Predictive factors and oncological outcomes of pathological T3a upstaging in patients with clinical T1 renal cell carcinoma undergoing partial nephrectomy.

OBJECTIVES: To investigate predictive factors and oncological outcomes of pathological T3a upstaging in renal cell carcinoma patients who were initially diagnosed as clinical T1 and treated with partial nephrectomy. METHODS AND MATERIALS: The clinical records and survival data of 1617 patients, who had undergone partial nephrectomy for clinical T1 renal cell carcinoma at Tokyo Women's Medical University, Tokyo, Japan between January 2011 and December 2020, were analyzed retrospectively. RESULTS: Of 1617 clinical T1 renal cell carcinoma patients who underwent partial nephrectomy, 28 (1.73%) had pathological T3a upstaging. In the multivariable analysis for pathological T3a upstaging using logistic regression models, male sex and clinical T1b were significant factors associated with pathological T3a upstaging (male sex: odds ratio = 5.07, 95% confidence interval: 1.18-21.8, clinical T1b: odds ratio = 8.36, 95% confidence interval: 3.56-19.6). The Kaplan-Meier method of the recurrence-free survival showed shorter recurrence-free survival in patients with pathological T3a upstaging than in those with pathological T1 (P < 0.0001). In the multivariable analysis using Cox proportional hazards regression models, pathological T3a upstaging was no longer significantly associated with recurrence-free survival after adjustment for other pathological factors (hazard ratio = 1.59, 95% confidence interval: 0.58-4.36). In a sensitivity analysis that analyzed its components individually instead of whole pathological T3a, neither perinephric fat invasion, sinus fat invasion, nor renal vein invasion was associated with recurrence-free survival. CONCLUSIONS: Male sex and clinical T1b were significant predictors for pathological T3a upstaging after partial nephrectomy in clinical T1 renal cell carcinoma patients. Although patients with pathological T3a upstaging had worse recurrence-free survival compared with those without upstaging, multivariable analyses revealed that pathological T3a upstaging was not an independent predictor for poor recurrence-free survival.

First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

BACKGROUND: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. METHODS: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. RESULTS: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). CONCLUSION: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

[Transurethral Resection of Necrotic Tissue in the Bladder Caused by Emphysematous Cystitis].

Emphysematous cystitis is a relatively rare form of urinary tract infection. A 72-year-old man with diabetes mellitus and long-term indwelling urethral catheterization was diagnosed with emphysematous cystitis. The clinical findings were resolved by conservatively managing the patient with antibiotics. However, cystoscopy subsequently revealed a yellowish-white soft tissue mass in the bladder, which was unlikely to be a bladder tumor. The mass could not be removed easily and frequently caused urinary catheter obstruction. We successfully removed this mass by performing transurethral resection twice. Through histopathological examination, the mass was identified as necrotic tissue comprising bacteria, fibrin, and suspected bladder mucosa.

Real-world efficacy and safety of cabozantinib following immune checkpoint inhibitor failure in Japanese patients with advanced renal cell carcinoma.

BACKGROUND: Real-world data of cabozantinib after failure of immune checkpoint inhibitors for advanced renal cell carcinoma in Japanese population are limited. Additionally, prognostic factors of cabozantinib in this setting are still unknown. METHODS: We retrospectively evaluated data of 56 patients treated with cabozantinib subsequent to failed immune checkpoint inhibitors at four institutions. Regarding the efficacy profile, progression-free survival, overall survival and objective response rate were assessed. In terms of the safety profile, rate of adverse events, dose reduction and treatment interruption were assessed. Furthermore, risk factors of progression-free survival were analyzed. RESULTS: Twenty-nine patients (52%) were treated with cabozantinib as second-line therapy. Most frequent prior immune checkpoint inhibitor treatment was nivolumab plus ipilimumab combination therapy as first-line therapy (n = 30, 54%). Median progression-free survival and overall survival were 9.76 and 25.5 months, respectively, and objective response rate was 34%. All patients experienced at least one adverse event, and grade ≥ 3 adverse events were observed in 31 patients (55%). Forty-four (79%) and 31 (55%) patients needed dose reduction and treatment interruption, respectively. Multivariate analysis showed that reduced initial dose (i.e. <60 mg) (hazard ratio: 2.50, P = 0.0355) and presence of lymph node metastasis (hazard ratio: 2.50, P = 0.0172) were independent factors of shorter progression-free survival. CONCLUSION: Cabozantinib in Japanese patients with advanced renal cell carcinoma who failed immune checkpoint inhibitors was efficacious and had a manageable safety profile. These results appear to be similar to those of previous clinical trials.

Impact of sex on prognosis in patients with advanced renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal cell carcinoma. METHODS: We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n = 73) or nivolumab as later-line therapy (n = 111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes. RESULTS: Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3 months, P = 0.0005), but overall survival (median: 39.2 vs. 45.1 months, P = 0.283) and objective response rate (29% vs. 42%, P = 0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P = 0.007, P = 0.017), but overall survival (P = 0.914, P = 0.117) and objective response rate (P = 0.109, P = 0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0 months, P < 0.0001). CONCLUSIONS: This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.

Association between lung immune prognostic index and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab.

INTRODUCTION AND OBJECTIVE: Lung immune prognostic index score (LIPI), calculated using the derived neutrophil-lymphocyte ratio and lactate dehydrogenase level, is reported for use in numerous malignancies, while its role on metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains limited. We aimed to investigate association between LIPI and outcomes in this setting. METHODS: We retrospectively evaluated 90 patients with mUC treated with pembrolizumab at four institutions. The associations between three LIPI groups and progression-free survival (PFS), overall survival (OS), objective response rates (ORRs) or disease control rates (DCRs) were assessed. RESULTS: Based on the LIPI, good, intermediate, and poor groups were observed in 41 (45.6%), 33 (36.7%), and 16 (17.8%) patients, respectively. The PFS and OS were significantly correlated with the LIPI (median PFS: 21.2 vs. 7.0 vs. 4.0 months, p = 0.001; OS: 44.3 vs. 15.0 vs. 4.2 months, p < 0.001 in the LIPI good vs. intermediate vs. poor groups). Multivariable analysis further revealed that LIPI good (vs. intermediate or poor, hazard ratio: 0.44, p = 0.004) and performance status = 0 (p = 0.015) were independent predictors of a longer PFS. In addition, LIPI good (hazard ratio: 0.29, p < 0.001) were shown to be associated with a longer OS together with performance status = 0 (p < 0.001). The ORRs tended to be different among patients with Good LIPI compared with Poor, and DCRs were significantly different among the three groups. CONCLUSIONS: LIPI, a simple and convenient score, could be a significant prognostic biomarker of OS, PFS, and DCRs for mUC treated with pembrolizumab.

Outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma: a real-world multi-institution data with a minimum of 2 years of follow-up.

OBJECTIVES: To investigate the long-term follow-up outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma, using real-world data. METHODS: A total of 121 patients were treated with nivolumab monotherapy as subsequent therapy after the failure of prior tyrosine kinase inhibitor therapy between January 2013 and December 2021 at four affiliated institutions. To evaluate the outcome after 2 years or more, we selected patients in whom nivolumab therapy was started in December 2019 or earlier because data collection was performed until the end of December 2021. RESULTS: Seventy-four patients were evaluated. During the median follow-up period of 25.8 months, 62 (84%) and 40 (54%) patients had disease progression and died, respectively. Nivolumab was administered as second-line therapy in 43 patients (58%). The median progression-free survival and overall survival were 5.52 and 31.1 months, respectively, and objective response rate was 36%. There was no difference in progression-free survival or overall survival based on the treatment line of nivolumab (P = 0.915, P = 0.559). The magnitude of tumor response and development of immune-related adverse events were significantly associated with progression-free survival (P < 0.0001, P < 0.0001, respectively) and overall survival (P < 0.0001, P = 0.0002, respectively). Treatment-related adverse events developed in 38 patients (51%), including 33 (45%) who had immune-related adverse events. Steroid administration was needed in nine patients (12%). CONCLUSIONS: The present real-world multi-institution study with long-term follow-up data demonstrates that nivolumab monotherapy is effective for previously treated metastatic renal cell carcinoma, prolonging survival, improving tumor response and has a manageable safety profile.

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Prognostic Impact of Trial-Eligibility Criteria in Patients with Metastatic Renal Cell Carcinoma.

OBJECTIVE: The aim of the study was to evaluate the prognostic impact of trial-eligibility criteria on outcome in real-world metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: mRCC patients treated with TKIs as first-line systemic therapy were retrospectively evaluated. The patients were determined as trial-ineligible when they met at least 1 following trial-ineligible criteria; Karnofsky performance status score <70, hemoglobin <9.0 g/dL, creatinine >2.4 mg/dL (male) or >2.0 mg/dL (female), calcium >12.0 mg/dL, platelet <100,000 /µL, neutrophil <1,500 /µL, nonclear-cell histology, and brain metastasis. RESULTS: Of 238 patients, 101 patients (42%) were determined as trial-ineligible. Progression-free survival (PFS) and overall survival (OS) after the TKI initiation were significantly shorter in the trial-ineligible patients than in the trial-eligible patients (median PFS: 5.53 vs. 15.8 months, p < 0.0001; OS: 13.8 vs. 43.4 months, p < 0.0001). Objective response rate was also significantly lower in the trial-ineligible patients (15% vs. 37%, p = 0.0003). Multivariate analysis further showed that the trial-eligibility was an independent factor for PFS (hazard ratio [HR]: 2.46, p < 0.0001) and OS (HR: 2.39, p < 0.0001). In addition, the number of trial-ineligible factors were negatively correlated with PFS and OS. CONCLUSIONS: In real-word, the substantial number of mRCC patients did not meet the trial-eligibility criteria, and their outcome was worse than that in the trial-eligible patients. Further studies focusing on the outcome in real-world trial-ineligible patients in the immune checkpoint inhibitor era are warranted.

Assessing improvements in metastatic renal cell carcinoma systemic treatments from the pre-cytokine to the immune checkpoint inhibitor eras: a retrospective analysis of real-world data.

OBJECTIVE: Studies assessing outcome improvements over a long period according to systemic therapy strategies for metastatic renal cell carcinoma using real-world data, including the results of the recent era of immune checkpoint inhibitors, are limited. Herein, we retrospectively evaluated patients who were diagnosed with metastatic renal cell carcinoma over a 40-year span. METHODS: Patients were classified into four groups based on when their metastases were diagnosed as follows: (i) the pre-cytokine era (1980-1986), (ii) the cytokine era (1987-2007), (iii) the molecular-targeted therapy (mTT) era (2008 to August 2016) and (iv) the immune checkpoint inhibitor era (September 2016 to 2018). The immune checkpoint inhibitor era consisted of second- or later-line nivolumab. Overall survival from the diagnoses of metastases was evaluated. RESULTS: In total, 576 patients were evaluated, including 22 (3.82%), 231 (40.1%), 253 (43.9%) and 70 (12.2%) patients from the pre-cytokine, cytokine, molecular-targeted therapy and immune checkpoint inhibitor eras, respectively. The overall survival significantly improved with each successive era (median: 13.1 vs. 24.5 vs. 44.4 months vs. not reached in pre-cytokine vs. cytokine vs. molecular-targeted therapy vs. immune checkpoint inhibitor eras, P < 0.0001). The implementation of molecular-targeted therapy improved overall survival compared with that of cytokine (cytokine vs. molecular-targeted therapy eras, P < 0.0001). Multivariate analysis demonstrated that the era was an independent factor for overall survival (P < 0.0001), together with histopathological type; metastasis status (i.e. synchronous or metachronous); systemic therapy status (i.e. absence or presence) and bone, liver or lymph node metastasis status (all, P < 0.05). CONCLUSION: This retrospective study of real-world data indicated that metastatic renal cell carcinoma outcomes improved with successive systemic therapy paradigms.

Modest efficacy of nivolumab plus ipilimumab in patients with papillary renal cell carcinoma.

PURPOSE: Combined immunotherapy of nivolumab plus ipilimumab for intermediate- and poor-risk metastatic clear cell renal cell carcinoma showed prolonged progression-free survival and high objective response rate in a randomized phase III clinical trial. However, the efficacy of this treatment for papillary renal cell carcinoma remains unclear. In the present study, we analysed the efficacy of nivolumab plus ipilimumab therapy for papillary renal cell carcinoma compared with that for clear cell renal cell carcinoma. MATERIALS AND METHODS: This is a retrospective study of 30 patients with metastatic renal cell carcinoma who received nivolumab and ipilimumab as first-line therapy between December 2015 and May 2020. The objective response rate, progression-free survival and toxicity were compared between the two groups (clear cell renal cell carcinoma and papillary renal cell carcinoma). RESULTS: Out of 30 patients, 7 and 23 were diagnosed with papillary renal cell carcinoma and clear cell renal cell carcinoma, respectively. With a median follow-up of 7.2 months, the median progression-free survival was significantly shorter in papillary renal cell carcinoma than in clear cell renal cell carcinoma (2.4 vs. 28.1 months, P = 0.014). Of the seven patients with papillary renal cell carcinoma, one had partial response, one had stable disease and five had progressive disease, resulting in an objective response rate of 14.2%, which was lower compared to that of clear cell renal cell carcinoma (14.2 vs. 52.1%, P = 0.06). Discontinuation due to toxicity was not observed with papillary renal cell carcinoma, meanwhile 60.8% of patient with clear cell renal cell carcinoma discontinued treatment due to toxicity. CONCLUSION: Nivolumab plus ipilimumab had modest efficacy for papillary renal cell carcinoma compared with that for clear cell renal cell carcinoma. Nivolumab plus ipilimumab remains an option for a limited number of patients with intermediate- or poor-risk papillary renal cell carcinoma.

Prognostic impact of systemic therapy change in metastatic renal cell carcinoma treated with cytoreductive nephrectomy.

OBJECTIVE: Limited data are available regarding the effect of systemic therapy change in the post-cytokine era on survival of metastatic renal cell carcinoma (mRCC) patients undergoing cytoreductive nephrectomy (CN). METHODS: Overall, 161 patients with synchronously mRCC were retrospectively evaluated. The patients were classified into three groups based on the time of diagnosis: (i) early molecular-targeted therapy (mTT) (2008-2011), (ii) late mTT (2012-8/2016) and (iii) immune checkpoint inhibitor (ICI) eras (9/2016-2018). Overall survival (OS) after the diagnosis was compared among the eras. RESULTS: Of the 161 patients, 52 (32%), 75 (46%), and 34 patients (21%) were classified into the early mTT, late mTT and ICI eras, respectively. OS was significantly longer in the ICI and late mTT eras than that in the early mTT era (P = 0.0065 and P = 0.0010, respectively) but did not significantly differ between the ICI and late mTT eras (P = 0.389). In 112 patients undergoing CN and systemic therapy, OS was significantly longer in the ICI and late mTT eras than that in the early mTT era (P = 0.0432 and P = 0.0498, respectively) but did not significantly differ between the ICI and late mTT eras (P = 0.320). Multivariate analysis of OS in the 161 synchronous mRCC patients revealed that the era was an independent factor (P < 0.0001), together with the histopathological type (P = 0.0130), CN status (P = 0.0010), International Metastatic Renal Cell Carcinoma Database Consortium risk (P = 0.0002) and liver metastasis status (P = 0.0124). CONCLUSION: This retrospective analysis showed that systemic therapy change in the post-cytokine era improved OS of mRCC patients undergoing CN.

Association of tumor burden with outcome in first-line therapy with nivolumab plus ipilimumab for previously untreated metastatic renal cell carcinoma.

OBJECTIVES: To investigate the prognostic impact of tumor burden in patients receiving nivolumab plus ipilimumab as first-line therapy for previously untreated metastatic renal cell carcinoma (mRCC). METHODS: We retrospectively evaluated 62 patients with IMDC intermediate- or poor-risk mRCC, treated with nivolumab plus ipilimumab as first-line therapy at five affiliated institutions. Tumor burden was defined as the sum of diameters of baseline targeted lesions according to the RECIST version.1.1. We categorized the patients into two groups based on the median value of tumor burden (i.e., high vs. low). The association of tumor burden with progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with nivolumab plus ipilimumab treatment was analyzed. RESULTS: The median tumor burden was 63.0 cm (interquartile range: 34.2-125.8). PFS was significantly shorter in patients with high tumor burden (n = 31) than in those with low tumor burden (n = 31) (median: 6.08 [95% CI: 2.73-9.70] vs. 12.5 [4.77-24.0] months, P = 0.0134). In addition, OS tended to be shorter in patients with high tumor burden; however, there was no statistically significant difference (1-year rate: 77.3 vs. 96.7%, P = 0.166). ORR was not significantly different between patients with high and low tumor burden (35 vs. 55%, P = 0.202). Multivariate analysis of PFS further showed that tumor burden was an independent factor (HR: 2.22 [95% CI: 1.11-4.45], P = 0.0242). CONCLUSIONS: Tumor burden might be a useful factor for outcome prediction, at least for PFS prediction, in patients receiving nivolumab plus ipilimumab for mRCC. Further prospective studies are warranted to confirm our findings.

Outcome of advanced renal cell carcinoma arising in end-stage renal disease: comparison with sporadic renal cell carcinoma.

BACKGROUND: The data regarding oncological outcome in advanced renal cell carcinoma (RCC) arising in end-stage renal disease (ESRD) are limited. METHODS: Patients diagnosed with advanced RCC on maintenance dialysis therapy (ESRD-RCC) and treated with tyrosine kinase inhibitors (TKIs) were retrospectively evaluated. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) after initiation of first-line TKI therapy in ESRD-RCC patients were compared to those in RCC arising in the general population (sporadic RCC). RESULTS: A total of 36 and 240 patients were diagnosed with advanced ESRD-RCC and sporadic RCC, respectively. PFS and OS were significantly shorter in patients with ESRD-RCC than in those with sporadic RCC (p = 0.0004 and p = 0.0045). After adjusting for histopathological type, MSKCC risk and liver metastasis status, ESRD status (ESRD-RCC vs. sporadic RCC) was not an independent risk factor for PFS or OS (both, p > 0.05). The ORR tended to be lower in patients with ESRD-RCC than in those with sporadic RCC (11% vs. 28%, p = 0.0833). In 34 patients with ESRD-RCC treated with sorafenib, longer duration of dialysis was an independent prognostic factor for shorter OS (hazard ratio 3.21, p = 0.0370). CONCLUSIONS: Outcome of advanced ESRD-RCC was poorer than that of sporadic RCC, but this finding was affected by other prognostic factors. Nevertheless, the study suggested that advanced ESRD-RCC was not an indolent disease. Additionally, patients with a longer duration of dialysis therapy might require careful monitoring.

Predictive role of γ-glutamyltransferase in patients receiving nivolumab therapy for metastatic renal cell carcinoma.

INTRODUCTION: γ-Glutamyltransferase is reportedly associated with survival in local and metastatic renal cell carcinoma patients; however, its predictive role among patients treated with immune-checkpoint inhibitors are unknown. This study aimed to investigate the role of γ-glutamyltransferase as a predictive marker among metastatic renal cell carcinoma patients undergoing nivolumab therapy. METHODS: We retrospectively evaluated 69 nivolumab-treated metastatic renal cell carcinoma patients upon failure of one or more systematic therapies. Serum γ-glutamyltransferase levels were determined at baseline and 2 months after nivolumab treatment initiation. Patients were classified as high (≥ 49 U/L) and low (< 49 mg/dL) from baseline GGT levels and the outcomes were compared between the two groups. Furthermore, increased (after/baseline ≥ 2) and non-increased (after/baseline < 2) groups were compared. Progression-free survival and overall survival were evaluated after nivolumab initiation. RESULTS: Overall survival was significantly shorter in the high baseline γ-glutamyltransferase group (20.3%) than in the low group (79.7%) (median 2.33 vs not reached [months], p = 0.0051). Progression-free survival and the overall survival were significantly shorter in the increased than in the non-increased group (24.6% and 75.4%, respectively) (median PFS: 4.43 vs 7.23 [months], p = 0.0373/OS: 24.00 vs not reached, p = 0.0467). On multivariate analyses, high baseline γ-glutamyltransferase was an independent factor for overall survival (p = 0.0345) and increased γ-glutamyltransferase was an independent factor for progression-free survival (p = 0.0276) and overall survival (p = 0.0160). CONCLUSIONS: High baseline γ-glutamyltransferase and its early increase are associated with a poor prognosis in metastatic renal cell carcinoma patients receiving nivolumab. Serum γ-glutamyltransferase levels may help predict treatment outcomes.

Limited impact of warm ischemic threshold for partial nephrectomy in the robotic surgery era: A propensity score matching study.

OBJECTIVES: To evaluate the association between extended (≥30 min) warm ischemic time and renal function in patients undergoing robot-assisted partial nephrectomy. METHODS: This multi-institutional study retrospectively recruited 1131 patients who underwent robot-assisted partial nephrectomy. Patients were classified into shorter (<30 min; n = 1038) and longer (≥30 min; n = 92) groups based on the ischemic time required, and 1:2 propensity score matching was used to minimize selection bias. The perioperative outcomes, including acute kidney injury and trifecta attainment, and mid/long-term renal function were assessed before and after matching. RESULTS: Patients in the longer group had tumors with a significantly larger diameter and RENAL nephrometry score. The decline in the nadir of the estimated glomerular filtration rate was significantly greater in the longer than the shorter group in the unmatched and matched cohorts (-16.2 vs -5.5%, P < 0.001; 15.5 vs -9.5%, P = 0.003, respectively). A higher incidence of acute kidney injury (9.8 vs 2.6%, P = 0.002) was observed in the longer group before matching, whereas the difference was comparable after matching. Before matching, the decline in estimated glomerular filtration rate at 6 months postoperatively was greater (-8.2 vs -5.1%, P = 0.005) and trifecta attainment was lower (50.0 vs 63.5%, P < 0.001) in the longer group. However, the differences were comparable for both the parameters between the groups in the matched cohort. CONCLUSIONS: While extended warm ischemia during robot-assisted partial nephrectomy can be demanded in case of large and complex tumors, its impact on postoperative renal function is limited.

Efficacy of nivolumab versus molecular-targeted therapy as second-line therapy for metastatic renal cell carcinoma: Real-world data from two Japanese institutions.

OBJECTIVES: To compare the efficacy of nivolumab with that of molecular-targeted therapy as a second-line therapy for metastatic renal cell carcinoma using real-world data. METHODS: We retrospectively evaluated patients who received nivolumab or molecular-targeted therapy after the failure of first-line molecular-targeted therapy between January 2008 and December 2019 at two Japanese institutions. Progression-free survival and overall survival after the initiation of second-line therapy were calculated using the Kaplan-Meier method and compared using the log-rank test. Objective response rate was assessed based on the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Among 159 patients, 43 (27%) and 116 (73%) patients received nivolumab and molecular-targeted therapy as second-line therapy, respectively. During follow up (median 11.1 months), 129 (81%) and 98 (62%) patients had disease progression and died, respectively. Progression-free survival was comparable between the two treatments (median 5.06 vs 5.95 months, P = 0.881), whereas overall survival was significantly longer with nivolumab than with molecular-targeted therapy (not reached vs 13.0 months, P = 0.0008). Multivariate analysis further showed that nivolumab therapy was an independent favorable factor for overall survival (hazard ratio 0.33, P = 0.0007). In 151 patients with eligible radiographic data, the objective response rate was significantly higher in nivolumab than in molecular-targeted therapy (n = 14/41 [34%] vs n = 20/110 [18%], P = 0.0485). CONCLUSIONS: Real-world data analysis suggests superior efficacy of nivolumab over molecular-targeted therapy as second-line therapy for metastatic renal cell carcinoma.

Comparable efficacy and safety between second-line and later-line nivolumab therapy for metastatic renal cell carcinoma.

BACKGROUND: The aim of this study was to compare the efficacy and safety of nivolumab as second-line and later-line (third-line or thereafter) therapy in metastatic renal cell carcinoma (mRCC). METHODS: Sixty-seven patients who received nivolumab after the failure of at least one molecular-targeted therapy were evaluated. The patients were divided into two groups based on the line of nivolumab: second-line and later-line groups. Efficacy was assessed using progression-free survival and overall survival (OS) after nivolumab initiation, and objective response rate. Safety was assessed using the incidence of immune-related adverse events. These outcomes were compared between the second-line and later-line groups. RESULTS: Forty-two patients (62.7%) received nivolumab as second-line therapy. There was no significant difference in the progression-free survival (median: 5.06 vs. 6.28 months, p = 0.691) or objective response rate (35.7% vs. 32.0%, p = 0.757) between the second-line and later-line groups. The OS tended to be longer in the second-line group (not reached vs. 26.0 months, p = 0.118), and the rate of patients who received subsequent therapy after nivolumab failure was significantly higher in the second-line group (90.9% vs. 55.0%, p = 0.0025). There was no difference in the incidences of immune-related adverse events between the second-line and later-line groups (any grade: 54.8% vs. 48.0%, p = 0.592; grade ≥ 3: 19.1% vs. 20.0%, p = 0.924). CONCLUSIONS: The efficacy of nivolumab did not deteriorate and the tolerability was also maintained even in later-line therapy. However, a tendency of longer OS and a higher chance of subsequent therapy after nivolumab failure were observed with nivolumab as second-line therapy.

Decreased relative dose intensity during the early phase of treatment impacts the therapeutic efficacy of sunitinib in metastatic renal cell carcinoma.

BACKGROUND: Relative dose intensity is an indicator of therapeutic efficacy in sunitinib treatment for metastatic renal cell carcinoma. However, the number of studies investigating the influence of decreased relative dose intensity during the early phase on oncological outcome is limited. METHODS: A total of 105 patients who received first-line sunitinib treatment for metastatic renal cell carcinoma were evaluated. We assessed the relative dose intensity during the initial first cycle (1c-RDI). We found that an optimal threshold of 1c-RDI was associated with progression-free survival and overall survival after the initiation of sunitinib treatment. Additionally, predictive factors for decreased 1c-RDI were analyzed. RESULTS: The 1c-RDI threshold was determined at 60%. Patients with low 1c-RDI (<60%, n = 26, [24.8%]) had significantly shorter median progression-free survival (5.79 vs. 14.0 months, P = 0.0014) and overall survival (13.3 vs. 34.4 months, P = 0.0005) durations than those with high 1c-RDI (≥60%, n = 79 [75.2%]). Multivariate analysis showed that the development of dose-limiting toxicity was an independent factor for low 1c-RDI (odds ratio: 3.09, 95% confidence interval: 1.14-8.37, P = 0.0266) after adjustment with an initial dose of sunitinib. CONCLUSIONS: More than 60% of 1c-RDI is needed for effective sunitinib treatment. Patient tolerability should be carefully monitored to avoid the development of dose-limiting toxicity during the early phase of treatment.

Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy.

BACKGROUND: The number of studies evaluating the efficacy and safety of third-line molecular-targeted therapy for metastatic renal cell carcinoma (mRCC) is limited. METHODS: The data for 48 patients with disease progression after first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI) and second-line targeted therapy were evaluated. Patients with prior cytokine therapy were excluded. Overall survival (OS) after first- and second-line therapy initiation was compared between patients with and without third-line therapy. In addition, dose-limiting toxicities (DLTs) were evaluated. RESULTS: Twenty-two of 48 patients (45.8%) received third-line therapy, and TKI and mammalian target of rapamycin inhibitor were each administered in 11 patients (50%). Patients with third-line therapy had significantly longer median OS after first-line therapy (26.6 vs. 14.6 months, p = 0.0010) and second-line therapy (18.2 vs. 7.4 months, p < 0.0001) compared to those without third-line therapy. Multivariate analysis showed that the use of third-line therapy following second-line therapy was an independent prognosticator for longer OS (hazard ratio 0.29, 95% confidence interval 0.14-0.58, p = 0.0005). The median progression-free survival and OS after third-line therapy was 2.76 and 8.71 months, respectively. Although a high frequency of DLTs was observed (n = 10, 45.5%), the frequencies were similar among the sequential therapies. CONCLUSIONS: Third-line therapy has a beneficial therapeutic effect in patients with mRCC that is resistant to previous therapies. However, there is a need to evaluate in detail the high frequency of adverse events, including DLTs.