Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Chromophobe Renal Cell Carcinoma with Sarcomatoid Differentiation.

Chromophobe renal cell carcinoma (chRCC) is one of the less common types of kidney cancer and generally portends a more favorable prognosis. RCC with sarcomatoid differentiation has a more aggressive clinical course with poor outcomes. Four cases of chRCC with varying degrees of sarcomatoid differentiation were retrospectively reviewed at our institution, and clinicopathologic data as well as clinical courses were reported. Patients with higher degrees of sarcomatoid differentiation and larger tumors at presentation generally had and worse overall survival. chRCC with sarcomatoid differentiation portends a poor prognosis with limited data on systemic treatment options for metastatic disease.

Factors associated with clinical trial participation for patients with renal cell carcinoma.

OBJECTIVE: Recruitment of a diverse and representative study population is critical to the external validity of oncology clinical trials. The primary objective of this study was to characterize the factors associated with clinical trial participation for patients with renal cell carcinoma and the secondary objective was to examine differences in survival outcomes. MATERIALS AND METHODS: We used a matched case-control design by querying the National Cancer Database for patients with renal cell carcinoma who were coded as having enrolled in a clinical trial. Trial patients were matched in a 1:5 ratio to the control cohort based on clinical stage and then sociodemographic variables were compared between the 2 groups. Multivariable conditional logistic regression models evaluated factors associated with clinical trial participation. The trial patient cohort was then matched again in a 1:10 ratio based on age, clinical stage, and comorbidities. Log-rank test was used to compare overall survival (OS) between these groups. RESULTS: From 2004 to 2014, 681 patients enrolled in clinical trials were identified. Clinical trial patients were significantly younger and had a lower Charlson-Deyo comorbidity score. On multivariate analysis, male patients and white patients were more likely to participate compared to their Black counterparts. Having Medicaid or Medicare negatively associated with trial participation. Median OS was greater among clinical trial participants. CONCLUSION: Patient sociodemographic factors remain significantly associated with clinical trial participation and trial participants experienced superior OS to their matched counterparts.

Pilot Study Evaluating Cross-Disciplinary Educational Material to Improve Patients' Knowledge of Palliative Radiation Therapy.

Palliative radiation therapy (PRT) is underutilized, partially due to misconceptions about its risks, benefits, and indications. The objective of this pilot study was to determine if patients with metastatic cancer would gain knowledge from educational material describing PRT and perceive it as useful in their care. A one-page handout conveying information about the purpose, logistics, benefits, risks, and common indications for PRT was offered to patients undergoing treatment for incurable, metastatic solid tumors in one palliative care clinic and four medical oncology clinics. Participants read the handout, then completed a questionnaire assessing its perceived value. Seventy patients participated between June and December 2021. Sixty-five patients (93%) felt they learned from the handout (40% learned "lots"), and 69 (99%) felt the information was useful (53% "very useful"). Twenty-one patients (30%) were previously unaware that PRT can relieve symptoms, 55 (79%) were unaware that PRT can be delivered in five treatments or less, and 43 (61%) were unaware that PRT usually has few side effects. Sixteen patients (23%) felt they currently had symptoms not being treated well enough, and 34 (49%) felt they had symptoms that radiation might help with. Afterwards, most patients felt more comfortable bringing symptoms to a medical oncologist's (n = 57, 78%) or radiation oncologist's (n = 51, 70%) attention. Patient-directed educational material about PRT, provided outside of a radiation oncology department, was perceived by patients as improving their knowledge and adding value in their care, independent of prior exposure to a radiation oncologist.

Renal Cell Carcinoma with Testicular Metastases: A Case Report and Review of the Literature.

Renal cell carcinoma (RCC) metastases to the testicle are an extremely rare clinical entity. Here, we describe the case of a man with metastatic RCC who developed a new testicular mass. Pathologic analysis after surgical removal of this testicle confirmed the diagnosis of metastatic RCC. This report highlights the unique diagnostic and therapeutic challenges associated with such a disease process.

Factors Associated With Palliative Intervention Utilization for Metastatic Renal Cell Carcinoma.

INTRODUCTION: Several guidelines have adopted early integration of palliative intervention (PI) into oncologic care to improve quality of life among patients with advanced malignancies. However, PI utilization patterns and factors associated with its use in metastatic renal cell carcinoma are poorly understood. PATIENTS AND METHODS: Using the National Cancer Database (NCDB), we abstracted patients diagnosed with Stage IV RCC from 2004 to 2014 and evaluated the utilization of PI within this cohort. Socioeconomic and clinical factors were compared for patients receiving and not receiving PI for metastatic RCC. Multivariable logistic regression (MLR) models identified factors that were associated with receipt of PI within overall cohort and treatment-based cohorts. RESULTS: We identified 42,014 patients with Stage IV RCC, of which 7,912 patients received PI. From 2004 to 2014, the use of PI minimally increased from 17% to 20% for Stage IV RCC. MLR analysis demonstrated that increased comorbidities, insurance status, higher education status, facility location, care at a comprehensive cancer program or integrated network, sarcomatoid histology, and treatment type significantly increased the likelihood of PI use. Various socioeconomic, clinical, and geographical factors that are associated with use of PI-based on the treatment received for Stage IV RCC. CONCLUSIONS: While PI utilization has minimally increased for Stage IV RCC, there are several geographic, socioeconomic, and clinical factors that predict its use among patients with Stage IV RCC in a treatment-specific manner. Taken together, this suggests the need for earlier initiation of PI in a more equitable and systematic fashion among patients with metastatic RCC.

Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.

BACKGROUND: Phase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. OBJECTIVE: To compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. DESIGN SETTING AND PARTICIPANTS: Patients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. INTERVENTION: Patients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. RESULTS AND LIMITATIONS: For the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1-17%], arm 2: 17.1% [95% CI: 7-32%], arm 3: 11.9% [95% CI: 4-26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9-36.1]) relative to degarelix (52.9 wk [95% CI: 49.0-56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. CONCLUSIONS: Rates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. PATIENT SUMMARY: We evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.

Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma.

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05-5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation.

Impact of pathologic lymph node-positive renal cell carcinoma on survival in patients without metastasis: Evidence in support of expanding the definition of stage IV kidney cancer.

BACKGROUND: Stage III renal cell carcinoma (RCC) encompasses both lymph node-positive (pT1-3N1M0) and lymph node-negative (pT3N0M0) disease. However, prior institutional studies have indicated that among patients with stage III disease, those with lymph node disease have worse oncologic outcomes and experience survival that is similar to that of patients with American Joint Committee on Cancer (AJCC) stage IV disease. The objective of the current study was to validate these findings using a large, nationally representative sample of patients with kidney cancer. METHODS: Patients with AJCC stage III or stage IV RCC were identified using the National Cancer Data Base (NCDB). Patients were categorized as having lymph node-positive stage III (pT1-3N1M0), lymph node-negative stage III (pT3N0M0), or stage IV metastatic (pT1-3 N0M1) disease. Cox proportional hazards models compared outcomes while adjusting for comorbidities. Kaplan-Meier estimates illustrated relative survival when comparing staging groups. RESULTS: A total of 8988 patients met the inclusion criteria, with 6587 patients classified as having lymph node-negative stage III disease, 2218 as having lymph node-positive stage III disease, and 183 as having stage IV disease. Superior survival was noted among patients with lymph node-negative stage III disease, but similar survival was noted between patients with lymph node-positive stage III and stage IV RCC, with 5-year survival rates of 61.9% (95% confidence interval [95% CI], 60.3%-63.4%), 22.7% (95% CI, 20.6%-24.9%), and 15.6% (95% CI, 11.1%-23.8%), respectively. CONCLUSIONS: Current RCC staging systems group pT1-3N1M0 and pT3N0M0 disease as stage III disease. However, the results of the current validation study suggest the need for further stratification and even placement of patients with pT1-3N1M0 disease into the stage IV category. Staging that accurately reflects oncologic prognosis may help clinicians better counsel and select patients who might derive the most benefit from lymphadenectomy, adjuvant systemic therapy, more rigorous imaging surveillance, and clinical trial participation.

Phase I neoadjuvant study of intravesical recombinant fowlpox-GM-CSF (rF-GM-CSF) or fowlpox-TRICOM (rF-TRICOM) in patients with bladder carcinoma.

Intravesical BCG is a highly effective treatment for high-grade nonmuscle invasive bladder cancer and carcinoma in situ (CIS); however, for patients who are either resistant or become unresponsive to BCG therapy there is a need for alternative treatment approaches. This study examined the safety and feasibility of intravesically administered recombinant fowlpox virus encoding GM-CSF (Arm A) or TRICOM (Arm B); and the local and systemic immunologic responses generated to the vector(s). Twenty bladder cancer patients scheduled for cystectomy as their standard of care received preoperatively four weekly doses of intravesical recombinant fowlpox. Treatment was well tolerated, however, three patients experienced transient elevations of liver transaminases, with one rising to the level of a DLT. Cystectomy derived tumor and normal bladder mucosa demonstrated mRNA for the virally encoded LacZ gene supporting effective infection/transfection. Detected serum antibody to the LacZ encoding ß-galactosidase indicated successful expression of vector-encoding gene products and the ability to immunize via the bladder site. H&E and IHC using a panel of immune cell specific antigens demonstrated immune cell infiltration of the bladder wall. These findings demonstrate good safety profile, successful infection/transfection, ability to generate systemic immune response, and local recruitment of immune cell populations with intravesical administration of fowlpox-based constructs encoding for GM-CSF(rF-GM-CSF) or TRICOM (rF-TRICOM), and support further evaluation of this treatment modality for bladder cancer.

Retroperitoneal Lymph Node Dissection as Primary Treatment for Men With Testicular Seminoma: Utilization and Survival Analysis Using the National Cancer Data Base, 2004-2014.

BACKGROUND: The role of retroperitoneal lymph node dissection (RPLND) as first-line treatment for testicular seminoma is less well defined than for testicular nonseminomatous germ-cell tumors. We describe utilization of primary RPLND in the United States and report on overall survival (OS) after surgery for these men. PATIENTS AND METHODS: Using 2004-2014 data from the National Cancer Data Base, we identified 62,727 men with primary testicular cancer, 31,068 of whom were diagnosed as having seminoma. After excluding men with benign, non-germ cell, and nonseminomatous germ-cell tumor histologies, those who did not undergo RPLND, those where clinical stage and survival data were unavailable, and those with testicular seminoma who underwent RPLND in the postchemotherapy setting (n = 47), 365 men comprised our final cohort. Descriptive statistics were used to summarize clinical and demographic factors. The Kaplan-Meier method was used to determine OS. RESULTS: A total of 365 men with testicular seminoma underwent primary RPLND. At a median follow-up of 4.1 years, there were 16 deaths in the entire cohort. Five-year OS was 94.2%. Subset analysis of men with stage I and IIA/B disease who underwent primary RPLND revealed 5-year OS rates of 97.3% and 92.0%, respectively (P = .035). OS did not significantly differ in patients with stage IIA versus IIB disease (91.8% vs. 92.3%, respectively, P = .907). CONCLUSION: Although RPLND is rarely used as primary therapy in testicular seminoma, OS rates appear to be comparable to rates reported in the literature for primary chemotherapy or radiotherapy. Ongoing prospective trials will clarify the role of RPLND in the management of testicular seminoma.

Effect of alvimopan on gastrointestinal recovery and length of hospital stay after retroperitoneal lymph node dissection for testicular cancer.

OBJECTIVE: Alvimopan use has reduced the length of hospital stay in patients undergoing major abdominal surgeries and radical cystectomy. Retroperitoneal lymph node dissection for testicular cancer may be associated with delayed gastrointestinal recovery prolonging hospital length of stay. We evaluate whether alvimopan is associated with enhanced gastrointestinal recovery and shorter hospital length of stay in men undergoing retroperitoneal lymph node dissection for testicular cancer. MATERIALS AND METHODS: From 2010 to 2016, 29 patients underwent open, transperitoneal bilateral template retroperitoneal lymph node dissection. Data for patients who received alvimopan were prospectively collected and compared to a historical cohort of patients who did not receive alvimopan. Primary outcome measures were length of stay and recovery of gastrointestinal function. Descriptive statistics were reported. Time-to-event outcomes were evaluated using cumulative incidence curves and log rank test. Factors associated with length of stay were analyzed for correlation using multiple linear regression. RESULTS: Of 29 men undergoing retroperitoneal lymph node dissection, eight received alvimopan and 21 did not. The two cohorts were well matched, with no significant differences. In the alvimopan cohort compared with those who did not receive alvimopan median time to return of flatus was 2 versus 4 days (p=0.0002), and median time to first bowel movement was 2.5 versus 5 days (p=0.046), respectively. Median length of stay in the alvimopan cohort was 4 days versus 6 days in those who did not receive alvimopan (p=0.074). In adjusted analyses, receipt of alvimopan did not influence length of stay. CONCLUSION: Alvimopan may facilitate gastrointestinal recovery after retroperitoneal lymph node dissection for testicular cancer. Whether this translates into reduced length of stay needs to be determined by randomized controlled trials using larger cohorts. LEVEL OF EVIDENCE: 3b.

Metastatic Prostate Cancer to the Renal Pelvis and Proximal Ureter: A Case Report and Review of the Literature.

Prostate cancer metastases are commonly seen in the skeleton, lymph nodes, lungs, or liver, and are associated with a poor five-year survival rate. Renal pelvis and ureteral metastasis are exceedingly uncommon and can present with obstructive symptoms or as an asymptomatic mass on imaging. We report the case of a 60-year-old patient who was initially diagnosed with prostate adenocarcinoma and experienced eventual metastasis to the right renal pelvis and proximal ureter. Following the diagnosis, he was started on docetaxel and pembrolizumab as part of a clinical trial protocol. A high index of suspicion and thorough metastatic work-up is necessary when patients with prostate cancer present with symptoms of obstructive uropathy or new visceral disease is identified.

Trends and outcomes of lymphadenectomy for nonmetastatic renal cell carcinoma: A propensity score-weighted analysis of the National Cancer Database.

PURPOSE: Lymph node (LN) involvement in renal cell carcinoma (RCC) is associated with a poor prognosis. While lymph node dissection (LND) may provide diagnostic information, its therapeutic benefit remains controversial. Thus, the aim of our study is to analyze survival outcomes after LND for nonmetastatic RCC and to characterize contemporary practice patterns. MATERIALS AND METHODS: The National Cancer Database was queried for patients with nonmetastatic RCC who underwent either partial or radical nephrectomy from 2010 to 2014. A total of 11,867 underwent surgery and LND. Chi-square tests were used to examine differences in patient demographics. To minimize selection bias, propensity score matching (PSM) was used to select one control for each LND case (n = 19,500). Cox regression analyses were conducted to examine overall survival (OS) in patients who received LND compared to those who did not. RESULTS: Of all patients undergoing LND for RCC (n = 11,867), 5%, 23%, 31%, 47% were performed for tumors of clinical T stage 1, 2, 3, and 4, respectively. Proportions of LND have not significantly changed from 2010 to 2014. No significant improvement in median OS for patients undergoing LND compared to no LND was shown (34.7 vs. 34.9 months, respectively; P = 0.98). Similarly, no significant improvement in median OS was found for clinically LN positive patients undergoing LND compared to no LND (P = 0.90). On Cox regression analysis, LND dissection was not associated with an OS benefit (hazard ratio: 1.00; 95% confidence interval 0.97 to 1.04). CONCLUSIONS: Among all RCC patients, LNDs are often performed for low stage disease, suggesting a potential overutilization of LND. No OS benefit was seen in any subgroup of patients undergoing LND. Further investigation is needed to determine which patient populations may benefit most from LND.