intermediate to IMDC-poor risk group in the disagreement group. The main factors for the disagreement was an abnormal neutrophil count, hemoglobin, and CRP. These results suggested that systemic inflammatory markers which were not included in the MSKCC risk criteria may be a useful predictor for poor prognosis in the patients with first-line TKI therapy. Several studies suggested the impact of poor prognosis in patients with mRCC when an abnormal inflammatory response such as neutrophil-to-lymphocyte ratio (NLR) and CRP is seen.1,2,14-17 Previous studies examined the impact of CRP (cutoff values, 0.3-0.8 mg/dL) on OS in patients with mRCC treated with TKIs.17-19 Also, the addition of the baseline CRP to the IMDC model increased the c-index of OS from 0.65 to 0.70.19 Similarly, NLR (cutoff values, 2-4) may predict OS in patients with mRCC treated with molecular-targeted therapy.17,20,21 The addition of NLR to the IMDC model instead of neutrophil count significantly improves the predictive accuracy for OS.22 Although the optimal cutoff point remains unclear, the addition of abnormal inflammatory response to a prognostic model is meaningful and has the potential to improve the accuracy of risk models.
The abnormal inflammatory response might apply as a useful biomarker in the era of checkpoint inhibitors. Previous studies suggested that the impact of NLR on prognosis in immunotherapy treated patients.23,24 Further studies are necessary to address the relationship between an inflammatory marker and response to checkpoint inhibitors.
Although several limitations of the present study must be acknowledged, to our knowledge, this study represents the first study evaluating the influence of disagreement on oncologic outcomes between the MSKCC and IMDC models in real-world patients with treatment-naive mRCC. The clinical implication of the disagreement on risk stratifications on the era of checkpoint inhibitors requires further study.
Written by: Kazutaka Okita, MD, Toshikazu Tanaka, MD, Naoki Fujita, MD, and Shingo Hatakeyama, MD, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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