Treatment Landscape of Renal Cell Carcinoma.

OPINION STATEMENT: The treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to extirpative therapy in appropriately selected patients. Stereotactic body radiation therapy (SBRT) is an emerging noninvasive alternative to treat primary RCC tumors. The advent of immune checkpoint inhibitors (ICIs) has greatly improved the overall survival of advanced RCC, and now the ICI-based doublet (dual ICI-ICI doublet; or ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor, ICI-TKI doublet) has become the standard frontline therapy. Based on unprecedented outcomes in the metastatic with ICIs, they are also being explored in the neoadjuvant and adjuvant setting for patients with high-risk disease. Adjuvant pembrolizumab has proven efficacy to reduce the risk of RCC recurrence after nephrectomy. Historically considered a radioresistant tumor, SBRT occupies an expanding role to treat RCC with oligometastasis or oligoprogression in combination with systemic therapy. Furthermore, SBRT is being investigated in combination with ICI-doublet in the advanced disease setting. Lastly, given the treatment paradigm is shifting to adopt ICIs at earlier disease course, the prospective studies guiding treatment sequencing in the post-ICI setting is maturing. The effort is ongoing in search of predictive biomarkers to guide optimal treatment option in RCC.

Outcomes of Consolidative Nephrectomy following Primary Immunotherapy in Advanced Renal Cell Carcinoma: A Multicenter Analysis.

BACKGROUND: To evaluate effect and outcomes of combination primary immunotherapy (IO) and nephrectomy for advanced renal cell carcinoma (RCC). METHODS: We conducted a multicenter, retrospective analysis of patients with advanced/metastatic RCC who received IO followed by nephrectomy. Primary outcome was Bifecta (negative surgical margins and no 30-day surgical complications). Secondary outcomes included progression-free survival (PFS) following surgery, reduction in tumor/thrombus size, RENAL score, and clinical/pathologic downstaging. Cox regression multivariable analysis was conducted for predictors of Bifecta and PFS. Kaplan-Meier analysis assessed PFS, comparing Bifecta and non-Bifecta groups. RESULTS: A total of 56 patients were analyzed (median age 63 years; median follow-up 22.5 months). A total of 40 (71.4%) patients were intermediate IMDC risk. Patients were treated with immunotherapy for median duration of 8.1 months. Immunotherapy resulted in reductions in tumor size (P < .001), thrombus size (P = .02), and RENAL score (P < .001); 38 (67.9%) patients were clinically downstaged on imaging (P < .001) and 25 (44.6%) patients were pathologically downstaged following surgery (P < .001). Bifecta was achieved in 38 (67.9%) patients. Predictors for bifecta achievement included decreasing tumor size (HR 1.08, P = .043) and pathological downstaging (HR 2.13, P = .047). Bifecta (HR 5.65, P = .009), pathologic downstaging (HR 5.15, P = .02), and increasing reduction in tumor size (HR 1.2, P = .007) were associated with improved PFS. Bifecta patients demonstrated improved 2-year PFS (84% vs. 71%, P = .019). CONCLUSIONS: Primary immunotherapy reduced tumor/thrombus size and complexity. Pathologically downstaged patients were more likely to achieve bifecta, and these patients displayed improved 2-year PFS. Our study supports further inquiry in the use of CRN following primary immunotherapy for advanced renal cancer.

Metastatic renal cell carcinoma to the pancreas and other sites-a multicenter retrospective study.

Background: Metastatic renal cell carcinoma (mRCC) is a heterogenous disease with poor 5-year overall survival (OS) at 14%. Patients with mRCC to endocrine organs historically have prolonged OS. Pancreatic metastases are uncommon overall, with mRCC being the most common etiology of pancreatic metastases. In this study, we report the long-term outcomes of patients with mRCC to the pancreas in two separate cohorts. Methods: We performed a multicenter, international retrospective cohort study of patients with mRCC to the pancreas at 15 academic centers. Cohort 1 included 91 patients with oligometastatic disease to the pancreas. Cohort 2 included 229 patients with multiples organ sites of metastases including the pancreas. The primary endpoint for Cohorts 1 and 2 was median OS from time of metastatic disease in the pancreas until death or last follow up. Findings: In Cohort 1, the median OS (mOS) was 121 months with a median follow up time of 42 months. Patients who underwent surgical resection of oligometastatic disease had mOS of 100 months with a median follow-up time of 52.5 months. The mOS for patients treated with systemic therapy was not reached. In Cohort 2, the mOS was 90.77 months. Patients treated with first-line (1L) VEGFR therapy had mOS of 90.77 months; patients treated with IL immunotherapy (IO) had mOS of 92 months; patients on 1L combination VEGFR/IO had mOS of 74.9 months. Interpretations: This is the largest retrospective cohort of mRCC involving the pancreas. We confirmed the previously reported long-term outcomes in patients with oligometastatic pancreas disease and demonstrated prolonged survival in patients with multiple RCC metastases that included the pancreas. In this retrospective study with heterogeneous population treated over 2 decades, mOS was similar when stratified by first-line therapy. Future research will be needed to determine whether mRCC patients with pancreatic metastases require a different initial treatment strategy. Funding: Statistical analyses for this study were supported in part by the University of Colorado Cancer Center Support Grant from the NIH/NCI, P30CA046934-30.

Pathological Outcomes of Patients With Advanced Renal Cell Carcinoma Who Receive Nephrectomy Following Immunotherapy.

BACKGROUND: Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO). MATERIALS AND METHODS: This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs. RESULTS: Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9). CONCLUSIONS: IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era.

Leukocytoclastic Vasculitis Induced by Immune Checkpoint Inhibition in a Patient With Advanced Renal Cell Carcinoma.

A Mexican woman, aged 60 years, presented with fevers and abdominal pain. She had initially presented to an outside emergency department with weakness, malaise, nausea, vomiting, tachycardia to 110s, and fever to 102 °F. Her medical history was relevant for hypertension, prediabetes, and tobacco use (4-5 cigarettes/day for 12 years). There was no significant family history. Pertinent labs included hemoglobin 8.0 g/dL, white blood cells 13.1 × 109/L, absolute neutrophil count 10.2 × 109/L, creatinine 1.3 mg/dL, calcium 9.2 mg/dL, and lactate dehydrogenase 682 U/L. Initial imaging showed a large 14-cm right renal mass, with tumor in vein in the right renal vein and inferior vena cava, and extensive bilateral pulmonary emboli. A pulmonary thrombectomy was performed, with pathology on the right lung thrombus consistent with metastatic clear cell renal cell carcinoma (RCC), cT4N0M1, categorized as intermediate risk per the International Metastatic RCC Database Consortium.

Analysis of CDK12 alterations in a pan-cancer database.

BACKGROUND: CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan-cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real-world clinical-grade sequencing. METHODS: This was a single-center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described. RESULTS: In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12-altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow-up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11-5.74). Ten patients with CDK12-altered tumors received at least one immune checkpoint inhibitor-containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression-free survival for patients who had metastatic disease and received a checkpoint inhibitor-containing regimen was 1.16 years (95% CI: 0.32-2.00). CONCLUSION: CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12-altered tumors.

Prognostic Significance of Pancreatic Metastases in Patients With Advanced Renal Cell Carcinoma Treated With Systemic Therapy.

BACKGROUND: Pancreatic metastases (PM) are rare in renal cell carcinoma. It has been suggested that patients with metastases to the pancreas have a more favorable prognosis, but little is known about the long-term outcomes with systemic therapy. We sought to understand the outcomes of patients with metastatic renal cell carcinoma with PM treated with systemic therapy. PATIENTS AND METHODS: We conducted a pooled analysis of 4736 patients with metastatic renal cell carcinoma treated on phase II/III clinical trials. Systemic therapies included anti-vascular endothelial growth factor targeted therapy, mammalian target of rapamycin-targeted therapy, and cytokine therapy. RESULTS: The primary end point was overall survival (OS) in patients with versus without PM. Statistical analyses were performed using Kaplan-Meier analysis and Cox regression. Among 4736 patients, 235 (5.0%) were identified to have baseline PM at therapy initiation. The median OS in patients with PM was significantly prolonged with OS of 41.7 months versus 19.0 months (adjusted hazard ratio, 0.52; P < .0001). Similarly, progression-free survival was significantly prolonged in patients with PM (10.9 vs. 6.9 months; adjusted hazard ratio, 0.72; P = .004). The effect of PM on OS and progression-free survival was independent of other sites of metastasis or International mRCC Database Consortium risk group. CONCLUSION: The presence of PM in RCC is an independent positive predictor for survival and improved response to systemic therapy. These findings suggest RCC with PM is associated with favorable outcomes and further work to understand the underlying disease biology of these patients is warranted.

The Impact of Age and Gender on Outcomes of Patients With Advanced Renal Cell Carcinoma Treated With Targeted Therapy.

BACKGROUND: A growing body of evidence suggests that age and gender play a role in cancer outcomes. The objective of this study was to investigate the effect of age and gender on survival of patients with metastatic renal cell carcinoma (RCC). METHODS: We conducted a pooled analysis of patients with metastatic RCC treated on phase II and III clinical trials. Patients were stratified by age (young [<50 years], intermediate [50-70 years], versus elderly [>70 years]) and gender. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: We identified 4736 patients with metastatic RCC. Overall, there was no difference in overall survival (OS) when stratified by age (21.0 vs. 17.3 months for elderly vs. intermediate age groups, P = .382; 20.0 vs. 17.3 months for young vs. intermediate age groups, P = .155) or gender (19.8 vs. 19.0 for male vs. female, P = .510). Progression-free survival (PFS) was shorter in younger individuals compared with the intermediate age patients (6.0 vs. 7.1 months, P < .001), but similar across gender groups. Although all grade adverse events were more common in elderly patients (fatigue, diarrhea, decreased appetite, and weight), serious adverse events were similar between groups. CONCLUSIONS: Although OS was similar between age groups, younger individuals had a shorter PFS. Gender was not an independent determinant of survival. Elderly patients experienced more adverse events than their younger counterparts. These findings are important to guide clinicians when counseling patients about expectations and toxicity associated with therapy.

Systemic Treatment of Bone Disease in Metastatic Urinary Malignancies.

CONTEXT: Bone metastasis is a common site of metastatic disease in patients with genitourinary malignancies. Given that the presence of bone metastasis decreases survival and has a negative impact on quality of life impact, it is critical to optimize management of this patient population. OBJECTIVE: To systematically review literature on the systemic treatment of bone metastasis in prostate cancer, renal cell carcinoma, urothelial carcinoma, and germ cell tumors. EVIDENCE ACQUISITION: We performed a nonsystematic critical review of PubMed/Medline, clinicaltrials.gov, and the Cochrane Library from January 2001 to February 2019. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials, and selected based on reporting skeletal related events and symptomatic skeletal events for patients with urologic malignancies. EVIDENCE SYNTHESIS: Skeletal metastases occur frequently in genitourinary malignancies, at rates around 80% for patients with metastatic prostate cancer and 30% for patients with metastatic renal cell and urothelial carcinoma, and are uncommon in patients with germ cell tumors. Skeletal related events and symptomatic skeletal events can occur in these patients. Optimization of bone health involves dietary and lifestyle modifications, and use of osteoclast-targeted agents in select individuals. Additionally, disease-modifying agents, such as radiopharmaceutical, immunotherapy, and cMET inhibitors, which have activity in the bone, have improved outcomes for patients, including skeletal-related events and symptomatic skeletal events. CONCLUSIONS: While the presence of bone metastases is associated with increased mortality and worse outcomes in patients with genitourinary malignancies, strategies have been developed to improve quality of life and survival for patients with skeletal metastases. Future studies investigating novel therapeutic options and bone supporting agents are warranted to target this patient population. PATIENT SUMMARY: In this report, we reviewed the current literature and recent clinical trials involving treatment of bone metastases in urinary cancers. The use of bone-targeting agents can improve outcomes for patients, and additional lifestyle modification can optimize bone health in this population.

Management of bone complications in patients with genitourinary malignancies.

Skeletal metastases are common in genitourinary malignancies-including prostate cancer, renal cell carcinoma, and urothelial cancer-and portend significant morbidity and poor prognosis. The presence of skeletal metastases can result in decreased quality of life and increased morbidity. Strategies can be employed to prevent bone-related complications including lifestyle modifications and dietary supplementation. Additionally, pharmacologic agents exist to prevent bone loss and may be appropriate for patients at high risk of fragility-related or skeletal complications, such as pathologic fracture related to bone metastases. Finally, advancement in effective systemic treatments, particularly novel hormone-targeted agents and immunotherapies, may limit the morbidity of advanced disease and delay the onset of skeletal-related complications.