Predictive Impact of Prognostic Nutritional Index on Pembrolizumab for Metastatic Urothelial Carcinoma Resistant to Platinum-based Chemotherapy.

BACKGROUND/AIM: We investigated the prognostic nutritional index (PNI), comprised of lymphocytes and albumin, as a potential prognosticator of metastatic urothelial carcinoma (mUC) patients receiving pembrolizumab. PATIENTS AND METHODS: Sixty-five patients were retrospectively enrolled and classified as low (<40) and high (≥40) based on pretreatment PNI. Progression-free survival (PFS), overall survival (OS) and response rates were evaluated. RESULTS: In the low PNI group, significantly shorter PFS and OS were observed. PNI was shown to be an independent predictor of PFS and OS in the multivariate analysis. C-index for both PFS and OS improved with the addition of PNI to the model described in the KEYNOTE-045 study. Significantly more patients experienced initial disease progression in the low PNI group. CONCLUSION: PNI is a useful predictor of prognosis and disease progression in mUC patients receiving pembrolizumab.

Prognostic Markers for Refined Stratification of IMDC Intermediate-Risk Metastatic Clear Cell Renal Cell Carcinoma Treated with First-Line Tyrosine Kinase Inhibitor Therapy.

BACKGROUND: Patients in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk group have heterogeneous prognoses and thus may benefit from improved risk stratification. OBJECTIVE: The aim of this study was to analyze inflammatory parameters such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic markers for IMDC intermediate-risk patients. METHODS: Patients with metastatic clear cell renal cell carcinoma (n = 71) with IMDC intermediate risk who received tyrosine kinase inhibitors as first-line therapy were included in this retrospective study. Multivariate Cox regression analyses were performed to identify prognostic factors for overall survival (OS). RESULTS: As first-line systemic therapy, 46 (65%), 19 (27%), and 6 (8%) patients received sunitinib, sorafenib, and pazopanib, respectively. An IMDC prognostic score of 1 and 2 were observed in 34 (48%) and 37 (52%) patients, respectively. Mean CRP level was 1.06 mg/dL, and mean NLR was 3.0. Multivariate Cox regression revealed several factors significantly associated with poor OS, including NLR ≥ 3 (vs NLR < 3; hazard ratio [HR] 2.57; p = 0.0228), CRP level ≥ 1 mg/dL (vs CRP < 1 mg/dL; HR 2.89; p = 0.0279), and two or more metastatic organs (vs one organ; HR 3.77; p = 0.0008). Using these risk factors, patients were stratified into the following three risk categories: F0 (no prognostic factors; n = 20), in which the median OS (mOS) was not achieved; F1 (1 prognostic factor; n = 31), in which the mOS was 31 months; and F2-3 (2 or 3 prognostic factors; n = 20) in which the mOS was 13 months (log-rank p < 0.0001). CONCLUSION: CRP, NLR, and the number of metastatic organs were independent prognostic factors in IMDC intermediate-risk patients.

Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma.

BACKGROUND: The change in renal function induced by first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma remains unclear. METHODS: One hundred and thirty-four patients were evaluated. Sunitinib (SU) and sorafenib (SO) were administered to 91 (67.9%) and 43 (32.1%) patients, respectively. The change in estimated glomerular filtration rate (ΔeGFR) was calculated as [(eGFR at each time point - pre-treatment eGFR)/pre-treatment eGFR] × 100. ΔeGFR was compared between SU- and SO users using a mixed-effects model for repeated measures data with two or greater. Additionally, predictors for ΔeGFR ≤ -10% at 6 months after therapy initiation were evaluated using multivariate logistic regression analysis. RESULTS: Throughout the 24 months after therapy initiation, ΔeGFR was negatively greater in SU users, compared with that in SO users (P < 0.0001). In SU users, renal dysfunction was observed regardless of pre-treatment chronic kidney disease (CKD) status, whereas the magnitude of renal dysfunction was milder in SO users. In SO users without pre-treatment CKD, renal function did not significantly deteriorate. Moreover, ΔeGFR ≤ -10% was more frequently observed in SU users after 3 months (P = 0.0121) and 6 months (P = 0.0009). Finally, SU usage was an independent predictor for ΔeGFR ≤ -10% at 6 months (odds ratio 8.87, P = 0.0053), along with pre-treatment hypertension (odds ratio 4.69, P = 00072). CONCLUSIONS: Deterioration of renal function was stronger with SU than SO. During SU therapy, renal function should be monitored and pre-treatment kidney function should be taken into consideration for therapy selection.

Effect of the timing of best tumor shrinkage on survival of patients with metastatic renal cell carcinoma who received first-line tyrosine kinase inhibitor therapy.

BACKGROUND: To evaluate the association between the timing of best tumor shrinkage (bTS) and metastatic renal cell carcinoma (mRCC) patient survival after first-line tyrosine kinase inhibitor (TKI) therapy. METHODS: The tumors of 91 patients with mRCC showed a response to TKIs. None of the patients had received prior cytokine therapy. The magnitude of bTS was categorized according to the Response Evaluation Criteria in Solid Tumors v. 1.1. The patients were divided into two subgroups according to the timing of bTS: early responders (≤3 months) and late responders (>3 months). Overall survival (OS) and progression-free survival (PFS) after first-line TKI therapy were evaluated, and factors predicting survival were examined. RESULTS: Sunitinib, sorafenib, and pazopanib were used in 62, 25, and 4 responders, respectively. In total, 52 (57.1 %) and 39 (42.9 %) patients were early and late responders, respectively. Early responders had significantly lower PFS compared to late responders (median survival, 11.4 vs. 19.1 months; log-rank test, p = 0.0263), although there were no significant differences in the OS of early and late responders (27.0 vs. 30.1 months, p = 0.306). Multivariate analyses revealed that the timing of bTS was an independent predictor of PFS and OS (PFS, hazard ratio 4.09, p < 0.0001; OS, hazard ratio 2.32, p = 0.0107). CONCLUSION: The timing of bTS was an independent predictor of survival in patients with mRCC who received first-line TKIs.

Efficacy and safety of sorafenib for treatment of Japanese metastatic renal cell carcinoma patients undergoing hemodialysis.

BACKGROUND: Little information has been published on the use of tyrosine kinase inhibitors for treatment of patients undergoing hemodialysis (HD). We investigated the efficacy and safety of sorafenib for metastatic renal cell carcinoma (mRCC) patients undergoing HD. METHODS: Twenty patients undergoing HD were treated with sorafenib as first-line therapy for mRCC at our hospital between April 2008 and August 2014. Patient medical records were retrospectively reviewed to evaluate the response to sorafenib and treatment-related toxicity. RESULTS: Fifteen and 5 patients were classified in the intermediate and poor risk groups, respectively, of the Memorial Sloan-Kettering Cancer Center risk model. Eighteen patients had 3 or more metastatic lesions, and 7 patients had metastases in 2 or more organs. Of 16 patients who had previously undergone nephrectomy, 8 were pathologically diagnosed with non-clear-cell carcinoma. The median duration of sorafenib therapy was 4.7 months. Sorafenib was discontinued owing to progressing disease for 15 patients and because of serious adverse events (AE) (≥grade 3) for 4 patients, i.e. subarachnoid hemorrhage, cerebral hemorrhage, sepsis, and syncope for 1 patient each. Median time to progression was 6.3 months, and median overall survival was 14.2 months. CONCLUSIONS: In this study, many patients had unfavorable clinical features, for example poor risk classification and metastases in multiple organs. Although sorafenib treatment of HD patients seems feasible, careful monitoring is needed because of the tendency for a high incidence of serious AE, even when a reduced dose is administered.

[A CASE OF SOLITARY ADRENAL TUMOR METASTASIZED FROM RECTAL CANCER].

Solitary adrenal metastasis of rectal cancer is comparatively rare condition and it is difficult to be diagnosed because it doesn't have any characteristic symptoms. We report a case of this type of adrenal tumor that could be figured out by tumor markers and the analysis of CT scan image. A 67-year-old man visited our department with the right adrenal tumor. He has a past medical history of rectal cancer and a low anterior resection was performed in 2011. After the surgery, he received adjuvant chemotherapy for 6 months. There has been no finding of recurrence or metastasis after chemotherapy. However, his follow-up abdominal CT in 2013 showed the right adrenal tumor which was 23 mm in diameter. Serum CEA level has also increased to 4.1 ng/ml, but there was no abnormal finding with hormonal study. The tumor size and CEA level gradually increased up to 46 mm in size and 10.4 ng/ml during 6 months. Enhanced CT also showed 39% at rate of absolute percentage wash out, which was not the finding of typical functional adrenal tumor. Based on these findings, we diagnosed that the origin of this adrenal tumor should be solitary metastasis of the rectal cancer. For the treatment of surgical procedure, we performed laparoscopic right adrenalectomy. The pathological finding showed adenocarcinoma, the origin of which was the previous rectal cancer. Six months have passed since the surgery, but CEA level still has remained normal range and neither finding of recurrence nor metastasis has been found.

Clinical results and pharmacokinetics of sorafenib in chronic hemodialysis patients with metastatic renal cell carcinoma in a single center.

OBJECTIVE: We investigated the safety and feasibility of sorafenib in patients with end-stage renal disease undergoing hemodialysis by examining the influence of pharmacokinetic parameters to their benefit and also the occurrence of drug-related adverse events of sorafenib. METHODS: Ten patients with metastatic renal cell carcinoma undergoing hemodialysis received sorafenib. Initial dose was 200 mg once daily, and the dose was increased up to the maintenance dose of 200 mg twice daily. The pharmacokinetic study was performed after a steady state was reached with 200 mg twice daily in six patients. RESULTS: Complete response occurred in one patient, partial response in three, stable disease in four and progressive disease in two. Median progression-free survival was 6.3 months. Serious adverse events were found in nine patients, including a Grade 5 subarachnoid hemorrhage and a Grade 4 cerebellar hemorrhage. In the pharmacokinetic study, the geometric mean of maximum concentration and area under the curve from 0 to 10 h of plasma concentration were similar on the day of hemodialysis and the day off hemodialysis. These data were lower than those from Japanese people with healthy kidneys and normal kidney function. There was no association between objective response or the occurrence of serious adverse events and pharmacokinetic parameters. CONCLUSIONS: Treatment with sorafenib of patients with metastatic renal cell carcinoma undergoing hemodialysis appears to be feasible, but we express some concern about the higher incidence of serious adverse events even with the reduced dose. However, clinical efficacy was not compromised.

Presurgical targeted therapy with tyrosine kinase inhibitors for advanced renal cell carcinoma: clinical results and histopathological therapeutic effects.

OBJECTIVES: We retrospectively analyzed our patients with advanced renal cell carcinoma who underwent presurgical targeted therapy with tyrosine kinase inhibitors to clarify the safety and clinical benefit. The histopathological effect of this treatment was also examined. METHODS: Between July 2005 and February 2010, nine patients with advanced renal cell carcinoma who were treated with tyrosine kinase inhibitors before surgery were the subjects of this study. Consolidative surgery was considered when these tumors showed clinical response or stable disease while on targeted therapy without evidence of disease progression at other sites. RESULTS: The agents used were sorafenib in seven patients and sunitinib in two. The median duration of presurgical therapy was 12.2 weeks, and seven patients had less than 4 months of treatment. Tumor reduction at 10-30% was obtained in all patients but one. Perioperative complications were observed in five of nine patients. Major complications occurred in two patients, including intraoperative excessive bleeding and delayed localized intraperitoneal abscess. Minor complications were found in three. The characteristics of the histopathological effect of tyrosine kinase inhibitors consisted of marked atrophy of the capillary sinus, confirming the pharmacological mechanisms of these agents. Other findings included nuclear pyknosis and degeneration of tumor cells. CONCLUSIONS: Presurgical targeted therapy with tyrosine kinase inhibitors appears to be feasible in most patients with advanced renal cell carcinoma. However, the indications, the clinical benefit and the standard protocol still remain to be determined. Therapeutic effects in the histology were compatible to their pharmacological effects.