Radiation therapy (RT) has traditionally been disregarded in the primary or adjuvant treatment of renal cell carcinoma (RCC), but recent advances have necessitated a re-examination of the role radiation therapy may be able to play. The advent of stereotactic ablative radiotherapy (SABR), which allows for targeting of disease with higher doses in a shorter window of time, may open up new avenues for RT’s role in the treatment of RCC, a cancer with a relatively low alpha/beta ratio. Thus, this review examines both the history and future of RT in the treatment of RCC with an aim to expand the discussion on treatment options for RCC.
Cell-free Circulating Tumor DNA (ctDNA) in Metastatic Renal Cell Carcinoma (mRCC): Current Knowledge and Potential Uses
Historically, tumor biopsies and clinical laboratory testing have been the gold standard for diagnosis and prognosis in metastatic renal cell carcinoma (mRCC). Genomic profiling in mRCC has traditionally been performed on tumor tissue; however, challenges and limitations in obtaining tissue biopsies led to the discovery of alternative biological specimens, namely circulating cell-free DNA (cfDNA). Rapidly evolving technologies, with increased sensitivity and specificity, have been used to query cfDNA in the clinical research setting. These investigations are rapidly establishing cfDNA and liquid biopsies as valuable complementary specimens to the gold standard, and in some instances surpassing these with unique insight into the contemporary genomic landscape and tumor heterogeneity. In this review, we will discuss recent research into the prognostic, diagnostic, and predictive utility of liquid biopsies in mRCC. We will explore their potential role in precision treatment of mRCC and conclude with what is needed in order to translate them to clinical practice.
The ‘Achilles Heel’ of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy
An important hallmark of cancer is ‘metabolic reprogramming’ or the rewiring of cellular metabolism to support rapid cell proliferation [1–5]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell carcinoma (RCC) globally impacts energy production as well as glucose and glutamine utilization in RCC cells, which can promote dependence on glutamine supply to support cell growth and proliferation [6, 7]. Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC). Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC. This overview provides scientific rationale for targeting this pathway in patients with mRCC. We will summarize the current understanding of cellular and molecular mechanisms underlying anti-tumor efficacy of glutaminase inhibitors in RCC, provide an overview of clinical efforts targeting glutaminase in mRCC, and review approaches for identifying biomarkers for patient stratification and detecting therapeutic response early on in patients treated with this novel class of anti-cancer drug. Ultimately, results of ongoing clinical trials will demonstrate whether glutaminase inhibition can be a worthy addition to the current armamentarium of drugs used for patients with mRCC.
Metastasectomy for advanced renal cell carcinoma has been practiced for over 80 years. However, there is uncertainty regarding the clinical benefit of this procedure and the optimum selection of appropriate patients.
Materials and Methods:
A systematic literature search was conducted according to the PRISMA statement to identify studies that reported outcomes in patients who underwent metastasectomy at any time. Primary endpoints were overall and disease-free survival. Radiation therapy studies were not included. Case reports and series with less than 20 patients were not included.
Forty-four studies were identified that met the criteria for inclusion, with a total of 4195 patients. No studies that randomized patients to surgery versus no surgery were identified. Disease-free interval, number of metastatic sites and completeness of resection were prognostic for overall survival in many of the included studies. Seventeen studies included patients with lung metastases only (1465 patients in total).
Case series have documented patients with prolonged disease-free interval and survival after metastasectomy. However, without randomized data, the impact of metastasectomy on outcomes in patients with metastatic renal cell carcinoma (mRCC) remains unknown, especially in the evolving landscape of systemic therapies.
Real-World Outcome of 173 Metastatic Non-Clear Cell Renal Cell Carcinoma (nccRCC) Cases: The Experience of the Center Group for Genitourinary Tumors
Non-clear cell renal cell carcinoma (nccRCC) represents a group of multiple histologic subtypes, with different clinical outcomes and an uncertain optimal treatment. Data collected in clear cell tumors are routinely extrapolated to nccRCC, despite a different underlying biology. The Center Group for Genitourinary tumors is a network of medical oncologists from hospitals in Madrid and surrounding provinces that are focused on genitourinary tumors. A retrospective, multicenter study of the outcome of patients with nccRCC diagnosed and treated at the Center Group hospitals between 1995 and 2015 was performed. Baseline clinical features, histologic subtypes, therapeutic management and survival status were analyzed. Data was collected from 173 patients, with a median age at diagnosis of 65 years [24–90], 67.1% were male. Histologic subtypes comprised 55.5% papillary carcinoma, 23.1% sarcomatoid, 13.9% chromophobe, 6.9% unclassified tumors and 0.6% oncocytoma. 159 patients received first line therapy including tyrosine kinase inhibitors (67.9%) and mammalian target of rapamycin inhibitors (11.9%). The response rates (RR) in evaluable patients (142) were: complete response 5.6%, partial response 17.6%, stable disease 40.8% and progression in 35.9% of cases. 90 patients (52.0%) received second line treatment. At the time of the data cut-off point (April 1, 2016), 126 patients had died, with a median overall survival (OS) of 17.9 months [95% CI 15.0–20.9]. The clinical outcome reported in this study has a similar OS to other published studies. Nevertheless, there are substantial differences among the distinct subtypes. Overall, prognosis in nccRCC remains poor. No significant differences were observed in the activity of systemic agents, used as either first or second line therapy.
Randomized Phase 2 Study of Trebananib (AMG 386) with or without Continued Anti-Vascular Endothelial Growth Factor Therapy in Patients with Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib – Results of NCI/CTEP Protocol 9048
In renal cell carcinoma (RCC), angiopoietin (Ang) 2 is elevated at the time of progression on anti-vascular endothelial growth factor (VEGF) therapy and may contribute to resistance.
We tested trebananib, an Ang 1 and 2 neutralizing peptibody in patients with RCC progressing on anti-VEGF treatment.
Patients with measurable RCC progressing despite an anti-VEGF agent within 12 weeks, any number of prior treatments, and good PS were randomized to trebananib 15 mg/kg IV weekly without (Arm A) or with (Arm B) continuation of the prior anti-VEGF agent. The primary endpoint for each arm was tumor response (RECIST 1.1). Secondary endpoints included progression free survival and adverse events.
Of 41 enrolled patients, 35 were eligible and started treatment (17 Arm A, 18 Arm B) with median age 60 (46–76) and 3 prior treatments (1–8). Four died prior to documented progression and 27 progressed as their first event. Both arms were stopped after interim analysis, 2 responses (11%; 95% C.I. 1–35%) were observed in Arm B. Median PFS of 2.7 (95% C.I. 2.3–4.7) months in Arm A and 5.2 (95% C.I. 2.7–10.8) months in Arm B did not support continued study. Common adverse events including fatigue, nausea, and increased creatinine were generally grade 1–2 and numerically higher in Arm B. The most common grade 3 or higher adverse events were hypertension and dyspnea.
While tolerable, trebananib either without or with continued anti-VEGF therapy did not show promising activity in RCC patients who recently progressed on anti-VEGF therapy alone.
Targeted Therapy and Immunotherapy: Effect of Body Mass Index on Clinical Outcomes in Patients Diagnosed with Metastatic Renal Cell Carcinoma
Previous research has identified an association between high body mass index (BMI) and better overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs).
The current study sought to determine whether the effect of BMI on OS extends beyond VEGF-TKIs to mTOR inhibitors or immunotherapy (IO).
Design, Setting and Participants:
A retrospective study was conducted among patients diagnosed with mRCC treated at a single institution from 2009 to 2017. Demographic and clinical variables were collected. BMI was characterized as high (≥25 kg/m2) versus low (<25 kg/m2).
Outcomes Measurement and Statistical Analysis:
The Kaplan-Meier method was used to estimate the difference in OS, with comparisons based on BMI and by treatment type.
Results and Limitations:
Among 353 patients (M = 64 years old, 73% male) 66% were overweight or obese (BMI≥25 kg/m2). Patients were treated with VEGF-TKI (65%), mTOR (23%), or IO (12%). Among patients treated with VEGF-TKI with low BMI, median OS was 24.0 months (95% CI, 20.7–27.2) versus 36.0 months (95% CI, 18.6–53.3) among patients with high BMI (P = 0.02). The median OS for patients with low BMI treated with mTOR was 18.0 months (95% CI, 2.8–33.1), versus 25.0 months (95% CI, 16.6–33.4) among patients with high BMI (P = 0.04). In contrast, patients with low BMI treated with IO had a median OS of 23.6 months (95% CI, 17.5–29.7) versus 19.9 months (95% CI, 10.6–29.2) among patients with high BMI (P = 0.26). The retrospective nature and the small sample size are the main limitations of this study.
High-BMI was associated with improved OS in patients with mRCC treated with VEGF-TKI and mTOR, but the inverse trend was observed among patients receiving IO. Our data highlight the need to reassess this phenomenon in the context of IO-based regimens.
Stereotactic Body Radiation Therapy for Renal Cell Carcinoma with Inferior Vena Cava Thrombus – Initial Experience Report and Literature Review
Renal cell carcinoma (RCC) with inferior vena cava thrombus (IVC-TT) represents a relatively infrequent presentation. Curative treatment includes extirpative surgery; however, this is associated with high rates of recurrence and complications. Stereotactic body radiation therapy (SBRT) has been used to treat metastatic RCC with good results. SBRT may be used as part of multimodal therapy to provide local control of IVC-TT.
We report our initial experience with SBRT to IVC-TT, including extended follow-up, and review the literature.
We report on two patients with level IV IVC-TT. Both had progressive disease while receiving systemic therapy and were eventually treated with SBRT to the IVC-TT, which showed good local control. Overall survival from the time of SBRT was 18 and 34 months, with no additional systemic therapy; one patient underwent additional SBRT and resection of metastatic sites.
SBRT to RCC IVC-TT may be considered in selected patients for local tumor control.
A Randomized Phase 2 Trial of Axitinib/Nivolumab Combination Therapy vs Single Agent Axitinib or Nivolumab for the Treatment of TFE/Translocation Renal Cell Carcinoma (tRCC) Across All Age Groups
This study is the first prospective trial studying patients with tRCC, and will require awareness and participation from all oncologists treating genitourinary malignancies to successfully accrue. While the study will undoubtedly include a large pediatric cohort, adult patients also need to be studied to see if clinical behavior and response to therapies are similar. The study may help to better elucidate the pathophysiology of this particular subtype to better explain its aggressive behavior. It may also contribute to our understanding of response or lack of response to targeted and immune checkpoint therapies for this patient population.
Prospective Phase II Study of Gemcitabine Plus Platinum Salt in Combination with Bevacizumab (Avastin) for Metastatic Collecting Duct Carcinoma
This study is noteworthy in that collecting duct kidney cancer is rare, aggressive and has only been studied in a limited manner in clinical trials. Typically these patients are excluded from trials evaluating regimens for mRCC, or are enrolled in too small numbers to derive any conclusions. Given the similarities collecting duct kidney cancer shares histopathologically with urothelial carcinoma, the use of platinum-based chemotherapy is rational. On the other hand, the study is permitting enrollment of patients with medullary RCC. Though this subtype has some overlapping features with collecting duct kidney cancer, it is a distinct entity. For example, while it does also confer a poor prognosis with an aggressive phenotype, medullary RCC occurs more frequently in patients with sickle cell disease and is characterized by loss of INI1 expression. Thus, there could be some potential confounding with enrollment of both subtypes into this trial. Nevertheless, it is commendable to evaluate this rare subset of patients with platinum-based chemotherapy. Immune checkpoint inhibitors, having now demonstrated efficacy in both urothelial and renal cell carcinomas, are being studied in patients with non-clear cell RCC as a broad category, which will also provide additional information about new potential approaches towards these aggressive subtypes.