Significance of timing of therapeutic line on effectiveness of nivolumab for metastatic renal cell carcinoma.

Objectives: This study aimed to clarify the significance of therapeutic timing on the effectiveness of nivolumab for treating metastatic renal cell carcinoma. Marterials and methods: Fifty-eight patients with metastatic renal cell carcinoma treated with nivolumab monotherapy were retrospectively studied. Patients who were treated with nivolumab as second-line therapy were included in the second-line group, while the others were included in the later-line group. The clinicopathological characteristics, effects of nivolumab, and prognoses of these groups were compared. Results: Twenty and thirty-eight patients were included in the second-line and later-line groups, respectively. There were no significant differences in the distribution of International Metastatic Renal Cell Carcinoma Database Consotium risk and other clinicopathological characteristics between the 2 groups. The proportion of patients whose objective best response was progressive disease in the second-line group was significantly lower than that in the later-line group (15% vs. 50%, p = 0.0090). The 50% progression-free survival with nivolumab in the second-line group was significantly better than that in the later-line group (not reached and 5 months, p = 0.0018). Multivariate analysis showed that the second-line setting was an independent predictive factor for better progression-free survival (p = 0.0028, hazard ratio = 0.108). The 50% overall survival after starting nivolumab in the second-line and later-line groups was not reached and 27.8 months, respectively (p = 0.2652). Conclusions: The therapeutic efficacy of nivolumab as second-line therapy is expected to be better than that of later therapy.

Impact of modified Glasgow prognostic score on predicting prognosis and modification of risk model for patients with metastatic renal cell carcinoma treated with first line tyrosine kinase inhibitor.

INTRODUCTION AND OBJECTIVES: Intermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria is thought to consist of patients with different prognoses. This study investigated the impact of a pretreated modified Glasgow prognostic score (mGPS), which is defined on the basis of the pretreated serum albumin and C-reactive protein level, on predicting the prognosis of patients with metastatic renal cell carcinoma (mRCC) and its usefulness for the re-stratification of patients into a more improved risk model. MATERIALS AND METHODS: One hundred ninety-six mRCC patients treated with first-line tyrosine kinase inhibitor (TKI) were retrospectively investigated. All patients were classified into either a high-mGPS or a low-mGPS group on the basis of mGPS score upon starting systemic therapy, the overall survival (OS) and cancer specific survival (CSS) rates in each group were compared. We use decision curve analysis and calculate C-index based on OS and CSS to compare IMDC+mGPS model and IMDC model. RESULTS: The categories of favorable, intermediate, and poor risk groups in the IMDC model were assessed in 32, 113, and 51 cases, respectively. The low- and high-mGPS groups consisted of 149 and 47 cases. The median OS in the high- and low-mGPS groups were 38.4 months and 5.6 months, and their median CSSs were 41.0 months and 5.6 months, respectively (P < 0.0001). Multivariate analysis showed that a high mGPS, multiple metastatic organs, and hypercalcemia were independent predictive factors for a worse OS (P = 0.0260). Next, we divided the intermediate risk group into two subgroups using the mGPS score. The OS and CSS for the high-mGPS subgroup were significantly worse than those for the low-mGPS one (P = 0.0024, median OS: 21.0 months and 33.7 months, P = 0.0007, median CSS: 21.0 months and 39.8 months), and there was no significant difference in OS between the high-mGPS subgroup in the intermediate risk group and poor risk group (P = 0.2250). The value of C-index based on OS at IMDC and IMDC+mGPS model were 0.6771 and 0.6967, and those based on CSS were 0.6850 and 0.7080, respectively. In decision curve analysis to evaluate the clinical net benefit using the IMDC+mGPS model compared to the IMDC model, there was no significant difference between the two groups. CONCLUSION: mGPS is useful for establishing a more improved prognostic model that is able to stratify mRCC patients treated with first-line TKI.

Prognostic model of upfront cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors and/or targeted agents.

INTRODUCTION AND OBJECTIVES: The aim of this study was to investigate prognostic factors and to establish a prognostic model using them for upfront cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitor (ICI) and/or tyrosine kinase inhibitor (TKI). MATERIALS AND METHODS: Two hundred eleven patients who were diagnosed as mRCC at initial diagnosis and were treated with TKI and/or ICI were classified into 2 groups: those undergoing CN (upfront CN group, 117 cases) and those who initially underwent systemic therapy (non-upfront CN group, 94 cases). In the upfront CN group, the patients' background and overall survival (OS) were compared with those in the other two groups, and prognostic factors were analyzed. A prognostic model of the upfront CN group was established. RESULTS: The median of the observation period for the upfront CN group was 25 months. The rates of patients with clear cell histology, with a Karnofsky performance status (KPS) of ≥ 80%, with a single metastatic organ, with a normal pretreated C-reactive protein level, and with an intermediate risk according to the International mRCC Database Consortium (IMDC) model were significantly higher than those in the non-upfront CN group (87.2% and 30.9%, p < 0.0001; 92.3% and 77.7%, p = 0.0025; 41.9% and 24.5%, p = 0.0080; 47.9% and 13.8%, p < 0.0001; 66.7% and 45.7%, p = 0.0023, respectively). The 50% OS in the upfront CN group was 33.1 months, significantly better than that in the non-upfront CN group (11.1 months, p < 0.0001), and these results were consistent regardless of their prognostic risk level. Multivariate analysis showed that multiple metastatic organs and a KPS of < 80% were independent predictive factors for OS (hazard ratio: 1.653 and 2.995, p = 0.0339 and 0.0054, respectively). Using these two parameters to stratify the upfront CN group, the 50% OSs in cases with no risk factors, in those with one factor, and in those with two factors were 43.4 months, 29.1 months, and 7.7 months, respectively (p < 0.0001). CONCLUSION: The upfront CN group was able to be stratified by our prognostic model into three subgroups with different prognoses. This model can provide useful information for making decisions in consideration of upfront CN in patients with mRCC.

Erratum: Improved prognosis for elderly patients with metastatic renal cell carcinoma in the era of targeted therapy.

[This corrects the article DOI: 10.3892/mco.2020.2020.].

Prediction of early progression of metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitor.

BACKGROUND: There are various alternative first-line therapeutic options besides tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). To inform therapeutic decision-making for such patients, this study aimed to identify predictive factors for resistance to TKI. MATERIALS AND METHODS: A total of 239 cases of mRCC patients who received first-line TKI therapy were retrospectively studied. Patients with a radiologic diagnosis of progressive disease within 3 months after initiating therapy were classified as primary refractory cases; the others were classified as non-primary refractory cases. The association between primary refractory cases and age, gender, pathology findings, serum c-reactive protein (CRP) level, metastatic organ status, and 6 parameters defined by the International Metastatic Renal Cell Carcinoma Database Consortium were analyzed. RESULTS: Of 239 cases, 32 (13.3%) received a radiologic diagnosis of progressive disease within 3 months after initiating therapy. The rates of sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, presence of liver metastasis, anemia, and time from diagnosis to treatment interval of less than a year were significantly higher in the primary refractory group. Multivariate analysis showed that sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, and liver metastasis were independently associated with primary refractory disease. A risk-stratified model based upon the number of patients with these factors indicated rates of primary refractory disease of 4.0%, 10.1%, and 45.0% for patients with 0, 1, and 2 or more factors, respectively. CONCLUSIONS: Sarcomatoid differentiation, hypercalcemia, an elevated serum CRP level, and presence of liver metastasis were associated with primary refractory disease in mRCC patients receiving first-line TKI therapy. These results provide clinicians with useful information when selecting a first-line therapeutic option for mRCC patients.

Impact of the systemic immune-inflammation index for the prediction of prognosis and modification of the risk model in patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors.

INTRODUCTION: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are the most representative risk model for patients with metastatic renal cell carcinoma (mRCC). However, the intermediate-risk group of IMDC criteria is thought to include patients with different prognoses because many of the patients are classified into the intermediate-risk group. In this study, we investigated the impact of systemic immune-inflammation index (SII), which is calculated based on neutrophil count, platelet count, and lymphocyte count, on predicting the prognosis in patients with mRCC, and its usefulness for re-classification of patients with a more sophisticated risk model. METHODS: From January 2008 to January 2018, 179 mRCC patients with a pretreatment and SII were retrospectively investigated. All patients were classified into either a high-SII group or a low-SII group based on the cutoff value of a SII at 730, as reported in previous studies; the overall survival (OS) rates in each group were compared. RESULTS: The median age was 65 years old. Males and females comprised 145 and 34 cases, respectively. The categories of favorable-, intermediate-, and poor-risk groups in the IMDC model were assessed in 39, 102, and 38 cases, respectively. The median observation period was 24 months. The low-SII and high-SII groups consisted of 73 and 106 cases, respectively. The 50% OS in the high-SII group was 21.4 months, which was significantly worse than that in the low-SII group (49.7 months; p<0.0001). Multivariate analysis showed that a high SII was an independent predictive factor for a worse OS. Next, we constructed a modified IMDC risk model that included the SII instead of a neutrophil count and a platelet count. By using this modified IMDC model, all cases were re-classified into four groups of 33, 52, 81, and 13 cases with 50% OS of 88.8, 45.9, 29.4, and 4.8 months, respectively. CONCLUSIONS: The SII is useful for establishing a more sophisticated prognostic model that can stratify mRCC patients into four groups with different prognoses.

Improved prognosis for elderly patients with metastatic renal cell carcinoma in the era of targeted therapy.

The present study investigated the outcomes of targeted therapy for elderly patients with metastatic renal cell carcinoma (mRCC). A total of 277 patients with mRCC who were treated with tyrosine kinase inhibitor as a first-line therapy from January 2008 to May 2018 were retrospectively investigated by reviewing clinicopathological data. Patients 75 years or older were classified into the older-aged group (n=55) while all others were classified into the younger-aged group (n=222). The preoperative clinicopathological characteristics and the overall survival (OS) rate for these two groups were subsequently compared. The median age in the older- and younger-aged groups was 78 and 63 years (P<0.0001), respectively. A total of 7, 42 and 6 cases in the older-aged group and 46, 118 and 58 cases in the younger-aged group were classified into favorable, intermediate, and poor risk groups, respectively. The rate of patients with cardiovascular diseases (29.1%) and malignant diseases other than RCC (20.0%) was significantly higher in the older-aged group compared with the younger-aged group (6.8%; P<0.0001 and 7.2%; P=0.0042, respectively). There was a significant improvement in the OS rate for patients beginning targeted therapy after 2011 compared with those starting therapy prior to 2010. The 50% OS rate in patients starting targeted therapy before 2010 and after 2011 was, respectively, 17.1 and 38.6 months for the older-aged group (P=0.0066), while there was no significant difference for the younger-aged group (P=0.1441; 50% OS; 35.9 vs. 30.5 months). The results of the present study indicated that the prognosis for older patients has improved since the introduction of targeted therapy.

The effect of kinetics of C-reactive protein in the prediction of overall survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitor.

INTRODUCTION AND OBJECTIVES: The aim of this study was to investigate the effect of kinetics of C-reactive protein (CRP) in the prediction of overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with a tyrosine kinase inhibitor. MATERIALS AND METHODS: The CRP in 118 cases of molecular-targeted therapy for mRCC was measured before starting the prescription of the first-line targeted agents and at the first time a CT scan was conducted during treatments. All cases were classified into higher-CRP groups and lower ones according to their data at the time of starting treatments. A higher-CRP group was further classified into 2 subgroups based on the kinetics after first-line targeted therapy: "decreased-CRP subgroup" and "nondecreased CRP subgroup." RESULTS: The median of the observation period was 23.4 months. The OS in cases with CRP higher than 0.5mg/dl was significantly worse than those in other cases (P<0.0001). Multivariate analysis revealed that the pretreated CRP (hazard ratio = 2.093; 95% CI: 1.176-3.858; P = 0.0179) was an independent predictive factor of OS. In the higher-CRP group, the OS for the decreased-CRP subgroup (1 year, 85.0%) was significantly better than those for the nondecreased CRP subgroup (1 year, 37.2%, P<0.0001). Multivariate analyses in the higher-CRP group revealed that the decrease in the CRP was an independent predictive factor for OS (hazard ratio = 0.176; 95% CI: 0.064-0.488; P = 0.0008). CONCLUSION: A decrease in CRP as well as pretreatment CRP can be a predictive factor for OS in patients with mRCC treated with a tyrosine kinase inhibitor. Cases with mRCC could be stratified into 3 groups with different prognoses using the pretreated CRP and its changes.

[CUTANEOUS METASTASIS OF UROTHERIAL CARCINOMA FOR WHICH MOHS PASTE WAS USEFUL: A CASE REPORT].

The patient was a 71-year-old man referred to our department because of asymptomatic gross hematuria. Detailed examination led to a diagnosis of bilateral ureteral cancer and prostate cancer. Total nephroureterectomy was performed for bilateral ureteral cancers on separate occasions, while prostate cancer was managed with hormone therapy. Because multiple bladder tumors were found by cystoscopy conducted after 3 months, total cystectomy was performed. Neither distant metastasis nor local recurrence had developed, 2 years later, when the patient visited our department again because of glans enlargement and received a diagnosis of penile cancer. Partial penectomy was performed, and a 1-cm indurated nodule was found in the skin of the hypogastric region during surgery and treated by simultaneous wedge-shaped excision. Histopathologically, the lesions were urothelial carcinomas. Multiple metastatic foci occurred in the skin postoperatively centering on the hypogastric region, growing rapidly and accompanied by bleeding and exudate causing a bad odor. Topical application of Mohs paste resulted in dramatic improvement of the pain and exudate, which thereby improved the patient's quality of life (QOL) to a level enabling discontinuation of narcotic drug therapy for cancer-related pain. Thereafter, hepatic metastasis was found and chemotherapy with gemcitabine and paclitaxel was administered. The patient did not respond to this chemotherapy and died of cancer 3 months later. Cutaneous metastasis of urothelial carcinoma, which is a very rare condition, is often managed with palliative therapy due to the lack of response to anticancer chemotherapy. In such cases, the use of Mohs paste appears to be of great value for maintaining the patient's QOL which otherwise might deteriorate markedly.