Impact of brain metastases on systemic renal cell carcinoma treatment outcomes: A systematic literature review.

Survival benefit with resection of brain metastases from renal cell carcinoma in the setting of molecular targeted therapy and/or immune therapy

Renal cell carcinoma (RCC) and melanoma brain metastases have traditionally been considered radioresistant lesions when treated with conventional radiotherapeutic modalities. Radiosurgery provides high-dose radiation to a defined target volume with steep fall off in dose at lesion margins. Recent evidence suggests that stereotactic radiosurgery (SRS) is effective in improving local control and overall survival for a number of tumor subtypes including RCC and melanoma brain metastases. The purpose of this study was to compare the response rate to SRS between RCC and melanoma patients and to identify predictors of response to SRS for these 2 specific subtypes of brain metastases. We retrospectively reviewed a prospectively maintained database of all brain metastases treated with Gamma Knife SRS at the University Health Network (Toronto, Ontario) between October 2007 and June 2010, studying RCC and melanoma patients. Demographics, treatment history and dosimetry data were collected; and MRIs were reviewed for treatment response. Log rank, Cox proportional hazard ratio and Kaplan-Meier survival analysis using SPSS were performed. A total of 103 brain metastases patients (41 RCC; 62 melanoma) were included in the study. The median age, Karnofsky performance status score and Eastern Cooperative Oncology Group performance score was 52 years (range 27–81), 90 (range 70–100) and 1 (range 0–2), respectively. Thirty-four lesions received adjuvant chemotherapy and 56 received pre-SRS whole brain radiation therapy. The median follow-up, prescription dose, Radiation Therapy Oncology Group conformity index, target volume and number of shots was 6 months (range 1–41 months), 21 Gy (range 15–25 Gy), 1.93 (range 1.04–9.76), 0.4 cm3 (range 0.005–13.36 cm3) and 2 (range 1–22), respectively. Smaller tumor volume (P=0.007) and RCC pathology (P=0.04) were found to be positive predictors of response. Actuarial local control rate for RCC and melanoma combined was 89% at 6 months, 84% at 12 months, 76% at 18 months and 61% at 24 months. Local control at 12 months was 91 and 75% for RCC and melanoma, respectively. SRS is a valuable treatment option for local control of RCC and melanoma brain metastases. Smaller tumor volume and RCC pathology, predictors of response, suggest distinct differences in tumor biology and the extent of radioresponse between RCC and melanoma.

INTRODUCTION Patient survival with renal cell carcinoma (RCC) has improved with the use of molecular targeted agents and immunotherapy. Given the potential activity of these agents in treating brain metastases (BM), the role of aggressive local management with surgery and/or radiation may diminish. This study evaluated the benefit of aggressive local therapy of RCC BM in the setting of molecular targeted agents and/or immunotherapy. METHODS A retrospective single-center review between 2011 and 2018 identified 1659 patients treated for RCC. The study group included patients that developed BM and received molecular targeted agents and/or immunotherapy during the course of their disease. Data analyzed included demographic information, systemic treatments, and local BM treatment modalities. Kaplan-Meier curves and log-rank values were used to assess progression free survival (PFS) and overall survival (OS) following RCC and BM diagnosis. RESULTS Of 1659 patients, 108 (6.5%) were diagnosed with BM during their clinical course. Mean OS from diagnosis of RCC for these 108 patients was 44.5 ± 40.1 mo, with 1-, 3-, and 5-yr survival of 76.9%, 43.3%, and 38.1%. All patients were treated with molecular targeted agents and/or immunotherapy. OS was analyzed based on three treatment groups: systemic therapy only (26.1 ± 31.2, n = 21), systemic and radiotherapy (41.4 ± 34.9, n = 54), and systemic and radiotherapy plus BM resection (61.4 ± 46.9, n = 33). Survival benefit was seen with surgery compared to systemic therapy alone (P = .002) and the systemic and radiotherapy cohort (P = .038). PFS did not differ significantly between cohorts. Variables such as pre-treatment performance status (ECOG P = .085; KPS P = .231), number of BM (median 2, P = .685) and status of systemic disease at the time of BM diagnosis did not differ significantly. CONCLUSION In the setting of molecular targeted agents and immunotherapy, BM resection maximizes OS in surgical candidates. Prospective clinical trials are needed to elucidate activity of newer molecular targeted agents and immunotherapy in RCC BM treatment.

e15066 Background: Historically, the frequency of BMs from RCC is ~11%. Recent reports have suggested an improvement in the incidence of BMs with tyrosine kinase inhibitors (TKIs). What is not known is the impact of MTAs on the prevalence of BMs in metastatic RCC. Methods: We conducted a retrospective review of all pts with metastatic RCC treated with MTAs at a tertiary care center, UT Southwestern Harold C. Simmons Comprehensive Cancer Center, from 2006–2010. Statistical analyses were performed using the Cox proportional hazards model and the Kaplan-Meier method. Results: Fifty nine pts met inclusion criteria. 8 more pts presented with BMs and were not included in the incidence and survival analyses. Median age was 64.6 yrs. Per MSKCC criteria, 3 pts were in favorable (5%), 41 in intermediate (70%), and 15 in poor (25%) prognostic groups. Sites of metastases at presentation included lungs (65%), lymph nodes (40%), bones (30%), and liver (25.4%). Mean follow up time was 16 months, and at last follow up 24 pts were alive. The incidence of BMs was 11.9% (7/59) and the prevalence was 22% (15/67). Median overall survival was 1.97 yrs (95% CI, 1.04-3.89). Median survival for pts who developed BMs vs. without BMs was 1.21 yrs vs. 1.98 yrs (p=0.17). In multivariable analyses, only lack of nephrectomy was associated with increased risk of BMs, HR=9.819 (95 CI, 1.65-58.38; p=0.012). Conclusions: In our study, the incidence of BMs in RCC pts treated with MTAs was similar to what has been historically reported. In contrast, the prevalence of BMs was much higher at 22%. This is the first study to report the prevalence of BMs in patients with metastatic RCC treated with MTAs. As in other tumor types, the life-time risk of BMs appears to increase with the availability of highly-active MTAs.

4526 Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p<0.05). Conclusions: To our knowledge, this is the largest study investigating mutational profiles of RCC BM. SMARCA4 alterations were enriched in BM samples and a trend towards improved iPFS was seen in SETD2 variant BMs, warranting further investigation.[Table: see text]

Brain Metastasis From Renal-Cell Carcinoma: An Institutional Study.

Immune checkpoint inhibitor (ICI) efficacy in the treatment of metastatic renal cell carcinoma (RCC) without brain metastases (BMs) is well established in several clinical trials; however, patients with BMs were typically excluded from these trials. Therefore, the efficacy of ICI in the treatment or prevention of BM remains unclear. The primary aim of the study was to address the efficacy of ICI in treatment of patients with RCC BMs compared with patients receiving targeted therapies. A secondary aim was to evaluate the risk of RCC BM development among patients who received ICI versus targeted therapies early in their treatment course. A retrospective single-center review between 2011 and 2018 identified 425 patients treated for metastatic RCC. The study group included patients who received ICI and/or targeted therapies during their disease. Data analyzed included demographic information, systemic treatments, overall survival from RCC diagnosis (OSRCC) and from BM diagnosis (OSBM), and BM development. Fisher's exact test was used to evaluate the frequency of BM occurrence. Survival was assessed using Kaplan-Meier curves and log-rank tests. Of the 425 patients, 125 received ICI and 300 were treated with molecular targeted agents only during their clinical course. BMs occurred in 113 (9.5%) of the 425 patients. Among patients with BMs, OSRCC was improved with the use of ICI (77.2 vs 25.2 months, p < 0.001), with 1-, 2-, and 5-year survival rates of 93.9%, 81.8%, and 62.6%, respectively. The use of ICI was associated with increased OSBM (21.7 vs 8.9 months, p = 0.001). The rate of BM development was lower when patients were treated with ICI (8/100 [8.0%]) compared with targeted therapy (47/267 [17.6%]) (OR 0.41, 95% CI 0.18-0.89; p = 0.021). ICI was associated with improved OSRCC and OSBM in patients with BMs and decreased the probability of BM development in patients with metastatic RCC. Prospective trials are needed to further evaluate optimal use of ICI in treatment of RCC BMs.

The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n = 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.

727 Background: Brain metastases (BM) are frequently observed in metastatic RCC (mRCC) with a tendency to present with hemorrhagic BM. Distribution patterns of BM in RCC and associations with clinical outcomes are not well understood. Here we present a detailed distribution analysis in a surgically resected BM RCC cohort with a focus on clinically relevant associations. Methods: A retrospective analysis was performed on patients (pts) with mRCC who underwent craniotomy for BM at our institution. We reviewed gadolinium-enhanced MRI brain and CT head (if available) at the time of BM diagnosis. We assessed the presence of hemosiderin on MRI or hemorrhage on CT in the BM lesion and marked each at their corresponding anatomic location. Public brain atlases were used for distribution analysis. Overall survival (OS) from the date of BM diagnosis and CNS progression free survival (CNS-PFS) from the date of craniotomy were calculated. Results: A total of 67 BM were analyzed from 46 pts. 23 with synchronous BM, 9 with two and 6 with 3 concurrent BM. Most patients were male (n=35, 76%) with a median age at diagnosis of 63 years. Primary histology was clear cell in 42 pts (91%) and 10 pts (22%) had renal vein thrombosis (RVT) at primary diagnosis. IMDC scores at time of BM diagnosis were favorable in 20%, intermediate in 60% and poor in 20%. Hemosiderin (MRI) or hemorrhage (CT) was seen in 82% and 80% of BM, respectively. 55% of lesions were left sided, 45% frontal, 21% parietal, 18% occipital, 7% temporal and 6% cerebellar. Posterior circulation and posterior cerebral artery territories contained 42% and 34% of BM despite supplying only 30% and 16% of the brain volume, respectively. Patients with solitary BM had higher Karnofsky performance status (p=0.006) and lower disease burden (p=0.004) than those with multiple BM. Shorter CNS-PFS was seen in association with hemosiderin on MRI (log-rank p=0.04) and RVT in primary specimen (log-rank p=0.002). IMDC risk scores (log-rank p&lt;0.001) predicted OS. On multivariable OS analysis, BM lateralized to the right (HR 2.6, p=0.06), hemosiderin in BM (HR 6.5, p=0.02) and IMDC risk groups (intermediate HR 2.9, poor risk HR 25.6, p&lt;0.04) were independent prognostic factors for shorter OS. Conclusions: The above-presented lesion mapping method shows clinically relevant findings in RCC BM. Tumoral hemosiderin deposits appear a potential parameter to predict outcomes in RCC BM which deserve further study and validation.

Artificial Intelligence-Driven Measurement of Brain Metastases' SRS Response – A Comparison with Current Standards for Assessment

The 7th American Urological Association and the Japanese Urological Association International Affiliate Society Meeting

Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN. Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow-up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole-brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06-42.38 cm3 ); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27-111.22 cm3 ). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.

Introduction: The discovery of immune checkpoint inhibitors has revolutionized metastatic renal cell carcinoma (RCC) treatment. However, in patients with RCC brain metastases, response rates are low and survival outcomes poor. To understand the tumor microenvironmental differences between primary kidney tumors, extracranial metastases, and brain metastases, we developed a detailed single-cell atlas of RCC brain metastases along with their matched extracranial and primary tumors. Methods: We performed single-nucleus RNA-seq on 27 samples (nearly 200,000 cells) from RCC patients; samples included 14 brain metastases, 8 matched primary kidney tumors, and 5 matched extracranial metastases. We performed multiplex IHC to validate selected transcriptomic findings. We used Nanostring CosMx 960-plex RNA spatial molecular imaging technique on selected samples to validate cellular interactions in a spatial context. Results: We established a multi-tissue single-cell atlas of RCC brain metastases by identifying 9 major and 37 minor malignant, immune, and stromal cell clusters. Brain metastases had higher neuronal and glial cells interacting with immune and tumor cells. Brain metastasis tumor cells were also transcriptomically reprogrammed to adapt to the brain microenvironment through enrichment of MYC targets, MTORC1 signaling, epithelial-mesenchymal transition, fatty-acid metabolism, oxidative phosphorylation, and reactive oxygen species pathways. Moreover, cell-to-cell communication and downstream target gene expression analyses showed that brain metastasis tumor cells expressed ligands and receptors that induce tumor cell proliferation in both autocrine and paracrine fashions. Among T-cell populations, we found fewer proliferating cytotoxic T lymphocytes in the brain than in other sites. Moreover, T cells in brain metastases expressed higher levels of several targetable inhibitory checkpoints than did extracranial metastases. In addition, we found that naïve/memory T cells in brain metastases were a favorable prognostic marker for overall survival after craniotomy. Our characterization of myeloid cell populations across the 3 disease sites found fewer dendritic cells and monocytes in the brain compared to other sites. Macrophages in brain metastases more highly expressed an M2 immunosuppressive gene signature than did those in primary RCC tumors. Conclusion: Our findings from the largest single-cell atlas of RCC brain metastases with matched primary and extracranial metastases suggest several unique targetable, immunosuppressive biological mechanisms in the brain microenvironment. These results provide a foundation for a deeper understanding of RCC brain metastasis biology and can serve as a resource for the scientific community to further explore therapeutically targetable tumor and immune-related mechanisms. Citation Format: Elshad Hasanov, Truong Nguyen Anh Lam, Jerome Lin, Patrick K. Reville, Merve Hasanov, Anna K. Casasent, David Shih, Sahin Hanalioglu, Mehmet Asim Bilen, Omar Alhalabi, Berrin Babaoglu, Baylar Baylarov, Adeboye O. Osunkoya, Lisa M. Norberg, Joy Gumin, Tuan M. Tran, Jianzhuo Li, Anh G. Hoang, Haidee D. Chancoco, Brittany C. Parker Kerrigan, Erika J. Thompson, Betty YS Kim, Dima Suki, Melike Mut, Figen Soylemezoglu, Giannicola Genovese, Kadir C. Akdemir, Hussain A. Tawbi, Nizar M. Tannir, Florencia McAllister, Michael A. Davies, Padmanee Sharma, Jason Huse, Frederick Lang, Nicholas Navin, Eric Jonasch. Single-cell and spatial transcriptomic mapping of human renal cell carcinoma brain metastases uncovers actionable immune-resistance targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5788.

5097 Background: Patients with renal cell carcinoma brain metastasis (RCCBM) are frequently excluded from clinical trials. NCCN guidelines do not give clear recommendations regarding central nervous system (CNS) surveillance or therapy. We set out to define who should be screened and who should be considered for clinical trials after treatment of CNS lesions. Methods: A database of information was reviewed to determine presentation, clinical symptoms, number and size of lesions, use of and response to systemic therapy, treatment of BM, CNS disease free survival after treatment of original BM (CNS recurrence), and overall survival from time of diagnosis of BM. Results: A total of 138 patients with RCCBM were identified of whom 95% underwent treatment for their BM. Clear cell histology accounted for 92% of patients and 93% of patients had concomitant metastasis. Patients had CNS symptoms in 67% of cases. Symptomatic CNS tumors were larger (2.1 vs 1.3 cm, p <0.001) and more likely to receive a craniotomy (p<...

ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma