Abstract
Background/Aim: The therapeutic outcomes of patients with metastatic renal cell carcinoma (mRCC) have dramatically improved with the introduction of molecular-targeted agents. The observational multicenter study was conducted to develop a novel stratification system for the intermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. Patients and Methods: The present study included 252 Japanese patients with mRCC who received first-line molecular-targeted therapy at four institutions. Results: The 252 patients were classified into the favorable, intermediate, and poor risk groups by the IMDC model. For the intermediate risk group, multivariate analysis of the six factors included in the IMDC model revealed that a low performance status, anemia, and a high platelet count were independent predictors of poor overall survival (OS). The intermediate risk group was subsequently divided into the following two groups (int -group 1 and 2) by the three independent OS predictors. Significant differences in the OS were noted among the IMDC favorable risk group, int-group 1, int-group 2, and poor risk group. Conclusion: The novel stratification presented in this study could be a useful tool for further prognostication of patients with mRCC classified into the intermediate risk group according to the IMDC model after first-line molecular-targeted therapy.
- Metastatic renal cell carcinoma
- International Metastatic Renal Cell Carcinoma Database Consortium
- novel stratification system
- Japanese patients
The therapeutic outcomes of patients with metastatic renal cell carcinoma (mRCC) have dramatically improved with the introduction of molecular-targeted agents directly targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways (1, 2). Moreover, blocking major molecules involved in immune checkpoint pathways is effective for patients with various types of malignant tumors, and these new therapies are among the standards of care for patients with mRCC (3). Martini et al. suggested a novel risk scoring system for patients with mRCC treated with immune checkpoint inhibitors (4). However, current therapeutic strategies for mRCC have become markedly complex owing to the recent introduction of multiple agents, occasionally resulting in difficulties associated with decision-making in real-world clinical practice.
The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification model advocated by Heng et al. was established in the area of molecular-targeted therapy (5). This IMDC risk classification model includes six parameters, namely the time from RCC diagnosis to systemic therapy initiation, Karnofsky performance status (PS), anemia, neutrophilia, thrombophilia, and serum-corrected calcium. Although the IMDC model is the most widely accepted tool for the prognostication of patients with mRCC, there are several issues associated with the application of this model to routine clinical practice for patients with mRCC. Specifically the high proportion of patients classified into the intermediate risk group has been highlighted as a critical disadvantage of the IMDC model. In fact, several studies have shown the prognostic heterogeneity of the intermediate risk group classified according to the IMDC model (6-9). Accordingly, the selection of first-line agents for mRCC patients in the intermediate risk group remains arguable.
Considering these findings, it is necessary to properly re-classify the prognosis of patients corresponding to the intermediate risk group; therefore, we retrospectively analyzed the prognostic outcomes of mRCC patients receiving first-line molecular-targeted agents by focusing on the intermediate risk group and developed a novel system stratifying the prognosis of this category of patients.
Patients and Methods
In the current study, we retrospectively reviewed the clinicopathological data of 252 consecutive Japanese patients with mRCC who received first-line molecular-targeted therapy between January 2001 and November 2018 at four institutions belonging to the Tokai Urologic Oncology Research Seminar, including the Fujita Health University School of Medicine, Nagoya City University Graduate School of Medical Sciences, Hamamatsu University School of Medicine, and Aichi Medical University School of Medicine. The design of this study was approved by the ethics committee of these four institutions (approval number of Fujita Health University School of Medicine: HM19-144). The need for informed consent from all patients included in this study was waived because of the retrospective design.
In this series, all the patients received one of the six molecular-targeted agents (axitinib, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus) currently available in Japanese clinical practice as first-line therapy for mRCC, and the first-line agent was generally selected based on the preference of the physicians and patients without strictly determined criteria. Each molecular-targeted agent was administered according to standard dosing schedules, as previously reported (10-15); however, the dose modification of each agent was permitted considering the severity of adverse events.
The clinicopathological data of each patient were collected from medical records. Baseline assessments were performed prior to the introduction of the first-line molecular-targeted agent: the PS was assessed by using the Karnofsky PS scale (16), and laboratory data were measured by standard methods. In addition, all patients underwent radiological examinations including computed tomography of the brain, chest, and abdomen and/or radionuclide bone scanning. On the basis of the findings on these assessments, the risk classification of each patient was evaluated according to the IMDC system (5). Tumor measurements were generally performed by using computed tomography every 12 weeks after initiating first-line targeted therapy, and an investigator determined the tumor responses according to the Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 (17). Overall survival (OS) was defined as the duration between the start of first-line targeted therapy and the date of death from any cause or censorship on the day of the last visit.
Statistical analysis. All data were analyzed using IBM SPSS Statistics version 23 (SPSS Japan Inc., Tokyo, Japan), and a p-value <0.05 was considered significant in all statistical analyses. The comparison between two groups was performed using the chi-square test or Fisher's exact test. OS was estimated using the Kaplan-Meier method, and the differences were determined using the log-rank test. The prognostic significance of certain factors was assessed by multivariate analysis.
Patient characteristics.
Results
The clinical characteristics of the 252 patients with mRCC included in this study are summarized in Table I. Although all patients were clinically diagnosed with primary RCC with metastatic spread, a histopathological diagnosis was not made in 33 patients (13.1%). According to the IMDC model, the 252 patients were classified into the favorable, intermediate, and poor risk groups with 40 (15.9%), 145 (57.5%), and 67 patients (26.6%), respectively. During the observation period, 124 of the 252 patients (49.2%) died, and the median OS in the 252 patients was 38 months.
To investigate the impact of six factors consisting the IMDC model on the OS of the intermediate risk group patients, Cox regression analysis was performed. Of these six factors, a low PS score (<80), anemia (less than the lower limit of the normal value), and a high platelet count (greater than the upper limit of the normal value) were independently associated with OS of the intermediate risk group (p=0.003, 0.025, and 0.048, respectively; Table II).
Multivariate analysis of the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classification for the intermediate risk group (n=145).
Patients characteristics of the intermediate risk group (n=145).
Considering the three independent predictors of OS, we stratified the 145 patients in the intermediate risk group into the following two groups: int-group 1 included 46 patients negative for the three independent OS predictors, and the int-group 2 included 99 patients positive for at least one of the three independent OS predictors. As shown in Table III, the proportion of patients with liver metastasis was significantly higher in the int-group 2 than in the int-group 1 (p=0.037); however, there were no significant differences in the remaining characteristics between these two groups.
On stratifying the intermediate risk group into the two groups by using our new system, the proportions of patients in the favorable risk group, int-group 1, int-group 2, and poor risk group were 15.9%, 18.2%, 39.3%, and 26.6%, respectively. The median OS in the favorable risk group, int-group 1, int-group 2, and poor risk group was not reached, 55 months, 35 months, and 7 months, respectively. As shown in Figure 1, OS was significantly better in the int-group 1 than in the int-group 2 (p=0.014). Furthermore, there was a significant difference in OS among the favorable risk group, int-group 1, int-group 2, and poor risk group (p<0.001).
Discussion
Owing to the recent introduction of multiple efficacious agents into routine clinical practice, the therapeutic strategies for patients with mRCC have become highly complex (18-21); therefore, it is very important to utilize useful prognostic models, as they enable the selection of suitable agents as well as aid in the prediction of the clinical course of each patient with mRCC. In fact, several investigators have advocated a wide variety models as prognostic tools for both treatment-naïve and previously treated patients with mRCC, of which the IMDC model is currently regarded as the most widely accepted system classifying patients with mRCC into the favorable, intermediate or poor prognosis group (22, 23). However, more than 50% of patients with mRCC are classified into the intermediate risk group according to the IMDC model, indicating the presence of prognostic heterogeneity within the intermediate risk category. Collectively, these findings suggest that further prognostication of the intermediate risk group should be conducted to provide more precise information regarding the treatment of patients with mRCC. Accordingly, for the development of a novel stratification system of the intermediate risk group, in the current study, we retrospectively analyzed the data of 252 patients with mRCC who received first-line targeted agents.
Overall survival (OS) of the modified International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups.
Several recent studies focused on the prognostic stratification of patients with mRCC corresponding to the intermediate risk group classified according to the IMDC model (6-9). For example, Takamatsu et al. reported that the measurement of baseline C-reactive protein levels could be used to divide the intermediate risk group into two prognostic subgroups on the basis of the data of 107 patients with mRCC who received first-line targeted therapy (6). Sella et al. evaluated the prognostic outcomes of the intermediate risk group of patients with mRCC treated with sunitinib according to the positive number of risk factors, and they showed that both the progression-free survival and OS were significantly superior in patients with one risk factor than in those with two risk factors (7). However, to date, the sub-classification of the intermediate risk group has not been widely introduced into real-world clinical practice.
In the current study, we attempted to develop a novel system for the prognostic stratification of the patients with mRCC in the intermediate risk group by using a unique approach. Initially, we investigated the effect of the six factors included in the IMDC model on the OS of 145 of the 252 patients classified into the intermediate risk group. We found that a low PS score, anemia, and a high platelet count were independently associated with the poor OS of these 145 patients. We then divided these patients into the int-group 1 or int-group 2 based on the presence of none or at least one of the three independent risk factors, respectively. Thus, the unbalanced distribution of patients into the three risk groups according to the original IMDC classification was partially resolved by dividing them into the following four groups: the favorable risk group (15.9%), int-group 1 (18.2%), int-group 2 (39.3%), and poor risk group (26.6%). Furthermore, a significant difference in the OS was noted between the int-group 1 and int-group 2. These findings support that our novel stratification system, in which the intermediate risk group is subdivided into two groups according to the positive numbers of independent poor prognostic risk factors, could help guide decision-making for the treatment of patients with mRCC who received first-line molecular-targeted agents.
The current study had several limitations. The study was retrospective and included a comparatively small number of patients with mRCC. In addition, treatment was provided without any strictly determined therapeutic strategy among the four different institutions. Accordingly, a prospective study with a much larger sample size is required to confirm the findings obtained in the current study. Moreover, the recent introduction of immune checkpoint inhibitor-based combination therapies has affected the first-line treatment of patients with mRCC (3); thus, separate prognostic model systems are needed for patients with mRCC receiving this type of treatment. Furthermore, the current study investigated the significance of the novel stratification system of the intermediate risk group with a focus on treatment-naïve patients with mRCC; however, it will be of interest to determine whether this system could be used in the future for subgrouping of previously treated patients with intermediate risk mRCC.
Conclusion
We identified that a low PS score, anemia, and a high platelet count were independent predictive factors of poor OS in patients with mRCC receiving first-line molecular-targeted therapy who were classified into the intermediate risk group by using the IMDC model. In addition, we developed a novel prognostic stratification system for the intermediate risk group of patients with mRCC according to the number of these three independent risk factors. This novel stratification may be a useful tool for further prognostication of patients with mRCC classified into the IMDC intermediate risk group.
Footnotes
Authors' Contributions
The types of contribution by each author are as follows: Study conception and design, Makoto Sumitomo, Hideaki Miyake, Takahiro Yasui, Ryoichi Shiroki; Acquisition of data, Kiyoshi Takahara, Ryosuke Ando, Toshiki Ito, Kent Kanao; Analysis and interpretation of data, Kiyoshi Takahara, Hideaki Miyake; Drafting of manuscript, Kiyoshi Takahara, Hideaki Miyake, Ryoichi Shiroki.
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received May 9, 2020.
- Revision received June 10, 2020.
- Accepted June 22, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
