Kidney Cancer - Volume 8, issue 1

Authors: Jonasch, Eric | Balijepalli, Chakrapani | Yan, Kevin | Gullapalli, Lakshmi | Li, Joyce | Sundaram, Murali

Article Type: Systematic Review

Abstract: Background: A small proportion of renal cell carcinoma (RCC) are associated with hereditary syndromes such as von Hippel-Lindau disease (VHL) and are commonly treated with surgical interventions. More recently, systemic treatments for VHL-associated RCC have been assessed as an alternative to surgery. Methods: A systematic literature review was conducted by searching MEDLINE, EMBASE, and Cochrane Registry of Controlled Trials to collect and interpret published evidence on treatments for VHL-associated RCC patients to better understand the treatment landscape. Results: This review identified 32 primary studies, comprised of single-arm clinical trials and real-world studies assessing systemic, surgical, radiological, …or image guided ablation interventions. In clinical trials, treatment with sunitinib and pazopanib showed an objective response in 33% and 52% of RCC lesions respectively. For patients treated with belzutifan, 64% of patients showed an objective response, of which 7% were complete response and 57% were partial responses with a 24-month PFS rate of 96%. In real-world studies, treatment with sunitinib, pazopanib, axitinib, and sorafenib showed an objective response in 40%, 0%, 33%, and 25% of RCC lesions respectively, and all the responses were partial. In the studies assessing surgical, radiological, or image guided ablation interventions primary failure/re-intervention rates ranged from 2% to 84%. Conclusion: Local procedures are still a mainstay in the management of patients with non-metastatic VHL-associated RCC although multiple procedures incur an increasing rate of complications. A limited number of clinical trials and real-world studies evaluated VEGF-TKIs for the treatment of VHL-RCC, while responses were observed, long term treatment was limited by toxicities. Show more

Keywords: Von Hippel Lindau, renal cell carcinoma, VEGF, TKI, systematic literature review

DOI: 10.3233/KCA-230021

Citation: Kidney Cancer, vol. 8, no. 1, pp. 1-15, 2024

Authors: Jackson-Spence, Francesca | Young, Matthew | Jovaisaite, Agne | Szabados, Bernadett | Powles, Thomas

Article Type: Review Article

Abstract: A number of adjuvant trials have attempted to improve outcomes for patients following nephrectomy for renal cell carcinoma (RCC). This was initially with cytokines and then Vascular Endothelial Growth Factor (VEGF) targeted therapies. More recently, a series of adjuvant immune checkpoint inhibitor (ICI) studies have been published. To date, only the KEYNOTE— 564 study using adjuvant pembrolizumab has positive Disease-Free Survival (DFS) data with an acceptable toxicity profile. There are many negative ICI and anti-VEGF adjuvant trials, which raises uncertainty. Further randomised trials may be required but importantly biomarker studies are needed to identify those individuals who may benefit from …adjuvant therapy. Show more

Keywords: Adjuvant, immune checkpoint inhibitors, anti-VEGF TKIs, post nephrectomy, renal cell carcinoma

DOI: 10.3233/KCA-230013

Citation: Kidney Cancer, vol. 8, no. 1, pp. 17-22, 2024

Authors: Gulati, Shuchi | Lara, Primo Nery

Article Type: Article Commentary

DOI: 10.3233/KCA-230024

Citation: Kidney Cancer, vol. 8, no. 1, pp. 23-24, 2024

Authors: Parikh, Mamta

Article Type: Other

DOI: 10.3233/KCA-239003

Citation: Kidney Cancer, vol. 8, no. 1, pp. 25-26, 2024

Authors: Parikh, Mamta

Article Type: Other

DOI: 10.3233/KCA-239004

Citation: Kidney Cancer, vol. 8, no. 1, pp. 27-29, 2024

Authors: Amann-Arévalo, Marta | Ballestín Martínez, Pablo | Vidal Cassinello, Natalia | Moreno Perez, Ignacio | de la Torre-Serrano, Montserrat | Puente, Javier

Article Type: Review Article

Abstract: RCC has witnessed a significant increase in its incidence over the last five decades, ranking as the ninth most common cancer globally. Although survival rates have improved substantially, RCC remains one of the deadliest urological cancers. Traditionally, RCC subtypes were classified based on histopathological features. However, in recent years, there has been a paradigm shift towards molecular and genomic characterization of RCC, leading to the recognition of distinct molecular subtypes. The 2022 World Health Organization (WHO) classification introduced a new category called “molecularly defined renal carcinomas,” encompassing various subtypes, including SMARCB1-deficient medullary carcinoma, ALK-rearranged RCC, FH-deficient RCC, SDH-deficient RCC, …ELOC-mutated RCC, TFEB-altered RCC, and TFE3-rearranged RCC. These molecular subgroups have significant consequences for diagnosis, prognosis, and treatment. Molecularly defined RCCs are frequently underrepresented in clinical trials, encouraging additional research to identify beneficial therapeutics. Immune checkpoint inhibitors and tyrosine- kinase inhibitors have shown promising results in some subtypes, while others may benefit from specific inhibitors targeting their molecular drivers. Additionally, these classifications have important prognostic implications, guiding treatment decisions and genetic counseling. Show more

Keywords: Renal cell carcinoma, anaplastic lymphoma kinase, fumarate hydratase, succinate dehydrogenase, elongin C, TFEB protein, TFE3 protein, review

DOI: 10.3233/KCA-230015

Citation: Kidney Cancer, vol. 8, no. 1, pp. 31-44, 2024

Authors: Lee, Albert | Runcie, Karie D. | Yu, James B.

Article Type: Review Article

Abstract: Over the past decade, innovations in radiation technology and technique have led to the increasing use of stereotactic body radiotherapy (SBRT) for the treatment of renal cell carcinoma. We provide an overview of SBRT and review the role of SBRT for treatment of localized and oligometastatic RCC. We also provide a brief overview of the current state of knowledge with regards to the combination of SBRT and novel systemic agents commonly used in the treatment of RCC. As outcomes from trials investigating SBRT mature, showing excellent efficacy and tolerability, it is likely that SBRT use will continue to increase in …future years. Show more

Keywords: SBRT, renal cell carcinoma, radiotherapy

DOI: 10.3233/KCA-230020

Citation: Kidney Cancer, vol. 8, no. 1, pp. 45-50, 2024

Authors: van den Brink, Luna | van den Kroonenberg, Daniel L. | Graafland, Niels M. | Bex, Axel | Beerlage, Harrie P. | van Moorselaar, Jeroen R.A. | Zondervan, Patricia J.

Article Type: Research Article

Abstract: BACKGROUND: It remains unclear which patients with cT1b renal cell carcinoma (RCC) benefit most from partial nephrectomy (PN) versus radical nephrectomy (RN) considering oncological outcomes and renal function. OBJECTIVE: To compare oncological and functional outcomes of RN with PN for cT1b RCC. METHODS: This is a retrospective analysis of patients who underwent RN or PN for cT1b between 2010 and 2022 (n  = 241). Patients were grouped by RN or PN and matched by age, sex, Charlson Comorbidity Index, BMI, PADUA score, RENAL score, ASA score, and preoperative kidney function (eGFR) using propensity score matching. The 10-year …overall survival (OS), 10-year cancer-specific survival (CSS), and 10-year recurrence-free survival (RFS) were compared. Change in eGFR from baseline to 5-year follow-up was assessed. RESULTS: After matching, 100 patients remained in each group for analysis. The 10-year OS, CSS, and RFS rates were similar between groups. For patients classified as low risk, the PN group displayed a higher recurrence rate compared to RN (7 vs. 0, p  = 0.01). Patients who underwent RN had worse 1-year postoperative eGFR than PN (RN: 57 [44–65], PN: 73 [60–87], p  < 0.001). RN was more likely to induce new-onset chronic kidney disease (CKD) stage ≥3b compared to PN (p  < 0.001). Complication rate after PN was significantly higher (p  = 0.003). CONCLUSION: 10-year survival rates were similar, despite more recurrences in the PN group. Our data shows that post-surgical renal function is superior for PN. Nevertheless, RN is a reliable treatment option when preservation of renal function is not a priority. Show more

Keywords: Oncological outcome, partial nephrectomy, radical nephrectomy, renal cell carcinoma, renal function, cT1b

DOI: 10.3233/KCA-230019

Citation: Kidney Cancer, vol. 8, no. 1, pp. 51-59, 2024

Authors: Jang, Albert | Hobeika, Charbel S. | Gupta, Shilpa

Article Type: Review Article

Abstract: Papillary renal cell carcinoma (pRCC) comprises 15-20% of all patients with renal cell carcinoma (RCC). Although in the localized setting where pRCC appears to have better outcomes than clear cell RCC (ccRCC), patients with metastatic pRCC have significantly worse outcomes than patients with metastatic ccRCC. Because of the overall rarity of pRCC, there have been less research and clinical trials devoted to this subtype. Therefore, treatment of pRCC has generally been extrapolated from approved therapies for ccRCC. Recent data shows promise with newer tyrosine kinase inhibitors, and there is emerging evidence on their combination with immune checkpoint inhibitors. However, more …dedicated clinical trials to pRCC are urgently needed, as response rates and outcomes still lag behind ccRCC. This review summarizes the pathophysiology, genetic features, the evolution of treatment approaches since the systemic cytokine era, and current challenges of managing pRCC. Show more

Keywords: Papillary renal cell carcinoma, targeted molecular therapies, cabozantinib, immune checkpoint inhibitors

DOI: 10.3233/KCA-230027

Citation: Kidney Cancer, vol. 8, no. 1, pp. 61-79, 2024

Authors: Distante, Alfredo | Bertolo, Riccardo | Campi, Riccardo | Erdem, Selcuk | Calio, Anna | Palumbo, Carlotta | Pavan, Nicola | Ciccarese, Chiara | Carbonara, Umberto | Marchioni, Michele | Roussel, Eduard | Wu, Zhenjie | Mulders, Peter F.A. | Muselaers, Constantijn H.J.

Article Type: Systematic Review

Abstract: BACKGROUND: The role of active surveillance (AS) has been recognized as a management strategy for localized small renal masses (SRMs). The EAU guidelines suggest AS can be offered to frail and/or comorbid patients diagnosed with SRM due to the low cancer-specific-mortality (CSM) and higher competing-cause mortality. As specific cut-offs defining the characteristics of frail and comorbid patients who may benefit from AS remain less clear, our objective is to conduct a systematic review aiming to identify potential characteristics that could assist physicians in shared decision-making. METHODS: The systematic literature review was conducted following the Preferred Reporting Items for …Systematic Reviews and Meta-Analyses statement. Two authors independently screened the literature according to the PICOs criteria previously outlined in our registered review protocol (via Pubmed, Embase, and the Cochrane Central Register of Controlled Trials), extracted data, and assessed the risk of bias, using Newcastle-Ottawa Scale. Studies that analyzed differences in patient’s tumor-related and molecular characteristics associated with any differences in growth rate (GR), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS), were considered eligible. RESULTS: Nineteen studies comprising a total of 5105 patients were analyzed. Patient-specific factors such as age and cardiovascular index, which demonstrated a predominant impact on OS, exhibited a high degree of consistency across the analyzed studies. Less concordance was found when exploring GR, with the main predictors being ethnicity, age, sex, comorbidity, symptoms, and eGFR. The analysis of tumor-related characteristics, such as tumor size, nephrometry score, and mass histology, among others, yielded contradictory outcomes concerning their impact on GR and CSS. CONCLUSION: Age, cardiovascular index, and chronic kidney disease have shown to be reliable predictors of OS. Nonetheless, significant debates persist regarding tumor characteristics or molecular markers that may influence survival and GR. Further research is awaited to shed light on the potential to identify prognostic factors. This would aid in pinpointing the subgroup of patients who could experience additional benefits from AS, potentially leading to a reduced risk of progression. It is imperative to standardize approaches to AS and reporting of results, as this will be pivotal for future quantitative analyses. Show more

Keywords: Active surveillance, small renal masses, renal cell carcinoma, kidney cancer

DOI: 10.3233/KCA-230025

Citation: Kidney Cancer, vol. 8, no. 1, pp. 81-92, 2024

Authors: Zaemes, Jacob | McDermott, David F. | Regan, Meredith M. | Atkins, Michael B.

Article Type: Short Communication

Abstract: Over the past several years, four regimens incorporating immune checkpoint inhibitors have become widely used in the front-line setting to treat metastatic clear cell renal cell carcinoma: nivolumab with ipilimumab, axitinib with pembrolizumab, cabozantinib with nivolumab, and lenvatinib with pembrolizumab. These regimens all demonstrated favorable response rates and survival outcomes compared to sunitinib in phase III trials. As these data have matured, nivolumab with ipilimumab has been most clearly associated with durable long-term disease response and stable survival benefit. Moreover, responses obtained using nivolumab with ipilimumab are more likely to persist after treatment discontinuation compared to regimens containing a VEGFR-TKI. …These outcomes underline the value of using nivolumab with ipilimumab to pursue durable response in patients with advanced clear cell renal cell carcinoma. Show more

Keywords: Checkpoint inhibitor, metastatic ccRCC

DOI: 10.3233/KCA-240011

Citation: Kidney Cancer, vol. 8, no. 1, pp. 93-97, 2024

Authors: Heng, Daniel Y.C. | Doshi, Gurjyot K. | Dutailly, Pascale | Houchard, Aude | Lothgren, Mickael | Monnette, Alisha | Wang, Yunfei | Perrot, Valérie | Lalani, Aly-Khan A.

Article Type: Research Article

Abstract: BACKGROUND: Checkpoint inhibitor (CPI)-based therapy is recommended for first-line treatment of advanced/metastatic renal cell carcinoma (mRCC). Cabozantinib is a tyrosine kinase inhibitor (TKI) approved in the USA for treating mRCC, including after CPI-based therapy. However, data on the benefits of subsequent TKI therapy are limited. OBJECTIVE: To study the real-world use and outcomes of cabozantinib versus other TKIs after CPI-based therapy for mRCC. METHODS: This retrospective study used data from the US Oncology Network electronic health record database supplemented by chart review. Patients initiated TKI therapy between 2016 and 2021 after CPI-based therapy. The primary endpoint …was real-world response rate in the first 6 months of treatment (RR-6m; physician assessment). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Covariates were adjusted by inverse probability of treatment weighting. RESULTS: Of 485 included patients, 331 received cabozantinib and 154 another TKI. Baseline characteristics were generally similar between arms. For cabozantinib versus other TKIs, adjusted RR-6m (available for 69.3% of patients) was 62.5% versus 46.0% (rate difference: superiority, 16.5% [95% CI: 7.8–25.1], p  = 0.0002), adjusted ORR was 62.4% versus 49.4% (p  = 0.0020), adjusted median OS was 19.2 versus 19.1 months (p  = 0.7353) and adjusted median PFS was 7.9 versus 9.2 months (p  = 0.8752). CONCLUSIONS: Cabozantinib following CPI-based therapy was effective for treating mRCC in the US real-world setting. Differences in adjusted RR-6m and ORR significantly favored cabozantinib versus other TKIs. The lack of OS difference may reflect differences in post-index therapy. Show more

Keywords: Cabozantinib, renal cell carcinoma, immunotherapy, retrospective study, tyrosine kinase inhibitor

DOI: 10.3233/KCA-240005

Citation: Kidney Cancer, vol. 8, no. 1, pp. 99-114, 2024

Authors: Monda, Steven | Lara, Primo N. | Gulati, Shuchi

Article Type: Systematic Review

Abstract: BACKGROUND: Pembrolizumab is established as adjuvant therapy for patients with high-risk clear cell renal cell carcinoma (ccRCC) after resection. Patients with completely resected metastatic disease (M1 NED) seem to have greater benefit from adjuvant pembrolizumab in both disease-free survival (DFS) and overall survival (OS); yet, with other agents, adjuvant therapy has not been shown to improve survival. As newer therapies evolve, it is important to understand the efficacy of systemic agents in this patient population. OBJECTIVE: We aimed to systematically review available trials investigating adjuvant therapy after metastasectomy in RCC. METHODS: Following PRISMA guidelines, we performed …a systematic literature search using PubMed and Embase through January 2024. For inclusion, studies were required to include completely resected patients with known metastatic RCC. Patients with only locally advanced and/or regional nodal involvement (N1) alone were excluded. Titles and abstracts were screened to identify articles for full-text, and then a descriptive review was performed. RESULTS: A total of 149 articles were initially identified. Ultimately 9 articles published before the end of January 2024 met our inclusion criteria and were included in the analysis. Data were extracted and organized to reflect the role of adjuvant treatment - both targeted therapies as well as immunotherapy in patients who had undergone metastasectomy and rendered M1 NED. With the exception of pembrolizumab, adjuvant therapy in M1 NED was not found to be associated with improved survival. CONCLUSIONS: Pembrolizumab appears to benefit M1 NED ccRCC patients after resection even more than other high-risk ccRCC patients. Yet, this same benefit has not been seen with other agents. Future research should focus on trying to establish which M1 NED patients benefit from adjuvant treatment. Show more

Keywords: Kidney cancer, metastasectomy, adjuvant, systemic therapy

DOI: 10.3233/KCA-240006

Citation: Kidney Cancer, vol. 8, no. 1, pp. 115-123, 2024

Authors: Ntowe, Koumani W. | McAdoo, Sallie | Haas, Naomi B. | Karam, Jose A. | Lara Jr. , Primo N. | Fashoyin-Aje, Ibilola | Saraiya, Biren P. | Maskens, Deborah | Pickering, Lisa | Master, Viraj A. | Zhang, Tian | Kaye, Deborah R.

Article Type: Research Article

Abstract: Background: Kidney cancer is amongst the deadliest genitourinary malignancies. Neoadjuvant systemic therapy has the potential to improve survival and overall outcomes in select patients. Enrolling patients in trials of neoadjuvant treatment for kidney cancer is challenging, which limits neoadjuvant treatment development. Objective: This study aims to develop a better understanding of the barriers patients face in kidney cancer clinical trial participation, with a particular focus on neoadjuvant trials for renal cell carcinoma. Methods: From 2022–2023, we recruited participants with a history of kidney cancer through a Qualtrics survey that was sent to the Kidney Cancer Association …(KCA) and Kidney Cancer Cure (KCCure) mailing lists and social media pages. Patient responses on demographics, clinical information, and perspectives were evaluated. Results: Ninety-four individuals completed the survey. Eighty-one percent of respondents reported not participating in clinical trials due to not being informed about potential applicable trials. Importantly, many (76%) respondents reported that prevention of cancer return was a highly important reason to participate in clinical trials. Most respondents reported a willingness to undergo a kidney biopsy (59%), and/or additional appointments (58%) and surgery delays. Conclusions: Increased patient awareness about clinical trials with the potential to delay cancer recurrence may increase patient participation in clinical trials. Clinical trial design, including additional appointments or interventions and/or minor surgery delays are not major barriers to trial participation. Show more

Keywords: Renal cell carcinoma, neoadjuvant therapy, clinical trials, enrollment, survey

DOI: 10.3233/KCA-240009

Citation: Kidney Cancer, vol. 8, no. 1, pp. 125-134, 2024

Authors: Narang, Arshit | Gebrael, Georges | Jo, Yeonjung | Thomas, Vinay Mathew | Li, Haoran | Fortuna, Gliceida Galarza | Sayegh, Nicolas | Tandar, Clara | Tripathi, Nishita | Chigarira, Beverly | Srivastava, Ayana | Hage Chehade, Chadi | Nordblad, Blake | Maughan, Benjamin L. | Agarwal, Neeraj | Swami, Umang

Article Type: Research Article

Abstract: Background: Cabozantinib, a tyrosine kinase inhibitor (TKI), is a prevalent second-line (2 L) therapy and was approved for use after progression on TKIs. However, the 1 L treatment setting has changed since the approval of cabozantinib monotherapy in salvage therapy settings. Objective: To assess the differential effectiveness of cabozantinib after prior progression on 1 L ipilimumab with nivolumab (IPI + NIVO) compared to programmed death receptor-1 (PD-1) or PD-1 ligand (PD-L1) inhibitors (PD1/L1i) with TKIs. Methods: Utilizing a nationwide electronic health record (EHR)-derived de-identified database, we included patients with metastatic clear cell renal cell carcinoma (mccRCC) who received 1 L treatment with …an immune checkpoint inhibitor (ICI)-based combination and 2 L treatment with cabozantinib monotherapy. These patients were categorized based on the type of 1 L ICI-based combination received: IPI + NIVO vs. PD1/L1i with TKI. Real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) were summarized using Kaplan-Meier curves and compared using Cox-proportional hazard models adjusted for International mRCC Database Consortium (IMDC) risk groups. Results: Among 12,285 patients with metastatic renal cell carcinoma, 237 were eligible and included. Median rwTTNT was 8 months for the IPI + NIVO subgroup and 7.5 months for the PD1/L1i + TKI subgroup (HR 1.05, 95% CI: 0.74–1.49, p  = 0.8). Median rwOS was 17 months for IPI + NIVO and 16 months for PD1/L1i + TKI subgroup (HR 0.79, 95% CI: 0.52–1.20, p  = 0.3). Conclusions: Cabozantinib remains effective as a 2 L therapy for mccRCC independent of the type of prior 1 L ICI-based combination. Further research is needed to validate these findings and explore the ideal sequencing of therapies. Show more

Keywords: Immunotherapy, metastasis, renal cell carcinoma, survival outcomes, tyrosine kinase inhibitors

DOI: 10.3233/KCA-240016

Citation: Kidney Cancer, vol. 8, no. 1, pp. 135-142, 2024