An Analysis of 20 Cases of Radiation-Associated Sarcoma, Including 4 Cases Treated by Carbon Ion Radiotherapy.

INTRODUCTION: Radiation-associated sarcoma (RAS) is one of the most life-threatening complications associated with the treatment of malignant neoplasms. Because all RAS patients have a history of radiotherapy, there have been no effective treatment options when RAS is not completely resected. METHODS: We retrospectively reviewed 20 RAS patients, including 4 unresectable cases treated by carbon ion radiotherapy (CIRT). RESULTS: The primary diseases targeted by radiotherapy included malignant lymphoma (n = 4), cervical cancer (n = 3), pharyngeal cancer (n = 3), breast cancer (n = 2), lung cancer (n = 1), rectal cancer (n = 1), maxillary cancer (n = 1), synovial sarcoma (n = 1), and benign neoplasms (n = 4). The histological diagnoses of RAS included osteosarcoma (n = 8), leiomyosarcoma (n = 3), undifferentiated pleomorphic sarcoma (n = 3), rhabdomyosarcoma (n = 1), angiosarcoma (n = 1), malignant peripheral nerve sheath tumor (n = 1), spindle cell sarcoma NOS (n = 1), and sarcoma not further specified (n = 2). The median survival time from the diagnosis of RAS was 26 months. Eleven patients underwent surgery. Five of these patients achieved a continuous disease free (CDF) status or showed no evidence disease. Four patients underwent CIRT. One of these patients with leiomyosarcoma achieved a CDF status, and the other patient with osteosarcoma achieved a partial response. On the other hand, 2 patients experienced grade 3 toxicities that required surgical treatment. CONCLUSION: RAS originates from various types of diseases that are treated by radiotherapy and shows diverse pathological features. Complete resection achieves a good prognosis. CIRT can be an effective and feasible option for unresectable RAS.

Dissociated response among multiple metastatic lesions in the patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors.

INTRODUCTION: Metastases from renal cell carcinoma develop in various organs. However, the breadth of discrepancy in response to immune checkpoint inhibitors across tumor sites within the same individual remains unclear. PATIENTS AND METHODS: We reviewed 50 patients with metastatic renal cell carcinoma who had target lesions at multiple sites and received nivolumab monotherapy (n = 36) or nivolumab plus ipilimumab (n = 14). When the best overall response in tumor burden increased at one site but decreased at other sites, the response was defined as a dissociated response. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1, and patients who met the definition of dissociated response were categorized as dissociated response. The rate of dissociated response and prognosis were evaluated. RESULTS: Eight of 36 (22%) and 4 of 14 (29%) patients treated with nivolumab and nivolumab plus ipilimumab were categorized as having dissociated response, respectively. The median overall survival of the patients treated with nivolumab was 20.2 months for those with a partial response, 6.8 months for those with stable disease, and 13.2 months for those with progressive disease, while dissociated response was not reached. There was no significant difference in the median overall survival between patients categorized as having progressive disease and those with dissociates response (P = 0.224). CONCLUSION: A certain proportion of patients with metastatic renal cell carcinoma show dissociated response when treated with immune checkpoint inhibitors. The prognosis of patients with dissociated response and progressive disease was not shown to be significantly different.

Predictive factors of late biochemical recurrence after radical prostatectomy.

OBJECTIVE: To assess the characteristics of biochemical recurrence in the late period (>5 years after radical prostatectomy) and the differences in the predictors of biochemical recurrence in different periods, we conducted a multicenter retrospective study. METHODS: We reviewed 478 men who underwent radical prostatectomy for clinically localized prostate cancer. All of the patients were followed up for at least 5 years. The cohort was then divided into three groups; no recurrence group, recurrence <5 years after surgery group and recurrence ≥5 years after surgery group. The background characteristics of each group were compared using the χ2 test. A Cox multivariate regression analysis was performed to determine the predictors of biochemical recurrence in each period. RESULTS: Biochemical recurrence occurred in 135 men. In 113 (84%) of the patients, biochemical recurrence occurred at <5 years after surgery; in 22 (16%), it occurred at ≥5 years after surgery. The proportion of men with a low preoperative prostate-specific antigen level was significantly larger in the latter group (P = 0.0023). A preoperative prostate-specific antigen level and a positive surgical margin were significant predictors of biochemical recurrence at <5 years after surgery (hazard ratio: 1.03 and 3.20). A positive surgical margin was also a significant predictor of biochemical recurrence at ≥5 years after surgery (hazard ratio: 3.03); however, a high preoperative prostate-specific antigen level was not. CONCLUSIONS: Biochemical recurrence occurred at ≥5 years after surgery in 16% of the patients. A positive surgical margin predicted biochemical recurrence in both the early and late periods.

Biochemical failure after radical prostatectomy in intermediate-risk group men increases with the number of risk factors.

INTRODUCTION: We aimed to determine whether the number and type of risk factors are associated with biochemical recurrence-free survival after radical prostatectomy in men with D'Amico intermediate-risk prostate cancer. MATERIALS AND METHODS: Between August 1998 and May 2013, 481 Japanese patients underwent antegrade radical prostatectomy. The relationships between the rate of PSA failure after radical prostatectomy and the number and type of risk factors were examined in the intermediate-risk group. RESULTS: According to the D'Amico criteria, the low-, intermediate-, and high-risk groups comprised 107, 222, and 152 patients, respectively. The median follow-up period after surgery was 54.1 months. The 5-year PSA failure-free rates in the low-, intermediate-, and high-risk groups were 96.5%, 88.9%, and 72.6%, respectively (P < 0.001). The 5-year PSA failure-free rate in the intermediate-risk group with one, two, and three intermediate risk factors was 94.9%, 88.4%, and 49.0%, respectively (P < 0.001). The difference between the high- and intermediate-risk group with three intermediate risk factors was statistically significant based on the log-rank test (P = 0.039). CONCLUSION: The number of intermediate risk factors is significantly associated with the PSA failure-free survival rate after radical prostatectomy in the intermediate-risk group. Patients classified into the intermediate-risk group based on all three intermediate risk factors are less likely to achieve a complete cure through surgery alone.

Change in the Neutrophil-to-Eosinophil Ratio After Avelumab Maintenance for Advanced Urothelial Carcinoma: The UROKYU Study.

BACKGROUND/AIM: The association between clinical outcomes and posttreatment changes in the neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-eosinophil ratio (NER) in patients receiving avelumab maintenance therapy for advanced urothelial carcinoma (UC) is unclear. PATIENTS AND METHODS: We retrospectively analyzed data from advanced UC patients who received avelumab and had not progressed with first-line platinum-based chemotherapy. The association between the changes in NLR and NER from pretreatment to week 6 of avelumab treatment and therapeutic efficacy was evaluated. RESULTS: Thirty-two patients were enrolled in this study (male, n=25; female, n=7; median age, 71 years). At six weeks, 19 patients (59.4%) had a decreased NLR and 18 patients (56.3%) had a decreased NER. When the change in NER from pretreatment to six weeks was compared, there was a significant decrease in responders (without progressive disease) (p=0.008); however, there was no significant decrease in non-responders (progressive disease) (p=0.855). The NLR showed no significant change in either group (p=0.099, 0.358). When patients were compared according to the change in the NLR at six weeks, progression-free survival (PFS) and overall survival (OS) did not differ between the decreased NLR and increased NLR groups (p=0.116, 0.256). When patients were compared according to the change in the NER, the decreased and increased groups showed significant differences in PFS and OS (p<0.001, 0.030). CONCLUSION: In the present real-world study, the responders showed a significantly decreased NER at six weeks. This was associated with improved PFS and OS in patients with advanced UC.

Prognostic Impact of Histologic Subtype and Divergent Differentiation in Patients with Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multicenter Retrospective Study.

Subtype of urothelial carcinoma (SUC), defined here as urothelial carcinoma with any histologic subtype or divergent differentiation, is a clinically aggressive disease. However, the efficacy of enfortumab vedotin (EV) against SUC remains unclear. Hence, this study aimed to assess the oncological outcomes of patients with SUC treated with EV for metastatic disease. We retrospectively evaluated consecutive patients with advanced lower and upper urinary tract cancer who received EV after platinum-based chemotherapy and immune checkpoint blockade therapy at six institutions. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with SUC. We identified 44 and 18 patients with PUC and SUC, respectively. Squamous differentiation was the most common subtype element, followed by glandular differentiation and sarcomatoid subtype. Although patients with SUC had a comparable ORR to those with PUC, the duration of response for SUC was short. Patients with SUC had poorer PFS than those with PUC; however, no significant difference was observed in OS. Multivariate analysis revealed that SUC was significantly associated with shorter PFS. Although the response of metastatic SUC to EV was similar to that of PUC, SUC showed faster progression than PUC.

Cutaneous and Renal Toxicities of Enfortumab Vedotin for Advanced Urothelial Carcinoma: The UROKYU Study.

BACKGROUND/AIM: The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear. PATIENTS AND METHODS: We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023. RESULTS: There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938). CONCLUSION: EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function.

A Case of Cystic Retroperitoneal Dedifferentiated Liposarcoma Diagnosed by Percutaneous Image-Guided Biopsy.

Introduction: Dedifferentiated liposarcoma (DDLP) was initially defined as a tumor containing differentiated liposarcoma and distinct regions of nonlipogenic spindle cell or pleomorphic sarcoma. Retroperitoneal liposarcomas feature a characteristic appearance with a predominantly fatty component, and cystic liposarcomas are rare. We describe a case of retroperitoneal DDLP predominantly consisting of multilocular cysts. Case Presentation: A 77-year-old man previously visited a doctor because an echo scan unexpectedly revealed an abdominal tumor. Contrast computed tomography (CT) disclosed a large multilocular cystic tumor spanning from the left upper abdomen to the retroperitoneum, and poorly marginated soft tissue structures were present around the abdominal aorta, inferior vena cava, pancreas, mesentery, and left kidney. CT also revealed a right lung mass. The soft tissue structures in the retroperitoneal cystic tumor and right lung mass were strongly enhanced on 2-deoxy-2-[fluorine-18] fluoro-d-glucose positron emission tomography, suggesting a malignant retroperitoneal tumor and lung metastasis. CT-guided percutaneous biopsy targeting the left perirenal soft tissue structure was performed, and the tumor was diagnosed as DDLP. Lung metastasis was present, and the retroperitoneal tumor surrounded multiple organs. Therefore, the tumor was not suitable for surgical resection but it was indicated for chemotherapy based on multidisciplinary discussion. Conclusion: We experienced a case of retroperitoneal cystic DDLP diagnosed by percutaneous image-guided biopsy and treated appropriately based on the pathological diagnosis.

Organ-specific Tumor Response to Avelumab Maintenance Therapy for Advanced Urothelial Carcinoma: A Multicenter Retrospective Study.

BACKGROUND/AIM: The organ-specific therapeutic effects of avelumab for the maintenance treatment of advanced urothelial carcinoma (UC) are unclear. PATIENTS AND METHODS: Patients who received avelumab for advanced UC that had not progressed with first-line platinum-based chemotherapy and who had measurable disease were retrospectively analyzed. The organ-specific response was evaluated, and progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: We analyzed 42 patients (male, n=31; median age, 72 years). The overall response rate [complete response (CR)+ partial response (PR)] and disease control rate (CR+PR+stable disease) were 2.4% and 47.6%, respectively. In total, 27, 11, 8 and 5 patients had measurable lymph node [organ-specific response rate (OSRR) 7.4%, organ-specific disease control rate (OSDCR) 59.3%], lung (OSRR 18.2%, OSDCR 36.4%), primary tumor organ (OSRR 0%, OSDCR 100%) and liver (OSRR 0%, OSDCR 100%) disease, respectively. The median PFS and OS was 3.8 months and 20.2 months, respectively. Regarding organ-specific PFS, a log-rank test confirmed significant differences between patients with and without primary tumor organ disease (p=0.009) and patients with and without liver metastasis (p=0.015). Regarding organ-specific OS, a log-rank test revealed no significant differences between patients with and without metastatic disease for all organs (lung: p=0.835; lymph node: p=0.914; bone: p=0.257; primary tumor: p=0.057; liver: p=0.893). CONCLUSION: In patients receiving avelumab maintenance therapy, no significant differences in OS were observed between patients with and without metastasis to any organ, including the primary organ, although metastases and the primary tumor organ disease showed different responses.

Early Phase Persistent Changes in the White Blood Cell Fraction in Patients With Advanced Urothelial Carcinoma Treated With Pembrolizumab: A Multicenter Retrospective Study.

BACKGROUND/AIM: The association of clinical outcomes with posttreatment persistent changes in eosinophils and other white blood cell (WBC) subtypes in patients with advanced urothelial cancer (UC) treated with pembrolizumab after the failure of platinum-based chemotherapy is unclear. PATIENTS AND METHODS: We retrospectively analyzed 87 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The changes in WBC subtypes from pretreatment were evaluated three and six weeks after pembrolizumab administration. The association between the changes in the WBC subtypes and clinical outcomes was then evaluated using the Kaplan-Meier method and a Cox regression model. RESULTS: Among WBC subtypes, significant changes in the absolute (AEC) and relative eosinophil count (REC) and the neutrophil-to-eosinophil ratio (NER) were observed at three and six weeks compared with pretreatment (p<0.001). Multivariable Cox regression analyses revealed that a persistent decrease in AEC and REC and a persistent increase in NER were associated with poor overall survival. CONCLUSION: Persistent increase in AEC and REC and decrease in NER in the early phase after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab.

Cutaneous ureterostomy using the transverse mesocolon.

Cutaneous ureterostomy cannot be carried out by the retroperitoneal method in cases showing an insufficient length of the available ureter. We therefore proposed and carried out cutaneous ureterostomy transperitoneally on a ureter of minimum length using the transverse mesocolon. The right and left ureters are drawn from the retroperitoneum into the peritoneal cavity in the renal hilus area. The right ureter is then led from the root of the transverse mesocolon to the area attached to the transverse colon under the subserous part of the transverse mesocolon, and penetrates the gastrocolic ligament. The left ureter is led to the area attached to the transverse mesocolon under the subserous part of the transverse mesocolon, and penetrates the transverse mesocolon, bursa omentalis and gastrocolic ligament. Next, both the right and left ureters are drawn up to the abdominal wall and a ureterstoma is constructed. The transverse mesocolon can be used as supporting tissue for the ureter. Furthermore, this also ensures blood flow in the ureter.

Change of genitourinary cancer patients' perception and expectations over the course of pharmacotherapy.

To determine the course of treatment while considering the patients' desires, we examined trends regarding patients' perception and expectations over the course of cancer pharmacotherapy. We retrospectively reviewed interview sheets filled in by patients with advanced urogenital cancers when they started a new pharmacotherapy regimen between 2014 and 2020. The responses to the following questions were analyzed: 1) How did your doctor explain the treatment objectives?; 2) Are you willing to receive treatment?; and 3) When the standard treatment becomes difficult to continue, would you like to try another treatment even if it may cause severe side effects? A total of 277 patients answered the interview sheet. The percentage of patients who accurately perceived the treatment objectives among patients receiving 1st, 2nd, and 3rd line regimens was 67%, 79%, and 93%, respectively. The percentage significantly improved over the course of pharmacotherapy (p = 0.0057). The percentage of patients who indicated that they were willing to receive treatment in 1st, 2nd, and 3rd line regimens was 80%, 83%, and 86%, respectively. The percentage of patients who indicated that they wanted to try another treatment when the standard treatment became difficult to continue in 1st, 2nd, and 3rd line regimens was 56%, 64%, and 59%, respectively. The percentage of patients who accurately perceived the objective of pharmacotherapy increased over the course of pharmacotherapy. The rate of patients who were willing to receive treatment and try other treatments when the standard treatment became too difficult to continue remained consistently high.

Cytoreductive Nephrectomy After Combination of Nivolumab Plus Ipilimumab for Mucinous Tubular and Spindle Cell Carcinoma of the Kidney With Bone Metastases: A Case Report.

BACKGROUND/AIM: Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare subtype of renal cell carcinoma and generally considered a low-grade renal epithelial neoplasm. However, MTSCC with distant metastases often shows a poor prognosis. This is the first reported case of cytoreductive nephrectomy after nivolumab plus ipilimumab combination treatment. CASE REPORT: A 26-year-old man had a 72-mm tumor at the left kidney with multiple osteolytic bone metastases. A biopsy of the renal tumor and bone metastases resulted in the diagnosis of MTSCC of the kidney with bone metastases. After nivolumab plus ipilimumab combined treatment, he underwent cytoreductive nephrectomy. The excised specimen showed higher PD-L1 expression in the spindle components than in the tubular components, but CD4- and CD8-positve T-cells showed greater infiltration in the tubular components than the spindle components. CONCLUSION: Combination immunotherapy of nivolumab and ipilimumab may be an effective treatment option for metastatic MTSCC of the kidney.

Optimal Timing of Switching from Platinum-based Chemotherapy to Pembrolizumab for Advanced Urothelial Carcinoma Based on Real-world Data: A Multi-institutional Retrospective Study.

BACKGROUND/AIM: The optimal timing of switching from platinum-based chemotherapy to pembrolizumab in patients with advanced urothelial carcinoma (UC) remains unclear. PATIENTS AND METHODS: Thirty-four patients who received pembrolizumab as second-line treatment after first-line platinum-based chemotherapy were retrospectively evaluated. RESULTS: According to overall survival (OS) from pembrolizumab, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (7.0 and 25.5 months, p=0.034), but not between ≤6 and >6 cycles (11.3 and 6.6 months, p=0.658). According to the Cox proportional hazards regression model, the number of chemotherapy cycles was not correlated with better OS in pembrolizumab-treated patients. According to the OS from the first-line treatment, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (17.3 and 37.1 months, p<0.001), but not between ≤6 and >6 cycles (18.6 and 27.3 months, p=0.276). CONCLUSION: The optimal timing of switching from platinum-base chemotherapy to pembrolizumab in advanced UC is around six cycles.

Association Between Immune-Related Adverse Events and Efficacy and Changes in the Relative Eosinophil Count Among Patients with Advanced Urothelial Carcinoma Treated by Pembrolizumab.

Background: To evaluate the association between immune-related adverse events (irAEs) and the clinical outcomes and also between irAEs and the post-treatment changes in the relative eosinophil count (REC) in advanced urothelial carcinoma (UC) patients treated with pembrolizumab. Materials and Methods: This retrospective study analyzed 105 advanced UC patients treated with pembrolizumab after disease progression on platinum-based chemotherapy between January 2018 and June 2021. The association between the occurrence of irAEs and the efficacy of pembrolizumab was investigated. The change in the REC from before the initiation of pembrolizumab therapy, to three weeks after treatment and the incidence of irAEs were determined. Results: Overall irAEs were associated with a significantly higher objective response rate (ORR) (58.8% vs 25.4%, P<0.001), a longer progression-free survival (PFS) (25.1 months vs 3.1 months, P< 0.001) and overall survival (OS) (31.2 months vs 11.5 months, P< 0.001) compared to patients without irAEs; however, grade ≥3 irAEs were not associated with the ORR (36.4% vs 36.2%, P=0.989), PFS (9.5 vs 5.5 months, P=0.249), or OS (not reached vs 13.7 months, P=0.335). Compared to a decreased REC at 3 weeks after pembrolizumab, an increased relative REC at 3 weeks was not associated with the incidence of any-grade irAEs (32.3% vs 32.5%, P=0.984) or of grade ≥3 irAEs (10.8% vs 10.0%, P=0.900). Multivariate analyses revealed a female sex (P=0.005), Eastern Cooperative Oncology Group Performance Status ≥1 (P=0.024), albumin <3.7 g/dl (P<0.001), decreased REC (3 weeks later) (P<0.001), and the absence of irAEs of any grade (P=0.002) to be independently associated with a worse OS. Conclusion: Patients with irAEs showed a significantly better survival compared to patients without irAEs in advanced UC treated with pembrolizumab. An increased posttreatment REC may be a marker predicting improved clinical outcomes and it had no significant relationship with the incidence of irAEs.

Efficacy of Pembrolizumab in Patients With Variant Urothelial Carcinoma: A Multicenter Retrospective Study.

INTRODUCTION: Although variant urothelial carcinoma (VUC, defined here as urothelial carcinoma with any histological variant) is a clinically aggressive disease, the efficacy of pembrolizumab against VUC is not well characterized. This study assessed the therapeutic response and survival outcomes in patients with advanced VUC treated with pembrolizumab for unresectable recurrent or metastatic disease. PATIENTS AND METHODS: We retrospectively evaluated 103 patients with advanced bladder and upper urinary tract cancer who received pembrolizumab after failure of platinum-based chemotherapy at 6 institutions between January 2018 and June 2021. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with VUC. RESULTS: We identified 81 and 22 patients with PUC and VUC, respectively. Squamous differentiation (n = 14) was the most common variant element, followed by glandular differentiation (n = 3) and micropapillary variant (n = 3). Baseline characteristics were comparable between the groups. Patients with VUC showed significantly better ORR (59.1% vs. 29.6%, P = .014) and comparable DCR (68.2% vs. 49.4%, P = .150) compared to those with PUC. There were no significant differences between the PUC and VUC groups with respect to PFS (median 5.0 months vs. 10.4 months, P = .222) or OS (median 13.5 months vs. 23.8 months, P = .497). CONCLUSION: Response of VUC to pembrolizumab was not inferior to that of PUC in patients with advanced-stage bladder and upper urinary tract cancer.

The Eosinophil Changes, Efficacy and Safety of Pembrolizumab in Advanced Urothelial Carcinoma Patients with an Older Age and a Poor Performance Status.

Background: To evaluate the eosinophil changes, efficacy and safety of pembrolizumab treatment in advanced urothelial carcinoma patients of older age and those with a poor performance status (PS). Materials and Methods: Consecutive patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy between January 2018 and June 2021 were retrospectively examined. Results: 105 patients (median age, 72 years), 71.4% of whom were men, were enrolled. Patients of ≥75 years of age were considered to be older patients (n=40), and patients with PS ≥2 were considered to have a poor PS (n=10). The objective response and disease control rates were 42.5% and 52.5%, respectively, in older patients and 0% and 10.0%, respectively, in patients with a poor PS. Overall survival (OS) in the older and younger groups did not differ to a statistically significant extent. However, a poor PS was significantly associated with poor survival. Safety analyses demonstrated no significant difference in the occurrence of any immune-related adverse events (irAEs), including grade ≥3, between the older and younger groups. However, a poor PS was significantly associated with the low occurrence of any irAEs. The change of the eosinophil count, the increase of the relative eosinophil count (REC) and the decrease of the neutrophil-to-eosinophil ratio (NER) did not differ to a statistically significant extent between the older and younger groups, but showed significant differences between the poor and good PS (PS 0-1) groups. Conclusion: Pembrolizumab for advanced UC demonstrated similar changes in the eosinophil count, efficacy and toxicity in both older and younger patients. In patients with a poor PS, although toxicity was significantly lower, survival was significantly worse, and neither an increase in REC nor a decrease in NER were observed, but these values showed significant changes in patients with a good PS.

Paclitaxel and carboplatin chemotherapy after platinum-based chemotherapy and pembrolizumab for metastatic urothelial carcinoma.

Pembrolizumab has been available for the treatment of radical resectable urothelial carcinoma (UC) when it is exacerbated after chemotherapy since December 2017 in Japan. However, the efficacy of chemotherapy for cases progressing after pembrolizumab is unclear. The present study compared the outcomes and toxicities in patients with metastatic UC after failure of platinum-based chemotherapy and pembrolizumab, who were selected to receive paclitaxel and carboplatin (TC) chemotherapy, with those in patients who received the best supportive care (BSC). A total of 36 patients received pembrolizumab for metastatic UC at four institutions between January 2018 and August 2019. Of the 21 patients who progressed after pembrolizumab, 7 received TC chemotherapy (TC group) and 14 selected BSC (BSC group). The median observation period was 4.1 months. The 7 aforementioned patients who received TC chemotherapy (4 male and 3 female; median age, 62 years; range, 57-79 years) were analyzed in the present study. The ECOG performance status was 0 in three patients, 1 in one patient, 2 in two patients and 3 in one patient. Two patients had upper urinary tract UC, two had bladder UC and three had both types of UC. Six patients had visceral metastasis. The number of chemotherapy regimens before pembrolizumab was one in four patients, two in two patients and three in one patient. The objective response rate was 28.6% (partial response, 2 patients; stable disease, 4 patients; progressive disease, 1 patient), the median progression-free survival time was 3.4 months and the median overall survival time was 10.9 months (vs. 2.7 months in BSC group; P=0.0156). Although grade ≥3 adverse events developed in five patients, there were no treatment-associated deaths. The present results suggested that TC chemotherapy may be a preferred option for patients who require aggressive treatment after the failure of platinum-based chemotherapy and pembrolizumab.

Clinical Outcomes of Mixed Response to Pembrolizumab in Advanced Urothelial Carcinoma After Platinum-based Chemotherapy.

BACKGROUND/AIM: Despite the presence of a mixed response (MR) in patients with urothelial carcinoma (UC) who receive immune checkpoint inhibitors, the clinical outcome of these patient has not been reported. We evaluated the clinical outcome of MR to pembrolizumab for advanced UC. PATIENTS AND METHODS: Advanced UC patients who received pembrolizumab after platinum-based chemotherapy failure with measurable disease in multiple organs were retrospectively analyzed. RESULTS: Among 31 patients, MR [including progressive disease (PD)+complete response (CR) or partial response (PR)] was confirmed in 4 (12.9%). The median overall survival (OS) of the CR+PR (including CR+SD±PR), stable disease (SD), PD (including PD±SD) and MR groups was 16.0, 5.1, 5.4 and 4.3 months, respectively. There was no significant difference in the OS between the MR and CR+PR response groups (log-rank test, p=0.069). CONCLUSION: A mixed response to pembrolizumab in advanced UC was not uncommon. Despite the non-significant difference in the OS between the mixed and CR+PR response groups, the OS of the MR group tended to be similar to that of the SD and PD response groups.

The Association of Clinical Outcomes with Posttreatment Changes in the Relative Eosinophil Counts and Neutrophil-to-Eosinophil Ratio in Patients with Advanced Urothelial Carcinoma Treated with Pembrolizumab.

BACKGROUND: To evaluate the association of clinical outcomes with posttreatment changes in the relative eosinophil count (REC) and neutrophil-to-eosinophil ratio (NER) in patients with advanced urothelial cancer (UC) treated with pembrolizumab. MATERIALS AND METHODS: We retrospectively analyzed 105 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The REC and NER before and three weeks after pembrolizumab were recorded. A receiver operating characteristic curve was used to determine the optimal cut-off values for analyzing the risk. RESULTS: There were no significant differences in the overall survival (OS) between the REC ≥4.8% and <4.8% groups and the NER ≥13.7 and <13.7 groups before pembrolizumab (p=0.997 and 0.669, respectively). However, a significant difference in the OS was confirmed between the increased and decreased REC groups and between the decreased and increased NER groups at 3 weeks after pembrolizumab (p<0.001 and 0.002, respectively). Multivariate analyses revealed that an Eastern Cooperative Oncology Group Performance Status ≥2 (P=0.003), albumin <3.7 g/dl (p=0.002), LDH >246 U/L (p=0.011), disease site ≥3 organs (p=0.019), decreased posttreatment REC (3 weeks later) (p=0.002) and increased posttreatment NER (3 weeks later) (p=0.022) were independent prognostic factors for a worse OS. CONCLUSION: An increased REC and decreased NER after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab.