Management of Renal Cell Carcinoma With Supradiaphragmatic Inferior Vena Cava Thrombus Diagnosed During Acute COVID-19 Infection.

Renal cell carcinoma (RCC) tends to undergo intravascular tumor growth along the renal vein, forming tumor thrombi that may extend into the inferior vena cava (IVC) or even the right atrium (Level IV). Managing such cases requires a multidisciplinary approach, especially in patients with acute coronavirus disease 2019 (COVID-19) infection, who face increased risks from surgical interventions. We present a case of RCC with Level IV thrombus and concurrent COVID-19 managed with systemic therapy. We also summarize current literature on treating RCC with IVC thrombus and COVID-19's impact on prognosis. The patient was a 70-year-old female with incidental detection of a 9-cm right heterogeneous renal mass with a supradiaphragmatic tumor thrombus during COVID-19 infection. Due to ongoing pulmonary symptoms, systemic therapy with a combination of ipilimumab and nivolumab was initiated. After an excellent initial response, the patient continued systemic therapy, maintaining a necrotic response in the renal mass and tumor thrombus. The patient continues to tolerate systemic therapy well. We report a rare case of RCC with Level IV tumor thrombus and synchronous acute COVID-19 infection. Our report depicts successful management utilizing systemic therapy with a combination of ipilimumab and nivolumab. The management of such cases necessitates a comprehensive, multidisciplinary approach, considering the risks associated with surgery in the context of recent COVID-19 infection. The case presentation and ensuing literature discussion of the dynamic landscape of RCC management highlights the need for more research to improve treatment plans and guide clinicians in handling such complex situations.

Sequential endoluminal gemcitabine and docetaxel vs. Bacillus Calmette-Guérin for the treatment of upper tract carcinoma in situ.

INTRODUCTION: Nephroureterectomy is commonly performed for high-grade (HG) upper tract (UT) urothelial carcinoma (UC). However, some patients may benefit from a de-escalation of surgical management, particularly for noninvasive disease and carcinoma in situ (CIS). Bacillus Calmette-Guerin (BCG) is currently the only guideline-recommended endoluminal treatment option. Gemcitabine/Docetaxel (Gem/Doce) has shown promising efficacy as a treatment for noninvasive HG UTUC, though a comparison to BCG is lacking. We report the outcomes of patients treated with endoluminal Gem/Doce vs. BCG for UT-CIS. METHODS: A single-institutional retrospective review of patients treated with Gem/Doce vs. BCG for UT-CIS was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. In both treatment groups, induction consisted of 6 weekly instillations. Maintenance was initiated if disease-free and consisted of 6 monthly instillations in the Gem/Doce group and a reduced dose (one-tenth) 3-week course at 3 months in the BCG group. Recurrence was defined as biopsy-proven disease or HG cytology. RESULTS: The final cohort included 53 patients with 65 upper tract units; 31 received BCG and 34 received Gem/Doce. Median follow-up was 88 and 29 months in the BCG and Gem/Doce groups, respectively. Presenting pathology included biopsy-proven CIS and HG cytology in 9.7% and 90% of the BCG group, and 8.8% and 91% of the Gem/Doce group, respectively. The 2-year estimates for recurrence-free and nephroureterectomy-free survival were 61% and 89% for the BCG group and 54% and 100% for the Gem/Doce group, respectively. Upon multivariable analysis, instillation via percutaneous nephrostomy tube was associated with an increased risk of recurrence (HR 3.89, 95% CI 1.59-9.53). The development of any symptom was not statistically different between treatment groups (P = 0.12). There were 2 treatment-related deaths that occurred, 1 within each treatment group. CONCLUSION: Endoluminal Gem/Doce and BCG have similar oncological outcomes and major adverse event rates in the treatment of UT-CIS. Further prospective evaluation is warranted.

Combination intravesical chemotherapy for non-muscle invasive bladder cancer (NMIBC) as first-line or rescue therapy: where do we stand now?

INTRODUCTION: The combination of intravesical gemcitabine (Gem) with docetaxel (Doce) or with mitomycin C (MMC) has been used in the primary setting as an alternative to Bacillus Calmette-Guerin (BCG) to treat high-risk (HR) and intermediate-risk (IR) non-muscle invasive bladder cancer (NMIBC), as well in the rescue setting for patients in whom BCG has failed. AREA COVERED: Efficacy and safety of Gem/Doce and Gem/MMC to treat NMIBC in BCG-naive and failure settings. EXPERT OPINION: In the BCG-naive setting, Gem/Doce was the primary alternative combination therapy reported, with a weighted mean of 12- and 24-month recurrence-free survival (RFS) of 79% and 77% for HR disease and 84% and 76% for IR disease, respectively. In the HR BCG-failure setting, the weighted mean of 12- and 24-month RFS was 60% and 42% for Gem/Doce and 63% and 40% for Gem/MMC. While patients without BCG exposure and papillary disease only benefit the most from Gem/Doce, there is also reasonable efficacy in BCG refractory disease and CIS. Combination therapy is well tolerated, with grade III toxicity reported in less than 1% of patients. Unlike single-agent chemotherapy, intravesical Gem/Doce is considered effective and safe regardless of risk-stratification.

Sequential endoluminal gemcitabine and docetaxel for the treatment of clinically non-invasive high-grade upper tract urothelial carcinoma.

PURPOSE: There is an unmet need for effective renal sparing treatments for upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown favorable efficacy in nonmuscle invasive bladder cancer. We report the outcomes of patients treated with endoluminal Gem/Doce for noninvasive high-grade UTUC. METHODS: A retrospective review of patients treated with Gem/Doce for clinically noninvasive high-grade UTUC with no radiographic or endoscopically visible disease, either at diagnosis or following ablation, was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks, followed by 6 monthly instillations if disease-free. Recurrence was defined as biopsy-proven disease or high-grade (HG) cytology. Progression was defined by development of muscle invasion, metastases, or death due to cancer. Survival was assessed with the Kaplan-Meier method. RESULTS: The final cohort included 31 patients with 41 upper tract units, 51% of which would have been dialysis dependent with nephroureterectomy. Median (IQR) age was 74 years (68-81). Median follow-up was 29 months (IQR 20-58). Prior to treatment, 37 (90%) units presented with a localizing HG cytology (presumed occult CIS), and 4 (9.8%) with HG biopsy-proven disease. Sixteen (52%) patients reported any side effects; 5 were Grade 3 and 1 was Grade 5. Recurrence-free survival was 76%, 54%, and 40% at 1, 2, and 3 years, respectively. Five patients died from urothelial carcinoma. The 3-year progression-free and overall survival were 75% and 75%, respectively. CONCLUSIONS: Gem/Doce demonstrates promising safety and efficacy as a renal-sparing treatment option for high-grade UTUC in appropriately selected patients.

Recurrent heterotopic ossification following open radical nephrectomy.

A 46-year-old male presented with a localized left renal mass and underwent an open radical nephrectomy via a midline incision. He recovered uneventfully and was discharged. After one month he reported persistent incisional pain; CT demonstrated heterotopic bone formation under the fascial closure. He underwent resection of calcified preperitoneal fat. Final pathology revealed benign bone tissue. He received a course of celecoxib. The patient developed recurrence of a smaller calcification. He underwent a second resection and was treated with adjuvant radiation. The patient had improvement of pain and no ossification visualized on CT imaging at 1-year follow up.

Neoadjuvant systemic and intravesical chemotherapy with partial cystectomy for muscle invasive bladder cancer with concomitant CIS.

The presence of carcinoma in situ (CIS) is traditionally a contraindication to bladder-sparing approaches for muscle invasive bladder cancer (MIBC). Strategies that might aid in bladder preservation for this population require further investigation. We report a case of MIBC with CIS treated with both neoadjuvant systemic and intravesical chemotherapy prior to partial cystectomy.

Sequential intravesical gemcitabine and docetaxel for treatment-naïve and previously treated intermediate-risk nonmuscle invasive bladder cancer.

INTRODUCTION: Adjuvant intravesical therapy is recommended for patients with intermediate-risk NMIBC. While intravesical gemcitabine-docetaxel (Gem/Doce) has demonstrated favorable outcomes for high-risk NMIBC, its utility in the intermediate-risk setting is not well described. We report outcomes of Gem/Doce as an adjuvant treatment for intermediate-risk NMIBC. METHODS: We retrospectively identified patients with intermediate-risk NMIBC by AUA criteria treated with Gem/Doce following TURBT between 2012 and 2022. Patients received weekly sequential intravesical instillations of 1 g gemcitabine and 37.5 mg docetaxel for 6 weeks. Monthly maintenance of 2 years was initiated if disease-free at first surveillance. The primary outcome was recurrence-free survival (RFS), assessed using the Kaplan-Meier method. RESULTS: The cohort included 77 patients with median follow-up of 26 (IQR 14-50) months. Prior to induction, 67 (87%) patients presented with Ta low-grade (LG) lesions, 3 (3.9%) with Ta high-grade (HG), 5 (6.5%) with TaLG plus focal TaHG, and 2 (2.6%) with T1LG. Thirty-three (43%) patients received previous intravesical therapy including BCG (23), mitomycin (13), and docetaxel monotherapy (12). The 2-year RFS was 71% among all patients. Treatment-naïve patients had superior RFS compared to previously treated patients (P = 0.04); 2-year estimates were 79% and 64%, respectively. Twenty-nine (38%) patients experienced adverse events; all were Grade 1 to 2 except 1 (1.3%) Grade 3 (acute oxygen desaturation). Three (3.9%) patients did not tolerate a full induction course. CONCLUSIONS: In this retrospective review of a heterogenous population of patients with intermediate-risk NMIBC, Gem/Doce was an effective and well-tolerated adjuvant therapy. Further prospective evaluation in this setting is needed.

Sequential Intravesical Gemcitabine and Docetaxel is an Alternative to Bacillus Calmette-Guérin for the Treatment of Intermediate-risk Non-muscle-invasive Bladder Cancer.

Adjuvant treatment with either chemotherapy or bacillus Calmette-Guérin (BCG) is recommended for patients with intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC). In this multi-institutional retrospective review, we evaluated oncological outcomes for 182 patients with IR-NMIBC treated with BCG (n = 100) or intravesical sequential gemcitabine and docetaxel (Gem/Doce; n = 82). Median follow-up was 48.6 mo (interquartile range 24.9-70.9). No patient had a previous diagnosis of high-grade disease. Recurrence rates were similar in the two treatment groups (hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.65-1.73; p = 0.8). Results were consistent after adjusting for International Bladder Cancer Group (IBCG) risk subgroups, use of single-instillation postoperative chemotherapy, use of blue light cystoscopy, and receipt of maintenance therapy (HR 0.88, 95% CI 0.47-1.64; p = 0.7). Similarly, there was no difference in the rate of stage/grade progression between the treatment groups (HR 0.66, 95% CI 0.21-2.12; p = 0.5). Rates of progression to muscle-invasive disease/metastasis (2.2%) and cancer-specific mortality (1.7%) were low in the cohort. Our results support the use of Gem/Doce as an alternative to BCG in patients with IR-NMIBC. PATIENT SUMMARY: We compared cancer control outcomes for two different treatments for intermediate-risk non-muscle-invasive bladder cancer. Our results show that a chemotherapy combination of docetaxel and gemcitabine is as effective as the BCG (bacillus Calmette-Guérin) treatment traditionally used for this type of bladder cancer.

Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer.

Importance: Due to the ongoing bacillus Calmette-Guérin (BCG) shortage, sequential intravesical gemcitabine and docetaxel has been increasingly used as first-line therapy for high-risk non-muscle-invasive bladder cancer (NMIBC). However, data directly comparing these 2 therapies are lacking. Objective: To compare the outcomes of patients with high-risk NMIBC treated with gemcitabine and docetaxel vs BCG. Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2011, to December 31, 2021. The median (IQR) duration of follow-up was 23 (12-33) months for patients receiving gemcitabine and docetaxel and 49 (27-79) months for patients receiving BCG. All patients were treated at the University of Iowa tertiary care center. A total of 312 patients with high-risk treatment-naive NMIBC were included; 174 patients were treated with BCG therapy and 138 were treated with gemcitabine and docetaxel therapy. Exposures: After undergoing complete transurethral resection of bladder tumor, patients received either sequential intravesical gemcitabine, 1 g, and docetaxel, 37.5 mg, or 1 vial of BCG. Induction treatments were administered once per week for 6 weeks. Maintenance regimens were initiated if the patient was disease free at the first follow-up visit. Main Outcomes and Measures: The primary outcome was high-grade recurrence-free survival (RFS). Survival probabilities were estimated using the Kaplan-Meier method. Cox regression models were used to evaluate the association of covariates with outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events, version 5. Results: Among 312 patients, the median (IQR) age was 73 (66-79) years; 255 patients (81.7%) were male and 292 (93.6%) were White. Baseline clinicopathological characteristics such as sex, smoking status, and pretreatment tumor pathology were similar between treatment groups. High-grade RFS estimates were 76% (95% CI, 69%-82%) at 6 months, 71% (95% CI, 64%-78%) at 12 months, and 69% (95% CI, 62%-76%) at 24 months in the BCG group and 92% (95% CI, 86%-95%) at 6 months, 85% (95% CI, 78%-91%) at 12 months, and 81% (95% CI, 72%-87%) at 24 months in the gemcitabine and docetaxel group. Multivariable Cox regression analyses controlled for age, sex, treatment year, and presence of carcinoma in situ revealed that treatment with gemcitabine and docetaxel was associated with better high-grade RFS (hazard ratio, 0.57; 95% CI, 0.33-0.97; P = .04) and RFS (hazard ratio, 0.56; 95% CI, 0.34-0.92; P = .02) than treatment with BCG. Induction therapy for BCG was associated with greater treatment discontinuation than induction therapy for gemcitabine and docetaxel (9.2% vs 2.9%; P = .02). Conclusions and Relevance: In this cohort study, gemcitabine and docetaxel therapy was associated with less high-grade disease recurrence and treatment discontinuation than BCG therapy. These findings suggest that, while awaiting results from an ongoing randomized clinical trial during the current BCG shortage, use of gemcitabine and docetaxel can be considered for recommendation in updated practice guidelines.

Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer.

INTRODUCTION: Intravesical gemcitabine and docetaxel (Gem/Doce) has been established as a safe and efficacious salvage treatment for recurrent NMIBC since 2015. Despite widespread adoption of this regimen, long-term outcomes have not been described. We report our experience with intravesical Gem/Doce following BCG failure in a large cohort of patients with extended follow-up. METHODS: We retrospectively identified 97 patients at our institution treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Monthly maintenance for 2 years was initiated if disease free at first follow-up. Outcomes included recurrence-free survival (RFS), high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS). Survival probabilities were estimated using the Kaplan-Meier method. RESULTS: Median follow-up was 49 months. Median age was 73 years, and 71% of the cohort had CIS containing disease. Thirty five percent of the cohort had BCG-unresponsive disease. Complete response at 3-month surveillance was 74% and median duration of response was 25 months. At 1, 2, and 5 years, HG-RFS was 60%, 50%, and 30%, respectively. HG-RFS was similar among BCG-unresponsive patients and the overall cohort. During follow-up, 20 patients underwent cystectomy and 15 patients experienced disease progression. Five-year PFS, CFS, CSS, and OS were 82%, 75%, 91%, and 64%, respectively. CONCLUSIONS: In this long-term analysis, intravesical Gem/Doce for high-risk NMIBC after BCG failure yielded a 75% 5-year bladder preservation rate and a 91% 5-year cancer-specific survival rate. Further prospective trials are warranted.

Sequential Intravesical Gemcitabine and Docetaxel for bacillus Calmette-Guérin-Naïve High-Risk Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Bacillus Calmette-Guérin (BCG) is currently recommended as adjuvant therapy following complete transurethral resection of bladder tumor for high-risk nonmuscle-invasive bladder cancer (NMIBC). In response to the BCG shortage, gemcitabine plus docetaxel (Gem/Doce) has been utilized at our institution in the BCG-naïve setting. We report the outcomes of patients with high-risk BCG-naïve NMIBC treated with Gem/Doce. MATERIALS AND METHODS: We retrospectively reviewed patients with BCG-naïve high-risk NMIBC treated with Gem/Doce from May 2013 through April 2021. Patients received 6 weekly intravesical instillations of sequential 1 gm gemcitabine and 37.5 mg docetaxel after complete transurethral resection of bladder tumor. Monthly maintenance of 2 years was initiated if disease-free at first followup. The primary outcome was recurrence-free survival. Survival was assessed with the Kaplan-Meier method, indexed from the first Gem/Doce instillation. Adverse events were reported using CTCAE (Common Terminology Criteria for Adverse Events) v5 (National Cancer Institute, Bethesda, Maryland). Differences were assessed with the log-rank test. RESULTS: There were 107 patients with a median followup of 15 months included in the analysis. Patients had high-risk characteristics including 47 with any carcinoma in situ and 55 with T1 disease. Recurrence-free survival was 89%, 85% and 82% at 6, 12 and 24 months, respectively. Recurrence rates were similar between patients with or without carcinoma in situ (p=0.42). No patient had disease progression or died of bladder cancer. One patient underwent cystectomy due to end-stage lower urinary tract symptoms. Overall survival was 84% at 24 months. There were 92 adverse events (1 ≥grade 3), and 4 (4%) patients were unable to receive a full induction course. CONCLUSIONS: Gem/Doce is an effective and well-tolerated therapy for BCG-naïve NMIBC. Further investigation is warranted.

Sequential Intravesical Valrubicin and Docetaxel for the Salvage Treatment of Non-Muscle-Invasive Bladder Cancer.

PURPOSE: Intravesical gemcitabine-docetaxel has emerged as an efficacious and well-tolerated salvage therapy for non-muscle-invasive bladder cancer. However, further rescue therapies are needed for subsequent recurrences or intolerance, particularly when cystectomy is refused or precluded. Valrubicin is a U.S. Food and Drug Administration-approved agent for bacillus Calmette-Guérin unresponsive disease, yet as monotherapy has demonstrated poor efficacy. We report our experience with sequential intravesical valrubicin and docetaxel as a rescue therapy for non-muscle-invasive bladder cancer. MATERIALS AND METHODS: We retrospectively identified all patients with recurrent non-muscle-invasive bladder cancer treated with valrubicin and docetaxel between April 2013 and June 2021. Patients received weekly sequential intravesical instillations of 800 mg valrubicin and 37.5 mg docetaxel for 6 weeks. If disease-free at first follow-up, monthly maintenance of 2 years was initiated. The primary outcome was recurrence-free survival, assessed using the Kaplan-Meier method. RESULTS: The analysis included 75 patients with median follow-up of 21 months (IQR: 13-37). Twelve patients with low-grade disease had a 73% recurrence-free survival at 2 years. Sixty-three patients with recurrent high-grade disease had a 38% 2-year high-grade recurrence-free survival. Forty-two (56%) patients had carcinoma in situ present; recurrence-free survival was similar for those with and without carcinoma in situ (P = .63). Two patients died of metastatic bladder cancer while 10 underwent cystectomy. Among patients with high-grade disease, overall, cancer-specific, and cystectomy-free survivals were 87%, 96%, and 84% at 2 years, respectively. Adverse events included bladder spasms (n = 18), urinary frequency (n = 10), and dysuria (n = 8). Two patients could not tolerate valrubicin and docetaxel induction. CONCLUSIONS: In a heavily pretreated population, our results suggest valrubicin and docetaxel is an effective rescue treatment for patients with recurrent non-muscle-invasive bladder cancer. Further prospective evaluation is needed.