Renal Function: Implications on the Surgical Treatment of RCC
Abstract
The good oncologic results after partial nephrectomy for stage 1 RCC show that radical nephrectomy is an overtreatment in most cases, and that many healthy nephrons are removed unnecessarily. However, partial nephrectomy is a difficult operation, with increased blood loss and a higher risk of complications. Therefore, the advantage of preserved function has to be weighed up against the increased trauma of surgery in each individual patient, and the assessment of preoperative function may influence this decision, among other factors such as comorbidities and age.
In most studies, renal function has been assessed by means of estimated glomerular filtration rate, and this parameter is very helpful for long-term studies in large populations. However, more precise measurement based on clearance studies are sometimes required for more sophisticated investigations.
The technique of partial nephrectomy has evolved substantially in recent years, resulting in the preservation of more nephrons, less damage to the remaining parenchyma, less blood loss, and a decreased risk of complications. The introduction of minimally invasive surgery for this purpose has also decreased the overall morbidity of surgery.
In the long-term, chronic kidney disease may result in increased cardiac mortality. There is ongoing discussion on this problem, however, this potential negative influence on overall survival is not only influenced by the rate of renal insufficiency, but also to a great extent by other comorbidities such as hypertension and diabetes. Therefore, in addition to providing the best surgery for any given patient, we have to make sure that the treatment of the comorbidities will also be part of our patient management, since the risk of cardiac failure may be greater than the risk of poor oncologic outcome.
Adjuvant Therapy in Renal Cell Carcinoma: Current Status and Future Directions
Abstract
In recent years, incredible progress has been made in the treatment of metastatic renal cell carcinoma, with a paradigm shift from the use of cytokines to tyrosine kinase inhibitors, and more recently, immune checkpoint inhibitors (ICIs). Despite advances in the metastatic setting, effective therapies in the adjuvant setting are a largely unmet need. Currently, sunitinib (Sutent, Pfizer) is the only therapy for the adjuvant treatment of RCC included in the National Comprehensive Cancer Network guidelines, which was approved by the FDA based on the improvement in disease-free survival (DFS) seen in the S-TRAC trial. However, improvement in DFS has not translated into an overall survival (OS) benefit for patients at high-risk of relapse post-nephrectomy, illustrating the need for more effective therapies. This manuscript will highlight attributes of both historical and current drug trials and their implications on the landscape of adjuvant therapy. Additionally, we will outline strategies for selecting patients in whom treatment would be most beneficial, as optimal patient selection is a crucial step towards improving outcomes in the adjuvant setting. This is especially critical, given the financial cost and pharmacological toxicity of therapeutic agents. Furthermore, we will review the design of clinical trials including the value of utilizing OS as an endpoint over DFS. Finally, we will discuss how the incorporation of genomic data into predictive models, the use of more sensitive imaging modalities for more accurate staging, and more extensive surgical intervention involving lymph node dissection, may impact outcomes.
Real-Word Experience of Cabozantinib in Metastatic Renal Cell Carcinoma (mRCC): Results from the Canadian Kidney Cancer information system (CKCis)
Abstract
BACKGROUND:
Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in metastatic renal-cell carcinoma (mRCC) randomized trials.
OBJECTIVE:
To explore the real-world effectiveness of cabozantinib in pretreated patients with mRCC, including patients who progressed on immune-oncology checkpoint inhibitor (ICI) therapy.
METHODS:
Using the Canadian Kidney Cancer information system (CKCis), patients with mRCC treated with cabozantinib monotherapy as second-line or later from January 1, 2011 to September 1, 2019 were identified. Patients were stratified based on line of cabozantinib received. We reported overall survival (OS), time to treatment failure (TTF) and disease control rate (DCR). Prognostic variables were analyzed using multivariable analysis.
RESULTS:
157 patients received cabozantinib (median TTF 8.0 months; median OS 15.8 months): 37 (24%) in the second line (median TTF 10.4 months; median OS 18.9 months) 66 (42%) in third line (median TTF 5.9 months; median OS 13.3 months) and 54 (34%) in either 4th or 5th line (median TTF 9.4 months; median OS 16.8 months). One hundred sixteen patients (74%) received cabozantinib after prior ICI therapy (median TTF of 7.6 months; median OS of 15.8 months). DCR in all patients was 63% with 46%, 65% and 72% in 2nd line, 3rd line and 4th/5th line patients respectively. DCR in patients who received cabozantinib after prior ICI therapy was 64%.
CONCLUSIONS:
Cabozantinib is effective in a real-world, unselected population of mRCC patients, including in those who have progressed on prior ICI therapy, and in those exposed to multiple lines of therapy.
PD-L1 Expression and Treatment Implications in Metastatic Clear Cell Renal Cell Carcinoma: A Systematic Review
Abstract
BACKGROUND:
Over the past decade, immune checkpoint inhibitors (ICIs) have increasingly become the standard of care for various advanced malignancies, including metastatic clear cell renal cell carcinoma (mccRCC). Most ICIs currently used in clinical practice inhibit the interaction between the programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) complex. A deeper understanding of this interaction and PD-L1 expression in tumors has led to more effective therapies in the treatment of advanced cancers, but the debate regarding the utility of PD-L1 as a biomarker continues.
OBJECTIVE:
We aimed to systematically evaluate the role of PD-L1 in mccRCC in terms of expression and treatment implications.
METHODS:
Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through August 31, 2020. Titles and abstracts were screened to identify articles for full-text review. A hand search was also performed using Google Scholar and the bibliography to relevant studies.
RESULTS:
A total of 26 articles were identified, and relevant data were extracted and organized. The available information regarding PD-L1 expression in mccRCC from both prospective clinical trials and retrospective studies were summarized. We discussed the utility of PD-L1 as a predictive and prognostic biomarker in mccRCC, its association with other potential biomarkers, and the pattern and level of expression of PD-L1 in primary versus metastatic tumors.
CONCLUSIONS:
Although significant progress has been made, much more remains to be learned regarding the differences between PD-L1+ and PD-L1- ccRCC tumors, in terms of both the underlying biology and clinical responses to immunotherapy and other agents.
Cost-Effectiveness of Immunotherapy Treatments for Renal Cell Carcinoma: A Systematic Review
Abstract
BACKGROUND:
Kidney cancer exerts significant disease burden in the United States and possesses a rapidly evolving treatment landscape. The expansion of novel systemic treatment approaches and the use of immunotherapy has been accompanied by increased costs over time. However, the cost-effectiveness of immunotherapy in renal cell carcinoma (RCC) has not been fully assessed. The current study presents a systematic review of cost-effectiveness studies of immunotherapy-based treatment in the context of RCC.
METHODS:
A literature search utilizing PubMed, Embase, Web of Science, and the Cochrane Library was undertaken to find articles related to the cost-effectiveness of immunotherapy treatment in renal cell carcinoma (RCC). The inclusion criteria for articles were as follows: English, published between 1983 and 2020 and evaluated cost-effectiveness in any of the currently approved immunotherapies for RCC. Exclusion criteria included being a review article, commentary or editorial, as well as possessing no specific cost-effectiveness evaluation or analysis relevant to the current review.
RESULTS:
The current review identified 23 studies, published between 2008 and 2020, across 9 different countries. The studies identified tended to focus on patients with locally advanced or metastatic RCC and examined the cost-effectiveness of immunotherapy across various lines of treatment (first-line treatment (n = 13), second-line treatment (n = 8), and first-line and beyond (n = 2). Eight studies examined the use of interferon-alpha (IFN-alpha), with some reports supporting the cost-effectiveness of these agents and an equal number of studies demonstrating the opposite, with sunitinib often demonstrating superior cost bases. The majority, fourteen studies, included the use of novel immune checkpoint inhibitors (nivolumab, ipilimumab, pembrolizumab), half of which found that checkpoint inhibitors were more cost-effective when compared to oral systemic therapies (sunitinib, everolimus, axitinib, pazopanib, and cabozantinib).
DISCUSSION:
Novel immune checkpoint inhibitors constituted the most frequently examined agents and were likely to be deemed cost-effective as compared to other treatments; although this often required higher willingness-to-pay (WTP) thresholds or healthcare systems that possessed more cost-constraints. These observations have clinical and health system applicability, with the ability to potentially reduce the cost of treatment for locally advanced or metastatic RCC.
